Heterocyclic compound, preparation method therefor and use thereof

Abstract

Provided are a heterocyclic compound, a preparation method therefor and a use thereof. Specifically provided is a heterocyclic compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which can be used for preparing drugs, in particular for preparing drugs for preventing and / or treating c-kit-mediated diseases or disorders. Groups in formula (I) are as defined in the description.

Description

Heterocyclic compounds, processes for their preparation and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024111280071, filed on August 16, 2024, Chinese Patent Application No. 2024112381864, filed on September 5, 2024, and Chinese Patent Application No. 2024115758684, filed on November 6, 2024. This application incorporates the entirety of the above-mentioned Chinese patent applications. TECHNICAL FIELD

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

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

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

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

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

[0007] wherein T is

[0008] is a single bond or a double bond;

[0009] Ring A is a 5-membered heteroaryl group;

[0010] X is C, and Y is N; or, X is N, and Y is C;

[0011] G 1 For CR 0 Or N;

[0012] G 3 For O or S;

[0013] R 0 Selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0014] R 1 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and selectively constituting one or more R groups. A Replaced;

[0015] R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2) p -C 3-8 Cycloalkyl groups and -(CH2) p -(3-8 membered heterocyclic group), the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2) p -C 3-8 Cycloalkyl groups and -(CH2) p -(3-8 membered heterocyclic groups) are each independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups;

[0016] or 2 R A with the atom to which it is attached to form a C 5-8 cycloalkyl, 5-8 membered heterocyclyl, or 5-8 membered heteroaryl, each independently optionally substituted with one or more of R 5-8 cycloalkyl, 5-8 membered heterocyclyl, or 5-8 membered heteroaryl, each independently optionally substituted with one or more of R 1-6 alkyl, C 1- 6alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, each independently optionally substituted with one or more of R

[0017] R 2 selected from H, halo, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0018] R 3 selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, each independently optionally substituted with one or more of R 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, each independently optionally substituted with one or more of R 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

[0019] R 4 and R 5 are the same or different, each independently selected from halo, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, each independently optionally substituted with one or more of R 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, each independently optionally substituted with one or more of R E ;

[0020] R 6 and R 7 together with the atom to which they are attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, optionally substituted with one or more of R E ;

[0021] R 9and R 10 together with the atom to which they are attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally substituted with one or more R E ;

[0022] R 11 and R 12 together with the atom to which they are attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally substituted with one or more R E ;

[0023] R E is selected from the group consisting of H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3-8 deutero-cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and the C 1-6 alkyl, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3-8 deutero-cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R k ;

[0024] each R k is the same or different, and each is independently selected from the group consisting of halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 hydroxyalkyl, -C(O)OR k1 , -NHC(O)R k1 , -NHS(O)2R k2 , -S(O)2R k2 , -C(O)NR k3 R k4 , -S(O)2NR k3 R k4 , -NR k3 R k4 , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

[0025] R k1 is H, C 1-6 alkyl or C 1-6 alkoxy;

[0026] R k2 is hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl;

[0027] R k3 and R k4 are the same or different, and each independently is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl;

[0028] R a , R b , R g and R h 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;

[0029] t is 0, 1, 2, 3 or 4;

[0030] m is 1 or 2;

[0031] n is 1 or 2;

[0032] p is 1 or 2;

[0033] the heteroatoms in said heteroaryl or heterocyclyl are O, S or N, the number of heteroatoms being 1, 2, 3 or 4.

[0034] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein two R A together with the atom to which they are attached form a 5-8 membered heterocyclyl or 5-8 membered heteroaryl, each independently optionally substituted with one or more selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0035] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein RE selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3- 8deuteroalkyl and 3-12 membered heterocyclyl, said C 1-6 alkyl, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3-8 deuteroalkyl and 3-12 membered heterocyclyl are each independently optionally substituted with one or more R k ;

[0036] each R k is the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

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

[0038] Ring A is 5-membered heteroaryl;

[0039] G 1 is CR 0 or N;

[0040] G 2 is O or S;

[0041] R 0 selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0042] R 3 selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8each independently optionally substituted with one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

[0043] R 4 and R 5 are the same or different, each independently selected from the group consisting of H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3- 8cycloalkyl, and 3-8 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, each independently optionally substituted with one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

[0044] R 6 and R 7 together with the atom to which they are attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, said 3-12 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

[0045] R 8 selected from the group consisting of H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;

[0046] R a , R b , R g and R h are the same or different, each independently selected from the group consisting of 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;

[0047] m is 1 or 2;

[0048] n is 1 or 2;

[0049] the heteroatom in the heteroaryl or heterocyclyl group is O, S or N, and the number of heteroatoms is 1, 2, 3 or 4.

[0050] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, satisfies one or more of the following conditions:

[0051] (1) the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl, for example methyl or ethyl;

[0052] (2) the halo is fluoro, chloro, bromo or iodo, for example fluoro or chloro;

[0053] (3) the C 3-8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl;

[0054] (4) the 3-12 membered heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, hexahydropyranyl, piperidinyl,

[0055] (5) the 5-10 membered heteroaryl or 5 membered heteroaryl is pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridazinyl, pyridyl, 1,2,4-triazinyl, pyrimidinyl or pyrazinyl.

[0056] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is

[0057] Ring A is oxazolyl, triazolyl or tetrazolyl;

[0058] G 2 is O or S;

[0059] R c , R d , R e and R f 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;

[0060] Or, R c and R d The carbon atom attached to it forms C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more of the haloalkoxy groups are substituted;

[0061] Or, R e and R f The carbon atom attached to it forms C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 One or more of the haloalkoxy groups are substituted;

[0062] R 3 R 4 R 5 R E R a R b R g and R h As defined in equation (I).

[0063] In some implementation schemes, R c R d R e and R f Independently selected from H or C 1-6 Alkyl groups, such as H or methyl.

[0064] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0065] Ring A is an oxazolyl, triazolyl, or tetrazolyl group;

[0066] G 2 For O or S;

[0067] R c R d R e and R fthe same or different, are 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;

[0068] or, R c and R d form, together with the carbon atom to which they are attached, a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl are each independently optionally substituted with one or more selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

[0069] or, R e and R f form, together with the carbon atom to which they are attached, a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl are each independently optionally substituted with one or more selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

[0070] R 3 , R 4 , R 5 , R E , R a , R b , R g and R h are as defined in formula (I).

[0071] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein T is

[0072] R B and R C are the same or different, each independently selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0073] R 8 selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

[0074] In some embodiments, R B and R C are independently selected from H or C 1-6 alkyl, for example H or methyl.

[0075] In some embodiments, R 8 is selected from C 3-8 cycloalkyl, for example cyclopropyl.

[0076] In some embodiments, a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is

[0077] R E is as defined for Formula (I).

[0078] In some embodiments, a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is

[0079] R E is as defined for Formula (I).

[0080] In some embodiments, a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is

[0081] Ring A is oxazolyl, triazolyl, or tetrazolyl;

[0082] R 3 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, each of which C 1-6 alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl is independently optionally substituted with one or more selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

[0083] R 4 and R 5Whether the groups are the same or different, they are each independently selected from halogens, cyano groups, and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0084] R a R b R g and R h Whether the elements are the same or different, they are each independently selected from H, halogens, and C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0085] R c R d R e and R f Whether the elements are the same or different, they are each independently selected from H, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0086] Or, R c and R d The carbon atom attached to it forms C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 One or more of the haloalkoxy groups are substituted;

[0087] Or, R e and R f The carbon atom attached to it forms C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 One or more of the haloalkoxy groups are substituted;

[0088] R E Selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8deuteroalkyl, C 1-6 alkyl, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3-8 deuteroalkyl, C k each independently optionally substituted with one or more R

[0089] each R k are the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0090] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is

[0091] R 8 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy.

[0092] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is

[0093] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (II),

[0094] wherein, ring A, X, Y, R 1 , R 2 , m, n and t are as defined in Formula (I).

[0095] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (III),

[0096] wherein, G 2 is O or S;

[0097] X, Y, R 1R 2 R E and t are defined as in Formula (I).

[0098] In some embodiments, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein is

[0099] In some embodiments, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein is R 2A and R 2B are the same or different, each being independently selected from H, halogen, cyano, and C 1-6 alkyl.

[0100] In some embodiments, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein ring A is oxazolyl, triazolyl, or tetrazolyl.

[0101] In some embodiments, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein is preferably, is

[0102] In some embodiments, a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein is

[0103] In some embodiments, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, and 5-10 membered heteroaryl, each of which is independently optionally substituted with 1 or more R 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, and 5-10 membered heteroaryl, each of which is independently optionally substituted with 1 or more R A ;

[0104] R A is selected from H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2)-C 3-8cycloalkyl, 3-8 membered heterocyclyl, -(CH2)-C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2)-C 3-8 cycloalkyl and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkoxy and C 1-6 hydroxyalkyl;

[0105] or, 2 R A together with the atom to which they are attached form a 5-8 membered heterocyclyl, said 5-8 membered heterocyclyl is optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0106] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is

[0107] R A1 , R A2 , R A3 , R A4 and R A5 are the same or different, each independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2)-C 3-8 cycloalkyl and -(CH2)-(3-8 membered heterocyclyl), said C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2)-C 3-8 cycloalkyl and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, C 1-6 alkoxy and C 1-6 hydroxyalkyl;

[0108] or, R A4 and R A5 together with the atom to which they are attached form C 5-8 cycloalkyl or 5-8 membered heterocyclyl, said C 5-8 cycloalkyl or 5-8 membered heterocyclyl is optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8It is substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups.

[0109] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 H, Cl, methyl

[0110] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, halogen, cyano and C 1-6 alkyl.

[0111] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, halogens and C 1-6 alkyl.

[0112] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen; preferably, R 2 It is chlorine or fluorine.

[0113] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R 2 C 1-6 Alkyl; preferably, R 2 It is a methyl group.

[0114] In some embodiments, the compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein t is 2.

[0115] In some embodiments, the compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein t is 1.

[0116] In some implementations, T is selected from

[0117] In some embodiments, ring A is selected from triazole and tetrazolium, for example, tetrazolium, and so on. The "1" position is connected to a phenyl group.

[0118] In some implementations, R a and R b Halogens, for example, F.

[0119] In some implementations, R 4 and R 5 Independent of halogen, C 1-6 Alkyl or C 3-8 Cycloalkyl groups, such as chlorinated or cyclopropyl groups.

[0120] In some implementations, R 0 For H.

[0121] In some implementations, R 6 and R 7 Together with the atoms attached thereto, they form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R E What it replaced.

[0122] In some implementations, R 9 and R 10 Together with the atoms attached thereto, a 5-6 membered heteroaryl group is formed, wherein the 5-6 membered heteroaryl group is optionally bonded to one or more R... E What it replaced.

[0123] In some implementations, R E Independent of halogen, C 1-6 Alkyl or C 3-8 cycloalkyl, such as C 1-6 Alkyl or C 3-8 Cycloalkyl, such as methyl or cyclopropyl.

[0124] In some implementations, R g and R h H stands for H independently.

[0125] In some implementations, R 1 The 5-10 nucleotide heteroaryl group is optionally coupled with one or more R groups. A Instead, preferably, R 1 The 5-6 membered heteroaryl group is optionally coupled with one or more R groups. A What it replaced.

[0126] In some implementations, R A C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from hydroxyl and C. 1-6 One or more of the alkyl groups are substituted, such as the C13 group described above. 1-6 Alkyl groups may be optionally replaced by hydroxyl groups.

[0127] In some implementations, R 1 for R A2 and RA5 independently H or C 1-6 alkyl, R A4 is C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more selected from the group consisting of hydroxy and C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with hydroxy.

[0128] In some embodiments, the compound of Formula (I) is:

[0129] T is selected from the group consisting of

[0130] Ring A is triazolyl or tetrazolyl,

[0131] m is 1 or 2;

[0132] n is 1 or 2;

[0133] R a and R b are independently halogen;

[0134] R 4 and R 5 are independently halogen, C 1-6 alkyl or C 3-8 cycloalkyl;

[0135] G 1 is CR 0 or N;

[0136] R 0 is H;

[0137] R 6 and R 7 together with the atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, said 5-6 membered heterocyclyl or 5-6 membered heteroaryl being optionally substituted with one or more R E ;

[0138] R 9 and R 10 together with the atom to which they are attached form a 5-6 membered heteroaryl, said 5-6 membered heteroaryl being optionally substituted with one or more R E ;

[0139] R E are independently halogen, C 1-6 alkyl or C 3-8 cycloalkyl;

[0140] R g and R h are independently H;

[0141] R 2 H, halogen or C 1-6 alkyl;

[0142] t can be 0, 1, 2, 3, or 4;

[0143] X is C and Y is N; or, X is N and Y is C;

[0144] R 1 The 5-6 membered heteroaryl group is optionally coupled with one or more R groups. A Replaced;

[0145] R A C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally selected from hydroxyl and C. 1-6 One or more of the alkyl groups are substituted.

[0146] In some embodiments, exemplary specific compounds of the compound shown in formula (I) include any of the compounds shown in Table A.

[0147] In some embodiments, exemplary specific compounds of the compound shown in formula (I) include any of the compounds shown in Table B.

[0148] Another aspect of this application provides isotope labels for compounds shown in formula (I), formula (II), or formula (III), or in Table A or Table B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0149] Another aspect of this application provides a method for preparing the compound shown in formula (I), wherein the compound shown in formula (A) undergoes a condensation reaction with the compound shown in formula (B) to obtain the compound shown in formula (I).

[0150] Among them, R B For H or C 1-6 alkyl;

[0151] T, X, Y, R 1 R 2 And t as defined in any of these claims.

[0152] In another aspect, this application provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0153] In another aspect, the present application provides the use of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting c-kit.

[0154] In another aspect, the present application provides the use of a compound of Formula (I), Formula (II), or Formula (III), 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.

[0155] In another aspect, the present application provides the use of a compound of Formula (I), Formula (II), or Formula (III), 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.

[0156] In another aspect, the present application provides a method of inhibiting c-kit, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the same.

[0157] In another aspect, the present application provides a method of preventing and / or treating a c-kit-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the same.

[0158] In another aspect, the present application provides a method of preventing and / or treating a mast cell-related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0159] The application also provides a method of preventing and / or treating mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0160] The application also provides a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament.

[0161] The application also provides a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a c-kit inhibitor.

[0162] The application also provides a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for preventing and / or treating a c-kit mediated disease or disorder.

[0163] The application also provides a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for preventing and / or treating a mast cell related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer.

[0164] The application also provides a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for preventing and / or treating a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0165] 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.

[0166] In some embodiments, the c-kit mediated disease is selected from a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0167] In some embodiments, the c-kit mediated disease is mast cell leukemia.

[0168] In some implementations, the mast cell-related disease is mast cell leukemia.

[0169] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0170] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotope-labeled form thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotope-labeled form thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotope-labeled form thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotope-labeled form thereof.

[0171] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable one or more excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable one or more excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable one or more excipients.

[0172] When administered as a medicine, the compounds of this application may be given in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be local (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powder or aerosol, including via nebulizer; intratracheal, intranasal, oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single large dose or via, for example, a continuous infusion pump.

[0173] In preparing the compositions of this application, the active ingredient is typically mixed with excipients, and the compositions may be in the following forms: tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in liquid solvents), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0174] The "excipient" described in the present application means a component other than the active ingredient, for example, including diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants, etc.

[0175] On the other hand, the pharmaceutically acceptable salt of the compound described in the present application can be an inorganic salt or an organic salt, and if the compound has a basic center, it can form an acid addition salt; if the compound has an acidic center, it can form a base addition salt; if the compound contains both an acidic center (for example, a carboxyl group) and a basic center (for example, an amino group), it can also form an internal salt.

[0176] On the other hand, the compound of the present application can exist in a specific geometric or stereoisomeric form. For example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, and enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0177] The "plural" described above indicating the number of substituents or the number of heteroatoms means 2, 3, 4, or 5.

[0178] In the chemical structure of the compound described in the present application, the bond indicates unspecified configuration, indicates absolute configuration, that is, if there is a chiral isomer in the chemical structure, the bond may be or simultaneously contain both configurations.

[0179] The bond indicates unspecified configuration, including cis (E) or trans (Z) configuration.

[0180] In addition, the compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included within the scope of the present application. "Tautomers" refer to different energy structural isomers that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversion 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 name of a compound named in a single manner does not exclude any tautomers.

[0181] The present application also includes isotopically-labeled compounds of the present application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such 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, and the like. All isotopic variations of compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0182] Unless otherwise stated, when a position is designated specifically as deuterium (D), the position is understood to have deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). Exemplary compounds having deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. One skilled in the art would be able to synthesize compounds in deuterated form by reference to the relevant literature. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques employing deuterated reagents, including but not limited to deuterated borane, trideuteroborane in tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide, and deuterated methyl iodide, and the like.

[0183] A "therapeutically effective amount" of the present application refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by person of skill in the art, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed to the disease, disorder and condition but has not yet experienced or displayed the pathology or symptomatology of the disease; (2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptomatology of the disease, disorder or condition (i.e., retarding the further development of the pathology and / or symptomatology); (3) relieving the disease: for example, relieving a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptomatology of the disease, disorder or condition (i.e., reversing the pathology and / or symptomatology). For a pharmaceutical or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the agent to provide the desired effect, without being toxic to the subject. The effective amount will vary depending on the subject's age, general condition and the particular active agent, and appropriate effective amounts can be determined by one of skill in the art using routine trials.

[0184] "Pharmaceutically acceptable" means, within the scope of sound medical judgment, that these compounds, materials, compositions, and / or dosage forms are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0185] "Patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, goats, horses, or primates, most preferably humans.

[0186] Definitions and explanations

[0187] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0188] In the present application means that the respective group is attached to the other fragment, group in the compound.

[0189] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched-chain groups, preferably containing from 1 to 20 carbon atoms, more preferably alkyl groups containing from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and even more preferably alkyl groups containing from 1 to 6 carbon atoms (C1-C6alkyl). Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, hexyl, 2-hexyl, 3-hexyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2-methyl-4-pentyl, 3-methyl-4-pentyl, 2, 3-dimethyl-3-pentyl, 2, 3-dimethyl-4-pentyl, 2, 4-dimethyl-3-pentyl, 2, 4-dimethyl-4-pentyl, 3, 3-dimethyl-3-pentyl, 3, 3-dimethyl-4-pentyl, 2-ethyl-3-pentyl, 2-ethyl-4-pentyl, 3-ethyl-3-pentyl, 3-ethyl-4-pentyl, 2-ethyl-2-hexyl, 3-ethyl-2-hexyl, 3-ethyl-3-hexyl, 4-ethyl-2-hexyl, 4-ethyl-3-hexyl, 4-ethyl-4-hexyl, 2-propyl-3-pentyl, 2-butyl-3-pentyl, 2-pentyl-4-hexyl, 3-hexyl-3-hexyl, 3-heptyl, 3-octyl, and the like. 1-6alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-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.

[0190] The term "alkenyl" is to be understood as preferably denoting a straight-chained or branched hydrocarbon group, which contains one or more double bonds and has 2 to 20 carbon atoms, preferably "C 2-10 alkenyl". "C 2-10 The term "alkenyl" is to be understood as preferably denoting a straight-chained or branched monovalent hydrocarbon group, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-6 alkenyl). The term "alkynyl" is to be understood as preferably denoting a straight-chained or branched monovalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-3(E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-l-methylbut-2-enyl, (Z)-l-methylbut-2-enyl, (E)-3-methylbut-l-enyl, (Z)-3-methylbut-l-enyl, (E)-2-methylbut-l-enyl, (Z)-2-methylbut-l-enyl, (E)-l-methylbut-l-enyl, (Z)-l-methylbut-l-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-l-enyl, 1-propylvinyl, 1-isopropylvinyl. The alkenyl group can be substituted or unsubstituted.

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

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

[0193] The term "spirocycloalkyl" refers to a 5- to 20-membered, polycyclic group in which each single ring 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 according to the number of spiro atoms shared between rings, preferably mono- and bi- spirocycloalkyl groups. 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 monospriocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0194] 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, wherein 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 polycyclic according to the number of constituent rings, preferably bi- or tri-cyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0195] 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 polycyclic according to the number of constituent rings, preferably bi-, tri-, or tetra-cyclic, more preferably bi- or tri-cyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0196] The cycloalkyl ring includes cycloalkyl groups as described herein (including monocyclic, spirocyclic, fused, and bridged cycloalkyl groups) fused to aryl groups, where the rings that are connected together with the parent structure can be cycloalkyl rings or aryl rings, non-limiting examples include etc.; preferably The cycloalkyl group can be substituted or unsubstituted.

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

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

[0199] The term "fused heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 20 members, each ring in the system sharing a pair of adjacent atoms with another ring in the system, one or more rings can contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), 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). It can be bicyclic, tricyclic, tetracyclic, or polycyclic, 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. Non-limiting examples of fused heterocyclyl groups include:

[0200] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 14 members, any two rings sharing 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). It can be bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0201] The heterocyclyl ring includes heterocyclyl groups 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 can be a heterocyclyl, or an aryl, heteroaryl, or cycloalkyl ring, non-limiting examples of which include:

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

[0203] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares a pair of adjacent carbon atoms with another ring) radical that has a conjugated pi-electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl group can be substituted or unsubstituted.

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

[0205] and the like. Heteroaryl can be substituted or unsubstituted.

[0206] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" and the like herein can be substituted or unsubstituted; when substituted, they can be substituted at any available attachment point with one or more, the same or different, substituents independently optionally selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0207] The above cycloalkyl, heterocyclyl, aryl and heteroaryl include residues derived from removal of one hydrogen atom from a parent ring atom, or two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heterocyclene", "heteroarylene".

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

[0209] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0210] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.

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

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

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

[0214] The term "hydroxy" refers to -OH.

[0215] The term "amino" refers to -NH2.

[0216] The term "cyano" refers to -CN.

[0217] The term "nitro" refers to -NO2.

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

[0219] The term "carbonyl" refers to C=O.

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

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

[0222] "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, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl.

[0223] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the 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, as to whether a substitution is possible or not. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0224] The above-mentioned preferred conditions can be combined in any way, without departing from the general knowledge of a person skilled in the art, to obtain preferred embodiments of the present application.

[0225] The reagents and starting materials used in the present application are commercially available. Advantageous effects:

[0226] The present application provides a small molecule compound with a heterocyclic structure, which can be used as a c-kit inhibitor. The compound or pharmaceutical composition has a strong inhibitory effect on the c-kit receptor and excellent pharmacokinetic effects, and can be used for the effective treatment or prevention of c-kit-mediated diseases. DETAILED DESCRIPTION

[0227] 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 illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application. The experimental methods not specified in the following examples are selected according to the conventional methods and conditions, or according to the product instructions.

[0228] The experimental methods not specified in the following examples are selected according to the conventional methods and conditions, or according to the product instructions.

[0229] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a Bruker Avance III 400MHz nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0230] The mass spectrometry (MS) is measured by a Waters 2767HPLC / Waters SQD, Waters H-class UPLC-SQD2, Agilent HPLC / Waters liquid chromatography-mass spectrometry.

[0231] The chiral HPLC analysis measurement uses a Shimadzu LC-20AD.

[0232] The thin layer chromatography silica gel plate uses a GF254 silica gel plate from Shanghai Chemical Reagent Co., Ltd. The silica gel plate used in the thin layer chromatography (TLC) has a specification of 0.2-0.25mm, and the thin layer chromatography separation and purification product has a specification of 0.4-0.5mm.

[0233] The column chromatography generally uses 100-200 mesh silica gel from Shanghai Chemical Reagent Co., Ltd. as the carrier.

[0234] The high-performance liquid chromatography preparation uses a Waters HPLC, a Gilson HPLC and a Biotage MPLC preparative chromatograph.

[0235] The chiral separation column chromatography uses a Gilson GX-281 preparative HPLC.

[0236] Unless otherwise specified, the reactions in the examples are carried out under a nitrogen atmosphere.

[0237] The nitrogen atmosphere refers to that the reaction bottle is connected with a nitrogen balloon with a volume of about 1 liter.

[0238] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.

[0239] Unless otherwise specified, the reaction temperature in the examples is room temperature, and the temperature range is 20-30°C.

[0240] Those skilled in the art will understand that chiral compounds can be distinguished by the order of retention time in a chiral chromatographic column, therefore, chiral compounds separated by the order of 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 a compound is listed in the structural formula, it does not mean that it corresponds one-to-one to the compound with the number suffix P1, P2, but only indicates the two existing forms of absolute configuration. The absolute configuration of the compound with the number suffix P1, P2 is objectively corresponding to the absolute configuration of a specific retention time.

[0241] Reagent English abbreviation corresponding to reagent name:

[0242] Intermediate compound A1

[0243] Step 1: Synthesis of compound A1-2

[0244] At room temperature, lithium hydroxide monohydrate (0.42 g, 17.52 mmol) was added to a mixture solution of compound A1-1 (2.0 g, 6.09 mmol, synthesis method reference to patent WO2024118887A1 specification P169 page synthesis of intermediate 70) in ethanol and water (15 mL / 15 mL), and the reaction mixture was stirred at 80°C for 6 hours. After the reaction was completed, the reaction liquid was diluted with water (30 mL), extracted with ethyl acetate (50 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 (dichloromethane / methanol = 0-20%) to obtain compound A1-2 (1.6 g). MS m / z (ESI): 315.1 [M+1] + .

[0245] Step 2: Synthesis of compound A1

[0246] DIEA (492 mg, 3.81 mmol), HATU (724 mg, 1.91 mmol) were added to a solution of compound A1-2 (400 mg, 1.27 mmol) in DMF (20 mL) at room temperature. The reaction mixture was stirred at 25 °C for 1 h. Then ammonium chloride (135 mg, 2.54 mmol) was added and the reaction mixture was stirred at 25 °C for another 5 h. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0-20%) to give compound A1 (300 mg). MS m / z (ESI): 314.1 [M+1] + .

[0247] Intermediate compound A2

[0248] Compound A2-1 (1.0 g, 4.46 mmol) was dissolved in 1,4-dioxane (20 mL). Bis(pinacolato)diboron (1.36 g, 5.35 mmol), potassium acetate (1.31 g, 13.38 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.33 g, 0.45 mmol) were added successively. The reaction mixture was heated to 90 °C under nitrogen protection and stirred 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 (ethyl acetate / petroleum ether = 5%-20%) to give compound A2 (970 mg). MS m / z (ESI): 272.1 [M+1] + .

[0249] Example 1 (compound 42)

[0250] First step: synthesis of compound 42b

[0251] Triflic anhydride (4.85 g, 16.4 mmol) was added to a solution of compound 42a (3.67 g, 16.4 mmol) in dichloromethane (60 mL) under ice bath. Triethylamine (1.65 g, 16.4 mmol) was added slowly. The reaction mixture was stirred at ice bath for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give compound 42b (4.0 g, crude), which was used directly in the next step.

[0252] Second step: synthesis of compound 42c

[0253] Compound 42b (4.0 g, 16.4 mmol) was dissolved in azidotrimethylsilane (40 mL) under nitrogen protection, and the reaction mixture was stirred at 95 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, the residue was diluted with ethyl acetate (30 mL), saturated sodium bicarbonate solution (40 mL) was added, the collected aqueous phase was adjusted to pH = 3 with dilute hydrochloric acid (2N), and then extracted with ethyl acetate (40 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 42c (1.62 g). 1 H NMR (400 MHz, DMSO-d6) δ 14.87 (s, 1H), 8.21 (d, J = 7.4 Hz, 1H), 8.07 (d, J = 10.0 Hz, 1H).

[0254] Third step: synthesis of compound 42d

[0255] Compound 42c (100 mg, 0.34 mmol) was dissolved in anhydrous DMF (5 mL), and iodoethane (106.1 mg, 0.68 mmol) and cesium carbonate (166.2 mg, 0.51 mmol) were added successively, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5% to 15%) to obtain compound 42d (100 mg, MS m / z (ESI): 320.9 [M+1] + .

[0256] Fourth step: synthesis of compound 42

[0257] Compound 42d (30 mg, 0.093 mmol) was dissolved in 1,4-dioxane (3 mL), and compound A1 (29.1 mg, 0.093 mmol), cesium carbonate (60.6 mg, 0.19 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.8 mg, 0.019 mmol), and tris(dibenzylideneacetone)dipalladium (8.5 mg, 0.0093 mmol) were added successively. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by thin layer silica gel plate chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 42 (14.0 mg). MS m / z (ESI): 554.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.82 (d, J = 8.0 Hz, 1H), 8.76 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 9.9 Hz, 1H), 7.29 (dd, J = 7.3, 2.0 Hz, 1H), 4.74 (s, 1H), 4.05 - 4.00 (m, 2H), 3.98 (s, 2H), 2.41 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H), 1.10 (s, 6H).

[0258] Example 2 (Compound 72)

[0259] First Step: Synthesis of compound 72b

[0260] Hydrazine hydrate (11.0 g, 186.90 mmol) was added to a solution of compound 72a (5.0 g, 18.69 mmol) in EtOH (100 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 6 h. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-20%) to give compound 72b (3.7 g). MS m / z (ESI): 266.8 [M+1] + .

[0261] Second Step: Synthesis of compound 72c

[0262] Trimethylsilyl isothiocyanate (1.4 g, 10.84 mmol) was added to a solution of compound 72b (2.9 g, 10.84 mmol) in a mixture of ethanol and water (20 mL / 20 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 3 h. After the addition of sodium hydroxide (0.8 g, 21.68 mmol), the reaction mixture was stirred at 80 °C for another 6 h. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-20%) to give compound 72c (1.7 g). MS m / z (ESI): 307.1 [M+1] + .

[0263] Third Step: Synthesis of compound 72d

[0264] Bromoacetone (532.17 mg, 3.88 mmol), potassium carbonate (1.1 g, 7.77 mmol) were added to a solution of compound 72c (800 mg, 2.59 mmol) in DMF (20 mL) at room temperature. The reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction was diluted with water (30 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 72d (560 mg). MS m / z (ESI): 363.8 [M+1] + .

[0265] Fourth step: synthesis of compound 72e

[0266] Compound 72d (510 mg, 1.40 mmol) was added to concentrated sulfuric acid (10 mL) at room temperature. The reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-25%) to give compound 72e (500 mg). MS m / z (ESI): 345.8 [M+1] + .

[0267] Fifth step: synthesis of compound 72

[0268] Compound A1 (134.74 mg, 0.43 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (49.76 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (39.38 mg, 0.04 mmol), cesium carbonate (420.31 mg, 1.29 mmol) were added to a solution of compound 72e (150 mg, 0.43 mmol) in 1,4-dioxane (5 mL) at room temperature under nitrogen. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction was diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-25%) to give compound 72 (40.5 mg). MS m / z (ESI): 579.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.83-8.76 (m, 2H), 8.34 (d, J = 7.4 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J = 10.3 Hz, 1H), 7.29-7.25 (m, 2H), 4.74 (s, 1H), 3.99 (s, 2H), 2.54 (d, J = 1.2 Hz, 3H), 2.41 (s, 3H), 1.10 (s, 6H).

[0269] Example 3 (Compound 73)

[0270] First Step: Synthesis of compound 73b

[0271] Compound 73b (2.2 g) was obtained by the method described in example 1, first step. MS m / z (ESI): 295.9 [M+1] + .

[0272] Second Step: Synthesis of compound 73c

[0273] Compound 73c (1.1 g) was obtained by the method described in example 1, second step. MS m / z (ESI): 376.9 [M+1] + .

[0274] Third Step: Synthesis of compound 73d

[0275] Sodium methoxide (0.19 g, 1.06 mmol) was added to a mixture of compound 73c (400 mg, 1.06 mmol) in dichloromethane and methanol (4.5 mL / 0.5 mL) at room temperature. The reaction mixture was stirred at 25 °C for 1 h. After completion of the reaction, the reaction solution was diluted with water (30 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 1:0 ~ 5:1) to give compound 73d (70 mg). MS m / z (ESI): 329.0 [M+1] + .

[0276] Fourth step: synthesis of compound 73e

[0277] Zinc powder (47.10 mg, 0.72 mmol) and ammonium chloride (38.51 mg, 0.72 mmol) were added to a mixture of compound 73d (60 mg, 0.18 mmol) in ethanol and water (2 mL / 0.5 mL) at room temperature. The reaction mixture was stirred at 85 °C for 4 h. After completion of the reaction, the reaction solution was filtered, the filter cake was washed with dichloromethane, the filtrate was washed with saturated sodium chloride solution (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 73e (50 mg). MS m / z (ESI): 299.0 [M+1] + .

[0278] Fifth step: synthesis of compound 73g

[0279] Trimethylaluminum (0.016 g, 0.22 mmol) was added to a mixture of compound 73e (30 mg, 0.10 mmol) and compound 73f (30 mg, 0.11 mmol, purchased from Bide Pharmatech) in toluene (2 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 4 h. After completion of the reaction, sodium sulfate decahydrate was added to quench the reaction, and the residue was purified by column chromatography on silica gel (DCM:MeOH = 1:0 ~ 10:1) to give compound 73g (15 mg).

[0280] Sixth step: synthesis of compound 73

[0281] To a mixture of compound 73g (15 mg, 0.029 mmol), compound 73h (12 mg, 0.044 mmol, for the synthesis method, refer to CN105777756A specification page 305 paragraph 2536-2543, step 1 and step 2 of example 99), cesium carbonate (19 mg, 0.058 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, dichloromethane complex (2.4 mg, 0.0029 mmol) were added sequentially 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 2 h under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 1:0 ~ 15:1) to obtain compound 73 (1.9 mg). MS m / z (ESI): 595.1 [M+1] + .

[0282] Example 4 (compound 46)

[0283] First step: synthesis of compound 46b

[0284] Compound 42a (800 mg, 3.56 mmol) was added to hydrochloric acid (6 M, 20 mL), and sodium nitrite (271 mg, 3.92 mmol) was added slowly at -10 to 0 °C. After the mixture was stirred at this temperature for 1 h, stannous chloride (1.01 g, 5.35 mmol) was added and stirred at -10 to 0 °C for 0.5 h, and then continued to stir at room temperature for 2 h. Then water (30 mL) and compound 46a (300 mg, 2.67 mmol) were added, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-5%) to obtain compound 46b (600 mg). MS m / z (ESI): 335.2 [M+1] + .

[0285] Second step: synthesis of compound 46c

[0286] Compound 46b (500 mg, 1.50 mmol) was dissolved in toluene (10 mL), DPPA (494 mg, 1.80 mmol) and triethylamine (152 mg, 1.50 mmol) were added, the reaction mixture was stirred at 110 °C under nitrogen protection for 2 hours, after the reaction was completed, the reaction liquid was quenched with saturated aqueous sodium chloride solution (30 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain compound 46c (550 mg, crude). The crude product was further purified by combi-Flash rapid preparation instrument (C18 reverse phase column, mobile phase: acetonitrile-water (10 mmol NH4HCO3); gradient: 25-40%) to obtain compound 46c (400 mg). MS m / z (ESI): 332.2 [M+1] + .

[0287] Step 3: Synthesis of compound 46d

[0288] Compound 46c (200 mg, 0.60 mmol) was dissolved in phosphorus oxychloride (2 mL), the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the excess phosphorus oxychloride was removed by concentrating the reaction liquid under reduced pressure, quenched with saturated aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (EA / PE = 0-20%) to obtain compound 46d (200 mg). MS m / z (ESI): 352.1 [M+1] + .

[0289] Step 4: Synthesis of compound 46e

[0290] Compound 46d (200 mg, 0.57 mmol) was dissolved in 1,4-dioxane (5 mL), Pd2(dba)3 (52 mg, 0.06 mmol), xantphos (66 mg, 0.11 mmol), Cs2CO3 (557 mg, 1.71 mmol) and tert-butyl carbamate (134 mg, 1.14 mmol) were added in turn, the reaction mixture was stirred at 100 °C under nitrogen protection for 3 hours. After the reaction was completed, the reaction liquid was quenched with water (50 mL), extracted with dichloromethane (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (EA / PE = 0-15%) to obtain compound 46e (220 mg). MS m / z (ESI): 387.3 [M+1] + .

[0291] Step 5: Synthesis of compound 46f

[0292] Compound 46e (200 mg, 0.52 mmol) was dissolved in hydrogen chloride solution in 1,4-dioxane (3 mL, 4 M). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was quenched by adding saturated aqueous sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE = 0-20%) to obtain compound 46f (110 mg). MS m / z (ESI): 287.3 [M+1] + .

[0293] Step 6: Synthesis of compound 46

[0294] Under nitrogen protection, n-hexane solution of trimethylaluminum (0.06 mL, 1 M) was added to a solution of compound 46f (10 mg, 0.03 mmol) and compound A1-1 (12 mg, 0.03 mmol) in toluene (2 mL), and the reaction mixture was stirred at 100°C for 1 hour. After the reaction was completed, the reaction solution was quenched by adding saturated sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain compound 46 (20 mg, crude). The crude product was purified by high performance liquid preparative chromatography (column: Durashell C18(A) 21.2 x 250 mm, 10 nm; mobile phase: acetonitrile-water (10 mM NH4HCO3); gradient: 45-77%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 46 (6.89 mg). MS m / z (ESI): 583.4 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.85-8.79 (m, 1H), 8.75 (s, 1H), 8.24 (d, J = 1.4 Hz, 1H), 8.17 (s, 1H), 8.02 (dd, J = 9.8, 8.8 Hz, 2H), 7.29 (dd, J = 7.4, 2.1 Hz, 1H), 4.75 (s, 1H), 3.98 (s, 2H), 2.41 (s, 3H), 2.12-2.01 (m, 1H), 1.10 (s, 6H), 1.05-0.97 (m, 2H), 0.91-0.85 (m, 2H).

[0295] Example 5 (Compound 74)

[0296] First Step: Synthesis of compound 74b

[0297] Compound 74a (2.78 g, 9.89 mmol, synthesis method refer to the synthesis of intermediate 60 in the specification of patent WO2011086098A1, page 80) was dissolved in DMF (120 mL), and triethylamine (8.01 g, 79.12 mmol), SPhos Pd G2 (712.7 mg, 0.99 mmol) and SPhos (812 mg, 1.98 mmol) were added successively. The reaction mixture was heated to 100°C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Then diluted with water (30 mL), extracted with ethyl acetate (40 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5%~20%) to obtain compound 74b (1.2 g). MS m / z (ESI): 200.0, 202.0 [M+1, M+3] + .

[0298] Second Step: Synthesis of compound 74c

[0299] Compound 74b (100 mg, 0.5 mmol) was dissolved in 1,4-dioxane and water (8 mL / 2 mL), and compound A2 (136 mg, 0.5 mmol), potassium carbonate (207 mg, 1.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (41 mg, 0.05 mmol) were added successively. The reaction mixture was heated to 80°C under nitrogen protection and stirred for 3 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 = 5%~50%) to obtain compound 74c (70 mg). MS m / z (ESI): 265.1 [M+1] + .

[0300] Third Step: Synthesis of compound 74

[0301] Compound 74c (23 mg, 0.087 mmol) and compound A1-1 (20 mg, 0.058 mmol) were dissolved in anhydrous toluene (2 mL) at 0 °C, and a solution of trimethylaluminum in n-hexane (0.06 mL, 2 M) was added dropwise slowly under nitrogen protection. The reaction mixture was heated to 100 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (15 mL x 2). 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 thin layer chromatography on silica gel plate (dichloromethane / methanol = 12 / 1) to obtain compound 74 (21.6 mg). MS m / z (ESI): 561.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.82 (d, J = 7.2 Hz, 1H), 8.76 (s, 1H), 8.28 (d, J = 7.5 Hz, 2H), 8.17 (s, 1H), 7.72 (d, J = 10.3 Hz, 1H), 7.28 (dd, J = 7.3, 2.0 Hz, 1H), 5.78 (s, 1H), 5.39 (s, 1H), 4.74 (s, 1H), 4.40 - 4.15 (m, 2H), 3.98 (s, 2H), 3.41 - 3.36 (m, 2H), 2.41 (s, 3H), 1.10 (s, 6H).

[0302] Example 6 (compound 75)

[0303] First step: synthesis of compound 75a

[0304] Platinum dioxide (20 mg) was added to a solution of compound 74c (20 mg, 0.076 mmol) in anhydrous ethanol (3 mL), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 75a (20 mg).

[0305] Second step: synthesis of compound 75

[0306] A solution of trimethylaluminum in n-hexane (0.044 mL, 2 M) was slowly added dropwise to compound 75a (20 mg, 0.075 mmol) and compound A1-1 (15 mg, 0.044 mmol) in anhydrous toluene (2 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 with water (10 mL), and extracted with ethyl acetate (15 mL x 2). 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 thin-layer chromatography on silica gel (dichloromethane / methanol = 12 / 1) to give compound 75 (11.6 mg). MS m / z (ESI): 563.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.81 (d, J = 7.2 Hz, 1H), 8.75 (s, 1H), 8.25 (dd, J = 9.7, 4.4 Hz, 2H), 8.17 (s, 1H), 7.68 (d, J = 10.3 Hz, 1H), 7.28 (dd, J = 7.3, 2.0 Hz, 1H), 4.74 (s, 1H), 4.30 - 4.20 (m, 1H), 4.18 - 4.07 (m, 1H), 3.98 (s, 2H), 2.93 - 2.85 (m, 1H), 2.41 (s, 3H), 2.33 - 2.18 (m, 1H), 2.06 - 1.88 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.10 (s, 6H).

[0307] Example 7 (compound 76)

[0308] First step: synthesis of compound 76b

[0309] Compound 73b (2.93 g, 9.94 mmol) was dissolved in ethanol (50 mL), and 76a (1.40 g, 9.94 mmol) was added. The reaction mixture was heated to reflux at 80 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE / EA = 0-10%) to give compound 76b (600 mg). MS m / z (ESI): 339.2 [M+H] + .

[0310] Second step: synthesis of compound 76c

[0311] Compound 76b (600 mg, 1.78 mmol) was dissolved in a mixture of tetrahydrofuran and water (50 mL / 5 mL), iron powder (991 mg, 17.75 mmol) and ammonium chloride (4.75 g, 88.76 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 80 °C under nitrogen protection for 8 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with methanol three times. The combined filtrate was concentrated under reduced pressure, the residue was diluted with water (200 mL), extracted with ethyl acetate (50 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 (PE / EA = 0-50%) to obtain compound 76c (260 mg). MS m / z (ESI): 309.2 [M+H] + .

[0312] Step 3: Synthesis of compound 76

[0313] Compound 76c (5 mg, 0.01 mmol) and compound A1-1 were dissolved in toluene (2 mL), and a solution of trimethylaluminum in n-hexane (0.05 mL, 1 M) was added to the reaction mixture under nitrogen protection. The reaction mixture was heated at 90 °C for 3 hours. After the reaction was completed, the reaction solution was quenched with methanol, and the methanol and toluene were removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain the crude product compound 76 (10 mg). The crude product was further purified by high performance liquid preparative chromatography (column: Durashell C18(A); 21.2 x 250 mm, 10 um; 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) to obtain compound 76 (3.14 mg). MS m / z (ESI): 605.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.81 (d, J = 7.4 Hz, 1H), 8.76 (s, 1H), 8.41 (d, J = 3.8 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 1.4 Hz, 1H), 8.17 (s, 1H), 7.66 (d, J = 10.6 Hz, 1H), 7.28 (dd, J = 7.4, 2.0 Hz, 1H), 4.74 (s, 1H), 3.98 (s, 2H), 2.58 - 2.53 (m, 1H), 2.41 (s, 3H), 1.26 (dd, J = 8.2, 2.8 Hz, 2H), 1.12 (dd, J = 4.8, 2.6 Hz, 2H), 1.10 (s, 6H).

[0314] Example 8 (Compound 77)

[0315] First Step: Synthesis of compound 77b

[0316] A solution of t-BuOK (1.27 g, 11.35 mmol) in DMF (10 mL) was slowly added to a solution of compound 77a (2 g, 11.35 mmol) and difluoromethyl(2-pyridyl)sulfone (1.75 g, 9.08 mmol) in DMF (30 mL) at -50 °C. After the reaction mixture was stirred at -45 °C for 1 h, saturated aqueous ammonium chloride (6 mL) and 3 M hydrochloric acid (6 mL) were added to the reaction. After the reaction was completed, the reaction was poured into water (100 mL) and extracted with ethyl acetate (70 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 = 0-10%) to give compound 77b (580 mg). 1 H NMR (400 MHz, CDCl3) δ 7.38-7.28 (m, 5H), 4.44 (s, 2H), 4.22-4.10 (m, 1H), 2.96-2.86 (m, 2H), 2.74-2.62 (m, 2H).

[0317] Second Step: Synthesis of compound 77c

[0318] A solution of boron tribromide in dichloromethane (5.52 mL, 5.52 mmol, 1 M) was slowly added to a solution of compound 77b (580 mg, 2.76 mmol) in DCM (6 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 2 h. After the reaction was completed, the reaction was poured into saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered to give a dichloromethane solution of compound 77c (30 mL, 332 mg of theoretical product) which was directly used in the next step.

[0319] Third Step: Synthesis of compound 77d

[0320] To a solution of compound 77c (60 mg, 0.22 mmol) in dichloromethane (30 mL, theoretical content 332 mg, 2.76 mmol) was added sodium hydride (166 mg, 4.15 mmol, 60%) at 0 °C, after stirring for 30 min, TsCl (527 mg, 2.76 mmol) was added, the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction liquid was poured into water (50 mL), extracted with ethyl acetate (40 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 77d (290 mg). MS m / z (ESI): 275.2 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ 7.84-7.76 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.94-4.82 (m, 1H), 3.02-2.90 (m, 2H), 2.88-2.76 (m, 2H), 2.46 (s, 3H).

[0321] Fourth step: synthesis of compound 77f

[0322] Compound 77e (69 mg, 0.22 mmol, synthesized according to the first and second steps of the synthesis of intermediate 73 in the specification of patent WO2024118887A1, page 170) and potassium carbonate (60 mg, 0.44 mmol) were added to a solution of compound 77d (60 mg, 0.22 mmol) in DMF (5 mL), the reaction mixture was stirred at 100 °C for 5 h. After the reaction was completed, the reaction liquid was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 77f (29 mg). MS m / z (ESI): 416.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.76 (d, J = 10.2 Hz, 1H), 5.82-5.70 (m, 1H), 3.54-3.38 (m, 4H), 1.48 (s, 9H).

[0323] Fifth step: synthesis of compound 77g

[0324] Compound 77f (29 mg, 0.07 mmol) was dissolved in hydrogen chloride solution in 1,4-dioxane (4 mL, 4 M), 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, the residue was added to saturated aqueous sodium bicarbonate solution (20 mL) to adjust the pH to 9-10, extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 77g (20 mg, crude). MS m / z (ESI): 316.3 [M+1] + .

[0325] Sixth step: synthesis of compound 77

[0326] Under a nitrogen atmosphere, n-hexane solution of trimethylaluminum (0.24 mL, 0.24 mmol, 1 M) was added to a solution of compound 77g (15 mg, 0.05 mmol) and compound A1-1 (16 mg, 0.05 mmol) in anhydrous toluene (2 mL), and the reaction mixture was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was quenched with methanol (2 mL) and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 77 (9.16 mg). MS m / z (ESI): 612.6 [M+1] + . 1 H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.82 (d, J = 7.2 Hz, 1H), 8.78 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.86 (d, J = 10.2 Hz, 1H), 7.28 (dd, J = 7.4, 1.8 Hz, 1H), 5.84 - 5.72 (m, 1H), 4.74 (s, 1H), 3.98 (s, 2H), 3.54 - 3.40 (m, 4H), 2.42 (s, 3H), 1.10 (s, 6H).

[0327] Example 9 (compound 86)

[0328] First step: synthesis of compound 86b

[0329] NaH (0.34 g, 8.42 mmol) was added to a solution of compound 86a (1.5 g, 7.65 mmol) in DMSO (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. Then, compound 72a (1.19 g, 8.42 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was diluted with ethyl acetate (100 mL), washed with water (40 mL x 3) and saturated sodium chloride solution (40 mL) successively, and the combined organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100:1 ~ 40:1) to obtain compound 86b (1.07 g). MS m / z (ESI): 336.90 [M+1] + .

[0330] Second Step: Synthesis of compound 86c

[0331] I2 (0.90 g, 3.53 mmol), KI (0.73 g, 4.41 mmol) and K2CO3 (1.22 g, 8.82 mmol) were sequentially added to a solution of compound 86b (0.99 g, 2.94 mmol) in DMSO (10 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 6 h. After completion of the reaction, the reaction solution was quenched with saturated Na2S2O3 solution (30 mL), and the aqueous solution was extracted with ethyl acetate (100 mL), washed with water (40 mL x 3) and saturated sodium chloride solution (40 mL) successively, and the combined organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10:1 ~ 4:1) to obtain compound 86c (84 mg). MS m / z (ESI): 335.0 [M+1] + .

[0332] Third Step: Synthesis of compound 86d

[0333] Benzophenone imine (54.37 mg, 0.30 mmol), XantPhos (28.93 mg, 0.050 mmol), Pd2(dba)3 (22.89 mg, 0.025 mmol) and Cs2CO3 (162.91 mg, 0.50 mmol) were sequentially added to a solution of compound 86c (84 mg, 0.25 mmol) in 1,4-Dioxane (1 mL) at room temperature, and the reaction solution was stirred at 100 °C for 2 h. After completion of the reaction, the reaction solution was extracted with ethyl acetate (30 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, and the combined organic phase was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 86d (61 mg). MS m / z (ESI): 436.1 [M+1]+ .

[0334] Fourth Step: Synthesis of compound 86e

[0335] A 4N solution of hydrogen chloride in 1,4-dioxane (0.3 mL, 1.4 mmol) was added to a solution of compound 86d (61 mg, 0.14 mmol) in 1,4-dioxane (3 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was added to a saturated sodium carbonate solution to adjust pH to about 9, extracted with ethyl acetate (30 mL x 3), washed with water (10 mL x 3) and saturated sodium chloride solution (10 mL) successively, and the combined organic phase was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 86e (34 mg). MS m / z (ESI): 272.0 [M+1] + .

[0336] Fifth Step: Synthesis of compound 86

[0337] Trimethylaluminum (2M in n-hexane, 0.058 mL, 0.12 mmol) was added to a solution of compound A1-1 (20 mg, 0.058 mmol) and compound 86e (17.31 mg, 0.064 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 solution was quenched with a saturated ammonium chloride solution (2 mL), extracted with ethyl acetate (30 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL) successively, and the organic phase was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 15 / 1) to obtain compound 86 (16.71 mg). MS m / z (ESI): 568.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.81 (d, J = 7.4 Hz, 1H), 8.75 (s, 1H), 8.29 (d, J = 1.3 Hz, 1H), 8.16 (s, 2H), 7.84 (dd, J = 7.9, 1.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.26 (dd, J = 7.3, 2.0 Hz, 1H), 4.76 - 4.71 (m, 1H), 3.99 (s, 2H), 2.61 - 2.58 (m, 1H), 2.41 (s, 3H), 2.35 (s, 3H), 1.31 - 1.29 (m, 2H), 1.18 - 1.16 (m, 2H), 1.10 (s, 6H).

[0338] Example 10 (Compound 97)

[0339] First Step: Synthesis of compound 97a

[0340] Compound 97a (30 mg) was obtained by adding l-cyclopropyl-2-bromoethanone (31.30 mg, 0.19 mmol) into a solution of compound 72c (50 mg, 0.16 mmol) in ethanol (5 mL) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel plate with thin layer chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 97a (30 mg). MS m / z (ESI): 371.9 [M+1] + .

[0341] Second Step: Synthesis of compound 97

[0342] Compound 97 (5 mg) was obtained by adding compound Al (20 mg, 0.064 mmol), XantPhos (7.41 mg, 0.013 mmol), Pd2(dba)3(5.86 mg, 0.0064 mmol) and cesium carbonate (41.70 mg, 0.13 mmol) into a solution of compound 97a (26.23 mg, 0.070 mmol) in 1,4-Dioxane (1 mL) at room temperature. The reaction mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel plate with thin layer chromatography (methanol / dichloromethane = 1 / 20) to give compound 97 (5 mg). MS m / z (ESI): 605.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) d 9.90 (s, 1H), 8.82 (d, J = 7.3 Hz, 1H), 8.76 (s, 1H), 8.32 (d, J = 7.4 Hz, 1H), 8.27 (d, J = 1.3 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J = 10.3 Hz, 1H), 7.28 (dd, J = 7.3, 2.0 Hz, 1H), 7.18 (s, 1H), 4.74 (s, 1H), 3.98 (s, 2H), 2.41 (s, 3H), 2.29 - 2.22 (m, 1H), 1.27 - 1.22 (m, 2H), 1.09 (s, 6H), 1.05 - 1.03 (m, 2H).

[0343] Example 11 (Compound 102)

[0344] First Step: Synthesis of compound 102b

[0345] N,N-dimethylformamide (17 mg, 0.24 mmol), oxalyl chloride (3.61 g, 28.40 mmol) were added to a solution of compound 102a (6 g, 23.67 mmol) in dichloromethane (60 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude compound 102b (5 g, crude).

[0346] Second Step: Synthesis of compound 102d

[0347] 102c (aminoguanidine carbonate) (5.01 g, 36.78 mmol), tetrabutylammonium bromide (590 mg, 1.84 mmol) were added to a solution of 1,4-dioxane (50 mL) at 0 °C, and then compound 102c (5 g, 18.39 mmol) was slowly added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was filtered, and the filter cake was added to water (50 mL) and stirred at reflux at 120 °C for 48 h. After filtration and drying, crude compound 102d (1.45 g) was obtained. MS m / z (ESI): 290.8, 292.8 [M+1, M+3] + .

[0348] Third Step: Synthesis of compound 102e

[0349] Chloroacetaldehyde diethyl acetal (0.83 g, 5.47 mmol), cesium carbonate (3.24 g, 9.94 mmol) were added to a solution of compound 102d (1.45 g, 4.97 mmol) in N,N-dimethylformamide (14 mL) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature, and then poured into water (30 mL) to precipitate a brown solid, which was filtered to obtain crude compound 102e (1.7 g, crude). MS m / z (ESI): 406.9, 408.9 [M+1, M+3] + .

[0350] Fourth Step: Synthesis of compound 102f

[0351] Compound 102e (1.7 g, 4.17 mmol) was dissolved in trifluoroacetic acid (17 mL) at room temperature, and the mixture was stirred at 70 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 100% - 5%) to obtain compound 102f (670 mg). MS m / z (ESI): 314.9, 316.9 [M+1, M+3]

[0352] + .

[0353] ​Step 5: Synthesis of compound 102g

[0354] To a solution of compound 102f (340 mg, 1.08 mmol) in 1,4-dioxane (10 mL) was added potassium tetrafluorocyclopropanide (320 mg, 2.16 mmol), sodium carbonate (230 mg, 2.16 mmol), copper acetate (39 mg, 0.22 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (58 mg, 0.22 mmol) sequentially at room temperature. The reaction mixture was stirred at 65 °C open to air 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 (ethyl acetate / petroleum ether = 10% - 40%) to give compound 102g (48 mg). MS m / z (ESI): 354.9, 356.9 [M+1, M+3] + .

[0355] Step 6: Synthesis of compound 102h

[0356] To a solution of compound 102g (48 mg, 0.13 mmol) in 1,4-dioxane (4 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.5 mg, 0.013 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol), cesium carbonate (85 mg, 0.26 mmol) and benzophenone imine (47 mg, 0.26 mmol) sequentially at room temperature. The reaction mixture was stirred at 80 °C under nitrogen atmosphere 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 (ethyl acetate / petroleum ether = 10% - 30%) to give compound 102h (50 mg). MS m / z (ESI): 456.0 [M+1] + .

[0357] Step 7: Synthesis of compound 102i

[0358] To a solution of compound 102h (50 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was added 4 M hydrochloric acid / 1,4-dioxane (5 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. The residue was filtered to give compound 102i (30 mg) as a crude product. MS m / z (ESI): 292.1 [M+1] + .

[0359] Step 8: Synthesis of compound 102

[0360] Compound 102j (17 mg, 0.051 mmol, 29 mg, 0.12 mmol, synthesis method refer to WO2024118887A1 page 170 synthesis of compound intermediate 73) was added to a solution of compound 102i (15 mg, 0.051 mmol) in toluene (2 mL) under ice bath, 2M trimethylaluminum in n-hexane (0.03 mL, 0.051 mmol) was added dropwise slowly. After the addition was completed, the reaction mixture was heated to 100 °C under nitrogen atmosphere and stirred for 4 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 102 (7 mg).

[0361] MS m / z (ESI): 588.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.82 (d, J = 7.2 Hz, 1H), 8.76 (s, 1H), 8.28 (d, J = 3.7 Hz, 2H), 8.18 (s, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 10.3 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 4.75 (s, 1H), 3.98 (s, 2H), 3.49 (d, J = 3.8 Hz, 1H), 2.41 (s, 3H), 1.25 - 1.23 (m, 2H), 1.10 (s, 6H), 1.04 - 1.01 (m, 2H).

[0362] Example 12 (Compound 78)

[0363] First Step: Synthesis of compound 78c

[0364] Compound 78b (15 mg, 0.06 mmol), Cs2CO3 (62 mg, 0.19 mmol) and Pd(dppf)Cl2 (5 mg, 0.01 mmol) were added to a mixture solution of compound 78a (30 mg, 0.09 mmol) in 1,4-dioxane and water (5 mL / 1 mL) at room temperature, and the reaction mixture was heated to 80 °C under nitrogen atmosphere and stirred for 16 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 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 column chromatography on silica gel (methanol / dichloromethane = 0-5%) to obtain compound 78c (25 mg). MS m / z (ESI): 343.3 [M+1] + .

[0365] Second Step: Synthesis of compound 78

[0366] To a solution of compound 78c (10 mg, 0.03 mmol) and compound 76c (9 mg, 0.03 mmol) in toluene (2 mL) was added n-hexane solution of trimethylaluminum (0.15 mL, 0.15 mmol, 1 M) under nitrogen atmosphere, and the reaction mixture was heated to 100 °C and stirred for 3 hours. After completion of the reaction, the reaction was quenched by the addition of methanol (2 mL), and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 0-5%) to give compound 78 (6.83 mg). MS m / z (ESI): 605.5 [M+1] + .

[0367] 1 HNMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.56 (s, 1H), 8.60 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.71 - 7.67 (m, 2H), 4.72 (s, 1H), 3.97 (s, 2H), 3.17 (s, 1H), 2.34 (s, 3H), 1.27 - 1.24 (m, 2H), 1.14 - 1.11 (m, 2H), 1.09 (s, 6H).

[0368] Biological Examples

[0369] 1. Inhibition of wild-type c-kit kinase

[0370] 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, double duplicate wells. Incubate at 28°C for 90 minutes, add 25 μL of stop 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 to terminate the reaction. 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 "negative control well" is the reading of the control sample well without enzyme; "positive control well" is the reading of the control well with DMSO as the control, and the concentration-effect curve (Y = Bottom + (Top-Bottom) / (1 + (IC 50 50) HillSlope)) is fitted using GraphPad Prism 8 software, and the compound concentration at 50% inhibition, IC 50 , is calculated. The test results are shown in Table 1. Wherein A represents: IC 50 ≤ 300 nM; B represents: 300 nM < IC 50 ≤ 600 nM; C represents: 600 nM < IC 50 ≤ 1000 nM; D represents: 1000 nM < IC 50 .

[0371] Table 1

[0372] 2, Inhibition of wild-type c-kit kinase

[0373] 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).

[0374] Dilute 5X enzyme reaction buffer to IX with distilled water and add DTT, MgCl2, MnCl2 at final concentration of 1 mM, 5 mM, 1 mM respectively as IX enzyme reaction buffer. Prepare test articles in IX enzyme reaction buffer to a maximum concentration of 10 mM, 10 concentrations in 4-fold dilution series for testing, final DMSO concentration is 1%. In a 10 pL reaction system, containing 4 pL of compound working solution and 2 pL of KIT kinase (Carna, 08-156) at a final concentration of 0.29 ng / pL, diluted with IX enzyme reaction buffer 20 minutes before adding to the reaction system and placed on ice. 2 pL of TK Substrate-biotin (Revvity, 61TK0BLC) at a final concentration of 0.25 pM and 2 pL of ATP (Promega, V9158) at a final concentration of 8 pM are both configured using IX enzyme reaction buffer, sequentially added to the wells of a 384-well plate to start the reaction, where the negative control wells do not contain compounds and kinases, and the positive control wells do not contain compounds. After incubation at 25 degrees Celsius for 1 hour, 5 pL of TK Antibody-Cryptate diluted 100-fold with detection buffer (Revvity, 62SDBRDF) and SA-XL665 (Revvity, 610SAXLG) at a final concentration of 15.625 nM are added, and the incubation is continued at 25 degrees Celsius for 1 hour. The Molecular Device SpectraMax i3x enzyme marker HTRF module is used for detection, with an excitation wavelength of 340 nm and emission wavelengths of 616 nm and 665 nm. The following formula is used to calculate the inhibition rate of the test article:

[0375] Wherein

[0376] The concentration-effect curve is fitted using GraphPad Prism 8 software (Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)HillSlope)), and the compound concentration at 50% inhibition, IC 50 , is calculated. The test results are shown in Table 2. 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.

[0377] Table 2

[0378] 3. Inhibition of c-kit phosphorylation in SCF-stimulated M-07e cells

[0379] M-07e cells (Promocell, CL-0686) were plated in 96-well plates (Corning, 3599) at a density of 2 x 10^6 cells / mL in 50 μL Opti-MEM medium (Gibco, 11058021) containing 1% penicillin-streptomycin (Gibco, 15140-122). After incubation at 37 °C, 5% CO2for 4 hours, 6.25 μL of the test compound was added to each well to give a maximum final concentration of 1000 nM, 8 concentrations with 5-fold dilution, and a final DMSO concentration of 0.22%. After incubation at 37 °C, 5% CO2for 60 minutes, 6.25 μL of Human Recombinant SCF (STEMCELL, 78062) was added to give a final SCF concentration of 50 ng / mL. The positive control (max) wells contained no compound, and the negative control (min) wells contained no compound and no SCF. After incubation at room temperature for 15 minutes on a 450 rpm shaker, 16 μL of 5X cell lysis buffer (CST, 9803) containing protease and phosphatase inhibitors (Biocytex, P1045) was added, and the cells were lysed by gentle shaking at 4 °C for 30 minutes. The cell lysate was collected by centrifugation. The protein concentration was quantified using the BCA method (Biocytex, P0009), and the degree of p-kit phosphorylation was detected using the PathScan® Phospho-c-Kit (Tyr719) Sandwich ELISA Kit according to the kit manual. The OD values of the measured ELISA were normalized using the protein concentration, and the inhibition rate was calculated using the following formula, and the concentration-effect curve was fitted using GraphPad Prism 8 software (Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope)), and the compound concentration at 50% inhibition, IC 50 , was calculated. The test results are shown in Table 3.

[0380] ODmax: normalized absorbance of the control group containing cells, SCF, and no compound

[0381] ODmin: normalized absorbance of the control group containing cells, no SCF, and no compound

[0382] ODcpd: normalized absorbance of the control group containing cells, SCF, and different concentrations of compound

[0383] Table 3

[0384] The above has described the specific embodiments of the present application. It should be understood that the present application is not limited to the above-mentioned embodiments, and the above-mentioned embodiments and descriptions in the specification are only for illustrating the principles of the present application. Those skilled in the art can make various non-essential changes and improvements to the present application without departing from the concept of the present application, and these all fall within the scope of the present application.

Claims

A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is is a single or double bond; ring A is a 5-membered heteroaryl; X is C and Y is N; or, X is N and Y is C; G 1 CR 0 or N; G 3 is O or S; R 0 selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 1 selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, each independently optionally substituted with 1 or more R 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, each independently optionally substituted with 1 or more R A ; R A selected from H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2) p -C 3-8 cycloalkyl and -(CH2) p -(3-8 membered heterocyclyl), each independently optionally substituted with one or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2) p -C 3-8 cycloalkyl and -(CH2) p -(3-8 membered heterocyclyl) each independently optionally substituted with one or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; or 2 R A together with the atom to which they are attached form C 5-8 Cycloalkyl, 5-8 membered heterocyclyl, or 5-8 membered heteroaryl, each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, C 5-8 Cycloalkyl, 5-8 membered heterocyclyl, or 5-8 membered heteroaryl, each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 5-8 membered heterocyclyl, or 5-8 membered heteroaryl, each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, C 1- Cycloalkyl, 5-8 membered heterocyclyl, or 5-8 membered heteroaryl, each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, C 3-8 Cycloalkyl, 5-8 membered heterocyclyl, or 5-8 membered heteroaryl, each of which is independently R 2 selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R 3 selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, each independently optionally substituted with one or more selected from halo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, each independently optionally substituted with one or more selected from halo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; R 4 and R 5 are the same or different, each being independently selected from the group consisting of H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3- 8cycloalkyl and 3-8 membered heterocyclyl, each of which C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl is independently optionally substituted with one or more R E groups; R 6 and R 7 together with the atom to which they are attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally substituted with one or more R E . R 9 and R 10 together with the atom to which they are attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally substituted with one or more R E . R 11 and R 12 together with the atom to which they are attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally substituted with one or more R E . R E selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3-8 deutero-cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and The C 1-6 alkyl, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3-8 deutero-cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R k substituents; Each R k They may be the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-alkoxy, C 1-6 Hydroxyalkyl, -C(O)OR k1 -NHC(O)R k1 -NHS(O)2R k2 -S(O)2R k2 -C(O)NR k3 R k4 -S(O)2NR k3 R k4 -NR k3 R k4 C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups; R k1 is H, C 1-6 alkyl or C 1-6 alkoxy; R k2 is hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl; R k3 and R k4 are the same or different and each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl; R a , R b , R g and R h 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; t is 0, 1, 2, 3 or 4; m is 1 or 2; n is 1 or 2; p is 1 or 2; the heteroatom in the heteroaryl or heterocyclyl group is O, S or N, and the number of heteroatoms is 1, 2, 3 or 4. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, wherein T is ring A is oxazolyl, triazolyl or tetrazolyl; G 2 is O or S; R c , R d , R e and R f 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; or R c and R d form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl is each independently optionally substituted with one or more selected from halo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; or R e and R f form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl is each independently optionally substituted with one or more selected from halo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; Preferably, R c , R d , R e and R f are independently selected from H or C 1-6 alkyl, for example H or methyl. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, wherein T is ring A is a 5-membered heteroaryl; G 1 CR 0 or N; G 2 is O or S; R 0 selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 3 selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, each independently optionally substituted with one or more selected from halo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3- to 8-membered heterocyclyl, each independently optionally substituted with one or more selected from halo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; R 4 and R 5 are the same or different, each being independently selected from the group consisting of H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3- 8cycloalkyl, and 3-8 membered heterocyclyl, each of which C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl is independently optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; R 6 and R 7 together with the atom to which they are attached form a 3-12 membered heterocyclyl or 5-10 membered heteroaryl, said 3-12 membered heterocyclyl or 5-10 membered heteroaryl being optionally substituted with one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; R 8 selected from H, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; R a , R b , R g and R h 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 1 or 2; n is 1 or 2; the heteroatom in the heteroaryl or heterocyclyl group is O, S or N, and the number of heteroatoms is 1, 2, 3 or 4. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, wherein T is Preferably, T is R 8 selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, which satisfies one or more of the following conditions: (1) R E selected from H, halo, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3-8 deutero-cycloalkyl and 3- to 12-membered heterocyclyl, each independently optionally substituted with one or more R 1-6 alkyl, C 1-6 deuteroalkyl, C 3-8 cycloalkyl, C 3-8 deutero-cycloalkyl and 3- to 12-membered heterocyclyl, each independently optionally substituted with one or more R k ; Each R k They may be the same or different, and each is independently selected from halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1- 6-alkoxy, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; (2) For (3) Ring A is oxazolyl, triazolyl or tetrazolyl, preferably, For (4) R 2 selected from H, halogen, cyano and C 1-6 alkyl; preferably, R 2 selected from H, halogen and C 1-6 alkyl. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, wherein T is The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, wherein R 1 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, each of which is independently and optionally substituted with 1 or more R 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, and 5- to 10-membered heteroaryl, each of which is independently and optionally substituted with 1 or more R A substituents; R A selected from H, halogen, hydroxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2)-C 3-8 cycloalkyl and -(CH2)-(3-8 membered heterocyclyl), said C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl-(CH2)-C 3-8 cycloalkyl and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkoxy and C 1-6 hydroxyalkyl; or 2 R A with the attached atoms form a 5-8 membered heterocyclyl group, optionally substituted with one or more selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; Preferably, R 1 is R A1 , R A2 , R A3 , R A4 and R A5 are the same or different, each being independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2)-C 3-8 cycloalkyl, and -(CH2)-(3-8 membered heterocyclyl), each of said C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2)-C 3-8 cycloalkyl, and -(CH2)-(3-8 membered heterocyclyl) being independently optionally substituted with one or more selected from the group consisting of halogen, hydroxy, C 1-6 alkoxy, and C 1-6 hydroxyalkyl; or R A4 and R A5 together with the atom to which they are attached form a C 5-8 cycloalkyl or 5-8 membered heterocyclyl, said C 5-8 cycloalkyl or 5-8 membered heterocyclyl is optionally substituted with one or more selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, wherein R 1 is H, Cl, methyl, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, which is selected from Scheme 1 or Scheme 2: Scheme 1: wherein the compound of formula (I) is a compound of formula (II), wherein, Rings A, X, Y, R 1 R 2 m, n, and t are as defined in claims 1-8; Scheme 2: The compound of formula (I) is a compound of formula (III), Among them, G 2 For O or S; X, Y, R 1 , R 2 , R E and t are as defined in any of claims 1 to 8. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, which satisfies one or two of the following conditions: (1) T is selected from the group consisting of (2) R 1 is 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted by one or more R A , preferably R 1 is 5-6 membered heteroaryl, said 5-6 membered heteroaryl being optionally substituted by one or more R A . The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, which satisfies one or more of the following conditions: (1) Ring A is selected from triazolyl and tetrazolyl, for example tetrazolyl, and further for example wherein the "1" position is attached to the phenyl group; (2) R a and R b independently halogen, for example F; (3) R 4 and R 5 independently halogen, C 1-6 alkyl or C 3-8 cycloalkyl, for example chloro or cyclopropyl; (4) R 0 is H; (5) R 6 and R 7 together with the atom to which they are attached form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by one or more R E substituents; (6) R 9 and R 10 together with the atom to which they are attached form a 5-6 membered heteroaryl, said 5-6 membered heteroaryl being optionally substituted by one or more R E ; (7) R E independently halogen, C 1-6 alkyl or C 3-8 cycloalkyl, for example C 1-6 alkyl or C 3-8 cycloalkyl, for example methyl or cyclopropyl; (8) R g and R h independently H; (9) R A is C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more selected from the group consisting of hydroxy and C 1-6 alkyl, for example said C 1-6 alkyl is optionally substituted with hydroxy; Preferably, R 1 is R A2 and R A5 are independently H or C 1-6 alkyl, R A4 is C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more selected from the group consisting of hydroxy and C 1-6 alkyl, for example said C 1-6 alkyl is optionally substituted with hydroxy. a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is any one of the compounds shown in Table A: Table A a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is any one of the compounds shown in Table B: Table B A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula (I) according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Use of a compound of formula (I) according to any one of claims 1-13, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for inhibiting c-kit. Use of a compound of formula (I) according to any one of claims 1-13, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for preventing and / or treating a c-kit-mediated disease; Preferably, the c-kit-mediated disease is selected from mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary arterial hypertension, primary pulmonary hypertension or cancer. More preferably, the c-kit-mediated disease is selected from mast cell tumors, mastocytosis, urticaria, inflammatory bowel disease or diabetes; still more preferably, the c-kit-mediated disease is mast cell leukemia. Use of a compound of formula (I) according to any one of claims 1-13, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament, preferably for the manufacture of a medicament for preventing and / or treating mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary arterial hypertension, primary pulmonary hypertension or cancer, for example for preventing and / or treating mast cell tumors, mastocytosis, urticaria, inflammatory bowel disease or diabetes, and for example for preventing and / or treating a mast cell-related disease which is mast cell leukemia.

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