(4-phenoxy) piperidine-1-ketone compound as well as preparation method and application thereof

Abstract

The invention discloses a (4-phenoxy) piperidine-1-ketone compound as well as a preparation method and application thereof, and relates to the technical field of medicinal chemistry, the structural formula of the (4-phenoxy) piperidine-1-ketone compound is shown in the specification, in the formula, X is CO or CH2; r1 is any one of substituted or unsubstituted aryl, cycloalkyl and heteroaromatic ring; and R2 is heteroaromatic ring. A series of (4-phenoxy) piperidine-1-ketone compounds with novel structures are designed and synthesized, and in-vitro cell experiments prove that the compounds have a good selective inhibition effect on CSF1R and can be used as CSF1R inhibitors for preventing or treating diseases, obstacles or symptoms related to CSF1R activity.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, in particular to a (4-phenoxy)piperidin-1-one compound and a preparation method and application thereof. BACKGROUND

[0002] Colony-stimulating factor 1 receptor (CSF1R) is a receptor-type tyrosine kinase encoded by the proto-oncogene c-fms, also known as M-CSF1R or CD115, which belongs to the type III receptor tyrosine kinase family (RTK) together with KIT, FLT3, PDGFRa and PDGFRb, and is a key pathway for regulating the proliferation, survival and differentiation of macrophages. The CSF1 / CSF1R axis may lead to abnormal expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6), through downstream pathways such as PI3K / AKT / NF-kappa B. The increase of these pro-inflammatory cytokines can promote various types of cancer and bone diseases. The binding of ligand to CSF1R causes dimerization of the kinase, leading to autophosphorylation of the tyrosine sites in the intracellular domain, thus activating CSF1R kinase. The activated CSF1R kinase interacts with the corresponding substrate protein, dephosphorylates and internalizes itself, phosphorylates the tyrosine sites of the substrate, triggers a series of intracellular signal cascade reactions and activates various transcription factors, maintains the survival of macrophages, amplifies the inflammatory cascade reaction, and promotes osteoclast-mediated bone resorption through the imbalance of the RANKL / OPG axis. Therefore, targeting CSF1R can simultaneously inhibit inflammation and bone destruction, prevent erosion, alleviate rheumatoid arthritis (RA) and osteolysis symptoms, and achieve "double regulation". In the development of RA, the level of synovial macrophages and the inflammatory cytokines released by them affect the progression and activity of RA. The binding of CSF1 to CSF1R activates the relevant signaling pathway, which not only helps the proliferation and survival of inflammatory macrophages in the synovium, but also promotes the continuous secretion of various inflammatory mediators, thereby aggravating the local inflammatory response. The CSF1R-mediated signaling pathway can regulate the adhesion, proliferation of osteoclast precursor cells and the generation of osteoclasts, and by specifically inhibiting the activity of CSF1R, it can block the conduction of downstream inflammatory signals and control the development of inflammation, thereby playing a role in treating RA.

[0003] In recent years, the treatment of RA has been constantly improved, and the existing therapies include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and biological agents (such as TNF-α inhibitors), but there are still many difficulties in the treatment process, and some patients have poor efficacy of existing drugs, and there are problems such as insufficient response, drug resistance or increased risk of infection, and long-term use may also cause adverse reactions related to immune suppression, especially for refractory RA patients, the process of bone destruction is difficult to completely inhibit, and it is urgent to find safe and effective drugs for treating rheumatoid arthritis with novel mechanism of action in the current medical field. The first generation of CSF1R inhibitors (such as plinabulin) cause severe liver toxicity due to multi-target inhibition (such as FLT3, KIT), and FDA requires black box warning, which limits its use; in addition, clinical data shows that the objective remission rate (ORR) of plinabulin in the treatment of tenosynovial giant cell tumor is only 38%, and the drug discontinuation rate is high due to side effects, which is difficult to meet the long-term drug demand of RA. Although CSF1R monoclonal antibody (such as Emactuzumab) has higher selectivity, it has immunogenicity risk, and due to its large molecular weight, it is difficult to penetrate the synovial tissue, and the clinical efficacy is limited. In addition, the antibody drug cannot completely block the CSF1R bypass activation mediated by IL-34, leading to drug resistance. Therefore, it is of great practical significance to design a new generation of CSF1R small molecule inhibitors targeting CSF1. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a (4-phenoxy) piperidin-1-ketone compound having selective inhibitory effect on CSF1R, and a preparation method and use thereof.

[0005] The technical problem to be solved by the present application is solved by the following technical solution:

[0006] The first object of the present application is to provide a (4-phenoxy) piperidin-1-ketone compound, the structural formula of which is as follows:

[0007]

[0008] In the formula, X is CO or CH2; R1 is any one of substituted or unsubstituted aryl, cycloalkyl, aromatic heterocycle; R2 is aromatic heterocycle.

[0009] Further, the aromatic heterocycle is any one of pyridine, pyrimidine, pyrrole, imidazole, pyrazole, oxazole, isoxazole and thiazole.

[0010] Further, the substituted group is any one of halogen, methyl, trifluoromethyl, methoxy and trifluoromethoxy.

[0011] Further, the structural formula of the (4-phenoxy) piperidin-1-ketone compound is as follows:

[0012]

[0013]

[0014] A second object of the present application is to provide a preparation method of the (4-phenoxy)piperidin-1-one compound, comprising the following steps:

[0015] (1) reacting 2-methyl-5-nitrophenol with tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate to obtain an intermediate M1;

[0016] (2) subjecting the intermediate M1 to a reduction reaction to obtain an intermediate M2;

[0017] (3) reacting the intermediate M2 with R1-CHO or R1-COOH to obtain an intermediate M3;

[0018] (4) subjecting the intermediate M3 to a deprotection reaction to obtain an intermediate M4;

[0019] (5) reacting the intermediate M4 with R2-COOH to obtain the (4-phenoxy)piperidin-1-one compound.

[0020] The synthetic route is as follows:

[0021]

[0022] A third object of the present application is to provide the use of the (4-phenoxy)piperidin-1-one compound in the preparation of a CSF1R inhibitor.

[0023] A fourth object of the present application is to provide the use of the (4-phenoxy)piperidin-1-one compound in the preparation of a medicament for treating or preventing a disease, disorder or condition modulated by or affected by or involving CSF1R activity.

[0024] Further, the disease, disorder or condition includes a neurodegenerative disease, an autoimmune disease, diabetes, a blood disease, an inflammatory disease, a cardiovascular disease, atherosclerosis or an inflammatory sequelae of infection.

[0025] Still further, the autoimmune disease includes arthritis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, lupus, inflammatory bowel disease, psoriatic arthritis, osteoarthritis, juvenile arthritis, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hepatitis, Takayasu's arteritis, temporal arteritis, optic neuritis.

[0026] A fifth object of the present application is to provide a pharmaceutical composition comprising the (4-phenoxy)piperidin-1-one compound or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

[0027] The present application has the beneficial effect that a series of novel (4-phenoxy)piperidin-1-one compounds are designed and synthesized, and it is proved by in vitro cell experiments that these compounds have good selective inhibitory effect on CSF1R, and can be used as CSF1R inhibitors for preventing or treating diseases, disorders or conditions related to CSF1R activity. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figures 1-8 NMR spectra of the compounds synthesized in Examples 1, 2, 6, 7, 9, 13, 22, and 29;

[0029] Figures 9-16 Mass spectra of the compounds synthesized in Examples 1, 2, 6, 7, 9, 13, 22, and 29. DETAILED DESCRIPTION

[0030] In order to make the technical means, creative features, purposes and effects of the present application easy to understand, the present application is further described below in combination with specific examples and drawings.

[0031] Example 1: Preparation of Compound 1

[0032]

[0033] Preparation of Intermediate M1: 2-methyl-5-nitrophenol (6.5 mmol), 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (13 mmol) and potassium carbonate (13 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 90°C overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate, the organic phases were combined and dried with anhydrous sodium sulfate, filtered, concentrated, and column chromatographed to obtain Intermediate M1 with a yield of 90%.

[0034] Preparation of Intermediate M2: Intermediate M1 (5 mmol) was added to a 4N hydrochloric acid / ethyl acetate solution (20 mL) and stirred at room temperature for 5 h. The reaction solution was suction filtered, the filter residue was washed with ethyl acetate and dried to obtain Intermediate M2 with a yield of 77%.

[0035] Preparation of intermediate M3-1: Intermediate M2 (0.2 mmol) and 3-trifluoromethylbenzaldehyde (0.2 mmol) were dissolved in methanol (5 mL), the reaction was stirred at room temperature for 5 h, then sodium borohydride (0.2 mmol) was slowly added under ice-bath condition, the reaction was stirred at room temperature for 2 h, 2 drops of glacial acetic acid was added. The reaction was distilled under reduced pressure to remove methanol, extracted with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution and saturated brine solution successively, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give intermediate M3-1 with a yield of 79%.

[0036] Preparation of intermediate M4-1: Intermediate M3-1 (3 mmol) was dissolved in ethyl acetate (5 mL), then 10% Pd / C (0.15 mmol) was added, and the reaction was carried out under hydrogen atmosphere at one atmosphere for 6 h. The reaction was filtered with diatomite, the filtrate was collected, and ethyl acetate was distilled under reduced pressure to give intermediate M4-1 with a yield of 95%.

[0037] Preparation of compound 1: Nicotinic acid (4 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.8 mmol) and N,N-diisopropylethylamine (6 mmol) were added to N,N-dimethylformamide (10 mL), stirred at room temperature for 30 min, then intermediate M4-1 (4 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give compound 1 with a yield of 82% and a purity of 98%. MS (ESI) m / z (M+1) + :470.2050. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J = 4.6 Hz, 2H), 7.67 (d, J = 23.0 Hz, 2H), 7.54 (d, J = 4.4 Hz, 2H), 7.41 (d, J = 4.6 Hz, 2H), 6.79 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 4.0 Hz, 1H), 6.18-6.06 (m, 2H), 4.47-4.41 (m, 1H), 4.34 (d, J = 5.5 Hz, 2H), 3.86-3.75 (m, 1H), 3.59-.50 (m, 1H), 3.44-3.37 (m, 1H), 3.24-3.13 (m, 1H), 1.99 (s, 3H), 1.91-1.76 (m, 2H), 1.68-1.52 (m, 2H).

[0038] Example 2: Preparation of compound 2

[0039] The procedure for the preparation of compound 2 was the same as in example 1, except that 3-trifluoromethylbenzaldehyde was replaced with 5- (trifluoromethyl)pyridine-2-carboxaldehyde. Yield 79%, purity 98%. MS (ESI) m / z (M+1) 403.2. + :471.2003. 1 H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J = 2.3 Hz, 1H), 8.69-8.65 (m, 2H), 8.14 (dd, J = 8.5, 2.3 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.42-7.39 (m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 6.28 (t, J = 6.3 Hz, 1H), 6.18 (d, J = 2.1 Hz, 1H), 6.07 (dd, J = 8.1, 2.1 Hz, 1H), 4.44 (d, J = 6.3 Hz, 2H), 4.43-4.38 (m, 1H), 3.84-3.78 (m, 1H), 3.57-3.49 (m, 1H), 3.41-3.35 (m, 1H), 3.22-3.12 (m, 1H), 1.99 (s, 3H), 1.91-1.73 (m, 2H), 1.66-1.50 (m, 2H).

[0040] Example 3: Preparation of compound 3

[0041] The procedure for the preparation of compound 3 was the same as in example 1, except that 3-trifluoromethylbenzaldehyde was replaced with 5- (trifluoromethyl)pyridine-2-carboxaldehyde. Yield 76%, purity 97%. MS (ESI) m / z (M+1) 403.2. + :403.2129. 1 H NMR (500 MHz, DMSO-d6) δ 8.69-8.65 (m, 2H), 8.57 (d, J = 2.2 Hz, 1H), 8.41 (dd, J = 4.7, 1.6 Hz, 1H), 7.73 (dt, J = 7.9, 2.0 Hz, 1H), 7.44-7.39 (m, 2H), 7.32 (dd, J = 7.8, 4.8 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 2.2 Hz, 1H), 6.13-6.02 (m, 2H), 4.50-4.43 (m, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.81 (t, J = 12.2 Hz, 1H), 3.55 (t, J = 10.6 Hz, 1H), 3.41 (t, J = 10.5 Hz, 1H), 3.20 (t, J = 12.4 Hz, 1H), 1.99 (s, 3H), 1.93-1.77 (m, 2H), 1.68-1.55 (m, 2H).

[0042] Example 4: Preparation of compound 4

[0043] The preparation of compound 4 was performed according to the procedure of Example 1, except that 3-trifluoromethylbenzaldehyde was replaced by 6- trifluoromethylpyridine-3-carboxaldehyde. Yield 79%, purity 98%. MS (ESI) m / z (M+1) + :471.2003. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (d, J = 2.1 Hz, 1H), 8.70-8.63 (m, 2H), 7.99 (dd, J = 8.1, 2.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.43-7.38 (m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 6.25-6.17 (m, 2H), 6.10 (dd, J = 8.1, 2.1 Hz, 1H), 4.49-4.44 (m, 1H), 4.40 (d, J = 6.2 Hz, 2H), 3.86-3.77 (m, 1H), 3.58-3.48 (m, 1H), 3.43-3.36 (m, 1H), 3.22-3.11 (m, 1H), 1.99 (s, 3H), 1.91-1.71 (m, 2H), 1.67-1.49 (m, 2H).

[0044] Example 5: Preparation of compound 5

[0045] The preparation of compound 5 was performed according to the procedure of Example 1, except that 3-trifluoromethylbenzaldehyde was replaced by 4- fluorobenzaldehyde. Yield 80%, purity 96%. MS (ESI) m / z (M+1) + :420.2082. 1 H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J = 4.8 Hz, 2H), 7.41 (d, J = 4.9 Hz, 2H), 7.37 (t, J = 6.9 Hz, 2H), 7.14-7.08 (m, 2H), 6.78 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 6.09 (d, J = 8.1 Hz, 1H), 5.98 (t, J = 6.1 Hz, 1H), 4.46-4.40 (m, 1H), 4.21 (d, J = 6.0 Hz, 2H), 3.85-3.79 (m, 1H), 3.23-3.14 (m, 1H), 1.99 (s, 3H), 1.92-1.77 (m, 2H), 1.67-1.54 (m, 2H).

[0046] Example 6: Preparation of compound 6

[0047] The preparation procedure of compound 6 was the same as example 1, except that 3- trifluoromethylbenzaldehyde was replaced by cyclohexylcarboxaldehyde. Yield 76%, purity 97%. MS (ESI) m / z (M+1) + :408.2646. 1 H NMR (500 MHz, DMSO-d6) δ 8.69-8.65 (m, 2H), 7.44-7.40 (m, 2H), 6.79 (d, J = 8.1 Hz, 1H), 6.23 (d, J = 2.1 Hz, 1H), 6.05 (dd, J = 8.1, 2.1 Hz, 1H), 5.30 (t, J = 5.8 Hz, 1H), 4.54-4.48 (m, 1H), 3.85-3.78 (m, 1H), 3.66-3.59 (m, 1H), 3.48-3.40 (m, 1H), 3.27-3.20 (m, 1H), 2.79 (t, J = 6.1 Hz, 2H), 2.01 (s, 3H), 1.99-1.85 (m, 2H), 1.79-1.61 (m, 7H), 1.53-1.45 (m, 1H), 1.24-1.12 (m, 3H), 0.96-0.87 (m, 2H).

[0048] Example 7: Preparation of compound 7

[0049]

[0050] Preparation of intermediate M3-7: 6-trifluoromethylnicotinic acid (0.16 mmol), 2-(7- azobenzo triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.2 mmol) and N,N- diisopropyl ethylamine (0.32 mmol) were added into N,N-dimethyl formamide (5 mL), stirred at room temperature for 20 min, then intermediate M2 (0.16 mmol) was added, stirred at room temperature for 2 h. The reaction solution was extracted with ethyl acetate, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, concentrated, and column chromatography to obtain intermediate M3-7, yield 86%.

[0051] Preparation of intermediate M4-7: intermediate M3-7 (3 mmol) was dissolved in ethyl acetate (5 mL), then 10% Pd / C (0.15 mmol) was added, and reacted under hydrogen atmosphere at one atmosphere for 6 h. The reaction solution was filtered with diatomite, the filtrate was collected, and the ethyl acetate was removed by distillation under reduced pressure to obtain intermediate M4-7, yield 93%.

[0052] Preparation of compound 7: nicotinic acid (4 mmol), 2-(7-azobenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate (4.8 mmol) and N,N-diisopropylethylamine (6 mmol) were added into N,N-dimethylformamide (10 mL), stirred at room temperature for 30 min, then intermediate M4-7 (4 mmol) was added, stirred at room temperature for 2 h. The reaction solution was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to obtain compound 7. Yield 77%, purity 96%. MS (ESI) m / z (M+1) + :485.1795. 1 H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.24 (s, 1H), 8.71-8.64 (m, 2H), 8.56 (dd, J = 8.3, 2.2 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.46-7.41 (m, 2H), 7.28 (dd, J = 8.1, 1.9 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 4.64-4.57 (m, 1H), 3.89-3.79 (m, 1H), 3.73-3.63 (m, 1H), 3.52-3.43 (m, 1H), 3.31-3.24 (m, 1H), 2.17 (s, 3H), 2.09-1.94 (m, 2H), 1.85-1.70 (m, 2H).

[0053] Example 8: Preparation of compound 8

[0054] Preparation of compound 8: the preparation steps were the same as example 7, except that 6- trifluoromethylnicotinic acid was replaced by 4-trifluoromethylbenzoic acid. Yield 81%, purity 97%. MS (ESI) m / z (M+1) + :484.1843. 1 H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.24 (s, 1H), 8.71-8.64 (m, 2H), 8.56 (dd, J = 8.3, 2.2 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.46-7.41 (m, 2H), 7.28 (dd, J = 8.1, 1.9 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 4.64-4.57 (m, 1H), 3.89-3.79 (m, 1H), 3.73-3.63 (m, 1H), 3.52-3.43 (m, 1H), 3.31-3.24 (m, 1H), 2.17 (s, 3H), 2.09-1.94 (m, 2H), 1.85-1.70 (m, 2H).

[0055] Example 9: Preparation of compound 9

[0056] The preparation procedure of compound 9 was the same as example 7, except that 6- trifluoromethylnicotinic acid was replaced by cyclohexylcarboxylic acid. Yield 79%, purity 96%. MS (ESI) m / z (M+1) + :422.2438. 1 H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.70-8.64 (m, 2H), 7.44-7.38 (m, 3H), 7.06-7.00 (m, 2H), 4.56-4.50 (m, 1H), 3.88-3.77 (m, 1H), 3.69-3.60 (m, 1H), 3.49-3.42 (m, 1H), 3.29-3.22 (m, 1H), 2.32-2.24 (m, 1H), 2.11 (s, 3H), 2.04-1.89 (m, 2H), 1.80-1.62 (m, 7H), 1.44-1.34 (m, 2H), 1.30-1.20 (m, 3H).

[0057] Example 10: Preparation of compound 10

[0058] The preparation procedure of compound 10 was the same as example 7, except that 6- trifluoromethylnicotinic acid was replaced by 4-chlorobenzoic acid. Yield 78%, purity 98%. MS (ESI) m / z (M+1) + :450.1579. 1 H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.69-8.66 (m, 2H), 7.99-7.95 (m, 2H), 7.62-7.59 (m, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.44-7.42 (m, 2H), 7.30-7.26 (m, 1H), 7.12 (d, J = 8.2 Hz, 1H), 4.61-4.57 (m, 1H), 3.89-3.80 (m, 1H), 3.71-3.63 (m, 1H), 3.50-3.45 (m, 1H), 3.30-3.26 (m, 1H), 2.16 (s, 3H), 2.07-1.93 (m, 2H), 1.83-1.69 (m, 2H).

[0059] Example 11: Preparation of compound 11

[0060] The preparation procedure of compound 11 was the same as example 7, except that 6- trifluoromethylnicotinic acid was replaced by 3-fluorobenzoic acid. Yield 78%, purity 97%. MS (ESI) m / z (M+1) + :434.1875.1 H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.68 (d, J = 4.7 Hz, 2H), 7.81 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 9.6 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.46 - 7.42 (m, 3H), 7.29 (dd, J = 8.2, 1.9 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 4.62 - 4.57 (m, 1H), 3.88 - 3.81 (m, 1H), 3.70 - 3.63 (m, 1H), 3.52 - 3.44 (m, 1H), 3.31 - 3.24 (m, 1H), 2.16 (s, 3H), 2.08 - 1.93 (m, 2H), 1.84 - 1.69 (m, 2H).

[0061] Example 12: Preparation of compound 12

[0062] The preparation of compound 12 followed the procedure of Example 7, except that 6- trifluoromethylnicotinic acid was replaced by 3-chlorobenzoic acid. Yield 79%, purity 96%. MS (ESI) m / z (M+1) + : 450.1579. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.68 (d, J = 4.7 Hz, 2H), 7.81 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 9.6 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.46 - 7.42 (m, 3H), 7.29 (dd, J = 8.2, 1.9 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 4.62 - 4.57 (m, 1H), 3.88 - 3.81 (m, 1H), 3.70 - 3.63 (m, 1H), 3.52 - 3.44 (m, 1H), 3.31 - 3.24 (m, 1H), 2.16 (s, 3H), 2.08 - 1.93 (m, 2H), 1.84 - 1.69 (m, 2H).

[0063] Example 13: Preparation of compound 13

[0064] The preparation of compound 13 followed the procedure of Example 7, except that 6- trifluoromethylnicotinic acid was replaced by 3-methylbenzoic acid. Yield 75%, purity 95%. MS (ESI) m / z (M+1) + : 430.2125. 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.70-8.65 (m, 2H), 7.89-7.84 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.35-7.29 (m, 3H), 7.10 (d, J = 8.2 Hz, 1H), 4.62-4.56 (m, 1H), 3.91-3.81 (m, 1H), 3.71-3.62 (m, 1H), 3.52-3.45 (m, 1H), 3.30-3.25 (m, 1H), 2.39 (s, 3H), 2.16 (s, 3H), 2.07-1.93 (m, 2H), 1.77 (d, J = 40.0 Hz, 2H).

[0065] Example 14: Preparation of compound 14

[0066] The preparation of compound 14 followed the procedure of Example 7, except that 6- trifluoromethylnicotinic acid was replaced by 4-methylbenzoic acid. Yield 73%, purity 97%. MS (ESI) m / z (M+1) + : 430.2125. 1 H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.70-8.65 (m, 2H), 7.89-7.84 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.35-7.29 (m, 3H), 7.10 (d, J = 8.2 Hz, 1H), 4.62-4.56 (m, 1H), 3.91-3.81 (m, 1H), 3.71-3.62 (m, 1H), 3.52-3.45 (m, 1H), 3.30-3.25 (m, 1H), 2.39 (s, 3H), 2.16 (s, 3H), 2.07-1.93 (m, 2H), 1.77 (d, J = 40.0 Hz, 2H).

[0067] Example 15: Preparation of compound 15

[0068] The preparation of compound 15 followed the procedure of Example 7, except that 6- trifluoromethylnicotinic acid was replaced by 3-methoxybenzoic acid. Yield 78%, purity 98%. MS (ESI) m / z (M+1) + : 446.2075. 1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.62-8.58 (m, 2H), 7.47-7.43 (m, 2H), 7.41-7.39 (m, 1H), 7.38-7.34 (m, 3H), 7.21 (dd, J = 8.1, 1.9 Hz, 1H), 7.08 (dd, J = 8.7, 3.1 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 4.54-4.49 (m, 1H), 3.76 (s, 4H), 3.63-3.55 (m, 1H), 3.43-3.37 (m, 1H), 3.23-3.14 (m, 1H), 2.08 (s, 3H), 2.00-1.85 (m, 2H), 1.76-1.61 (m, 2H).

[0069] Example 16: Preparation of compound 16

[0070] The preparation of compound 16 followed the procedure of Example 7, except that 6- trifluoromethylnicotinic acid was replaced by 2-trifluoromethoxybenzoic acid. Yield 80%, purity 98%. MS (ESI) m / z (M+1) + : 500.1792. 1 H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.70-8.64 (m, 2H), 7.71-7.61 (m, 2H), 7.56-7.46 (m, 2H), 7.45-7.39 (m, 3H), 7.24-7.18 (m, 1H), 7.11 (d, J = 8.1 Hz, 1H), 4.60-4.52 (m, 1H), 3.88-3.79 (m, 1H), 3.72-3.63 (m, 1H), 3.50-3.42 (m, 1H), 3.28-3.19 (m, 0H), 2.15 (s, 3H), 2.07-1.92 (m, 2H), 1.83-1.68 (m, 2H).

[0071] Example 17: Preparation of compound 17

[0072] The preparation of compound 17 followed the procedure of Example 7, except that 6- trifluoromethylnicotinic acid was replaced by 3-trifluoromethoxybenzoic acid. Yield 80%, purity 98%. MS (ESI) m / z (M+1) + : 500.1792. 1HNMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.70-8.65 (m, 2H), 8.01 (d, J = 7.7 Hz, 1H), 7.90 (s, 1H), 7.69-7.66 (m, 1H), 7.63-7.59 (m, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.31-7.25 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 4.64-4.57 (m, 1H), 3.89-3.81 (m, 1H), 3.72-3.64 (m, 1H), 3.52-3.46 (m, 1H), 3.30-3.26 (m, 1H), 2.16 (s, 3H), 2.09-1.93 (m, 2H), 1.84-1.69 (m, 2H).

[0073] Example 18: Preparation of Compound 18

[0074] The preparation of Compound 18 followed the procedure of Example 7, except that 6- trifluoromethylnicotinic acid was replaced by 4-trifluoromethoxybenzoic acid. Yield 81%, purity 97%. MS (ESI) m / z (M+1) + :500.1792. 1 HNMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.70-8.65 (m, 2H), 8.01 (d, J = 7.7 Hz, 1H), 7.90 (s, 1H), 7.69-7.66 (m, 1H), 7.63-7.59 (m, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.31-7.25 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 4.64-4.57 (m, 1H), 3.89-3.81 (m, 1H), 3.72-3.64 (m, 1H), 3.52-3.46 (m, 1H), 3.30-3.26 (m, 1H), 2.16 (s, 3H), 2.09-1.93 (m, 2H), 1.84-1.69 (m, 2H).

[0075] Example 19: Preparation of Compound 19

[0076] The preparation of Compound 19 followed the procedure of Example 18, except that nicotinic acid was replaced by 2-picolinic acid. Yield 76%, purity 98%. MS (ESI) m / z (M+1) + :500.1792. 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.59 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.95 - 7.91 (m, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.50 - 7.46 (m, 2H), 7.29 (d, J = 9.8 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 4.62 - 4.58 (m, 1H), 3.92 - 3.85 (m, 1H), 3.69 - 3.63 (m, 1H), 3.62 - 3.56 (m, 1H), 3.41 - 3.35 (m, 1H), 2.16 (s, 3H), 2.08 - 1.95 (m, 2H), 1.82 - 1.70 (m, 2H).

[0077] Example 20: Preparation of compound 20

[0078] The preparation of compound 20 was the same as example 18, except that nicotinic acid was replaced by 3-pyridinecarboxylic acid. Yield 75%, purity 96%. MS (ESI) m / z (M+1) + : 500.1792. 1 H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.59 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.95 - 7.91 (m, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.50 - 7.46 (m, 2H), 7.29 (d, J = 9.8 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 4.62 - 4.58 (m, 1H), 3.92 - 3.85 (m, 1H), 3.69 - 3.63 (m, 1H), 3.62 - 3.56 (m, 1H), 3.41 - 3.35 (m, 1H), 2.16 (s, 3H), 2.08 - 1.95 (m, 2H), 1.82 - 1.70 (m, 2H).

[0079] Example 21: Preparation of compound 21

[0080] The preparation of compound 21 was the same as example 18, except that nicotinic acid was replaced by pyrimidine-2-carboxylic acid. Yield 76%, purity 96%. MS (ESI) m / z (M+1) + : 501.1744. 1H NMR (500 MHz, DMSO-de) δ 10.23 (s, 1H), 8.91 (d, J = 5.0 Hz, 2H), 8.08 - 8.05 (m, 2H), 7.60 (t, J = 4.9 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.2, 2.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 4.63 - 4.59 (m, 1H), 3.89 - 3.84 (m, 1H), 3.71 - 3.66 (m, 1H), 3.37 - 3.32 (m, 1H), 3.19 - 3.14 (m, 1H), 2.16 (s, 3H), 2.07 - 1.92 (m, 2H), 1.81 - 1.67 (m, 2H).

[0081] Preparation of compound 22

[0082] The preparation of compound 22 followed the procedure of Example 18, except that nicotinic acid was replaced by pyrimidine-4-carboxylic acid. Yield 75%, purity 98%. MS (ESI) m / z (M+1) + :501.1744. 1 H NMR (500 MHz, DMSO-de) δ 10.23 (s, 1H), 9.26 (d, J = 1.4 Hz, 1H), 8.97 (d, J = 5.0 Hz, 1H), 8.08 - 8.05 (m, 2H), 7.71 (dd, J = 5.1, 1.5 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.2, 2.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 4.63 - 4.59 (m, 1H), 3.88 - 3.83 (m, 1H), 3.71 - 3.66 (m, 1H), 3.56 - 3.51 (m, 1H), 3.37 - 3.33 (m, 1H), 2.16 (s, 3H), 2.08 - 1.96 (m, 2H), 1.83 - 1.71 (m, 2H).

[0083] Preparation of compound 23

[0084] The preparation of compound 23 followed the procedure of Example 18, except that nicotinic acid was replaced by 1H-pyrrole-3-carboxylic acid. Yield 71%, purity 96%. MS (ESI) m / z (M+1) + :488.1792. 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.23 (s, 1H), 8.12-8.04 (m, 2H), 7.56-7.46 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 7.16-7.09 (m, 2H), 6.77 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 1.7 Hz, 1H), 4.60-4.53 (m, 1H), 3.93-3.83 (m, 2H), 3.63-3.53 (m, 2H), 2.15 (s, 3H), 2.02-1.95 (m, 2H), 1.74-1.65 (m, 2H).

[0085] Example 24: Preparation of compound 24

[0086] The preparation of compound 24 was performed as in example 18, except that nicotinic acid was replaced by imidazole-2-carboxylic acid. Yield 74%, purity 96%. MS (ESI) m / z (M+1) + : 489.1744. 1 H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 10.23 (s, 1H), 8.12-8.04 (m, 2H), 7.56-7.46 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 7.16-7.09 (m, 2H), 6.77 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 1.7 Hz, 1H), 4.60-4.53 (m, 1H), 3.93-3.83 (m, 2H), 3.63-3.53 (m, 2H), 2.15 (s, 3H), 2.02-1.95 (m, 2H), 1.74-1.65 (m, 2H).

[0087] Example 25: Preparation of compound 25

[0088] The preparation of compound 25 was performed as in example 18, except that nicotinic acid was replaced by 1H-pyrazole-4-carboxylic acid. Yield 76%, purity 95%. MS (ESI) m / z (M+1) + : 489.1744. 1H NMR (500 MHz, DMSO-d6) δ 13.15 (s, 1H), 10.23 (s, 1H), 8.09-8.06 (m, 2H), 7.80 (s, 1H), 7.54-7.51 (m, 2H), 7.49 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.1, 1.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 4.61-4.57 (m, 1H), 4.24-4.05 (m, 1H), 3.92-3.81 (m, 2H), 3.65-3.57 (m, 1H), 2.16 (s, 3H), 2.03-1.98 (m, 2H), 1.77-1.69 (m, 2H).

[0089] Example 26: Preparation of compound 26

[0090] The preparation of compound 26 was performed as in example 18, except that nicotinic acid was replaced by 1H-imidazole-4-carboxylic acid. Yield 74%, purity 97%. MS (ESI) m / z (M+1) + : 489.1744. 1 H NMR (500 MHz, DMSO-d6) δ 13.15 (s, 1H), 10.23 (s, 1H), 8.09-8.06 (m, 2H), 7.80 (s, 1H), 7.54-7.51 (m, 2H), 7.49 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.1, 1.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 4.61-4.57 (m, 1H), 4.24-4.05 (m, 1H), 3.92-3.81 (m, 2H), 3.65-3.57 (m, 1H), 2.16 (s, 3H), 2.03-1.98 (m, 2H), 1.77-1.69 (m, 2H).

[0091] Example 27: Preparation of compound 27

[0092] The preparation of compound 27 was performed as in example 18, except that nicotinic acid was replaced by 1H-pyrazole-3-carboxylic acid. Yield 74%, purity 97%. MS (ESI) m / z (M+1) + : 489.1744. 1H NMR (500 MHz, DMSO-d6) δ 13.15 (s, 1H), 10.24 (s, 1H), 8.10-8.05 (m, 2H), 7.80 (s, 1H), 7.55-7.47 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.58 (s, 1H), 4.63-4.56 (m, 1H), 4.25-4.07 (m, 1H), 3.94-3.80 (m, 2H), 3.61 (t, J = 18.2 Hz, 1H), 2.16 (s, 3H), 2.04-1.98 (m, 2H), 1.78-1.69 (m, 2H).

[0093] Example 28: Preparation of compound 28

[0094] The preparation of compound 28 followed the procedure of Example 18, except that nicotinic acid was replaced by oxazole-5-carboxylic acid. Yield 74.7%, purity 97%. MS (ESI) m / z (M+1) + :490.1585. 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.55 (s, 1H), 8.09-8.06 (m, 2H), 7.72 (s, 1H), 7.54-7.50 (m, 3H), 7.29 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 4.64-4.60 (m, 1H), 3.89-3.80 (m, 2H), 3.71-3.65 (m, 2H), 2.16 (s, 3H), 2.06-2.01 (m, 2H), 1.82-1.76 (m, 2H).

[0095] Example 29: Preparation of compound 29

[0096] The preparation of compound 29 followed the procedure of Example 18, except that nicotinic acid was replaced by isoxazole-5-carboxylic acid. Yield 78%, purity 95%. MS (ESI) m / z (M+1) + :490.1585. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.09-8.06 (m, 2H), 7.54-7.49 (m, 3H), 7.29 (dd, J = 8.1, 1.9 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 1.9 Hz, 1H), 4.64-4.60 (m, 1H), 3.84-3.78 (m, 1H), 3.74-3.67 (m, 2H), 3.57-3.51 (m, 1H), 2.16 (s, 3H), 2.07-2.01 (m, 2H), 1.83-1.77 (m, 2H).

[0097] Example 30: Preparation of compound 30

[0098] The preparation of compound 30 was the same as example 18, except that nicotinic acid was replaced by thiazole-5-carboxylic acid. Yield 74%, purity 96%. MS (ESI) m / z (M+1) + : 506.1356. 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.23 (s, 1H), 8.22 (s, 1H), 8.09-8.06 (m, 2H), 7.54-7.49 (m, 3H), 7.29 (dd, J = 8.1, 2.0 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 4.64-4.59 (m, 1H), 3.85-3.79 (m, 2H), 3.68-3.63 (m, 2H), 2.17 (s, 3H), 2.06-2.01 (m, 2H), 1.83-1.77 (m, 2H).

[0099] Activity and selectivity studies were performed on compounds 1-30 of the present application:

[0100] 1. The proliferation inhibition effect of compounds 1-30 on BaF3 cells:

[0101] 1) BaF3 cells with a density of 4 x 10 4 cells / mL were mixed with different concentrations of compounds 1-30, and 100 μL of the mixed solution was taken and placed in a 96-well plate;

[0102] 2) The 96-well plate was placed in a cell incubator and incubated at 37°C for 72 h;

[0103] 3) The CellTiter-Glo kit was used, and the fluorescence data were read by a multi-label reader (Envision, PerkinElmer, USA) at the time of testing. The test data were all referenced with DMSO;

[0104] 4) The GI values were calculated by using the data processing software Prism 7.0 (GraphPad Software, San Diego, CA). The results are shown in Table 1. 50

[0105] 2, In vitro proliferation inhibition of compounds 1-30 on Tel-CSF1R-BaF3:

[0106] Different concentrations (0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, 1 mM, 3 mM, 10 mM) of compounds 1-30 and pesydafatin were added to Tel-CSF1R-BaF3 cells and incubated for 72 h. The CCK-8 cell viability detection kit (purchased from Shanghai HuaYun Chemical Technology Co., Ltd.) was used to detect the incubated cells. The number of living cells was quantified by an enzyme marker, and the GI values of each compound and the control compound were calculated. The results are shown in Table 1. 50

[0107] Table 1

[0108]

[0109]

[0110] As shown in Table 1, the present application uses pesydafatin as a positive control to test the safety and anti-proliferation activity of compounds 1-30 on BaF3 and Tel-CSF1R-BaF3 cells. The results show that most of the compounds have good safety on BaF3 cells, and some of the compounds have strong inhibition on the proliferation of Tel-CSF1R-BaF3 cells expressing CSF1R kinase, showing an anti-proliferation effect comparable to that of pesydafatin.

[0111] ​​The above shows and describes the basic principles and main features of the present application and the advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above embodiments, and the above embodiments and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the claimed present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A (4-phenoxy)piperidine-1-methyl ketone compound, characterized in that, The structural formula of the (4-phenoxy)piperidin-1-one compound is as follows: X is CO or CH2; R1 is any one of substituted or unsubstituted aryl, cycloalkyl, aromatic heterocycle; R2 is aromatic heterocycle.

2. The (4-phenoxy)piperidin-1-one compound according to claim 1, characterized by: The aromatic heterocycle is any one of pyridine, pyrimidine, pyrrole, imidazole, pyrazole, oxazole, isoxazole, and thiazole.

3. The (4-phenoxy)piperidin-1-one compound according to claim 1, characterized by: The substituted group is any one of halogen, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

4. A process for the production of (4-phenoxy)piperidin- 1 -one compounds according to any one of claims 1 to 3, characterized in that, The preparation method comprises the following steps: (1) reacting 2-methyl-5-nitrophenol with 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester to obtain an intermediate M1; (2) subjecting the intermediate M1 to a reduction reaction to obtain an intermediate M2; (3) reacting the intermediate M2 with R1-CHO or R1-COOH to obtain an intermediate M3; (4) subjecting the intermediate M3 to a deprotection reaction to obtain an intermediate M4; (5) reacting the intermediate M4 with R2-COOH to obtain the (4-phenoxy)piperidin-1-one compound; The synthesis route is as follows:

5. Use of the (4-phenoxy)piperidin-1-one compound according to any one of claims 1-3 in the preparation of a CSF1R inhibitor.

6. Use of the (4-phenoxy)piperidin-1-one compound according to any one of claims 1-3 in the preparation of a medicament for treating or preventing a disease, disorder or condition modulated by, affected by or involving CSF1R activity.

7. Use according to claim 6, characterized in that: The disease, disorder or condition includes neurodegenerative disease, autoimmune disease, diabetes, blood disease, inflammatory disease, cardiovascular disease, atherosclerosis or inflammatory sequelae of infection.

8. Use according to claim 7, characterized in that: The autoimmune disease includes arthritis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, lupus, inflammatory bowel disease, psoriatic arthritis, osteoarthritis, juvenile arthritis, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hepatitis, Takayasu's arteritis, temporal arteritis, optic neuritis.

9. A pharmaceutical composition comprising the (4-phenoxy)piperidin-1-one compound according to any one of claims 1-3 or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.

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