Substituted arene compounds, compositions, and uses

Abstract

The application discloses a substituted aromatic compound, a composition and an application, and belongs to the field of medicinal chemistry. The application provides a substituted aromatic compound or a pharmaceutically acceptable salt thereof as shown in formula (I). The compound or the pharmaceutically acceptable salt thereof has more excellent GPR133 / ADGRD1 agonist activity and metabolic stability than AP-503, and can better prevent or treat muscle atrophy, muscle weakness and bone weakness.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of substituted aromatic compounds, compositions, and uses. Background Technology

[0002] G protein-coupled receptors (GPCRs) are a large class of membrane protein receptors, representing the most numerous cell surface receptors. These receptors share the characteristic of having seven transmembrane α-helices in their three-dimensional structure, and G protein (guanylate-binding protein) binding sites on the C-terminus of their polypeptide chain and the intracellular loop (the third intracellular loop) connecting the 5th and 6th transmembrane helices (counting from the N-terminus). Studies show that GPCRs are found only in eukaryotes and participate in many cell signal transduction processes. In these processes, GPCRs can bind to chemicals in the cellular environment and activate a series of intracellular signaling pathways, ultimately leading to changes in cell state. Known ligands that bind to GPCRs include odorants, pheromones, hormones, neurotransmitters, chemokines, and more. These receptors can be small molecules such as carbohydrates, lipids, and peptides, or large biomolecules such as proteins. Some specific GPCRs can also be activated by non-chemical stimuli; for example, rhodopsin in photoreceptor cells can be activated by light. There are numerous diseases associated with G protein-coupled receptors, and approximately 40% of modern drugs target G protein-coupled receptors.

[0003] Adhesion G protein-coupled receptors (aGPCRs) are the second largest subfamily in the GPCR superfamily and are involved in many physiological processes and disease mechanisms. The structural features of adhesion GPCRs include an intracellular C-terminus, a seven-transmembrane fragment domain, and a large extracellular N-terminus. Although the N-terminus is thought to mediate specific interactions between the receptor and neighboring cells or the extracellular matrix, almost all aGPCRs share a common GPCR N-terminal autoproteolytic induction (GAIN) domain. This domain catalyzes intramolecular autoproteolysis at the GPCR cleavage site (GPS) at the N-terminus, producing an N-terminal fragment (NTF) and a C-terminal fragment (CTF). A common assumption in this field is that ligands from neighboring cells or the extracellular matrix bind to the N-terminus, and mechanical stimulation induces conformational changes or NTF-CTF dissociation. However, the exact activation mechanisms of different aGPCR members may differ and are not yet well characterized.

[0004] G protein-coupled receptor 133 (ADGRD1) is an important member of this family, and it is an orphan receptor. While the function of GPR133 is not fully understood, its role in specific diseases is gradually being revealed, making it a potential novel drug target. Screening data and cell-based reporter gene experiments show that GPR133 can be activated by androgens, including endogenous DHT and its derivative steroid mesinolone, with high potency. A high-quality, long life is a human dream, but problems such as muscle fragility and bone fragility are becoming a reality. Therefore, discovering highly effective GPR133 agonists to enhance muscle strength without inducing the adverse effects of selective androgens is extremely important for human diseases such as wasting syndrome, osteoporosis, or sarcopenia. Summary of the Invention

[0005] This invention provides a compound represented by general formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof:

[0006]

[0007] in:

[0008] R1 is selected from -OR a -COOR b -C(O)NR c R d -NR e R f -NC(O)R g -C(O)R h -P(O)(OR) i )2、-P(O)R j R k -S(O)NR l R m -S(O)2NHR n -S(O)2R o -S(O)(NH)R p , 3-10 alkylcycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl; and the 3-10 cycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl are not substituted or are substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy;

[0009] R a R b R c R d R eR f R g R h R i R j R k R l R m R n R o R p Each is independently selected from H, C1-C3 alkyl, or hydroxyl-substituted C1-C3 alkyl groups;

[0010] Cy is selected from 3-10 membered cycloalkyl, 4-10 membered alicyclic, phenyl, and 5-10 membered aromatic heterocyclic;

[0011] n is the number of substituents R2 on Cy, n is 0-4, and each substituent is independently selected from: halogen (F, Cl, Br, I), hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl;

[0012] R3 is selected from phenyl, 5-10-membered aromatic heterocyclic group, and the phenyl, 5-10-membered aromatic heterocyclic group is not substituted or is substituted by one or more of the following substituents: halogen, hydroxyl, methoxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino;

[0013] X1, X2, and X3 are each independently selected from CR4 or N, and X1, X2, and X3 are all CH, while R1 is -OR. a -COOR a 、or -C(O)NR a R b At that time, Cy was not for

[0014] R4 is independently selected from H, halogen, methoxy, and C1-C3 alkyl.

[0015] In one embodiment of the present invention, Cy is selected from the following structures:

[0016] In one embodiment of the present invention, Cy is R1 is -NR e R f -NC(O)R g -C(O)R h -P(O)(OR) i )2、-P(O)R j R k -S(O)NR l R m -S(O)2NHR n -S(O)2Ro -S(O)(NH)R p , 3-10 alkylcycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl; and the 3-10 cycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl are not substituted or are substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy.

[0017] In one embodiment of the present invention, the 4-10 member alicyclic group is selected from: R5 is selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0018] In one embodiment of the present invention, Cy is R1 is selected from -OR a -COOR b -C(O)NR c R d -NR e R f -NC(O)R g -C(O)R h -P(O)(OR) i )2、-P(O)R j R k -S(O)NR l R m -S(O)2NHR n -S(O)2R o -S(O)(NH)R p , 3-10 alkylcycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl; and the 3-10 cycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl are not substituted or are substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy.

[0019] In one embodiment of the present invention, the above-mentioned compounds are specifically selected from:

[0020]

[0021] In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt. The inorganic salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate. The organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, and salicylate.

[0022] The present invention also provides a pharmaceutical composition comprising (I) a compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, prodrug, and a pharmaceutically acceptable carrier, excipient, or diluent thereof.

[0023] The present invention also provides the use of the above-mentioned substituted aromatic compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug in the preparation of a medicament used as a GPR133 / ADGRD1 agonist.

[0024] The present invention also provides the use of the above-mentioned substituted aromatic compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug in the preparation of a medicament for treating GPR133 / ADGRD1-mediated diseases.

[0025] The present invention also provides the use of the above-mentioned substituted aromatic compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug in the preparation of a medicament for the prevention or treatment of muscle atrophy, muscle weakness, or bone weakness.

[0026] Beneficial effects:

[0027] The substituted aromatic compound provided by this invention has superior activity and metabolic stability compared to AP-503, and can better prevent or treat diseases such as muscle atrophy, muscle weakness, and bone weakness. Detailed Implementation

[0028] The technical solution of the present invention will be described in detail below with reference to the embodiments.

[0029] The present invention also provides pharmaceutical compositions comprising the above-described compound of general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0030] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compound of general formula (I) of the present invention is mixed as the active ingredient with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate. Or it may be mixed with the following components: (1) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silica; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) slowing agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, such as kaolin; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium dodecyl sulfate, etc., or mixtures thereof. Buffers may also be included in capsules, tablets and pills.

[0031] The solid dosage forms, such as tablets, sugar pills, capsules, pellets, and granules, can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They may contain opaque agents, and the release of the active ingredient from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0032] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compound of general formula (I) or its pharmaceutically acceptable salt as the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc., or mixtures thereof. In addition to these inert diluents, the liquid dosage forms of the present invention may also include conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0033] The suspending agent includes, for example, ethoxylated octadecyl alcohol, polyoxyethylene sorbitol, and dehydrated sorbitol, microcrystalline cellulose, agar, or mixtures thereof.

[0034] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, and excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0035] The compounds of this invention or pharmaceutically acceptable salts thereof can be formulated into dosage forms for topical administration, including ointments, powders, suppositories, drops, sprays, and inhalers. The compounds of general formula (I) of this invention or pharmaceutically acceptable salts thereof, as active ingredients, are mixed under sterile conditions with a physiologically acceptable carrier and optionally with preservatives, buffers, and propellants, if necessary.

[0036] The pharmaceutical compositions of the present invention comprise a compound of general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient, and diluent. In preparing the pharmaceutical compositions, the compound of general formula (I) or a pharmaceutically acceptable salt thereof is typically mixed with a pharmaceutically acceptable carrier, excipient, or diluent. The content of the compound of general formula (I) or a pharmaceutically acceptable salt thereof can be 0.01-1000 mg, for example 0.05-800 mg, 0.1-500 mg, 0.01-300 mg, 0.01-200 mg, 0.05-150 mg, 0.05-50 mg, etc.

[0037] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions.

[0038] Synthesis of intermediates:

[0039] Example 1: Preparation of methyl 3-(2-(2,4-dimethylphenoxy)acetamido)-4-(6-ethyl-2,6-diazaspiro[3.3]heptane-2-yl)benzoate

[0040]

[0041] Step 1: Preparation of tert-butyl 6-(4-(methoxycarbonyl)-2-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (intermediate a-3)

[0042] Methyl 4-fluoro-3-nitrobenzene (a-1, 2.0 g, 10.0 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid (a-2, 2.0 g, 10.0 mmol) were dissolved in acetonitrile (20 mL), and triethylamine (1.84 g, 18.2 mmol) was added. The reaction solution was heated to 50 °C and reacted for 2 hours. After the reaction was completed, the solution was diluted with ethyl acetate (50 mL), washed with water (50 mL x 3), and the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Further purification by column chromatography yielded the target compound (intermediate a-3, 2.7 g, yield: 71%), MS (ESI) m / z = 378.13 [M+H]. + .

[0043] Step 2: Preparation of methyl 3-nitro-4-(2,6-diazaspiro[3.3]heptane-2-yl)benzoate (intermediate a-4)

[0044] Intermediate a-3 (377.1 mg, 1.0 mmol) and a 1.25 M hydrogen chloride solution of 1,4-dioxane (8.0 mL, 10.0 mmol) were added to ethanol (40 mL). The resulting mixture was stirred at 50 °C for 17 hours. The reaction mixture was directly concentrated to give a white solid, which was further dried under high vacuum to give intermediate a-4 (283.5 mg, 75%). No further purification was required for the next step. MS-ESI (m / z): 278.15 [M+l] + .

[0045] Step 3: Preparation of methyl 4-(6-ethyl-2,6-diazaspiro[3.3]heptane-2-yl)-3-nitrobenzoate (intermediate a-5)

[0046] Methyl 4-fluoro-3-nitrobenzene (a-4, 139.0 mg, 0.5 mmol) and bromoethane (108.0 mg, 1.0 mmol) were dissolved in acetonitrile (10 mL), and DIPEA (154.8 mg, 1.2 mmol) was added. The reaction solution was heated to 50 °C and reacted for 4 hours. After the reaction was completed, the mixture was diluted with ethyl acetate (10 mL), washed with water (20 mL x 3), and the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Further purification by column chromatography yielded the target compound (intermediate a-5, 94.6 mg, yield: 63%), MS (ESI) m / z = 306.13 [M+H]. + .

[0047] Step 4: Preparation of methyl 3-amino-4-(6-ethyl-2,6-diazaspiro[3.3]heptane-2-yl)benzoate (intermediate a-6)

[0048] Intermediate a-5 (550.8 mg, 1.8 mmol) was dissolved in ethanol (50 mL), and iron powder (520.0 mg, 9.3 mmol) and calcium chloride (1.03 g, 9.3 mmol) were added. The reaction solution was heated to 90 °C and reacted for 5 hours. After the reaction was completed, diatomaceous earth was filtered while hot, the filtrate was concentrated, and the crude product was further purified by column chromatography to obtain the target compound (intermediate a-6, 308.0 mg, yield: 62%). MS (ESI) m / z = 276.11 [M+H] +

[0049] Step 5: Preparation of methyl 3-(2-(2,4-dimethylphenoxy)acetamido)-4-(6-ethyl-2,6-diazaspiro[3.3]heptane-2-yl)benzoate (Example 1)

[0050] DIPEA (275.0 mg, 2.1 mmol) and HATU (250.0 mg, 0.65 mmol) were added to a solution of intermediate a-6 (166.0 mg, 0.6 mmol) in THF (10 mL). The resulting solution was stirred at room temperature for 10 minutes. Then, compound 2,4-dimethylphenoxyacetic acid (intermediate a-7, 108.0 mg, 0.6 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 19 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (10 mL), washed with water (20 mL x 3), the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Further purification by column chromatography yielded the target compound (Example 1, 139.0 mg, yield: 53%).

[0051] MS-ESI(m / z): 438.24 [M+1] + .

[0052] 1 H NMR (400MHz, CDCl3) δ9.27 (brs, 1H), 9.09 (d, J = 1.8Hz, 1H), 7.78 (dd, J = 8.4, 1.8Hz, 1H), 7.19 (d, J = 8.2Hz, lH), 6.97 (brs, 1H), 6.92 (d, J = 8.8Hz, 1H) ,6.71(d,J=8.4Hz,1H),4.69(s,2H),3.87(s,3H),3.51(s,4H),3.27(s,4H ), 2.43 (t, J = 7.2Hz, 2H), 2.38 (s, 3H), 2.29 (s, 3H), 1.09 (t, J = 7.2Hz, 3H).

[0053] Example 2: Preparation of methyl 3-(2-(4-(tert-butyl)phenoxy)acetamido)-4-(6-ethyl-2,6-diazaspiro[3.3]heptane-2-yl)benzoate

[0054]

[0055] Example 2 was obtained by a synthesis method similar to that of Example 1.

[0056] MS-ESI(m / z): 466.21 [M+1] + .

[0057] 1 H NMR (400MHz, CDCl3) δ9.47 (brs, 1H), 9.07 (d, J = 1.9Hz, 1H), 7.81 (dd, J = 8.3, 2.0Hz, 1H), 7.37-7.35 (m, 2H), 7.15 (d, J = 8.3Hz, 1 H), 6.92 (m, 2H), 4.66 (s, 2H), 3.90 (s, 3H), 3.51 (s, 4H), 3.27 (s, 4H), 3.06 (t, J = 7.2Hz, 2H), 1.31 (s, 9H), 1.09 (t, J = 7.2Hz, 3H).

[0058] Example 3: Preparation of (R)-3-(2-(2,4-dimethylphenoxy)acetamido)-4-(4-ethyl-3-methylpiperazin-1-yl)benzoate

[0059]

[0060] Step 1: Preparation of (R)-4-(4-ethyl-3-methylpiperazin-1-yl)-3-nitrobenzoate (intermediate b-2)

[0061] Methyl 4-fluoro-3-nitrobenzene (a-1, 1.0 g, 5.0 mmol) and (R)-1-ethyl-2-methylpiperazine (b-1, 640.0 mg, 5.0 mmol) were dissolved in acetonitrile (15 mL), and triethylamine (900.0 mg, 9.0 mmol) was added. The reaction solution was heated to 50 °C and reacted for 2 hours. After the reaction was completed, the solution was diluted with ethyl acetate (30 mL), washed with water (30 mL x 3), and the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Further purification by column chromatography yielded the target compound (intermediate b-2, 1.1 g, yield: 73%), MS (ESI) m / z = 308.19 [M+H]. + .

[0062] Step 2: Preparation of (R)-4-(4-ethyl-3-methylpiperazin-1-yl)-3-aminobenzoate (intermediate b-3)

[0063] Intermediate b-3 was obtained by a synthesis method similar to that used for intermediate a-6 in Example 1.

[0064] MS(ESI)m / z = 278.14 [M+H] + .

[0065] Step 3: Preparation of (R)-3-(2-(2,4-dimethylphenoxy)acetamido)-4-(4-ethyl-3-methylpiperazin-1-yl)benzoate (Example 3)

[0066] Example 3 was obtained by a synthesis method similar to that used in Example 1.

[0067] MS-ESI(m / z): 440.29 [M+1] + .

[0068] 1 H NMR (400MHz, CDCl3) δ9.22 (brs, 1H), 9.11 (d, J = 1.7Hz, 1H), 7.76 (dd, J = 8.3, 1.7Hz, 1H ),7.21(d,J=8.4Hz,lH),6.99(brs,1H),6.94(d,J=8.6Hz,1H),6.73(d,J=8.5Hz,1H), 4.64(s,2H),3.89(s,3H),3.51(m,1H),3.28-3.11(m,3H),2.89-2.71(m,3H),2.42(t, J=7.4Hz,2H),2.39(s,3H),2.27(s,3H),1.14(d,J=6.8Hz,3H),1.06(t,J=7.4Hz,3H).

[0069] Example 4: Preparation of 2-(2,4-dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(N-methylaminosulfonyl)phenyl)acetamide

[0070]

[0071] Example 4 was obtained by a synthesis method similar to that of Example 1 (see Table 1 for product structure information).

[0072] Example 5: Preparation of 2-(2,4-dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(2-methyl-2H-tetrazole-5-yl)phenyl)acetamide

[0073]

[0074] Example 5 was obtained by a synthesis method similar to that of Example 1 (see Table 1 for product structure information).

[0075] Intermediate 5-1 was synthesized according to existing literature (Chen, Y., Wu, Mf., Xie, Mm. et al. Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis. Acta Pharmacol Sin. 45, 1673–1685 (2024).).

[0076] Example 6: Preparation of 2-(2,4-dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide

[0077]

[0078] Step 1: Preparation of 2-(4-fluoro-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole (intermediate 6-2)

[0079] Nitric acid (1.39 mL, 28.0 mmol) was added to a concentrated (fuming) H₂SO₄ (8 mL) suspension of 2-(4-fluoro-phenyl)-5-methyl-1,3,4-oxadiazole (intermediate 6-1, 2.0 g, 11.2 mmol) at 0 °C (the solution turned orange-yellow). After reacting at 0 °C for 30 min, the reaction solution was poured into cold water (approximately 300 mL). The resulting solid was collected by filtration and washed with water. The pale yellowish-brown solid was dried overnight at 50 °C in a vacuum drying oven to give 2-(4-fluoro-3-nitrophenyl)-5-methyl-1,3,4-oxadiazole (2.3 g, 10.2 mmol, 91% yield).

[0080] Example 6 was obtained by a synthesis method similar to that of Example 1 (see Table 1 for product structure information).

[0081] Example 7: Preparation of 2-(2,4-dimethylphenoxy)-N-(2-(4-ethylpiperazin-1-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)acetamide

[0082]

[0083] Example 7 was obtained by a synthesis method similar to that of Example 6 (see Table 1 for product structure information).

[0084] Table 1: Structure and Data of Examples 4-7

[0085]

[0086]

[0087] Example 8: Activity test of the compound for GPR133 / ADGRD1 activation:

[0088] The stock solution of the test compound (dissolved in DMSO) was diluted with HBSS buffer to prepare solutions of 10... -11 M to 10 - 4 Eight working solutions were diluted 10-fold. Different concentrations (10 M) were added to HEK293 cells overexpressing GPR133 / ADGRD1 and G protein. -11 M to 10 -4 The compound M was used for stimulation. The positive control group was the reference compound AP-503. Fluorescence signals were monitored in real time using a multi-functional microplate reader, and the experimental results were statistically analyzed and plotted. The results are shown in Table 2.

[0089] Table 2: Agonistaltic activity of compounds against GPR133

[0090] Test compound <![CDATA[EC 50 (nM)]]> Reference AP-503 1.38±0.16 Example 1 0.90±0.11 Example 2 0.94±0.09 Example 3 0.83±0.15 Example 4 0.72±0.16 Example 5 0.77±0.08 Example 6 0.73±0.09 Example 7 0.81±0.17

[0091] The reference AP-503 involved in this invention has the following structure;

[0092] Experimental results showed that, within the same batch of experiments, Examples 1-7 significantly activated the Gs-cAMP signaling pathway downstream of GPR133 / ADGRD1, exhibiting superior activation compared to the positive control. This demonstrates that Examples 1-7 can effectively activate GPR133 / ADGRD1, possessing potential agonist or modulatory properties, warranting further investigation into their pharmacological effects and application prospects.

[0093] Example 9

[0094] Metabolic stability study of the compound in human liver microsomes:

[0095] 1. Experimental Materials

[0096] Human liver microsomes were purchased from Sigma; NADPH was purchased from Bidex.

[0097] 2. Experimental Methods

[0098] Microparticles (20 mg / mL) are stored at -80°C. Before use, they are thawed in a 37°C water bath and then placed on ice.

[0099] 10 μL of microsomes (20 mg / mL, final concentration 0.5 mg / mL), 200 μL of phosphate buffer (200 mM, final concentration 100 mM), 40 μL of magnesium chloride (50 mM, final concentration 5 mM), and 106 μL of purified water were added to a 96-well plate. The system was pre-incubated in a 37°C water bath for 10 minutes. 40 μL of NADPH solution (10 mM, final concentration 1 mM) was added to the reaction system; 40 μL of ultrapure water was used as a negative control instead of NADPH solution.

[0100] The reaction was initiated by adding 4 μL of 100 mM of the test compound and the control drug (Verapamil), with the final drug concentration being 1 μM.

[0101] At 0, 5, 15, 30, and 60 min, 50 μL of the reaction sample was collected and quenched with 4 volumes of cold acetonitrile containing internal standards (3% formic acid, 100 nM alprazolam, 200 nM labetalol, 2 μM ketoprofen, and 200 nM caffeine). The sample was centrifuged at 3220 g for 45 min. After centrifugation, 100 μL of the supernatant was mixed with 100 μL of ultrapure water and used for LC-MS / MS analysis.

[0102] 3. Data Analysis

[0103] Peak areas were detected by extracting ion spectra. The in vitro half-life (t) of the parent drug was determined by linearly fitting the percentage disappearance of the parent drug with time. 1 / 2 ).

[0104] In vitro half-life (t) 1 / 2 ) Calculated by slope:

[0105] In vitro t 1 / 2 = 0.693 / k (k = -slope value)

[0106] The following formula is used to measure the in vitro t 1 / 2 Converted to in vitro clearance rate (CL) int (μL / min / mg protein):

[0107]

[0108] The incubation volume was 400 μL, and the protein content was 0.2 mg.

[0109] 4. Conclusion: As shown in Table 3.

[0110] Table 3

[0111]

[0112] The results in Table 3 show that, compared with the reference compound AP-503, the human liver microsomal clearance rates of compounds 1-7 in the present invention are lower, indicating that the compounds of the present invention have better metabolic stability.

[0113] For compounds of general formula (I), the linking and substituent groups have a significant impact on the pharmacokinetic properties of the compound. Although the invention has been described through specific examples, it should not be construed as limiting; rather, the invention covers the general aspects previously disclosed. Various modifications and embodiments are possible without departing from the spirit and scope of the invention.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug thereof: in: R1 is selected from -OR a -COOR b -C(O)NR c R d -NR e R f -NC(O)R g -C(O)R h -P(O)(OR) i )2、-P(O)R j R k -S(O)NR l R m -S(O)2NHR n -S(O)2R o -S(O)(NH)R p , 3-10 alkylcycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl; and the 3-10 cycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl are not substituted or are substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy; R a R b R c R d R e R f R g R h R i R j R k R l R m R n R o R p Each is independently selected from H, C1-C3 alkyl, or hydroxyl-substituted C1-C3 alkyl groups; Cy is selected from 3-10 membered cycloalkyl, 4-10 membered alicyclic, phenyl, and 5-10 membered aromatic heterocyclic; n is the number of substituents R2 on Cy, n is 0-4, and each substituent is independently selected from: halogen (F, Cl, Br, I), hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; R3 is selected from phenyl, 5-10-membered aromatic heterocyclic group, and the phenyl, 5-10-membered aromatic heterocyclic group is not substituted or is substituted by one or more of the following substituents: halogen, hydroxyl, methoxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, amino; X1, X2, and X3 are each independently selected from CR4 or N, and X1, X2, and X3 are all CH, while R1 is -OR. a -COOR a 、or -C(O)NR a R b At that time, Cy was not for R4 is independently selected from H, halogen, methoxy, and C1-C3 alkyl.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, characterized in that, Cy is R1 is -NR e R f -NC(O)R g -C(O)R h -P(O)(OR) i )2、-P(O)R j R k -S(O)NR l R m -S(O)2NHR n -S(O)2R o -S(O)(NH)R p , 3-10 alkylcycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl; and the 3-10 cycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl are not substituted or are substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy.

3. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, characterized in that, Cy is R1 is selected from -OR a -COOR b -C(O)NR c R d -NR e R f -NC(O)R g -C(O)R h -P(O)(OR) i )2、-P(O)R j R k -S(O)NR l R m -S(O)2NHR n -S(O)2R o -S(O)(NH)R p , 3-10 alkylcycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl; and the 3-10 cycloalkyl, 4-10 alicyclic cycloalkyl, phenyl, 5-10 aromatic heterocyclic cycloalkyl are not substituted or are substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy.

4. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, characterized in that, The 4-10 membered alicyclic groups are selected from: R5 is selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

5. The compound according to claim 1, or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, characterized in that, The compounds are specifically selected from:

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, characterized in that, The pharmaceutically acceptable salt is an inorganic or organic salt. The inorganic salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate. The organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, benzenesulfonate, and salicylate.

7. A pharmaceutical composition, characterized in that, The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, prodrug, or pharmaceutical excipient thereof.

8. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical excipients include acceptable carriers, excipients, or diluents.

9. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug in the preparation of a medicament for treating GPR133 / ADGRD1-mediated diseases.

10. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug in the preparation of a medicament for the prevention or treatment of muscle atrophy, muscle weakness, or bone weakness.

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