CN117430561A - GPR139 receptor agonist and preparation method thereof - Google Patents

Abstract

The invention provides a compound shown as a formula (I), or pharmaceutically acceptable salt thereof, wherein R ₁ 、R ₂ 、R ₃ 、R ₄ And R is ₅ Etc. have the definitions given in the description. In addition, the invention also provides a preparation method of the compound and pharmaceutically acceptable salts thereof and application of the compound in preparation of medicines for treating GPR139 receptor related diseases.

Description

A kind of GPR139 receptor agonist and preparation method thereof

Technical field

The present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a type of ligand molecule for G protein-coupled receptor 139 (GProtein-coupled Receptor 139, GPR139 for short).

Background technique

G Protein-coupled Receptor 139 (GPR139 for short) was first discovered by Gloriam et al. in 2005 (Biochim Biophys Acta 2005; 1722:235-246), and is also known as GPCR12, PGR3, KOR3L, and GPRg1. GPR139 is mainly expressed in the habenula, striatum, thalamus, hypothalamus and pituitary gland in the central nervous system (CNS). Its amino acid sequence is highly conserved in different species. For example, the human GPR139 protein sequence is similar to that of mice, chickens and zebras. The homology of fish is 96%, 92% and 70% respectively. When the GPR139 receptor is expressed on the cell surface, it consists of an N-terminal fragment, seven membrane-penetrating fragments, and a C-terminal fragment. The N-terminal fragment consists of 26 amino acids and contains a cysteine. Wang et al. reported that the GPR139 receptor and the dopamine receptor D2 are co-expressed in different tissues of the mouse brain, and confirmed through in vitro cell experiments that GPR139 can promote the agonist of the dopamine receptor D2 to produce calcium flow signals, and this calcium flow signal can both It is inhibited by antagonists of dopamine receptor D2 and can also be inhibited by antagonists of GPR139 (Frontiers in Neuroscience, March 2019, Volume 13, Article 281). In addition, Nepomuceno et al. confirmed that GPR139 can act synergistically through melanocortin receptor 3 or 5 (MC3/MC5). These results indicate that GPR139 can form heterodimers with other receptors on the cell surface to exert physiological effects. In addition, our experiments have confirmed that the GPR139 receptor can form homodimers through the N-terminal cysteine.

While different research teams are looking for ligands of GPR139, including agonists and antagonists, Liu et al. reported that L-phenylalanine and L-tryptophan are endogenous agonists of GPR139 (Mol Pharmacol 2015; 88: 911-925).

Existing research shows that the GPR139 receptor has important physiological functions and is a potential drug target for anti-anxiety, anti-depression, anti-schizophrenia, treatment of Parkinson's syndrome, treatment of drug and alcohol abuse, and treatment of metabolism-related diseases. Information on the structure, expression, pharmacology, and physiological functions of relevant GPR139 provides a solid foundation for the design and synthesis of new GPR139 agonists.

Contents of the invention

In a first aspect of the present invention, a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, is provided,

where L ₁ is selected from the group consisting of: None, or

R1 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy;

Ring A is a C3-10 carbocyclic group, or a 3-10 membered heterocyclic group;

Wherein, the carbocyclyl or heterocyclyl is optionally substituted with a substituent selected from the following group: halogen, oxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy , C1-4 haloalkoxy;

Furthermore, the carbocyclyl and heterocyclyl groups include paracyclic, bridged and spirocyclic structures.

In some embodiments, the compound has a structure represented by formula (II):

Among them, the dotted bond represents a single bond or a double bond;

W is selected from the following group: C, N;

X is selected from the following group: C=O or CR2; wherein, R2 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl;

Y is selected from the following group: CH, NR3; wherein, R3 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 alkoxy, C1- 4 haloalkoxy;

Z is selected from the following group: CR4, wherein R4 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl;

D is selected from the following group: N, CH;

E is selected from the following group: CR5, N, NR6, wherein R5 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl; R6 is selected from the following group: hydrogen, halogen, C1-4 alkyl base, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 alkoxy, C1-4 haloalkoxy;

Alternatively, any two adjacent ones of R2, R3, R4 and R5, namely R2 and R3, R3 and R4 or R4 and R5, and the carbon atoms connected to them together form a substituted or unsubstituted C5-7 carbocyclic ring or 5-7 membered heterocycle;

The definitions of L1 and R1 are as mentioned above.

In some embodiments, the R1 is selected from the group consisting of: -OCF3.

In some embodiments, the ring A has a structure selected from the following group:

In some embodiments, the compound is selected from the group consisting of:

In the second aspect of the present invention, there is provided a method for preparing the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, including the steps:

or

Among them, R’ is selected from the following group: hydrogen, C1-4 alkyl;

R1, L1, and ring A are defined as described above.

In a third aspect of the present invention, a pharmaceutical composition is provided, which is characterized by comprising the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In the fourth aspect of the present invention, there is provided a method for preparing a pharmaceutical composition as described in the third aspect of the present invention, which is characterized in that it includes the step of: adding the compound described in the first aspect of the present invention, or its pharmaceutical An acceptable salt is mixed with a pharmaceutically acceptable carrier to form a pharmaceutical mixture.

In the fifth aspect of the present invention, there is provided a compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition as described in the third aspect of the present invention, which is characterized by It is used to prepare drugs for treating GPR139 receptor-related diseases.

In another preferred embodiment, the GPR139 receptor-related diseases include anxiety, depression, Parkinson's disease, drug and alcohol abuse.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.

Detailed ways

After extensive and in-depth research, the inventor unexpectedly found that the compound of the present invention has excellent GPR139 receptor agonistic activity, and thus conducted a series of synthesis and biological activity tests. On this basis, the present invention was completed.

Experimental methods without specifying specific conditions in the following examples of the present invention usually follow conventional conditions or conditions recommended by the manufacturer. Various commonly used chemical reagents used in the examples are all commercially available products.

Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings commonly understood by those skilled in the technical field belonging to the present invention. The terms used in the description of the present invention are only for the purpose of describing specific embodiments and are not used to limit the present invention.

the term

The terms "including" and "having" and any variations thereof herein are intended to cover a non-exclusive inclusion. For example, a process, method, device, product or equipment that includes a series of steps is not limited to the listed steps or modules, but optionally also includes unlisted steps, or optionally also includes steps for these processes, Other steps inherent to the method, product, or device.

The "plurality" mentioned in the present invention means two or more. "And/or" describes the relationship between related objects, indicating that there can be three relationships. For example, A and/or B can mean: A exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the related objects are in an "or" relationship.

In the compounds of the present invention, when any variable occurs more than once in any component, the definition for each occurrence is independent of the definitions for each other occurrence. Likewise, combinations of substituents and variables are allowed as long as the combination renders the compound stable. A line drawn from a substituent into a ring system indicates that the bond indicated can be attached to any substitutable ring atom. If a ring system is polycyclic, it means that such bonds are only to any appropriate carbon atoms adjacent to the ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns of the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by techniques in the art and the methods set forth below. If a substituent is itself substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.

The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms. For example, the definition of "C ₁ -C ₈ " in "C ₁ -C ₈ alkyl" includes groups having 1, 2, 3, 4, 5, or 8 carbon atoms arranged in a straight or branched chain. . The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.

As used herein, the term "alkoxy" represents an alkyl-oxy group, where alkyl is as defined above.

As understood by those skilled in the art, "halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.

As used herein, the term "haloalkyl" represents an alkyl group in which one or more hydrogen atoms are substituted by halogen, wherein alkyl is as defined above.

As used herein, the term "haloalkoxy" represents an alkyl-oxy group having one or more hydrogen atoms substituted by halogen, wherein alkyl is as defined above.

active ingredients

In the present invention, an active ingredient that can effectively stimulate the GPR139 receptor is provided. The active ingredient is a compound represented by general formula (I), and the active ingredient can effectively prevent, treat and/or alleviate GPR139-related diseases.

Tests have shown that the active ingredients of the present invention can effectively stimulate GPR139 receptors, thereby preventing, treating and/or alleviating GPR139-related diseases.

It should be understood that the active ingredients of the present invention include compounds represented by general formula (I), or pharmaceutically acceptable salts thereof, or prodrugs thereof. It should be understood that the active ingredient of the present invention also includes the crystalline form, amorphous compound, deuterated compound and other forms of the compound of general formula (I).

The term "pharmaceutically acceptable salts" refers to salts of compounds of the invention with acids or bases suitable for use as pharmaceuticals. Pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; and proline Acid, phenylalanine, aspartic acid, glutamic acid and other amino acids. Another preferred class of salts are salts of the compounds of the invention with bases, for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g. lower alkanol ammonium salts) salts and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine respectively.

Preparation

The preparation methods of the compound of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be optionally prepared by combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 80°C, preferably 0°C to 50°C). The reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.

The following general preparation route can be used to synthesize the compound of formula (I) of the present invention.

or

Among them, R’, R”, R”’, R1, R2, R3, R4, R5 and R6 are as defined above.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has excellent GPR139 receptor agonistic activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the compound of the present invention contain the compound of the present invention as the main active ingredient The pharmaceutical composition can be used to treat, prevent and alleviate diseases related to GPR139.

The pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount. The “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg/kg) mg of the compound of the invention/dose, more preferably, it contains 10-2000 mg of the compound of the invention/dose. Preferably, the "dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility" here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.

Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dose is The dosage is usually 1 to 2000 mg, preferably 6 to 600 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. The starting materials used in the present invention are all commercially purchased unless otherwise specified.

Example

Example 1

Preparation of compound NRB104

first step:

It will contain 2-iodoaniline (1000mg, 4.57mmol), 3-butyn-1-ol (560mg, 7.99mmol), triethylamine (700mg, 6.92mmol), palladium (PPh3)4 (530mg, 0.459mmol) and A 20 mL aqueous solution of copper iodide (170 mg, 0.893 mmol) was stirred at 80°C for 2 hours, then diluted with 150 mL of water, and extracted with ethyl acetate (3x100 mL). Wash the organic phase with 150 mL of brine and dry over anhydrous sodium sulfate. After filtration, the mixture was concentrated to obtain 800 mg of intermediate 4-(2-aminophenyl)but-3-yn-1-ol.

Step two:

Add 1 mL of sulfuric acid to 9.0 mL of water, then add 4-(2-aminophenyl)but-3-yn-1-ol (800 mg, 4.96 mmol), cool to 0°C, and drop 4 mL of sulfuric acid containing sulfuric acid at 0°C. Sodium nitrate NaNO2 (520mg, 7.537mmol, 1.52equiv) aqueous solution. The mixture was stirred at room temperature overnight, the suspension was cooled to 0°C, filtered and washed with 2 mL of water to obtain 400 mg of the intermediate 3-(2-hydroxyethyl)-1H-cinnolin-4-one.

third step:

A 5mL DMF solution containing 3-(2-hydroxyethyl)-1H-cinnolin-4-one (400mg, 2.17mmol, 1equiv), methyl iodide (360mg, 2.54mmol) and potassium carbonate (440mg, 3.18mmol) was added to Stir at room temperature for 12 hours, and purify with a C18 reverse-phase column to obtain 100 mg of the intermediate 3-(2-hydroxyethyl)-1-methylcinnolin-4-one.

the fourth step:

To a 1mL acetonitrile solution containing 3-(2-hydroxyethyl)-1-methylcinnolin-4-one (100mg, 0.490mmol) and sodium periodate (420mg, 1.96mmol), add 1.5mL water, 1mL Ethyl acetate, mix well, add ruthenium trichloride (55 mg, 0.244 mmol), and then stir at room temperature for 48 hours. After the reaction mixture was concentrated in vacuo, it was purified using a C18 reverse-phase column to obtain 30 mg of the intermediate (1-methyl-4-oxocinolin-3-yl)acetic acid.

the fifth step:

A solution containing (1-methyl-4-oxosinolin-3-yl)acetic acid (30.0mg, 0.137mmol), hydroxybenzotriazole (23.0mg, 0.170mmol) and diisopropylethylamine (55.0mg ,0.426mmol) of 1mL DMF was stirred at room temperature for 15 minutes, then (1S)-1-[4-(trifluoromethoxy)phenyl]ethylamine (30.0mg, 0.146mmol,) and EDCI (40mg, 0.209mmol) were added ), stir at room temperature for 2 hours. The above mixture was purified by preparative HLPC to obtain the final product compound NRB104: 2-(1-methyl-4-oxocinolin-3-yl)-N-[(1S)-1-[4-(trifluoromethyl Oxy)phenyl]ethyl]acetamide.

1H NMR (300MHz, DMSO-d6) δ8.54(d,J＝7.8Hz,1H),8.12(d,J＝8.1Hz,1H),7.89–7.85(m,1H),7.74(d,J＝ 8.7Hz,1H),7.51–7.46(m,3H),7.32(d,J＝8.1Hz,2H),5.00–4.89(m,1H),4.07(s,3H),3.60(s,2H), 1.38(d,J＝7.0Hz,3H).

Example 2

Preparation of compound NRB103

first step:

The 1,4-dioxane solution containing 2,3-dibromopyridine (2.00g, 8.44mmol) was stirred at 110°C overnight, and after concentration, 1.4g of the intermediate 3-bromo-2-hydrazinopyridine was obtained.

Step two:

Stir 5.0 mL of trimethyl orthoformate solution containing 3-bromo-2-hydrazinopyridine (1.40 g, 7.45 mmol) at 105°C for 4 hours, then concentrate under reduced pressure, then add trimethyl orthoformate, and stir at 110°C. After stirring overnight, the mixture was concentrated under reduced pressure to obtain 1 g of intermediate 8-bromo-[1,2,4]triazolo[4,3-a]pyridine.

third step:

It will contain 8-bromo-[1,2,4]triazolo[4,3-a]pyridine (600mg, 3.03mmol), ethyl cyanoacetate (415mg, 3.67mmol), potassium tert-butoxide (853mg, 7.61 mmol) and 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (223 mg, 0.304 mmol) in 6 mL of 1,4-dioxane was stirred at 70°C for 4 hours. The solvent was removed in vacuo and then purified by silica gel chromatography to obtain 200 mg of the intermediate ethyl 2-cyano-2-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}ethyl Acid ester (200mg, 14%).

the fourth step:

Dissolve ethyl 2-cyano-2-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetate (200mg, 0.869mmol) in 1mL DMSO, add 0.5 mL of brine, treated at 120°C for 2 hours, and extracted with ethyl acetate (3x8mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to obtain the intermediate 2-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetonitrile.

the fifth step:

A mixture containing 2-{[1,2,4]triazolo[4,3-a]pyridin-8-yl}acetonitrile (100mg, 0.564mmol), EDCI (162mg, 0.847mmol), hydroxybenzotriazole ( 91.6 mg, 0.678 mmol) of 1 mL DMF solution was reacted with N,N-diisopropylethylamine (146 mg, 1.130 mmol) at room temperature for 30 minutes, and then (1S)-1-[4-(trifluoromethoxy ) phenyl]ethylamine (140 mg, 0.682 mmol), reacted at room temperature for 1.5 hours, and then purified with a reversed-phase chromatography column to obtain the final product compound NRB103: 2-{[1,2,4]triazolo[4,3 -a]pyridin-8-yl}-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide.

¹ H NMR (400MHz, DMSO-d6) δ9.25(d,J＝2.0Hz,1H),8.77(d,J＝6.4Hz,1H),8.45(d,J＝6.8Hz,1H),7.48( d,J＝8.4Hz,2H),7.28(d,J＝8.4Hz,2H),7.18(d,J＝6.8Hz,1H),6.95–6.89(m,1H),4.98–4.95(m,1H ),3.88(s,2H),1.39(d,J＝7.0Hz,3H).

Example 3

Preparation of compound NRB105

first step:

Dimethyl butynedioate (1.56g, 11.0mmol) was added to 10 mL of methanol containing 2-hydrazopyridine (1.00g, 9.16mmol), and the reaction was carried out at room temperature for 3 hours. The mixture was concentrated to 1 g of the intermediate 1,4-dimethyl(2Z)-2-[2-(pyridin-2-yl)hydrazin-1-ylidene]succinate.

Step two:

Dissolve 1,4-dimethyl(2Z)-2-[2-(pyridin-2-yl)hydrazin-1-ylidene]succinate (1.00g, 3.98mmol) in 10mL acetic acid at room temperature. After stirring, microwave irradiation was performed at 140°C for 40 minutes. The reaction was poured into 50 mL of water and extracted with ethyl acetate (3x80 mL). The organic phase was washed with brine, then dried over sodium sulfate, filtered and concentrated to prepare 1.2g of the intermediate 2-{4-oxopyrido[2,1-c][1,2,4]triazine-3- Base} methyl acetate.

third step:

Dissolve (1S)-1-[4-(trifluoromethoxy)phenyl]ethylamine (122mg, 0.593mmol) in 13mL of xylene, add trimethylaluminum (256.8mg) and react at 0°C for 30 minutes, then add methyl 2-{4-oxopyrido[2,1-c][1,2,4]triazin-3-yl}acetate (130 mg, 0.634mmol) and react at 110°C for 6 hours , and then stirred at 140°C for 6 hours. The reactant was concentrated in vacuo and purified using a reverse-phase column to obtain the final product compound NRB105: 2-{4-oxopyrido[2,1-c][1,2,4]triazin-3-yl} -N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide.

1H NMR (400MHz, DMSO-d6) δ8.74(d,J＝7.2Hz,1H),8.58(d,J＝8.0Hz,1H),7.95–7.91(m,1H),7.82(d,J＝ 9.2Hz,1H),7.47(d,J＝8.8Hz,2H),7.42–7.34(m,1H),7.31(d,J＝8.4Hz,2H),4.99–4.96(m,1H),3.85( s,2H),1.38(d,J=6.9Hz,3H).

Example 4

Preparation of compound NRB115

first step:

To 6 mL of dichloromethane solution containing tert-butoxycarbonylaminoacetic acid (300 mg, 1.713 mmol), (1S)-1-[4-(trifluoromethoxy)phenyl]ethylamine (316.24 mg, 1.541 mmol) was added , hydroxybenzotriazole (462.83 mg, 3.425 mmol), and EDCI (656.58 mg, 3.425 mmol), stirred at room temperature for 16 hours. The reaction was extracted with ethyl acetate (3x40 mL) and water (80 mL). The organic phase was concentrated in vacuo and then purified on a silica gel column to obtain 300 mg of the intermediate {[(1S)-1-(4-trifluoromethoxy-phenyl)-ethylcarbamoyl]-methyl}-carbamic acid. Tert-butyl ester.

Step two:

{[(1S)-1-(4-Trifluoromethoxy-phenyl)-ethylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (300 mg, 1.713mmol) was added to hydrochloric acid (4 mL ,0.773mmol), stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give 175 mg of 2-amino-N-[(1S)-1-(4-trifluoromethoxy-phenyl)-ethyl]-acetamide.

third step:

To a solution of 2-amino-N-[(1S)-1-(4-trifluoromethoxy-phenyl)-ethyl]-acetamide (175 mg, 0.667 mmol) in 3 mL of pyridine was added compound 5 (82.16 mg, 0.667mmol), phosphorus oxychloride (0.093mL, 1.001mmol), stirred at room temperature for 1 hour. The reaction was extracted with ethyl acetate (3x50 mL) and saturated sodium bicarbonate (100 mL). After vacuum drying, it was crystallized with 10 mL of methanol to obtain the final product compound NRB115 (D15).

1H NMR (400MHz, DMSO-d6) δ8.84(d,J＝5.1Hz,1H),8.66(d,J＝4.2Hz,1H),8.51(d,J＝7.6Hz,1H),8.02(dt ,J＝15.3,7.6Hz,2H),7.65–7.58(m,1H),7.45(d,J＝8.4Hz,2H),7.31(d,J＝8.1Hz,2H),4.98(t,J＝ 6.9Hz, 1H), 3.98 (dd, J＝11.9, 8.1Hz, 2H), 1.38 (d, J＝7.0Hz, 3H).

Example 5

Preparation of compound NRB118

first step:

To a 5mL dimethylformamide solution containing 2H-cinnolin-3-one (300mg, 2.053mmol), add methyl chloroacetate (267.31mg, 2.463mmol) and potassium carbonate (851.04mg, 6.158mmol) at room temperature. Stir for 4 hours. The reaction was extracted with ethyl acetate (3x40 mL) and saturated sodium chloride (100 mL). The organic phase was separated by vacuum concentration, and then purified with a silica gel column to obtain 200 mg of the intermediate (3-oxo-3H-cinolin-2-yl)-acetic acid methyl ester.

Step two:

To a solution containing (3-oxo-3H-cinolin-2-yl)-acetic acid methyl ester (200 mg, 0.917 mmol) in tetrahydrofuran (3 mL) was added lithium hydroxide (115.38 mg, 2.750 mmol, 1 mL H2O). The organic phase was separated by concentration in vacuo, then acidified with 1M hydrochloric acid, and extracted with ethyl acetate (5x30mL) and water (100mL). Concentrate in vacuo to obtain 80 mg of intermediate (3-oxo-3H-cinolin-2-yl)-acetic acid.

third step:

To a solution of (3-oxo-3H-cinolin-2-yl)-acetic acid (80 mg, 0.392 mmol) in dimethylformamide (3 mL) was added compound 5 (80.39 mg, 0.392 mmol), hydroxybenzo Triazole (105.89 mg, 0.784 mmol), triethylamine (203 mg, 2.32 mmol) and EDCI (150.21 mg, 0.784 mmol) were stirred at room temperature for 1 hour. The reaction was extracted with ethyl acetate (3x30 mL) and water (80 mL). The organic phase was separated, washed with saturated sodium chloride (80 mL), concentrated in vacuo, and purified with a silica gel column to obtain the final product compound NRB118 (D18): 2-(3-oxosinolin-2-yl)-N-[( 1S)-1-{4-[(trifluoromethyl)oxy]phenyl}ethyl]acetamide.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.79 (d, J = 7.6 Hz, 1H), 7.55 ( d, J = 9.0 Hz, 1H), 7.48 ( dd, J = 8.5, 4.2 Hz, 3H) ,7.36–7.24(m,5H),5.04(s,2H),4.95(dd,J＝14.1,7.0Hz,1H),1.40(d,J＝7.0Hz,3H).

Example 6

Determination of GPR139 receptor activity of compounds of the present invention

1. Experimental methods

HEK293 cells were grown in a 10cm culture dish containing DMEM complete medium (containing glutamine, sodium pyruvate, penicillin/streptomycin, and 10% fetal calf serum) and cultured to 90 in a 37°C, 5% CO2 incubator. % confluence. Then passaged twice a week at 1:5. When cells are passaged, first completely aspirate the culture medium, wash once with 4 mL of DPBS, add 3 mL of trypsin digestion solution, and shake gently. When the cells split, aspirate the trypsin digestion liquid and add 5 mL of DMEM complete culture medium. Use a pipette to disperse the cells and then add 1 mL of dispersed cell solution to each of five new 10 cm culture dishes. Then add 7 mL of DMEM complete culture medium to each of them, mix well and place them in a 37°C, 5% CO2 incubator.

On the day of transfection, digest the cells into a 10cm culture dish at an appropriate density, add 6 mL of DMEM/F12 medium (containing glutamine, sodium pyruvate, HEPES, and fetal calf serum), and incubate at 37°C for 5 % CO2 incubator for 5 hours. Take a 50 mL sterile centrifuge tube A, add 1 mL of serum-free DMEM/F12 medium (containing glutamine, sodium pyruvate, and HEPES), add 10 μg of GPR139 DNA, and mix evenly. Take another 50 mL sterile centrifuge tube B, add 1 mL of serum-free DMEM medium (containing glutamine, sodium pyruvate, and HEPES), then add 60 μL of Fugene HD transfection reagent, and mix evenly. Take 1 mL of Fugene HD transfection reagent from centrifuge tube B, add it to centrifuge tube A, mix evenly, and leave it at room temperature for 20 minutes. Add 2 mL of DMEM/F12 culture medium (containing glutamine, sodium pyruvate, HEPES, and fetal calf serum) to centrifuge tube A, mix evenly, then take out the mixture (4 ml) in centrifuge tube A and add it to the above 10cm petri dish of cells (a total of 10 mL of liquid), mix well and culture in a 37°C, 5% CO2 incubator for 20-24 hours.

The next day, digest the transfected cells with trypsin digestion solution, add appropriate DMEM/F12 medium (containing glutamine, sodium pyruvate, HEPES, penicillin/streptomycin, fetal bovine serum), and inoculate the cells In Matrigel-coated 384-well plates, the cell density was 6.67×106 cells/mL, 30 μL/well. Place the 384-well plate in a 37°C, 5% CO2 incubator.

On the third day, add 10 μL/well FLIPR dye (diluted in HEPES solution containing Pluronic and Probenicid) to the 384-well cell plate, and incubate for 40 minutes at 37°C in a 5% CO2 incubator. Add the diluted compound to the cell plate and read the calcium flux signal in a FLIPR plate reader.

Data analysis was performed using XL-fit software and the EC50 value of each compound was obtained.

1.Experimental results

Table 1. EC50 values of GPR139 FLIPR cell calcium flow signal detection compounds

All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (9)

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, where L ₁ is selected from the group consisting of: None, or R1 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy; Ring A is a C3-10 carbocyclic group, or a 3-10 membered heterocyclic group; Wherein, the carbocyclyl or heterocyclyl is optionally substituted with a substituent selected from the following group: halogen, oxy, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy , C1-4 haloalkoxy; Furthermore, the carbocyclyl and heterocyclyl groups include paracyclic, bridged and spirocyclic structures. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (II): Among them, the dotted bond represents a single bond or a double bond; W is selected from the following group: C, N; X is selected from the following group: C=O or CR2; wherein, R2 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl; Y is selected from the following group: CH, NR3; wherein, R3 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 alkoxy, C1- 4 haloalkoxy; Z is selected from the following group: CR4, wherein R4 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl; D is selected from the following group: N, CH; E is selected from the following group: CR5, N, NR6, wherein R5 is selected from the following group: hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl; R6 is selected from the following group: hydrogen, halogen, C1-4 alkyl base, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 alkoxy, C1-4 haloalkoxy; Alternatively, any two adjacent ones of R2, R3, R4 and R5, namely R2 and R3, R3 and R4 or R4 and R5, and the carbon atoms connected to them together form a substituted or unsubstituted C5-7 carbocyclic ring or 5-7 membered heterocycle; L1 and R1 are as defined in claim 1. 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said R1 is selected from the following group: -OCF3. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the ring A has a structure selected from the group consisting of: 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 6. The preparation method of the compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, comprising the steps: or Among them, R’ is selected from the following group: hydrogen, C1-4 alkyl; R1, L1 and ring A are as defined in claim 1. 7. A pharmaceutical composition, characterized by comprising the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 8. The preparation method of pharmaceutical composition as claimed in claim 7, characterized in that it includes the step of: combining the compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable salt. The received carriers are mixed to form a drug mixture. 9. The compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition as claimed in claim 7, characterized in that it is used to prepare the treatment of GPR139 receptors Drugs for related diseases. In another preferred embodiment, the GPR139 receptor-related diseases include anxiety, depression, Parkinson's disease, drug and alcohol abuse.