Compounds for inhibiting IL-17

Abstract

The invention discloses a compound for inhibiting IL-17 (interleukin-17), which is a compound as shown in a formula (I) or a pharmaceutically acceptable salt of the compound, and # imgabs0 # formula (I).

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a class of compounds that inhibit IL-17. Background Art

[0002] The interleukin-17 (IL-17) family is a group of proinflammatory cytokines that participate in the immune response of tissues and play a key role in chronic inflammation. The secretion of IL-17 can stimulate the production of other proinflammatory cytokines (IL-1, IL-6, G-CSF, GM-CSF and TNF) and chemokines (CXCL1, CXCL2, CXCL5, CCL2, CCL7, CCL20 and IL-8), matrix metalloproteinases (MMP1, MMP3, MMP9 and MMP13) and antimicrobial peptides (β-defensins, S-100 protein). The IL-17 family consists of 7 members including IL17A to IL17F and vIL-17A. IL-17A, as the most widely studied founding member, is associated with host defense against various microbial pathogens and tissue inflammation. IL-17A consists of 155 amino acids, and the molecular weight of the homodimer is 30-35kDa. IL-17F, the closest relative of IL-17A, has about 50% amino acid sequence homology with IL-17A in its 163 amino acids and is usually co-expressed with IL-17A. IL-17A is involved in regulating a variety of important biological processes, such as bacterial and fungal infections, wound repair, and promoting inflammation.

[0003] The IL-17A pathway also plays an important role in autoimmune / inflammatory diseases. Preclinical studies have shown that IL-23 or IL-17A knockout mice are resistant to imiquimod (IMQ)-induced psoriasis; IL-17 monoclonal antibodies can effectively inhibit IMQ- or IL-23-induced psoriasis. IL-17-related therapeutic antibodies (Secukinumab, Ixekizumab, Brodalumab, Bimekizumab, etc.) have also been approved for the treatment of psoriasis, ankylosing spondylitis and other diseases, with excellent clinical efficacy and mild and controllable toxic side effects.

[0004] IL-17 related therapeutic antibodies are expensive and require subcutaneous or intravenous injections, which are less accessible and convenient for patients with autoimmune / inflammatory diseases who require long-term administration. Therefore, there is an urgent need to develop highly active oral IL-17 small molecule inhibitors. Summary of the invention

[0005] The present invention provides an IL-17 inhibitor with a novel structure.

[0006] In the first aspect of the present invention, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0007]

[0008] Formula (I),

[0009] m is 0 or 1;

[0010] R 1 H or C 1-6 alkyl.

[0011] In some embodiments of the present invention, R 1 H or C 1-3 The remaining variables are as defined herein.

[0012] In some embodiments of the present invention, R 1 is H or methyl, and the remaining variables are as defined in the present invention.

[0013] In some embodiments of the present invention, m is 0, and the remaining variables are as defined in the present invention.

[0014] In some embodiments of the present invention, m is 1, and the remaining variables are as defined in the present invention.

[0015] In some embodiments of the present invention, the structure of the compound represented by formula (I) is as follows:

[0016] .

[0017] In some embodiments of the present invention, the structure of the compound represented by formula (I) is as follows:

[0018] .

[0019] In some embodiments of the present invention, the structure of the compound represented by formula (I) is as follows:

[0020] .

[0021] In another aspect of the present invention, the present invention provides a pharmaceutical composition, which comprises the aforementioned compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0022] In another aspect of the present invention, the present invention provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a drug for treating IL-17-mediated diseases.

[0023] In some embodiments of the present invention, the IL-17-mediated disease is an autoimmune disease.

[0024] In some embodiments of the invention, the autoimmune disease is selected from psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis or non-infectious uveitis.

[0025] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids or organic acids, such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or coordination compounds formed with organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. In addition to the form of salts, compounds provided by the present invention also exist in prodrug forms. Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0026] The compounds represented by formula (I) of the present invention can be prepared using a synthetic method known in the art or using a method known in the art in combination with the method described in the present invention. The solvents, temperatures and other reaction conditions given in the present invention are exemplary and can be varied according to methods well known in the art. The example compounds described in the present invention can be synthesized according to the methods described in the examples using appropriate starting materials according to their specific structures, or can be synthesized using methods similar to those described in the examples. The starting materials used to synthesize the example compounds of the present invention can be prepared by known synthetic methods or similar methods described in the literature or obtained from commercial sources. The compounds can be further separated by methods well known in the art, such as crystallization, chromatography, etc. to obtain their stereoisomers as needed, and the separation conditions are easily obtained by those skilled in the art through conventional means or limited experiments. As a further illustration, the compounds of formula (I) of the present invention can be synthesized using the following method, wherein the solvents, temperatures and other reaction conditions in each step can be the same or similar to those described in the following examples, or reaction conditions known in the art can be used. DETAILED DESCRIPTION

[0027] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0028] The present invention is described in detail below by way of examples, but it is not intended to limit the present invention in any adverse way. The present invention has been described in detail herein, and its specific embodiments are also disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0029] Example 1 Synthesis of Compound 1

[0030]

[0031] Step 1: Dissolve compound 1-1 (200 mg, 0.584 mmol) in pyridine (3 mL), add compound 1-2 (238 mg, 1.168 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (223 mg, 1.168 mmol). The reaction system was stirred at room temperature for 2 hours under nitrogen protection, quenched with water (15 mL), and extracted with ethyl acetate (15 ⅹ 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 1-3 (219 mg). LCMS: 528.4 [M+H] + .

[0032] Step 2: Dissolve compound 1-3 (200 mg, 0.379 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. The reaction system was concentrated to obtain compound 1-4 (150 mg), and the crude product was directly used for the next reaction. LCMS: 372.2 [M+H] + .

[0033] Step 3: Dissolve compound 1-4 (100 mg, 0.269 mmol) in dichloromethane (20 mL), add diethylamine (0.141 mL, 0.808 mmol) and n-butylphosphonic anhydride (194 mg, 0.539 mmol). Stir at room temperature for 1 hour under nitrogen protection. Quench with water (10 mL), extract with dichloromethane (10 ⅹ 3 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The crude product is purified by silica gel column chromatography to obtain compound 1-5 (71 mg). LCMS: 354.2 [M+H] + .

[0034] Step 4: Dissolve compound 1-5 (66 mg, 0.187 mmol) in methanol (2 mL), add palladium carbon (19, 88 mg, 0.187 mmol), introduce hydrogen and heat to 30°C for 2 hours. The reaction solution was cooled and filtered, and the filtrate was concentrated to obtain compound 1-6 (60 mg). LCMS: 324.2 [M+H] + .

[0035] Step 5: Dissolve compound 1-6 (60 mg, 0.186 mmol) in pyridine (1 mL), add compound 1-7 (100 mg, 0.371 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.371 mmol). Stir the reaction system at room temperature for 2 hours, quench with water (10 mL), and extract with ethyl acetate (10 x 3 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. The crude product is purified by silica gel column chromatography to obtain compound 1-8. LCMS: 575.5 [M+H] + .

[0036] Step 6: Dissolve compound 1-8 (97 mg, 0.169 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 2 hours. The reaction system was concentrated to obtain compound 1-9. LCMS: 475.4 [M+H] + .

[0037] Step 7: Compound 1-9 (75 mg, 0.158 mmol) was dissolved in dimethylformamide (2 mL), and compound 1-10 (33 mg, 0.237 mmol), diethylamine (0.083 mL, 0.474 mmol) and 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (90 mg, 0.237 mmol) were added. The reaction system was stirred at room temperature for 2 hours under nitrogen protection, quenched with water (15 mL), and extracted with ethyl acetate (15 ⅹ 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 1. LCMS: 597.5 [M+H] + . 1 H NMR: (400 MHz, DMSO-d6) 9.89 (s, 1H), 8.41 (d, J = 9.1 Hz, 1H), 8.21 (d, J = 10.0 Hz, 1H), 7.70 (t, J = 8.1 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.31–7.01 (m, 3H), 6.98 (d, J = 1.8 Hz, 1H), 4.97–4.93 (m, 1H), 4.49–4.46 (m, 2H), 4.15–4.02 (m, 3H), 3.48 (d, J = 12.4 Hz, 2H), 3.18–3.15 (m, 1H), 2.65–2.51 (m, 2H), 1.72–1.45 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H), 1.19–1.14 (m, 3H), 0.95–0.82 (m, 2H), 0.78–0.74 (m, 1H), 0.47–0.30 (m, 4H), 0.28–0.14 (m, 4H).

[0038] Example 2 Synthesis of Compound 2

[0039]

[0040] Referring to the synthesis method of compound 1, compound 2 can be prepared from the corresponding raw materials. LCMS: 611.5 [M+H] + . 1HNMR: (400 MHz, DMSO-d6) 9.89 (d, J = 5.8 Hz, 1H), 8.41 (s, 1H), 8.23 ​​(s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 6.3 Hz, 1H), 7.13 (s, 2H), 7.03 (s, 1H), 6.98 (d, J = 6.7 Hz, 1H), 4.93 (d, J = 7.1 Hz, 1H), 4.47 (s, 2H), 4.36 (s, 1H), 4.20 (s, 1H), 4.00 (s, 1H), 3.41 (s, 1 H), 3.21–3.15 (m, 2H), 2.67 (s, 2H), 1.66 (s, 2H), 1.51 (s, 1H), 1.28 (d, J = 7.2 Hz, 3H), 1.22 (s, 1H), 1.17 (s, 3H), 1.01 (s, 1H), 0.89 (s, 1H), 0.80 (d, J = 6.5 Hz, 3H), 0.46 (s, 2H), 0.35 (s, 2H), 0.28 (s, 2H), 0.20 (s, 2H).

[0041] Example 3 Synthesis of Compound 3

[0042]

[0043] Referring to the synthesis method of compound 1, compound 3 can be prepared from the corresponding raw materials. LCMS: 583.4 [M+H] + . 1 HNMR: (400 MHz, DMSO-d6) 9.90 (s, 1H), 8.41 (d, J = 9.0 Hz, 2H), 7.78 (d, J = 5.3 Hz, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.41–7.26 (m, 2H), 7.16 (d, J = 11.5 Hz, 1H), 7.04–6.97 (m, 2H), 5.11 (t, J = 10.4 Hz, 1H), 4.94 (t, J = 7.9 Hz, 1H), 4.52–4.48 (m, 2H), 3.88–3.84 (m, 1H), 3.06–2.96 (m, 4H), 2.03 (s, 2H), 1.58 (s, 1H), 1.42–1.33 (m, 1H), 1.29–1.24 (m, 6H), 0.89–0.85 (m, 2H), 0.53–0.08 (m, 6H).

[0044] Example A HTRF Assay of Human IL-17A x IL-17RA

[0045] The ability of compounds to block the binding of IL-17A to its receptor IL-17RA was determined by HTRF. Tag1-IL17A and Tag2-IL17RA stock solutions were diluted 10-fold in PPI Europium Assay Buffer. Test compounds were diluted in DMSO and serially diluted 20-fold in PPI Europium Assay Buffer to concentrations ranging from 50 µM to 2.5 nM. Tag1-IL17A protein was added to each well, test compounds were added, and incubated at 25°C for 60 minutes. Tag2-IL17RA protein was added. Anti-Tag1-Eu Cryptate reagent and anti-Tag2-XL655 antibody stock solutions were diluted 50-fold in PPI Europium Assay Buffer, and the two ready-to-use anti-Tag assay solutions were premixed. Premixed anti-Tag donor and acceptor reagents were added to each well and incubated overnight at 25°C. Fluorescence values ​​were read at 665nm and 615nm on an Envision plate reader. The % inhibition values ​​and the logarithm of compound concentration were fitted to nonlinear regression using GraphPad 8.0 to calculate the IC 50 . Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)), X: logarithmic value of concentration; Y: % inhibition value. The data of test A are shown in Table 1.

[0046] Table 1

[0047]

[0048] IL-17A / 17RA HTRF IC 50 : 0 < A ≤ 500 nM; 500 nM < B ≤ 30 µM; 30 µM <C。

[0049] Although the specific embodiments of the present invention have been described in detail, according to all the teachings disclosed, those skilled in the art can make various modifications and substitutions to the details of the technical solution of the present invention, and these changes are within the protection scope of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, Formula (I), m is 0 or 1; R 1 H or C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 H or C 1-3 alkyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is H or methyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The structure of the compound represented by formula (I) is shown below: 。 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The structure of the compound represented by formula (I) is shown below: 。 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The structure of the compound represented by formula (I) is shown below: 。 7. A pharmaceutical composition, wherein: The pharmaceutical composition comprises the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating IL-17-mediated diseases.

9. The use according to claim 8, wherein: The IL-17 mediated disease is an autoimmune disease.

10. The use according to claim 9, wherein: The autoimmune disease is selected from psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis or non-infectious uveitis.

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