Heterocyclic compound, preparation method therefor and use thereof

Abstract

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

Description

Heterocyclic compounds, processes for their preparation and uses thereof

[0001] This application claims priority to Chinese patent application 2024110691090 with a filing date of 2024 / 8 / 6. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

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

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

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

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

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

[0007] wherein T is

[0008] G 1 and G 2 are the same or different, each independently CR 1 or N;

[0009] Ring B is a 5-membered heteroaryl;

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

[0011] is a single bond or a double bond;

[0012] R 0 selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2) t -C 3-8 cycloalkyl and -(CH2) t -(3-8 membered heterocyclyl), each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2) t -C 3-8 cycloalkyl and -(CH2) t -(3-8 membered heterocyclyl) each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0013] R 1 selected from H, halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0014] R 2 is C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;

[0015] R 2A and R 2B are the same or different, each independently selected from H, halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0016] R 3 and R 4 are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0017] or, any group of R 1 and R 3 , R 1 and R 4 together with the atom to which they are attached form a 5-12 membered carbocyclic or heterocyclic ring, said 5-12 membered carbocyclic or heterocyclic ring being optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0018] each R 5 is independently selected from the group consisting of H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0019] R 6 is selected from the group consisting of H, halogen, cyano, amino, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and said C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl is each independently optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6hydroxyalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, one or more of which are optionally substituted;

[0020] R a and R b are the same or different, each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0021] t is 1 or 2;

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

[0023] p is 1, 2 or 3;

[0024] q is 1, 2 or 3;

[0025] the heteroatoms in said "heterocycle", "heterocyclyl" or "heteroaryl" are selected from the group consisting of O, N and S, in a number of 1, 2, 3 or 4.

[0026] In some embodiments, any one of R 1 and R 3 , R 1 and R 4 together with the atom to which they are attached form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl being optionally substituted with one or more selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0027] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, satisfies one or more of the following conditions:

[0028] (1) said C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl, for example methyl;

[0029] (2) said halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine, for example fluorine;

[0030] (3) the C 3-8 Cycloalkyl is independently C 3-6 Cycloalkyl is independently C

[0031] (4) the 3-8 membered heterocyclyl is independently a 4-6 membered heterocyclyl having 1 heteroatom selected from O;

[0032] (5) the 5-10 membered heteroaryl or 5 membered heteroaryl is independently a monocyclic 5 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N and O (e.g., pyrazolyl, oxazolyl, triazolyl, tetrazolyl, or ) or a monocyclic 5 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected from N and S (e.g., thiazolyl);

[0033] (6) the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, preferably methoxy;

[0034] (7) the C 1-6 Hydroxyalkyl is independently C 1-6 alkyl, e.g., -CH2OH;

[0035] (8) when any one of R 1 and R 3 , R 1 and R 4 , together with the atom to which they are attached, form a 5-12 membered heterocycle, the 5-12 membered heterocycle is an unsaturated 7 membered heterocycle having 1 heteroatom selected from O.

[0036] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is: is is R 3 , R 4 , and T are as defined in Formula (I).

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

[0038] wherein R 3 and R 4 are the same or different, each being independently selected from H, halogen, and C 1-6alkyl;

[0039] Ring B, R 0 R 1 R 5 R 6 And n is as defined by equation (I).

[0040] In some embodiments, the compound represented by formula (I), formula (II-1), formula (II-2), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 All are H.

[0041] In some embodiments, the compound represented by formula (I), formula (II-1), formula (II-2), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, 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 1-6 Alkoxy, 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 Alkyl, C 1-6 Hydroxyalkyl and C 1-6 One or more substitutions in the alkoxy group;

[0042] R 1 Selected from H, halogens, C 1-6 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups.

[0043] 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 (IV).

[0044] L is C 1-6 Alkylene or C 1-6 Heteroalkylene, the C 1-6 Alkylene or C 1-6 The heteroalkylene group is optionally selected from halogen, cyano, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 alkoxy and C 1-6 one or more of the substituents in haloalkoxy;

[0045] ring B, R 0 , R 5 , R 6 and n are as defined in Formula (I).

[0046] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein ring B is oxazolyl, triazolyl, or tetrazolyl.

[0047] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein ring B is 1,2,4-oxadiazolyl or tetrazolyl.

[0048] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 6 as defined in Formula (I).

[0049] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein

[0050] R 6 is H, halo, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, or the C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl is each independently optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl;

[0051] R a and R​​b the same or different, each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0052] p is 1, 2 or 3;

[0053] q is 1, 2 or 3.

[0054] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein is

[0055] In some embodiments, R 6 is C 1-6 alkyl, C 3-8 cycloalkyl, or the C 1-6 alkyl or C 3-8 cycloalkyl is each independently optionally substituted with halogen or hydroxyl;

[0056] R a and R b the same or different, each independently selected from halogen;

[0057] p is 1;

[0058] q is 1.

[0059] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein is is preferably

[0060] In some embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 0 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl), the C 1-6 alkyl, C 1-6 alkoxy, C3-8 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C

[0061] In some embodiments, a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 0 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C

[0062] In some embodiments, a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 0 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C

[0063] In some embodiments, a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 0 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 0 Cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl) are each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C

[0064] In some embodiments, a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R1 selected from H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

[0065] In some embodiments, a compound of Formula (I), (II-1), (II-2), (III-1), (III-2), or a pharmaceutically acceptable salt thereof, wherein R 1 selected from halogen, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; preferably C 1-6 alkyl.

[0066] In some embodiments, a compound of Formula (I), (II-1), (II-2), (III-1), (III-2), or a pharmaceutically acceptable salt thereof, wherein R 1 selected from H, Cl, methyl, cyclopropyl, cyclobutyl and oxetanyl.

[0067] In some embodiments, a compound of Formula (I), (II-1), (II-2), (III-1), (III-2), or a pharmaceutically acceptable salt thereof, wherein R 1 selected from Cl, methyl, cyclopropyl, cyclobutyl and oxetanyl.

[0068] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with one or more selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy.

[0069] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 hydroxyalkyl.

[0070] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0071] In some embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, wherein R 2A and R 2B are each independently selected from H, halogen, C 1-6 alkyl.

[0072] In some embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, wherein R 2A and R 2B are each H.

[0073] In some embodiments, compounds of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV) or pharmaceutically acceptable salts thereof, wherein each R 5 are each independently selected from H, halogen, and C 1-6 alkyl.

[0074] In some embodiments, compounds of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV) or pharmaceutically acceptable salts thereof, wherein R 5 is halogen; preferably, R 5 is chloro or fluoro.

[0075] In some embodiments, compounds of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV) or pharmaceutically acceptable salts thereof, wherein n is 1 or 2.

[0076] In some embodiments, T is selected from any of the following fragments: preferably

[0077] In some embodiments, R 5 is selected from F, Cl, and methyl, preferably F and Cl. In some embodiments, exemplary specific compounds of Formula (I) include, but are not limited to, the structures in Table A below:

[0078] Table A

[0079] In some embodiments, exemplary specific compounds of Formula (I) include, but are not limited to, the structures in Table B below:

[0080] Table B

[0081] Another aspect of the present application provides an isotopically-labeled compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a compound of Table A or Table B, preferably deuterium (D or 2 H) substituted hydrogen 1 H).

[0082] Another aspect of the present application provides a method for preparing a compound of Formula (I) by condensation of a compound of Formula (A) with a compound of Formula (B) to obtain a compound of Formula (I),

[0083] wherein, R A is H or C 1-6 alkyl;

[0084] T, ring B, X, Y, R 3 , R 4 , R 5 , R 6 and n are as defined in any one of the present application.

[0085] Another aspect of the present application provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0086] Another aspect of the present application also provides the use of a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a compound of Table A or Table B, or a pharmaceutically acceptable salt thereof, or a compound of any one of the foregoing isotopically-labeled compounds, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting c-kit.

[0087] Another aspect of the present application also provides the use of a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a compound of Table A or Table B, or a pharmaceutically acceptable salt thereof, or a compound of any one of the foregoing isotopically-labeled compounds, or a pharmaceutical composition comprising the same, in the manufacture of a c-kit inhibitor.

[0088] The present application also provides the use of a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a compound of Table A or Table B, or a pharmaceutically acceptable salt thereof, or a compound of any one of the foregoing isotopically-labeled compounds, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for preventing and / or treating a c-kit-mediated disease or disorder.

[0089] The present application also provides the use of a compound represented by Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled material, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for preventing and / or treating a mast cell-related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer; preferably, for preventing and / or treating a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0090] The present application also provides a method of inhibiting c-kit, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled material, or a pharmaceutical composition comprising the same.

[0091] The present application also provides a method of preventing and / or treating a c-kit-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled material, or a pharmaceutical composition comprising the same.

[0092] The present application also provides a method of preventing and / or treating a mast cell-related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled material, or a pharmaceutical composition comprising the same.

[0093] The present application also provides a method of preventing and / or treating a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled material, or a pharmaceutical composition comprising the same.

[0094] The present application also provides a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled compound, or the aforementioned pharmaceutical composition, for use as a medicament.

[0095] The present application also provides a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled compound, or the aforementioned pharmaceutical composition, for use as a c-kit inhibitor.

[0096] The present application also provides a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled compound, or the aforementioned pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating a c-kit-mediated disease or disorder.

[0097] The present application also provides a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled compound, or the aforementioned pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating a mast cell-related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer.

[0098] The present application also provides a compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Formula (IV), or a pharmaceutically acceptable salt thereof, or the aforementioned isotopically-labeled compound, or the aforementioned pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0099] In some embodiments, the c-kit-mediated disease is selected from a mast cell-related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer.

[0100] In some embodiments, the c-kit-mediated disease is selected from a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

[0101] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0102] In some embodiments, the pharmaceutical composition contains 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled material thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1 to 99.9% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled material thereof. In certain embodiments, the pharmaceutical composition contains 0.5 to 99.5% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled material thereof. In certain embodiments, the pharmaceutical composition contains 1 to 99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, or an isotopically-labeled material thereof.

[0103] In certain embodiments, the pharmaceutical composition contains 0.01 to 99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1 to 99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1 to 99% of one or more pharmaceutically acceptable excipients.

[0104] As a pharmaceutical, the compounds of the present application can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the art of pharmacy, and can be administered by a variety of routes depending upon whether local or systemic treatment is desired and upon the area to be treated. They can be administered topically (e.g., transdermal, transcutaneous, opthalmic, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal, oral or parenteral administration. Parenteral administration includes subcutaneous, intracutaneous, intramuscular, intra- peritoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular administration. They can be administered parenterally, e.g., by injection or continuous infusion, in a single daily dose, or can be administered by, e.g., a continuous perfusion pump.

[0105] In preparing the compositions of this application, the active ingredient will generally be mixed with a excipient, and the resulting compositions can be in unit dosage form. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments containing, e.g., up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0106] The "excipient" as used herein refers to an ingredient other than the active ingredient, and includes, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0107] In another aspect, pharmaceutically acceptable salts of the compounds described herein can be inorganic or organic salts, acid addition salts if the compounds have a basic center, base addition salts if the compounds have an acidic center, and internal salts if the compounds contain both an acidic center and a basic center (e.g., a carboxylate group and a tertiary nitrogen).

[0108] In another aspect, the compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such isomers, including cis and trans isomers, (-)- and (+)-enantiomeric forms, (R)- and (S)-enantiomeric forms, diastereomeric forms, (D)- isomer forms, (L)-isomer forms, racemic mixtures and other mixtures, and enantiomeric or diastereomeric enrichments thereof, all of which are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0109] The term "plurality" as used above in reference to the number of substituents or the number of heteroatoms means two, three, four, or five.

[0110] In the chemical structures of the compounds described herein, the bond indicates unspecified configuration, indicates absolute configuration, i.e., if chiral isomers are present in the chemical structure, the bond may be or both configurations.

[0111] The bond indicates unspecified configuration, including the cis (E) or trans (Z) configuration.

[0112] In addition, the compounds and intermediates of the present application can exist in different tautomeric forms, and all such forms are embraced within the scope of the present application. "Tautomers" refer to different energy structures that can interconvert through a low energy barrier. For example, prototropic tautomers (also known as proton-shift tautomers) include interconversions through the migration of a proton, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds of the present application are within the scope of the present application. The naming of a compound in a single form does not exclude any tautomers.

[0113] The present application also includes isotopically-labeled compounds of the present application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as​2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, and the like. All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0114] Unless otherwise indicated, when a position is designated specifically as deuterium (D), the position is understood to have deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). Exemplary compounds having deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium can have deuterium in an abundance of at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art are capable of synthesizing compounds in deuterated form by reference to the literature. In preparing deuterated forms of compounds, the deuterated starting materials can be obtained from commercial sources or they can be synthesized using conventional techniques employing deuterated reagents including, but not limited to, deuterated borane, trideuteroborane in tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, and the like.

[0115] A "therapeutically effective amount" of the present application refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by person of skill in the art, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed to the disease, disorder and condition but has not yet experienced or displayed the pathology or symptomatology of the disease; (2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptomatology of the disease, disorder or condition (i.e., retarding the further development of the pathology and / or symptomatology); (3) relieving the disease: for example, relieving a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptomatology of the disease, disorder or condition (i.e., reversing the pathology and / or symptomatology). For a pharmaceutical or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the agent to provide the desired effect, without being toxic to the subject. The effective amount will vary depending on the subject's age and general condition, as well as the particular active agent, and appropriate effective amounts for a given situation will be ascertainable by one of skill in the art using only routine testing techniques.

[0116] "Pharmaceutically acceptable" means, within the scope of sound medical judgment, that the compounds, materials, compositions, and / or dosage forms are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0117] "Patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, goats, horses, or primates, most preferably humans.

[0118] Definitions and explanations of terms

[0119] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0120] In the present application means that the corresponding group is attached to the to other moieties, groups in the compounds.

[0121] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which can be straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms (C1-C6alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. The term "alkyl" also includes haloalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl, and the like. 1-6Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0122] The term "alkoxy" means -O-(alkyl), where alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. More preferred are alkoxyl groups containing 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, and 6). Most preferred are methoxy, ethoxy, propyloxy, and butyloxy. Alkoxy groups can be substituted or unsubstituted. 1-12 The term "alkoxy" means -O-(alkyl), where alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. More preferred are alkoxyl groups containing 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, and 6). Most preferred are methoxy, ethoxy, propyloxy, and butyloxy. Alkoxy groups can be substituted or unsubstituted. 1- The term "alkoxy" means -O-(alkyl), where alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. More preferred are alkoxyl groups containing 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, and 6). Most preferred are methoxy, ethoxy, propyloxy, and butyloxy. Alkoxy groups can be substituted or unsubstituted.

[0123] The term "heterocycle" means a saturated or partially unsaturated monocyclic or polycyclic ring hydrocarbon substituent which can contain 5 to 20 ring atoms, of which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which sulfur can optionally be oxidized (i.e., form a sulfoxide or sulfone), but does not include ring members of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferred are rings containing 5 to 12 ring atoms (e.g., 5, 6, 7, and 8), of which 1, 2, 3, or 4 ring atoms are heteroatoms.

[0124] The term "heterocycle" means a saturated or partially unsaturated monocyclic or polycyclic ring hydrocarbon substituent which can contain 5 to 20 ring atoms, of which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which sulfur can optionally be oxidized (i.e., form a sulfoxide or sulfone), but does not include ring members of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferred are rings containing 5 to 12 ring atoms (e.g., 5, 6, 7, and 8), of which 1, 2, 3, or 4 ring atoms are heteroatoms.

[0125] The term "heterocycle" means a saturated or partially unsaturated monocyclic or polycyclic ring hydrocarbon substituent which can contain 5 to 20 ring atoms, of which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which sulfur can optionally be oxidized (i.e., form a sulfoxide or sulfone), but does not include ring members of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferred are rings containing 5 to 12 ring atoms (e.g., 5, 6, 7, and 8), of which 1, 2, 3, or 4 ring atoms are heteroatoms.

[0126] The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged) fused to an aryl, heteroaryl, or heterocyclyl ring as described herein, wherein the ring that is attached to the parent structure is a cycloalkyl, non-limiting examples of which include etc.; preferably The cycloalkyl group can be substituted or unsubstituted.

[0127] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring-like substituent that can contain from 3 to 20 ring atoms, of which one or more are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), but not ring moieties of -O-O-, -O-S-, or -S-S-, with the remaining ring atoms being carbon. Preferably, there are from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, there are from 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, there are from 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, there are 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups.

[0128] The heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused, and bridged) fused to an aryl, heteroaryl, or cycloalkyl ring as described herein, wherein the ring that is attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0129] etc. The heterocyclyl group can be substituted or unsubstituted.

[0130] The term "aryl" refers to a fully carbon-based monocyclic or fused polycyclic (fused polycyclic is a ring sharing pairs of adjacent carbon atoms) group having a conjugated pi-electron system, which can contain from 6 to 14 members, preferably from 6 to 10 members, e.g., phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described herein, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include: The aryl group can be substituted or unsubstituted.

[0131] The term "heteroaryl" refers to a heteroaromatic system which can contain from 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 or 6 membered, e.g., furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring, as described herein, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include: The heteroaryl group can be substituted or unsubstituted.

[0132] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl", and "heteroaryl" and the like herein can be substituted or unsubstituted; when substituted, it can be substituted at any available attachment point with one or more of the same or different substituents, preferably independently optionally selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0133] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived from removal of one hydrogen atom from a ring atom of the parent, or two hydrogen atoms from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heterocyclene", "heteroarylene".

[0134] The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined herein.

[0135] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0136] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl and halogen are as defined herein.

[0137] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy and halogen are as defined herein.

[0138] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined herein.

[0139] The term "halogen" refers to F, Cl, Br, or I.

[0140] The term "hydroxy" refers to -OH.

[0141] The term "amino" refers to -NH2.

[0142] The term "cyano" refers to -CN.

[0143] The term "nitro" refers to -NO2.

[0144] The term "oxo" or "keto" refers to "=O".

[0145] The term "carbonyl" refers to C=O.

[0146] The term "carboxyl" refers to -C(O)OH.

[0147] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined herein.

[0148] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl.

[0149] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort, as to whether a substitution is possible or not. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0150] The above-mentioned preferred conditions can be combined in any way, without departing from the ordinary knowledge of a person skilled in the art, to obtain preferred embodiments of the present application.

[0151] The reagents and starting materials used in the present application are commercially available. Advantages:

[0152] The present application provides a small molecule compound with a heterocyclic structure, which can be used as a c-kit inhibitor. The compound or pharmaceutical composition has a strong inhibitory effect on the c-kit receptor and excellent pharmacokinetic effects, and can be used for the effective treatment or prevention of c-kit-mediated diseases. DETAILED DESCRIPTION

[0153] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application. The experimental methods not specified in the following examples are selected according to the conventional methods and conditions, or according to the product instructions.

[0154] The experimental methods not specified in the following examples are selected according to the conventional methods and conditions, or according to the product instructions.

[0155] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a Bruker Avance III 400MHz nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0156] The mass spectrometry (MS) is measured by a Waters 2767HPLC / Waters SQD, Waters H-class UPLC-SQD2, Agilent HPLC / Waters liquid chromatography-mass spectrometry.

[0157] The chiral HPLC analysis is measured by a Shimadzu LC-20AD.

[0158] The thin layer chromatography silica gel plate is used by Shanghai Chemical Reagent (Group) Co., Ltd. GF254 silica gel plate, and the silica gel plate used in the thin layer chromatography (TLC) has a specification of 0.2-0.25mm, and the thin layer chromatography separation and purification product has a specification of 0.4-0.5mm.

[0159] The column chromatography generally uses 100-200 mesh silica gel as the carrier by Shanghai Chemical Reagent (Group) Co., Ltd.

[0160] The high performance liquid chromatography preparation uses a Waters HPLC, a Gilson HPLC and a Biotage MPLC preparative chromatograph.

[0161] The chiral separation column chromatography uses a Gilson GX-281 preparative HPLC.

[0162] Unless otherwise specified, the reactions in the examples are carried out under a nitrogen atmosphere.

[0163] The nitrogen atmosphere refers to that the reaction bottle is connected with a nitrogen balloon with a volume of about 1 liter.

[0164] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.

[0165] Unless otherwise specified, the reaction temperature in the examples is room temperature, and the temperature range is 20-30°C.

[0166] Those skilled in the art will understand that chiral compounds can be distinguished by the order of retention time in a chiral chromatographic column, therefore, chiral compounds separated by the order of retention time are distinguished by the number suffix P1, P2, etc. That is, the suffix P1 corresponds to the chiral structure separated first, and the suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of a compound is listed in the structural formula, it does not mean that it corresponds one-to-one to the compound with the number suffix P1, P2, but only indicates the two existing forms of absolute configuration. The absolute configuration of the compound with the number suffix P1, P2 is objectively corresponding to the absolute configuration of a specific retention time.

[0167] Reagent English abbreviation corresponding to reagent name:

[0168] Examples

[0169] Example 1 (compound 4)

[0170] First step: synthesis of compound 4b

[0171] At room temperature, 4-bromopyrazole (2.98 g, 14.97 mmol) and potassium carbonate (3.10 g, 22.46 mmol) were added to a solution of compound 4a (2.2 g, 14.97 mmol) in DMF (20 mL) in turn, and the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction liquid was diluted with saturated brine (20 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain compound 4b (3.1 g). MS m / z (ESI): 273.0 [M+1] + .

[0172] Second step: synthesis of compound 4c

[0173] To a solution of compound 4b (200 mg, 0.73 mmol) in THF (5 mL) was added lithium aluminum hydride (0.73 mL, 0.73 mmol) dropwise at 0 °C. The reaction mixture was stirred at ice bath for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated brine (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 4c (180 mg, crude). The crude compound was used directly in the next step without purification. MS m / z (ESI): 231 [M+1] + .

[0174] Step 3: Synthesis of compound 4e

[0175] To a solution of compound 4c (160 mg, crude), compound 4d (161 mg, 0.69 mmol, synthesis method refer to patent CN114380818A specification page P37 synthesis of compound 9-2), Cs2CO3 (449.63 mg, 1.38 mmol) and Pd(dppf)Cl2 (56.35 mg, 0.069 mmol) in 1,4-Dioxane (5 mL) was added at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 85 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to give compound 4e (120 mg). MS m / z (ESI): 341.1 [M+1] + .

[0176] Step 4: Synthesis of compound 4

[0177] To a solution of compound 4e (10 mg, 0.029 mmol) and compound 4f (8.09 mg, 0.029 mmol, synthesis method refer to patent WO2024118887A1 specification page 170 synthesis of compound intermediate 73) in toluene (2 mL) was added trimethylaluminum (2M in n-hexane, 0.029 mL, 0.058 mol) dropwise at ice bath. The reaction mixture was stirred at 110 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plate (methanol:dichloromethane = 1:10) to give compound 4 (3.79 mg). MS m / z (ESI): 547.9 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.83 (d, J = 7.1 Hz, 1H), 8.75 (s, 1H), 8.57 - 8.52 (m, 1H), 8.42 - 8.35 (m, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 5.6, 4.0 Hz, 1H), 4.66 - 4.63 (m, 1H), 4.58 - 4.47 (m, 1H), 3.47-3.45 (m, 2H), 2.90 - 2.84 (m, 1H), 2.38 - 2.30 (m, 2H), 1.88-1.81 (m, 1H), 1.64 (t, J = 8.0 Hz, 2H), 1.46 - 1.37 (m, 2H), 1.34 - 1.29 (m, 2H).

[0178] Example 2 (Compound 1)

[0179] First Step: Synthesis of Compound 1b

[0180] Under nitrogen atmosphere, n-butyllithium tetrahydrofuran solution (1.6 M, 18.9 mL, 30.25 mmol) was slowly added to a solution of compound 1a (2.5 g, 25.21 mmol) in tetrahydrofuran (25 mL), the mixture was stirred at -78 °C for 1 h, then a solution of acetone (1.76 g, 30.25 mmol) in tetrahydrofuran (5 mL) was slowly added to the reaction, the reaction mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction was quenched by adding saturated ammonium chloride (15 mL), the aqueous phase was extracted with dichloromethane (3 x 50 mL), the combined organic layers were washed with saturated brine (3 x 30 mL), the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to give compound 1b (4 g). MS m / z (ESI): 158.1 [M+1] + .

[0181] Second Step: Synthesis of Compound 1c

[0182] N-bromosuccinimide (2.04 g, 11.45 mmol) was added to a solution of compound 1b (1.5 g, 9.54 mmol) in dichloromethane (20 mL) at room temperature, the reaction mixture was stirred at 25 °C for 4 h. After the reaction was completed, the reaction was diluted with water (50 mL), the aqueous phase was extracted with dichloromethane (3 x 50 mL), the combined organic layers were washed with saturated brine (3 x 20 mL), the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to give compound 1c (2 g). MS m / z (ESI): 235.9, 237.9 [M+1, M+3]+ .

[0183] Step 3: Synthesis of compound 1d

[0184] Sulfuric acid (0.75 g, 7.62 mmol) was added to a solution of compound 1c (1.8 g, 7.62 mmol) in acetic acid (18 mL) at room temperature, and the reaction mixture was stirred at 85 °C for 12 h. After completion of the reaction, the reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 3 / 1) to give compound 1d (400 mg). MS m / z (ESI): 217.9, 219.9 [M+1, M+3] + .

[0185] Step 4: Synthesis of compound 1e

[0186] Potassium carbonate (0.29 g, 2.07 mmol), potassium ferricyanide (1.14 g, 3.45 mmol), and potassium osmate (5.1 mg, 0.014 mmol) were sequentially added to a solution of compound 1d (150 mg, 0.69 mmol) in a mixture of tert-butanol and water (3 mL / 3 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 12 h. After completion of the reaction, the aqueous phase was extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were washed with aqueous sodium sulfite solution (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1e (160 mg). MS m / z (ESI): 251.9, 253.9 [M+1, M+3] + .

[0187] Step 5: Synthesis of compound 1f

[0188] Compound 1e (100 mg, 0.40 mmol), compound 4d (190 mg, 0.60 mmol, synthesis method referring to compound 9-2 on page P37 of patent CN114380818A), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (33 mg, 0.040 mmol), and cesium carbonate (260 mg, 0.80 mmol) were sequentially added to a mixture of 1,4-dioxane and water (2 mL / 0.4 mL) at room temperature, and the reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 0 / 1) to give compound 1f (70 mg). MS m / z (ESI): 362.0 [M+1]+ .

[0189] Step 6: Synthesis of compound 1

[0190] A 2M solution of trimethylaluminum in n-hexane (0.06 mL, 0.12 mmol) was added to a solution of compound 4f (15 mg, 0.059 mmol, synthesis method refer to patent WO2024118887A1 page 170 synthesis of compound intermediate 73) and compound 1f (21 mg, 0.059 mmol) in toluene (2 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 3 hours. After the reaction was completed, the reaction was quenched by adding sodium sulfate decahydrate (1 g) to the reaction solution. The mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0 / 1 ~ 1 / 15) to obtain compound 1 (15 mg). MS m / z (ESI): 569.0 [M+1] + .

[0191] 1 H NMR (400 MHz, DMSO-d6) d 10.02 (s, 1H), 8.91 (dd, J = 7.2, 0.7 Hz, 1H), 8.83 (s, 1H), 8.28 (dd, J = 13.4, 4.3 Hz, 2H), 7.85 (d, J = 10.1 Hz, 1H), 7.24 (dd, J = 7.2, 2.1 Hz, 1H), 5.91 (s, 1H), 4.91 (t, J = 6.1 Hz, 1H), 4.57 - 4.46 (m, 1H), 3.57 (dd, J = 6.1, 2.3 Hz, 2H), 1.47 (s, 3H), 1.44 - 1.39 (m, 2H), 1.32 - 1.28 (m, 2H), 1.23 (s, 3H).

[0192] Example 3 (compound 2)

[0193] Step 1: Synthesis of compound 2c

[0194] Compound 2a (500 mg, 2.81 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, replaced with nitrogen and cooled to -65 °C, 2.5 M n-butyllithium solution in n-hexane (1.4 mL, 3.5 mmol) was added dropwise slowly, after the addition was completed, it was continuously stirred for 1 hour, compound 2b (243.1 mg, 3.37 mmol) was added dropwise slowly, after the addition was completed, it was reacted at room temperature for 1 hour. After the reaction was completed, saturated ammonium chloride (20 mL) was slowly added to the reaction mixture to quench, the mixture was extracted with ethyl acetate (20 mL x 2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain compound 2c (133 mg). MS m / z (ESI): 172.1 [M+1] + .

[0195] Second step: synthesis of compound 2d

[0196] NBS (123.9 mg, 0.70 mmol) was added to a solution of compound 2c (100 mg, 0.58 mmol) in N,N-dimethylformamide (1 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated brine (5 mL) was added to quench, extracted with methyl tert-butyl ether (5 mL x 2), the combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to obtain compound 2d (110 mg). MS m / z (ESI): 249.9, 251.9 [M+1] + .

[0197] Third step: synthesis of compound 2e

[0198] Compound 2d (50 mg, 0.20 mmol), compound 4d (63.2 mg, 0.20 mmol), Pd(dppf)Cl2(14.6 mg, 0.020 mmol) and potassium carbonate (55.3 mg, 0.40 mmol) were sequentially added to a mixed solvent of 1,4-dioxane and water (0.5 mL / 0.1 mL) at room temperature, and the reaction mixture was heated to 100 °C under nitrogen atmosphere and stirred for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain compound 2e (70 mg). MS m / z (ESI): 360.0 [M+1] + .

[0199] Fourth step: synthesis of compound 2

[0200] A 2 M solution of trimethylaluminum in n-hexane (0.12 mL, 0.24 mmol) was slowly added to a solution of compound 2e (30 mg, 0.083 mmol) and compound 4f (21.1 mg, 0.083 mmol, synthesis method refer to patent WO2024118887A1 page 170 synthesis of compound Intermediate 73) in toluene (0.5 mL) at room temperature. The reaction mixture was heated to 100 °C under nitrogen atmosphere with stirring for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (dichloromethane / methanol = 10 / 1) to obtain compound 2 (17 mg). MS m / z (ESI): 567.0 [M+H] + .

[0201] 1 H NMR (400 MHz, CDC13) δ 9.13 (d, J = 7.1 Hz, 1H), 8.50 (d, J = 7.2 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.30 (d, J = 9.5 Hz, 1H), 7.01 (dd, J = 7.2, 2.1 Hz, 1H), 4.26 - 4.20 (m, 1H), 3.90 (s, 1H), 3.05 (s, 2H), 2.54 (s, 3H), 1.53 - 1.48 (m, 2H), 1.26 (s, 6H), 1.26 - 1.21 (m, 2H).

[0202] Biological Examples

[0203] 1. Inhibition of wild-type c-kit kinase

[0204] Mobility Shift Assay method was used to evaluate the inhibition of wild-type c-kit kinase by the test substance, and the reaction was carried out in a 384-well plate (Corning, 3573). 50 mM HEPES, pH 7.5, 0.01% Triton X-100, 10 mM MgCl2, 2 mM DTT as reaction buffer, 20 μL of reaction system containing 6 nM c-kit (Carna, 08-156), 6 μM ATP (Sigma, 2383-5G) and 3 μM substrate FAM-labeled peptide (KKKKEEIYFFF-CONH2, GL, 263631), the initial concentration of compound was 10 μM, 1% DMSO, 4-fold dilution, 10 concentrations, double duplicate wells. Incubate at 28°C for 90 minutes, add 25 μL of stop solution (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA) to the 384-well plate reaction plate to terminate the reaction. Read the conversion rate data on the Caliper EZ Reader II, and use the formula: % inhibition = (positive control well - compound well) / (positive control well - negative control well) * 100 to calculate, where "negative control well" is the reading of the control sample well without enzyme; "positive control well" is the reading of the control sample well with DMSO as the control, and the concentration-effect curve (Y = Bottom + (Top-Bottom) / (1 + (IC 50 50) HillSlope)) is fitted by GraphPad Prism 8 software, and the compound concentration at 50% inhibition, IC 50 , is calculated. The test results are shown in Table 1. Wherein A represents: IC 50 value ≤ 300 nM; B represents: 300 nM < IC 50 value ≤ 600 nM; C represents: 600 nM < IC 50 value ≤ 1000 nM; D represents: 1000 nM < IC 50 value.

[0205] Table 1

[0206] 2, Inhibition of c-kit phosphorylation in SCF-stimulated M-07e cells

[0207] M-07e cells (Promocell, CL-0686) were plated in 96-well plates (Corning, 3599) at a density of 2 x 106cells / mL in 50 μL Opti-MEM medium (Gibco, 11058021) containing 1% penicillin-streptomycin (Gibco, 15140-122). After incubation at 37 °C, 5% CO2for 4 hours, 6.25 μL of compounds at gradient concentrations were added to each well, so that the maximum final concentration of the compounds was 1000 nM, 8 concentrations with 5-fold dilution, and the final concentration of DMSO was 0.22%. After continuing to incubate at 37 °C, 5% CO2for 60 minutes, 6.25 μL of Human Recombinant SCF (STEMCELL, 78062) was added, and the final concentration of SCF was 50 ng / mL. The positive control well (max) did not contain the compound, and the negative control well (min) did not contain the compound and SCF. After incubation at room temperature on a 450 rpm shaker for 15 minutes, 16 μL of 5X cell lysis buffer (CST, 9803) containing protease and phosphatase inhibitors (Biocytex, P1045) was added, and the cells were lysed at 4 °C with gentle shaking for 30 minutes. The cell lysate was collected by centrifugation. The protein was quantified by BCA (Biocytex, P0009), and the degree of phosphorylation of p-kit was detected using the PathScan® Phospho-c-Kit (Tyr719) Sandwich ELISA Kit according to the kit operation manual. After the OD value of the measured ELISA was normalized by the protein concentration, the inhibition rate was calculated using the following formula, and the concentration-effect curve was fitted using GraphPad Prism 8 software (Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope)), and the compound concentration at 50% inhibition, IC 50 , was calculated. The test results are shown in Table 2.

[0208] ODmax: normalized absorbance of the control group containing cells, SCF, and no compound

[0209] ODmin: normalized absorbance of the control group containing cells, no SCF, and no compound

[0210] ODcpd: normalized absorbance of the control group containing cells, SCF, and different concentrations of compounds

[0211] Table 2

[0212] The above has described the specific embodiments of the present application. It should be understood that the present application is not limited to the above-mentioned embodiments, and the above-mentioned embodiments and descriptions in the specification are only for illustrating the principles of the present application. Those skilled in the art can make various non-essential changes and improvements to the present application without departing from the concept of the present application, and these all fall within the scope of the present application.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein T is G 1 and G 2 are the same or different, each independently CR 1 or N; Ring B is a 5-membered heteroaryl; X is C and Y is N; or, X is N and Y is C; is a single or double bond; R 0 selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2) t -C 3-8 cycloalkyl and -(CH2) t -(3-8 membered heterocyclyl), each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH2) t -C 3-8 cycloalkyl and -(CH2) t -(3-8 membered heterocyclyl), each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 1 selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 2 C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl or 3-8 membered heterocyclyl optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, and C 1-6 Haloalkoxy; R 2A and R 2B are the same or different, each being independently selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl; R 3 and R 4 are the same or different, each being independently selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl; or R 1 and R 3 , R 1 and R 4 , together with the atom to which they are attached, form a 5-12 membered carbocyclic or heterocyclic ring, optionally substituted with one or more selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; each R 5 identically or differently, each independently selected from the group consisting of H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R 6 selected from H, halogen, cyano, amino, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and The C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; R a and R b are the same or different, each being independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl; t is 1 or 2; n is 0, 1, 2, 3 or 4; p is 1, 2 or 3; q is 1, 2 or 3; the heteroatoms in said "heterocycle", "heterocyclyl" or "heteroaryl" are independently selected from O, N and S, in a number of 1, 2, 3 or 4.

2. The compound of formula (I) according to claim 1, wherein R 1 and any one of R 3 , R 1 and R 4 together with the atom to which they are attached form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl group, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl group being optionally substituted with one or more selected from halo, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one or more of the following: (1) the C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, for example methyl; (2) said halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine, for example fluorine; (3) the C 3-8 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl. (4) said 3-8 membered heterocyclyl is independently a 4-6 membered heterocyclyl with a heteroatom selected from O, in a number of 1, for example oxetanyl; (5) said 5-10 membered heteroaryl or 5 membered heteroaryl is independently a monocyclic 5 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N and O, for example pyrazolyl, oxazolyl, triazolyl, tetrazolyl or or a monocyclic 5-membered heteroaryl with a heteroatom selected from N and S, in a number of 1, 2, 3 or 4, for example thiazolyl; (6) the C 1-6 alkoxy is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy, preferably methoxy; (7) said C 1-6 hydroxyalkyl is independently C 1-6 alkyl, for example -CH2OH; and (8) when any one of R 1 and R 3 , R 1 and R 4 together with the atoms to which they are attached form a 5-12 membered heterocyclic ring, the 5-12 membered heterocyclic ring is partially unsaturated, and the heteroatoms are selected from O, the 7-membered heterocyclic ring has 1 heteroatom.

4. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), ###0000107### (II-1) (II-2) (III-1) (III-2) wherein R 3 and R 4 are the same or different, each independently selected from the group consisting of H, halogen and C 1-6 alkyl; Ring B, R 0 , R 1 , R 5 , R 6 and n are as defined in claim 1 or 2.

5. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound of Formula (I) is a compound of Formula (IV), L is C 1-6 alkylene or C 1-6 heteroalkylene, said C 1-6 alkylene or C 1-6 heteroalkylene is optionally substituted with one or more selected from halo, cyano, hydroxy, oxo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; Ring B, R 0 , R 5 , R 6 and n are as defined in claim 1 or 2.

6. The compound of formula (I) according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein one or more of the following: (1) For (2) R 3 and R 4 are each H; (3) R 0 is C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl), each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1- 6alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, and -(CH2)-(3-8 membered heterocyclyl), each independently optionally substituted with one or more selected from halo, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 alkoxy; (4) R 1 selected from H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; (5) R 2 is C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with one or more selected from the group consisting of halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; (6) R 2A and R 2B are the same or different, each independently selected from H, halogen, C 1-6 alkyl; (7) each R 5 the same or different, each independently selected from H, halogen and C 1-6 alkyl; (8) is oxazolyl, triazolyl, tetrazolyl or 1,2,4-oxadiazolyl; and (9) R 6 is C 1-6 alkyl, C 3-8 cycloalkyl or The C 1-6 alkyl or C 3-8 cycloalkyl groups are each independently optionally substituted with halo or hydroxy; R a and R b are the same or different, each independently selected from halogen; p is 1; q is 1.

7. The compound of Formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein, one or more of the following: (1) R 0 is C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, or -(CH2)-(3-8 membered heterocyclyl), each of which is independently optionally substituted with one or more of hydroxy, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, or -(CH2)-(3-8 membered heterocyclyl), each of which is independently optionally substituted with one or more of hydroxy, C 1-6 hydroxyalkyl, and C 1-6 alkoxy; (2) R 1 selected from halogen, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; (3) R 2 is C 3-8 cycloalkyl, said C 3-8 cycloalkyl is optionally substituted with C 1-6 hydroxyalkyl; (4) R 2A and R 2B are each H; (5) R 5 halogen; (6) For and (7) n is 1 or 2.

8. The compound of Formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, one or more of the following: (1) R 0 is C 1-6 alkyl or C 3-8 cycloalkyl, each independently optionally substituted with one or more selected from the group consisting of hydroxy and C 1-6 alkyl or C 3-8 cycloalkyl, each independently optionally substituted with one or more selected from the group consisting of hydroxy and C 1-6 hydroxyalkyl; Preferably, R 0 C 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally substituted with hydroxyl groups; (2) R 1 is C 1-6 alkyl; and (3) For 9. The compound of Formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein, one or more of the following: (1) For Preferably (2) T is Preferably (3) R 1 is H, Cl, methyl, cyclopropyl, cyclobutyl or oxetanyl; preferably Cl, methyl, cyclopropyl, cyclobutyl or oxetanyl; and (4) R 5 is F, CI or methyl, preferably F and CI.

10. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein the compound of Formula (I) has the structure: ###00003### 11. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the compound of Formula (I) has the structure: ###00003### (I).

12. An isotopically-labeled form of a compound of formula (I) according to any one of claims 1-11, wherein the isotopic labels are deuterium for hydrogen.

13. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

14. Use of a compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, an isotopically-labeled form according to claim 12, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for inhibiting c-kit, or a c-kit inhibitor.

15. Use of a compound of formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, an isotopically-labeled form according to claim 12, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the prevention and / or treatment of a c-kit-mediated disease; said c-kit-mediated disease is selected from the group consisting of mast cell-related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, dermatological diseases, pulmonary arterial hypertension, primary pulmonary hypertension and cancer, for example mastocytoma, mastocytosis, urticaria, inflammatory bowel disease and diabetes.

16. Use of a compound of Formula (I) according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, an isotopically-labeled form thereof according to claim 12, or a pharmaceutical composition thereof according to claim 13, for the manufacture of a medicament for the prevention and / or treatment of a mast cell-related disease, a respiratory disease, an autoimmune disease, an inflammatory disease, a metabolic disease, a fibrotic disease, a dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or a cancer, such as a mastocytoma, mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

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