Azaindole derivative compound and application thereof

Abstract

The invention discloses an azaindole derivative compound as well as a preparation method and application thereof. The compound has CSF1R inhibitory activity and can be widely applied to drugs for treating cancers, tumors, autoimmune diseases, neurodegenerative diseases, metabolic diseases or metastatic diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and provides a class of azaindole-derived compounds, their preparation methods and pharmaceutical uses. Compounds of this class have CSF1R inhibitory activity and can be widely used in drugs for treating cancer, tumors, autoimmune diseases, neurodegenerative diseases, metabolic diseases or metastatic diseases. Background Art

[0002] CSF-1R is a tyrosine kinase transmembrane receptor and also belongs to the growth factor CSF-1 / platelet-derived growth factor (PDGF) receptor family. This receptor family has inherent tyrosine-specific protein kinase activity. CSF-1R is involved in the survival, proliferation, differentiation, recruitment and function of mononuclear phagocytes (such as microglia, macrophages, monocytes). IL-34 has biological characteristics similar to those of CSF-1, but their main differences come from different spatio-temporal regulations. In addition, CSF-1 can act through autocrine and paracrine manners, while IL-34 only acts locally. Small molecule inhibitors or antibodies developed targeting the CSF-1R target have the activity of inhibiting the survival and proliferation of microglia, inflammatory macrophages, and tumor-associated macrophages (TAMs), thereby exerting anti-tumor, immunomodulatory and neuroinflammation-reducing pharmacodynamic effects, and have currently been used in the drug development of various cancers, central neurodegenerative diseases and chronic graft-versus-host disease and other diseases.

[0003] High levels of CSF-1 have been reported in breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, kidney cancer and many other types of cancers. The overexpression of CSF-1 and its receptor CSF-1R in tumors is also associated with poor prognosis. Targeting the colony-stimulating factor 1 receptor (CSF-1R) / CSF-1 pathway can regulate the function of tumor-associated macrophages TAMs. Microglia mediate neuroinflammatory responses, and neuroinflammation plays a core role in the pathogenesis of various neurodegenerative diseases (MS, AD, ALS). Studies have shown that CSF1R inhibitors can inhibit and kill over-activated microglia in the nervous system with high affinity and selectivity, effectively block the neuroinflammatory response that drives disease development, and slow down nerve damage and promote nerve cell repair. In addition to its important role in the tumor field and central neurodegenerative diseases, CSF-1R inhibitors also have broad application prospects, covering multiple fields such as inflammation, metabolism and bone-related diseases. Therefore, the drug development targeting the CSF-1R target has become a research hotspot for scholars and pharmaceutical companies at home and abroad.

[0004] Compared with the early approved multi-target CSF-1R inhibitors, such as Surufatinib, Pexidartinib, Vorolanib, etc., the new generation of CSF-1R inhibitors need to have better selectivity to reduce the side effects caused by off-target effects. At the same time, the pharmacokinetic properties of small molecule drugs also need to be further optimized. The purpose of this invention is to discover orally active CSF1R inhibitors with high activity, high selectivity, and excellent pharmacokinetic properties through the structural modification of Pexidartinib. Summary of the Invention

[0005] Technical Problem to be Solved: This invention provides a class of azaindole-derived compounds, which have CSF1R inhibitory activity and can be widely used in drugs for treating cancer, tumors, autoimmune diseases, neurodegenerative diseases, metabolic diseases or metastatic diseases.

[0006] Technical Solution: A class of azaindole compounds shown in Formula I, their stereoisomers or their pharmaceutically acceptable salts, hydrates or solvates.

[0007]

[0008] Wherein,

[0009] R1, R2 and R3 are each independently selected from hydrogen, chlorine, fluorine, trifluoromethyl, difluoromethyl or C1-C3 alkyl;

[0010] R4 is selected from hydrogen, chlorine or fluorine;

[0011] R5 and R6 are both hydrogen at the same time, or R5 and R6 are both fluorine at the same time, or R5 and R6 together with the connected carbon atom form an alkyl three-membered ring;

[0012] A is selected from indole, pyridine, substituted pyridine, pyrrole or azamethylpyrrole;

[0013] n is selected from the numbers 0, 1, 2, 3 or 4.

[0014] Preferably, wherein,

[0015] R1, R2 and R3 are each independently selected from hydrogen, chlorine, fluorine, trifluoromethyl or methyl;

[0016] R4 is selected from hydrogen, chlorine or fluorine;

[0017] R5 and R6 are both hydrogen at the same time, or R5 and R6 are both fluorine at the same time, or R5 and R6 together with the connected carbon atom form an alkyl three-membered ring;

[0018] A is selected from indole, pyridine, substituted pyridine, pyrrole or azamethylpyrrole;

[0019] n is selected from the numbers 0, 1, 2, 3 or 4.

[0020] Preferably, among them,

[0021] R1, R2, and R3 are each independently selected from hydrogen, chlorine, or fluorine;

[0022] R4 is selected from hydrogen or fluorine;

[0023] R5 and R6 are both hydrogen at the same time, or R5, R6, and the connected carbon atom together form an alkyl three-membered ring;;

[0024] A is selected from indole, pyridine, substituted pyridine, N-methylpyrrole;

[0025] n is selected from the numbers 0, 1, or 2.

[0026] Preferably, the compound is:

[0027]

[0028] Compound 1: As shown in S1;

[0029]

[0030] Compound 2: As shown in S2;

[0031]

[0032] Compound 3: As shown in S3;

[0033]

[0034] Compound 4: As shown in S4;

[0035]

[0036] Compound 5: As shown in S5;

[0037]

[0038] Compound 6: As shown in S6;

[0039]

[0040] Compound 7: As shown in S7;

[0041]

[0042] Compound 8: As shown in S8.

[0043] The compounds provided by the present invention also include pharmaceutically acceptable equivalents of the compound or mixtures of two or more thereof.

[0044] Preferably, the compounds provided by the present invention may include one or a mixture of two or more of pharmaceutically acceptable salts, hydrates, solvates, metabolites, and prodrugs.

[0045] Preferably, the compounds provided by the present invention include acid salts or base salts of the compounds provided by the present invention. The pharmaceutically acceptable salts have the pharmaceutical activity of the compound and meet the requirements both biologically and in practical applications.

[0046] The present invention provides a pharmaceutical composition comprising a compound represented by formula I, its stereoisomers or its pharmaceutically acceptable salts, hydrates or solvates, and a pharmaceutically acceptable carrier.

[0047] The present invention provides an application of a compound represented by formula I, its stereoisomers or its pharmaceutically acceptable salts, hydrates or solvates in the preparation of a drug for treating cancer, tumor, autoimmune disease, neurodegenerative disease, metabolic disease or metastatic disease.

[0048] The present invention provides an application of a compound represented by formula I, its stereoisomers or its pharmaceutically acceptable salts, hydrates or solvates in the preparation of a drug for treating giant cell tumor of tendon sheath, ovarian cancer, pancreatic cancer, prostate cancer, non-small cell lung cancer, breast cancer, renal cell carcinoma, liver cancer, cervical cancer, papillary thyroid carcinoma, colorectal cancer, gastrointestinal stromal tumor, melanoma, mesothelioma, osteosarcoma, head and neck cancer, glioblastoma, leukemia, peritoneal malignancy, peripheral T-cell lymphoma, bone metastatic cancer, multiple myeloma, metastasis of primary tumor site, myeloproliferative disease, hyperproliferative disease, metabolic disease, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, pigmented villonodular synovitis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, neurodegenerative disease, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis or mast cell leukemia;

[0049] Preferably, it is used in the preparation of drugs for treating giant cell tumor of tendon sheath, multiple myeloma, glioblastoma, metastasis of primary tumor site or bone metastatic cancer, metabolic disease, graft-versus-host disease, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease. Detailed implementation manners

[0050] The present invention discloses azaindole compounds and their uses. Those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve them. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments. It is obvious that relevant personnel can make changes or appropriate alterations and combinations to the methods and applications described herein without departing from the content, spirit, and scope of the present invention to implement and apply the technology of the present invention.

[0051] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way.

[0052] Example 1: Synthesis of Compound S1

[0053] Synthesis route:

[0054]

[0055] Synthesis process:

[0056] First step: 2-Amino-5-formylpyridine (1 eq, 2 g, 16.38 mmol) was dissolved in THF (40 ml), TEA (3 eq, 4.97 g, 49.14 mmol) and DMAP (0.2 eq, 0.4 g, 3.28 mmol) were added, and then (Boc)2O (2.3 eq, 8.22 g, 37.67 mmol) was added. After addition, the reaction was carried out at room temperature for 12 h. TLC (PE:EA = 5:1, Rf of raw material = 0.3, Rf of product = 0.6), the reaction was complete. After post-treatment, the system was directly concentrated to dryness and purified by column chromatography. 4.3 g of white solid was obtained (yield 80%).

[0057] ESI-MS: 323.1[M+H]+

[0058] Second step: Chlorinated azaindole (1 eq, 0.94 g, 6.21 mmol) and the product of the first step (1 eq, 2 g, 6.21 mmol) were added to isopropanol (20 ml) and water (4 ml), and finally tetramethylguanidine (0.5 eq, 0.36 g, 3.11 mmol) was added. The reaction was carried out at 25 °C for 12 h. TLC (DCM:ME = 15:1, Rf of raw material indole = 0.5, Rf of raw material aldehyde = 0.95, Rf of product = 0.3), the indole reaction was complete. The system was diluted with EA (150 ml), washed with water 3 times, dried and concentrated, and the crude product was purified by column chromatography. 2.5 g of brown solid was obtained (yield 85%).

[0059] ESI-MS: 475.1[M+H]+

[0060] Step 3: The pure product from Step 2 (2.5 g, 1 eq, 5.28 mmol) was added to acetonitrile (25 ml) and trifluoroacetic acid (5 ml). Triethylsilane (2.46 g, 4 eq, 21.12 mmol) was added, and the reaction was carried out at 60 °C for 20 h. TLC (DCM:ME = 15:1, starting material Rf = 0.3, product Rf = 0.2). After the reaction was complete and the system was cooled to room temperature, the reaction solution was concentrated. EA (200 ml) was added, washed once with saturated sodium bicarbonate, washed twice with water, dried and concentrated, and then purified by column chromatography. 1.3 g of yellow solid was obtained (yield 95%).

[0061] ESI-MS: 259.0 [M+H]+

[0062] Step 4: Indoleacetic acid (0.5 g, 1.2 eq, 2.86 mmol) was taken, dissolved in DMF (5 ml), DIPEA (0.92 g, 3 eq, 7.14 mmol) was added, then TBTU (0.95 g, 1.25 eq, 2.97 mmol) was added, and stirred for 2 min. Finally, the pure product from Step 3 (0.62 g, 1 eq, 2.38 mmol) was added, and the reaction was carried out at room temperature for 24 h. TLC (DCM:ME = 15:1, starting material Rf = 0.2, product Rf = 0.35), and more starting material remained. The system was diluted with EA (100 ml), washed 3 times with saturated sodium bicarbonate, dried and concentrated, and then purified by column chromatography. 0.4 g of light yellow solid was obtained (yield 40%).

[0063] ESI-MS: 416.1 [M+H]+

[0064] 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.99 (s, 1H), 10.59 (s, 1H), 8.31 (dd, J = 2.4, 0.8 Hz, 1H), 8.17 (d, J = 2.3 Hz, 1H), 7.99 (dt, J = 4.0, 2.8 Hz, 2H), 7.69 (dd, J = 8.6, 2.4 Hz, 1H), 7.47–7.38 (m, 2H), 7.32 (dq, J = 8.1, 0.9 Hz, 1H), 7.01 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 6.93 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 6.27 (dd, J = 2.1, 0.9 Hz, 1H), 4.01 (s, 2H), 3.87 (s, 2H).

[0065] Example 2: Synthesis of Compound S2

[0066] Synthesis route:

[0067]

[0068] Synthesis process:

[0069] First step: 2-Amino-5-formylpyridine (1 eq, 2 g, 16.38 mmol) was dissolved in THF (40 ml), and TEA (3 eq, 4.97 g, 49.14 mmol) and DMAP (0.2 eq, 0.4 g, 3.28 mmol) were added. Then, (Boc)2O (2.3 eq, 8.22 g, 37.67 mmol) was added, and the reaction was carried out at room temperature for 12 h. TLC (PE:EA = 5:1, Rf of raw material = 0.3, Rf of product = 0.6), the reaction was complete. After post-treatment, the system was directly concentrated to dryness and purified by column chromatography. 4.3 g of white solid was obtained (yield 80%).

[0070] ESI-MS: 323.1 [M+H]+

[0071] Second step: Chlorinated azaindole (1 eq, 0.94 g, 6.21 mmol) and the product of the first step (1 eq, 2 g, 6.21 mmol) were added to isopropanol (20 ml) and water (4 ml). Finally, tetramethylguanidine (0.5 eq, 0.36 g, 3.11 mmol) was added, and the reaction was carried out at 25 °C for 12 h. TLC (DCM:ME = 15:1, Rf of raw material indole = 0.5, Rf of raw material aldehyde = 0.95, Rf of product = 0.3), the indole reaction was complete. After the system was diluted with EA (150 ml), it was washed with water 3 times, dried and concentrated, and the crude product was purified by column chromatography. 2.5 g of brown solid was obtained (yield 85%).

[0072] ESI-MS: 475.1 [M+H]+

[0073] Third step: The pure product of the second step (2.5 g, 1 eq, 5.28 mmol) was added to acetonitrile (25 ml) and trifluoroacetic acid (5 ml), and triethylsilane (2.46 g, 4 eq, 21.12 mmol) was added. The reaction was carried out at 60 °C for 20 h. TLC (DCM:ME = 15:1, Rf of raw material = 0.3, Rf of product = 0.2), the reaction was complete. After the system was cooled to room temperature, the reaction solution was concentrated. EA (200 ml) was added, and it was washed once with saturated sodium bicarbonate and twice with water. After drying and concentrating, it was purified by column chromatography. 1.3 g of yellow solid was obtained (yield 95%).

[0074] ESI-MS: 259.0 [M+H]+

[0075] Step 4: Take 2-pyridineacetic acid (0.39 g, 1.2 eq, 2.86 mmol), dissolve it in DMF (5 ml), add DIPEA (0.92 g, 3 eq, 7.14 mmol), then add TBTU (0.95 g, 1.25 eq, 2.97 mmol), stir for 2 min, and finally add the pure product from the third step (0.62 g, 1 eq, 2.38 mmol). React at room temperature for 24 h. TLC (DCM:ME = 15:1, starting material Rf = 0.2, product Rf = 0.35), and there was still a large amount of starting material remaining. The system was diluted with EA (100 ml), washed 3 times with saturated sodium bicarbonate, dried and concentrated, and then purified by column chromatography. Obtained 0.358 g of a pale yellow solid (yield 40%).

[0076] ESI-MS: 378.1[M+H]+

[0077] 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.67 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 8.04–7.89 (m, 2H), 7.75 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.47–7.32 (m, 2H), 7.26 (t, J = 6.1 Hz, 1H), 4.01 (s, 2H), 3.91 (s, 2H).

[0078] Example 3: Synthesis of Compound S3

[0079] Synthesis route:

[0080]

[0081] Synthesis process:

[0082] Step 1: Dissolve 2-amino-5-formylpyridine (1 eq, 2 g, 16.38 mmol) in THF (40 ml), add TEA (3 eq, 4.97 g, 49.14 mmol) and DMAP (0.2 eq, 0.4 g, 3.28 mmol), then add (Boc)2O (2.3 eq, 8.22 g, 37.67 mmol). After addition, react at room temperature for 12 h. TLC (PE:EA = 5:1, starting material Rf = 0.3, product Rf = 0.6), and the reaction was complete. For post-treatment, the system was directly concentrated to dryness and purified by column chromatography. Obtained 4.3 g of a white solid (yield 80%).

[0083] ESI-MS: 323.1[M+H]+

[0084] Step 2: Fluoroazaindole (1 eq, 0.84 g, 6.21 mmol) and the product of Step 1 (1 eq, 2 g, 6.21 mmol) were added to isopropanol (20 ml) and water (4 ml). Finally, tetramethylguanidine (0.5 eq, 0.36 g, 3.11 mmol) was added, and the reaction was carried out at 25 °C for 12 h. TLC (DCM:ME = 15:1, starting indole Rf = 0.5, starting aldehyde Rf = 0.95, product Rf = 0.3), the indole reaction was complete. The system was diluted with EA (150 ml), washed with water 3 times, dried and concentrated, and the crude product was purified by column chromatography. A brown solid of 2.56 g (yield 85%) was obtained.

[0085] ESI-MS: 459.2 [M+H]+

[0086] Step 3: The pure product of Step 2 (1 eq, 5.28 mmol) was added to acetonitrile (25 ml) and trifluoroacetic acid (5 ml). Triethylsilane (2.46 g, 4 eq, 21.12 mmol) was added, and the reaction was carried out at 60 °C for 20 h. TLC (DCM:ME = 15:1, starting material Rf = 0.3, product Rf = 0.2), the reaction was complete. After the system was cooled to room temperature, the reaction solution was concentrated. EA (200 ml) was added, washed once with saturated sodium bicarbonate and twice with water, dried and concentrated, and then purified by column chromatography. A yellow solid of 1.21 g (yield 95%) was obtained.

[0087] ESI-MS: 243.1 [M+H]+

[0088] Step 4: Indoleacetic acid (0.5 g, 1.2 eq, 2.86 mmol) was dissolved in DMF (5 ml), DIPEA (0.92 g, 3 eq, 7.14 mmol) was added, then TBTU (0.95 g, 1.25 eq, 2.97 mmol) was added, and the mixture was stirred for 2 min. Finally, the pure product of Step 3 (1 eq, 2.38 mmol) was added, and the reaction was carried out at room temperature for 24 h. TLC (DCM:ME = 15:1, starting material Rf = 0.2, product Rf = 0.35), a large amount of starting material remained. The system was diluted with EA (100 ml), washed 3 times with saturated sodium bicarbonate, dried and concentrated, and then purified by column chromatography. A pale yellow solid of 0.38 g (yield 40%) was obtained.

[0089] ESI-MS: 400.1 [M+H]+

[0090] 11H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 10.98 (s, 1H), 10.58 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.77 (dd, J = 9.5, 2.8 Hz, 1H), 7.69 (dd, J = 8.5, 2.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 1H), 7.01 (dd, J = 7.7, 6.4 Hz, 1H), 6.96–6.89 (m, 1H), 6.27 (s, 1H), 4.00 (s, 2H), 3.87 (s, 2H).

[0091] Example 4: Synthesis of Compound S4

[0092] Synthetic route:

[0093]

[0094] Synthesis process:

[0095] First step: 2-Amino-5-formyl-6-fluoropyridine (1 eq, 2.3 g, 16.38 mmol) was dissolved in THF (40 ml), TEA (3 eq, 4.97 g, 49.14 mmol) and DMAP (0.2 eq, 0.4 g, 3.28 mmol) were added, then (Boc)2O (2.3 eq, 8.22 g, 37.67 mmol) was added. After addition, the reaction was carried out at room temperature for 12 h. TLC (PE:EA = 5:1, starting material Rf = 0.3, product Rf = 0.6), the reaction was complete. After post-treatment, the system was directly concentrated to dryness and purified by column chromatography. 4.45 g of white solid was obtained (yield 80%).

[0096] ESI-MS: 341.1 [M+H]+

[0097] Second step: Chlorinated azaindole (1 eq, 0.94 g, 6.21 mmol) and the product of the first step (1 eq, 2.11 g, 6.21 mmol) were added to isopropanol (20 ml) and water (4 ml), and finally tetramethylguanidine (0.5 eq, 0.36 g, 3.11 mmol) was added. The reaction was carried out at 25 °C for 12 h. TLC (DCM:ME = 15:1, starting material indole Rf = 0.5, starting material aldehyde Rf = 0.95, product Rf = 0.3), the indole reaction was complete. The system was diluted with EA (150 ml), washed with water 3 times, dried and concentrated, and the crude product was purified by column chromatography. 2.6 g of brown solid was obtained (yield 85%).

[0098] ESI-MS: 493.1 [M+H]+

[0099] Step 3: The pure product from Step 2 (2.6 g, 1 eq, 5.28 mmol) was added to acetonitrile (25 ml) and trifluoroacetic acid (5 ml). Triethylsilane (2.46 g, 4 eq, 21.12 mmol) was added, and the reaction was carried out at 60 °C for 20 h. TLC (DCM:ME = 15:1, starting material Rf = 0.3, product Rf = 0.2). After the reaction was complete, the reaction solution was concentrated after the system was cooled to room temperature. EA (200 ml) was added, washed once with saturated sodium bicarbonate, washed twice with water, dried and concentrated, and then purified by column chromatography. 1.38 g of yellow solid was obtained (yield 95%).

[0100] ESI-MS: 277.0 [M+H]+

[0101] Step 4: Cyclopropyl-2-pyridineacetic acid (0.466 g, 1.2 eq, 2.86 mmol) was dissolved in DMF (5 ml), DIPEA (0.92 g, 3 eq, 7.14 mmol) was added, then TBTU (0.95 g, 1.25 eq, 2.97 mmol) was added, and the mixture was stirred for 2 min. Finally, the pure product from Step 3 (1 eq, 2.38 mmol) was added, and the reaction was carried out at room temperature for 24 h. TLC (DCM:ME = 15:1, starting material Rf = 0.2, product Rf = 0.35), and a large amount of starting material remained. The system was diluted with EA (100 ml), washed 3 times with saturated sodium bicarbonate, dried and concentrated, and then purified by column chromatography. 0.4 g of light yellow solid was obtained (yield 40%).

[0102] ESI-MS: 422.1 [M+H]+

[0103] 1 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 11.53 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.86 (m, 2H), 7.38 (s, 1H), 7.31 (dd, J = 11.6, 6.5 Hz, 2H), 4.01 (s, 2H), 1.60 (q, J = 4.2 Hz, 2H), 1.39 (q, J = 4.2 Hz, 2H).

[0104] Example 5: Synthesis of Compound S5

[0105] Synthesis route:

[0106]

[0107] Synthesis process:

[0108] Step 1: 2-Amino-5-formyl-6-fluoropyridine (1 eq, 2.3 g, 16.38 mmol) was dissolved in THF (40 ml), and TEA (3 eq, 4.97 g, 49.14 mmol) and DMAP (0.2 eq, 0.4 g, 3.28 mmol) were added. Then, (Boc)2O (2.3 eq, 8.22 g, 37.67 mmol) was added, and the reaction was carried out at room temperature for 12 h. TLC (PE:EA = 5:1, Rf of raw material = 0.3, Rf of product = 0.6), the reaction was complete. After post-treatment, the system was directly concentrated to dryness and purified by column chromatography. 4.45 g of white solid was obtained (yield 80%).

[0109] ESI-MS: 341.1 [M+H]+

[0110] Step 2: Chlorinated azaindole (1 eq, 0.94 g, 6.21 mmol) and the product of the first step (1 eq, 2.11 g, 6.21 mmol) were added to isopropanol (20 ml) and water (4 ml). Finally, tetramethylguanidine (0.5 eq, 0.36 g, 3.11 mmol) was added, and the reaction was carried out at 25 °C for 12 h. TLC (DCM:ME = 15:1, Rf of raw material indole = 0.5, Rf of raw material aldehyde = 0.95, Rf of product = 0.3), the indole reaction was complete. After the system was diluted with EA (150 ml), it was washed with water 3 times, dried and concentrated, and the crude product was purified by column chromatography. 2.6 g of brown solid was obtained (yield 85%).

[0111] ESI-MS: 493.1 [M+H]+

[0112] Step 3: The pure product of the second step (2.6 g, 1 eq, 5.28 mmol) was added to acetonitrile (25 ml) and trifluoroacetic acid (5 ml), and triethylsilane (2.46 g, 4 eq, 21.12 mmol) was added. The reaction was carried out at 60 °C for 20 h. TLC (DCM:ME = 15:1, Rf of raw material = 0.3, Rf of product = 0.2), the reaction was complete. After the system was cooled to room temperature, the reaction solution was concentrated. EA (200 ml) was added, and it was washed once with saturated sodium bicarbonate and twice with water. After drying and concentration, it was purified by column chromatography. 1.38 g of yellow solid was obtained (yield 95%).

[0113] ESI-MS: 277.0 [M+H]+

[0114] Step 4: Take 2-pyridineacetic acid (0.39 g, 1.2 eq, 2.86 mmol), dissolve it in DMF (5 ml), add DIPEA (0.92 g, 3 eq, 7.14 mmol), then add TBTU (0.95 g, 1.25 eq, 2.97 mmol), stir for 2 min, and finally add the pure product from the third step (1 eq, 2.38 mmol). React at room temperature for 24 h. TLC (DCM:ME = 15:1, starting material Rf = 0.2, product Rf = 0.35), there was still a large amount of starting material remaining. The system was diluted with EA (100 ml), washed 3 times with saturated sodium bicarbonate, dried and concentrated, and then purified by column chromatography. Obtained 0.376 g of a pale yellow solid (yield 40%).

[0115] ESI-MS: 396.1[M+H]+

[0116] 1 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.89 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.45 (dd, J = 4.8, 1.7 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.88–7.78 (m, 2H), 7.72 (dt, J = 7.9, 2.0 Hz, 1H), 7.39–7.32 (m, 2H), 4.00 (s, 2H), 3.75 (s, 2H).

[0117] Example 6: Synthesis of Compound S6

[0118] Synthesis route:

[0119]

[0120] Synthesis process:

[0121] Step 1: Dissolve 2-amino-5-formyl-6-fluoropyridine (1 eq, 2.3 g, 16.38 mmol) in THF (40 ml), add TEA (3 eq, 4.97 g, 49.14 mmol) and DMAP (0.2 eq, 0.4 g, 3.28 mmol), then add (Boc)2O (2.3 eq, 8.22 g, 37.67 mmol). After addition, react at room temperature for 12 h. TLC (PE:EA = 5:1, starting material Rf = 0.3, product Rf = 0.6), the reaction was complete. For post-treatment, the system was directly concentrated to dryness and purified by column chromatography. Obtained 4.45 g of a white solid (yield 80%).

[0122] ESI-MS: 341.1[M+H]+

[0123] Step 2: Chlorinated aza-indole (1 eq, 0.94 g, 6.21 mmol) and the product of the first step (1 eq, 2.11 g, 6.21 mmol) were added to isopropanol (20 ml) and water (4 ml). Finally, tetramethylguanidine (0.5 eq, 0.36 g, 3.11 mmol) was added, and the reaction was carried out at 25 °C for 12 h. TLC (DCM:ME = 15:1, starting indole Rf = 0.5, starting aldehyde Rf = 0.95, product Rf = 0.3), the indole reaction was complete. The system was diluted with EA (150 ml), washed with water 3 times, dried and concentrated, and the crude product was purified by column chromatography. 2.6 g of brown solid was obtained (yield 85%).

[0124] ESI-MS: 493.1 [M+H]+

[0125] Step 3: The pure product of the second step (2.6 g, 1 eq, 5.28 mmol) was added to acetonitrile (25 ml) and trifluoroacetic acid (5 ml). Triethylsilane hydride (2.46 g, 4 eq, 21.12 mmol) was added, and the reaction was carried out at 60 °C for 20 h. TLC (DCM:ME = 15:1, starting material Rf = 0.3, product Rf = 0.2), the reaction was complete. After the system was cooled to room temperature, the reaction solution was concentrated. EA (200 ml) was added, washed once with saturated sodium bicarbonate and twice with water, dried and concentrated, and then purified by column chromatography. 1.38 g of yellow solid was obtained (yield 95%).

[0126] ESI-MS: 277.0 [M+H]+

[0127] Step 4: 2-Pyridinebutyric acid (0.47 g, 1.2 eq, 2.86 mmol) was taken, dissolved in DMF (5 ml), DIPEA (0.92 g, 3 eq, 7.14 mmol) was added, then TBTU (0.95 g, 1.25 eq, 2.97 mmol) was added, and the mixture was stirred for 2 min. Finally, the pure product of the third step (1 eq, 2.38 mmol) was added, and the reaction was carried out at room temperature for 24 h. TLC (DCM:ME = 15:1, starting material Rf = 0.2, product Rf = 0.35), there was still a lot of starting material left. The system was diluted with EA (100 ml), washed 3 times with saturated sodium bicarbonate, dried and concentrated, and then purified by column chromatography. 0.4 g of light yellow solid was obtained (yield 40%).

[0128] ESI-MS: 424.1 [M+H]+

[0129] 11H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.52 (s, 1H), 8.50–8.43 (m, 1H), 8.18 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.82 (t, J = 9.2 Hz, 1H), 7.72–7.64 (m, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.19 (dd, J = 7.4, 5.0 Hz, 1H), 3.99 (s, 2H), 2.74 (t, J = 7.7 Hz, 2H), 2.40 (t, J = 7.4 Hz, 2H), 2.01–1.92 (m, 2H).

[0130] Example 7: Synthesis of Compound S7

[0131] Synthetic route:

[0132]

[0133] Synthesis process:

[0134] First step: 2-Amino-5-formylpyridine (1 eq, 2 g, 16.38 mmol) was dissolved in THF (40 ml), TEA (3 eq, 4.97 g, 49.14 mmol) and DMAP (0.2 eq, 0.4 g, 3.28 mmol) were added, and then (Boc)2O (2.3 eq, 8.22 g, 37.67 mmol) was added. After the addition, the reaction was carried out at room temperature for 12 h. TLC (PE:EA = 5:1, starting material Rf = 0.3, product Rf = 0.6), the reaction was complete. After post-treatment, the system was directly concentrated to dryness and purified by column chromatography. 4.3 g of white solid was obtained (yield 80%).

[0135] ESI-MS: 323.1 [M+H]+

[0136] Second step: 4,6-Dichloroazaindole (1 eq, 1.15 g, 6.21 mmol) and the product of the first step (1 eq, 2 g, 6.21 mmol) were added to isopropanol (20 ml) and water (4 ml), and finally tetramethylguanidine (0.5 eq, 0.36 g, 3.11 mmol) was added. The reaction was carried out at 25 °C for 12 h. TLC (DCM:ME = 15:1, starting material indole Rf = 0.5, starting material aldehyde Rf = 0.95, product Rf = 0.3), the indole reaction was complete. The system was diluted with EA (150 ml), washed with water 3 times, dried and concentrated, and the crude product was purified by column chromatography. 2.68 g of brown solid was obtained (yield 85%).

[0137] ESI-MS: 509.1 [M+H]+

[0138] Step 3: The pure product from the second step (2.68 g, 1 eq, 5.28 mmol) was added to acetonitrile (25 ml) and trifluoroacetic acid (5 ml). Triethylsilane (2.46 g, 4 eq, 21.12 mmol) was added, and the reaction was carried out at 60 °C for 20 h. TLC (DCM:ME = 15:1, Rf of the starting material = 0.3, Rf of the product = 0.2). After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. EA (200 ml) was added, and it was washed once with saturated sodium bicarbonate and twice with water. After drying and concentration, it was purified by column chromatography. 1.46 g of a yellow solid was obtained (yield 95%).

[0139] ESI-MS: 293.0 [M+H]+

[0140] 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.24 (s, 1H), 7.19 (dd, J = 8.4, 2.5 Hz, 1H), 6.37 (dd, J = 8.4, 0.8 Hz, 1H), 5.68 (s, 2H), 4.00 (s, 2H).

[0141] Step 4: 5-Chloro-2-pyridineacetic acid (0.49 g, 1.2 eq, 2.86 mmol) was dissolved in DMF (5 ml). DIPEA (0.92 g, 3 eq, 7.14 mmol) was added, then TBTU (0.95 g, 1.25 eq, 2.97 mmol) was added, and the mixture was stirred for 2 min. Finally, the pure product from the third step (0.62 g, 1 eq, 2.38 mmol) was added, and the reaction was carried out at room temperature for 24 h. TLC (DCM:ME = 15:1, Rf of the starting material = 0.2, Rf of the product = 0.35), and a large amount of the starting material remained. The reaction mixture was diluted with EA (100 ml), washed 3 times with saturated sodium bicarbonate, dried and concentrated, and then purified by column chromatography. 0.42 g of a pale yellow solid was obtained (yield 40%).

[0142] ESI-MS: 446.0 [M+H]+

[0143] 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 7.88–7.79 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.24 (s, 1H), 7.22–7.19 (m, 1H), 6.41–6.34 (m, 2H), 4.01 (s, 2H), 3.75 (s, 2H).

[0144] Example 8: Synthesis of Compound S8

[0145] Synthesis route:

[0146]

[0147] Synthesis process:

[0148] First step: 2-Amino-5-formylpyridine (1 eq, 2 g, 16.38 mmol) was dissolved in THF (40 ml), TEA (3 eq, 4.97 g, 49.14 mmol) and DMAP (0.2 eq, 0.4 g, 3.28 mmol) were added, and then (Boc)2O (2.3 eq, 8.22 g, 37.67 mmol) was added. After addition, the reaction was carried out at room temperature for 12 h. TLC (PE:EA = 5:1, Rf of raw material = 0.3, Rf of product = 0.6), the reaction was complete. After post-treatment, the system was directly concentrated to dryness and purified by column chromatography. 4.3 g of white solid was obtained (yield 80%).

[0149] ESI-MS: 323.1 [M+H]+

[0150] Second step: 4,6-Dichloroazaindole (1 eq, 1.15 g, 6.21 mmol) and the product of the first step (1 eq, 2 g, 6.21 mmol) were added to isopropanol (20 ml) and water (4 ml), and finally tetramethylguanidine (0.5 eq, 0.36 g, 3.11 mmol) was added. The reaction was carried out at 25 °C for 12 h. TLC (DCM:ME = 15:1, Rf of raw material indole = 0.5, Rf of raw material aldehyde = 0.95, Rf of product = 0.3), the indole reaction was complete. After the system was diluted with EA (150 ml), it was washed with water 3 times, dried and concentrated, and the crude product was purified by column chromatography. 2.68 g of brown solid was obtained (yield 85%).

[0151] ESI-MS: 509.1 [M+H]+

[0152] Third step: The pure product of the second step (2.68 g, 1 eq, 5.28 mmol) was added to acetonitrile (25 ml) and trifluoroacetic acid (5 ml), and triethylsilane (2.46 g, 4 eq, 21.12 mmol) was added. The reaction was carried out at 60 °C for 20 h. TLC (DCM:ME = 15:1, Rf of raw material = 0.3, Rf of product = 0.2), the reaction was complete. After the system was cooled to room temperature, the reaction solution was concentrated. EA (200 ml) was added, and it was washed once with saturated sodium bicarbonate and twice with water. After drying and concentrating, it was purified by column chromatography. 1.46 g of yellow solid was obtained (yield 95%).

[0153] ESI-MS: 293.0 [M+H]+

[0154] 1 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.24 (s, 1H), 7.19 (dd, J = 8.4, 2.5 Hz, 1H), 6.37 (dd, J = 8.4, 0.8 Hz, 1H), 5.68 (s, 2H), 4.00 (s, 2H).

[0155] Step 4: Take methyl N-methylpyrroleacetate (0.43 g, 1.2 eq, 2.86 mmol), dissolve it with THF (10 ml), add the pure product from the third step (0.62 g, 1 eq, 2.38 mmol), cool the system to 0 °C, and finally add dropwise NaHMDS (1.2 eq, 2.86 mmol). After adding, let it rise to room temperature naturally and react for 12 h. TLC (DCM:ME = 15:1, Rf of the raw material = 0.2, Rf of the product = 0.35), and there was still a large amount of the raw material remaining. Pour the system into 60 ml of water, extract it 4 times with EA (40 ml), combine the organic phases, dry and concentrate, and then purify by column chromatography. Obtain 0.39 g of a pale yellow solid (yield 40%).

[0156] ESI-MS: 414.0 [M+H]+

[0157] 1 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 7.88–7.79 (m, 1H), 7.31 (m, 1H), 7.24 (s, 1H), 7.22–7.19 (m, 1H), 6.59 (t, J = 2.3 Hz, 1H), 6.41–6.34 (m, 2H), 5.96–5.74 (m, 2H), 3.9 (s, 2H), 3.51 (s, 3H), 2.75 (s, 2H).

[0158] Enzymatic activity evaluation of the compound in Example 9

[0159] 1. In vitro biochemical kinase experiment of CSF1R

[0160] The present invention uses ADP-Glo TMKinase Detection Kit (Promega, cat. No. V9101), which quantifies the amount of ADP generated during the kinase reaction to evaluate the kinase inhibitory activity of compounds. The specific experimental procedure is as follows: The kinase reaction is carried out in a 384-well plate (Greiner, cat. No. 784075), with each well containing 0.4 nM CSF1R, 100 μM ATP, and 0.1 mg / ml polypeptide; A kinase reaction system containing Hepes, MgCl2, Brij35, EGTA, and DTT is prepared and used to prepare 2×ATP and substrate solutions as well as 2×kinase solutions respectively; 20 nL of serially diluted compounds are transferred to the 384-well detection plate by Echo 655. Then 3 μL of 2×kinase solution is added thereto, mixed well, and incubated at 25 °C for 20 min; 3 μL of 2×substrate and ATP solution is added to the wells and incubated at 25 °C for 30 min; 4 μL of ADP-Glo reagent is added to the wells and incubated at 25 °C for 40 min; 6 μL of Kinase Detection Reagent is added to the wells and incubated at 25 °C for 40 min; The RLU (Relative luminescence unit) signal is read using a BMG multi-functional microplate reader. The signal intensity is used to characterize the kinase activity level, and the four-parameter curve in Graphpad Prism is used to determine the IC50 value of the compound.

[0161] 2. In Vitro Biochemical Kinase Assays for C-KIT / FLT3 / PDGFRα / PDGFRβ

[0162] The detection kit HTRF KinEASE-TK kit was used to detect the selectivity of compounds for tyrosine kinase targets (C-KIT, FLT3, PDGFRα, PDGFRβ). The specific experimental procedure is as follows: The kinase reaction carried out in this invention was performed in a 384-well plate (Greiner, cat. No. 784075), containing 1 nM of C-KIT, 6 μM of ATP and 1 μM of TK substrate respectively; containing 0.024 nM of FLT3, 2 μM of ATP and 1 μM of TK substrate; containing 0.12 nM of PDGFRα (Carna, cat. No. 08-157), 0.5 μM of ATP and 1 μM of TK substrate; containing 0.23 nM of PDGFRβ, 1 μM of ATP and 1 μM of TK substrate; preparing a 1× kinase reaction system containing MgCl2, MnCl, SEB, and DTT for preparing 2×ATP and substrate solution and 2× kinase solution; transferring 25 nL of the compound to a 384-well assay plate. Adding 2.5 μL of 2× kinase solution, mixing evenly, and incubating at 25 °C for 10 min; adding 2.5 μL of 2× substrate and ATP solution to the wells, and incubating at 25 °C for 30 min; preparing a 2×XL665 and antibody solution with the detection buffer; adding 5 μL of Kinase Detection Reagent to the wells, and incubating at 25 °C for 60 min; using a BMG multi-functional microplate reader to read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665), and using a four-parameter curve in Graphpad Prism to determine the IC50 value of the compound. The results are shown in Table 1.

[0163] Cell activity detection of the compound in Example 10

[0164] The mouse myeloid leukemia lymphocyte line M-NFS-60 (RPMI1640 + 0.05 mM β-mercaptoethanol + 62 ng / mL CSF-1 + 10% FBS), the human monocytic leukemia cell line THP-1 (RPMI1640 + 10% FBS + 0.05 mM β-mercaptoethanol + 1% P / S), and the mouse microglial cell line BV2 (MEM + 1% NEAA + 10% FBS + 1% P / S) were all purchased from Wuhan Pusai Biotechnology Co., Ltd. and maintained normal growth under the culture conditions of 37 °C and 5% CO2. Take the BV2, M-NFS-60, and THP-1 cells in the logarithmic growth phase, and respectively at 8×10 per well 3 、3×10 4 、4×10 4Cells were seeded in 96-well plates, with each well containing 100 μL of medium, and three replicate wells were set for each drug concentration. After BV2 cells were seeded, they were cultured overnight under the conditions of 37 °C and 5% CO2. After the cells adhered to the wall, CSF1R inhibitor was added and the cells were treated for 72 h. After the suspension cells M-NFS-60 and THP-1 were allowed to stand for an appropriate time, drug treatment could be directly carried out, and then they were incubated for 72 hours. CellTiter-Glo Luminescent Cell Viability Assay (Promega, cat. No. G7571) was used

[0165] to evaluate cell viability. According to the reagent usage instructions, CellTiter-Glo Buffer was thawed in advance before detection, and it was balanced to room temperature with the freeze-dried substrate. The two were mixed evenly to prepare CellTiter-Glo Reagent detection reagent. At the same time, the cell culture plate and its contents were balanced at room temperature. 100 μL of CellTiter-Glo Reagent was added to the medium containing cells or complete medium without cells, and a orbital shaker was used to mix for 2 min to induce cell lysis. Then the culture plate was incubated at room temperature for 10 min to stabilize the luminescence signal. An enzyme-linked immunosorbent assay reader was used to read the RLU (Relative luminescence unit) signal. The signal intensity was used to characterize the level of cell viability, and a four-parameter curve in Graphpad Prism was used to determine the IC50 value of the compound. The results are shown in Table 1

[0166] Table 1 Results of compound enzyme activity and cell activity

[0167]

[0168] Note: "+" means the IC50 of the compound CSF1R kinase inhibitory activity > 30 nM; "++" means the IC50 of the compound CSF1R kinase inhibitory activity is 10 nM < IC50 < 30 nM; "+++" means the IC50 of the compound CSF1R kinase inhibitory activity < 10 nM

[0169] Example 11 Compound PK experiment:

[0170] In the PK experiment of the compound drug in the embodiments of the present invention, male SD rats were used. One day before the experiment, the animals were fasted (about 12 h), and a single oral administration was adopted. The dose was 5 mg / Kg or 10 mg / kg, and the formulation was suspended in 0.5% CMC-Na. After the rats were administered, the blood sampling time points were 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 24 h after administration. All the above samples were placed in heparin sodium anticoagulated EP tubes and ice-bathed after collection, centrifuged at 4°C, 8000 rpm for 5 minutes, and the plasma was transferred to -20°C for storage and waiting for detection as soon as possible. The concentration of the compound in the collected samples was determined by the LC-MS / MS detection method that had been investigated for specificity, standard curve, precision, accuracy and dilution accuracy. Winnonlin 5.2 was used to calculate the pharmacokinetic parameters. The PK data of the compound in the specific examples are shown in the following table.

[0171] Table 2 Compound PK parameters (i.g. 5.0 mg / kg)

[0172] Serial number t1 / 2 (h) Tmax (h) Cmax (ng / ml) AUC (h*ng / ml) F(％) S4 2.71 4.00 4023 24746 38.9％

Claims

1. A class of azaindole compounds represented by formula I, their stereoisomers, or their pharmaceutically acceptable salts, hydrates or solvates, characterized in that, Wherein, R1, R2 and R3 are each independently selected from hydrogen, chlorine, fluorine, trifluoromethyl, difluoromethyl or C1-C3 alkyl; R4 is selected from hydrogen, chlorine or fluorine; R5 and R6 are both hydrogen, or R5 and R6 are both fluorine, or R5 and R6 together with the connected carbon atom form an alkyl three-membered ring; A is selected from indole, pyridine, substituted pyridine, pyrrole or N-methylpyrrole; n is selected from the numbers 0, 1, 2, 3 or 4.

2. The compound according to claim 1, and its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, Wherein, R1, R2 and R3 are each independently selected from hydrogen, chlorine, fluorine, trifluoromethyl or methyl; R4 is selected from hydrogen, chlorine or fluorine; R5 and R6 are both hydrogen, or R5 and R6 are both fluorine, or R5 and R6 together with the connected carbon atom form an alkyl three-membered ring; A is selected from indole, pyridine, substituted pyridine, pyrrole or N-methylpyrrole; n is selected from the numbers 0, 1, 2, 3 or 4.

3. The compound according to claim 1, its stereoisomers or its pharmaceutically acceptable salts, characterized in that, Wherein, R1, R2 and R3 are each independently selected from hydrogen, chlorine or fluorine; R4 is selected from hydrogen or fluorine; R5 and R6 are both hydrogen, or R5, R6 and the connected carbon atom together form an alkyl three-membered ring; A is selected from indole, pyridine, substituted pyridine, N-methylpyrrole; n is selected from the numbers 0, 1 or 2.

4. The compound according to the claim, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that, The compounds are: Compound 1: as shown in S1; Compound 2: as shown in S2; Compound 3: as shown in S3; Compound 4: as shown in S4; Compound 5: as shown in S5; Compound 6: as shown in S6; Compound 7: as shown in S7; Compound 8: as shown in S8.

5. Use of the compound according to any one of claims 1 to 4, its stereoisomers or its pharmaceutically acceptable salts in the treatment of cancer, tumor, autoimmune disease, neurodegenerative disease, metabolic disease or metastatic disease.

6. Use of the compound according to any one of claims 1 to 4, its stereoisomers or its pharmaceutically acceptable salts in the preparation of drugs for treating tenosynovial giant cell tumor, ovarian cancer, pancreatic cancer, prostate cancer, non-small cell lung cancer, breast cancer, renal cell carcinoma, liver cancer, cervical cancer, papillary thyroid cancer, colorectal cancer, gastrointestinal stromal tumor, melanoma, mesothelioma, osteosarcoma, head and neck cancer, glioblastoma, leukemia, peritoneal malignancy, peripheral T cell lymphoma, bone metastatic cancer, multiple myeloma, metastasis of primary tumor site, myeloproliferative disease, hyperproliferative disease, metabolic disease, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, pigmented villonodular synovitis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, neurodegenerative disease, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic syndrome, mastocytosis or mast cell leukemia; Or in the preparation of drugs for treating tenosynovial giant cell tumor, multiple myeloma, glioblastoma, metastasis of primary tumor site or bone metastatic cancer, metabolic disease, graft-versus-host disease, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease.

7. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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