Fused heterocyclic compound, and preparation method therefor and use thereof

Abstract

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

Description

A fused heterocyclic compound, a preparation method and use thereof

[0001] This application claims priority to Chinese patent application 2024108093794 with the filing date of 2024 / 06 / 21, Chinese patent application 2024109716824 with the filing date of 2024 / 07 / 19, Chinese patent application 2024109993117 with the filing date of 2024 / 07 / 24, Chinese patent application 2024112755203 with the filing date of 2024 / 09 / 12, Chinese patent application 2024118750665 with the filing date of 2024 / 12 / 19 and Chinese patent application 2025107970878 with the filing date of 2025 / 06 / 13. 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 fused heterocyclic compound, a preparation method and use 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 disclosed patents include WO2015057873A1, WO2016022569A1 and WO2020210293A1, etc. SUMMARY

[0006] The technical problem to be solved by the present application is to overcome the defect of single structure of existing c-kit receptor modulators. Thus, the present application provides a fused heterocyclic compound, a preparation method and use thereof. The fused heterocyclic compound provided by the present application has good biological activity and good drug prospects.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides a compound of formula (IG) or a pharmaceutically acceptable salt thereof.

[0009] Where T is

[0010] G 1 For CR 8 Or N;

[0011] Ring A is a 5-12 membered heterocyclic group or C 5-12 cycloalkyl, the 5-12 membered heterocyclic group or C 5-12 cycloalkyl groups are optionally surrounded by one or more R A replace;

[0012] R A Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2 and S(O) m C 1-6 Alkyl, the C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups are optionally selected from cyano, hydroxyl, halogen, amino, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, SC 1-6 Alkyl groups and S(O)2C 1- One or more substitutions in the 6 alkyl group;

[0013] Or, 2 Rs A A carbon-carbon double bond is formed on the same carbon atom, and the carbon-carbon double bond is optionally selected from halogens and C. 1-6 One or more of the alkyl groups are substituted;

[0014] Cycle B is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally coupled with one or more R groups. B replace;

[0015] R Bthe same or different, are each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1- hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0016] Ring C is 5-membered heteroaryl;

[0017] X is C and Y is N; or, X is N and Y is C;

[0018] R 0 is selected from the group consisting of H, 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 1 and R 2 are the same or different, and are each independently selected from the group consisting of H, halogen, cyano, hydroxyl, oxo, amino, 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;

[0020] or R 0 and R 2 together with the atom to which they are attached form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl being optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0021] R 3 and R 4 are the same or different, and are each independently selected from the group consisting of H, halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0022] or, R 1 and R 4 , R 2 and R 3 , R 1 and R 3 any one group together with the atom to which it is attached form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl being optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; or, wherein one R B and R 3 any one group together with the atom to which it is attached form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl being optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0023] or, wherein one R B and R 4 , one R B and R 3 any one group together with the atom to which it is attached form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl being optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0024] each R 5 is the same or different, independently selected from H, halo, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C1-6 haloalkoxy;

[0025] R 6 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl or the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 halo, hydroxy, cyano, amino, oxo, carboxylic acid, ester, 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;

[0026] R 7 selected from H, halo, cyano, hydroxy, 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;

[0027] or, any one of R 7 and R 3 , R 7 and R 4 together with the atom to which they are attached form a 5-12 membered heterocyclyl, said 5-12 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0028] R 8 selected from H, halo, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0029] R 9 selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 1-6 alkylene-C 3-8 cycloalkyl and -C 1-6 alkylene-(3-8 membered heterocyclyl), said -C 1-6 alkylene-C 3-8 cycloalkyl and -C 1-6 alkylene-(3-8 membered heterocyclyl) is optionally substituted with one or more of halogen, hydroxy, amino and amino;

[0030] or, R 8 and R 9 together with the atom to which they are attached form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl is optionally substituted with one or more of halogen, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0031] R 6a and R 6b are the same or different, each independently selected from H, halogen, cyano, 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;

[0032] m is 0, 1 or 2;

[0033] n is 0, 1, 2, 3 or 4;

[0034] p is 1 or 2;

[0035] q is 1 or 2;

[0036] the heteroatoms in said heterocyclyl or heteroaryl are selected from O, N and S, in a number of 1, 2, 3 or 4;

[0037] is a single or double bond;

[0038] provided that when T is then R 1 and R 4 , R 2 and R 3 , R 1 and R 3 are taken together with the atoms to which they are attached to form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; and the non-cyclic groups of R 1 , R 2 , R 3 and R 4 are as defined above;

[0039] when T is then R 7 and R 3 , R 7 and R 4 are taken together with the atoms to which they are attached to form a 5-12 membered heterocyclyl, said 5-12 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

[0040] In some embodiments, the compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein one R B and R 4 are taken together with the atoms to which they are attached to form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

[0041] In some embodiments, the compounds of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein ring A is 5-12 membered heterocyclyl or C 5-12 cycloalkyl, said 5-12 membered heterocyclyl or C 5-12 cycloalkyl is optionally substituted with one or more R A substituents;

[0042] R A is selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, and S(O) m C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more R 1-6 alkyl and S(O)2C 1-6 alkyl;

[0043] m is 0, 1, or 2.

[0044] In some embodiments, the compounds of the present application or a pharmaceutically acceptable salt thereof, certain groups are defined as follows, and the definition of groups not mentioned is as described in any of the aspects of the present application (hereinafter referred to as "in some embodiments" or "in a certain aspect").

[0045] In some embodiments, the compounds of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein T is

[0046] R a is selected from H, halo, cyano, hydroxy, oxo, amino, 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;

[0047] t is 1, 2, 3, or 4;

[0048] ring D is 5-12 membered heterocyclyl or C 5-12 cycloalkyl;

[0049] R A is as defined in Formula (IG).

[0050] In some embodiments, the compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein ring D is 5-8 membered mono-heterocyclyl, 6-12 membered spiro-heterocyclyl, 6-12 membered fused-heterocyclyl, or 6-12 membered bridged-heterocyclyl.

[0051] In some embodiments, ring D is 3-8 membered mono-heterocyclyl, 6-12 membered spiro-heterocyclyl, 6-12 membered fused-heterocyclyl, or 6-12 membered bridged-heterocyclyl.

[0052] In some embodiments, the compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein R A are the same or different, each independently selected from H, halogen, cyano, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more selected from cyano, hydroxyl, halogen, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, SC 1-6 alkyl and S(O) 1-6 alkyl.

[0053] In some embodiments, the compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein

[0054] wherein T is

[0055] ring A is 5-12 membered heterocyclyl or C 5-12 cycloalkyl, said 5-12 membered heterocyclyl or C 5-12 cycloalkyl is optionally substituted with one or more R A ;

[0056] R A are the same or different, each independently selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 and S(O) m C 1-6 alkyl, said C1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of cyano, hydroxy, halo, amino, SC 1-6 alkyl and S(O)2C 1-6 alkyl;

[0057] B is a 5-membered heteroaryl, said 5-membered heteroaryl being optionally substituted with one or more R B substituents;

[0058] R B are the same or different, each independently selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1- hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0059] C is a 5-membered heteroaryl;

[0060] X is C and Y is N; or, X is N and Y is C;

[0061] R 0 is selected from the group consisting of H, 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;

[0062] R 1 and R 2 are the same or different, each independently selected from the group consisting of H, halo, cyano, hydroxy, 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;

[0063] or R 0 and R 2 together with the atom to which they are attached form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C1-6 One or more substitutions in a haloalkoxy group;

[0064] R 3 and R 4 Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, hydroxyl, and 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 cycloalkyl and 3-8 membered heterocyclic groups;

[0065] Or, R 1 and R 4 R 2 and R 3 R 1 and R 3 Any group of atoms connected to it together forms C. 5-12 Cycloalkyl or 5-12 membered heterocyclic groups, wherein the C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0066] Or, one of the R B and R 3 Together with the atoms attached to it, they form C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups, wherein the C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0067] Or, one of the R B and R 4 Together with the atoms attached to it, they form C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups, wherein the C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6alkyl, C 1-6 one or more substituents selected from halo, hydroxyl, cyano, amino, oxo, carboxylic acid, ester, C

[0068] each R 5 is 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;

[0069] R 6 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 substituents selected from halo, hydroxyl, cyano, amino, oxo, carboxylic acid, ester, 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; 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, amino, oxo, carboxylic acid, ester, 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;

[0070] m is 0, 1, or 2;

[0071] n is 0, 1, 2, 3, or 4;

[0072] the heteroatoms in the heterocyclyl or heteroaryl are selected from O, N, and S, in a number of 1, 2, 3, or 4;

[0073] is a single or double bond;

[0074] provided that when T is R 1 and R 4 , R 2 and R 3 , R 1 and R 3 at least one group together with the atoms to which they are attached form a C 5-12cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl is optionally substituted with one or more R 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R 1 , R 2 , R 3 and R 4 are as defined above.

[0075] 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 (I),

[0076] wherein ring A, ring B, ring C, X, Y, R 3 , R 4 , R 5 , R 6 and n are as defined for Formula (IG).

[0077] 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 (I),

[0078] wherein ring A, ring B, ring C, X, Y, R 3 , R 4 , R 5 , R 6 and n are as defined for Formula (IG).

[0079] In some embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein the compound is of the following formula:

[0080] wherein,

[0081] ring A is 5-12 membered heterocyclyl or C 5-12 cycloalkyl, said 5-12 membered heterocyclyl or C 5-12 cycloalkyl is optionally substituted with one or more R A ;

[0082] R A are the same or different, each independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2and S(O) m C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more selected from the group consisting of cyano, hydroxy, halo, amino, SC 1-6 alkyl and S(O)2C 1-6 alkyl;

[0083] Ring B is 5-membered heteroaryl, said 5-membered heteroaryl is optionally substituted with one or more R B ;

[0084] R B , which are the same or different, each is independently selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1- hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0085] Ring C is 5-membered heteroaryl;

[0086] X is C and Y is N; or, X is N and Y is C;

[0087] R 3 and R 4 , which are the same or different, each is independently selected from the group consisting of H, halo, cyano, hydroxy, 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;

[0088] or, wherein one R B and R 3 together with the atom to which they are attached form a C 6-8 cycloalkyl or 6-8 membered heterocyclyl, said C 6-8 cycloalkyl or 6-8 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0089] or one of R B and R 4 together with the atom to which they are attached form a C 6-8 cycloalkyl or 6-8 membered heterocyclyl, said C 6-8 cycloalkyl or 6-8 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0090] each R 5 is the same or different, independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0091] R 6 is C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, said C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl 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;

[0092] m is 0, 1, or 2;

[0093] n is 0, 1, 2, 3, or 4;

[0094] is a single or double bond;

[0095] the heteroatoms in said heterocyclyl or heteroaryl are selected from O, N, and S, in a number of 1, 2, 3, or 4.

[0096] In some embodiments, the compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein Formula (IG) is a compound of Formula (IIG-1) or Formula (IIG-2),

[0097] wherein L is C1-6 alkylene or C 1-6 heteroalkylene, said C 1-6 alkylene or C 1-6 heteroalkylene optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0098] R 1 selected from the group consisting of H, halo, cyano, hydroxy, 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] R 3 and R 4 are the same or different, each being independently selected from the group consisting of H, halo, cyano, hydroxy, 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;

[0100] ring C, X, Y, R 0 , R 2 , R 5 , R 6 or n are as defined in formula (IG).

[0101] In some embodiments, the compound of formula (IG) or a pharmaceutically acceptable salt thereof, wherein formula (IG) is a compound of formula (IIG-3),

[0102] L is C 1-6 alkylene or C 1-6 heteroalkylene, said C 1-6 alkylene or C 1-6 heteroalkylene optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0103] G 1 CH or N;

[0104] Ring C, X, Y, R 5 , R 6 , R 9 or n are as defined in formula (IG).

[0105] In some embodiments, a compound of Formula (IIG-3) as shown below or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from C 1-6 hydroxyalkyl, -C 1-6 alkylene-C 3-8 cycloalkyl and -C 1-6 alkylene-(3-8 membered heterocyclyl), said -C 1-6 alkylene-C 3-8 cycloalkyl and -C 1-6 alkylene-(3-8 membered heterocyclyl) is optionally substituted with one or more of halo, hydroxy, amino and amino.

[0106] In some embodiments, a compound of Formula (IIG-3) as shown below or a pharmaceutically acceptable salt thereof, wherein R 9 is

[0107] In some embodiments, a compound of Formula (I) or Formula (IG) as shown below or a pharmaceutically acceptable salt thereof, wherein X is N and Y is C.

[0108] In some embodiments, a compound of Formula (I) or Formula (IG) as shown below or a pharmaceutically acceptable salt thereof, wherein X is C and Y is N.

[0109] In some embodiments, a compound of Formula (I) or Formula (IG) as shown below or a pharmaceutically acceptable salt thereof, wherein ring C is oxazolyl, triazolyl or tetrazolyl.

[0110] In some embodiments, a compound of Formula (I) or Formula (IG) as shown below or a pharmaceutically acceptable salt thereof, wherein ring C is

[0111] In some embodiments, the compound of Formula (IG) as shown below or a pharmaceutically acceptable salt thereof,

[0112] wherein, T is

[0113] Ring A is 5-12 membered heterocyclyl, said 5-12 membered heterocyclyl is optionally substituted with one or more R Asubstituted;

[0114] R A the same or different, each independently halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more selected from the group consisting of cyano, hydroxyl, halogen, amino, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, SC 1-6 alkyl and S(O)2C 1-6 alkyl;

[0115] or, 2 R A form a carbon-carbon double bond on the same carbon atom, and the carbon-carbon double bond is optionally substituted with one or two selected from the group consisting of halogen and C 1-6 alkyl;

[0116] Ring B is 5-membered heteroaryl, said 5-membered heteroaryl is optionally substituted with one or more R B ;

[0117] R B the same or different, each independently selected from halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0118] Ring C is 5-membered heteroaryl;

[0119] X is C and Y is N; or, X is N and Y is C;

[0120] each R 5 the same or different, independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0121] R 6 is C 1-6 alkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, or the C 1-6 alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl are each independently optionally substituted with one or more selected from halo, hydroxyl, cyano, amino, oxo, carboxylic acid, ester, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;

[0122] R 6a and R 6b are the same or different, each independently selected from H, halo, cyano, 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;

[0123] n is 0, 1, 2, 3, or 4;

[0124] p is 1 or 2;

[0125] q is 1 or 2;

[0126] the heteroatoms in the heterocyclyl or heteroaryl are selected from O, N, and S, in a number of 1, 2, 3, or 4;

[0127] is a single bond or a double bond.

[0128] In some embodiments, in the compound of Formula (IG), or a pharmaceutically acceptable salt thereof,

[0129] wherein T is

[0130] Ring A is a 5-8 membered single heterocyclyl, 6-12 membered spiro heterocyclyl, or 6-12 membered fused heterocyclyl, each of which is independently optionally substituted with one or more R A substituents;

[0131] R A are the same or different, each independently halo, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-8 cycloalkyl, the C 1-6 alkyl, and C 3-8Cycloalkyl is optionally substituted with one or two substituents selected from the group consisting of hydroxy, C 1-6 alkoxy, halogen and amino;

[0132] Ring B is a 5-membered heteroaryl, which is optionally substituted with one or more R B substituents;

[0133] R B are the same or different, each independently C 1-6 alkyl;

[0134] Ring C is a 5-membered heteroaryl;

[0135] X is C and Y is N; or, X is N and Y is C;

[0136] each R 5 is the same or different, independently selected from H, halogen or C 1-6 alkyl;

[0137] R 6 is C 1-6 alkyl, C 3-8 ycloalkyl or 3-8 membered heterocyclyl, which C 1-6 alkyl, C 3-8 ycloalkyl and 3-8 membered heterocyclyl are each independently optionally substituted with one or two substituents selected from the group consisting of halogen and hydroxy;

[0138] n is 0, 1, 2, 3 or 4;

[0139] p is 1 or 2;

[0140] q is 1 or 2;

[0141] the heteroatoms in the heterocyclyl or heteroaryl group are selected from O, N and S, in a number of 1, 2, 3 or 4;

[0142] is a single or double bond.

[0143] In some embodiments, the compound of Formula (I) or Formula (IG) is a compound of Formula (II-1), Formula (II-2), Formula (III-1) or Formula (III-2),

[0144] wherein ring A, ring B, R 3 , R 4 , R 5 , R 6 and n are as defined in Formula (I) or Formula (IG).

[0145] In some embodiments, the compound of Formula (I) or Formula (IG) is a compound of Formula (III-3) or Formula (III-4),

[0146] wherein ring A, ring B, R 3 , R 4 , R 5 , R 6 and n are as defined in Formula (I) or Formula (IG).

[0147] In some embodiments, ring A (e.g., ring A is ring D) is

[0148] In some embodiments, the compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein is

[0149] R a is selected from H, halo, cyano, hydroxyl, oxo, amino, 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;

[0150] R b , R c , R d , R e , R f , R g , R k , R m and R n are the same or different, each independently selected from H, halo, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, and S(O) m C 1-6 alkyl, C 1-6 cycloalkyl, and 3-8 membered heterocyclyl are optionally substituted with one, two, or three substituents selected from cyano, hydroxyl, halo, amino, -NHC 3-8 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, SC 1-6 Alkyl groups and S(O)2C 1-6 One or more substitutions in alkyl groups;

[0151] Or, R b and R c 、or R d and R e 、or R f and R g 、or R m and R n Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0152] Or, R b and R d 、or R b and R e 、or R e and R f 、or R d and R f 、or R f and R m Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0153] Or, R b and R f 、or R b and R n 、or R d and R k Any group of atoms in the matrix, together with the atoms attached to it, forms C.3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0154] m is 1 or 2.

[0155] In some embodiments, the compound according to Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein

[0156] R a is selected from H, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl;

[0157] R b , R c , R d , R e , R f , R g , R k , R m and R n are the same or different, each independently selected from H, halo, cyano, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, said C 1-6 alkyl and C 3-8 cycloalkyl is optionally substituted with one or more selected from the group consisting of cyano, hydroxy, amino, halo, SC 1-6 alkyl and S(O)2C 1-6 alkyl;

[0158] Alternatively, any pair of R b and R c , or R d and R e , or R f and R g , or R m and R n together with the atom to which they are attached form a C 3-6 ​cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of hydroxy, oxo, C 1-3 alkyl and C 1-6 hydroxyalkyl;

[0159] or, any one group of R b and R d , or R b and R e , or R e and R f , or R d and R f , or R f and R m together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of halogen and C 1-6 hydroxyalkyl;

[0160] or, any one group of R b and R f , or R b and R n , or R d and R k together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with C 1-6 hydroxyalkyl.

[0161] In some embodiments, the compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein

[0162] R a is selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0163] R b , R c , R d ​R e R f and R g Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, hydroxyl, oxo, amino, and C. 1- 6-alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -N(C) 1-6 Alkyl)2 and S(O) m C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from cyano, hydroxyl, amino, halogen, and SC groups. 1-6 Alkyl groups and S(O)2C 1-6 One or more substitutions in alkyl groups;

[0164] Or, R b and R c 、or R d and R e 、or R f and R g Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0165] Or, R b and R d 、or R d and R f Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0166] Or, R b and R f Together with the atoms attached to it, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6cycloalkyl or 3-6 membered heterocyclyl optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0167] m is 1 or 2.

[0168] In some embodiments, the compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein is

[0169] R a selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl;

[0170] R b , R c , R d , and R e are the same or different, each independently selected from the group consisting of H, halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -N(C 1-6 alkyl)2, and S(O) m C 1-6 alkyl, said C 1- 6alkyl is optionally substituted with one or more selected from the group consisting of cyano, hydroxy, amino, halo, SC 1-6 alkyl, and S(O)2C 1-6 alkyl;

[0171] Alternatively, any group of R b and R c , or R d and R e together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6Cycloalkyl or 3-6 membered heterocyclyl optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, and C 1-6 Haloalkoxy;

[0172] or R b and R d together with the atom to which they are attached form a C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 Cycloalkyl or 3-6 membered heterocyclyl optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, and C 1-6 Haloalkoxy;

[0173] m is 1 or 2.

[0174] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable salt thereof, wherein

[0175] R a , R b , R c , R d , R e , R f , and R g are the same or different, each independently selected from the group consisting of H, halo, cyano, hydroxy, oxo, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, -N(C 1-6 Alkyl)2, and S(O) m C 1-6 Alkyl, said C 1-6 Alkyl is optionally substituted with one or more selected from the group consisting of cyano, hydroxy, amino, halo, SC 1-6 Alkyl, and S(O)2C 1-6 Alkyl;

[0176] or R b and R c , or R d and R​e 、or R f and R g Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0177] Or, R b and R d 、or R d and R f Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0178] Or, R b and R f Together with the atoms attached to it, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group.

[0179] In some embodiments, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (III-3), or formula (III-4), or a pharmaceutically acceptable salt thereof, wherein for

[0180] R a Selected from H, halogen, cyano, hydroxyl, oxo, amino, C 1-6alkyl, 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;

[0181] R b , R c , R d , R e , R k , R f and R g are the same or different, each being independently selected from the group consisting of H, halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -N(C 1-6 alkyl)2and S(O) m C 1-6 alkyl, said C 1-6 alkyl and C 3-8 cycloalkyl are optionally substituted with one or more selected from the group consisting of cyano, hydroxyl, amino, halogen, SC 1-6 alkyl and S(O)2C 1-6 alkyl; and m is 1 or 2.

[0182] In some embodiments, the compound according to Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein is

[0183] R a is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl;

[0184] R b , R c , R d , R e , R k , R f and R g are the same or different, each being independently selected from the group consisting of H, halogen, cyano, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, said C 1-6 alkyl and C3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of cyano, hydroxy, amino, halogen, SC 1-6 alkyl and S(O)2C 1-6 alkyl.

[0185] In some embodiments, the compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein

[0186] R a selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0187] R b , R c , R d , R e , R f and R g are the same or different, each independently selected from H, halogen, cyano, hydroxy, oxo, amino, C 1- 6alkyl, C 1-6 alkoxy, C 1-6 6haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -N(C 1-6 alkyl)2and S(O) m C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of cyano, hydroxy, amino, halogen, SC 1-6 alkyl and S(O)2C 1-6 alkyl.

[0188] m is 1 or 2.

[0189] In some embodiments, the compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein

[0190] R a ​​selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1- 6haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0191] R b , R c , R d or R e are the same or different, each independently selected from H, halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -N(C 1-6 alkyl)2and S(O) m C 1-6 alkyl, said C 1- 6alkyl is optionally substituted with one or more selected from cyano, hydroxyl, amino, halogen, SC 1-6 alkyl and S(O)2C 1-6 alkyl; and m is 1 or 2.

[0192] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), or a pharmaceutically acceptable salt thereof, wherein

[0193] R a , R b , R c , R d , R e , R f and R g are the same or different, each independently selected from H, halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -N(C 1-6 alkyl)2and S(O) m C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more selected from cyano, hydroxyl, amino, halogen, SC 1-6 alkyl and S(O)2C 1-6 alkyl.​

[0194] In some embodiments of a compound of Formula (I), (IG), (II-l), (II-2), (III-l), (III-2), (III-3), or (III-4), or a pharmaceutically acceptable salt thereof, wherein is

[0195] R b and R c , or R d and R e , or R f and R g any one of which forms, together with the atoms to which they are attached, a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; and the other variables are as defined herein.

[0196] In some embodiments of a compound of Formula (I), (IG), (II-l), (II-2), (III-l), (III-2), (III-3), or (III-4), or a pharmaceutically acceptable salt thereof, wherein is R b and R c , or R d and R e , or R f and R g , or R m and R n any one of which forms, together with the atoms to which they are attached, a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; and the other variables are as defined herein.

[0197] In some embodiments of a compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein is R b and R c , or R d and R e , together with the atoms to which they are attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; the other variables are as defined herein.

[0198] In some embodiments of a compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein is

[0199] R b and R d , or R e and R f , or R f and R m , together with the atoms to which they are attached, form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; the other variables are as defined herein.

[0200] In some embodiments of a compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein is

[0201] R b and R d 、or R d and R f Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in the haloalkoxy group; other variables as defined in this application.

[0202] In some embodiments, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (III-3), or formula (III-4), or a pharmaceutically acceptable salt thereof, wherein for R b and R f 、or R b and R n Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in the haloalkoxy group; other variables as defined in this application.

[0203] In some embodiments, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (III-3), or formula (III-4), or a pharmaceutically acceptable salt thereof, wherein for R b and R f Together with the atoms attached to it, they form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; the other variables are as defined herein.

[0204] In some embodiments, the compound according to Formula (I), (IG), (II-1), (II-2), (III-1), (III-2), (III-3), or (III-4), or a pharmaceutically acceptable salt thereof, is according to Formula (II-1):

[0205] R b and R d together with the atoms to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; the other variables are as defined herein.

[0206] In some embodiments, the compound according to Formula (I), (IG), (II-1), (II-2), (III-1), (III-2), (III-3), or (III-4), or a pharmaceutically acceptable salt thereof, is according to Formula (II-1): R a and R 3 together with the atoms to which they are attached form a C 6-8 cycloalkyl or 6-8 membered heterocyclyl, said C 6-8 cycloalkyl or 6-8 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; the other variables are as defined herein.

[0207] or R a and R 4 together with the atoms to which they are attached form a C 6-8 cycloalkyl or 6-8 membered heterocyclyl, said C​​6-8 The cycloalkyl or 6-8 membered heterocyclic group is optionally selected from halogen, cyano, hydroxy, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0208] Other variables are as defined in this application.

[0209] In some embodiments, the compound represented by formula (I), formula (IG), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (III-3), or formula (III-4), or a pharmaceutically acceptable salt thereof, wherein for

[0210] R a and R 3 Together with the atoms attached to it, they form C 6-8 cycloalkyl or 6-8 membered heterocyclic groups, wherein the C 6-8 The cycloalkyl or 6-8 membered heterocyclic group is optionally selected from halogen, cyano, hydroxy, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0211] Or, R a and R 4 Together with the atoms attached to it, they form C 6-8 cycloalkyl or 6-8 membered heterocyclic groups, wherein the C 6-8 The cycloalkyl or 6-8 membered heterocyclic group is optionally selected from halogen, cyano, hydroxy, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group;

[0212] Other variables are as defined in this application.

[0213] In some embodiments, the compound represented by formula (I) or formula (IG) is the compound represented by formula (IV-1) or formula (IV-2).

[0214] Where L is C 1-6 Alkylene or C 1-6heteroalkylene, said C 1-6 alkylene or C 1-6 heteroalkylene is optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0215] p is 0, 1, 2, 3, 4, 5 or 6;

[0216] ring C, X, Y, R 5 , R 6 , R A or n are as defined in Formula (I) or Formula (IG).

[0217] In some embodiments, a compound of Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein L is -O-(CH2) t or -(CH2) t ; t is 1, 2 or 3.

[0218] In some embodiments, a compound of Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein L is -O-CH2, -O-(CH2)2, -(CH2)2- or -(CH2)3-.

[0219] In some embodiments, a compound of Formula (I) or Formula (IG), or a pharmaceutically acceptable salt thereof, wherein

[0220] is T, R 3 and R 4 are as defined in Formula (IG).

[0221] In some embodiments, a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein

[0222] In some embodiments, a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein is

[0223] In some embodiments, the compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein

[0224] In some embodiments, the compound of Formula (I), Formula (IG), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), or a pharmaceutically acceptable salt thereof, wherein

[0225] In some embodiments,

[0226] In some embodiments,

[0227] In some embodiments, the heterocyclyl is a saturated heterocycloalkyl, wherein the heterocycloalkyl is monocyclic, spirocyclic, or fused cyclic, the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4.

[0228] In some embodiments, R A are each independently halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, or C 3-8 cycloalkyl, said C 1-6 alkyl is optionally substituted with one or two selected from the group consisting of hydroxyl and halogen; for example, R A are each independently F, methyl, hydroxyl, methoxy, or oxo (=O).

[0229] In some embodiments, R B are each independently C 1-6 alkyl, for example methyl.

[0230] In some embodiments, R​​​​a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, such as methyl.

[0231] In some implementations, R b R c R d R e R f R g R k R m and R n Whether the elements are the same or different, they are each independently selected from H, halogen, hydroxyl, and C. 1-6 Alkyl, oxo, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 The alkyl group may optionally be substituted with one or more selected from hydroxyl and halogen;

[0232] In some implementations, R b and R c 、or R d and R e 、or R f and R g 、or R m and R n Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0233] In some implementations, R b and R d 、or R b and R e 、or R e and R f 、or R d and R f 、or R f and R m Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0234] In some embodiments, the compound represented by formula (I), formula (IG), formula (IIG-1), formula (IIG-2), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (III-3), or formula (III-4), or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 All are H.

[0235] In some embodiments, a compound of Formula (I), (IG), (IIG-1), (IIG-2), (IIG-3), (II-1), (II-2), (III-1), (III-2), (III-3), (III-4), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different, independently selected from H, cyano, halogen, and C 1-6 alkyl.

[0236] In some embodiments, a compound of Formula (I), (IG), (IIG-1), (IIG-2), (IIG-3), (II-1), (II-2), (III-1), (III-2), (III-3), (III-4), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different, independently C 1-6 alkyl, preferably methyl.

[0237] In some embodiments, a compound of Formula (I), (IG), (IIG-1), (IIG-2), (IIG-3), (II-1), (II-2), (III-1), (III-2), (III-3), (III-4), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different, independently halogen, preferably fluorine or chlorine.

[0238] In some embodiments, a compound of Formula (I), (IG), (IIG-1), (IIG-2), (IIG-3), (II-1), (II-2), (III-1), (III-2), (III-3), (III-4), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein each R 5 are the same or different, independently selected from H or cyano.

[0239] In some embodiments, each R 5 are the same or different, independently selected from H, halogen, or C 1-6 alkyl; for example, R 5 are the same or different, each independently H, F, Cl, or methyl.

[0240] In some embodiments of a compound of Formula (I), Formula (IG), Formula (IIG-l), Formula (IIG-2), Formula (IIG-3), Formula (II-l), Formula (II-2), Formula (III-l), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-l), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, R 6 is C 1- 6alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, or the C 1-6 alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocyclyl is each independently optionally substituted with one or more selected from halogen, hydroxyl, cyano, C(O)OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0241] R 6a and R 6b are the same or different, each being independently selected from H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3- to 8-membered heterocyclyl;

[0242] p is 1 or 2;

[0243] q is 1 or 2.

[0244] In some embodiments of a compound of Formula (I), Formula (IG), Formula (IIG-l), Formula (IIG-2), Formula (IIG-3), Formula (II-l), Formula (II-2), Formula (III-l), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-l), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, R 6 is C 1- 6alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocyclyl, the C 1-6 alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocyclyl is each independently optionally substituted with one or more selected from halogen, hydroxyl, cyano, C(O)OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C1-6 alkyl, C 1-6 haloalkyl, C

[0245] In some embodiments, a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R 6 is 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 halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

[0246] In some embodiments, a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R 6 is cyclopropyl or cyclobutyl, said cyclopropyl or cyclobutyl optionally substituted with one or more halo.

[0247] In some embodiments, a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R 6 is azetidinyl, said azetidinyl optionally substituted with one or more C(O)OC 1-6 alkyl.

[0248] In some embodiments, a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1-6 alkyl, said C 1-6 alkyl is substituted with one or more of hydroxy or halo.

[0249] In some embodiments, the compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or pharmaceutically acceptable salt thereof, is wherein R 6 is

[0250] In some embodiments, the compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or pharmaceutically acceptable salt thereof, is wherein n is 1 or 2.

[0251] In some embodiments, R 6 is cyclopropyl, cyclobutyl, or n-propyl, each of which is independently optionally substituted with one or two selected from halo and hydroxy; for example, R 6 is

[0252] In some embodiments, exemplary specific compounds of the compound of Formula (I) include, but are not limited to, the structures in Table A below:

[0253] Table A

[0254] In some embodiments, exemplary specific compounds of the compound of Formula (I) include, but are not limited to, the structures in Table B below:

[0255] Table B

[0256] Another aspect of the present application provides an isotopically-labeled compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or as shown in Table A or Table B, preferably deuterium (D or 2 H) substituted hydrogen 1 H).

[0257] Another aspect of the present application provides a method for preparing a compound of Formula (IG), condensation of a compound of Formula (AG) with a compound of Formula (B) to obtain a compound of Formula (IG),

[0258] wherein, T, ring C, X, Y, R 3 , R 4 , R 5 , R 6 and n are as described in Formula (IG).

[0259] Another aspect of the present application provides a compound of Formula (AG) or a pharmaceutically acceptable salt thereof,

[0260] wherein, T, X, Y, R 3 and R 4 are as defined in any aspect of the present application.

[0261] Preferably the compound of Formula (AG) is selected from:

[0262] Another aspect of the present application provides a method for preparing a compound of Formula (I), condensation of a compound of Formula (A) with a compound of Formula (B) to obtain a compound of Formula (I),

[0263] wherein, ring A, ring B, ring C, X, Y, R 3 , R 4 , R 5 , R 6 and n are as described in any aspect of the present application.

[0264] Another aspect of the present application provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0265] In another aspect, the present application provides the use of a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting c-kit.

[0266] In another aspect, the present application provides the use of a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for preventing and / or treating a c-kit-mediated disease or disorder.

[0267] In another aspect, the present application provides the use of a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in 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; preferably, in the manufacture of a medicament for preventing and / or treating mastocytoma, mastocytosis, inflammatory bowel disease, chronic urticaria, or diabetes.

[0268] In another aspect, the present application provides the use of a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in 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; preferably, in the manufacture of a medicament for preventing and / or treating mastocytoma, mastocytosis, inflammatory bowel disease, or diabetes.

[0269] The present application also provides a method of inhibiting c-kit comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled form, or the aforementioned pharmaceutical composition comprising the same.

[0270] The present application also 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 (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled form, or the aforementioned pharmaceutical composition comprising the same.

[0271] The present application also 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 (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled form, or the aforementioned pharmaceutical composition comprising the same.

[0272] The present application also provides a method of preventing and / or treating a mastocytoma, mastocytosis, chronic urticaria, inflammatory bowel disease, or diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled form, or the aforementioned pharmaceutical composition comprising the same.

[0273] The present application also provides a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition for use as a medicament.

[0274] The present application also provides a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition for use as a c-kit inhibitor.

[0275] The present application also provides a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition comprising the same for use as a medicament for preventing and / or treating a c-kit mediated disease or disorder.

[0276] The present application also provides a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition comprising the same 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.

[0277] The present application also provides a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for preventing and / or treating mastocytoma, mastocytosis, inflammatory bowel disease, or diabetes.

[0278] The present application also provides a compound of Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for preventing and / or treating chronic urticaria.

[0279] 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.

[0280] In some embodiments, the c-kit-mediated disease is selected from mastocytoma, mastocytosis, inflammatory bowel disease, or diabetes.

[0281] In some embodiments, the c-kit-mediated disease is chronic urticaria.

[0282] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0283] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of a compound of the preceding Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), 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 a compound of the preceding Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), 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 0.5-99.5% of a compound of the preceding Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), 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 1-99% of a compound of the preceding Formula (I), Formula (IG), Formula (IIG-1), Formula (IIG-2), Formula (IIG-3), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), Formula (III-4), Formula (IV-1), or Formula (IV-2), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled version thereof, based on the total weight of the composition.

[0284] 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, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 1-99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition.

[0285] As pharmaceuticals, the compounds of the present application can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner widely known 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, ophthalmic, 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 administration. Parenteral administration includes subcutaneous, intracutaneous, intramuscular, intra- peritoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular administration. They can be administered parenterally by injection, by continuous infusion pump, or by implantation devices known to those skilled in the art.

[0286] In making the compositions of the present 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. The compositions can take the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0287] The "excipient" as used herein refers to an ingredient other than the active ingredient, including diluents, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.

[0288] In another aspect, the pharmaceutically acceptable salts of the compounds described herein can be inorganic or organic salts, acid addition salts if the compounds have basic centers, base addition salts if the compounds have acidic centers, and internal salts if the compounds have both acidic and basic centers (e.g., carboxylic acid groups and amino groups).

[0289] In another aspect, the compounds of the present application can exist in particular geometric or stereoisomeric forms. The compounds can be in the syn or anti form, the (-)- and (+)-enantiomeric form, the (R)- and (S)-enantiomeric form, the diastereomeric form, the (D)- and (L)-isomeric form, racemic mixtures, and other mixtures thereof, and enantiomeric or diastereomeric enrichments thereof, all of which are intended to be within the scope of the present 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.

[0290] The "plurality" as used above to indicate the number of substituents or heteroatoms means 2, 3, 4, or 5.

[0291] In the chemical structures of the compounds described herein, the bond indicates unspecified configuration, indicates absolute configuration, i.e., if chiral isomers are present in the chemical structure, the bond may be or both. configurations.

[0292] bond denotes unspecified configuration, including cis (E) or trans (Z) configuration.

[0293] In addition, the compounds and intermediates of the present application can also exist in different tautomeric forms and all such forms are embraced within the scope of the present application. "Tautomers" refer to different energy structures that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton-shift tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present application are within the scope of the present application. The naming of a compound in a single form does not exclude any tautomers.

[0294] The present application also includes some 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 as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl. All isotopic variations of compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0295] Unless otherwise indicated, when a position is designated specifically as deuterium (D), the position is to be understood as having 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). The deuterium in the example compounds can have 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 will be able to synthesize compounds in deuterated form by reference to the relevant literature. Commercially available deuterated starting materials can be used in making deuterated forms of the compounds, or they can be synthesized using conventional techniques employing deuterated reagents, including but not limited to deuterated borane, trideuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, among others.

[0296] 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, 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 or 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 (i.e., retarding the pathology and / or symptomatology) in an individual that is experiencing or displaying the pathology or symptomatology of the disease, disorder or condition; (3) relieving the disease: for example, relieving a disease, disorder or condition (i.e., reversing the pathology and / or symptomatology) in an individual that is experiencing or displaying the pathology or symptomatology of the disease, disorder or condition. For a pharmaceutical or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the pharmaceutical or agent to provide the desired effect without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, as in the art. The exact amount required will vary depending on the particular active compound, the

[0297] "Pharmaceutically acceptable" means, within the scope of sound medical judgment, these compounds, materials, compositions, and / or dosage forms are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0298] "Patient" of the present application refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, most preferably humans.

[0299] Definitions and Descriptions

[0300] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0301] In this application means that the corresponding group is attached to the to other fragments, groups in the compounds.

[0302] is

[0303] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched-chain groups, preferably containing 1 to 20 carbon atoms, more preferably alkyl groups containing 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 1 to 6 carbon atoms (C1-C6alkyl). Non-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. 1-6 The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched-chain groups, preferably containing 1 to 20 carbon atoms, more preferably alkyl groups containing 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 1 to 6 carbon atoms (C1-C6alkyl). Non-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.

[0304] The term "alkylene" refers to saturated, divalent hydrocarbon groups, which are straight-chain or branched-chain groups, which can contain 1-20 carbon atoms, preferably including 1-12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably including 1-6 (e.g., 1, 2, 3, 4, 5, and 6) carbon atoms. The alkylene groups can be substituted or unsubstituted. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), -(CH2)5-, -CH(CH3)-(CH2)4-, -(CH2)6-, -CH(CH3)-(CH2)5-, -(CH2)7-, -CH(CH3)-(CH2)6-, -(CH2)8-, or -CH(CH3)-(CH2)7-, and the like.

[0305] The term "heteroalkylene" refers to one or more carbon atoms in an alkylene group, as defined above, replaced by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, said one or more can be 1, 2, 3, 4, or 5, preferably, it can comprise 1 to 20 carbon atoms and 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S, preferably comprising 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms and 1, 2, or 3 heteroatoms selected from N, O, or S, more preferably comprising 1 to 6 (e.g., 1, 2, 3, 4, 5, and 6) carbon atoms and 1 or 2 heteroatoms selected from N, O, or S.C 1-6 Heteroalkylene refers to a heteroalkylene group comprising 1 to 6 (e.g., 1, 2, 3, 4, 5, and 6) carbon atoms and 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S. The heteroalkylene group can be substituted or unsubstituted. Non-limiting examples include -CH2-O-, -(CH2)3-O-, -(CH2)4-O-, -CH(CH3)-(CH2)3-O-, -(CH2)5-O-, -CH(CH3)-(CH2)4-O-, -(CH2)2-O-(CH2)2-O-, -(CH2)2-NH-(CH2)2-O-, -(CH2)3-O-(CH2)2-O-, -(CH2)3-NH-(CH2)2-O-, -(CH2)7-O-, -CH(CH3)-(CH2)6-O-, -(CH2)4-O-(CH2)2-O-, -(CH2)4-NH-(CH2)2-O-.

[0306] 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 (C 1-12 alkoxy), more preferred are alkoxyl groups containing 1 to 6 carbon atoms (C 1-6 alkoxy). Non-limiting examples of alkoxyl groups include methoxy, ethoxy, propoxy, and butoxy. The alkoxyl group can be substituted or unsubstituted.

[0307] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent (preferably a saturated cycloalkyl), 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; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups (preferably monocyclic, spiro, or fused, e.g., monocyclic).

[0308] The term "spirocycloalkyl" refers to a 5- to 20-membered, polycyclic group in which each single ring shares one carbon atom (termed a spiro atom) between rings in the system, which can contain one or more double bonds. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spirocycloalkyl groups are classified as mono-, bi-, or polycycloalkyl groups, preferably mono- and bi- spirocycloalkyl groups, according to the number of spiro atoms shared between rings. More preferably, 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 mono- spirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0309] The term "fused cycloalkyl" refers to a 5- to 20-membered, polycyclic group in which each ring shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more double bonds. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Fused cycloalkyl groups are classified as bi-, tri-, tetra-, or polycycloalkyl groups, preferably bi- or tri-, 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 bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0310] The term "bridged cycloalkyl" refers to a 5- to 20-membered, polycyclic group in which any two rings share two non-adjacent carbon atoms, which can contain one or more double bonds. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Bridged cycloalkyl groups are classified as bi-, tri-, tetra-, or polycycloalkyl groups, preferably bi-, tri-, or tetra-, more preferably bi- or tri-bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

[0311] The cycloalkyl rings include cycloalkyl rings (including monocyclic, spirocyclic, fused, and bridged) as described herein fused to aryl, heteroaryl, or heterocyclyl rings, where the ring that is attached to the parent structure is a cycloalkyl, non-limiting examples include etc.; preferably The cycloalkyl groups can be substituted or unsubstituted.

[0312] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent (preferably a saturated heterocycloalkyl, cycloalkyl is defined above, and the heteroatom(s) are selected from one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms can be 1, 2, 3, or 4), which contains from 3 to 20 ring atoms, 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), but does not include ring portions of -0-0-, -0-S-, or -S-S-, and the remaining ring atoms are carbon. Preferably, it contains from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains from 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, it contains from 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 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, and the like. Polycyclic heterocyclyl groups include spirocyclic, fused, and bridged heterocyclyl groups.

[0313] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group (preferably a saturated spiroheterocycloalkyl) of 5 to 20 members (e.g., 5 to 12 members) in which each single ring shares one atom (referred to as a spiro atom) in the system, 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), and the remaining ring atoms are carbon. It can contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bi-spiroheterocyclyl groups, depending on the number of spiro atoms shared between rings. 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:

[0314] The term "fused heterocyclyl" refers to a polycyclic heterocyclyl group (preferably a saturated fused heterocycloalkyl), 5 to 20 members (preferably 5-12 members), each ring in the system sharing a pair of adjacent atoms with the other ring(s) 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), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, and 6 / 6 bicyclic fused heterocyclyl, according to the number of rings comprising the ring system. Non-limiting examples of fused heterocyclyl groups include:

[0315] The term "bridged heterocyclyl" refers to a polycyclic heterocyclyl group (preferably a saturated bridged heterocycloalkyl), 5 to 14 members (preferably 5-12 members), 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), the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be 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:

[0316] The heterocyclyl ring includes a heterocyclyl group as described herein (including monocyclic, spiro, fused, and bridged heterocyclyl) fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl ring, non-limiting examples of which include:

[0317] and the like. The heterocyclyl group can be substituted or unsubstituted.

[0318] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic rings are rings that share a pair of adjacent carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring 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:

[0319] The aryl group can be substituted or unsubstituted.

[0320] 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. The heteroaryl group 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:

[0321] The heteroaryl group can be substituted or unsubstituted.

[0322] 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 halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0323] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived from removal of one hydrogen atom from a ring atom of the parent, or two hydrogen atoms from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heterocyclene", "heteroarylene".

[0324] The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined herein.

[0325] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0326] In the present application, the term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group having a specified number of ring atoms (e.g., 5-12 membered, 3-10 membered, 3-6 membered, 3-12 membered), a specified number of heteroatoms (e.g., 1, 2, 3, or 4), a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic (e.g., fused, spiro, or bridged, e.g., monocyclic). The heterocycloalkyl group is attached to the remainder of the molecule through a carbon atom or a heteroatom.

[0327] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.

[0328] The term "haloalkoxy" means an alkoxy group as defined herein substituted with one or more halogen.

[0329] The term "hydroxyalkyl" means an alkyl group as defined herein substituted with one or more hydroxy groups.

[0330] The term "halogen" means F, CI, Br, or I.

[0331] The term "hydroxy" means -OH.

[0332] The term "amino" means -NH2.

[0333] The term "cyano" means -CN.

[0334] The term "nitro" means -NO2.

[0335] The term "oxo" or "keto" means "=O".

[0336] The term "carbonyl" means C=O.

[0337] The term "carboxy" means -C(O)OH.

[0338] The term "carboxylate" or ester 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, preferably -C(O)O(alkyl).

[0339] "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. When substituted, the number of substituents can be 1, 2, 3, or 4, and when the group is substituted with more than one substituent, the substituents are independent of one another.

[0340] "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 with a corresponding number of substituents. It is understood that substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort. For example, an amino or hydroxyl group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond. It is noted that the description "selected from", "are" "are each / individually independently" "are independently" as employed in the present application is to be interpreted broadly, and when a substituent is plural, each individual described is independent of the other, and can be the same or different specific group. In more detail, the description "are independently" can mean that the specific options expressed by the same symbol in different groups are independent of each other; or it can mean that the specific options expressed by the same symbol in the same group are independent of each other.

[0341] The above-mentioned preferred conditions can be combined in any manner without departing from the common general knowledge of the skilled person, thereby obtaining preferred embodiments of the present application.

[0342] The reagents and starting materials used in the present application are commercially available. Advantages:

[0343] The present application provides a small molecule compound with a condensed heterocyclic structure, which can be used as a c-kit inhibitor. The compound or pharmaceutical composition has a strong inhibitory effect on c-kit receptor, good selectivity, and excellent pharmacokinetic effect, and can be used for effectively treating or preventing c-kit-mediated diseases. DETAILED DESCRIPTION

[0344] 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 implemented based on the above description of the present application is covered by the scope of protection intended by the present application. The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the commodity.

[0345] The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the commodity.

[0346] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is expressed in 10 -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) or deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0347] Mass spectrometry (MS) was determined by Waters 2767 HPLC / Waters SQD, Waters H-class UPLC-SQD2, Agilent HPLC / Waters liquid chromatography-mass spectrometry.

[0348] Chiral HPLC analysis was determined using Shimadzu LC-20AD.

[0349] Thin layer chromatography silica gel plates used were GF254 silica gel plates from Cheng Chemicals (Shanghai) Co. Ltd. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.2-0.25 mm and the specifications of the silica gel plates used for thin layer chromatography separation and purification of products were 0.4-0.5 mm.

[0350] Column chromatography generally used 100-200 mesh silica gel as the carrier.

[0351] High performance liquid chromatography preparation used Waters HPLC, Gilson HPLC and Biotage MPLC preparative chromatographs.

[0352] Chiral separation column chromatography used Gilson GX-281 preparative HPLC.

[0353] Unless otherwise specified in the examples, the reactions were carried out under a nitrogen atmosphere.

[0354] A nitrogen atmosphere means that the reaction flask was connected to a nitrogen balloon with a volume of about 1 liter.

[0355] A hydrogen atmosphere means that the reaction flask was connected to a hydrogen balloon with a volume of about 1 liter.

[0356] Unless otherwise specified in the examples, the reaction temperature was room temperature, and the temperature range was 20-30 °C.

[0357] The skilled in the art should understand that the 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 distinguished by the number suffix P1, P2, etc. That is, the suffix P1 corresponds to the chiral structure separated first, and the suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of the compound is listed in the structural formula, it does not mean that it corresponds to the compound with the number suffix P1, P2 one by one, but only indicates the two existing forms of the absolute configuration. The absolute configuration of the compound with the number suffix P1, P2 is subject to the absolute configuration corresponding to the specific retention time.

[0358] English abbreviations and corresponding Chinese names:

[0359] Intermediate 89b has the following resonance structures:

[0360] Example 1 (compound 2)

[0361] Step 1: synthesis of compound 2c

[0362] Under nitrogen protection, Pd(dppf)Cl2(44 mg, 0.06 mmol) and Cs2CO3(295 mg, 0.90 mmol) were added to a mixed solution of compound 2a (79 mg, 0.30 mmol, purchased from Shanghai Bide) and compound 2b (89 mg, 0.30 mmol, purchased from Shanghai Bide) in 1,4-dioxane (5 mL / 1 mL), and the reaction mixture was stirred at 100°C for 16 h. After the reaction was completed, the reaction solution was diluted with water (40 mL), extracted with EtOAc (40 mL x 3), and 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 (MeOH / DCM = 0-5%) to obtain compound 2c (47 mg). MS m / z (ESI): 325.3 [M+1] + .

[0363] Step 2: synthesis of compound 2d

[0364] Lithium hydroxide monohydrate (18 mg, 0.43 mmol) was added to a mixture solution of compound 2c (47 mg, 0.14 mmol) in methanol and water (2 mL / 1 mL), the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was adjusted to pH 6-7 with 1M hydrochloric acid, and the reaction solution was purified by high performance liquid preparative chromatography (column: Xbridge-C18; 19x150mm, 5pm; mobile phase: acetonitrile-water 10 mM ammonium bicarbonate); gradient: 10-30%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 2d (45 mg). MS m / z (ESI): 297.2 [M+1] + .

[0365] Step 3: Synthesis of compound 2

[0366] POCl3(10 drops) was added dropwise to a solution of compound 2d (35 mg, 0.12 mmol) and compound 2e (31 mg, 0.12 mmol, synthesis method reference to the synthesis of compound 37 on page 96 of patent WO2013033070 A1) in pyridine (3 mL) at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution (35 mL), extracted with DCM (35 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 (EtOAc / PE = 0-20%) to obtain a crude product (30 mg). The crude product was purified by high performance liquid preparative chromatography (column: Xbridge-C18; 19x150mm, 5pm; mobile phase: acetonitrile-water 10 mM ammonium bicarbonate); gradient: 50-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 2 (5.49 mg). MS m / z (ESI): 544.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.53 (t, J = 1.4 Hz, 1H), 8.56 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.95 (s, 1H), 7.87 - 7.74 (m, 3H), 7.52 (d, J = 8.2 Hz, 1H), 3.93 - 3.83 (m, 3H), 3.26 - 3.01 (m, 4H), 2.90 (s, 2H), 2.36 (s, 3H), 1.27 (s, 6H).

[0367] Example 2 (compound 90)

[0368] First Step: Synthesis of compound 90c

[0369] To a mixture of compound 90a (76 mg, 14.97 mmol, synthesis method refer to patent CN117677622A specification page 78-81 paragraph 0456-0477 synthesis of compound 9-1), compound 90b (69 mg, 0.22 mmol, synthesis method refer to patent CN114380818A specification page P37 synthesis of compound 9-2), Cs2CO3(143.4 mg, 0.44 mmol) and Pd(dppf)Cl2(18 mg, 0.02 mmol,) in 1,4-dioxane (1 mL) and water (0.3 mL) was added at room temperature. The reaction mixture was stirred at 110 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL), the combined organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, and then concentrated under reduced pressure. Compound 90c (93 mg) was obtained by purification with thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1). MS m / z (ESI): 457.1 [M+1] + .

[0370] Second Step: Synthesis of compound 90e

[0371] To a mixture of compound 90c (35 mg, 0.077 mmol) and compound 90d (29 mg, 0.12 mmol, synthesis method refer to patent WO2024118887A1 specification page 170 synthesis of compound intermediate 73) in toluene (1 mL) was added trimethylaluminum (2M in n-hexane, 0.077 mL, 0.15 mmol) dropwise at 0 °C. The reaction mixture was stirred at 100 °C for 1 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (2 mL), extracted with ethyl acetate (30 mL), and the organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, and then concentrated under reduced pressure. Compound 90e (29 mg) was obtained by purification with thin layer chromatography on silica gel plate (dichloromethane / methanol = 15 / 1). MS m / z (ESI): 664.1 [M+1] + .

[0372] Third Step: Synthesis of compound 90

[0373] CsF (27.0 mg, 0.18 mmol) was added to a solution of compound 90e (24 mg, 0.036 mmol) in DMF (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was added with ethyl acetate (30 mL), washed with water (10 mL x 3) and saturated sodium chloride solution (10 mL) successively, and the organic phase was concentrated under reduced pressure. Purification by thin layer chromatography on silica gel plate (dichloromethane / methanol = 10 / 1) gave compound 90 (12.8 mg). MS m / z (ESI): 549.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.79 (d, J = 7.3 Hz, 1H), 8.72 (s, 1H), 8.30 (dd, J = 15.3, 7.4 Hz, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 5.47 (s, 1H), 4.62 - 4.42 (m, 1H), 4.31 (d, J = 9.4 Hz, 1H), 4.09 (d, J = 9.4 Hz, 1H), 3.72 (dd, J = 12.1, 5.0 Hz, 1H), 3.60 (dd, J = 12.1, 6.0 Hz, 1H), 1.59 (s, 3H), 1.46 - 1.41 (m, 2H), 1.34 - 1.27 (m, 2H).

[0374] Example 3 (compound 81)

[0375] First step: synthesis of compound 81b

[0376] Compound 81a (150 mg, 0.91 mmol), benzyloxyacetone (306.11 mg, 2.73 mmol) and p-toluenesulfonic acid (31.34 mg, 0.18 mmol) were added into toluene (3 mL) successively at room temperature, and the reaction mixture was stirred at 110 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate (10 ml x 3). The combined organic phase was 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 column chromatography on silica gel (ethyl acetate / petroleum ether = 0-100%) to give compound 81b (88 mg). MS m / z (ESI): 259.14 [M+1] + .

[0377] Second step: synthesis of compound 81c

[0378] Compound 81b (88 mg, 0.34 mmol), N-bromosuccinimide (60.51 mg, 0.34 mmol) were added into DMF (2 mL) successively under ice bath, the reaction mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction liquid was poured into water (20 mL), extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to give compound 81c (94 mg, crude). MS m / z (ESI): 337.05 [M+1] + .

[0379] Step 3: Synthesis of compound 81d

[0380] Compound 81c (90 mg, crude), compound 90b (216.04 mg, 0.41 mmol), potassium carbonate (111.95 mg, 0.81 mmol) and Pd(dppf)Cl2(39.51 mg, 0.054 mmol) were added into 1,4-dioxane and water (2 mL / 0.5 mL) successively at room temperature under nitrogen atmosphere, the reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 80%) to give compound 81d (72 mg). MS m / z (ESI): 447.20 [M+1] + .

[0381] Step 4: Synthesis of compound 81e

[0382] Compound 81d (72 mg, 0.16 mmol), palladium on carbon (14 mg), palladium hydroxide (14 mg) were added into methanol (2 mL) successively at room temperature, the reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 h. After the reaction was completed, the reaction liquid was filtered through celite, the filter cake was rinsed with methanol (20 mL), the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol = 100%) to give compound 81e (17 mg). MS m / z (ESI): 357.15 [M+1] + .

[0383] Step 5: Synthesis of compound 81

[0384] A solution of trimethylaluminum in n-hexane (0.1 mL, 2 M) was added dropwise to a solution of compound 81e (17 mg, 0.048 mmol) and compound 90d (12.18 mg, 0.048 mmol) in toluene (1 mL) under ice-bath and nitrogen atmosphere, 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 quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 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 (methanol:dichloromethane = 1:10) to give compound 81 (2.3 mg). MS m / z (ESI): 564.16 [M+1] + .

[0385] Example 4 (compound 89)

[0386] First step: synthesis of compound 89c

[0387] Compound 89b (0.83 g, 9.84 mmol) and potassium carbonate (6.80 g, 49.2 mmol) were sequentially added to a solution of compound 89a (3 g, 12.30 mmol) in N,N-dimethylformamide (30 mL) at room temperature, and the reaction mixture was stirred at 130 °C for 4 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), and the combined organic layer was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 89c (1.7 g). MS m / z (ESI): 167.1 [M+1] + .

[0388] Second step: synthesis of compound 89d

[0389] N-bromosuccinimide (2.41 g, 13.54 mmol) was added to a solution of compound 89c (1.5 g, 9.03 mmol) in acetonitrile (15 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 2 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 (DCM:MeOH = 1:0 ~ 10:1) to give compound 89d (2 g). MS m / z (ESI): 245.0 [M+1] + .

[0390] Third step: synthesis of compound 89e

[0391] Compound 89d (300 mg, 1.22 mmol), compound 90b (0.31 g, 0.98 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.10 g, 0.12 mmol) and cesium carbonate (0.80 g, 2.44 mmol) were added successively into a mixture of 1,4-dioxane (3 mL) and water (0.6 mL) at room temperature. The reaction mixture was stirred at 80 °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 = 1:0 ~ 0:1) to give compound 89e (80 mg). MS m / z (ESI): 355.1 [M+1] + .

[0392] Fourth step: synthesis of compound 89

[0393] Compound 90d (15 mg, 0.059 mmol) and compound 89e (21 mg, 0.059 mmol) in toluene (2 mL) was added with a solution of trimethylaluminum in n-hexane (2 M, 0.06 ml, 0.12 mmol) at 0 °C. The reaction mixture was stirred at 110 °C for 4 h under nitrogen atmosphere. After completion of the reaction, sodium sulfate decahydrate was added to quench the reaction. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH = 1:0 ~ 15:1) to give compound 89 (2.3 mg). MS m / z (ESI): 562.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.78 (d, J = 7.3 Hz, 1H), 8.72 (s, 1H), 8.34 (d, J = 1.3 Hz, 1H), 8.29 (d, J = 7.3 Hz, 1H), 7.99 (s, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.38 (dd, J = 7.3, 2.0 Hz, 1H), 4.71 (s, 2H), 4.57 - 4.49 (m, 5H), 4.45 (s, 2H), 1.45 - 1.37 (m, 2H), 1.36 - 1.28 (m, 2H).

[0394] Example 5 (compound 30)

[0395] First step: synthesis of compound 30b

[0396] Sodium hydride (0.076 g, 3.18 mmol,) was slowly added to a solution of dimethyl methylmalonate (0.46 g, 2.65 mmol) in DMF (12 mL) at 0 °C. After the mixture was stirred for 30 min, compound 30a (0.65 g, 2.65 mmol, synthesis method refer to patent WO2018191394A1 page 174 synthesis of compound S63) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. After the reaction was completed, water (20 ml) and ethyl acetate (40 ml) were added to the reaction solution. The organic phase was washed with water (5 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 (petroleum ether: ethyl acetate = 10:0 ~ 10:5) to give compound 30b (0.62 g). MS m / z (ESI): 311.1 [M+1] + .

[0397] Second step: synthesis of compound 30c

[0398] Compound 30b (0.56 g, 1.65 mmol) was dissolved in THF (10 mL) under ice bath conditions. Lithium aluminum hydride (0.13 g, 3.3 mmol) was slowly added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After the reaction was completed, sodium sulfate decahydrate was slowly added to the reaction solution and filtered. The filter cake was rinsed with dichloromethane (10 ml), and the filtrate was concentrated under reduced pressure to give crude compound 30c (330 mg). This compound was used directly in the next step without purification. MS m / z (ESI): 255.2 [M+1] + .

[0399] Third step: synthesis of compound 30d

[0400] Under ice bath conditions, imidazole (0.16 g, 2.28 mmol) and tert-butyl dimethylchlorosilane (0.19 g, 1.25 mmol) were sequentially added to a solution of compound 30d (0.29 g, 1.14 mmol) in DCM (30 mL). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After the reaction was completed, the reaction solution was washed with water (3 ml x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude compound 30d (0.4 g). This compound was used directly in the next step without purification. MS m / z (ESI): 369.2 [M+1] + .

[0401] Fourth step: synthesis of compound 30e

[0402] Compound 30d (0.4 g, 1.09 mmol) was dissolved in DCM (20 mL) at room temperature, and methylsulfonyl chloride (0.25 g, 2.18 mmol) and triethylamine (0.33 g, 3.27 mmol) were added slowly. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was washed with saturated aqueous sodium bicarbonate solution (10 mL x 2) and water (10 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 30e (0.5 g). The compound was used directly in the next reaction without purification. MS m / z (ESI): 447.2 [M+1] + .

[0403] Fifth step: synthesis of compound 30f

[0404] Trifluoroacetic acid (0.29 g, 2.5 mmol) was added dropwise to a solution of compound 30e (0.225 g, 0.50 mmol) in DCM (50 mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and evaporated to dryness to obtain crude compound 30f (0.18 g). The compound was used directly in the next reaction without purification. MS m / z (ESI): 363.2 [M+1] + .

[0405] Sixth step: synthesis of compound 30g

[0406] Potassium carbonate (0.69 g, 5 mmol) was added to a solution of compound 30f (0.18 g, 0.50 mmol) in DMF (15 mL) at room temperature, and the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (15 mL) were added to the reaction solution. The organic phase was washed with water (10 mL) in sequence, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 30g (0.1 g). MS m / z (ESI): 267.2 [M+1] + .

[0407] Seventh step: synthesis of compound 30h

[0408] N-Bromosuccinimide (0.10 g, 0.57 mmol) was added to a solution of compound 30g (0.1 g, 0.38 mmol) in DCM (10 mL) at room temperature, and the reaction mixture was continuously stirred for 3 hours. After the reaction was completed, the reaction solution was washed with water (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 = 10:0 ~ 10:1) to obtain compound 30h (60 mg). MS m / z (ESI): 267.2 [M+1] + .

[0409] Eighth Step: Synthesis of compound 30i

[0410] Compound 30h (50 mg, 0.22 mmol), compound 90b (70 mg, 0.22 mmol), cesium carbonate (0.22 g, 0.66 mmol) and Pd(dppf)Cl2(0.016 g, 0.022 mmol) were added successively into 1,4-dioxane (5 mL) at room temperature. The reaction mixture was stirred at 85 °C for 3 hours. After the reaction was completed, the reaction solution was 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 ~ 10:10) to obtain compound 30i (30 mg). MS m / z (ESI): 341.2 [M+1] + .

[0411] Ninth Step: Synthesis of compound 30

[0412] Compound 30i (10 mg, 0.029 mmol) and compound 90d (7.4 mg, 0.029 mmol) were added successively into toluene (1 mL) at room temperature. Trimethylaluminum n-hexane solution (0.03 mL, 2M) was added under ice bath. The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and sodium sulfate decahydrate was added to the reaction solution. The mixture was stirred for 5 minutes, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel (dichloromethane:methanol = 20:1) to obtain compound 30 (4.7 mg). MS m / z (ESI): 548.2 [M+1] + . 1 HNMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.86 (d, J = 7.2 Hz, 1H), 8.80 (s, 1H), 8.32 (d, J = 7.3 Hz, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.90 (d, J = 10.1 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 5.17 (t, J = 5.2 Hz, 1H), 4.61 - 4.51 (m, 1H), 4.14 (d, J = 10.9 Hz, 1H), 3.86 (d, J = 10.9 Hz, 1H), 3.45 (d, J = 5.1 Hz, 2H), 3.19 (d, J = 16.1 Hz, 1H), 2.86 (d, J = 16.0 Hz, 1H), 1.47 (d, J = 3.1 Hz, 2H), 1.30 (s, 3H), 1.28 (s, 2H).

[0413] Example 6 (compound 91)

[0414] First Step: Synthesis of compound 91b

[0415] Triethylamine (2.06 g, 20.38 mmol) and di-tert-butyl dicarbonate (2.67 g, 12.23 mmol) were added to a solution of compound 91a (1.0 g, 10.19 mmol) in DCM (20 mL), and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction solution was quenched with water (10 mL), extracted with DCM (15 mL x 3), and the combined organic phase was washed with saturated brine (10 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 (dichloromethane / methanol = 0-2%) to give compound 91b (1.10 g).

[0416] Second Step: Synthesis of compound 91c

[0417] Potassium carbonate (1.81 g, 13.12 mmol) was added to a solution of compound 91b (1.30 g, 6.56 mmol) and methyl epichlorohydrin (1.40 g, 13.12 mmol) in DMF (20 mL), and the reaction mixture was stirred at 80°C under nitrogen protection for 12 h. After completion of the reaction, the reaction solution was quenched with water (200 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (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 = 0-20%) to give compound 91c (800 mg). MS m / z (ESI): 213.2 [M-55] + .

[0418] Third Step: Synthesis of compound 91d

[0419] TFA (2 mL) was added to a solution of compound 91c (660 mg, 2.46 mmol) in DCM (4 mL),

[0420] The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was quenched with saturated aqueous sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (MeOH / DCM = 0-10%) to give compound 91d (230 mg). MS m / z (ESI): 169.2 [M+1] + .

[0421] Fourth Step: Synthesis of compound 91e

[0422] NBS (228 mg, 1.28 mmol) was added to a solution of compound 91d (215 mg, 1.28 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was quenched with saturated brine (50 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (50 mL x 2). The solution was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (MeOH / DCM = 0-10%) to give compound 91e (270 mg). MS m / z (ESI): 247.1 [M+1] + .

[0423] Step 5: Synthesis of compound 91f

[0424] Pinacolboronate (260 mg, 1.02 mmol), Pd(dppf)Cl2(68 mg, 0.09 mmol) and KOAc (274 mg, 2.79 mmol) were added to a solution of compound 91f (250 mg, 0.93 mmol) in 1,4-dioxane (2 mL) in turn, and the reaction mixture was stirred at 100 °C under nitrogen protection for 3 h. The reaction solution was cooled to room temperature, and potassium carbonate (212 mg, 1.53 mmol), Pd(dppf)Cl2(68 mg, 0.09 mmol), compound 91e (115 mg, 0.46 mmol), water (1 mL) and 1,4-dioxane (2 mL) were added directly to the above reaction mixture. The reaction mixture was stirred at 100 °C under nitrogen protection for 1 h. After the reaction was completed, the reaction solution was added to saturated brine (30 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (MeOH / DCM = 0-10%) to give compound 91f (30 mg). MS m / z (ESI): 357.4 [M+1] + .

[0425] Step 6: Synthesis of compound 91

[0426] n-hexane solution of trimethylaluminum (0.08 mL, 1M) was added to a solution of compound 91f (15 mg, 0.04 mmol)

[0427] and compound 90d (11 mg, 0.04 mmol) in anhydrous toluene (1 mL). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 1 h. After the reaction was completed, the reaction solution was added to saturated ammonium chloride (20 mL) to quench, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (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 = 0-10%) to give crude compound 91 (15 mg). Compound 91 (8.56 mg) was obtained by purification of the crude product by high performance liquid chromatography (column: Durashell C18(A) 21.2 x 250 mm, 10 nm; mobile phase: acetonitrile-water (10 mM NH4HCO3); gradient: 40-70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar). MS m / z (ESI): 564.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.79 (d, J = 7.4 Hz, 1H), 8.74 (s, 1H), 8.28 (d, J = 7.4 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 10.2 Hz, 1H), 7.21 (dd, J = 7.4, 2.0 Hz, 1H), 5.33 (t, J = 5.6 Hz, 1H), 5.18 (d, J = 8.8 Hz, 1H), 4.88 (d, J = 8.8 Hz, 1H), 4.60 - 4.44 (m, 1H), 3.70 - 3.59 (m, 1H), 3.56 - 3.46 (m, 1H), 2.42 (s, 3H), 1.50 - 1.39 (m, 5H), 1.34 - 1.26 (m, 2H).

[0428] Example 7 (compound 94)

[0429] First step: synthesis of compound 94a

[0430] Bis-pinacolboronate (61.33 mg, 0.24 mmol), KOAc (45.14 mg, 0.46 mmol) and Pd(dppf)Cl2.DCM (18.78 mg, 0.023 mmol) were added successively to a solution of compound 2b (62 mg, 0.23 mmol) in 1,4-Dioxane (1.5 mL) at room temperature, and the reaction solution was protected under a nitrogen atmosphere. The reaction solution was stirred at 100 °C for 2 h. After the reaction was completed, the reaction solution was directly used for the next step. MS m / z (ESI): 235.0 [M+1] + .

[0431] Second Step: Synthesis of compound 94b

[0432] The reaction solution of the previous step, Cs2CO3(150 mg, 0.46 mmol) and compound 90a (80 mg, 0.23 mmol) were added successively into a mixed solvent of 1,4-Dioxane (1 mL) and water (0.3 mL) at room temperature, and the reaction mixture was stirred at 110 °C for 2 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (30 mL), washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), and the organic phase was concentrated under reduced pressure. Purification by thin layer chromatography on silica gel plate (dichloromethane / methanol = 15 / 1) gave compound 94b (89 mg). MS m / z (ESI): 457.1 [M+1] + .

[0433] Third Step: Synthesis of compound 94c

[0434] CsF (144.31 mg, 0.95 mmol) was added to a solution of compound 94b (89 mg, 0.19 mmol) in DMF (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (30 mL), washed successively with water (10 mL x 3) and saturated sodium chloride solution (10 mL), and the organic phase was concentrated under reduced pressure. Purification of the residue by thin layer chromatography on silica gel plate (dichloromethane / methanol = 15 / 1) gave compound 94c (64 mg). MS m / z (ESI): 343.0 [M+1] + .

[0435] Fourth Step: Synthesis of compound 94

[0436] Al(Me)3 (2M in n-hexane, 0.06 mL, 0.12 mmol) was added to a solution of compound 94c (20 mg, 0.058 mmol) and compound 90d (16 mg, 0.064 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), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), and concentrated under reduced pressure. Purification of the residue by thin layer chromatography on silica gel plate (dichloromethane / methanol = 10 / 1) gave compound 94 (23.4 mg). MS m / z (ESI): 549.9 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.49 (s, 1H), 8.57 (s, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 10.1 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.72 (dd, J = 9.3, 1.7 Hz, 1H), 5.43 (t, J = 5.8 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.30 (d, J = 9.4 Hz, 1H), 4.07 (d, J = 9.5 Hz, 1H), 3.69 (dd, J = 12.2, 5.5 Hz, 1H), 3.58 (dd, J = 12.3, 5.9 Hz, 1H), 1.57 (s, 3H), 1.47 - 1.39 (m, 2H), 1.34 - 1.29 (m, 2H).

[0437] Example 8 (Compound 93-1)

[0438] First Step: Synthesis of compound 93b

[0439] DIPEA (1.14 g, 8.79 mmol) and hydroxylamine hydrochloride (0.49 g, 7.03 mmol) were added to a solution of compound 93a in EtOH (10 mL) at room temperature. The reaction mixture was stirred at 80 °C for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was added to H2O (150 mL). A white solid was precipitated, and the mixture was filtered. The filter cake was dried to give compound 93b (775 mg). MS m / z (ESI): 203.9 [M+1] + .

[0440] Second Step: Synthesis of compound 93d

[0441] CDI (1.09 g, 6.72 mmol) was added to a solution of compound 93c (0.64 g, 6.16 mmol) in NMP (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 min, and then compound 93b (1.14 g, 5.60 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, and then the temperature was increased to 120 °C. After stirring at 120 °C for 3 h, the reaction was completed. The reaction solution was diluted with ethyl acetate (100 mL), and then washed with water (30 mL x 3) and saturated sodium chloride solution (30 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound 93d (1.32 g). MS m / z (ESI): 271.9 [M+1] + .

[0442] Third Step: Synthesis of compound 93e

[0443] A solution of trimethylaluminum in n-hexane (2 M, 0.077 mL) was added to a solution of compound 90c (35 mg, 0.077 mmol) and compound 93d (25 mg, 0.092 mmol) in toluene (1 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 1 h. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (30 mL x 3). The combined 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 93e (46 mg). MS m / z (ESI): 682.1 [M+1] + .

[0444] Fourth Step: Synthesis of compound 93-1

[0445] CsF (50.89 mg, 0.34 mmol) was added to a solution of compound 93e (46 mg, 0.067 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, it was diluted with ethyl acetate (30 mL) and washed with water (10 mL x 3) and saturated sodium chloride solution (10 mL) successively. 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 give compound 93-1 (27.1 mg). MS m / z (ESI): 568.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.81 - 8.76 (m, 1H), 8.72 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.95 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.29 (dd, J = 7.3, 2.0 Hz, 1H), 5.48 (t, J = 5.7 Hz, 1H), 5.39 - 5.21 (m, 1H), 4.31 (d, J = 9.5 Hz, 1H), 4.09 (d, J = 9.4 Hz, 1H), 3.66 (ddd, J = 46.0, 12.3, 5.6 Hz, 2H), 3.17 - 3.03 (m, 1H), 2.01 - 1.92 (m, 1H), 1.66 - 1.60 (m, 1H), 1.59 (s, 3H).

[0446] Example 9 (compound 92-1)

[0447] Al(Me)3 (2M in n-hexane, 0.06 mL, 0.12 mmol) was added to a solution of compound 94b (20 mg, 0.058 mmol) and compound 93d (17.33 mg, 0.064 mm) in toluene (1 mL) at 0 °C, and the reaction mixture was stirred at 100 °C for 1 h. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel plate with thin layer chromatography (dichloromethane / methanol = 10 / 1) to give compound 92-1 (14.6 mg). MS m / z (ESI): 568.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.48 (s, 1H), 8.57 (s, 1H), 8.15 (d, J = 7.1 Hz, 1H), 7.90 (d, J = 10.1 Hz, 1H), 7.84 - 7.79 (m, 2H), 7.72 (dd, J = 9.3, 1.7 Hz, 1H), 5.44 (t, J = 5.8 Hz, 1H), 5.40 - 5.18 (m, 1H), 4.30 (d, J = 9.4 Hz, 1H), 4.07 (d, J = 9.4 Hz, 1H), 3.64 (ddd, J = 42.8, 12.2, 5.8 Hz, 2H), 3.16 - 3.05 (m, 1H), 2.01 - 1.92 (m, 1H), 1.65 - 1.58 (m, 1H), 1.57 (s, 3H).

[0448] Example 10 (Compound 4)

[0449] First Step: Synthesis of compound 4b

[0450] Compound 4a (2 g, 11.10 mmol), diethyl acetonylphosphonate (3.69 g, 22.2 mmol) and potassium carbonate (3.84 g, 27.75 mmol) were dissolved in a mixed solution of THF (10 mL) and water (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 4b (2 g). MS m / z (ESI): 221.1 [M+1] + .

[0451] Step 2: Synthesis of compound 4c

[0452] Palladium on carbon (0.97 g, 0.91 mmol) was added to a solution of compound 4b (2 g, 9.08 mmol) in methanol (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h under hydrogen atmosphere. After the reaction was completed, the reaction solution was directly filtered, the filter cake was washed with methanol (10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-35%) to give compound 4c (1.1 g). MS m / z (ESI): 223.1 [M+1] + .

[0453] Step 3: Synthesis of compound 4d

[0454] Sodium hydride (198.0 mg, 4.95 mmol) was slowly added to a solution of trimethylsulfoxonium iodide (990.3 mg, 4.5 mmol) in DMSO (6 mL) at room temperature. After the reaction mixture was stirred at room temperature for 30 min, a solution of compound 4c (0.5 g, 2.25 mmol) in DMSO (2 mL) was added. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into ice water (10 mL) and extracted with ethyl acetate (10 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 (ethyl acetate / petroleum ether = 15-50%) to give compound 4d (0.5 g). MS m / z (ESI): 237.1 [M+1] + .

[0455] Step 4: Synthesis of compound 4e

[0456] Methanesulfonic acid (81 mg, 0.84 mmol) was added dropwise to a solution of compound 4d (50 mg, 0.21 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was directly used in the next step. MS m / z (ESI): 153.1 [M+1] + .

[0457] Step 5: Synthesis of compound 4f

[0458] To a solution of compound 4a (0.1 g, 0.34 mmol) in DMF (1 mL) was added NaH (0.017 g, 0.42 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then stirred at room temperature for 1 h. The reaction mixture 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), 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 = 0-10%) to give compound 4b (0.1 g). MS m / z (ESI): 267.1 [M+1] + . 1 H NMR (400 MHz, CDC13) δ 7.63 (s, 1H), 6.00 (s, 1H), 3.91 (d, J = 10.0 Hz, 1H), 3.79 (d, J = 10.0 Hz, 1H), 3.09 - 2.82 (m, 3H), 2.53 - 2.36 (m, 1H), 1.62 (s, 3H), 0.93 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H).

[0459] Step six: synthesis of compound 4g

[0460] To a solution of compound 4f (45 mg, 0.17 mmol) in acetonitrile (1 mL) was added NBS (30.3 mg, 0.17 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate solution (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 concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-15%) to give compound 4g (40 mg). MS m / z (ESI): 345.0 [M+1] + .

[0461] Step seven: synthesis of compound 4i

[0462] Compound 4g (10 mg, 0.029 mmol), compound 4h (18 mg, 0.058 mmol, purchased from Bide Pharmatech Co., Ltd.), potassium acetate (12.02 mg, 0.087 mmol) and Pd(dppf)Cl2(4.24 mg, 0.0058 mmol) were added into 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 the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (ethyl acetate / petroleum ether = 1 / 3) to obtain compound 4i (7.0 mg). MS m / z (ESI): 455.0 [M+1] + .

[0463] Eighth step: synthesis of compound 4k

[0464] The n-hexane solution of trimethylaluminum (0.03 mL, 2M) was added dropwise to a solution of compound 4i (7.0 mg, 0.015 mmol) and compound 4j (6.0 mg, 0.022 mmol) (synthesized by referring to the synthesis of compound 37 on page 48 of the specification of US201359846A1) in toluene (1 mL) at 0 °C, and 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 sodium sulfate decahydrate (1 g), the mixture was filtered, the filter cake was rinsed with ethyl acetate (5 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 20) to obtain compound 4k (6 mg). MS m / z (ESI): 674.1 [M+1] + .

[0465] Ninth step: synthesis of compound 4

[0466] Cesium fluoride (6.8 mg, 0.044 mmol) was added to a solution of compound 4k (6 mg, 0.0089 mmol) in DMF (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was quenched by adding water (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, 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 obtain compound 4 (4.0 mg). MS m / z (ESI): 560.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.58 (s, 1H), 8.57 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.93 (s, 1H), 7.89 - 7.65 (m, 3H), 7.51 (d, J = 8.0 Hz, 1H), 5.03 (t, J = 5.5 Hz, 1H), 3.88 (dd, J = 9.3, 7.5 Hz, 1H), 3.60 (dd, J = 10.9, 5.8 Hz, 1H), 3.51 (dd, J = 9.7, 4.3 Hz, 1H), 3.24 - 2.97 (m, 5H), 2.93 - 2.65 (m, 3H), 2.37 (s, 3H), 1.23 (s, 3H).

[0467] Example 11 (Compound 71)

[0468] First Step: Synthesis of compound 71a

[0469] Compound 89b (2 g, 23.79 mmol), Boc20 (5.71 g, 26.17 mmol) and TEA (3.13 g, 30.93 mmol) were added to a solution of DCM (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain compound 71a (4.56 g). MS m / z (ESI): 369.1 [2M+1] + .

[0470] Second Step: Synthesis of compound 71b

[0471] Compound 71a (2.28 g, 12.38 mmol) was dissolved in acetonitrile (25 mL), and 3-bromo-2-methylpropene (2.17 g, 16.09 mmol) and K2CO3 (3.42 g, 24.76 mmol) were sequentially added to the solution at room temperature, and the reaction mixture was stirred at 80°C for 6 hours. After the reaction was completed, it was extracted with ethyl acetate (100 mL), and sequentially washed with water (50 mL x 2) and saturated sodium chloride solution (50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1-6:1) to obtain compound 71b (1.03 g). MS m / z (ESI): 183.1 [M-55] + .

[0472] Third Step: Synthesis of compound 71c

[0473] m-CPBA (380 mg, 1.89 mmol) was added to a solution of compound 71b (300 mg, 1.26 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, MsOH (484.39 mg, 5.04 mmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 12 h. The reaction was directly subjected to the next step without any treatment. MS m / z (ESI): 155.1 [M+1] + .

[0474] Fourth step: synthesis of compound 71d

[0475] Imidazole (1.29 g, 18.9 mmol) and TBSCl (0.95 g, 6.3 mmol) were added to the reaction solution from the previous step successively at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the mixture was extracted with petroleum ether (50 mL) and washed successively with saturated sodium thiosulfate (10 mL), saturated sodium carbonate (20 mL), water (20 mL), and saturated sodium chloride solution (20 mL). The organic phase was 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 = 10:0-5 / 1) to give compound 71d (150 mg). MS m / z (ESI): 269.1 [M+1] + .

[0476] Fifth step: synthesis of compound 71e

[0477] NBS (94.69 mg, 0.53 mmol) was added to a solution of compound 71d (150 mg, 0.56 mmol) in acetonitrile (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was extracted with ethyl acetate (50 mL) and washed successively with water (20 mL) and saturated sodium chloride solution (20 mL). The organic phase was 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 = 10:0-10:1) to give compound 71e (176 mg). MS m / z (ESI): 347.0 [M+1] + .

[0478] Sixth step: synthesis of compound 71f

[0479] Compound 71e (76.41 mg, 0.22 mmol), Cs2CO3(143.36 mg, 0.44 mmol), compound 91f (69.56 mg, 0.22 mmol) and Pd(dppf)Cl2(16 mg, 0.022 mmol) were added successively into a mixture of 1,4-Dioxane (1 mL) and water (0.3 mL) at room temperature, and the reaction mixture was replaced with nitrogen for 3 times. The reaction mixture was stirred at 110 °C for 2 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (30 mL), and the organic phase was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried and concentrated under reduced pressure, and purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to obtain compound 71f (61 mg). MS m / z (ESI): 457.0 [M+1] + .

[0480] Seventh step: synthesis of compound 71g

[0481] n-Hexane solution of trimethylaluminum (0.066 mL, 2M) was added to a solution of compound 71f (30 mg, 0.066 mmol) and compound 90d (16.74 mg, 0.066 mmol) in toluene (1 mL) at 0 °C, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride solution (2 mL), extracted with ethyl acetate (30 mL), washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), and dried, and then concentrated under reduced pressure. Purification by thin layer chromatography on silica gel plate (dichloromethane / methanol = 15 / 1) gave compound 71g (41 mg). MS m / z (ESI): 664.2 [M+1] + .

[0482] Eighth step: synthesis of compound 71

[0483] CsF (47.09 mg, 0.31 mmol) was added to a solution of compound 71g (41 mg, 0.062 mmol) in DMF (0.5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (30 mL), washed successively with water (10 mL x 3) and saturated sodium chloride solution (10 mL), dried, and then concentrated under reduced pressure. Purification by thin layer chromatography on silica gel plate (dichloromethane / methanol = 10 / 1) gave compound 71 (10.3 mg). MS m / z (ESI): 550.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.78 (d, J = 7.2 Hz, 1H), 8.72 (s, 1H), 8.31 (d, J = 7.3 Hz, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.84 (d, J = 10.1 Hz, 1H), 7.30 (dd, J = 7.3, 1.8 Hz, 1H), 5.35 (t, J = 5.4 Hz, 1H), 5.25 (d, J = 8.8 Hz, 1H), 4.97 (d, J = 8.7 Hz, 1H), 4.60 - 4.46 (m, 1H), 3.72 - 3.61 (m, 1H), 3.59 - 3.48 (m, 1H), 1.48 (s, 3H), 1.44 - 1.38 (m, 2H), 1.36 - 1.29 (m, 2H).

[0484] Example 12 (Compound 113)

[0485] First Step: Synthesis of compound 113b

[0486] Compound 71a (1 g, 5.43 mmol) was dissolved in acetonitrile (10 mL) at room temperature, and compound 113a (1.62 g, 10.86 mmol) and potassium carbonate (2.25 g, 16.29 mmol) were added successively. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20-40%) to obtain compound 113b (555 mg). MS m / z (ESI): 527.1 [2M+Na] + .

[0487] Second Step: Synthesis of compound 113c

[0488] Compound 113b (555 mg, 2.20 mmol) was dissolved in DCM (10 mL) at room temperature, and m-CPBA (569.5 mg, 3.30 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed, the reaction solution was directly used in the next step.

[0489] Third Step: Synthesis of compound 113d

[0490] MsOH (634.3 mg, 6.60 mmol) was added to the reaction solution of the previous step at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was directly used in the next step. MS m / z (ESI): 169.1 [M+1] + .

[0491] Fourth Step: Synthesis of compound 113e

[0492] To the reaction solution of the previous step, imidazole (2.19 g, 32.10 mmol) and TBSCl (1.61 g, 10.70 mmol) were added successively at room temperature. The reaction mixture was stirred at room temperature for 2 days. After the reaction was completed, the reaction solution was poured into saturated sodium sulfite solution (20 mL), extracted with petroleum ether (20 ml x 3), and the combined organic phase was washed with saturated sodium bicarbonate (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 (ethyl acetate / petroleum ether = 0-50%) to obtain compound 113e (234 mg). MS m / z (ESI): 283.1 [M+1] + .

[0493] Step 5: Synthesis of compound 113f

[0494] Compound 113e (200 mg, 0.71 mmol) was dissolved in ACN (3 mL) at room temperature, and NBS (63.2 mg, 0.35 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound 113f (113 mg). MS m / z (ESI): 360.9 [M+1] + .

[0495] Step 6: Synthesis of compound 113g

[0496] Compound 113f (25 mg, 0.07 mmol) was dissolved in a mixture of 1,4-dioxane and water (1 mL / 0.25 mL) at room temperature, and compound 91f (26.9 mg, 0.07 mmol), potassium carbonate (28.6 mg, 0.07 mmol), and Pd(dppf)Cl2 (10.1 mg, 0.01 mmol) were added successively. The reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 60%) to obtain compound 113g (38 mg). MS m / z (ESI): 471.1 [M+1] + .

[0497] Step 7: Synthesis of compound 113h

[0498] Compound 113g (38 mg, 0.07 mmol) was dissolved in DMF (1 mL) at room temperature, and CsF (49.4 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 ml x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 113h (19.4 mg). MS m / z (ESI): 357.1 [M+1] + .

[0499] Eighth step: synthesis of compound 113

[0500] Compound 113h (19 mg, 0.05 mmol) and compound 90d (9.4 mg, 0.04 mmol) were dissolved in toluene (1 mL) at room temperature, and a solution of trimethylaluminum in n-hexane (2M, 0.1 mL) was added dropwise under ice bath. The reaction mixture was stirred at 100°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (20 ml x 3), and the combined organic phase was 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 thin layer chromatography on silica gel plate (methanol / dichloromethane = 1:10) to obtain compound 113 (7 mg). MS m / z (ESI): 564.0 [M+1] + .

[0501] Example 13 (compound 140)

[0502] First step: synthesis of compound 140b

[0503] Sodium hydroxide aqueous solution (4.00 g, 99.88 mmol) was added to a solution of paraformaldehyde (27.29 g, 149.82 mmol) and compound 140a (5 g, 49.94 mmol) in water (50 mL) at 40°C, and the reaction mixture was stirred at 60°C for 4 hours. After the reaction was completed, the reaction solution was directly freeze-dried, methanol (50 mL) was added to the residue, and the mixture was stirred at room temperature for 30 minutes and then filtered. The filter cake was rinsed with methanol (20 mL), and the filtrate was concentrated under reduced pressure to obtain compound 140b (6 g). MS m / z (ESI): 133.1 [M+1] + .

[0504] Second step: synthesis of compound 140c

[0505] Methanesulfonyl chloride (13.00 g, 113.5 mmol) was added to a solution of compound 140b (6 g, 45.40 mmol) and triethylamine (18.38 g, 181.6 mmol) in dichloromethane (60 mL) at room temperature. The reaction mixture was stirred at 25 °C for 4 h. After the reaction was completed, the reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (50 mL). The aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 30), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 140c (7 g).

[0506] Step 3: Synthesis of compound 140d

[0507] Potassium carbonate (2.88 g, 20.82 mmol) was added to a solution of compound 89b (0.88 g, 10.41 mmol) and compound 140c (2 g, 6.94 mmol) in N,N-dimethylformamide (20 mL) at room temperature. The reaction mixture was stirred at 100 °C for 12 h. After the reaction was completed, the reaction solution was diluted with water (60 mL). The aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phase was washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 140d (800 mg). MS m / z (ESI): 181.1 [M+1] + .

[0508] Step 4: Synthesis of compound 140e

[0509] N-Bromosuccinimide (0.20 g, 1.11 mmol) was added to a solution of compound 140d (200 mg, 1.11 mmol) in acetonitrile (3 mL) at room temperature. The reaction mixture was stirred at 25 °C for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-70%) to give compound 140e (140 mg). MS m / z (ESI): 259.0 [M+1] + .

[0510] Step 5: Synthesis of compound 140f

[0511] Compound 140e (140 mg, 0.54 mmol), compound 91f (260 mg, 0.81 mmol), potassium carbonate (150 mg, 1.08 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (44 mg, 0.054 mmol) were added successively into a mixture of 1,4-dioxane (2 mL) and water (0.4 mL) at room temperature. The reaction mixture was stirred at 80 °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 (ethyl acetate / petroleum ether = 0-100%) to give compound 140f (30 mg). MS m / z (ESI): 369.1 [M+1] + .

[0512] Sixth step: synthesis of compound 140

[0513] Compound 140e (140 mg, 0.54 mmol), compound 91f (260 mg, 0.81 mmol), potassium carbonate (150 mg, 1.08 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (44 mg, 0.054 mmol) were added successively into a mixture of 1,4-dioxane (2 mL) and water (0.4 mL) at room temperature. The reaction mixture was stirred at 80 °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 (ethyl acetate / petroleum ether = 0-100%) to give compound 140f (30 mg). MS m / z (ESI): 369.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.78 (d, J = 7.3 Hz, 1H), 8.73 (s, 1H), 8.36 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.00 (s, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.40 (dd, J = 7.3, 1.9 Hz, 1H), 4.56 - 4.48 (m, 1H), 4.39 (s, 2H), 4.14 (q, J = 12.1 Hz, 2H), 3.92 - 3.82 (m, 2H), 3.69 (d, J = 9.1 Hz, 1H), 3.53 (d, J = 9.1 Hz, 1H), 1.98 - 1.88 (m, 1H), 1.86 - 1.76 (m, 1H), 1.46 - 1.40 (m, 2H), 1.33 - 1.28 (m, 2H).

[0514] Example 14 (compound 116)

[0515] First step: synthesis of compound 116b

[0516] Azidotrimethylsilane (3.53 g, 30.61 mmol), dibutyltin oxide (7.62 g, 30.61 mmol) were added to a solution of compound 116a (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 116b (7 g). MS m / z (ESI): 238.99 [M+1] + .

[0517] Second Step: Synthesis of compound 116c

[0518] 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 116b (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 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0% - 10%) to give compound 116c (1.4 g). MS m / z (ESI): 279.02 [M+1] + .

[0519] Third Step: Synthesis of compound 116d

[0520] 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 116c (1 g, 3.58 mmol) in 1,4-dioxane (10 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), the combined organic phase was 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 column chromatography on silica gel (ethyl acetate / petroleum ether = 0% - 10%) to give compound 116d (1.3 g). MS m / z (ESI): 380.18 [M+1] + .

[0521] Step 4: Synthesis of compound 116e

[0522] 4N hydrochloric acid / 1,4-dioxane (4 mL, 31.6 mmol) was added to a solution of compound 116d (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 hours. The reaction was completed, and the reaction solution was concentrated under reduced pressure to obtain compound 116e (0.5 g, crude). MS m / z (ESI): 216.12 [M+1] + .

[0523] Step 5: Synthesis of compound 116g

[0524] Compound 140c (3.57 g, 36.42 mmol) and potassium carbonate (13.42 g, 97.12 mmol) were added to a solution of compound 116f (14 g, 24.28 mmol) in DMF (100 mL) at room temperature, and the reaction mixture was stirred at 100°C for 12 hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 116g (4 g). MS m / z (ESI): 195.1 [M+1] + .

[0525] Step 6: Synthesis of compound 116h

[0526] NBS (1.51 g, 8.49 mmol) was added to a solution of compound 116g (2 g, 5.66 mmol) in acetonitrile (20 mL) at room temperature, and the reaction mixture was stirred at 25°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 2) to obtain compound 116h (1.3 g). MS m / z (ESI): 273.0 [M+1] + .

[0527] Step 7: Synthesis of compound 116i

[0528] Compound 90b (180 mg, 0.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (30 mg, 0.037 mmol) and cesium carbonate (0.24 g, 0.74 mmol) were added successively to a mixture of compound 116h (100 mg, 0.37 mmol) in 1,4-dioxane and water (2 mL / 0.4 mL) at room temperature. The reaction mixture was heated to 80 °C under nitrogen atmosphere for 4 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (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 (ethyl acetate / methanol = 1 / 0 ~ 50 / 1) to give compound 116i (60 mg). MS m / z (ESI): 383.2 [M+1] + .

[0529] Eighth step: synthesis of compound 116

[0530] 2M trimethylaluminum n-hexane solution (0.08 mL, 0.16 mmol) was added to a mixture of compound 116i (30 mg, 0.078 mmol) and compound 116e (17 mg, 0.078 mmol) in toluene (2 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 12 h. After completion of the reaction, the reaction mixture was quenched with sodium sulfate decahydrate (1 g), and the mixture was filtered, and the filter cake was washed with ethyl acetate (5 mL). The combined filtrate 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 116 (8.66 mg). MS m / z (ESI): 552.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.78 (dd, J = 7.3, 0.7 Hz, 1H), 8.73 (s, 1H), 8.27 (d, J = 1.3 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 7.9, 1.7 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 7.3, 2.1 Hz, 1H), 4.50 - 4.43 (m, 1H), 4.31 (s, 2H), 4.06 (q, J = 12.1 Hz, 2H), 3.90 - 3.81 (m, 2H), 3.69 (d, J = 9.1 Hz, 1H), 3.52 (d, J = 9.1 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 1.94 - 1.87 (m, 1H), 1.84 - 1.76 (m, 1H), 1.45 - 1.38 (m, 2H), 1.31 - 1.27 (m, 2H).

[0531] Example 15 (Compound 120)

[0532] First Step: Synthesis of compound 120b

[0533] Compound 120b (2.5 g) was obtained by adding 3,4-dihydro-2H-pyran (0.85 g, 10.10 mmol) to a solution of p-toluenesulfonic acid (0.47 g, 2.75 mmol) and compound 120a (2 g, 9.18 mmol) in tetrahydrofuran (20 mL) at room temperature, and stirring the reaction mixture at 25 °C for 12 hours. After completion of the reaction, the reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 3), 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 to obtain compound 120b (2.5 g). MS m / z (ESI): 300.9 [M+1] + .

[0534] Second Step: Synthesis of compound 120c

[0535] Potassium carbonate (2.54 g, 18.36 mmol) was added to a solution of compound 116f (0.6 g, 6.12 mmol) and compound 120b (2.03 g, 6.73 mmol) in DMF (10 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 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 x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 120c (1.2 g). MS m / z (ESI): 239.1 [M+1] + .

[0536] Step 3: Synthesis of compound 120d

[0537] NBS (0.45 g, 2.52 mmol) was added to a solution of compound 120c (500 mg, 2.10 mmol) in acetonitrile (5 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 4 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 / 2) to give compound 120d (600 mg). MS m / z (ESI): 317.0 [M+1] + .

[0538] Step 4: Synthesis of compound 120e

[0539] A 4M hydrochloric acid / 1,4-dioxane solution (2 mL) was added to a solution of compound 120d (100 mg, 0.32 mmol) in 1,4-dioxane (2 mL) at room temperature, and the reaction mixture was stirred at 20 °C for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give compound 120e (70 mg). MS m / z (ESI): 233.0 [M+1] + .

[0540] Step 5: Synthesis of compound 120f

[0541] To a solution of compound 90b (0.14 g, 0.45 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium dichloromethane complex (24 mg, 0.030 mmol) and potassium carbonate (83 mg, 0.60 mmol) in 1,4-dioxane / water (2 mL / 0.4 mL) was added compound 120e (70 mg, 0.30 mmol) 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 column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to give compound 120f (10 mg). MS m / z (ESI): 343.1 [M+1] + .

[0542] Step 6: Synthesis of compound 120

[0543] To a solution of compound 90d (7 mg, 0.028 mmol, synthesis method refer to WO2024118887A1 specification page 170 synthesis of compound intermediate 73) and compound 120f (9.6 mg, 0.028 mmol) in toluene (2 mL) was added 2M trimethylaluminum n-hexane solution (0.06 mL, 0.056 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °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 (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to give compound 120 (0.6 mg). MS m / z (ESI): 550.1 [M+1] + .

[0544] Example 16 (compound 121)

[0545] To a solution of compound 90d (16 mg, 0.065 mmol) and compound 116i (25 mg, 0.065 mmol) in toluene (2 mL) was added 2M trimethylaluminum n-hexane solution (0.07 mL, 0.13 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 20 / 1) to give compound 121 (16 mg). MS m / z (ESI): 590.2 [M+1] + .

[0546] 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.79 (dd, J = 7.4, 0.6 Hz, 1H), 8.75 (s, 1H), 8.28 (d, J = 7.3 Hz, 1H), 8.25 (d, J = 1.3 Hz, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.31 (dd, J = 7.3, 2.0 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.32 (s, 2H), 4.06 (q, J = 12.1 Hz, 2H), 3.91 - 3.80 (m, 2H), 3.69 (d, J = 9.1 Hz, 1H), 3.52 (d, J = 9.1 Hz, 1H), 2.35 (s, 3H), 1.96 - 1.87 (m, 1H), 1.85 - 1.76 (m, 1H), 1.46 - 1.39 (m, 2H), 1.33 - 1.28 (m, 2H).

[0547] Example 17 (Compound 139)

[0548] First Step: Synthesis of compound 139b

[0549] TBDPSCl (4.2 g, 15.29 mmol) was added dropwise to a solution of compound 139a (1 g, 10.19 mmol) and imidazole (1.39 g, 20.38 mmol) in DMF (20 mL) at room temperature. After the addition was completed, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was quenched by adding saturated aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and a solid was precipitated, which was filtered and washed with dichloromethane (5 mL). The filter cake was dried to give compound 139b (1 g). MS m / z (ESI): 337.1 [M+1] + .

[0550] Second Step: Synthesis of compound 139d

[0551] Compound 139c (24.7 mg, 0.18 mmol) and cesium carbonate (98 mg, 0.30 mmol) were added to a solution of compound 139b (50 mg, 0.15 mmol) in DMF (4 mL) at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was quenched with water (15 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 to give compound 139d (50 mg). MS m / z (ESI): 393.2 [M+1] + .

[0552] Step 3: Synthesis of compound 139e

[0553] Sodium borohydride (4.9 mg, 0.13 mmol) was added to a solution of compound 139d (50 mg, 0.13 mmol) in methanol (2 mL) at 0 °C, and after completion of the addition, the reaction mixture was stirred at 0 °C for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to quench, extracted with ethyl acetate (10 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 to give compound 139e (50 mg). MS m / z (ESI): 395.2 [M+1] + .

[0554] Step 4: Synthesis of compound 139f

[0555] Methyl sulfonyl chloride (0.015 mL, 0.20 mmol) was added to a solution of compound 139e (50 mg, 0.13 mmol) and triethylamine (0.054 mL, 0.39 mmol) in dichloromethane (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, water (10 mL) was added to the reaction solution to quench, 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 to give compound 139f (50 mg). MS m / z (ESI): 473.1 [M+1] + .

[0556] Step 5: Synthesis of compound 139g

[0557] Sodium hydroxide (8.8 mg, 0.22 mmol) was added to a solution of compound 139f (50 mg, 0.11 mmol) in tetrahydrofuran, methanol and water (3 mL / 1 mL / 1 mL) at room temperature. After the addition was completed, the reaction mixture was stirred at room temperature for 12 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 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 thin layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 139g (10 mg). MS m / z (ESI): 139.1 [M+1] + .

[0558] Step 6: Synthesis of compound 139h

[0559] NBS (12.8 mg, 0.072 mmol) was added to a solution of compound 139g (10 mg, 0.072 mmol) in acetonitrile (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated aqueous sodium thiosulfate solution (10 mL) was added to the reaction solution to quench the reaction, and the reaction solution was extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude compound 139h (15 mg), which was used directly in the next step. MS m / z (ESI): 217.0 [M+1] + .

[0560] Step 7: Synthesis of compound 139i

[0561] Compound 139h (15 mg, 0.069 mmol), compound 90b (32.7 mg, 0.10 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (5.6 mg, 0.0069 mmol), and potassium carbonate (19.1 mg, 0.14 mmol) were sequentially added to a mixed solvent of 1,4-dioxane and water (2 mL / 0.5 mL) at room temperature. The reaction mixture was replaced with nitrogen three times and stirred at 100 °C 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 thin layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 139i (10 mg). MS m / z (ESI): 327.1 [M+1] + .

[0562] Step 8: Synthesis of compound 139

[0563] A solution of 2M trimethylaluminum in n-hexane (0.05 mL, 0.093 mmol) was added dropwise to a solution of compound 139i (10 mg, 0.031 mmol) and compound 90d (9.4 mg, 0.037 mmol) in toluene (2 mL) at 0 °C, and the reaction mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction was cooled to room temperature, 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, and the residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 20) to give compound 139 (6 mg). MS m / z (ESI): 534.0 [M+1] + .

[0564] 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.90 (d, J = 7.3 Hz, 1H), 8.81 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.43 (s, 1H), 7.35 (dd, J = 7.3, 2.0 Hz, 1H), 4.92 (d, J = 15.4 Hz, 1H), 4.80 (d, J = 15.4 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.21 - 4.14 (m, 1H), 4.01 - 3.93 (m, 2H), 1.45 - 1.38 (m, 2H), 1.35 - 1.25 (m, 5H).

[0565] Example 18 (Compound 164)

[0566] First Step: Synthesis of compound 164b

[0567] Compound 89b (200 mg, 2.38 mmol) and cesium carbonate (1.55 g, 4.76 mmol) were added to a solution of compound 164a (183.2 mg, 2.08 mmol) in DMF (15 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h. After completion of the reaction, the reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 164b (50 mg). MS m / z (ESI): 171.1 [M+1] + .

[0568] Second Step: Synthesis of compound 164c

[0569] CMBP (106.4 mg, 0.44 mmol) was added dropwise to a solution of compound 164b (50 mg, 0.29 mmol) in toluene (2 mL) at 0 °C. After the addition was completed, the reaction was heated to 100 °C and stirred for 12 h. After the reaction was completed, the reaction 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), 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 164c (20 mg). MS m / z (ESI): 153.1 [M+1] + .

[0570] Step 3: Synthesis of compound 164d

[0571] NBS (23.1 mg, 0.13 mmol) was added to a solution of compound 164c (20 mg, 0.13 mmol) in acetonitrile (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction was quenched with saturated aqueous sodium thiosulfate solution (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 to give compound 164d (30 mg). MS m / z (ESI): 230.9 [M+1] + .

[0572] Step 4: Synthesis of compound 164e

[0573] Compound 164d (30 mg, 0.13 mmol), compound 90b (61.7 mg, 0.20 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.6 mg, 0.013 mmol) and potassium carbonate (35.9 mg, 0.26 mmol) were added successively to a mixed solvent of 1,4-dioxane and water (2 mL / 0.5 mL) at room temperature. The reaction mixture was stirred at 100 °C for 12 h under nitrogen. 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 (dichloromethane / methanol = 20 / 1) to give compound 164e (10 mg). MS m / z (ESI): 341.1 [M+1] + .

[0574] Step 5: Synthesis of compound 164

[0575] A 2 M solution of trimethylaluminum in n-hexane (0.04 mL, 0.087 mmol) was added dropwise to a solution of compound 164e (10.0 mg, 0.029 mmol) and compound 90d (8.8 mg, 0.035 mmol) in toluene (2 mL) at 0 °C under nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at 100 °C for 2 hours under nitrogen atmosphere. After the reaction was completed, 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 filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel (methanol / dichloromethane = 1 / 20) to give compound 164 (5.6 mg). MS m / z (ESI): 548.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.81 (d, J = 7.3 Hz, 1H), 8.74 (s, 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 6.25 (dd, J = 7.0, 3.7 Hz, 1H), 5.28 (dd, J = 6.9, 3.9 Hz, 1H), 4.50 - 4.55 (m, 1H), 4.31 (d, J = 11.8 Hz, 1H), 4.14 (d, J = 10.3 Hz, 1H), 3.65 - 3.72 (m, 2H), 1.48 - 1.37 (m, 2H), 1.30 - 1.35 (m, 2H).

[0576] Example 19 (Compound 212)

[0577] First Step: Synthesis of compound 212b

[0578] Compound 212a (6.64 g, 33.8 mmol) was dissolved in tetrahydrofuran and water (40 mL / 10 mL) at room temperature, and diethyl acetonediphosphonate (13.0 mL, 67.7 mmol) and potassium carbonate (11.69 g, 84.61 mmol) were added successively. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, saturated brine (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 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 column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 212b (2.8 g). MS m / z (ESI): 181.0 [M-56] + .

[0579] Second Step: Synthesis of compound 212c

[0580] Compound 212b (2.35 g, 10.0 mmol) was dissolved in methanol (20 mL) at room temperature, and Pd / C (0.74 g) was added. The reaction mixture was stirred at room temperature for 18 hours under hydrogen atmosphere. After the reaction was completed, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound 212c (2.2 g). MS m / z (ESI): 183.1 [M-56] + .

[0581] Step 3: Synthesis of compound 212d

[0582] Trimethylsulfoxonium iodide (3.06 g, 13.8 mmol) was dissolved in dimethyl sulfoxide (20 mL) at room temperature, and 1 M potassium tert-butoxide in tetrahydrofuran (13.8 mL, 13.8 mmol) was added. After being stirred at room temperature for 0.5 hours, compound 212c (2.2 g, 9.2 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, saturated brine (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (15 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 obtain compound 212d (6.5 g). MS m / z (ESI): 153.0 [M-100] + .

[0583] Step 4: Synthesis of compound 212e

[0584] Compound 212d (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. After being stirred at 120°C for 18 hours, the reaction was directly concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to obtain compound 212e (778 mg). MS m / z (ESI): 153.1 [M+1] + .

[0585] Step 5: Synthesis of compound 212f

[0586] N-bromosuccinimide (396.5 mg, 2.2 mmol) was added to a solution of compound 219e (678 mg, 2.2 mmol) in acetonitrile (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched by adding water (1 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to give compound 212f (778 mg). MS m / z (ESI): 230.9 / 232.9 [M+1] + .

[0587] Step 6: Synthesis of compound 212h

[0588] 2M trimethylaluminum in n-hexane (5.6 mL, 11.15 mmol) was slowly added to a solution of compound 212g (1 g, 3.716 mmol) and compound 90d (0.94 g, 3.716 mmol) in 1,4-dioxane (10 mL) at ice bath. The reaction mixture was stirred at 100 °C for 2 h. After the reaction was completed, the reaction was quenched by adding ethanol (20 mL) and stirred until the solid was dissolved. The solid was filtered out and the filter cake was dissolved in dichloromethane (500 mL). The mixture was filtered and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give compound 212h (1.02 g). MS m / z (ESI): 475.7 [M+1] + .

[0589] Step 7: Synthesis of compound 212i

[0590] Boronic acid pinacol ester (58.6 mg, 0.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (30.7 mg, 0.04 mmol) and potassium acetate (41.2 mg, 0.4 mmol) were added to a solution of compound 212h (100 mg, 0.2 mmol) in 1,4-dioxane (5 mL) at room temperature. After nitrogen was replaced for three times, the reaction mixture was stirred at 100 °C for 18 h. After the reaction was completed, the reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 212i (53 mg). MS m / z (ESI): 524.0 [M+1] + .

[0591] Step 8: Synthesis of compound 212

[0592] Compound 212i (31.7 mg, 0.06 mmol), [1,1’-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (4.4 mg, 0.006 mmol) and potassium carbonate (16.7 mg, 0.12 mmol) were added to a mixture solution of compound 212f (28 mg, 0.06 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 completion of the reaction, 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 212 (2.15 mg). MS m / z (ESI): 547.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.82 (d, J = 7.3 Hz, 1H), 8.76 (s, 1H), 8.29 (d, J = 7.3 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.36 (dd, J = 7.3, 1.9 Hz, 1H), 4.98 (s, 1H), 4.55-4.48 (m, 1H), 4.00 (s, 2H), 3.10-2.98 (m, 2H), 1.95-1.90 (m, 1H), 1.86–1.77 (m, 1H), 1.44-1.40 (m, 2H), 1.32 (s, 3H), 1.30–1.23 (m, 2H).

[0593] Example 20 (Compound 117)

[0594] First Step: Synthesis of compound 117a

[0595] Compound 81a (2 g, 17.8 mmol), tert-butyldimethylsilyl chloride (2.69 g, 17.8 mmol) and imidazole (2.43 g, 17.8 mmol) were added to a solution of dichloromethane (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 117a (3.28 g). MS m / z (ESI): 227.1 [M+1] + .

[0596] Second Step: Synthesis of compound 117b

[0597] Methyl epichlorohydrin (2.32 g, 21.7 mmol) and cesium carbonate (14.2 g, 43.5 mmol) were added to a solution of compound 117a (3.28 g, 14.5 mmol) in N,N-dimethylformamide (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then at 100 °C for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to give compound 117b (1.25 g). MS m / z (ESI): 183.1 [M+1] + .

[0598] Third Step: Synthesis of compound 117c

[0599] N-Bromosuccinimide (1.22 g, 6.9 mmol) was added to a solution of compound 117b (1.25 g, 6.9 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred at 0 °C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to give compound 117c (1.45 g). MS m / z (ESI): 261.0 / 263.0 [M+1 / M+3] + .

[0600] Fourth Step: Synthesis of compound 117d

[0601] Compound 117c (200 mg, 0.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (27.8 mg, 0.038 mmol) and potassium carbonate (105 mg, 0.76 mmol) were added to a mixture of compound 90b (171.6 mg, 0.38 mmol) in 1,4-dioxane and water (5 mL / 1 mL) at room temperature. The reaction mixture was stirred at 90 °C for 18 hours. After completion of the reaction, the reaction mixture was diluted with water (10 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 under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-30%) to give compound 117d (116 mg). MS m / z (ESI): 371.1 [M+1] + .

[0602] Fifth Step: Synthesis of compound 117

[0603] Trimethylaluminum (2M in n-hexane, 0.035 mL, 0.39 mmol) was added dropwise to a solution of compound 117d (50 mg, 0.13 mmol) and compound 90d (33 mg, 0.13 mmol) in toluene (5 mL) under ice-bath. 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. The residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 20) to give compound 117 (23.7 mg). MS m / z (ESI): 578.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.88 (d, J = 7.1 Hz, 1H), 8.80 (s, 1H), 8.30 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.04 (dd, J = 7.1, 1.8 Hz, 1H), 5.10 (s, 1H), 4.70 - 4.60 (m, 2H), 4.55 - 4.47 (m, 1H), 4.35-4.21 (m, 2H), 3.67 (s, 2H), 2.23 (s, 3H), 1.45 - 1.40 (m, 2H), 1.33-1.28 (m, 2H), 0.99 (s, 3H).

[0604] Example 21 (Compound 147)

[0605] First Step: Synthesis of compound 147a

[0606] Di-tert-butyl dicarbonate (22.3 g, 101.94 mmol) was added to a solution of compound 116f (10.0 g, 101.94 mmol) and triethylamine (11.4 g, 112.13 mmol) in dichloromethane (50 mL) at room temperature. After the addition was completed, the reaction mixture was stirred at 25 °C for 18 h. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated brine (100 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 / 1) to give compound 147a (12.87 g). MS m / z (ESI): 143.1 [M-55] + .

[0607] Second Step: Synthesis of compound 147b

[0608] Epoxy bromopropane (2.5 g, 18.16 mmol) was added to a solution of compound 147a (3.0 g, 15.13 mmol), potassium iodide (502.3 mg, 3.03 mmol) and potassium carbonate (3.1 g, 22.70 mmol) in N,N-dimethylformamide (20 mL) at room temperature. After the addition was completed, the reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 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 (petroleum ether / ethyl acetate = 5 / 1) to give compound 147b (2 g). MS m / z (ESI): 255.1 [M+H] + .

[0609] Step 3: Synthesis of compound 147c

[0610] Methylsulfonic acid (303.7 mg, 3.16 mmol) was added to a solution of compound 147b (200 mg, 0.79 mmol) in dichloromethane (2 mL) at 0 °C. After the addition was completed, the reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, the reaction mixture was used directly in the next step. MS m / z (ESI): 155.1 [M+1] + .

[0611] Step 4: Synthesis of compound 147d

[0612] Tert-butyldimethylsilyl chloride (587.8 mg, 3.90 mmol) and imidazole (1.1 g, 15.60 mmol) were added to the reaction mixture of compound 147c at 0 °C. The reaction mixture was stirred at room temperature for 18 hours under nitrogen protection. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL x 2). 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 = 100 / 1-5 / 1) to give compound 147d (100 mg). MS m / z (ESI): 269.1 [M+1] + .

[0613] Step 5: Synthesis of compound 147e

[0614] N-bromosuccinimide (62.6 mg, 0.35 mmol) was added to a solution of compound 147d (100 mg, 0.37 mmol) in acetonitrile (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 15 h. After completion of the reaction, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine solution (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 (dichloromethane / methanol = 20 / 1) to give compound 147e (90 mg). MS m / z (ESI): 347.1 [M+1] + .

[0615] Step 6: Synthesis of compound 147f

[0616] Compound 147e (90 mg, 0.26 mmol) was added to a mixture of compound 90b (90.4 mg, 0.29 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (19.0 mg, 0.026 mmol), potassium carbonate (71.9 mg, 0.52 mmol) in 1,4-dioxane and water (2 mL / 0.5 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. After completion of the reaction, it was extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine solution (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 (dichloromethane / methanol = 100 / 1-20 / 1) to give compound 147f (50 mg). MS m / z (ESI): 457.0 [M+1] + .

[0617] Step 7: Synthesis of compound 147g

[0618] Cesium carbonate (83.6 mg, 0.55 mmol) was added to a solution of compound 147f (50 mg, 0.11 mmol) in N,N-dimethylformamide (3 mL) at room temperature. The reaction mixture was stirred at 50 °C for 2 h. After completion of the reaction, it was extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine solution (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 (dichloromethane / methanol = 100 / 1-20 / 1) to give compound 147g (34 mg). MS m / z (ESI): 343.1 [M+1] + .

[0619] Step 8: Synthesis of compound 147h

[0620] Diethylaminosulfur trifluoride (31.9 mg, 0.20 mmol) was added to a solution of compound 147g (34 mg, 0.099 mmol) in dichloromethane (3 mL) at -78 °C. The reaction mixture was stirred at room temperature for 15 h. After completion of the reaction, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (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 column chromatography on silica gel (dichloromethane / methanol = 100 / 1-20 / 1) to give compound 147h (14 mg). MS m / z (ESI): 345.1 [M+1] + .

[0621] Ninth step: synthesis of compound 147

[0622] 2M solution of trimethylaluminum in n-hexane (0.04 mL, 0.08 mmol) was added to a solution of compound 147h (14 mg, 0.041 mmol) and compound 90d (13.4 mg, 0.053 mmol) in toluene (1 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 15 h under nitrogen atmosphere. After completion of the reaction, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 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 (dichloromethane / methanol = 100 / 1-20 / 1) to give compound 147 (15 mg). MS m / z (ESI): 552.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.84 (dd, J = 7.3, 0.7 Hz, 1H), 8.80 (s, 1H), 8.31 (d, J = 7.2 Hz, 2H), 7.89 (d, J = 10.1 Hz, 1H), 7.35 (dd, J = 7.3, 2.1 Hz, 1H), 7.24 - 6.70 (m, 1H), 5.54 (d, J = 43.9 Hz, 1H), 4.77 - 4.74 (m, 1H), 4.59 - 4.36 (m, 3H), 2.39 (s, 3H), 1.46 - 1.33 (m, 2H), 1.30 - 1.27 (m, 2H).

[0623] Example 22 (compound 118)

[0624] First step: synthesis of compound 118b

[0625] Sodium borohydride (1.5 g, 39.13 mmol) was added to a solution of compound 118a (5 g, 30.10 mmol) in tetrahydrofuran (50 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with water (80 mL) and saturated sodium chloride solution (80 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 118b (3.83 g). MS m / z (ESI): 169.1 [M+1] + .

[0626] Second Step: Synthesis of compound 118c

[0627] Sodium hydroxide (0.7 g, 17.85 mmol) was added to a solution of compound 118b (1 g, 5.95 mmol) in a mixture of ethanol and water (12 mL / 3 mL) at room temperature, and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with saturated sodium chloride solution (50 mL), and the pH was adjusted to about 5 by adding 6N aqueous hydrochloric acid solution. The reaction mixture was extracted with dichloromethane / isopropanol = 3 / 1 (80 mL x 3), and the combined organic phase was concentrated under reduced pressure to give compound 118c (690 mg). MS m / z (ESI): 141.1 [M+1] + .

[0628] Third Step: Synthesis of compound 118e

[0629] N,N'-carbonyldiimidazole (772.5 mg, 4.76 mmol) was added to a solution of compound 118c (611.8 mg, 4.37 mmol) in N-methylpyrrolidone (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 5 min. Compound 118d (775 mg, 3.97 mmol, synthesis method: refer to WO201333116A1 specification page 97, synthesis of compound intermediate 27) was added to the reaction mixture, and the reaction mixture was stirred at 120 °C for 3 h. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (80 mL). The organic phase was washed with water (50 mL x 3) and saturated sodium chloride solution (50 mL) successively, 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 118e (267 mg). MS m / z (ESI): 299.9 [M+1] + .

[0630] Fourth Step: Synthesis of compound 118f

[0631] Zinc powder (238.8 mg, 3.65 mmol) and ammonium chloride (195.2 mg, 3.65 mmol) were added successively to a mixture of compound 118e (217 mg, 0.73 mmol) in a mixture of ethanol and water (4 mL / 1 mL) at room temperature. The reaction mixture was stirred at 85 °C for 6 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was extracted with ethyl acetate (50 mL), washed successively with water (20 mL x 2) and saturated sodium chloride solution (30 mL), and concentrated under reduced pressure to give compound 118f (188 mg). MS m / z (ESI): 270.0 [M+1] + .

[0632] Fifth step: synthesis of compound 118g

[0633] Compound 147f (15 mg, 0.033 mmol) and compound 118f (8.9 mg, 0.033 mmol) were dissolved in toluene (0.5 mL) under nitrogen protection. 2M trimethylaluminum in n-hexane (0.05 mL, 0.01 mmol) was added slowly to the solution at 0 °C. After the addition was completed, the reaction mixture was warmed to 100 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-20%) to give compound 118g (27 mg, 50% purity). MS m / z (ESI): 680.1 [M+1] + .

[0634] Sixth step: synthesis of compound 118

[0635] Compound 118g (11 mg, 0.0083 mmol, 50% purity) was dissolved in acetonitrile (0.5 mL) at room temperature. Triethylamine trifluoride (4 mg, 0.025 mmol) was added to the solution. The reaction mixture was stirred at room temperature 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 (methanol / dichloromethane = 0-10%) to give compound 118 (4.7 mg). MS m / z (ESI): 566.2 [M+1] + .

[0636] Example 23 (compound 125)

[0637] First step: synthesis of compound 125a

[0638] To a solution of compound 147a (3 g, 14.53 mmol) in N,N-dimethylformamide (30 mL) were added methyl epichlorohydrin (1.70 g, 15.98 mmol) and potassium carbonate (4.02 g, 29.06 mmol) sequentially at room temperature. The reaction mixture was stirred at 80 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (150 mL). The combined organic phase was washed with water (50 mL x 3), saturated brine (50 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 = 10 / 1-3 / 1) to give compound 125a (1.78 g). MS m / z (ESI): 269.1 [M+1] + .

[0639] Second Step: Synthesis of compound 125b

[0640] To a solution of compound 125a (1.68 g, 6.26 mmol) in tetrahydrofuran (15 mL) were added lithium chloride (0.64 g, 10.64 mmol) and acetic acid (1.07 mL, 18.78 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (80 mL). The combined organic phase was washed with water (30 mL), saturated brine (30 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 = 10 / 1-2 / 1) to give compound 125b (1.42 g). MS m / z (ESI): 305.1 [M+1] + .

[0641] Third Step: Synthesis of compound 125c

[0642] To a solution of compound 125b (1.37 g, 4.50 mmol) in N,N-dimethylformamide (15 mL) were added potassium carbonate (2.49 g, 18 mmol) and potassium iodide (0.15 g, 0.90 mmol) sequentially at room temperature. The reaction mixture was stirred at 120 °C for 12 h. After completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (100 mL). The combined organic phase was washed with water (30 mL x 3), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 1-40 / 1) to give compound 125c (384 mg). MS m / z (ESI): 169.1 [M+1] + .

[0643] Step 4: Synthesis of compound 125d

[0644] N-bromosuccinimide (247.9 mg, 1.39 mmol) was added to a solution of compound 125c (334 mg, 1.99 mmol) in acetonitrile (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 1 ~ 40 / 1) to give compound 125d (433 mg). MS m / z (ESI): 246.9 [M+1] + .

[0645] Step 5: Synthesis of compound 125e

[0646] Compound 125d (150 mg, 0.61 mmol), compound 90b (212.1 mg, 0.67 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (49.8 mg, 0.061 mmol) and potassium carbonate (168.6 mg, 1.22 mmol) were added to a mixed solvent of 1,4-dioxane and water (2 mL / 0.5 mL) at room temperature successively, and the reaction mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (30 mL x 2), and the combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 1 ~ 40 / 1) to give compound 125e (103 mg). MS m / z (ESI): 357.0 [M+1] + .

[0647] Step 6: Synthesis of compound 125

[0648] Trimethylaluminum (2 M in n-hexane, 0.08 mL, 0.17 mmol) was added to a solution of compound 125e (30 mg, 0.084 mmol) and compound 90d (23.4 mg, 0.092 mmol) in toluene (1 mL) at 0 °C, and the reaction mixture was stirred at 100 °C for 1 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (2 mL), extracted with ethyl acetate (30 mL x 2), and the combined organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by trituration with acetonitrile (5 mL) to give compound 125 (17.5 mg). MS m / z (ESI): 564.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.79 (d, J = 7.3 Hz, 1H), 8.75 (s, 1H), 8.31 - 8.25 (m, 2H), 7.85 (d, J = 10.1 Hz, 1H), 7.32 (dd, J = 7.4, 1.8 Hz, 1H), 5.44 (s, 1H), 4.56 - 4.48 (m, 1H), 4.17 (s, 2H), 3.99 (d, J = 12.2 Hz, 1H), 3.87 (d, J = 12.3 Hz, 1H), 2.34 (s, 3H), 1.46 - 1.40 (m, 2H), 1.33 - 1.29 (m, 2H), 1.28 (s, 3H).

[0649] Example 24 (Compound 128)

[0650] First Step: Synthesis of compound 128b

[0651] Potassium carbonate (1.7 g, 12.24 mmol) was added to a solution of compound 128a (600 mg, 2.45 mmol) and compound 116f (300 mg, 3.06 mmol) in acetonitrile (3 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h. After the reaction was completed, the reaction liquid was diluted with water (50 mL) and extracted with dichloromethane (50 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 to give compound 128b (300 mg). MS m / z (ESI): 181.1 [M+1] + .

[0652] Second Step: Synthesis of compound 128c

[0653] NBS (0.30 g, 1.66 mmol) was added to a solution of compound 128b (300 mg, 1.66 mmol) in acetonitrile (4 mL) at room temperature, and the reaction mixture was stirred at room temperature 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 (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 5) to give compound 128c (200 mg). MS m / z (ESI): 259.0 [M+1] + .

[0654] Third Step: Synthesis of compound 128d

[0655] Compound 128c (200 mg, 0.77 mmol), compound 90b (0.37 g, 1.16 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (63 mg, 0.077 mmol) and potassium carbonate (0.2 g, 1.54 mmol) were added successively into a mixture of 1,4-dioxane / water (2 mL / 0.4 mL) 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 column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 0 / 1) to give compound 128d (80 mg). MS m / z (ESI): 369.1 [M+1] + .

[0656] Fourth step: synthesis of compound 128

[0657] 2M trimethylaluminum n-hexane solution (0.08 mL, 0.16 mmol) was added to a solution of compound 128d (29 mg, 0.079 mmol) and compound 90d (20 mg, 0.079 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 mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 1 / 0 ~ 20 / 1) to give compound 128 (16 mg). MS m / z (ESI): 576.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.80 (d, J = 7.3 Hz, 1H), 8.75 (s, 1H), 8.27 (d, J = 7.3 Hz, 1H), 8.23 (s, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.29 (dd, J = 7.3, 2.0 Hz, 1H), 4.65 (s, 2H), 4.56 - 4.48 (m, 5H), 4.37 (s, 2H), 2.33 (s, 3H), 1.46 - 1.40 (m, 2H), 1.34 - 1.28 (m, 2H).

[0658] Example 25 (compound 131)

[0659] First step: synthesis of compound 131b

[0660] Compound 131a (0.5 g, 4.46 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (1.9 mL, 13.38 mmol) and p-toluenesulfonyl chloride (1.9 g, 9.81 mmol) were added successively at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by adding water (20 mL) and extracted with dichloromethane (100 mL). The organic phase was washed successively with water (30 mL) 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 (petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain compound 131b (1.44 g). MS m / z (ESI): 421.0 [M+1] + .

[0661] Second Step: Synthesis of compound 131c

[0662] Compound 131b (1.37 g, 3.26 mmol) and potassium carbonate (1.35 g, 9.78 mmol) were added successively to a solution of compound 116f (0.32 g, 3.26 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (80 mL). The organic phase was 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 (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain compound 131c (530 mg). MS m / z (ESI): 175.1 [M+1] + .

[0663] Third Step: Synthesis of compound 131d

[0664] N-Bromosuccinimide (574.9 mg, 3.23 mmol) was added to a solution of compound 131c (562 mg, 3.23 mmol) in acetonitrile (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the organic phase was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1-40 / 1) to obtain compound 131d (516 mg). MS m / z (ESI): 252.9 [M+1] + .

[0665] Fourth Step: Synthesis of compound 131e

[0666] To a solution of compound 131d (150 mg, 0.59 mmol), compound 90b (223.8 mg, 0.71 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (48.2 mg, 0.059 mmol) and potassium carbonate (163.1 mg, 1.18 mmol) in 1,4-dioxane and water (2 mL / 0.5 mL) was added at room temperature, and the reaction mixture was heated to 100 °C under nitrogen atmosphere for 2 hours. After completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 ~ 30 / 1) to obtain compound 131e (145 mg). MS m / z (ESI): 363.1 [M+1] + .

[0667] Fifth step: Synthesis of compound 131

[0668] To a solution of compound 131e (20 mg, 0.055 mmol) and compound 90d (15.4 mg, 0.061 mmol) in toluene (1 mL) was added trimethylaluminum (2M in n-hexane, 0.06 mL, 0.12 mmol) at 0 °C, and the reaction mixture was heated to 100 °C for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride solution (1 mL) and extracted with dichloromethane / methanol (30 mL, 10 / 1). The organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, 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 obtain compound 131 (8.1 mg). MS m / z (ESI): 570.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.84 (d, J = 7.38 Hz, 1H), 8.79 (s, 1H), 8.32 - 8.25 (m, 2H), 7.85 (d, J = 10.1 Hz, 1H), 7.29 (dd, J = 7.3, 2.0 Hz, 1H), 4.78 (t, J = 11.0 Hz, 2H), 4.69 (t, J = 12.8 Hz, 2H), 4.50 - 4.55 (m, 1H), 2.37 (s, 3H), 1.46 - 1.40 (m, 2H), 1.34 - 1.28 (m, 2H).

[0669] Example 26 (Compound 142)

[0670] First Step: Synthesis of compound 142a

[0671] Sodium hydride (0.25 g, 10.41 mmol) was slowly added to a solution of 3- hydroxymethylpyrazole (400 mg, 4.16 mmol) in DMF (15 mL) at 0 °C. After the mixture was stirred at 0 °C for 1 h, a solution of compound 140c (1 g, 3.47 mmol) in DMF (5 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at 100 °C for 12 h. After the reaction was completed, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL). The mixture was extracted with dichloromethane (50 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. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 2 / 1) to give compound 142a (200 mg). MS m / z (ESI): 195.1 [M+1] + .

[0672] Second Step: Synthesis of compound 142b

[0673] NBS (140 mg, 0.77 mmol) was added to a solution of compound 142a (150 mg, 0.77 mmol) in acetonitrile (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 3) to give compound 142b (150 mg). MS m / z (ESI): 273.0 [M+1] + .

[0674] Third Step: Synthesis of compound 142c

[0675] Compound 142b (80 mg, 0.29 mmol), compound 90b (140 mg, 0.43 mmol), potassium carbonate (80 mg, 0.58 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (24 mg, 0.029 mmol) were added to a mixture of 1,4-dioxane / water (2 mL / 0.4 mL) at room temperature. The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 12 h. After the reaction was completed, 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 142c (25 mg). MS m / z (ESI): 383.2 [M+1] + .

[0676] Fourth Step: Synthesis of compound 142

[0677] A 2 M solution of trimethylaluminum in hexane (0.07 mL, 0.14 mmol) was added to a solution of compound 90d (18 mg, 0.071 mmol) and compound 142c (24.44 mg, 0.064 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 mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 20 / 1) to give compound 142 (8.8 mg). MS m / z (ESI): 590.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.94 (dd, J = 7.2, 0.6 Hz, 1H), 8.85 (s, 1H), 8.37 (d, J = 7.3 Hz, 1H), 8.14 (d, J = 1.1 Hz, 1H), 7.91 (d, J = 10.1 Hz, 1H), 7.83 (s, 1H), 7.24 (dd, J = 7.2, 2.0 Hz, 1H), 4.99 - 4.88 (m, 2H), 4.62 - 4.51 (m, 3H), 3.94 (s, 2H), 3.91 - 3.77 (m, 2H), 3.41 - 3.35 (m, 2H), 1.63 (t, J = 7.1 Hz, 2H), 1.52 - 1.45 (m, 2H), 1.39 - 1.34 (m, 2H).

[0678] Example 27 (Compound 146)

[0679] First Step: Synthesis of compound 146b

[0680] Compound 146a (892.5 mg, 7.14 mmol) was added to a solution of compound 89b (500 mg, 5.95 mmol), potassium iodide (197.5 mg, 1.19 mmol) and potassium carbonate (1.64 g, 11.9 mmol) in N,N-dimethylformamide (10 mL) at room temperature. After the addition was completed, the reaction mixture was stirred at 100 °C for 15 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine (30 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 = 20 / 1) to give compound 146b (140 mg). MS m / z (ESI): 136.9 [M+H] + .

[0681] Second Step: Synthesis of compound 146c

[0682] Manganese tris(2,2,6,6-tetramethyl-3,5-heptane acid) (35.7 mg, 0.059 mmol) and phenylsilane (127.7 mg, 1.18 mmol) were added to a solution of compound 146b (80 mg, 0.59 mmol) in dichloromethane and isopropanol (0.5 mL / 5 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at 25 °C for 15 hours under an oxygen atmosphere. After the reaction was completed, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine (30 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 = 20 / 1) to give compound 146c (60 mg). MS m / z (ESI): 155.2 [M+H] + .

[0683] Step 3: Synthesis of compound 146d

[0684] N-bromosuccinimide (30.4 mg, 0.17 mmol) was added to a solution of compound 146c (30 mg, 0.19 mmol) in acetonitrile (2 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 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 (dichloromethane / methanol = 20 / 1) to give compound 146d (45 mg). MS m / z (ESI): 235.1 [M+1] + .

[0685] Step 4: Synthesis of compound 146e

[0686] Compound 90b (61.0 mg, 0.193 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (14.1 mg, 0.019 mmol), and potassium carbonate (53.4 mg, 0.386 mmol) were added to a solution of compound 146d (45 mg, 0.193 mmol) in 1,4-dioxane and water (2 mL / 0.5 mL) at room temperature. The reaction mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. 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), 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 = 100 / 1-20 / 1) to give compound 146e (30 mg). MS m / z (ESI): 343.2 [M+1]+ .

[0687] Fifth Step: Synthesis of compound 146

[0688] A 2M solution of trimethylaluminum in n-hexane (0.09 mL, 0.18 mmol) was added to a solution of compound 146e (30 mg, 0.088 mmol) and compound 90d (24.5 mg, 0.096 mmol) in toluene (2 mL) at 0 °C. The reaction mixture was heated to 100 °C under nitrogen atmosphere and stirred for 15 hours. After the reaction was completed, the reaction was quenched 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 on silica gel (dichloromethane / methanol = 100 / 1-20 / 1) to give compound 146 (10.7 mg). MS m / z (ESI): 550.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.81 (d, J = 7.4 Hz, 1H), 8.76 (s, 1H), 8.42 (d, J = 1.1 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H), 8.01 (s, 1H), 7.90 (d, J = 10.1 Hz, 1H), 7.44 (dd, J = 7.3, 1.9 Hz, 1H), 5.51 (s, 1H), 4.52 - 4.58 (m, 1H), 4.31 - 4.24 (m, 2H), 4.11 (d, J = 12.3 Hz, 1H), 3.99 (d, J = 12.4 Hz, 1H), 1.48 (t, J = 6.0 Hz, 2H), 1.38 - 1.32 (m, 5H).

[0689] Example 28 (Compound 150)

[0690] First Step: Synthesis of compound 150a

[0691] Compound 71a (2.0 g, 10.86 mmol) was added to a solution of 1-cyclopropyl-2-bromoethanone (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 completed, the reaction mixture was stirred at 50 °C for 15 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The 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 (petroleum ether / ethyl acetate = 5 / 1) to give compound 150a (1.67 g). MS m / z (ESI): 267.1 [M+H] + .

[0692] Second Step: Synthesis of compound 150b

[0693] Sodium hydride (308.4 mg, 7.71 mmol) was added to a mixture of trimethylsulfoxonium iodide (1.7 g, 7.71 mmol) in dimethyl sulfoxide and tetrahydrofuran (10 mL / 10 mL) at 0 °C. After the addition was completed, the reaction mixture was stirred at room temperature for 0.5 hours. Then, a solution of compound 150a (1.37 g, 5.14 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was continued to be stirred at room temperature for 15 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The 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 (dichloromethane / methanol = 20 / 1) to give compound 150b (0.9 g, purity 40%). MS m / z (ESI): 181.1 [M+H] + .

[0694] Third Step: Synthesis of compound 150c

[0695] Cesium carbonate (0.65 g, 2 mmol) was added to a solution of compound 150b (900 mg, 2.00 mmol, purity 40%) in N,N-dimethylformamide (10 mL) at room temperature. After the addition was completed, the reaction mixture was stirred at 100 °C for 15 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The 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 (dichloromethane / methanol = 20 / 1) to give compound 150c (200 mg). MS m / z (ESI): 181.1 [M+H] + .

[0696] Step 4: Synthesis of compound 150d

[0697] N-bromosuccinimide (44.9 mg, 0.25 mmol) was added to a solution of compound 150c (50 mg, 0.28 mmol) in acetonitrile (2 mL) at 0 °C. After the addition was completed, the reaction mixture was stirred at room temperature for 15 h. After the reaction was completed, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 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 (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to give compound 150d (50 mg). MS m / z (ESI): 258.9 [M+1] + .

[0698] Step 5: Synthesis of compound 150e

[0699] Compound 150d (50 mg, 0.19 mmol) was added to a mixture of compound 90b (66.1 mg, 0.21 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (13.9 mg, 0.019 mmol) and potassium carbonate (52.5 mg, 0.38 mmol) in 1,4-dioxane and water (2 mL / 0.5 mL) at room temperature. After the addition was completed, the reaction mixture was heated to 80 °C under nitrogen protection and stirred for 2 h. After the reaction was completed, the reaction was quenched by the addition of water (20 mL) and extracted with ethyl acetate (10 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 (dichloromethane / methanol = 100 / 1-20 / 1) to give compound 150e (45 mg). MS m / z (ESI): 369.1 [M+1] + .

[0700] Step 6: Synthesis of compound 150

[0701] A 2M solution of trimethylaluminum in n-hexane (0.07 mL, 0.14 mmol) was added to a solution of compound 150e (25 mg, 0.068 mmol) and compound 90d (20.7 mg, 0.082 mmol) in toluene (1 mL) at 0 °C. After the addition was completed, the reaction mixture was stirred at 100 °C for 15 h. After the reaction was completed, the reaction was quenched by the addition of 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 column chromatography on silica gel (dichloromethane / methanol = 100 / 1-20 / 1) to give compound 150 (9.3 mg). MS m / z (ESI): 575.4 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.81 (d, J = 7.3 Hz, 1H), 8.76 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H), 8.02 (s, 1H), 7.88 (d, J = 10.1 Hz, 1H), 7.43 (dd, J = 7.3, 1.9 Hz, 1H), 5.14 (s, 1H), 4.60 - 4.52 (m, 1H), 4.42 (d, J = 11.0 Hz, 1H), 4.26 (dd, J = 11.1, 1.8 Hz, 1H), 4.19 (d, J = 12.4 Hz, 1H), 3.94 (d, J = 10.9 Hz, 1H), 1.49 - 1.41 (m, 2H), 1.36 - 1.31 (m, 2H), 1.00 - 0.92 (m, 1H), 0.53 - 0.50 (m, 2H), 0.44 - 0.33 (m, 2H).

[0702] Example 29 (Compound 152)

[0703] First Step: Synthesis of compound 152b

[0704] Triethylamine (5.9 g, 58.74 mmol) was added to a solution of compound 152a (2 g, 19.58 mmol) in dichloromethane (40 mL) under ice bath, and methylsulfonyl chloride (4.5 g, 39.16 mmol) was added dropwise slowly. After the addition was completed, the reaction mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction was quenched by the addition of saturated ammonium chloride solution (20 mL) and extracted with dichloromethane / methanol (10 / 1, 40 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 152b (1.7 g). MS m / z (ESI): 259.02 [M+1] + .

[0705] Step 2: Synthesis of compound 152c

[0706] Compound 89b (0.5 g, 6.21 mmol), potassium carbonate (1.7 g, 12.42 mmol) were added into a solution of compound 152b (1.7 g, 4.14 mmol) in N,N-dimethylformamide (17 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane / methanol = 10 / 1 (20 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 to give the crude compound 152c (1.1 g). MS m / z (ESI): 151.08 [M+1] + .

[0707] Step 3: Synthesis of compound 152d

[0708] N-bromosuccinimide (1.2 g, 6.66 mmol) was added into a solution of compound 152c (1 g, 6.66 mmol) in acetonitrile (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0%~10%) to give compound 152d (180 mg). MS m / z (ESI): 229 [M+1] + .

[0709] Step 4: Synthesis of compound 152e

[0710] Compound 152d (36.7 mg, 0.16 mmol), cesium carbonate (100 mg, 0.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13 mg, 0.016 mmol) were added into a mixture of compound 90b (50 mg, 0.16 mmol) in 1,4-dioxane and water (4 mL / 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 directly concentrated, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 10%~70%) to give compound 152e (36 mg). MS m / z (ESI): 339.14 [M+1] + .

[0711] Step 5: Synthesis of compound 152

[0712] Compound 90d (17 mg, 0.066 mmol) was added to a solution of compound 152e (15 mg, 0.044 mmol) in toluene (2 mL) under ice-bath cooling, 2M trimethylaluminum in n-hexane (0.04 mL, 0.088 mmol) was added dropwise slowly, after the addition was completed, the reaction mixture was heated to 100 °C and stirred for 4 hours under nitrogen atmosphere. 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 152 (4.7 mg). MS m / z (ESI): 546.15 [M+1] + .

[0713] Example 30 (Compound 156)

[0714] First Step: Synthesis of compound 156a

[0715] Compound epoxide bromopropane (0.98 mL, 11.95 mol) and potassium carbonate (3.0 g, 21.72 mmol) were added to a solution of compound 71a (2 g, 10.86 mmol) in N,N-dimethylformamide (20 mL) at room temperature, and the reaction mixture was stirred at 60 °C for 3 hours. After the reaction was completed, the reaction was directly subjected to the next step without treatment. MS m / z (ESI): 241.0 [M+1] + .

[0716] Second Step: Synthesis of compound 156b

[0717] Potassium carbonate (2.7 g, 19.62 mmol) was added to a solution of compound 156a (2.4 g, 9.81 mmol) in N,N-dimethylformamide (19 mL) at room temperature, and the reaction mixture was stirred at 130 °C for 12 hours. After the reaction was completed, the reaction was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 1-30 / 1) to obtain compound 156b (539 mg). MS m / z (ESI): 141.1 [M+1] + .

[0718] Third Step: Synthesis of compound 156c

[0719] Sodium hydride (62.9 mg, 1.57 mmol) was added to a solution of compound 156b (200 mg, 1.43 mmol) in tetrahydrofuran (5 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. Iodomethane (243.6 mg, 1.72 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (30 mL), washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 156c (258 mg). MS m / z (ESI): 155.1 [M+1] + .

[0720] Fourth step: synthesis of compound 156d

[0721] N-bromosuccinimide (204.7 mg, 1.15 mmol) was added to a solution of compound 156c (208 mg, 1.15 mmol) in acetonitrile (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 1 to 30 / 1) to give compound 156d (254 mg). MS m / z (ESI): 233.1 [M+1] + .

[0722] Fifth step: synthesis of compound 156e

[0723] Compound 156d (100 mg, 0.43 mmol), compound 90b (163.1 mg, 0.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (35.1 mg, 0.043 mmol), and potassium carbonate (118.9 mg, 0.86 mmol) were sequentially added to a mixed solvent of 1,4-dioxane and water (2 mL / 0.5 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 2 h under nitrogen. After the reaction was completed, the reaction solution was extracted with ethyl acetate (10 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, 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 (dichloromethane / methanol = 100 / 1 to 30 / 1) to give compound 156e (111 mg). MS m / z (ESI): 343.1 [M+1] + .

[0724] Sixth step: synthesis of compound 156

[0725] Trimethylaluminum (2M in n-hexane, 0.06 mL, 0.12 mmol) was added to a solution of compound 156e (20 mg, 0.058 mmol) and compound 90d (16.2 mg, 0.064 mmol) in toluene (1 mL) at 0 °C, and the reaction mixture was heated to 100 °C with stirring for 1 h. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride solution (1 mL) and extracted with a mixed solvent (dichloromethane / methanol = 10 / 1, 30 mL). The organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, 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 (dichloromethane / methanol = 20 / 1) to give compound 156 (19.2 mg). MS m / z (ESI): 550.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.78 (dd, J = 7.3, 0.7 Hz, 1H), 8.73 (s, 1H), 8.35 (dd, J = 1.9, 0.7 Hz, 1H), 8.28 (d, J = 7.3 Hz, 1H), 7.98 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.39 (dd, J = 7.3, 2.0 Hz, 1H), 4.73 - 4.65 (m, 1H), 4.53 - 4.44 (m, 1H), 4.43 (d, J = 11.4 Hz, 1H), 4.34 - 4.20 (m, 2H), 4.08 (s, 1H), 3.38 (s, 3H), 1.46 - 1.41 (m, 2H), 1.33 - 1.29 (m, 2H).

[0726] Example 31 (Compound 158)

[0727] First Step: Synthesis of compound 158b

[0728] Methanesulfonyl chloride (0.33 mL, 4.30 mmol) was added to a solution of compound 158a (200 mg, 1.72 mmol) and triethylamine (0.7 mL, 5.17 mmol) in dichloromethane (5 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with saturated brine solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 158b (468 mg), which was used directly in the next step.

[0729] Second Step: Synthesis of compound 158c

[0730] Compound 158b (388.7 mg, 1.43 mmol) was added to a solution of compound 88b (120 mg, 1.43 mmol), 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. After the reaction was completed, the reaction solution was added with water (10 mL), extracted with ethyl acetate (10 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 silica gel column chromatography (dichloromethane / methanol = 100 / 1-20 / 1) to obtain compound 158c (80 mg). MS m / z (ESI): 165.2 [M+1] + .

[0731] Step 3: Synthesis of compound 158d

[0732] Potassium carbonate (202 mg, 1.46 mmol), potassium hexacyanoferrate (802 mg, 2.44 mmol), and potassium osmate (VI) dihydrate (3.6 mg, 0.01 mmol) were sequentially added to a solution of compound 158c (80 mg, 0.49 mmol) in tert-butyl alcohol and water (2 mL / 2 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 158d (90 mg). MS m / z (ESI): 199.1 [M+1] + .

[0733] Step 4: Synthesis of compound 158e

[0734] NBS (80.8 mg, 0.45 mmol) was added to a solution of compound 158d (90 mg, 0.45 mmol) in acetonitrile (2 mL) at room temperature. The reaction mixture was stirred at room temperature 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 (petroleum ether / ethyl acetate = 1 / 0-0 / 1) to obtain compound 158e (120 mg). MS m / z (ESI): 277.0 [M+1] + .

[0735] Step 5: Synthesis of compound 158f

[0736] To a solution of compound 158e (100 mg, 0.36 mmol), compound 90b (171.1 mg, 0.54 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (29.5 mg, 0.036 mmol) and potassium carbonate (99.7 mg, 0.72 mmol) in 1,4-dioxane / water (4 mL / 0.8 mL) was added 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 ~ 10 / 1) to give compound 158f (21 mg). MS m / z (ESI): 387.2 [M+1] + .

[0737] Sixth step: synthesis of compound 158

[0738] To a solution of compound 90d (14.4 mg, 0.06 mmol) and compound 158f (20 mg, 0.05 mmol) in toluene (1 mL) was added trimethylaluminum (2M in n-hexane, 0.05 mL, 0.1 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 silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 15 / 1) to give compound 158 (2.98 mg). MS m / z (ESI): 594.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.84 (d, J = 7.3 Hz, 1H), 8.79 (s, 1H), 8.47 (d, J = 1.2 Hz, 1H), 8.36 (d, J = 7.3 Hz, 1H), 8.06 (s, 1H), 7.92 (d, J = 10.1 Hz, 1H), 7.47 (dd, J = 7.3, 2.0 Hz, 1H), 5.28 (s, 1H), 4.86 (s, 1H), 4.62 - 4.55 (m, 1H), 4.54 - 4.45 (m, 2H), 3.99 (d, J = 11.9 Hz, 1H), 3.92 (d, J = 12.6 Hz, 1H), 1.52 - 1.47 (m, 2H), 1.39 - 1.35 (m, 2H), 1.23 (s, 6H).

[0739] Example 32 (compound 160)

[0740] First step: synthesis of compound 160a

[0741] To a solution of compound 71a (1 g, 5.43 mmol) in N,N-dimethylformamide (10 mL) was added 1-bromo-3-methyl-2-butene (1.2 g, 8.14 mmol) and potassium carbonate (1.5 g, 10.86 mmol) sequentially at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate / petroleum ether = 0-30%) to afford compound 160a (600 mg). MS m / z (ESI): 196.9 [M-55] + .

[0742] Second Step: Synthesis of compound 160b

[0743] To a solution of compound 160a (1 g, 3.96 mmol) in dichloromethane (10 mL) was added meta-chloroperoxybenzoic acid (1.0 g, 4.36 mmol, 75% purity) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated. The residue was purified by column chromatography over silica gel (ethyl acetate / petroleum ether = 0-50%) to afford compound 160b (500 mg). MS m / z (ESI): 268.9 [M+1] + .

[0744] Third Step: Synthesis of compound 160c

[0745] To a solution of compound 160b (400 mg, 1.49 mmol) in N,N-dimethylformamide (4 mL) was added cesium carbonate (1.9 g, 5.96 mmol) at room temperature. The reaction mixture was heated to 130 °C and stirred for 16 hours. After completion of the reaction, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (methanol / dichloromethane = 0-10%) to afford compound 160c (190 mg). MS m / z (ESI): 169.2 [M+1] + .

[0746] Fourth Step: Synthesis of compound 160d

[0747] To a solution of compound 160c (100 mg, 0.59 mmol) in acetonitrile (1 mL) was added N-bromosuccinimide (157.5 mg, 0.89 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated. The residue was purified by column chromatography over silica gel (methanol / dichloromethane = 0-10%) to afford compound 160d (120 mg). MS m / z (ESI): 246.9 [M+1] + .

[0748] Fifth Step: Synthesis of compound 160e

[0749] Compound 160d (120 mg, 0.49 mmol), compound 90b (154.9 mg, 0.49 mmol), Pd(dppf)Cl2(35.9 mg, 0.049 mmol) and potassium carbonate (135.5 mg, 0.98 mmol) were added successively into a mixed solvent 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 and stirred for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 160e (87 mg). MS m / z (ESI): 357.0 [M+1] + .

[0750] Sixth step: synthesis of compound 160

[0751] 2M trimethylaluminum in n-hexane (0.25 mL, 0.48 mmol) was slowly added to a solution of compound 90d (40 mg, 0.16 mmol) and compound 160e (57 mg, 0.16 mmol) in toluene (1 mL) under ice bath. The reaction mixture was heated to 100 °C and stirred for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 160 (20 mg). MS m / z (ESI): 564.0 [M+1] + .

[0752] Example 33 (compound 162)

[0753] First step: synthesis of compound 162b

[0754] Benzaldehyde (2.1 g, 20 mmol) and p-toluenesulfonic acid (0.33 g, 1.9 mmol) were added to a solution of compound 162a (5 g, 19 mmol) in toluene (50 mL) at room temperature. 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 silica gel column chromatography (pure petroleum ether) to obtain compound 162b (6.36 g). MS m / z (ESI): 350.8 [M+1] + .

[0755] Second step: synthesis of compound 162c

[0756] Compound 89b (1.29 g, 15.3 mmol) and potassium carbonate (2.12 g, 15.3 mmol) were added to a solution of compound 162b (5.37 g, 15.3 mmol) in N,N-dimethylformamide (50 mL) at room temperature. The reaction mixture was stirred at 100 °C for 18 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 (ethyl acetate / petroleum ether = 0-50%) to give compound 162c (1.85 g). MS m / z (ESI): 273.0 [M+1] + .

[0757] Third Step: Synthesis of compound 162d

[0758] 4M Hydrochloric acid / 1,4-dioxane (5 mL) was added to a solution of compound 162c (1.65 g, 6 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature 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 (methanol / dichloromethane = 0-50%) to give compound 162d (794 mg). MS m / z (ESI): 185.1 [M+1] + .

[0759] Fourth Step: Synthesis of compound 162e

[0760] Compound 162d (744 mg, 4 mmol), p-toluenesulfonyl chloride (1.93 g, 10 mmol) and triethylamine (1.7 mL, 12 mmol) were added to a solution in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature 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 162e (369 mg). MS m / z (ESI): 493.0 [M+1] + .

[0761] Fifth Step: Synthesis of compound 162f

[0762] Compound 162e (580 mg, 1.2 mmol) and sodium sulfide (110 mg, 1.4 mmol) were added to a solution in N,N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at 80 °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 162f (98 mg). MS m / z (ESI): 183.1 [M+1] + .

[0763] Sixth Step: Synthesis of compound 162g

[0764] Compound 162f (75 mg, 0.41 mmol) and oxone (252 mg, 0.41 mmol) were added to a solution of acetone and water (3 mL / 3 mL) at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was poured into saturated brine (50 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain compound 162g (93 mg).

[0765] MS m / z (ESI): 214.8 [M+1] + .

[0766] Seventh step: synthesis of compound 162h

[0767] N-bromosuccinimide (32 mg, 0.18 mmol) was added to a solution of compound 162g (65 mg, 0.3 mmol) in acetonitrile (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was poured into saturated brine (5 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 162h (93 mg). MS m / z (ESI): 292.9 [M+1] + .

[0768] Eighth step: synthesis of compound 162i

[0769] Compound 162h (93 mg, 0.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (23.4 mg, 0.032 mmol), and potassium carbonate (88.5 mg, 0.64 mmol) were added to a mixed solution of compound 90b (94.8 mg, 0.32 mmol) in 1,4-dioxane and water (5 mL / 1 mL) at room temperature, and the reaction mixture was stirred at 90°C for 18 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL), 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 = 0-10%) to obtain compound 162i (38 mg). MS m / z (ESI): 403.2 [M+1] + .

[0770] Ninth step: synthesis of compound 162

[0771] To a solution of compound 162i (59 mg, 0.16 mmol) and compound 90d (44 mg, 0.16 mmol) in toluene (5 mL) was added trimethylaluminum (2 M in n-hexane, 0.24 mL, 0.48 mmol) dropwise under 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 and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 10) to give compound 162 (1.5 mg).

[0772] Example 34 (Compound 204-P1)

[0773] First Step: Synthesis of compound 204a

[0774] To a solution of compound 71a (21.8 g, 118.1 mmol) in DMF (5 mL) was added compound 1-bromo-3-methyl-2-butene (17.6 g, 118.1 mmol) and potassium carbonate (16.3 g, 118.1 mmol) successively. 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) 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. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 204a (7.82 g). MS m / z (ESI): 527.0 [2M+23] + .

[0775] Second Step: Synthesis of compound 204b

[0776] To a solution of compound 204a (5.1 g, 20.2 mmol) in DCM (5 mL) was added m-chloroperoxybenzoic acid (4.92 g, 24.3 mmol) 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 sodium thiosulfate (50 mL x 2) and stirred for another 2 h. Saturated sodium bicarbonate (20 mL) was added and the reaction 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 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 204b (2.24 g). MS m / z (ESI): 269.1 [M+1] + .

[0777] Third Step: Synthesis of compound 204c

[0778] Compound 204b (2.24 g, 8.3 mmol) was dissolved in DMF (30 mL) at room temperature, after the addition of potassium carbonate (3.46 g, 25.0 mmol), the reaction mixture was warmed to 120 °C and stirred for 18 h. 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 = 0-50%) to obtain compound 204c (962 mg). MS m / z (ESI): 169.1 [M+1] + .

[0779] Fourth step: synthesis of compound 204d

[0780] N-bromosuccinimide (916.2 mg, 5.1 mmol) was added to a solution of compound 204c (962 mg, 5.7 mmol) in acetonitrile (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. 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 silica gel column chromatography (dichloromethane / methanol = 1 / 0~10 / 1) to obtain compound 204d (1.37 g). MS m / z (ESI): 246.9 / 248.9 [M+1, M+3] + .

[0781] Fifth step: synthesis of compound 204e-P1, 204e-P2

[0782] Compound 204d (424 mg, 1.2 mmol) was dissolved in 1,4-dioxane and water (5 mL / 1 mL) at room temperature, and compound 90b (474 mg, 1.2 mmol), potassium carbonate (165.8 mg, 2.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (88 mg, 0.12 mmol) were added in sequence, and the reaction mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to obtain a colorless oil (365 mg). Further separation by chiral preparative chromatography (preparative column: DAICEL IC 4.6 mm L.D.*250 mm L, 5 μm; flow rate: 2.5 mL / min column temperature: room temperature; mobile phase: CO2 / MEOH [0.1% NH3(7M methanol solution)] = 60 / 40) gave compound 204e-P1 (100 mg) and compound 204e-P2 (100 mg).

[0783] 204e-P1: MS m / z (ESI): 356.9 [M+1] + .

[0784] 204 e-P2: MS m / z (ESI): 356.9 [M+1] + .

[0785] Step 6: Synthesis of compound 204-P1

[0786] Trimethylaluminum (2 M in n-hexane, 0.42 mL, 0.84 mmol) was added dropwise to a solution of compound 204e-P1 (100 mg, 0.28 mmol) and compound 90d (71 mg, 0.28 mmol) in toluene (5 mL) at ice bath. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by high performance liquid preparation 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 204-P1 (15 mg). MS m / z (ESI): 563.9 [M+1] + .

[0787] 1 H NMR (400 MHz, DMSO-d6) d 9.87 (s, 1H), 8.78 - 8.75 (m, 1H), 8.72 (s, 1H), 8.37 - 8.35 (m, 1H), 8.30 (d, J = 7.3 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.40 - 7.37 (m, 1H), 5.82 (d, J = 4.8 Hz, 1H), 4.56 - 4.51 (m, 2H), 4.39 - 4.34 (m, 1H), 3.97 - 3.94 (m, 1H), 1.49 (s, 6H), 1.45 - 1.42 (m, 2H), 1.33 - 1.30 (m, 2H).

[0788] Example 35 (compound 204-P2)

[0789] Step 1: Synthesis of compound 204-P2

[0790] Trimethylaluminum (2M in n-hexane, 0.42 mL, 0.84 mmol) was added dropwise to a solution of compound 204e-P2 (100 mg, 0.28 mmol) and compound 90d (71 mg, 0.28 mmol) in toluene (5 mL) at ice bath. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was concentrated under reduced pressure. The residue was purified by high performance liquid preparation 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 204-P2 (22.6 mg). MS m / z (ESI): 563.9 [M+1] + .

[0791] 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.78 - 8.75 (m, 1H), 8.72 (s, 1H), 8.38 - 8.35 (m, 1H), 8.30 (d, J = 7.2 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.39 (dd, J = 7.4, 2.0 Hz, 1H), 5.81 (d, J = 4.8 Hz, 1H), 4.57 - 4.50 (m, 2H), 4.39 - 4.34 (m, 1H), 3.98 - 3.94 (m, 1H), 1.49 (s, 6H), 1.45 - 1.42 (m, 2H), 1.32 - 1.29 (m, 2H).

[0792] Example 36 (Compound 205)

[0793] First Step: Synthesis of compound 205a

[0794] Compound 156b (336 mg, 2.4 mmol) was added to a solution of dichloromethane (10 mL) at 0 °C, and DAST (0.63 mL, 4.8 mmol) was added dropwise slowly. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction was poured into saturated brine (20 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to give compound 205a (200 mg).

[0795] MS m / z (ESI): 142.9 [M+1] + .

[0796] Second Step: Synthesis of compound 205b

[0797] N-bromosuccinimide (339 mg, 1.91 mmol) was added to a solution of compound 205a (180 mg, 1.27 mmol) in acetonitrile (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, the reaction was poured into saturated brine (5 mL), extracted with ethyl acetate (10 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 column chromatography on silica gel (ethyl acetate / petroleum ether = 0-50%) to give compound 205b (143 mg). MS m / z (ESI): 221.1 / 223.1 [M+1 / M+3] + .

[0798] Third Step: Synthesis of compound 205c

[0799] Compound 205b (143 mg, 0.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (47.6 mg, 0.065 mmol), and potassium carbonate (179.7 mg, 1.3 mmol) were added to a mixture of compound 90b (205.5 mg, 0.65 mmol) in 1,4-dioxane and water (5 mL / 1 mL) at room temperature, and the reaction mixture was stirred at 90°C for 18 h. After completion of the reaction, it was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, 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 give compound 205c (133 mg). MS m / z (ESI): 331.1 [M+1] + .

[0800] Fourth Step: Synthesis of compound 205

[0801] Trimethylaluminum (2 M in n-hexane, 0.60 mL, 1.2 mmol) was added dropwise to a solution of compound 205c (133 mg, 0.4 mmol) and compound 90d (101.5 mg, 0.4 mmol) in toluene (5 mL) at 0°C, and the reaction mixture was stirred at 100°C for 3 h. After completion of the reaction, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel (methanol / dichloromethane = 1 / 10) to give compound 205 (13.42 mg). MS m / z (ESI): 538.2 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.80 (d, J = 7.4 Hz, 1H), 8.74 (s, 1H), 8.38 (d, J = 5.9 Hz, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.43 - 7.39 (m, 1H), 5.54 (d, J = 44.1 Hz, 1H), 4.84 - 4.77 (m, 1H), 4.55 - 4.50 (m, 2H), 4.48 - 4.36 (m, 2H), 1.45 - 1.41 (m, 2H), 1.32 - 1.29 (m, 2H).

[0802] Example 37 (Compound 207)

[0803] First Step: Synthesis of compound 207b

[0804] Triethylamine (1.1 mL, 7.64 mmol) and tert-butyldiphenylsilyl chloride (2.1 g, 7.64 mmol) were added successively to a solution of compound 207a (2 g, 7.64 mmol) in dichloromethane (40 mL) at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was quenched with water (20 mL) and extracted with dichloromethane (100 mL), and the organic phase was washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), 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 to 5 / 1) to obtain compound 207b (2.98 g). MS m / z (ESI): 501.1 [M+1] + .

[0805] Second Step: Synthesis of compound 207c

[0806] Compound 89b (0.7 g, 8.63 mmol) and potassium carbonate (2.4 g, 17.27 mmol) were added successively to a solution of compound 207b (2.9 g, 5.76 mmol) in N,N-dimethylformamide (30 mL) at room temperature, and the reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (150 mL), and the organic phase was washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 15 / 1) to obtain compound 207c (813 mg). MS m / z (ESI): 423.1 [M+1] + .

[0807] Step 3: Synthesis of compound 207d

[0808] N-bromosuccinimide (321.4 mg, 1.81 mmol) was added to a solution of compound 207c (763 mg, 1.81 mmol) in acetonitrile (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was quenched by saturated sodium thiosulfate solution (10 mL), extracted with ethyl acetate (60 mL), washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100 / 1 to 30 / 1) to give compound 207d (819 mg). MS m / z (ESI): 500.9 [M+1] + .

[0809] Step 4: Synthesis of compound 207e

[0810] Compound 207d (830 mg, 1.964 mmol), compound 90b (745.2 mg, 2.36 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (160.8 mg, 0.20 mmol) and potassium carbonate (542.9 mg, 3.93 mmol) were added successively to a mixed solvent of 1,4-dioxane and water (10 mL / 2 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 2 h under nitrogen protection. After completion of the reaction, the reaction solution was extracted with ethyl acetate (80 mL), washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, 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 (dichloromethane / methanol = 100 / 1 to 30 / 1) to give compound 207e (499 mg).

[0811] MS m / z (ESI): 611.1 [M+1] + .

[0812] Step 5: Synthesis of compound 207f

[0813] Diethylaminosulfur trifluoride (52.8 mg, 0.33 mmol) was added to a solution of compound 207e (100 mg, 0.16 mmol) in dichloromethane (1 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into ice water (2 mL), and the pH was adjusted to about 9 by adding a saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL), washed with water (10 mL) and a saturated sodium chloride solution (10 mL) successively, 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 (dichloromethane / methanol = 100 / 1 to 30 / 1) to give compound 207f (67 mg). MS m / z (ESI): 613.0 [M+1] + .

[0814] Step 6: Synthesis of compound 207g

[0815] Trimethylaluminum (2 M in n-hexane, 0.1 mL, 0.20 mmol) was added to a solution of compound 207f (67 mg, 0.11 mmol) and compound 90d (41.60 mg, 0.16 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 a saturated ammonium chloride solution (1 mL), concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 207g (51 mg). MS m / z (ESI): 820.1 [M+1] + .

[0816] Step 7: Synthesis of compound 207

[0817] Cesium fluoride (62.0 mg, 0.41 mmol) was added to a solution of compound 207g (67 mg, 0.08 mmol) in N,N-dimethylformamide (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was extracted with ethyl acetate (30 mL), washed with water (10 mL x 3) and a saturated sodium chloride solution (10 mL) successively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel (dichloromethane / methanol = 15 / 1) to give compound 207 (13.4 mg). MS m / z (ESI): 582.1 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.79 (d, J = 7.4 Hz, 1H), 8.73 (s, 1H), 8.35 (d, J = 1.2 Hz, 1H), 8.29 (d, J = 7.3 Hz, 1H), 8.03 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.40 (dd, J = 7.3, 1.9 Hz, 1H), 5.29 (s, 1H), 4.60 (s, 1H), 4.56 - 4.50 (m, 1H), 4.48 (s, 1H), 4.43 (s, 2H), 4.12 - 4.01 (m, 2H), 3.51 (s, 2H), 1.46 - 1.40 (m, 2H), 1.34 - 1.28 (m, 2H).

[0818] Example 38 (Compound 209)

[0819] First Step: Synthesis of compound 209b

[0820] Potassium carbonate (24.7 g, 178.41 mmol) and compound 209a (7.4 g, 59.47 mmol) were added to a solution of compound 89b (5 g, 59.47 mmol) in DMF (50 mL) at room temperature, and the reaction mixture was stirred at 125 °C for 3 h. After the reaction was completed, 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 209b (1.3 g). MS m / z (ESI): 137.06 [M+1] + .

[0821] Second Step: Synthesis of compound 209c

[0822] Potassium ferricyanide (5.8 g, 17.63 mmol), potassium carbonate (3.7 g, 26.44 mmol), and potassium osmate (VI) dihydrate (324.7 mg, 0.88 mmol) were sequentially added to a solution of compound 209b (1.2 g, 8.81 mmol) in a mixture of tert-butyl alcohol and water (24 mL / 24 mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 h. After the reaction was completed, the layers were separated by standing, and the upper clear solution was directly concentrated to give compound 209c (1.2 g). MS m / z (ESI): 171.07 [M+1] + .

[0823] Third Step: Synthesis of compound 209d

[0824] Compound 209c (1.2 g, 6.76 mmol) was dissolved in dichloromethane (12 mL) and stirred at room temperature. Then imidazole (920.2 mg, 13.52 mmol) and tert-butyldimethylsilyl chloride (1.0 g, 6.76 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated brine (10 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 = 10 / 0 ~ 1 / 5) to obtain compound 209d (350 mg). MS m / z (ESI): 285.2 [M+1] + .

[0825] Fourth step: synthesis of compound 209e

[0826] N-bromosuccinimide (212.8 mg, 1.20 mmol) was added to a solution of compound 209d (340 mg, 1.20 mmol) in acetonitrile (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 0 ~ 10 / 4) to obtain compound 209e (360 mg).

[0827] MS m / z (ESI): 363.07 [M+1] + .

[0828] Fifth step: synthesis of compound 209f

[0829] Potassium carbonate (167.4 mg, 1.211 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (49.6 mg, 0.061 mmol), and compound 90b (191.4 mg, 0.61 mmol) were sequentially added to a mixture of compound 209e (220 mg, 0.61 mmol) in 1,4-dioxane and water (4 mL / 1 mL) at room temperature. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 4 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), 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 = 10 / 0 ~ 10 / 7) to obtain compound 209f (160 mg). MS m / z (ESI): 473.21 [M+1] + .

[0830] Step 6: Synthesis of compound 209g

[0831] Sodium hydride (7.1 mg, 0.30 mmol) was added to a solution of compound 209f (70 mg, 0.15 mmol) in DMF (4 mL) at 0 °C, stirred for half an hour, then iodomethane (0.01 mL, 0.15 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL x 3), 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 thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to obtain compound 209g (64 mg). MS m / z (ESI): 487.23 [M+1] + .

[0832] Step 7: Synthesis of compound 209h

[0833] 2M trimethylaluminum in n-hexane (0.12 mL, 0.25 mmol) was added to a solution of compound 90d (34.4 mg, 0.14 mmol) and compound 209g (60 mg, 0.12 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 under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to obtain compound 209h (64 mg). MS m / z (ESI): 694.24 [M+1] + .

[0834] Step 8: Synthesis of compound 209

[0835] Cesium fluoride (59.1 mg, 0.39 mmol) was added to a solution of compound 209h (54 mg, 0.078 mmol) in DMF (5 mL) at room temperature, and the reaction mixture was stirred at 50 °C for 2 hours. After the reaction was completed, the reaction solution was poured into water, and a solid was precipitated, which was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to obtain compound 209 (24.2 mg).

[0836] MS m / z (ESI): 580.15 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.78 (d, J = 7.3 Hz, 1H), 8.73 (s, 1H), 8.34 (d, J = 1.2 Hz, 1H), 8.30 (d, J = 7.3 Hz, 1H), 7.98 (s, 1H), 7.86 (d, J = 10.1 Hz, 1H), 7.39 (dd, J = 7.3, 2.0 Hz, 1H), 5.16 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 11.7 Hz, 1H), 4.56 - 4.49 (m, 1H), 4.36 (d, J = 11.8 Hz, 1H), 4.15 (s, 2H), 3.64 (d, J = 5.5 Hz, 2H), 3.27 (s, 3H), 1.47 - 1.40 (m, 2H), 1.34 - 1.29 (m, 2H).

[0837] Example 39 (Compound 208)

[0838] First Step: Synthesis of compound 208a

[0839] Diethylamine sulfide trifluoride (23.9 mg, 0.15 mmol) was added to a solution of compound 209f (70 mg, 0.15 mmol) in dichloromethane (7 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (10 mL), and the aqueous phase was extracted with dichloromethane (10 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 thin layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 208a (63 mg). MS m / z (ESI): 475.21 [M+1] + .

[0840] Second Step: Synthesis of compound 208b

[0841] 2M trimethylaluminum in n-hexane (0.12 mL, 0.25 mmol) was added to a solution of compound 90d (35.3 mg, 0.14 mmol) and compound 208a (60 mg, 0.13 mmol) in toluene (3 mL) at 0°C under a nitrogen atmosphere, 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 thin layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 208b (53 mg). MS m / z (ESI): 682.21 [M+1] + .

[0842] Third Step: Synthesis of compound 208

[0843] Cesium fluoride (59.0 mg, 0.39 mmol) was added to a solution of compound 208b (53 mg, 0.078 mmol) in DMF (5 mL) at room temperature, and the reaction mixture was stirred at 50 °C for 2 h. After the reaction was completed, the reaction solution was poured into water to precipitate a solid, which was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 208 (10.2 mg). MS m / z (ESI): 568.13 [M+1] + .

[0844] Example 40 (compound 210)

[0845] First step: synthesis of compound 210b

[0846] Compound 71a (2 g, 10.86 mmol) was dissolved in DMF (20 mL), and compound 210a (1.95 g, 11.94 mmol) and potassium carbonate (4.5 g, 32.57 mmol) were added successively, and the reaction mixture was heated to 85 °C and stirred for 12 h. After the reaction was completed, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phase was 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 column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 2) to give compound 210b (1.4 g). MS m / z (ESI): 211.1 [M+1-56] + .

[0847] Second step: synthesis of compound 210c

[0848] Compound 210b (1.3 g, 4.88 mmol) was dissolved in DCM (20 mL), and m-CPBA (1.0 g, 5.86 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (20 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 (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 1) to give compound 210c (1 g). MS m / z (ESI): 283.0 [M+1] + .

[0849] Third step: synthesis of compound 210d

[0850] Compound 210c (1.2 g, 4.25 mmol) was dissolved in DCM (30 mL), and methylsulfonic acid (1.6 g, 17.00 mmol) was added. The mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 4) to give compound 210d (100 mg). MS m / z (ESI): 183.1 [M+1] + . 1 H NMR (400 MHz, CDC13) δ 7.31 (d, J = 2.0 Hz, 1H), 5.52 (d, J = 2.2 Hz, 1H), 4.45 - 4.35 (m, 1H), 4.24 - 4.07 (m, 2H), 2.17 (dd, J = 12.2, 8.8 Hz, 1H), 2.02 (dd, J = 11.4, 8.4 Hz, 1H), 1.28 (s, 3H), 0.99 (s, 3H).

[0851] Fourth Step: Synthesis of compound 210e

[0852] NBS (70.3 mg, 0.40 mmol) was added to a solution of compound 210d (90 mg, 0.49 mmol) in acetonitrile (1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture 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 210e (120 mg). MS m / z (ESI): 261.2 [M+1] + .

[0853] Fifth Step: Synthesis of compound 210f

[0854] Compound 210e (120 mg, 0.46 mmol) was dissolved in a mixture of 1,4-dioxane and water (0.5 mL / 0.1 mL) at room temperature, and compound 90b (145.3 mg, 0.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (33.6 mg, 0.046 mmol), and potassium carbonate (127.0 mg, 0.92 mmol) were sequentially added. The reaction mixture was heated to 80°C under nitrogen protection and stirred for 12 h. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL x 2), 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 ~ 0 / 1) to give compound 210f (100 mg). MS m / z (ESI): 371.0 [M+1] + .

[0855] Step 6: Synthesis of compound 210

[0856] To a solution of compound 210f (100 mg, 0.27 mmol) and compound 90d (82.2 mg, 0.32 mmol) in 1,4-dioxane (2 mL) was added 2 M solution of trimethylaluminum in n-hexane (0.4 mL, 0.81 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction was cooled to room temperature, quenched with sodium sulfate decahydrate (1 g), filtered and concentrated. The residue was purified by reverse phase preparative purification (column: Xbridge-C18; 19 x 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-40%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm) to give compound 210 (5.08 mg). MS m / z (ESI): 577.9 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.81 (d, J = 7.4 Hz, 1H), 8.75 (s, 1H), 8.41 (m, 1H), 8.31 (d, J = 7.3 Hz, 1H), 8.08 (s, 1H), 7.88 (d, J = 10.2 Hz, 1H), 7.43 (dd, J = 7.4, 2.0 Hz, 1H), 5.30 (s, 1H), 4.78 - 4.67 (m, 1H), 4.57-4.52 (m, 1H), 4.48-4.38 (m, 1H), 4.21 (t, J = 6.8 Hz, 1H), 2.25 (m, 2H), 1.48 - 1.42 (m, 2H), 1.36-1.30 (m, 2H), 1.22 (s, 3H), 1.19 (s, 3H).

[0857] Example 41 (Compound 143)

[0858] Step 1: Synthesis of compound 143a

[0859] To a solution of compound 156a (2.05 g, 8.5 mmol) in dichloromethane (10 mL) was added methanesulfonic acid (3.28 g, 34.1 mmol) at room temperature. The reaction was stirred at room temperature for 18 h. After completion of the reaction, the reaction was concentrated under reduced pressure to give compound 143a (1.15 g, crude). MS m / z (ESI): 141.1 [M+1] + .

[0860] Step 2: Synthesis of compound 143b

[0861] Compound 143a (1.15 g, 8.2 mmol) was dissolved in dichloromethane (20 mL) and stirred at room temperature. Then, tert-butyldimethylsilyl chloride (4.95 g, 32.8 mmol) and imidazole (11.2 g, 164.2 mmol) were added successively. The reaction mixture was stirred at room temperature for 18 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 = 0-20%) to obtain compound 143b (1.06 g). MS m / z (ESI): 255.1 [M+1] + .

[0862] Third step: synthesis of compound 143c

[0863] N-bromosuccinimide (700.9 mg, 3.9 mmol) was added to a solution of compound 143b (910 mg, 3.6 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 solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to obtain compound 143c (1.24 g). MS m / z (ESI): 333.0 / 335.0 [M+1] +

[0864] Fourth step: synthesis of compound 143d

[0865] Compound 143c (100 mg, 0.29 mmol), Pd(dppf)Cl2(42.4 mg, 0.058 mmol), and potassium carbonate (80.2 mg, 0.58 mmol) were successively added to a mixture of compound 90b (137.5 mg, 0.43 mmol) in 1.4-dioxane (5 mL) and water (1 mL) at room temperature, and 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 silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 143d (118 mg). MS m / z (ESI): 443.1 [M+1] + .

[0866] Fifth step: synthesis of compound 143e

[0867] Trimethylaluminum (2M in n-hexane, 0.4 mL, 0.81 mmol) was added dropwise to a solution of compound 143d (118 mg, 0.27 mmol) and compound 90d (68.5 mg, 0.27 mmol) in toluene (5 mL) under ice-bath. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture 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 143e (179 mg). MS m / z (ESI): 650.2 [M+1] + .

[0868] Step 6: Synthesis of compound 143

[0869] Compound 143e (159 mg, 0.24 mmol) was added to a solution of hydrochloric acid / 1,4-dioxane (4M, 5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was poured into saturated brine (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel (methanol / dichloromethane = 1 / 10) to give compound 143 (27.9 mg). MS m / z (ESI): 536.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.79-8.76 (m, 1H), 8.72 (d, J = 2.6 Hz, 1H), 8.39-8.35 (m, 1H), 8.32-8.26 (m, 1H), 7.99 (d, J = 6.7 Hz, 1H), 7.85 (d, J = 10.1 Hz, 1H), 7.41-8.41 (m, 1H), 5.66 (d, J = 3.4 Hz, 1H), 4.55-4.50 (m, 1H), 4.40 (s, 2H), 4.36-4.34 (m, 1H), 4.31-4.26 (m, 1H), 2.34-2.31 (m, 1H), 1.44-1.42 (m, 2H), 1.32-1.28 (m, 2H).

[0870] Example 42 (Compound 148)

[0871] Compound 143 (15 mg, 0.028 mmol) was dissolved in dichloromethane (5 mL) under ice-bath, DAST (4.5 mg, 0.028 mmol) was added dropwise slowly, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction liquid was poured into saturated brine (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, the residue was purified by thin layer chromatography on silica gel plate (methanol / dichloromethane = 1 / 10) to obtain compound 148 (4.98 mg).

[0872] MS m / z (ESI): 538.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.83-8.78 (m, 1H), 8.76-8.73 (m, 1H), 8.41-8.36 (m, 1H), 8.32-8.27 (m, 1H), 8.09-8.04 (m, 1H), 7.86 (d, J = 10.2 Hz, 1H), 7.45-7.38 (m, 1H), 5.65-5.41 (m, 1H), 4.84-4.75 (m, 1H), 4.72-4.55 (m, 1H), 4.54-4.44 (m, 2H), 4.41-4.25 (m, 1H), 1.44-1.41 (m, 2H), 1.33-1.29 (m, 2H).

[0873] Example 43 (Compound 214)

[0874] First Step: Synthesis of compound 214b

[0875] Azidotrimethylsilane (3.23 g, 28.03 mmol) and dibutyltin oxide (1.99 g, 5.61 mmol) were added to a solution of compound 214a (6 g, 28.03 mmol) in 1,4-dioxane (30 mL) at room temperature, the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the reaction liquid was poured into water (100 mL), a solid was precipitated, filtered and dried to obtain compound 214b (5.1 g). MS m / z (ESI): 256.9, 258.9 [M+1, M+3] + .

[0876] Second Step: Synthesis of compound 214c

[0877] Sodium carbonate (4.12 g, 38.90 mmol), copper acetate (0.71 g, 3.89 mmol), bipyridine (0.71 g, 3.89 mmol) were added successively to a solution of potassium cyclopropanecarboxylate (5.76 g, 38.90 mmol) and compound 214b (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 with open flask. 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 214c (2.3 g). MS m / z (ESI): 296.9, 298.9 [M+1] + .

[0878] Third Step: Synthesis of compound 214d

[0879] Sodium hydroxide (0.24 g, 6.06 mmol), palladium acetate (0.18 g, 0.81 mmol), XantPhos (0.7 g, 1.21 mmol) were added successively to a solution of diphenylmethanimine (0.81 g, 4.44 mmol) and compound 214c (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 214d (1.3 g). MS m / z (ESI): 398.0 [M+1] + .

[0880] Fourth Step: Synthesis of compound 214e

[0881] Hydrochloric acid-1,4-dioxane solution (13 mL, 4 M) was added to a solution of compound 214d (1.3 g, 3.27 mmol) in 1,4-dioxane (13 mL) at room temperature. The reaction mixture was stirred at 25 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to give compound 214e (600 mg). MS m / z (ESI): 234.0 [M+1] + .

[0882] Fifth Step: Synthesis of compound 214

[0883] Trimethylaluminum (2 M in n-hexane) (0.07 mL, 0.13 mmol) was added to a solution of compound 158f (synthesis method refer to the synthesis of compound 158f in Example 31, Step 5, 15.1 mg, 0.065 mmol) and compound 214e (25 mg, 0.065 mmol) in 1,4-dioxane (3 mL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated 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 give compound 214 (1.77 mg). MS m / z (ESI): 573.8 [M+1] + .

[0884] 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.76 (d, J = 7.3 Hz, 1H), 8.69 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.98 (s, 1H), 7.44 - 7.36 (m, 2H), 5.42 (s, 1H), 4.88 (s, 1H), 4.54 - 4.48 (m, 1H), 4.47 - 4.38 (m, 2H), 4.34 (d, J = 12.6 Hz, 1H), 3.93 (d, J = 12.5 Hz, 1H), 2.36 (s, 3H), 1.46 - 1.40 (m, 2H), 1.33 - 1.27 (m, 2H), 1.20 (s, 6H).

[0885] Example 44 (Compound 216)

[0886] First Step: Synthesis of compound 216b

[0887] 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 216a (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 216b (450 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 181.05 [M+1] + .

[0888] Step 2: Synthesis of compound 216c

[0889] Methylmagnesium bromide in tetrahydrofuran (3.0 M, 2.77 mL, 8.32 mmol) was added to a solution of compound 216b (500 mg, 2.77 mmol) in tetrahydrofuran (5 mL) under ice-bath. The reaction mixture was stirred at room temperature for 4 hours under nitrogen atmosphere. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (30 mL x 3), 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 column chromatography on silica gel (methanol / dichloromethane = 5%) to give compound 216c (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).

[0890] Step 3: Synthesis of compound 216d

[0891] NBS (444.4 mg, 2.50 mmol) was added to a solution of compound 216c (450 mg, 2.50 mmol) in acetonitrile (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. 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 = 0:1 ~ 1:10) to give compound 216d (450 mg). MS m / z (ESI): 259.0, 261.0 [M+1, M+3] + .

[0892] Step 4: Synthesis of compound 216e

[0893] Compound 216d (100 mg, 0.38 mmol), potassium carbonate (160 mg, 1.16 mmol) and Pd(dppf)Cl2(28 mg, 0.04 mmol) were added successively to a mixture of compound 90b (122 mg, 0.38 mmol) in 1,4-dioxane and water (1 / 0.25 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 cooled to room temperature and concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 20 / 1) to give compound 216e (74 mg). MS m / z (ESI): 369.0 [M+1] + .

[0894] Fifth step: synthesis of compound 216

[0895] Compound 216e (74 mg, 0.21 mmol) and compound 214f (50 mg, 0.21 mmol) in toluene (1 mL) was added dropwise 2M trimethylaluminum in n-hexane (0.22 mL, 0.44 mmol) under nitrogen atmosphere at ice bath. The reaction mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched by the addition of sodium sulfate decahydrate (1 g). The mixture was filtered and 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 (methanol / dichloromethane = 1 / 20) to give compound 216 (28.33 mg). MS m / z (ESI): 556.0 [M+1] + .

[0896] 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.81 (d, J = 7.2 Hz, 1H), 8.73 (s, 1H), 8.21 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.98 (s, 1H), 7.40 (d, J = 11.2 Hz, 1H), 7.32 (dd, J = 7.2, 1.9 Hz, 1H), 4.53 (s, 1H), 4.52 - 4.46 (m, 1H), 4.30 (dd, J = 12.6, 5.0 Hz, 1H), 3.86 (t, J = 12.2 Hz, 1H), 3.13 (dd, J = 16.8, 4.0 Hz, 1H), 2.97 - 2.86 (m, 1H), 2.36 (s, 3H), 2.17 - 2.14 (m, 1H), 2.03 - 1.98 (m, 1H), 1.53 - 1.45 (m, 1H), 1.44 - 1.40 (m, 2H), 1.32 - 1.27 (m, 2H), 1.19 (s, 3H), 1.16 (s, 3H).

[0897] The following compounds can be synthesized according to the methods described in the above examples.

[0898] Biological Examples

[0899] 1. Inhibition of wild-type c-kit kinase

[0900] The Mobility Shift Assay method was used to evaluate the inhibition of wild-type c-kit kinase by the test substances, and the reaction was performed in a 384-well plate (Corning, 3573). 50 mM HEPES, pH 7.5, 0.01% Triton X-100, 10 mM MgCl2, 2 mM DTT were used as the reaction buffer, and 20 μL of the reaction system contained 6 nM c-kit (Carna, 08-156), 6 μM ATP (Sigma, 2383-5G), and 3 μM substrate FAM-labeled peptide (KKKKEEIYFFF-CONH2, GL, 263631). The initial concentration of the compound was 10 μM, 1% DMSO, 4-fold dilution, 10 concentrations, and double-replicate wells. Incubate at 28°C for 90 minutes, and terminate the reaction by adding 25 μL of the termination solution (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA) to the 384-well plate reaction plate. Read the conversion rate data on the Caliper EZ Reader II, and use the formula: % inhibition = (positive control well - compound well) / (positive control well - negative control well) * 100 to calculate, where the "negative control well" is the reading of the control sample well without enzyme; the "positive control well" is the reading of the control well with DMSO added as a control; and the GraphPad Prism 8 software is used to fit the concentration-effect curve (Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope)) and calculate the compound concentration at 50% inhibition, i.e. IC 50 . The test results are shown in Table 1. Wherein A represents: IC 50 value ≤ 300 nM; B represents: 300 nM < IC 50 value ≤ 600 nM; C represents: 600 nM < IC 50 value ≤ 1000 nM; D represents: 1000 nM < IC 50 value.

[0901] Table 1

[0902] 2. Inhibition of wild-type c-kit kinase

[0903] The commercial kit HTRF KINEASE TK KIT (Revvity, 62TK0PEC) was used to evaluate the inhibition of wild-type c-kit kinase by the test substances, and the reaction was performed in a 384-well plate (PE, 6008280).

[0904] Dilute the 5X enzyme reaction buffer to 1X with distilled water, and add DTT, MgCl2, and MnCl2 to final concentrations of 1mM, 5mM, and 1mM respectively to prepare the 1X enzyme reaction buffer. Prepare 10 serially diluted concentrations (maximum 10 μM) using the 1X enzyme reaction buffer for testing, with DMSO at a final concentration of 1%. In a 10 μL reaction system, add 4 μL of the compound working solution and 2 μL of KIT kinase (Carna, 08-156) at a final concentration of 0.29 ng / μL. Dilute with 1X enzyme reaction buffer and place on ice 20 minutes before adding to the reaction system. 2 μL of TK Substrate-biotin (Revity, 61TK0BLC) at a final concentration of 0.25 μM and 2 μL of ATP (Promega, V9158) at a final concentration of 8 μM were prepared using 1X enzyme reaction buffer and added sequentially to the wells of a 384-well plate to initiate the reaction. Negative control wells contained no compound or kinase, and positive control wells contained no compound. After incubation at 25°C for 1 hour, 5 μL of TK Antibody-Cryptate diluted 100-fold with detection buffer (Revity, 62SDBRDF) and SA-XL665 (Revity, 610SAXLG) at a final concentration of 15.625 nM were added, and incubation continued at 25°C for another hour. Detection was performed using the HTRF module of a Molecular Device SpectraMax i3x microplate reader at an excitation wavelength of 340 nm and emission wavelengths of 616 nm and 665 nm. The inhibition rate of the test substance was calculated using the following formula:

[0905] in

[0906] The concentration-effect curve (Y = Bottom + (Top - Bottom) / (1 + (IC)) was fitted using GraphPad Prism 8 software. 50 / X)^HillSlope)), and calculate the concentration of the compound with a 50% inhibition rate, i.e., IC50. 50 The test results are shown in Table 2. Where A represents: IC 50 Value ≤ 300nM; B represents: 300nM <IC 50 Value ≤ 600nM; C represents: 600nM <IC 50 Value ≤ 1000nM; D represents: 1000nM <IC 50 value.(

[0907] Table 2

[0908] 3. Inhibition of c-kit phosphorylation in SCF-stimulated M-07e cells

[0909] M-07e cells (Pronosai, CL-0686) were seeded at a density of 2 × 10^6 cells / mL in Opti-MEM medium (Gibco, 11058021) containing 1% penicillin (Gibco, 15140-122) in 96-well plates (Corning, 3599), with a volume of 50 μL per well. After incubation at 37°C and 5% CO2 for 4 hours, 6.25 μL of a gradient concentration of the compound was added to each well to achieve a maximum final concentration of 1000 nM. This was repeated 5-fold serially to achieve 8 concentrations, with a final DMSO concentration of 0.22%. After further incubation at 37°C and 5% CO2 for 60 minutes, 6.25 μL of Human Recombinant SCF (STEMCELL, 78062) was added to achieve a final SCF concentration of 50 ng / mL. Positive control wells (max) contained no compound, and negative control wells (min) contained neither the compound nor SCF. After incubation at room temperature on a shaker at 450 rpm for 15 minutes, 16 μL of 5X cell lysis buffer (CST, 9803) containing protease and phosphatase inhibitors (Beyotime, P1045) was added. The cells were lysed by gentle shaking at 4°C for 30 minutes, and the lysate was collected by centrifugation. Protein quantification was performed using the BCA (Beyotime, P0009) method. The phosphorylation level of the p-kit was detected using the PathScan@Phospho-c-Kit (Tyr719) Sandwich ELISA Kit according to the kit instruction manual. The OD values ​​of the measured ELISA were normalized to protein concentration, and the inhibition rate was calculated using the following formula. A concentration-response curve was fitted using GraphPad Prism 8 software: (Y = Bottom + (Top - Bottom) / (1 + (IC50)) 50 / X)^HillSlope)), and calculate the concentration of the compound with a 50% inhibition rate, i.e., IC50. 50 The test results are shown in Table 3.

[0910] ODmax: Normalized absorbance of the control group containing cells, SCF, and no compound.

[0911] ODmin: Normalized absorbance of the control group containing cells but without SCF and the compound.

[0912] ODcpd: Normalized absorbance of a control group containing cells, SCF, and different concentrations of compounds.

[0913] Table 3

[0914] As shown in the table above, the compound of this application has strong c-kit phosphorylation activity and produces significant drug efficacy in vivo at a lower dose.

[0915] 4. Inhibition of p-PDGFRα / β phosphorylation in PDGF-BB-stimulated SW579 cells

[0916] SW579 cells (Pronosai, CL-0224) were seeded at a density of 1.5 × 10^5 cells / mL in 96-well plates (Geniner, 655090) using DMEM medium (Gibco, 11995065) containing 1% penicillin (Gibco, 15140-122) and 10% fetal bovine serum (Gibco, 10099-141C), with a volume of 100 μL per well. After incubation overnight at 37°C in 5% CO2, 25 μL of a gradient concentration of the compound was added to each well to achieve a maximum final concentration of 3000 nM. The cells were serially diluted 3-fold, with 8 replicates per well, and the final DMSO concentration was 0.33%. After incubation for another 90 minutes, 25 μL of PDGF-BB protein (MCE, HY-P7055) was added, bringing the final PDGF-BB concentration to 100 μg / mL. Positive control wells contained no compound, and negative control wells contained neither compound nor PDGF-BB. After 10 minutes of incubation, the cell plate was removed and centrifuged. Cells were fixed for 20 minutes with 4% paraformaldehyde (Beyotime-P0099) and permeabilized four times with 0.1% Triton X-100 (Sigma#T8787). After blocking at room temperature for 1.5 hours, the cells were incubated overnight with primary antibody (Phospho-PDGF Receptorα(Tyr849) / PDGF Receptorβ(Tyr857)(C43E9) Rabbit mAb, 1:200, CST, 3170), diluted 1:500 and containing CellTag. TM 700Stain (IRDye, 926-41090) Cells were incubated with 800CW Goat anti-Rabbit IgG secondary antibody (IRDye, 926-32211) at room temperature in the dark for 1 hour, and then scanned using an Odyssey DLX dual-color near-infrared imaging system. Image Studio software was used to analyze p-PDGFRα / β and CellTag in each well of each cell plate. TM The fluorescence signal intensity of 700 Stain was calculated by subtracting the background signal (excluding the primary antibody control) from the signal intensity of p-PDGFRα / β and then using the internal control CellTag. TMNormalize the signal of 700Stain and calculate the inhibition rate, and use GraphPad Prism 8 software to fit the concentration-effect curve (Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)^HillSlope)), and calculate the compound concentration at 50% inhibition rate, that is, IC 50 . Ratio = IC50(p-PDGFRa / β) / IC50(p-kit). Ratio = IC 50 (p-PDGFRa / β) / IC 50 (p-kit). Among them, A represents: Ratio ≤ 10; B represents: 10 < Ratio ≤ 100; C represents: 100 < Ratio ≤ 1000; D represents: 1000 < Ratio. The test results are shown in Table 4.

[0917] Table 4

[0918] As can be seen from the above table, the compounds of this application have good selectivity, less possibility of off-target, and a larger safety window in vivo.

[0919] 8. For the experiment of inhibiting the proliferation of M-07e cells stimulated by SCF

[0920] Use RPMI-1640 medium (Gibco, 22400-089) containing 1% penicillin-streptomycin (Gibco, 15140-122), 10% fetal bovine serum (Gibco, 10099-141C) and 25 ng / mL Human Recombinant SCF (STEMCELL, 78062) to seed M-07e cells (Procell, CL-0686) in a 384-well plate (Greiner, 781091) at a density of 3×10^5 cells / mL. At the same time, set cell culture wells without 25 ng / mL SCF, and the volume of each well is 20 μL; after incubating overnight at 37 °C and 5% CO2, add 10 μL of gradient concentration compounds to each well, so that the maximum final concentration of the compounds is 3000 nM, diluted in a 4-fold serial dilution, with 8 concentrations, and the final concentration of DMSO is 0.66%; continue to incubate at 37 °C and 5% CO2 for 6 days, then add 25 μL of CellTiter-Glo (Promega, G7573), place it at room temperature for 30 minutes, and finally detect the proliferation of cells with a microplate reader; use the following formula to calculate the inhibition rate, use GraphPad Prism 8 software to fit the concentration-effect curve, and calculate the compound concentration at 50% inhibition effect, that is, IC 50 . The test results are shown in Table 5.

[0921] max: Contains cells, SCF, but contains no compounds.

[0922] min: Contains cells, but does not contain SCF or compounds.

[0923] CPD: Contains cells, SCF, and compounds of varying concentrations.

[0924] Table 5

[0925] The above describes specific embodiments of the present invention. It should be understood that the present invention is not limited to the limitations of the above embodiments; the embodiments and descriptions in the speci...

Claims

A compound of Formula (IG) or a pharmaceutically acceptable salt thereof, wherein T is G 1 CR 8 or N; A is a 5-12 membered heterocyclyl or C 5-12 cycloalkyl, said 5-12 membered heterocyclyl or C 5-12 cycloalkyl, said 5-12 membered heterocyclyl or C A substituted; R A the same or different, each independently selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, and S(O) m C 1-6 alkyl, the C 1-6 alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl are optionally substituted with one or more selected from cyano, hydroxyl, halogen, amino, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, SC 1-6 alkyl, and S(O)2C 1- 6alkyl; or, 2 R A forming a carbon-carbon double bond on the same carbon atom, and the carbon-carbon double bond is optionally substituted with one or more selected from halogen and C 1-6 alkyl; Ring B is a 5-membered heteroaryl group, said 5-membered heteroaryl group being optionally substituted by one or more R B substituents; R B the same or different, each independently selected from halogen, cyano, hydroxyl, oxo, amino, 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; CycloC is 5-membered heteroaryl; X is C and Y is N; or, X is N and Y is C; R 0 selected from H, 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 1 and R 2 are the same or different, each being independently selected from H, halogen, cyano, hydroxyl, 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; or R 0 and R 2 together with the atom to which they are attached form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 3 and R 4 are the same or different, each being independently selected from H, halogen, cyano, hydroxyl, 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; Or, R 1 and R 4 R 2 and R 3 R 1 and R 3 Any group of atoms connected to it together forms C. 5-12 Cycloalkyl or 5-12 membered heterocyclic groups, wherein the C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in the haloalkoxy group; or, one of the R... B and R 3 Together with the atoms attached to it, they form C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups, wherein the C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group; Or, one of the R B and R 4 An R B and R 3 Any group of atoms connected to it together forms C. 5-12 Cycloalkyl or 5-12 membered heterocyclic groups, wherein the C 5-12 Cycloalkyl or 5-12 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group; Each R 5 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; R 6 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl or The C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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, hydroxyl, cyano, amino, oxo, carboxylic acid, ester, 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 7 selected from H, halogen, cyano, hydroxy, 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; or R 7 and R 3 , R 7 and R 4 together with the atoms to which they are attached form a 5-12 membered heterocyclyl group, which is optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 8 selected from H, halogen, cyano, hydroxy, 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 9 selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -C 1-6 alkylene-C 3-8 cycloalkyl and -C 1-6 alkylene-(3-8 membered heterocyclyl), said -C 1-6 alkylene-C 3-8 cycloalkyl and -C 1-6 alkylene-(3-8 membered heterocyclyl) is optionally substituted with one or more of halogen, hydroxyl, amino and amino; or R 8 and R 9 together with the atom to which they are attached form a C 5-12 cycloalkyl or 5-12 membered heterocyclyl, said C 5-12 cycloalkyl or 5-12 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 6a and R 6b are the same or different, each independently selected from H, halogen, cyano, 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; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; q is 1 or 2. the heteroatoms in said heterocyclyl or heteroaryl are selected from O, N and S, in a number of 1, 2, 3 or 4; is a single or double bond; provided that when T is R 1 and R 4 , R 2 and R 3 , R 1 and R 3 are each independently selected from the group consisting of hydrogen, C 5-12 cycloalkyl, 5-12 membered heterocyclyl, aryl, and heteroaryl, wherein each of said C 5-12 cycloalkyl, 5-12 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; the non-cyclic groups of R 1 , R 2 , R 3 , and R 4 are as defined above; When T is At that time, R 7 and R 3 R 7 and R 4 At least one group of atoms bonded to it forms a 5-12 membered heterocyclic group, wherein the 5-12 membered heterocyclic group is optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group. The compound represented by Formula (IG) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, which satisfies one or more of the following conditions: (1) T is R a selected from H, halogen, cyano, hydroxyl, oxo, amino, 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; t is 1, 2, 3 or 4; Ring D is a 5-12 membered heterocyclyl or C 5-12 cycloalkyl; (2) R A the same or different, each independently selected from H, halo, cyano, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1- haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl and C 3-8 cycloalkyl is optionally substituted with one or more substituents selected from cyano, hydroxyl, halo, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, SC 1-6 alkyl and S(O)2C 1-6 alkyl; (3) R 3 and R 4 are each H; (4) each R is independently selected from the group consisting of H, cyano, halo, and C1-C6alkyl; 5 the same or different, are independently selected from the group consisting of H, cyano, halo, and C1-C6alkyl; 1-6 C1-C6alkyl; and (5) R 6 is C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl or The C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, C(O)OC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R 6a and R 6b are the same or different, each being independently selected from H, halogen, cyano, 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; p is 1 or 2; q is 1 or 2. The compound represented by Formula (IG) according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, which satisfies one or more of the following conditions: (1) CycloD is 5-8 membered mono-heterocyclyl, 6-12 membered spiro-heterocyclyl, 6-12 membered fused-heterocyclyl or 6-12 membered bridged-heterocyclyl; (3) For (4) For and (5) R 6 is The compound represented by Formula (IG) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula (IG) is a compound of formula (I), wherein ring A, ring B, ring C, X, Y, R 3 , R 4 , R 5 , R 6 and n are as defined in claim 1 ; Preferably, R 6 is 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 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 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 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl. The compound represented by Formula (IG) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, wherein the compound of Formula (IG) is a compound of Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (III-3), or Formula (III-4), wherein ring A, ring B, R 3 , R 4 , R 5 , R 6 and n are as defined in claim 1. The compound represented by Formula (IG) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, wherein the compound of formula (IG) is a compound of formula (IIG-1) or (IIG-2), wherein L is C 1-6 alkylene or C 1-6 heteroalkylene, said C 1-6 alkylene or C 1-6 heteroalkylene is optionally substituted with one or more selected from the group consisting of halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 1 selected from H, halogen, cyano, hydroxy, 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 3 and R 4 are the same or different, each being independently selected from H, halogen, cyano, hydroxyl, 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; C, X, Y, R 0 , R 2 , R 5 , R 6 or n are as defined in claim 1. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, characterized in that, wherein For R a selected from H, halogen, cyano, hydroxyl, oxo, amino, 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 b , R c , R d , R e , R f , R g , R k , R m and R n are the same or different, each being independently selected from H, halo, cyano, hydroxyl, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -NHC 1-6 alkyl, -N(C 1- 6alkyl)2, and S(O) m C 1-6 alkyl, said C 1-6 alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl being optionally substituted with one or more selected from cyano, hydroxyl, halo, amino, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, SC 1-6 alkyl, and S(O)2C 1-6 alkyl; Or, R b and R c 、or R d and R e 、or R f and R g 、or R m and R n Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group; or R b and R d , or R b and R e , or R e and R f , or R d and R f , or R f and R m , or any one of the groups R 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally substituted with one or more selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; Or, R b and R f 、or R b and R n 、or R d and R k Any group of atoms in the matrix, together with the atoms attached to it, forms C. 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 One or more substitutions in a haloalkoxy group; m is 1 or 2. The compound represented by formula (IG) according to claim 7 or a pharmaceutically acceptable salt thereof, characterized in that, For R a and R 3 together with the atom to which they are attached form a C 6-8 cycloalkyl or 6-8 membered heterocyclyl, said C 6-8 cycloalkyl or 6-8 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; or R a and R 4 together with the atom to which they are attached form a C 6-8 cycloalkyl or 6-8 membered heterocyclyl, said C 6-8 cycloalkyl or 6-8 membered heterocyclyl is optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R b , R c , R d , R e , R f , R g As defined in claim 7. The compound represented by formula (IG) or a pharmaceutically acceptable salt thereof according to claim 1 or 4, characterized in that, which satisfies one or more of the following conditions: (1) For (2) For and (3) For The compound represented by Formula (IG) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula (IG) is any one of the following compounds: Preferably, the compound of formula (IG) is any one of the following compounds: A process for the preparation of a compound of formula (IG) as claimed in claim 1, characterized in that, which comprises the step of condensing a compound represented by the formula (AG) with a compound represented by the formula (B) to obtain a compound represented by the formula (IG), wherein, T, Ring C, X, Y, R 3 , R 4 , R 5 , R 6 and n are as described in claim 1. A compound of Formula (AG) or a pharmaceutically acceptable salt thereof, wherein T, X, Y, R 3 and R 4 As in claim 1 ; Preferably, the compound of formula (AG) is selected from any one of the following compounds: A pharmaceutical composition comprising a compound of Formula (IG) as described in any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Use of a compound of Formula (IG), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, for the manufacture of a medicament for the inhibition of c-kit; Preferably, for the manufacture of a medicament for the prevention and / or treatment of a c-kit mediated disease; More preferably, for the manufacture of a medicament for the prevention and / or treatment of 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, such as for the prevention and / or treatment of a mastocytoma, mastocytosis, chronic urticaria, inflammatory bowel disease or diabetes. A pharmaceutical composition comprising a compound of Formula (IG) as described in any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Use of a compound of Formula (IG), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, for the manufacture of a medicament for the inhibition of c-kit; Preferably, for the manufacture of a medicament for the prevention and / or treatment of a c-kit mediated disease; More preferably, for the manufacture of a medicament for the prevention and / or treatment of 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, such as for the prevention and / or treatment of a mastocytoma, mastocytosis, chronic urticaria, inflammatory bowel disease or diabetes.

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