CN121471214A - Heterocyclic compound, preparation method and application thereof - Google Patents

Abstract

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

Description

Heterocyclic compound, preparation method and application thereof

The present application claims priority from China patent application 2024110691090 with application date 2024/8/6. The present application incorporates the entirety of the above-mentioned chinese patent application.

Technical Field

The application belongs to the field of medicines, and particularly relates to a heterocyclic compound, a preparation method and application thereof.

Background

KIT ligands are Stem Cell Factors (SCF) that bind to the extracellular domain of KIT to induce receptor dimerization and activate downstream signaling pathways that initiate the cell growth and proliferation signaling cascade upon SCF binding. SCF-linked c-kit receptors induce their dimerization, followed by transphosphorylation, leading to the recruitment and activation of various intracytoplasmic substrates. These activated substrates induce a variety of intracellular signaling pathways responsible for cell proliferation and activation. It is well known that these proteins are involved in many cellular mechanisms, which, once destroyed, can lead to abnormal cell proliferation and migration and inflammation.

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

The presently disclosed patents are WO2015057873A1, WO2016022569A1, WO2020210293A1, etc.

Disclosure of Invention

The application provides a compound shown in a formula (I) or pharmaceutically acceptable salt thereof,

Wherein T is

G ¹ and G ² are the same or different and are 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 bond or a double bond;

R ⁰ is selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, - (CH ₂)_t-C_3-8 cycloalkyl and- (CH ₂)_t - (3-8 membered heterocyclyl), said C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, - (CH ₂)_t-C_3-8 cycloalkyl and- (CH ₂)_t - (3-8 membered heterocyclyl) each independently being optionally substituted by one or more members 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, C _1-6 haloalkoxy, C _3-8 cycloalkyl and 3-8 membered heterocyclyl;

R ¹ is selected from H, halogen, 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;

R ² is C _3-8 cycloalkyl or 3-8 membered heterocyclyl, said C _3-8 cycloalkyl or 3-8 membered heterocyclyl being optionally substituted with one or more members selected from 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;

R ^2A and R ^2B are the same or different and are each independently selected from H, halogen, 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;

R ³ and R ⁴ are the same or different and are each independently selected from H, halogen, 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;

Or any of R ¹ and R ³、R¹ and R ⁴ taken together with the atoms to which they are attached form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, said 5-12 membered carbocyclic ring or 5-12 membered heterocyclic ring being optionally substituted with one or more members 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;

Each R ⁵, which are the same or different, is independently selected from H, halogen, 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;

r ⁶ is 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 members selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-8 cycloalkyl, and 3-8 membered heterocyclyl;

R ^a and R ^b are the same or different and are 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;

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 hetero atom in the heterocyclic ring, the heterocyclic group or the heteroaryl group is O, N and S, and the number of the hetero atom is 1,2,3 or 4.

In some embodiments, any of R ¹ and R ³、R¹ and R ⁴ together with the atoms to which they are attached form a C _3-12 cycloalkyl or a 3-12 membered heterocyclyl, said C _3-12 cycloalkyl or 3-12 membered heterocyclyl being optionally substituted with one or more members 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.

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

(1) The C _1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl;

(2) The halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine or chlorine, and such as fluorine;

(3) The C _3-8 cycloalkyl is independently C _3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, further such as cyclopropyl or cyclobutyl;

(4) The 3-8 membered heterocyclic group is independently a heteroatom selected from O, a 4-6 membered heterocyclic group having 1 heteroatom number, such as oxetanyl;

(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 heteroatom selected from N and S, a monocyclic 5-membered heteroaryl group having 1,2,3 or 4 heteroatoms (e.g., thiazolyl);

(6) The C _1-6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy;

(7) The C _1-6 hydroxyalkyl is independently C _1-6 alkyl substituted with hydroxy, such as-CH ₂ OH;

(8) When any of R ¹ and R ³、R¹ 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 an unsaturated heteroatom selected from O, 7-membered heterocyclic ring having 1 heteroatom.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinIs thatPreferably isR ³、R⁴ and T are as defined in formula (I).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II-1), formula (II-2), formula (III-1) or formula (III-2),

Wherein R ³ and R ⁴ are the same or different and are each independently selected from H, halogen and C _1-6 alkyl;

the rings B, R ⁰、R¹、R⁵、R⁶ and n are as defined in formula (I).

In some embodiments, a compound of 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 are both H.

In some embodiments, a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), or formula (III-2), 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, - (CH ₂)-C_3-8 cycloalkyl, and- (CH ₂) - (3-8 membered heterocyclyl), each of said C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, - (CH ₂)-C_3-8 cycloalkyl, and- (CH ₂) - (3-8 membered heterocyclyl) independently being optionally substituted with one or more members selected from halogen, hydroxy, cyano, amino, C _1-6 alkyl, C _1-6 hydroxyalkyl, and C _1-6 alkoxy;

R ¹ is selected from H, halogen, C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (IV),

L is C _1-6 alkylene or C _1-6 heteroalkylene, said C _1-6 alkylene or C _1-6 heteroalkylene being optionally substituted with one or more members selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy;

the rings B, R ⁰、R⁵、R⁶ and n are as defined in formula (I).

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 ring B is oxazolyl, triazolyl, or tetrazolyl.

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 ring B is 1,2, 4-oxadiazolyl or tetrazolyl.

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, whereinIs that R ⁶ is as defined in formula (I).

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, whereinIs that

R ⁶ is H, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl orEach of said C _1-6 alkyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl is independently optionally substituted with one or more members 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 and are 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;

p is 1, 2 or 3;

q is 1, 2 or 3.

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, whereinIs that

In some embodiments, R ⁶ is C _1-6 alkyl, C _3-8 cycloalkyl, orEach of said C _1-6 alkyl or C _3-8 cycloalkyl is independently optionally substituted with halogen or hydroxy;

R ^a and R ^b are the same or different and are each independently selected from halogen;

p is 1;

q is 1.

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, whereinIs that Preferably is

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 ⁰ is selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, and- (CH ₂) - (3-8 membered heterocyclyl), each of said C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, and- (CH ₂) - (3-8 membered heterocyclyl) is independently optionally substituted with one or more members selected from the group consisting of halogen, hydroxy, cyano, amino, C _1-6 alkyl, C _1-6 hydroxyalkyl, and C _1-6 alkoxy.

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 ⁰ is C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, or- (CH ₂) - (3-8 membered heterocyclyl), each of which is independently optionally substituted with one or more selected from the group consisting of hydroxy, C _1-6 hydroxyalkyl, and C _1-6 alkoxy.

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 ⁰ is C _1-6 alkyl or C _3-8 cycloalkyl, each independently optionally substituted with one or more selected from hydroxy and C _1-6 hydroxyalkyl.

In some embodiments, a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), or formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ⁰ is C _1-6 alkyl, said C _1-6 alkyl optionally being substituted with hydroxy. 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 is

In some embodiments, a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from H, halogen, C _1-6 alkyl, C _3-8 cycloalkyl, and 3-8 membered heterocyclyl.

In some embodiments, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from halogen, C _1-6 alkyl, C _3-8 cycloalkyl, and 3-8 membered heterocyclyl, preferably C _1-6 alkyl.

In some embodiments, a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from H, cl, methyl, cyclopropyl, cyclobutyl, and oxetanyl.

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

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 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.

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 optionally substituted with C _1-6 hydroxyalkyl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^2A and R ^2B are the same or different and are each independently selected from H, halogen, C _1-6 alkyl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^2A and R ^2B are both H.

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 each R ⁵ is the same or different and is each independently selected from H, halogen, and C _1-6 alkyl.

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 chlorine or fluorine.

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 n is 1 or 2.

In some embodiments, T is selected from any one of the following:

Preferably is

In some embodiments, R ⁵ is selected from F, cl and methyl, preferably F and Cl. In some embodiments, exemplary specific compounds of the compounds of formula (I) include, but are not limited to, the structures in table a below:

Table A

In some embodiments, exemplary specific compounds of the compounds of formula (I) include, but are not limited to, the structures shown in Table B

In another aspect of the application there is provided isotopic labels for compounds of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2) and formula (IV), or of Table A or Table B, preferably deuterium (D or ² H) substituted for hydrogen (¹ H).

In another aspect, the application provides a method for preparing a compound shown in formula (I), wherein the compound shown in formula (A) and the compound shown in formula (B) undergo condensation reaction to obtain the compound shown in formula (I),

Wherein R ^A is H or C _1-6 alkyl;

T, ring B, X, Y, R ³、R⁴、R⁵、R⁶ and n are as defined in any one of the present applications.

In another aspect of the application, a pharmaceutical composition is provided comprising at least one therapeutically effective amount of the foregoing compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In another aspect of the application, there is also provided the use of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2) and formula (IV), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotopic label, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting c-kit.

In another aspect of the application, there is also provided the use of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2) and formula (IV), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotopic label, or a pharmaceutical composition comprising the same, in the preparation of a c-kit inhibitor.

The application also provides application of the compounds shown in the formula (I), the formula (II-1), the formula (II-2), the formula (III-1), the formula (III-2) and the formula (IV), shown in the table A or the table B, or pharmaceutically acceptable salts thereof, or the isotope labels, or pharmaceutical compositions containing the isotope labels, in preparation of medicines for preventing and/or treating c-kit mediated diseases or conditions.

The application also provides application of the compounds shown in the formula (I), the formula (II-1), the formula (II-2), the formula (III-1), the formula (III-2) and the formula (IV), the compounds shown in the table A or the table B, or pharmaceutically acceptable salts thereof, or the isotope labels or the pharmaceutical compositions containing the isotope labels in preparation of medicines for preventing and/or treating mast cell related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrosis diseases, dermatological diseases, pulmonary arterial hypertension, primary pulmonary hypertension or cancers, preferably, medicines for preventing and/or treating mastocytosis, urticaria, inflammatory bowel diseases or diabetes.

The present application also provides a method of inhibiting c-kit comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2) and formula (IV), or a pharmaceutically acceptable salt thereof, or an isotopic label of the foregoing, or a pharmaceutical composition comprising the same.

The present application also provides a method for preventing and/or treating a c-kit mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2) and formula (IV), table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotopic label as defined, or a pharmaceutical composition comprising the same.

The present application also provides a method 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 cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2) and formula (IV), a compound of table a or table B, or a pharmaceutically acceptable salt thereof, or an isotopic label of the foregoing, or a pharmaceutical composition comprising the same.

The present application also provides a method for preventing and/or treating mastocytosis, urticaria, inflammatory bowel disease, or diabetes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), and formula (IV), shown in table a or table B, or a pharmaceutically acceptable salt thereof, or an isotopic label of the foregoing, or a pharmaceutical composition comprising the same.

The application also provides a compound shown in a table A or a table B, or pharmaceutically acceptable salt thereof, or the isotope label, or the pharmaceutical composition shown in the formula (I), the formula (II-1), the formula (II-2), the formula (III-1), the formula (III-2) and the formula (IV), which are used as medicines.

The application also provides a compound shown in a table A or a table B, or pharmaceutically acceptable salt thereof, or the isotope label, or the pharmaceutical composition, shown in the formula (I), the formula (II-1), the formula (II-2), the formula (III-1), the formula (III-2) and the formula (IV), which are used as c-kit inhibitor.

The application also provides a compound shown in a table A or a table B, or a pharmaceutically acceptable salt thereof, or the isotope label, or the pharmaceutical composition containing the isotope label, as shown in the formula (I), the formula (II-1), the formula (II-2), the formula (III-1), the formula (III-2) and the formula (IV), which are used as medicines for preventing and/or treating c-kit mediated diseases or symptoms.

The application also provides a compound shown in a table A or a table B, or a pharmaceutically acceptable salt thereof, or the isotope label, or the pharmaceutical composition containing the isotope label, as shown in a formula (I), a formula (II-1), a formula (II-2), a formula (III-1), a formula (III-2) and a formula (IV), which are used as medicines for preventing and/or treating mast cell related diseases, respiratory diseases, autoimmune diseases, inflammatory diseases, metabolic diseases, fibrosis diseases, dermatological diseases, pulmonary arterial hypertension, primary pulmonary hypertension or cancers.

The application also provides a compound shown in a table A or a table B, shown in a formula (I), a formula (II-1), a formula (II-2), a formula (III-1), a formula (III-2) and a formula (IV), or pharmaceutically acceptable salts thereof, or the isotope labels, or the pharmaceutical compositions containing the isotope labels, which are used as medicines for preventing and/or treating mastocytosis, urticaria, inflammatory bowel disease or diabetes.

In some embodiments, the c-kit mediated disease is selected from the group consisting of mast cell related disease, respiratory disease, autoimmune disease, inflammatory disease, metabolic disease, fibrotic disease, dermatological disease, pulmonary arterial hypertension, primary pulmonary hypertension, or cancer.

In some embodiments, the c-kit mediated disease is selected from the group consisting of mastocytosis, urticaria, inflammatory bowel disease, or diabetes.

In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.

In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compounds, or pharmaceutically acceptable salts thereof, or isotopic labels thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical compositions comprise 0.1-99.9% of the aforementioned compounds, or pharmaceutically acceptable salts thereof, or isotopic labels thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or an isotopic label thereof. In certain embodiments, the pharmaceutical compositions comprise 1% to 99% of the compound as set forth above, or a pharmaceutically acceptable salt thereof, or an isotopic label thereof.

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.

When used as a medicament, the compounds of the present application may be administered in the form of a pharmaceutical composition. These compositions may be prepared in a manner well known in the pharmaceutical arts and may be administered by a variety of routes, depending upon whether local or systemic treatment and the area being treated is desired. Topical (e.g., transdermal, dermal, ocular, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, or intracranial, such as intrathecal or intraventricular administration parenteral administration in single bolus form, or may be administered by, for example, a continuous infusion pump.

In preparing the compositions of the present application, the active ingredient is typically admixed with excipients and the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in a liquid vehicle), 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.

The "auxiliary materials" as used herein refer to components other than the active ingredient, and include, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.

In another aspect, pharmaceutically acceptable salts of the compounds of the application may be inorganic or organic salts, which may form acid addition salts if they have basic centers, base addition salts if they have acidic centers, and internal salts if they contain both acidic (e.g., carboxyl) and basic (e.g., amino) centers.

In another aspect, the compounds of the present application may exist in particular geometric or stereoisomeric forms. Such as cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic and other mixtures, and enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the 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 the present application.

The term "plurality" indicating the number of substituents or the number of heteroatoms means 2, 3, 4 or 5.

In the chemical structure of the compounds of the application, the bondIndicating that the configuration is not specified and that,Or (b)Indicating absolute configuration, i.e. bond if chiral isomer is present in chemical structureMay beOr (b)Or at the same time containAndTwo configurations.

Key with a keyIndicating unspecified configurations including cis (E) or trans (Z) configurations.

In addition, the compounds and intermediates of the application may also exist in different tautomeric forms, and all such forms are included within the scope of the 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 tautomers via proton transfer, such as keto-enol isomerisation, imine-enamine isomerisation and lactam-lactam isomerisation. All tautomeric forms of all compounds of the application are within the scope of the application. The names of compounds named in a singular manner do not exclude any tautomers.

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

Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds. Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

The "therapeutically effective amount" of the present application refers to that amount of an active compound or pharmaceutical agent that elicits a biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician or the like in a tissue, system, animal, individual or human, which includes one or more of (1) preventing a disease, disorder or condition, e.g., in an individual susceptible to the disease, disorder or condition but having not yet experienced or developed the pathology or symptomatology of the disease, (2) inhibiting the disease, disorder or condition, e.g., inhibiting the disease, disorder or condition (i.e., arresting the further development of the pathology and/or symptomatology) in an individual experiencing or developing the pathology or symptomatology of the disease, disorder or condition, (3) alleviating the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual experiencing or developing the pathology or symptomatology of the disease, disorder or condition. For a drug or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

By "pharmaceutically acceptable" is meant those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

The term "patient" according to the present application shall mean any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.

Definition and description of terms

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

In the present applicationOr (b)Meaning that the corresponding radical passes throughTo other fragments, groups in the compound.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which may be a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms (C _1-6 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and various branched isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined herein. Alkoxy groups (C _1-12 alkoxy groups) containing 1 to 12 (e.g., 1,2, 3, 4, 5,6,7,8, 9, 10, 11, and 12) carbon atoms are preferred, and alkoxy groups (C _1-6 alkoxy groups) containing 1 to 6 carbon atoms are more preferred. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted.

The term "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which can contain 5 to 20 carbon atoms, preferably 5 to 12 carbon atoms (e.g., 5, 6, 7, and 8 carbon atoms).

The term "heterocycle" refers to a saturated or partially unsaturated, monocyclic or polycyclic cyclic hydrocarbon substituent, which may contain 5 to 20 ring atoms, wherein one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but does not include the ring members of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably from 5 to 12 ring atoms (e.g., 5, 6, 7 and 8), wherein 1, 2,3 or 4 ring atoms are heteroatoms.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring may contain 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, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclyl ring as described herein, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include Etc., preferablyThe cycloalkyl group may be substituted or unsubstituted.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent which may contain from 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but does not include the ring members of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 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 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 3 to 6 ring atoms, of which 1 to 3 are heteroatoms, and most preferably 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 heterocyclic groups.

Such heterocyclyl rings include heterocyclyl (including monocyclic, spiro, fused and bridged heterocycles) fused to an aryl, heteroaryl or cycloalkyl ring as described herein, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

etc. The heterocyclic group may be substituted or unsubstituted.

The term "aryl" refers to groups that may contain 6 to 14 membered all-carbon monocyclic or fused polycyclic (fused polycyclic being a ring sharing adjacent pairs of carbon atoms), preferably 6 to 10 membered, e.g., phenyl and naphthyl, groups having conjugated pi-electron systems. Such aryl rings include aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described herein, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted.

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

Heteroaryl groups may be substituted or unsubstituted.

The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" and the like herein may be substituted or unsubstituted, and when substituted, may be substituted at any useful point of attachment, said substituents preferably being independently and optionally selected from one or more of the same or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

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

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

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

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

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

The term "halogen" refers to F, cl, br or I.

The term "hydroxy" refers to-OH.

The term "amino" refers to-NH ₂.

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂.

The term "oxo" or "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

The term "carboxy" refers to-C (O) OH.

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.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the 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.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The beneficial effects are that:

The application provides a small molecular compound with a heterocyclic structure, which can be used as a c-kit inhibitor, has a strong inhibition effect on a c-kit receptor by the compound or a pharmaceutical composition, has an excellent pharmacokinetic effect, and can be used for effectively treating or preventing c-kit mediated diseases.

Detailed Description

The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 ^-6 (ppm). NMR was performed using a Bruker AVANCE III MHz nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃ OD) and internal standard Tetramethylsilane (TMS).

Mass Spectrometry (MS) was determined by Waters 2767HPLC/WATERS SQD, waters H-class UPLC-SQD2, AGILENT HPLC/Waters liquid phase Mass Spectrometry.

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

The thin layer chromatography silica gel plate is used for forming GF254 silica gel plates of chemical industry (Shanghai) limited company, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.2-0.25 mm, and the specification of the thin layer chromatography separation and purification product is 0.4-0.5 mm.

Column chromatography is generally used for 100-200 mesh silica gel of chemical industry (Shanghai) limited company as a carrier.

High performance liquid phase preparation using WATERS HPLC, gilson HPLC and Biotage MPLC preparative chromatography.

Chiral separation column chromatography was performed using GilsonGX-281 preparative HPLC.

In the examples, unless otherwise specified, the reactions were carried out under nitrogen atmosphere.

The nitrogen atmosphere is defined as the reaction flask being connected to a nitrogen balloon of about 1 liter volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas having a volume of about 1 liter.

In the examples, the reaction temperature was room temperature and the temperature range was 20℃to 30℃unless otherwise specified.

It will be appreciated by those skilled in the art that resolved chiral compounds can be distinguished by the order of retention times in the chiral chromatographic column, and thus chiral compounds resolved sequentially for retention times are correspondingly distinguished by the numbered suffixes P1, P2, etc. Namely, the suffix P1 corresponds to the chiral structure which is split first, and the suffix P2 corresponds to the chiral structure which is split later. If absolute configurations of the compounds are listed in the structural formula, the absolute configurations do not mean that the absolute configurations are in one-to-one correspondence with the compounds with the numbers P1 and P2, and only two existing forms for indicating the absolute configurations are shown. The absolute configuration of the compounds numbered suffixes P1, P2 is subject to the absolute configuration that corresponds objectively to a particular retention time.

Reagent name corresponding to english abbreviation:

Reagent English abbreviation	Reagent name
		DMF	N, N-dimethylformamide
THF	Tetrahydrofuran (THF)
		Pd(dppf)Cl2	1,1' -Bis (diphenylphosphino) ferrocene palladium (II) dichloride
Cs2CO3	Cesium carbonate
		1,4-dioxane	1, 4-Dioxahexacyclic ring
DMSO-d6	Deuterated dimethyl sulfoxide
		NBS	N-bromosuccinimide

Examples

Example 1 (Compound 4)

First step Synthesis of Compound 4b

4-Bromopyrazole (2.98 g,14.97 mmol) and potassium carbonate (3.10 g,22.46 mmol) were added sequentially to a solution of compound 4a (2.2 g,14.97 mmol) in DMF (20 mL) at room temperature and the reaction mixture stirred at 80℃for 16 h. After completion of the reaction, the reaction solution was diluted with saturated brine (20 mL), extracted with ethyl acetate (20 ml×3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-10%) to give compound 4b (3.1 g). MSm/z (ESI): 273.0[ M+1] ⁺.

Second step Synthesis of Compound 4c

Lithium aluminum hydride (0.73 mL,0.73 mmol) was slowly added dropwise to a solution of compound 4b (200 mg,0.73 mmol) in THF (5 mL) at 0deg.C, and the reaction mixture was stirred under ice-bath for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated brine (20 mL), extracted with ethyl acetate (20 ml×3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 4c (180 mg, crude product). The crude compound was used in the next reaction without purification. MSm/z (ESI) 231[ M+1] ⁺.

Third step, synthesis of Compound 4e

Compound 4C (160 mg, crude), compound 4d (161 mg,0.69mmol, synthetic method see page P37 of the specification of CN114380818A, synthesis of Compound 9-2), cs ₂CO₃ (449.63 mg,1.38 mmol), and Pd (dppf) Cl ₂ (56.35 mg,0.069 mmol) were added sequentially to a1, 4-Dioxane (5 mL) solvent and the reaction mixture stirred at 85℃for 16 hours under nitrogen at room temperature. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL. Times.2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to give compound 4e (120 mg). MSm/z (ESI): 341.1[ M+1] ⁺.

Fourth step, synthesis of Compound 4

Trimethylaluminum (2M in n-hexane, 0.029mL,0.058 mol) was added dropwise to a toluene solution (2 mL) of compound 4e (10 mg,0.029 mmol) and compound 4f (8.09 mg,0.029 mmol) under ice bath, the synthesis method was referred to the synthesis of compound intemediate 73 at page 170 of the specification of patent WO2024118887A1, and the reaction mixture was stirred at 110 ℃ for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on a silica gel plate (methanol: dichloromethane=1:10) to give the compound 4(3.79mg).MSm/z(ESI):547.9[M+1]⁺.¹H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.83(d,J＝7.1Hz,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＝8.0Hz,1H),7.41(dd,J＝5.6,4.0Hz,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＝8.0Hz,2H),1.46–1.37(m,2H),1.34–1.29(m,2H).

Example 2 (Compound 1)

First step Synthesis of Compound 1b

A solution of n-butyllithium in tetrahydrofuran (1.6M, 18.9mL,30.25 mmol) was slowly added to a solution of compound 1a (2.5 g,25.21 mmol) in tetrahydrofuran (25 mL) under nitrogen at-78℃and after stirring the mixture at-78℃for 1 hour, a solution of acetone (1.76 g,30.25 mmol) in tetrahydrofuran (5 mL) was slowly added to the reaction mixture and the reaction mixture was stirred at 25℃for 2 hours. After completion of the reaction, saturated ammonium chloride (15 mL) was added to the reaction mixture to quench, the aqueous phase was extracted with methylene chloride (3×50 mL), the organic layers were combined and washed with saturated brine (3×30 mL), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 1b (4 g). MSm/z (ESI) 158.1[ M+1] ⁺.

Second step, synthesis of Compound 1c

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 and the reaction mixture stirred at 25℃for 4 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL), the aqueous phase was extracted with methylene chloride (3×50 mL), the organic layers were combined and washed with saturated brine (3×20 mL), the organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 1c (2 g). MSm/z (ESI): 235.9,237.9[ M+1, M+3] ⁺.

Third step, synthesis of Compound 1d

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 stirred at 85℃for 12 hours. After the completion of the reaction, the reaction mixture was diluted with water (50 mL), the aqueous phase was extracted with methylene chloride (3×50 mL), the organic layers were combined and washed with saturated aqueous sodium hydrogencarbonate (2×20 mL), the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/0 to 3/1) to give compound 1d (400 mg). MSm/z (ESI) 217.9,219.9[ M+1, M+3] ⁺.

Fourth step, synthesis of Compound 1e

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

Fifth step, synthesis of Compound 1f

Compound 1e (100 mg,0.40 mmol), compound 4d (190 mg,0.60mmol, synthesis of P37P-page compound 9-2, see patent CN114380818 a), the [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (33 mg,0.040 mmol) and cesium carbonate (260 mg,0.80 mmol) were added sequentially to a mixed solution of 1, 4-dioxane and water (2 mL/0.4 mL), and the reaction mixture was stirred under nitrogen atmosphere at 80 ℃ for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/0~0/1) to give compound 1f (70 mg). MSm/z (ESI) 362.0[ M+1] ⁺.

Sixth step, synthesis of Compound 1

A solution of 2M trimethylaluminum in n-hexane (0.06 mL,0.12 mmol) was added to a solution of compound 4f (15 mg,0.059mmol, synthesis of compound inte-mate 73, page 170 of WO2024118887A 1) and compound 1f (21 mg,0.059 mmol) in toluene (2 mL) at room temperature under nitrogen atmosphere, and the reaction mixture was stirred at 110℃for 3 hours. After the completion of the reaction, sodium sulfate decahydrate (1 g) was added to the reaction solution to quench, the mixture was filtered, the cake was washed with ethyl acetate (5 mL), the combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/dichloromethane=0/1 to 1/15) to give compound 1 (15 mg). MSm/z (ESI): 569.0[ M+1] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),8.91(dd,J＝7.2,0.7Hz,1H),8.83(s,1H),8.28(dd,J＝13.4,4.3Hz,2H),7.85(d,J＝10.1Hz,1H),7.24(dd,J＝7.2,2.1Hz,1H),5.91(s,1H),4.91(t,J＝6.1Hz,1H),4.57–4.46(m,1H),3.57(dd,J＝6.1,2.3Hz,2H),1.47(s,3H),1.44–1.39(m,2H),1.32–1.28(m,2H),1.23(s,3H).

Example 3 (Compound 2)

First step Synthesis of Compound 2c

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

Second step, synthesis of Compound 2d

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℃and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, saturated brine (5 mL) was added, extracted with methyl tert-butyl ether (5 ml×2), the combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-20%) to give compound 2d (110 mg). MSm/z (ESI): 249.9,251.9[ M+1] ⁺.

Third step, synthesis of Compound 2e

Compound 2d (50 mg,0.20 mmol), compound 4d (63.2 mg,0.20 mmol), pd (dppf) Cl ₂ (14.6 mg, 0.020mmol) and potassium carbonate (55.3 mg,0.40 mmol) were added sequentially 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℃under nitrogen atmosphere and stirred for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-40%) to give compound 2e (70 mg). MSm/z (ESI) 360.0[ M+1] ⁺.

Fourth step, synthesis of Compound 2

A solution of 2M trimethylaluminum in n-hexane (0.12 mL,0.24 mmol) was slowly heated to a solution of compound 2e (30 mg,0.083 mmol) and compound 4f (21.1 mg,0.083 mmol) in toluene (0.5 mL) at room temperature, the synthesis procedure was referred to on page 170 of compound Intermediate 73 of WO2024118887A1, and the reaction mixture was heated to 100℃under nitrogen and stirred for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on a silica gel plate (dichloromethane/methanol=10/1) to give compound 2 (17 mg). MSm/z (ESI): 567.0[ M+H ] ⁺.

¹H NMR(400MHz,CDCl₃)δ9.13(d,J＝7.1Hz,1H),8.50(d,J＝7.2Hz,1H),8.38(d,J＝2.0Hz,1H),8.28(s,1H),7.97(s,1H),7.30(d,J＝9.5Hz,1H),7.01(dd,J＝7.2,2.1Hz,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).

Biological examples

1. Inhibition of wild-type c-kit kinase

The inhibition of wild-type c-kit kinase by the test substances was evaluated by the Mobility SHIFT ASSAY method and the reaction was performed in 384 well plates (Corning, 3573). 50mM HEPES,pH 7.5,0.01% Triton X-100,10mM MgCl ₂, 2mM DTT as reaction buffer, and 20. Mu.L of the reaction system contained 6nM c-kit (Carna, 08-156), 6. Mu.M ATP (Sigma, 2383-5G) and 3. Mu.M substrate FAM-labeled peptide (KKKKEEIYFFF-CONH ₂, GL, 263631) at a starting compound concentration of 10. Mu.M, 1% DMSO, 4-fold dilution, 10 concentrations, double wells. The reaction was stopped by adding 25. Mu.L of stop solution (100mM HEPES,pH 7.5,0.015% Brij-35,0.2% Coating Reagent #3,50mM EDTA) to 384-well plates after incubation at 28℃for 90 min. Conversion data were read on CaliperEZ ReaderII using the formula%inhibition = (positive control well-compound well)/(positive control well-negative control well) ×100, where "negative control well" is the control well reading for the no enzyme addition reaction and "positive control well" is the control well reading with DMSO added, the concentration-response curve (y=bottom+ (Top-Bottom)/(1+ (IC ₅₀/X) ≡ HillSlope)) was fitted with GRAPHPAD PRISM software and the compound concentration at 50% inhibition was calculated, i.e. IC ₅₀. The test results are shown in Table 1. Wherein A represents IC ₅₀ value less than or equal to 300nM, B represents 300nM < IC ₅₀ value less than or equal to 600nM, C represents 600nM < IC ₅₀ value less than or equal to 1000nM, and D represents 1000nM < IC ₅₀ value.

TABLE 1

Examples numbering	Numbering of compounds	c-kit IC50(nM)
			1	4	A
2	1	A
			3	2	A

2. Experiment for inhibition of c-kit phosphorylation in SCF-stimulated M-07e cells

M-07e cells ((Pronoxel, CL-0686)) were plated in 96-well plates (Corning, 3599) at a density of 2X 10≡6/mL using Opti-MEM medium ((Gibco, 11058021)) containing 1% of penicillin (Gibco, 15140-122) at a volume of 50. Mu.L per well. After incubation for 4 hours at 37 ℃,5% CO ₂, 6.25 μl of gradient concentration compound was added per well, resulting in a maximum final concentration of 1000nm, 5-fold dilution, 8 concentrations, and DMSO final concentration of 0.22%. After further incubation in 5% CO ₂ at 37℃for 60 min, 6.25. Mu.L of Human Recombinant SCF (STEMCELL, 78062) was added, the final concentration of SCF being 50ng/mL, wherein the positive control wells (max) contained no compound and the negative control wells (min) contained no compound and SCF. After incubation on a shaking table at 450rpm for 15 min at room temperature, 16. Mu.L of 5X cell lysate (CST, 9803) containing protease and phosphatase inhibitors (Biyun Tian, P1045) was added, lysed by gentle shaking at 4℃for 30 min and the cell lysate was collected by centrifugation. Proteins were quantified using the BCA (Biyun, P0009) method and the extent of P-Kit phosphorylation was measured using the PathScan@Phospho-c-Kit (Tyr 719) SANDWICH ELISA KIT according to the Kit protocol. After the OD values of the ELISA were normalized with protein concentration, the inhibition was calculated using the following formula, and the concentration-effect curve (Y=bottom+ (Top-Bottom)/(1+ (IC ₅₀/X)/(HillSlope)) was fitted with GRAPHPAD PRISM software, and the compound concentration with 50% inhibition, IC ₅₀, was calculated. The test results are shown in Table 2.

ODmax normalized absorbance ODmin for control group containing cells, SCF, no compound normalized absorbance ODcpd for control group containing cells, SCF, different concentrations of compound

TABLE 2

The foregoing describes specific embodiments of the present invention. It is to be understood that the invention is not limited to the above-described embodiments, which are described in the foregoing description only for the purpose of illustrating the principles of the invention. Various insubstantial changes and modifications of the invention can be made by those skilled in the art without departing from the spirit of the invention, and such changes and modifications are intended to be within the scope of the invention as claimed.

Claims (16)

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 and are 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 bond or a double bond;

R ⁰ is selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, - (CH ₂)_t-C_3-8 cycloalkyl and- (CH ₂)_t - (3-8 membered heterocyclyl), said C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, - (CH ₂)_t-C_3-8 cycloalkyl and- (CH ₂)_t - (3-8 membered heterocyclyl) each independently being optionally substituted by one or more members 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, C _1-6 haloalkoxy, C _3-8 cycloalkyl and 3-8 membered heterocyclyl;

R ¹ is selected from H, halogen, 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;

R ² is C _3-8 cycloalkyl or 3-8 membered heterocyclyl, said C _3-8 cycloalkyl or 3-8 membered heterocyclyl being optionally substituted with one or more members selected from 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;

R ^2A and R ^2B are the same or different and are each independently selected from H, halogen, 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;

R ³ and R ⁴ are the same or different and are each independently selected from H, halogen, 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;

Or any of R ¹ and R ³、R¹ and R ⁴ taken together with the atoms to which they are attached form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, said 5-12 membered carbocyclic ring or 5-12 membered heterocyclic ring being optionally substituted with one or more members 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;

Each R ⁵, which are the same or different, is independently selected from H, halogen, 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;

r ⁶ is 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 members selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-8 cycloalkyl, and 3-8 membered heterocyclyl;

R ^a and R ^b are the same or different and are 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;

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 the heterocyclic ring, the heterocyclic group or the heteroaryl group are independently selected from O, N and S, and the number of the heteroatoms is 1, 2, 3 or 4.

2. A compound of formula (I) according to claim 1, wherein any one of R ¹ and R ³、R¹ and R ⁴ together with the atoms to which they are attached form a C _3-12 cycloalkyl group or a 3-12 membered heterocyclyl group, said C _3-12 cycloalkyl group or 3-12 membered heterocyclyl group being optionally substituted with one or more groups 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.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein it meets one or more of the following conditions:

(1) The C _1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl;

(2) The halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine or chlorine, such as fluorine;

(3) The C _3-8 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl;

(4) The 3-8 membered heterocyclic group is independently a heteroatom selected from O, a 4-6 membered heterocyclic group having 1 heteroatom number, such as oxetanyl;

(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 heteroatom selected from N and S, a monocyclic 5-membered heteroaryl group having 1,2,3 or 4 heteroatoms, such as thiazolyl;

(6) The C _1-6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy;

(7) The C _1-6 hydroxyalkyl groups are independently C _1-6 alkyl groups substituted with hydroxy groups, e.g., -CH ₂ OH, and

(8) When any of R ¹ and R ³、R¹ 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 a partially unsaturated heteroatom selected from O, 7-membered heterocyclic ring having 1 heteroatom.

4. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound represented by formula (I) is a compound represented by formula (II-1), formula (II-2), formula (III-1) or formula (III-2),

Wherein R ³ and R ⁴ are the same or different and are each independently selected from H, halogen and C _1-6 alkyl;

The rings B, R ⁰、R¹、R⁵、R⁶ and n are as defined in claim 1 or 2.

5. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound represented by formula (I) is a compound represented by formula (IV),

L is C _1-6 alkylene or C _1-6 heteroalkylene, said C _1-6 alkylene or C _1-6 heteroalkylene being optionally substituted with one or more members selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy;

The rings B, R ⁰、R⁵、R⁶ and n are as defined in claim 1 or 2.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which meets one or more of the following conditions:

(1) Is that

(2) R ³ and R ⁴ are both H;

(3) R ⁰ is C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and- (CH ₂) - (3-8 membered heterocyclyl), each of said C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and- (CH ₂) - (3-8 membered heterocyclyl) independently being optionally substituted with one or more members selected from halogen, hydroxy, cyano, amino, C _1-6 alkyl, C _1-6 hydroxyalkyl and C _1-6 alkoxy;

(4) R ¹ is 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 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 and are each independently selected from H, halogen, C _1-6 alkyl;

(7) Each R ⁵, the same or different, is 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 orEach of said C _1-6 alkyl or C _3-8 cycloalkyl is independently optionally substituted with halogen or hydroxy;

R ^a and R ^b are the same or different and are each independently selected from halogen;

p is 1;

q is 1.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which meets one or more of the following conditions:

(1) R ⁰ is C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl or- (CH ₂) - (3-8 membered heterocyclyl), said C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl or- (CH ₂) - (3-8 membered heterocyclyl) each independently being optionally substituted by one or more selected from hydroxy, C _1-6 hydroxyalkyl and C _1-6 alkoxy;

(2) R ¹ is 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 optionally substituted with C _1-6 hydroxyalkyl;

(4) R ^2A and R ^2B are both H;

(5) R ⁵ is halogen;

(6) Is that And

(7) N is 1 or 2.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which meets one or more of the following conditions:

(1) R ⁰ is C _1-6 alkyl or C _3-8 cycloalkyl, each of said C _1-6 alkyl or C _3-8 cycloalkyl independently optionally substituted with one or more groups selected from hydroxy and C _1-6 hydroxyalkyl;

Preferably, R ⁰ is C _1-6 alkyl, said C _1-6 alkyl optionally substituted with hydroxy;

(2) R ¹ is C _1-6 alkyl, and

(3)Is that

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, which meets one or more of the following conditions:

(1) Is that Preferably is

(2) T is Preferably is

(3) R ¹ is H, cl, methyl, cyclopropyl, cyclobutyl or oxetanyl, preferably Cl, methyl, cyclopropyl, cyclobutyl or oxetanyl, and

(4) R ⁵ is F, cl or methyl, preferably F and Cl.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the compound of formula (I) has the structure:

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the compound of formula (I) has the structure:

12. An isotopic label of a compound of formula (I) as claimed in any one of claims 1 to 11, wherein the isotopic label is deuterium substituted hydrogen.

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

14. Use of a compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, an isotopic label according to claim 12, or a pharmaceutical composition according to claim 13, for the preparation 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 to 11 or a pharmaceutically acceptable salt thereof, an isotopic label 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 c-kit mediated diseases;

The 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 cancers, such as mastocytosis, urticaria, inflammatory bowel diseases and diabetes.

16. Use of a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, an isotopic label 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 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 mastocytosis, urticaria, inflammatory bowel diseases or diabetes.