Heterocyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a heterocyclic compound as well as a preparation method and application thereof, and particularly provides a heterocyclic compound as shown in a formula (I) or pharmaceutically acceptable salt thereof, which can be used for preparing medicines, especially medicines for preventing and / or treating c-kit mediated diseases or symptoms. Each group in the formula (I) is as defined in the specification.

Description

[0001] This application claims priority to Chinese patent application 2024111280071, filed August 16, 2024; Chinese patent application 2024112381864, filed September 5, 2024; and Chinese patent application 2024115758684, filed November 6, 2024. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This application belongs to the pharmaceutical field, specifically relating to a heterocyclic compound, its preparation method, and its uses. Background Technology

[0003] KIT ligand is a stem cell factor (SCF). Its binding to the extracellular domain of KIT induces receptor dimerization and activates downstream signaling pathways, initiating a cascade of cell growth and proliferation signal transduction reactions upon SCF binding. SCF-liganding of the c-kit receptor induces dimerization, followed by transphosphorylation, leading to the recruitment and activation of various intracellular substrates. These activated substrates induce multiple intracellular signaling pathways responsible for cell proliferation and activation. These proteins are well-known to participate in many cellular mechanisms; disruption of these mechanisms can lead to abnormal cell proliferation and migration, as well as 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 crucial for maintaining normal hematopoiesis, melanin production, heredity, and mast cell growth and differentiation. Inhibition of c-kit kinase activity reduces mast cell growth and differentiation, thereby mediating mast cell-related diseases and / or conditions.

[0005] Currently published patents include WO2015057873A1, WO2016022569A1, and WO2020210293A1. Summary of the Invention

[0006] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0007]

[0008] Where T is

[0009] It can be a single bond or a double bond;

[0010] Ring A is a 5-membered heteroaryl group;

[0011] X is C and Y is N; or, X is N and Y is C;

[0012] G 1 For CR 0 Or N;

[0013] G 3 For O or S;

[0014] 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;

[0015] 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;

[0016] 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;

[0017] Or, 2 RsA Together with the atoms attached to it, they form C 5-8 Cycloalkyl, 5-8 membered heterocyclic or 5-8 membered heteroaryl, wherein the C 5-8 Cycloalkyl, 5-8 membered heterocyclic, or 5-8 membered heteroaryl groups are each independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups;

[0018] 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 Halogenated alkoxy groups;

[0019] R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each 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;

[0020] R 4 and R 5 Whether the groups are the same or different, they are each independently selected from halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally enclosed by one or more R groups. E Replaced;

[0021] R 6 and R 7 Together with the atoms attached thereto, they form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally surrounded by one or more R E Replaced;

[0022] R 9 and R10 Together with the atoms attached thereto, they form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally surrounded by one or more R E Replaced;

[0023] R 11 and R 12 Together with the atoms attached thereto, they form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally surrounded by one or more R E Replaced;

[0024] 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 3-8 Deuterated cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 member heteroaryl and The C mentioned 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Deuterated cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally constituting one or more R groups. k Replaced;

[0025] 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 and 5-10 heteroaryl groups;

[0026] Rk1 For H, C 1-6 Alkyl or C 1-6 Alkoxy;

[0027] R k2 Hydroxyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 3-8 cycloalkyl;

[0028] R k3 and R k4 They are the same or different, and each is independently H or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 3-8 cycloalkyl;

[0029] R a R b R g and R h Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, and 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;

[0030] t can be 0, 1, 2, 3, or 4;

[0031] m is 1 or 2;

[0032] n is 1 or 2;

[0033] p is 1 or 2;

[0034] The heteroatom in the heteroaryl or heterocyclic group is O, S or N, and the number of heteroatoms is 1, 2, 3 or 4.

[0035] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein 2 R A Together with the atoms attached thereto, they form a 5-8 membered heterocyclic group or a 5-8 membered heteroaryl group, wherein each of the 5-8 membered heterocyclic group or 5-8 membered heteroaryl group is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 It is substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups.

[0036] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R ESelected 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 3-8 Deuterated cycloalkyl groups and 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 The deuterated cycloalkyl group and the 3-12 membered heterocyclic group are each independently and optionally converted by one or more R groups. k Replaced;

[0037] 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.

[0038] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0039] Ring A is a 5-membered heteroaryl group;

[0040] G 1 For CR 0 Or N;

[0041] G 2 For O or S;

[0042] 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;

[0043] R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8The cycloalkyl group and the 3-8 membered heterocyclic group are each 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;

[0044] R 4 and R 5 Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each 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;

[0045] R 6 and R 7 Together with the atoms attached thereto, they form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally 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;

[0046] 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 Halogenated alkoxy groups;

[0047] R a R b R g and R h Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, and 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;

[0048] m is 1 or 2;

[0049] n is 1 or 2;

[0050] The heteroatom in the heteroaryl or heterocyclic group is O, S or N, and the number of heteroatoms is 1, 2, 3 or 4.

[0051] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0052] (1) The C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl;

[0053] (2) The halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine;

[0054] (3) The C 3-8 cycloalkyl is Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl;

[0055] (4) The 3-12 membered heterocyclic group is oxoheterobutyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, hexahydropyranyl, piperidinyl,

[0056]

[0057] (5) The 5-10 heteroaryl group or 5 heteroaryl group is pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridazinyl, pyridinyl, 1,2,4-triazinyl, pyrimidinyl or pyrazinyl.

[0058] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0059]

[0060] Ring A is an oxazolyl, triazolyl, or tetrazolyl group;

[0061] G 2 For O or S;

[0062] R c R d R e and R f Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0063] 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;

[0064] 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;

[0065] R 3 R 4 R 5 R E R a R b R g and R h As defined in equation (I).

[0066] 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.

[0067] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0068]

[0069] Ring A is an oxazolyl, triazolyl, or tetrazolyl group;

[0070] G 2 For O or S;

[0071] R c R d R e and R f Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, and 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;

[0072] 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;

[0073] 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;

[0074] R 3 R 4 R 5 R E R a R b R g and R h As defined in equation (I).

[0075] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0076] R B and R C Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0077] 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 Halogenated alkoxy groups.

[0078] In some implementations, R B and R C Independently selected from H or C 1-6 Alkyl groups, such as H or methyl.

[0079] In some implementations, R 8 Selected from C 3-8 Cycloalkyl groups, such as cyclopropyl groups.

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

[0081] R E As defined in equation (I).

[0082] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0083] R E As defined in equation (I).

[0084] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0085] Ring A is an oxazolyl, triazolyl, or tetrazolyl group;

[0086] R 3 Selected from C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each 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;

[0087] R 4 and R 5 Whether 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;

[0088] 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;

[0089] 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;

[0090] 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;

[0091] 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;

[0092] 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, C1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Deuterated cycloalkyl groups and 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 The deuterated cycloalkyl group and the 3-12 membered heterocyclic group are each independently and optionally converted by one or more R groups. k Replaced;

[0093] 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.

[0094] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0095] R 8 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

[0096] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is...

[0097] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (II).

[0098]

[0099] in, Rings A, X, Y, R 1 R 2 , m, n and t are as defined by equation (I).

[0100] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is the compound represented by formula (III),

[0101]

[0102] Among them, G 2 For O or S;

[0103] X, Y, R 1 R 2 R E And t is as defined by equation (I).

[0104] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein for

[0105] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein for R 2A and R 2B Whether the groups are the same or different, they are independently selected from H, halogen, cyano, and C. 1-6 alkyl.

[0106] In some embodiments, the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is oxazolyl, triazolyl, or tetrazolyl.

[0107] In some embodiments, the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein for Preferably, for

[0108] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein for

[0109] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12-membered heterocyclic and 5-10-membered heteroaryl groups are each independently and optionally constituting one or more R groups. A Replaced;

[0110] R A Selected from H, halogen, hydroxyl, C1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2)-C 3-8 Cycloalkyl and -(CH2)-(3-8 membered heterocyclic groups), the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2)-C 3-8 The cycloalkyl group and -(CH2)-(3-8 membered heterocyclic group) are each independently and optionally selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkoxy and C 1-6 One or more of the hydroxyalkyl groups are substituted;

[0111] Or, 2 Rs A Together with the attached atoms, they form a 5-8 membered heterocyclic group, wherein the 5-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 It is substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups.

[0112] In some embodiments, the compound represented by formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R 1 for

[0113] R A1 R A2 R A3 R A4 and R A5 Whether the two are the same or different, each is independently selected from H and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2)-C 3-8 Cycloalkyl and -(CH2)-(3-8 membered heterocyclic groups), the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2)-C 3-8 The cycloalkyl group and -(CH2)-(3-8 membered heterocyclic group) are each independently and optionally selected from halogens, hydroxyl groups, C 1-6 Alkoxy and C 1-6 One or more of the hydroxyalkyl groups are substituted;

[0114] Or, R A4 and R A5 Together with the atoms attached to it, they form C 5-8 Cycloalkyl or 5-8 membered heterocyclic groups, wherein the C 5-8The cycloalkyl or 5-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 It is substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups.

[0115] 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

[0116]

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] In some embodiments, the compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein t is 2.

[0122] In some embodiments, the compound represented by formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein t is 1.

[0123] In some implementations, T is selected from

[0124] 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.

[0125] In some implementations, R a and R b Halogens, for example, F.

[0126] 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.

[0127] In some implementations, R 0 For H.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] In some implementations, R g and R h H stands for H independently.

[0132] 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.

[0133] 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.

[0134] In some implementations, R 1 for R A2 and R A5 Independently H or C 1-6 Alkyl, R A4 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.

[0135] In some embodiments, the compound as shown in formula (I),

[0136] T is selected from

[0137] Ring A is triazole or tetraazole.

[0138] m is 1 or 2;

[0139] n is 1 or 2;

[0140] R a and R b Halogens are independent of each other;

[0141] R 4 and R 5 Independent of halogen, C 1-6 Alkyl or C 3-8 cycloalkyl;

[0142] G 1 For CR 0 Or N;

[0143] R 0 For H;

[0144] 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 Replaced;

[0145] 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 Replaced;

[0146] R E Independent of halogen, C1-6 Alkyl or C 3-8 cycloalkyl;

[0147] R g and R h H is independent;

[0148] R 2 H, halogen or C 1-6 alkyl;

[0149] t can be 0, 1, 2, 3, or 4;

[0150] X is C and Y is N; or, X is N and Y is C;

[0151] R 1 The 5-6 membered heteroaryl group is optionally coupled with one or more R groups. A Replaced;

[0152] 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.

[0153] In some embodiments, exemplary specific compounds of the compound shown in formula (I) include any of the compounds shown in Table A.

[0154] In some embodiments, exemplary specific compounds of the compound shown in formula (I) include any of the compounds shown in Table B.

[0155] 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).

[0156] 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).

[0157]

[0158] Among them, R B For H or C 1-6 alkyl;

[0159] T, X, Y, R 1 R 2 And t as defined in any of these claims.

[0160] 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.

[0161] In another aspect, this application also provides the use of compounds of formula (I), formula (II) or formula (III), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for inhibiting c-kit.

[0162] This application also provides the use of compounds of formula (I), formula (II) or formula (III), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the prevention and / or treatment of c-kit-mediated diseases or conditions.

[0163] This application also provides the use of compounds of formula (I), formula (II) or formula (III), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for the prevention and / or treatment of mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension, primary pulmonary hypertension, or cancer; preferably, in the preparation of medicaments for the prevention and / or treatment of mast cell tumors, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0164] This application also provides a method for inhibiting c-kit, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (II) or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope label, or the aforementioned pharmaceutical composition comprising the thereof.

[0165] This application also provides a method for preventing and / or treating c-kit-mediated diseases or conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II) or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope label, or the aforementioned pharmaceutical composition comprising the aforementioned.

[0166] This application also provides a method for preventing and / or treating mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension, primary pulmonary hypertension, or cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned.

[0167] This application also provides a method for preventing and / or treating mast cell tumor, mastocytosis, urticaria, inflammatory bowel disease, or diabetes, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned.

[0168] This application also provides a compound of formula (I), formula (II) or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a medicine.

[0169] This application also provides a compound of formula (I), formula (II) or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, as a c-kit inhibitor.

[0170] This application also provides a compound of formula (I), formula (II) or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the prevention and / or treatment of c-kit-mediated diseases or conditions.

[0171] This application also provides a compound of formula (I), formula (II) or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the prevention and / or treatment of mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension, primary pulmonary hypertension, or cancer.

[0172] This application also provides a compound of formula (I), formula (II) or formula (III), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the prevention and / or treatment of mast cell tumor, mastocytosis, urticaria, inflammatory bowel disease or diabetes.

[0173] In some embodiments, the c-kit-mediated diseases are selected from mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension, primary pulmonary hypertension, or cancer.

[0174] In some embodiments, the c-kit-mediated disease is selected from mast cell tumor, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0175] In some implementations, the disease mediated by c-kit is mast cell leukemia.

[0176] In some implementations, the mast cell-related disease is mast cell leukemia.

[0177] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] The term "excipients" as used in this application refers to components other than the active ingredient, such as diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0183] On the other hand, pharmaceutically acceptable salts of the compounds described in this application may be inorganic or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form inner salts.

[0184] On the other hand, the compounds of this application may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures and other mixtures, as well as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0185] The term "multiple" in the above-mentioned number of substituents or heteroatoms means 2, 3, 4, or 5.

[0186] In the chemical structure of the compound described in this application, the bond... This indicates that no configuration has been specified. or Indicates absolute configuration, that is, if chiral isomers exist in the chemical structure, the bonds... It can be or Or simultaneously include and Two configurations.

[0187] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0188] Furthermore, the compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactamimide isomerization. All tautomer forms of all compounds in this application are within the scope of this application. The name of a compound named in a single manner does not exclude any tautomer.

[0189] This application also includes compounds of this application with the same structure as described herein, but with one or more atoms replaced by isotopes of atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All isotopic variations of the compounds in this application, regardless of radioactivity, are included within the scope of this application.

[0190] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare compounds in their deuterated form, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0191] The "therapeutic effective amount" in this application refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians seek in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). For the purposes of a drug or pharmacologically active agent, "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0192] "Pharmaceutical acceptable" in this application means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0193] In this application, "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0194] Terminology Definitions and Explanations

[0195] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0196] In this application or This refers to the corresponding group passing through this It can be linked to other fragments or groups in a compound.

[0197] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6Alkyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted.

[0198] The term "alkenyl" should be understood to preferably refer to a linear or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C...). 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl. The alkenyl group may be substituted or unsubstituted.

[0199] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Preferably, alkoxy groups (C-) contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. 1-12 Alkoxy groups, more preferably alkoxy groups containing 1 to 6 carbon atoms (C 1-6 Alkoxy groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0200] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0201] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which each monocyclic ring in the system shares a carbon atom (called a spiro atom), and may 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). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0202]

[0203] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may 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). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0204]

[0205] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may 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). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0206]

[0207] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl group as described herein, wherein the ring attached to the parent structure can be a cycloalkyl ring or an aryl ring, and non-limiting examples include... etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0208] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0209] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each monocyclic ring in the system shares one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may 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). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 5-membered, or 5- / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0210]

[0211] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0212]

[0213]

[0214] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0215]

[0216] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure may be a heterocyclic group, or an aryl, heteroaryl, or cycloalkyl ring, and non-limiting examples include:

[0217] Etc. Etc. The heterocyclic group may be substituted or unsubstituted.

[0218] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl group can be substituted or unsubstituted.

[0219] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes heteroaryl groups as described herein, with non-limiting examples including:

[0220]

[0221] Etc. Heteroaryl groups can be substituted or unsubstituted.

[0222] The terms “alkyl,” “alkoxy,” “cycloalkyl,” “heterocyclic,” “aryl,” and “heteroaryl” used herein may be substituted or unsubstituted; when substituted, they may be substituted at any usable linking point, and the substituents are preferably independently selected independently from one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0223] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", "heterocyclic", and "heteroaryl".

[0224] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined herein.

[0225] The term “heterocyclic oxy group” refers to a heterocyclic group -O-, wherein the heterocyclic group is as defined herein.

[0226] The term “halogenated alkyl” refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined herein.

[0227] The term “haloalkoxy” refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined herein.

[0228] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined herein.

[0229] The term "halogen" refers to F, Cl, Br, or I.

[0230] The term "hydroxyl group" refers to -OH.

[0231] The term "amino" refers to -NH2.

[0232] The term "cyano" refers to -CN.

[0233] The term "nitro" refers to -NO2.

[0234] The term "oxo" or "oxo" refers to "=O".

[0235] The term "carbonyl" refers to C=O.

[0236] The term "carboxyl group" refers to -C(O)OH.

[0237] The term “carboxylic acid ester group” 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.

[0238] "Optional" or "optionally" means that the event or circumstance described below may, but does not have to, occur. This description includes situations in which the event or circumstance may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may, but does not have to, be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0239] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0240] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0241] The reagents and raw materials used in this invention are all commercially available.

[0242] Beneficial effects:

[0243] This application provides a small molecule compound with a heterocyclic structure that can be used as a c-kit inhibitor. This type of compound or pharmaceutical composition has a strong inhibitory effect on c-kit receptors and has excellent pharmacokinetic activity, and can be used to effectively treat or prevent c-kit-mediated diseases. Detailed Implementation

[0244] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention. Experimental methods in the following embodiments that do not specify specific conditions are performed according to conventional methods and conditions, or as selected according to the product instructions.

[0245] For experimental methods in the following examples where specific conditions are not specified, follow conventional methods and conditions, or select according to the product instructions.

[0246] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400MHz NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0247] Mass spectrometry (MS) was performed using a Waters 2767HPLC / Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC / Waters liquid chromatography-mass spectrometry system.

[0248] Chiral HPLC analysis was performed using Shimadzu LC-20AD.

[0249] The silica gel plates used in thin-layer chromatography are GF254 silica gel plates from Cheng Chemical (Shanghai) Co., Ltd. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.2–0.25 mm, while those used for separating and purifying products by thin-layer chromatography have a diameter of 0.4–0.5 mm.

[0250] Column chromatography typically uses 100-200 mesh silica gel as a carrier, as provided by Chenghua Chemical (Shanghai) Co., Ltd.

[0251] High-performance liquid chromatography (HPLC) was performed using Waters HPLC, Gilson HPLC, and Biotage MPLC preparative chromatographs.

[0252] Chiral separation column chromatography was performed using a preparative HPLC model, Gilson GX-281.

[0253] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0254] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1 liter.

[0255] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 liter.

[0256] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 20℃-30℃.

[0257] Those skilled in the art should understand that chiral compounds can be distinguished by their retention times in a chiral chromatographic column. Therefore, chiral compounds separated according to their retention times are distinguished by corresponding suffixes such as P1, P2, etc. That is, suffix P1 corresponds to the chiral structure separated first, and 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 imply a one-to-one correspondence with the compounds numbered with suffixes P1 and P2; it merely indicates two possible forms of absolute configuration. The absolute configuration of the compounds numbered with suffixes P1 and P2 is based on the absolute configuration objectively corresponding to a specific retention time.

[0258] Reagent names corresponding to English abbreviations:

[0259]

[0260]

[0261] intermediate compound A1

[0262]

[0263] Step 1: Synthesis of compound A1-2

[0264] At room temperature, lithium hydroxide monohydrate (0.42 g, 17.52 mmol) was added to a mixture of ethanol and water (15 mL / 15 mL) of compound A1-1 (2.0 g, 6.09 mmol, synthesis method referred to the synthesis of intermediate 70 on page 169 of patent WO2024118887A1). The reaction mixture was stirred at 80 °C for 6 hours. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (50 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-20%) to give compound A1-2 (1.6 g). MS m / z (ESI): 315.1 [M+1] + .

[0265] Step 2: Synthesis of compound A1

[0266] At room temperature, DIEA (492 mg, 3.81 mmol) and HATU (724 mg, 1.91 mmol) were added to a DMF (20 mL) solution of compound A1-2 (400 mg, 1.27 mmol). The reaction mixture was stirred at 25 °C for 1 hour. Then, ammonium chloride (135 mg, 2.54 mmol) was added, and stirring continued at 25 °C for 5 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0-20%) to give compound A1 (300 mg). MS m / z (ESI): 314.1 [M+1] + .

[0267] intermediate compound A2

[0268]

[0269] Compound A2-1 (1.0 g, 4.46 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of pinacol diboronate (1.36 g, 5.35 mmol), potassium acetate (1.31 g, 13.38 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.33 g, 0.45 mmol). The reaction mixture was heated to 90 °C under nitrogen protection and stirred for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5%–20%) to give compound A2 (970 mg). MS m / z (ESI): 272.1 [M+1] + .

[0270] Example 1 (Compound 42)

[0271]

[0272] Step 1: Synthesis of compound 42b

[0273] Under ice bath conditions, triphosgene (4.85 g, 16.4 mmol) was added to a dichloromethane (60 mL) solution of compound 42a (3.67 g, 16.4 mmol), followed by the slow addition of triethylamine (1.65 g, 16.4 mmol). The reaction mixture was stirred under ice bath conditions for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 42b (4.0 g, crude product), which was used directly in the next reaction step.

[0274] Step 2: Synthesis of compound 42c

[0275] Under nitrogen protection, compound 42b (4.0 g, 16.4 mmol) was dissolved in azidotrimethylsilane (40 mL), and the reaction mixture was stirred at 95 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), and 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 × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 42c (1.62 g). 1 H NMR (400MHz, DMSO-d6) δ14.87 (s, 1H), 8.21 (d, J = 7.4Hz, 1H), 8.07 (d, J = 10.0Hz, 1H).

[0276] Step 3: Synthesis of compound 42d

[0277] 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 sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic phases were 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 = 5%–15%) to give compound 42d (100 mg, MS m / z (ESI): 320.9 [M+1)). + .

[0278] Step 4: Synthesis of Compound 42

[0279] Compound 42d (30 mg, 0.093 mmol) was dissolved in 1,4-dioxane (3 mL), followed by the addition of compound A1 (29.1 mg, 0.093 mmol), cesium carbonate (60.6 mg, 0.19 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (10.8 mg, 0.019 mmol), and tris(dibenzylacetone)dipalladium (8.5 mg, 0.0093 mmol). Under nitrogen protection, the reaction mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by thin-layer chromatography on silica gel plates (dichloromethane / methanol = 10 / 1) to give compound 42 (14.0 mg). MS m / z (ESI): 554.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.95(s,1H),8.82(d,J=8.0Hz,1H),8.76(s,1H),8.25(s,1H),8.16(s,1H),8.04(d,J=7.5Hz,1H),7.98(d,J=9 .9Hz,1H),7.29(dd,J=7.3,2.0Hz,1H),4.74(s,1H),4.05–4.00(m,2H),3.98(s,2H),2.41(s,3H),1.40(t,J=7.3Hz,3H),1.10(s,6H).

[0280] Example 2 (Compound 72)

[0281]

[0282] Step 1: Synthesis of compound 72b

[0283] At room temperature, hydrazine hydrate (11.0 g, 186.90 mmol) was added to a solution of compound 72a (5.0 g, 18.69 mmol) in 100 mL of EtOH. The reaction mixture was stirred at 80 °C for 6 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (300 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-20%) to give compound 72b (3.7 g). MS m / z (ESI): 266.8 [M+1] + .

[0284] Step 2: Synthesis of compound 72c

[0285] At room temperature, trimethylsilyl isothiocyanate (1.4 g, 10.84 mmol) was added to a mixture of ethanol and water (20 mL / 20 mL) containing compound 72b (2.9 g, 10.84 mmol). The reaction mixture was stirred at 80 °C for 3 hours. Then, sodium hydroxide (0.8 g, 21.68 mmol) was added, and stirring continued at 80 °C for 6 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-20%) to give compound 72c (1.7 g). MS m / z (ESI): 307.1 [M+1] + .

[0286] Step 3: Synthesis of compound 72d

[0287] At room temperature, bromoacetone (532.17 mg, 3.88 mmol) and potassium carbonate (1.1 g, 7.77 mmol) were added to a DMF (20 mL) solution of compound 72c (800 mg, 2.59 mmol). The reaction mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 72d (560 mg). MS m / z (ESI): 363.8 [M+1] + .

[0288] Step 4: Synthesis of compound 72e

[0289] Compound 72d (510 mg, 1.40 mmol) was added to concentrated sulfuric acid (10 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (30 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-25%) to give compound 72e (500 mg). MS m / z (ESI): 345.8 [M+1] + .

[0290] Step 5: Synthesis of Compound 72

[0291] Compound A1 (134.74 mg, 0.43 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (49.76 mg, 0.08 mmol), tris(dibenzylacetone)dipalladium (39.38 mg, 0.04 mmol), and cesium carbonate (420.31 mg, 1.29 mmol) were added to a 1,4-dioxane (5 mL) solution of compound 72e (150 mg, 0.43 mmol). The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-25%) to give compound 72 (40.5 mg). MS m / z (ESI): 579.0 [M+1] + . 1H NMR(400MHz, DMSO-d6)δ9.90(s,1H),8.83–8.76(m,2H),8.34(d,J=7.4Hz,1H),8.27(d,J=1.2Hz,1H),8.17(s,1H),7 .76(d,J=10.3Hz,1H),7.29–7.25(m,2H),4.74(s,1H),3.99(s,2H),2.54(d,J=1.2Hz,3H),2.41(s,3H),1.10(s,6H).

[0292] Example 3 (Compound 73)

[0293]

[0294] Step 1: Synthesis of compound 73b

[0295] At room temperature, tribromopyrimidine (4.41 g, 13.79 mmol) was added to a tetrahydrofuran (20 mL) solution of compound 73a (2 g, 9.19 mmol), and the reaction mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:0–5:1) to give compound 73b (2.2 g). MS m / z (ESI): 295.9 [M+1] + .

[0296] Step 2: Synthesis of compound 73c

[0297] At room temperature, 1.82 g (10.13 mmol) of 2-amino-5-bromo-1,3,4-thiadiazole was added to a mixture of acetonitrile and isopropanol (10 mL / 10 mL) containing 2 g (6.75 mmol) of compound 73b. The reaction mixture was stirred at 150 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:0–2:1) to give compound 73c (1.1 g). MS m / z (ESI): 376.9 [M+1] + .

[0298] Step 3: Synthesis of compound 73d

[0299] Sodium methoxide (0.19 g, 1.06 mmol) was added to a mixture of dichloromethane and methanol (4.5 mL / 0.5 mL) containing compound 73c (400 mg, 1.06 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (30 mL), extracted with dichloromethane (50 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 1:0–5:1) to give compound 73d (70 mg). MS m / z (ESI): 329.0 [M+1] + .

[0300] Step 4: Synthesis of compound 73e

[0301] At room temperature, zinc powder (47.10 mg, 0.72 mmol) and ammonium chloride (38.51 mg, 0.72 mmol) were added sequentially to a mixed solution of compound 73d (60 mg, 0.18 mmol) in ethanol and water (2 mL / 0.5 mL). The reaction mixture was stirred at 85 °C for 4 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with dichloromethane, and the filtrate was washed with saturated sodium chloride solution (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 73e (50 mg). MS m / z (ESI): 299.0 [M+1] + .

[0302] Step 5: Synthesis of 73g of compound

[0303] Trimethylaluminum (0.016 g, 0.22 mmol) was added to a toluene (2 mL) solution of compound 73e (30 mg, 0.10 mmol) and compound 73f (30 mg, 0.11 mmol, purchased from Bio-Pharmaceutical) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 4 hours. After the reaction was complete, sodium sulfate decahydrate was added to quench the reaction mixture. The residue was purified by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1) to obtain compound 73 g (15 mg).

[0304] Step 6: Synthesis of Compound 73

[0305] At room temperature, compound 73 g (15 mg, 0.029 mmol), compound 73 h (12 mg, 0.044 mmol, synthesis method referred to in the specification of patent CN105777756A, page 305, paragraphs 2536-2543, steps 1 and 2 of Example 99), cesium carbonate (19 mg, 0.058 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (2.4 mg, 0.0029 mmol) were added sequentially to a mixed solution of 1,4-dioxane (2 mL) and water (0.4 mL). The reaction mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 1:0 to 15:1) to obtain compound 73 (1.9 mg). MS m / z (ESI): 595.1 [M+1] + .

[0306] Example 4 (Compound 46)

[0307]

[0308] Step 1: Synthesis of compound 46b

[0309] 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 slowly added at -10 to 0 °C. The mixture was stirred at this temperature for 1 hour, then stannous chloride (1.01 g, 5.35 mmol) was added and stirred at -10 to 0 °C for 0.5 hours, followed by stirring at room temperature for 2 hours. 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 hour. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with DCM (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-5%) to give compound 46b (600 mg) MS m / z (ESI): 335.2 [M+1]. + .

[0310] Step 2: Synthesis of compound 46c

[0311] Compound 46b (500 mg, 1.50 mmol) was dissolved in toluene (10 mL), and 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 complete, the reaction solution was quenched with saturated sodium chloride aqueous solution (30 mL), and extracted with ethyl acetate (30 mL × 3 times). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain compound 46c (550 mg, crude product). The crude product was further purified by a Combi-Flash rapid preparation system (C18 reversed-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] + .

[0312] Step 3: Synthesis of compound 46d

[0313] Compound 46c (200 mg, 0.60 mmol) was dissolved in phosphorus oxychloride (2 mL), and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove excess phosphorus oxychloride, quenched with saturated sodium bicarbonate aqueous solution (20 mL), and extracted with dichloromethane (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and 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] + .

[0314] Step 4: Synthesis of compound 46e

[0315] Compound 46d (200 mg, 0.57 mmol) was dissolved in 1,4-dioxane (5 mL), and 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 sequentially. The reaction mixture was stirred at 100 °C under nitrogen protection for 3 hours. After the reaction was complete, the reaction solution was quenched with water (50 mL), extracted with dichloromethane (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE = 0-15%) to give compound 46e (220 mg). MS m / z (ESI): 387.3 [M+1] + .

[0316] Step 5: Synthesis of compound 46f

[0317] Compound 46e (200 mg, 0.52 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (3 mL, 4 M). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was quenched with a saturated aqueous sodium bicarbonate solution (30 mL). The residue was extracted with dichloromethane (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE = 0-20%) to give compound 46f (110 mg). MS m / z (ESI): 287.3 [M+1] + .

[0318] Step 6: Synthesis of Compound 46

[0319] Under nitrogen protection, a hexane solution of trimethylaluminum (0.06 mL, 1 M) was added to a toluene solution of compound 46f (10 mg, 0.03 mmol) and compound A1-1 (12 mg, 0.03 mmol) (2 mL). The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to give compound 46 (20 mg, crude product). The crude product was purified by preparative high-performance liquid chromatography (HPLC) (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 (400MHz, DMSO-d6) δ9.97(s,1H),8.85–8.79(m,1H),8.75(s,1H),8.24(d,J=1.4Hz,1H),8.17(s,1H),8.02(dd,J=9.8,8.8Hz,2H),7. 29(dd,J=7.4,2.1Hz,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).

[0320] Example 5 (Compound 74)

[0321]

[0322] Step 1: Synthesis of Compound 74b

[0323] Compound 74a (2.78 g, 9.89 mmol, synthetic method referred to page 80 of patent WO2011086098A1, synthesis of intermediate 60) 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 sequentially. The reaction mixture was heated to 100 °C under nitrogen protection and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature. Then, it was diluted with water (30 mL), extracted with ethyl acetate (40 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5%–20%) to give compound 74b (1.2 g). MS m / z (ESI): 200.0, 202.0 [M+1, M+3] + .

[0324] Step 2: Synthesis of compound 74c

[0325] Compound 74b (100 mg, 0.5 mmol) was dissolved in 1,4-dioxane and water (8 mL / 2 mL), followed by the addition of compound A2 (136 mg, 0.5 mmol), potassium carbonate (207 mg, 1.5 mmol), and the [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (41 mg, 0.05 mmol). The reaction mixture was heated to 80 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5%–50%) to give compound 74c (70 mg). MS m / z (ESI): 265.1 [M+1] + .

[0326] Step 3: Synthesis of Compound 74

[0327] 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. Under nitrogen protection, a solution of trimethylaluminum in n-hexane (0.06 mL, 2 M) was slowly added dropwise. The reaction mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography on silica gel plates (dichloromethane / methanol = 12 / 1) to give compound 74 (21.6 mg). MS m / z (ESI): 561.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.86(s,1H),8.82(d,J=7.2Hz,1H),8.76(s,1H),8.28(d,J=7.5Hz,2H),8.17(s,1H),7.72(d,J=10.3Hz,1H),7.28( dd,J=7.3,2.0Hz,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).

[0328] Example 6 (Compound 75)

[0329]

[0330] Step 1: Synthesis of compound 75a

[0331] Platinum dioxide (20 mg) was added to a solution of compound 74c (20 mg, 0.076 mmol) in anhydrous ethanol (3 mL). The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 75a (20 mg).

[0332] Step 2: Synthesis of Compound 75

[0333] At 0 °C, a hexane solution of trimethylaluminum (0.044 mL, 2 M) was slowly added dropwise to anhydrous toluene (2 mL) of compound 75a (20 mg, 0.075 mmol) and compound A1-1 (15 mg, 0.044 mmol). The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 12 / 1) to give compound 75 (11.6 mg). MS m / z (ESI): 563.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.81(d,J=7.2Hz,1H),8.75(s,1H),8.25(dd,J =9.7,4.4Hz,2H),8.17(s,1H),7.68(d,J=10.3Hz,1H),7.28(dd,J=7.3,2.0Hz,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=7.0Hz,3H),1.10(s,6H).

[0334] Example 7 (Compound 76)

[0335]

[0336] Step 1: Synthesis of compound 76b

[0337] 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 under reflux at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 0-10%) to give compound 76b (600 mg). MS m / z (ESI): 339.2 [M+H] + .

[0338] Step 2: Synthesis of compound 76c

[0339] 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. The reaction mixture was stirred at 80 °C for 8 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed three times with methanol. The combined filtrates were concentrated under reduced pressure, and the residue was diluted with (200 mL) water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were 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 give compound 76c (260 mg). MS m / z (ESI): 309.2 [M+H] + .

[0340] Step 3: Synthesis of Compound 76

[0341] Compound 76c (5 mg, 0.01 mmol) and compound A1-1 were dissolved in toluene (2 mL). Under nitrogen protection, a trimethylaluminum solution in n-hexane (0.05 mL, 1 M) was added to the reaction mixture, and the reaction mixture was heated at 90 °C for 3 hours. After the reaction was completed, the reaction mixture 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 chromatography (HPLC) (column: Durashell C18(A); 21.2 x 250 mm, 10 μm; 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). MSm / z (ESI): 605.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.81(s,1H),8.81(d,J=7.4Hz,1H),8.76(s,1H),8.41(d,J= 3.8Hz,1H),8.32(d,J=7.8Hz,1H),8.27(d,J=1.4Hz,1H),8.17(s,1H),7.66(d,J=10 .6Hz,1H),7.28(dd,J=7.4,2.0Hz,1H),4.74(s,1H),3.98(s,2H),2.58–2.53(m,1H) ,2.41(s,3H),1.26(dd,J=8.2,2.8Hz,2H),1.12(dd,J=4.8,2.6Hz,2H),1.10(s,6H).

[0342] Example 8 (Compound 77)

[0343]

[0344] Step 1: Synthesis of compound 77b

[0345] At -50°C, a DMF (10 mL) solution of t-BuOK (1.27 g, 11.35 mmol) was slowly added dropwise to a DMF (30 mL) solution of compound 77a (2 g, 11.35 mmol) and difluoromethyl (2-pyridyl) sulfone (1.75 g, 9.08 mmol). The reaction mixture was stirred at -45°C for 1 hour, and then a saturated aqueous solution of ammonium chloride (6 mL) and 3M hydrochloric acid (6 mL) were added to the reaction mixture. After the reaction was complete, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (70 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to give compound 77b (580 mg). 1 H NMR (400MHz, CDCl3) δ7.38–7.28(m,5H),4.44(s,2H),4.22–4.10(m,1H),2.96–2.86(m,2H),2.74–2.62(m,2H).

[0346] Step 2: Synthesis of compound 77c

[0347] At -78°C, a dichloromethane solution of boron tribromide (5.52 mL, 5.52 mmol, 1 M) was slowly added dropwise to a DCM solution of compound 77b (580 mg, 2.76 mmol) (6 mL). The reaction mixture was stirred at -78°C for 2 hours. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered to obtain a dichloromethane solution of compound 77c (30 mL, theoretical product 332 mg), which was directly used in the next reaction step.

[0348] Step 3: Synthesis of compound 77d

[0349] At 0 °C, sodium hydride (166 mg, 4.15 mmol, 60%) was added to a dichloromethane solution (30 mL, theoretical content 332 mg, 2.76 mmol) of compound 77c. After stirring for 30 minutes, TsCl (527 mg, 2.76 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (40 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 77d (290 mg). MS m / z (ESI): 275.2 [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.84–7.76(m,2H),7.36(d,J=8.0Hz,2H),4.94–4.82(m,1H),3.02–2.90(m,2H),2.88–2.76(m,2H),2.46(s,3H).

[0350] Step 4: Synthesis of compound 77f

[0351] Compound 77e (69 mg, 0.22 mmol, synthesis referenced in the first and second steps of intermediate 73 synthesis, page 170 of patent WO2024118887A1) and potassium carbonate (60 mg, 0.44 mmol) were added to a DMF (5 mL) solution of compound 77d (60 mg, 0.22 mmol). The reaction mixture was stirred at 100 °C for 5 hours. After the reaction was complete, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 77f (29 mg). MS m / z (ESI): 416.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.26(d,J=7.2Hz,1H),7.76(d,J=10.2Hz,1H),5.82–5.70(m,1H),3.54–3.38(m,4H),1.48(s,9H).

[0352] Step 5: Synthesis of 77g of compound

[0353] Compound 77f (29 mg, 0.07 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 mL, 4 M), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH 9-10 by adding saturated sodium bicarbonate aqueous solution (20 mL). Extraction was performed with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 77 g (20 mg, crude product). MS m / z (ESI): 316.3 [M+1] + .

[0354] Step 6: Synthesis of Compound 77

[0355] Under a nitrogen atmosphere, a hexane solution of trimethylaluminum (0.24 mL, 0.24 mmol, 1 M) was added to a solution of compound 77 g (15 mg, 0.05 mmol) and compound A1-1 (16 mg, 0.05 mmol) in anhydrous toluene (2 mL). The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was quenched with methanol (2 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to give compound 77 (9.16 mg). MS m / z (ESI): 612.6 [M+1] + . 1 HNMR (400MHz, DMSO) δ9.94(s,1H),8.82(d,J=7.2Hz,1H),8.78(s,1H),8.34(d,J=7.2Hz,1H),8.28(s,1H),8.18(s,1H),7.86(d,J=1 0.2Hz,1H),7.28(dd,J=7.4,1.8Hz,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).

[0356] Example 9 (Compound 86)

[0357]

[0358] Step 1: Synthesis of compound 86b

[0359] At 0 °C, 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), and the reaction mixture was stirred at room temperature for 1 hour. The temperature was then lowered to 0 °C, and compound 72a (1.19 g, 8.42 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (100 mL), washed successively with water (40 mL × 3) and saturated sodium chloride solution (40 mL), the combined organic phases were concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = ...

[0360] Compound 86b (1.07 g) was obtained after purification at a ratio of 100:1 to 40:1. MS m / z (ESI): 336.90 [M+1] + .

[0361] Step 2: Synthesis of compound 86c

[0362] At room temperature, I₂ (0.90 g, 3.53 mmol), KI (0.73 g, 4.41 mmol), and K₂CO₃ (1.22 g, 8.82 mmol) were added sequentially to a DMSO (10 mL) solution of compound 86b (0.99 g, 2.94 mmol). The reaction mixture was stirred at 100 °C for 6 hours. After the reaction was complete, the reaction solution was quenched with saturated Na₂S₂O₃ solution (30 mL). The aqueous solution was extracted with ethyl acetate (100 mL), washed successively with water (40 mL × 3) and saturated sodium chloride solution (40 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1–4:1) to give compound 86c (84 mg). MS m / z (ESI): 335.0 [M+1] + .

[0363] Step 3: Synthesis of compound 86d

[0364] At room temperature, 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 added sequentially to a 1,4-Dioxane (1 mL) solution of compound 86c (84 mg, 0.25 mmol). The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (30 mL), washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), the combined organic phases were concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound 86d (61 mg). MS m / z (ESI): 436.1 [M+1] + .

[0365] Step 4: Synthesis of compound 86e

[0366] At room temperature, a 4N hydrogen chloride / 1,4-dioxane solution (0.3 mL, 1.4 mmol) was added to a 1,4-Dioxane (3 mL) solution of compound 86d (61 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH of the reaction mixture was adjusted to approximately 9 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (30 mL × 3), washed successively with water (10 mL × 3) and saturated sodium chloride solution (10 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound 86e (34 mg). MS m / z (ESI): 272.0 [M+1] + .

[0367] Step 5: Synthesis of Compound 86

[0368] At 0 °C, trimethylaluminum (2 M 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). The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride solution (2 mL), extracted with ethyl acetate (30 mL), washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), the organic phase was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 15 / 1) to give compound 86 (16.71 mg). MS m / z (ESI): 568.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.81 (d, J = 7.4Hz, 1H), 8.75 (s, 1H), 8.29 ( d,J=1.3Hz,1H),8.16(s,2H),7.84(dd,J=7.9,1.6Hz,1H),7.42(d,J=8.0Hz,1H) ,7.26(dd,J=7.3,2.0Hz,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).

[0369] Example 10 (Compound 97)

[0370]

[0371] Step 1: Synthesis of compound 97a

[0372] At room temperature, 1-cyclopropyl-2-bromoethylone (31.30 mg, 0.19 mmol) was added to a 5 mL ethanol solution of compound 72c (50 mg, 0.16 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel plates (ethyl acetate / petroleum ether = 1 / 3) to give compound 97a (30 mg). MS m / z (ESI): 371.9 [M+1] + .

[0373] Step 2: Synthesis of Compound 97

[0374] At room temperature, compound A1 (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) were added sequentially to a 1,4-Dioxane (1 mL) solution of compound 97a (26.23 mg, 0.070 mmol). Nitrogen gas was purged three times, and the reaction mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel plates (methanol / dichloromethane = 1 / 20) to obtain compound 97 (5 mg). MS m / z (ESI): 605.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.90 (s, 1H), 8.82 (d, J = 7.3Hz, 1H), 8.76 (s, 1H), 8.3 2(d,J=7.4Hz,1H),8.27(d,J=1.3Hz,1H),8.17(s,1H),7.76(d,J=10.3Hz,1H ),7.28(dd,J=7.3,2.0Hz,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).

[0375] Example 11 (Compound 102)

[0376]

[0377] Step 1: Synthesis of compound 102b

[0378] At room temperature, N,N-dimethylformamide (17 mg, 0.24 mmol) and oxaloyl chloride (3.61 g, 28.40 mmol) were added sequentially to a dichloromethane (60 mL) solution of compound 102a (6 g, 23.67 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain crude compound 102b (5 g, crude product).

[0379] Step 2: Synthesis of compound 102d

[0380] At 0 °C, 102c (aminoguanidine carbonate) (5.01 g, 36.78 mmol) and tetrabutylammonium bromide (590 mg, 1.84 mmol) were added sequentially to a 1,4-dioxane (50 mL) solution, followed by the slow addition of compound 102c (5 g, 18.39 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filter cake was added to water (50 mL). The mixture was refluxed and stirred at 120 °C for 48 hours. The mixture was then filtered and dried to obtain the crude compound 102d (1.45 g). MS m / z (ESI): 290.8, 292.8 [M+1, M+3] + .

[0381] Step 3: Synthesis of compound 102e

[0382] At room temperature, chloroacetaldehyde diethanolate (0.83 g, 5.47 mmol) and cesium carbonate (3.24 g, 9.94 mmol) were added sequentially to a solution of compound 102d (1.45 g, 4.97 mmol) in N,N-dimethylformamide (14 mL). The reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and poured into water (30 mL), precipitating a brown solid. The solid was filtered to give crude compound 102e (1.7 g, crude product). MS m / z (ESI): 406.9, 408.9 [M+1, M+3] + .

[0383] Step 4: Synthesis of compound 102f

[0384] Compound 102e (1.7 g, 4.17 mmol) was dissolved in trifluoroacetic acid (17 mL) at room temperature, and the solution was sealed and stirred at 70 °C for 16 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane / methanol = ...

[0385] Compound 102f (670 mg) was obtained after purification at 0%–5%. MS m / z (ESI): 314.9, 316.9 [M+1, M+3] + .

[0386] Step 5: Synthesis of 102g of compound

[0387] At room temperature, potassium tetrafluorocyclopropane (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'-dipyridine (58 mg, 0.22 mmol) were added sequentially to a 1,4-dioxane (10 mL) solution of compound 102f (340 mg, 1.08 mmol). The reaction mixture was stirred openly at 65 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%–40%) to give compound 102 g (48 mg). MS m / z (ESI): 354.9, 356.9 [M+1, M+3] + .

[0388] Step 6: Synthesis of compound 102h

[0389] At room temperature, 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (7.5 mg, 0.013 mmol), tris(dibenzylacetone)dipalladium (12 mg, 0.013 mmol), cesium carbonate (85 mg, 0.26 mmol), and benzophenone imine (47 mg, 0.26 mmol) were added sequentially to a 102 g (48 mg, 0.13 mmol) solution of compound 1,4-dioxane (4 mL). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%–30%) to give compound 102 h (50 mg). MS m / z (ESI): 456.0 [M+1] + .

[0390] Step 7: Synthesis of compound 102i

[0391] Compound 102i (50 mg, 0.11 mmol) was added to a 4 M hydrochloric acid / 1,4-dioxane (5 mL) solution at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to remove a portion of the 1,4-dioxane. The remaining fraction was directly filtered to give crude compound 102i (30 mg). MS m / z (ESI): 292.1 [M+1] + .

[0392] Step 8: Synthesis of Compound 102

[0393] Under ice bath conditions, compound 102j (17 mg, 0.051 mmol, 29 mg, 0.12 mmol, synthetic method referred to page 170 of patent WO2024118887A1, synthesis of intermediate 73) was added to a toluene (2 mL) solution of compound 102i (15 mg, 0.051 mmol), and a 2M trimethylaluminum solution in n-hexane (0.03 mL, 0.051 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was heated to 100 °C and stirred for 4 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to give compound 102 (7 mg).

[0394] MSm / z(ESI): 588.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.90 (s, 1H), 8.82 (d, J = 7.2Hz, 1H), 8.76 (s, 1H), 8.28 (d,J=3.7Hz,2H),8.18(s,1H),7.75(d,J=2.4Hz,1H),7.69(d,J=10.3Hz,1H),7 .41(d,J=2.4Hz,1H),7.28(d,J=7.3Hz,1H),4.75(s,1H),3.98(s,2H),3.49(d, J=3.8Hz,1H),2.41(s,3H),1.25–1.23(m,2H),1.10(s,6H),1.04–1.01(m,2H).

[0395] Example 12 (Compound 78)

[0396]

[0397] Step 1: Synthesis of compound 78c

[0398] At room temperature, 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 mixed solution of compound 78a (30 mg, 0.09 mmol) in 1,4-dioxane and water (5 mL / 1 mL). The reaction mixture was heated to 80 °C and stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to give compound 78c (25 mg). MS m / z (ESI): 343.3 [M+1] + .

[0399] Step 2: Synthesis of Compound 78

[0400] Under a nitrogen atmosphere, a hexane solution of trimethylaluminum (0.15 mL, 0.15 mmol, 1 M) was added to a toluene solution of compound 78c (10 mg, 0.03 mmol) and compound 76c (9 mg, 0.03 mmol). The reaction mixture was heated to 100 °C and stirred for 3 hours. After the reaction was complete, the mixture was quenched with methanol (2 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-5%) to give compound 78 (6.83 mg). MS m / z (ESI): 605.5 [M+1] + .

[0401] 1 HNMR (400MHz, DMSO-d6) δ10.17(s,1H),9.56(s,1H),8.60(s,1H),8.42(d,J=4.0Hz,1H),8.26(d,J=8.0Hz,1H),8.01(s,1H),7.82(d,J= 8.0Hz,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).

[0402] Biological Examples

[0403] 1. Inhibitory effect on wild-type c-kit kinase

[0404] The Mobility Shift Assay method was used to evaluate the inhibitory effect of the test substances on wild-type c-kit kinase. The reaction was carried out in 384-well plates (Corning, 3573). 50 mM HEPES, pH 7.5, 0.01% Triton X-100, 10 mM MgCl2, and 2 mM DTT were used as reaction buffers. A 20 μL reaction mixture contained 6 nM c-kit (Carna, 08-156), 6 μM ATP (Sigma, 2383-5G), and 3 μM of the substrate FAM-labeled peptide (KKKKEEIYFFF-CONH2, GL, 263631). The initial concentration of the compound was 10 μM, serially diluted 4-fold with 1% DMSO, with 10 concentrations per well and double-duplicates. The reaction was incubated at 28°C for 90 minutes. Then, 25 μL of stop solution (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA) was added to each well of the 384-well plate to terminate the reaction. Conversion data were read using CaliperEZ Reader II and calculated using the formula: Inhibition rate % = (Positive control wells - Compound wells) / (Positive control wells - Negative control wells) * 100, where "Negative control wells" are the readings of the control wells without enzyme addition, and "Positive control wells" are the readings of the wells with DMSO added as a control. Concentration-effect curves (Y = Bottom + (Top - Bottom) / (1 + (IC50)) were fitted using GraphPad Prism 8 software. 50 / X)^HillSlope)), and calculate the concentration of the compound with a 50% inhibition rate, i.e., IC50. 50 The test results are shown in Table 1. Where A represents: IC 50Value ≤ 300nM; B represents: 300nM <IC 50 Value ≤ 600nM; C represents: 600nM <IC 50 Value ≤ 1000nM; D represents: 1000nM <IC 50 value.

[0405] Table 1

[0406] Example number Compound numbering <![CDATA[c-kit / IC 50 (nM)]]> 2 72 A 3 73 A

[0407] 2. Inhibitory effect on wild-type c-kit kinase

[0408] The commercially available kit HTRF KINEASE TK KIT (Revvity, 62TK0PEC) was used to evaluate the inhibitory effect of the test substance on wild-type c-kit kinase. The reaction was performed in a 384-well plate (PE, 6008280).

[0409] Dilute the 5X enzyme reaction buffer to 1X with distilled water, and add DTT, MgCl2, and MnCl2 to final concentrations of 1mM, 5mM, and 1mM respectively to prepare the 1X enzyme reaction buffer. Prepare 10 serially diluted concentrations (maximum 10 μM) using the 1X enzyme reaction buffer for testing, with DMSO at a final concentration of 1%. In a 10 μL reaction system, add 4 μL of the compound working solution and 2 μL of KIT kinase (Carna, 08-156) at a final concentration of 0.29 ng / μL. Dilute with 1X enzyme reaction buffer and place on ice 20 minutes before adding to the reaction system. 2 μL of TK Substrate-biotin (Revity, 61TK0BLC) at a final concentration of 0.25 μM and 2 μL of ATP (Promega, V9158) at a final concentration of 8 μM were prepared using 1X enzyme reaction buffer and added sequentially to the wells of a 384-well plate to initiate the reaction. Negative control wells contained no compound or kinase, and positive control wells contained no compound. After incubation at 25°C for 1 hour, 5 μL of TK Antibody-Cryptate diluted 100-fold with detection buffer (Revity, 62SDBRDF) and SA-XL665 (Revity, 610SAXLG) at a final concentration of 15.625 nM were added, and incubation continued at 25°C for another hour. Detection was performed using the HTRF module of a Molecular Device SpectraMax i3x microplate reader at an excitation wavelength of 340 nm and emission wavelengths of 616 nm and 665 nm. The inhibition rate of the test substance was calculated using the following formula:

[0410]

[0411] in

[0412] The concentration-effect curve (Y = Bottom + (Top - Bottom) / (1 + (IC)) was fitted using GraphPad Prism 8 software. 50 / X)^HillSlope)), and calculate the concentration of the compound with a 50% inhibition rate, i.e., IC50. 50 The test results are shown in Table 2. Where A represents: IC 50 Value ≤ 300nM; B represents: 300nM <IC 50 Value ≤ 600nM; C represents: 600nM <IC 50 Value ≤ 1000nM; D represents: 1000nM <IC 50 value.

[0413] Table 2

[0414]

[0415]

[0416] 3. Inhibition of c-kit phosphorylation in SCF-stimulated M-07e cells

[0417] M-07e cells (Pronosai, CL-0686) were seeded at a density of 2 × 10^6 cells / mL in Opti-MEM medium (Gibco, 11058021) containing 1% penicillin (Gibco, 15140-122) in 96-well plates (Corning, 3599), with a volume of 50 μL per well. After incubation at 37°C and 5% CO2 for 4 hours, 6.25 μL of a gradient concentration of the compound was added to each well to achieve a maximum final concentration of 1000 nM. This was repeated 5-fold serially to achieve 8 concentrations, with a final DMSO concentration of 0.22%. After further incubation at 37°C and 5% CO2 for 60 minutes, 6.25 μL of Human Recombinant SCF (STEMCELL, 78062) was added to achieve a final SCF concentration of 50 ng / mL. The positive control wells (max) contained no compound, and the negative control wells (min) contained neither the compound nor SCF. After incubation at room temperature on a shaker at 450 rpm for 15 minutes, 16 μL of 5X cell lysis buffer (CST, 9803) containing protease and phosphatase inhibitors (Beyotime, P1045) was added. The cells were lysed by gentle shaking at 4°C for 30 minutes, and the lysate was collected by centrifugation. Protein quantification was performed using the BCA (Beyotime, P0009) method. The phosphorylation level of the p-kit was detected using the PathScan@Phospho-c-Kit (Tyr719) Sandwich ELISA Kit according to the kit manual. The OD values ​​of the measured ELISA were normalized to protein concentration, and the inhibition rate was calculated using the following formula. A concentration-response curve was fitted using GraphPad Prism 8 software: (Y = Bottom + (Top - Bottom) / (1 + (IC50)) 50 / X)^HillSlope)), and calculate the concentration of the compound with a 50% inhibition rate, i.e., IC50. 50 The test results are shown in Table 3.

[0418] ODmax: Normalized absorbance of the control group containing cells, SCF, and no compound.

[0419] ODmin: Normalized absorbance of the control group containing cells but without SCF and the compound.

[0420] ODcpd: Normalized absorbance of a control group containing cells, SCF, and different concentrations of compounds.

[0421] Table 3

[0422]

[0423] The above describes specific embodiments of the present invention. It should be understood that the present invention is not limited to the limitations of the above embodiments; the embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Those skilled in the art can make various non-substantial changes and modifications to the present invention without departing from its conceptual framework, and all such changes fall within the scope of protection claimed by the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, T is It can be a single bond or a double bond; Ring A is a 5-membered heteroaryl group; X is C and Y is N; or, X is N and Y is C; G 1 For CR 0 Or N; G 3 For 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 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; 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; 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; Or, 2 Rs A Together with the atoms attached to it, they form C 5-8 Cycloalkyl, 5-8 membered heterocyclic or 5-8 membered heteroaryl, wherein the C 5-8 Cycloalkyl, 5-8 membered heterocyclic, or 5-8 membered heteroaryl groups are each independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups; 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 Halogenated alkoxy groups; R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each 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; R 4 and R 5 Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently and optionally enclosed by one or more R groups. E Replaced; R 6 and R 7 Together with the atoms attached thereto, they form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally surrounded by one or more R E Replaced; R 9 and R 10 Together with the atoms attached thereto, they form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein one or more of the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group are selected from R. E Replaced; R 11 and R 12 Together with the atoms attached thereto, they form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein one or more of the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group are selected from R. E Replaced; 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 3-8 Deuterated cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 member heteroaryl and The C mentioned 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 Deuterated cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are each independently and optionally constituting one or more R groups. k Replaced; 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 For H, C 1-6 Alkyl or C 1-6 Alkoxy; R k2 Hydroxyl group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 3-8 cycloalkyl; R k3 and R k4 They are the same or different, and each is independently H or 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 Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, and 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; t can be 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 heterocyclic group is O, S or N, and the number of heteroatoms is 1, 2, 3 or 4.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Where T is Ring A is an oxazolyl, triazolyl, or tetrazolyl group; G 2 For O or S; R c R d R e and R f Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, and 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; 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; 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; Ideally, R c R d R e and R f Independently selected from H or C 1-6 Alkyl groups, such as H or methyl.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Where T is Ring A is a 5-membered heteroaryl group; G 1 For CR 0 Or N; G 2 For 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 Halogenated alkoxy groups, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; R 3 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each 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; R 4 and R 5 Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, hydroxyl, amino, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each 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; R 6 and R 7 Together with the atoms attached thereto, they form a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-12 membered heterocyclic group or the 5-10 membered heteroaryl group is optionally 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; 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 Halogenated alkoxy groups; R a R b R g and R h Whether the groups are the same or different, they are each independently selected from H, halogen, cyano, and 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; m is 1 or 2; n is 1 or 2; The heteroatom in the heteroaryl or heterocyclic group is O, S or N, and the number of heteroatoms is 1, 2, 3 or 4.

4. The compound of formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that, Where T is Ideally, T is R 8 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)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 3-8 Deuterated cycloalkyl groups and 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 cycloalkyl, C 3-8 The deuterated cycloalkyl group and the 3-12 membered heterocyclic group are each independently and optionally converted by one or more R groups. k Replaced; 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 an oxazolyl, triazolyl, or tetrazolyl group, preferably, for (4)R 2 Selected from H, halogen, cyano and C 1-6 Alkyl; preferably, R 2 Selected from H, halogens and C 1-6 alkyl.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Where T is 7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Where R 1 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12-membered heterocyclic and 5-10-membered heteroaryl groups are each independently and optionally constituting one or more R groups. A Replaced; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2)-C 3-8 Cycloalkyl and -(CH2)-(3-8 membered heterocyclic groups), the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group -(CH2)-C 3-8 The cycloalkyl group and -(CH2)-(3-8 membered heterocyclic group) are each independently and optionally selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkoxy and C 1-6 One or more of the hydroxyalkyl groups are substituted; Or, 2 Rs A Together with the attached atoms, they form a 5-8 membered heterocyclic group, wherein the 5-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups; Ideally, R 1 for R A1 R A2 R A3 R A4 and R A5 Whether the two are the same or different, each is independently selected from H and C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2)-C 3-8 Cycloalkyl and -(CH2)-(3-8 membered heterocyclic groups), the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, -(CH2)-C 3-8 The cycloalkyl group and -(CH2)-(3-8 membered heterocyclic group) are each independently and optionally selected from halogens, hydroxyl groups, C 1-6 Alkoxy and C 1-6 One or more of the hydroxyalkyl groups are substituted; Or, R A4 and R A5 Together with the atoms attached to it, they form C 5-8 Cycloalkyl or 5-8 membered heterocyclic groups, wherein the C 5-8 The cycloalkyl or 5-8 membered heterocyclic group is optionally selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 It is substituted with one or more of cycloalkyl and 3-8 membered heterocyclic groups.

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Where R 1 H, Cl, methyl 9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It is selected from either Option 1 or Option 2: Option 1: The compound represented by formula (I) is the same as the compound represented by formula (II). in, Rings A, X, Y, R 1 R 2 m, n, and t are as defined in claims 1-8; Option 2: The compound shown in formula (I) is the same as the compound shown in formula (III). Among them, G 2 For O or S; X, Y, R 1 R 2 R E And t as defined in any one of claims 1-8.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or two of the following conditions: (1) T is selected from (2)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.

11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Ring A is selected from triazole and tetrazolium, for example tetrazolium, and for example... The "1" position is connected to a phenyl group; (2)R a and R b Halogens, for example, F; (3)R 4 and R 5 Independent of halogen, C 1-6 Alkyl or C 3-8 Cycloalkyl groups, such as chloro or cyclopropyl groups; (4)R 0 For H; (5)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 Replaced; (6)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 Replaced; (7)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 groups, such as methyl or cyclopropyl groups; (8)R g and R h H is independent; (9)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 substituted with hydroxyl groups; Ideally, R 1 for R A2 and R A5 Independently H or C 1-6 Alkyl, R A4 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.

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is any of the compounds shown in Table A: Table A 13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is any of the compounds shown in Table B: Table B 14. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound of formula (I) as claimed in any one of claims 1-13 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

15. Use of a compound of formula (I) as described in any one of claims 1-13, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 14, in the preparation of a medicament for inhibiting c-kit.

16. Use of a compound of formula (I) as described in any one of claims 1-13, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 14, in the preparation of a medicament for the prevention and / or treatment of c-kit-mediated diseases; Preferably, the c-kit-mediated diseases are selected from mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension, primary pulmonary hypertension, or cancer. More preferably, the c-kit-mediated disease is selected from mast cell tumor, mastocytosis, urticaria, inflammatory bowel disease, or diabetes; even more preferably, the c-kit-mediated disease is mast cell leukemia.

17. Use in the preparation of a medicament 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, preferably, in the preparation of a medicament for the prevention and / or treatment of mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary hypertension, primary pulmonary hypertension, or cancer, for example, for the prevention and / or treatment of mast cell tumor, mastocytosis, urticaria, inflammatory bowel disease, or diabetes, and another example of mast cell-related diseases such as mast cell leukemia.

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