KR102145021B1 - Pyridine-based compound and selective androgen receptor agonist comprising the same - Google Patents

Abstract

The present invention relates to novel compounds, pharmaceutical compositions containing the compounds, and methods of preparing the compounds. The pyridine-based compound acts on the androgen receptor to increase the activity of the androgen receptor, thereby improving the symptoms or responding to the treatment due to the increase in androgen activity, such as various hormone-related diseases in men and women, muscle wasting. It may be usefully used as a treatment and/or prophylactic agent for disorders and osteoporosis.

Description

A pyridine-based compound and a selective androgen receptor agonist containing the same {PYRIDINE-BASED COMPOUND AND SELECTIVE ANDROGEN RECEPTOR AGONIST COMPRISING THE SAME}

The present invention relates to a novel compound of Formula 1, a pharmaceutical composition containing the compound, and a method for preparing the compound:

[Formula 1]

Androgen receptor (AR) is an intracellular receptor that has androgens such as testosterone or dihydrotestosterone as a ligand, and it plays a role in regulating DNA transcription that is activated by the binding of the ligand and translocated into the nucleus. It is a protein that does (Vitam Horm, 55:309-352, 1999).

Androgens play a critical role in the establishment and maintenance of the male phenotype Vitam Horm, 43:145-196, 1986: Endocr Rev 8:1-28, 1987). That is, androgens play a crucial role in the differentiation and growth of male genital organs, initiation and regulation of sperm formation, and regulation of male sexual behavior. In addition, androgens play an important role in development related to masculinization in tissues other than the genitals such as muscles, bones, hair, larynx, skin, adipose tissue, and kidney (J Endocrinol, 126:17-25, 1990). In women, the clear physiological role of androgens has not been fully elucidated, but symptoms such as decreased libido and sex life, lack of vitality, decreased euphoria, and decreased bone mineral density after menopause are reported as the amount of androgens in the blood decreases with age. Known (J Clin Endocrinol Metab, 81:2759-2763, 1996; J Clin Endocrinol Metab 84: 1886-1892, 1999; J Steroid Biochem Mol Biol, 69:177-184, 1999). Therefore, when androgens are reduced, men and women have various diseases, such as delayed puberty in boys, anemia, osteoporosis, hereditary vascular edema, endometriosis, estrogen receptor breast cancer, muscle related diseases, and decreased male fertility. Symptoms may occur (J Pharmocol Exp Ther, 304:1334-1340, 2003).

Androgen supplementation therapy, which is currently widely used, has the effect of increasing bone density, real weight and libido in men and women (Menopause, 13:387-396, 2006: J Clin Endocrinol Metab, 85:2839-2853, 2000: J Clin Endocrinol Metab, 85:2670-2677, 2000). However, these treatments are limited in their widespread clinical use due to the potential safety issues of androgens (N Engl J Med 350:482-492, 2004). For example, prostate stimulation in men and masculinization in women may cause serious side effects as well as hepatotoxicity.

Selective androgen receptor agonists (SARM agonists) are androgen receptor ligands that have a tissue-selective effect, and can exhibit a positive therapeutic effect of androgen without irritation to the prostate and skin, and can be administered orally (J Clin Endocrinol Metab, 84:3459-3462, 1999). In other words, although SARM agonists exhibit therapeutic effects, androgen side effects such as enlarged prostate, hirsutism, and virilization are not generally present. These compounds tissue-selectively act on androgen receptors to increase activity, thereby eliminating or reducing the negative or unwanted properties of androgens, while exerting the effect of androgens. Accordingly, the compounds can be effectively used to treat and/or prevent and/or ameliorate a disease or condition that may improve symptoms or respond to treatment due to increased androgen activity.

Therefore, there is a need to develop a selective androgen receptor agonist that can effectively treat and/or prevent and/or ameliorate a disease or condition that may respond to treatment or improve symptoms due to increased androgen activity while reducing the side effects of androgens. .

An example of the present invention provides a novel compound having a selective androgen activity effect.

Another example provides a composition for selective androgen activity increase comprising the compound.

Another example provides a pharmaceutical composition for preventing and/or treating a disease or condition that can respond to treatment or improve due to an increase in androgen activity containing a pharmaceutically effective amount of the compound as an active ingredient.

Another example provides a health functional food composition for preventing and/or improving a disease or condition that can respond to treatment or improve due to an increase in androgen activity containing the compound.

Another example provides a method of preparing the compound.

The present inventors have prepared novel compounds having activity as selective androgen receptor agonists and pharmaceutically acceptable salts thereof, and these compounds bind to androgen receptors and increase the activity, thereby improving symptoms or treatment due to increased androgen activity. The present invention was completed by confirming that it can be effectively used in the treatment of various diseases or conditions that can respond.

An example of the present invention provides a compound represented by the following Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In another example, there is provided a pharmaceutical composition containing as an active ingredient at least one pharmaceutically effective amount selected from the group consisting of the compound of Formula 1, isomers thereof, and pharmaceutically acceptable salts thereof. In one example, the pharmaceutical composition may exhibit a selective androgen receptor agonist effect. By this effect of the androgen receptor agonist, the pharmaceutical composition may be a pharmaceutical composition for increasing androgen activity. In another example, the pharmaceutical composition may be a pharmaceutical composition for preventing and/or treating a disease or condition that may be improved or respond to treatment due to increased androgen activity.

Hereinafter, unless specifically limited, the compound of Formula 1 as an active ingredient (active ingredient) of the pharmaceutical composition is meant to encompass both isomers of the compound and pharmaceutically acceptable salts of the compound or isomer, and these All of the compounds, isomers, and salts should be interpreted as being included within the scope of the present invention. However, for convenience, in the present specification, unless otherwise noted, at least one selected from the group consisting of the compound of Formula 1, isomers thereof, and pharmaceutically acceptable salts thereof as an active ingredient of the pharmaceutical composition is for convenience It is simply expressed as'a compound of formula 1'.

The compound of Formula 1 has a completely different structure from the existing androgen receptor agonists, and as can be seen in the following experimental examples, it has an excellent stimulating effect on the androgen receptor, so that symptoms are caused by increased androgen activity. It can be effectively used for the treatment, prevention, and/or amelioration of a disease or condition that can improve or respond to treatment.

The terms used in the present specification will be briefly described below.

The term "pharmaceutically acceptable salt" as used herein refers to a salt form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. , In the case of the present invention, the biological efficacy and properties of the compound of Formula 1 are equally retained, and any salts preferred in terms of pharmaceutical, biological or other properties may be collectively referred to. The pharmaceutically acceptable salts include acids forming non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, and the like; Alternatively, it may be an acid addition salt formed by a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or the like. As a specific example, an acid addition salt of the compound of one embodiment may be obtained by reacting a compound in the form of a free base and a stoichiometric amount of an appropriate acid. At this time, the reaction may be carried out in water, an organic solvent, or a mixture thereof, and specifically, it may be carried out in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In addition, depending on the form of the pharmaceutically acceptable salt, each form of salt may be obtained by a conventional reaction that is obvious to those skilled in the art. In addition, the pharmaceutically acceptable salts include alkali metal salts or alkaline earth metal salts formed of lithium, sodium, potassium, calcium, magnesium, etc.; Amino acid salts such as lysine, arginine, and guanidine; Alternatively, it may be an organic salt such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine.

The term "isomer" as used herein refers to a compound having the same chemical formula or molecular formula, but optically or sterically different, or a salt thereof. Such isomers, salts thereof, and racemic mixtures are also included within the scope of the present invention.

The term “aryl” as used herein refers to a carbocyclic group (eg, phenyl) group having a shared pi electron system and having at least one ring. The term includes groups of monocyclic or fused ring polycyclic (ie, rings that share adjacent pairs of carbon atoms).

The term "heteroaryl" as used herein refers to a heterocyclic aryl group having a shared pi electron system and having at least one ring, for example furan, thiophene, pyrrole, imidazole, oxazole, isoxazole, Oxadiazole, tetrazole, thiazole, imidazole, pyrazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, and the like, but are not limited thereto.

The term "alkyl" as used herein refers to an aliphatic hydrocarbon group. The alkyl moiety may be a “saturated alkyl” group that does not contain an alkene or alkyne moiety at all, or may be a “unsaturated alkyl” group that contains at least one alkene or alkyne moiety. "Alkene" moiety means a group consisting of at least one carbon-carbon double bond, and "alkyne" moiety means a group consisting of at least one carbon-carbon triple bond. For example, “alkyl” can be a saturated alkyl or unsaturated alkyl having a linear, branched or cyclic structure. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like. For example, C1-C4-alkyl has 1 to 4 carbon atoms in the alkyl chain, and in the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl Is selected.

The term "heterocycle" as used herein is a group in which a ring carbon is replaced with oxygen, nitrogen, sulfur, or the like, and may optionally include a double bond. Examples of heterocycles include pyrroline, pyrrolidine, tetrahydrofuran, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, piperazine, morpholine, thiomorpholine, etc. Can, but is not limited to these.

The term "pharmaceutically effective amount" as used herein refers to an amount of an active ingredient at which a desired pharmaceutical effect can be obtained, and in some cases, in a pharmaceutical composition for exerting a desired pharmaceutical effect. It can mean the concentration or dosage of the active ingredient.

The term "increased androgen activity" as used herein means that anabolic activity of androgens is increased by activation of androgen receptors.

Terms other than those described above may be interpreted as meanings commonly understood by those skilled in the art in the field to which the present invention belongs.

Hereinafter, the present invention will be described in more detail.

In one embodiment of the present invention, the following compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[Formula 1]

In Formula 1,

X is N or CH;

R ₁ And R ₂ Are each independently unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 6 carbon atoms;

R ₃ and R ₄ are each independently hydrogen, unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms, or halogen; And

R ₅ Is selected from the group consisting of cyano, oxo, and unsubstituted or substituted heteroaryl when X is N, and is selected from the group consisting of unsubstituted or substituted heteroaryl when X is CH, and when X is CH It may be unsubstituted or substituted heteroaryl.

Preferably, in the definition of R ₁ , the substituted alkyl may be a linear, branched or cyclic alkyl having 1 to 6 carbon atoms in which at least one of the hydrogens contained in the alkyl is independently substituted with halogen.

Preferably, in the definition of R ₂ , the substituted alkyl may be a linear, branched or cyclic alkyl having 1 to 6 carbon atoms in which at least one of the hydrogens contained in the alkyl is independently substituted with halogen.

Preferably, in the definition of R ₃ , the substituted alkyl may be a linear, branched or cyclic alkyl having 1 to 3 carbon atoms in which at least one of the hydrogens contained in the alkyl is independently substituted with halogen.

Preferably, in the definition of R ₄ , the substituted alkyl may be a linear, branched or cyclic alkyl having 1 to 3 carbon atoms in which at least one of the hydrogens contained in the alkyl is independently substituted with halogen.

The "each independently substituted" means that when the number of substituted hydrogens is two or more, each hydrogen may be substituted with the same or different substituents.

In one embodiment, the R ₅ May be a heteroaryl in which one or more hydrogens are substituted with oxo.

In another embodiment, the compound of Formula 1 (or isomer thereof) may be selected from the group consisting of the following compounds:

1) 5-(bis(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)pyridin-2(1H)-one;

2) 5-(bis(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;

3) 6-(1,2,4-oxadiazol-3-yl)-N,N-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyridin-3- Amine;

4) 4-(1,2,4-oxadiazol-3-yl)-N,N-bis(2,2,2-trifluoroethyl)-3-(trifluoromethyl)benzeneamine;

5) 3-(4-(bis(2,2,2-trifluoroethyl)amino)-2-(trifluoromethyl)phenyl)1,2,4-oxadiazole-5(4H)-one ;

6) 4-(2H-tetrazol-5-yl)-N,N-bis(2,2,2-trifluoroethyl)-3-(trifluoromethyl)benzeneamine;

7) 5-((2,2,2-trifluoroethyl)(1,1,1-trifluoropropan-2-yl)amino)-3-(trifluoromethyl)picolinonitrile;

8) 5-(isopropyl(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;

9) 5-((cyclopropylmethyl)(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;

10) 5-(isobutyl(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;

11) 5-(cyclobutyl(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;

12) 3-chloro-2-methyl-4-(1,2,4-oxadiazol-3-yl)-N,N-bis(2,2,2-trifluoroethyl)aniline.

The isomer of the compound of Formula 1 may be an optical isomer, a stereoisomer, or a mixture of the isomers of the compound of Formula 1 (racemic mixture). It is understood that in the compound of Formula 1 according to an embodiment, each substituent may be attached to the chiral center of a carbon atom. And, any asymmetric carbon atom on the compound of the above embodiment may exist in any form of (R)-, (S)- or (R, S)- configuration, suitably each separate form ( It may exist in the R)- or (S)- configuration. In addition, the compound of one embodiment may exist in any form of any possible isomers or mixtures thereof, for example, any form of pure geometric isomers, diastereomers, optical isomers, racemates, or mixtures thereof. Can exist as In addition, when the compound of one embodiment has a double bond, each substituent bonded to the double bond may be in the E or Z configuration.

The pharmaceutically acceptable salt of the compound of Formula 1 or an isomer thereof may be at least one selected from the group consisting of an acid addition salt, a metal salt, an amino acid salt, and an organic salt of the compound of Formula 1 or an isomer thereof. The acid addition salt may include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, and the like; Alternatively, it may be an acid addition salt formed by a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or the like. The metal salt may be an alkali metal salt or an alkaline earth metal salt formed of lithium, sodium, potassium, calcium, magnesium, or the like. The amino acid salt may be an amino acid salt formed by lysine, arginine, guanidine, or the like. The organic salt may be an organic salt formed of dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, or the like.

The compound of Formula 1 according to the present invention has a completely different structure from the previously known androgen receptor agonist, and as can be seen in the following experimental examples, it has excellent stimulating effect against the androgen receptor, due to increased androgen receptor activity. It can be used for the treatment and prevention of diseases or conditions that improve symptoms or respond to treatment, that is, various hormone-related diseases, muscle wasting diseases, and osteoporosis in men and women.

On the other hand, according to another embodiment of the present invention, the compound represented by Formula 1, its isomer, or a pharmaceutically used salt thereof is included as an active ingredient, and symptoms are improved due to an increase in androgen receptor activity, or It provides a pharmaceutical composition capable of treating and preventing a disease or condition that can respond, i.e., other disorders including those listed below.

Diseases that can improve symptoms or respond to treatment due to the increase in androgen receptor activity include sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, muscle dystropy due to decrease in the number or content of muscle cells, cachexia. (cachexia), muscular dystrophy, postoperative muscle loss, neuromuscular disease due to neurotransmitter system abnormalities, rheumatic diseases, sarcopenic obesity, cognitive and emotional changes, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer , Ovarian cancer, muscle wasting disorder, osteopenia and osteoporosis may be selected from the group consisting of.

Diseases or conditions that can improve symptoms or respond to treatment due to the increase in androgen activity include various hormone-related diseases, sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, and muscle cell count in men and women. Or muscle dystropy, cachexia, cognitive and emotional changes, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer, ovarian cancer, muscle wasting disorder, osteopenia, and It may be selected from the group consisting of osteoporosis, such as one or more of those listed below:

a) Male androgens such as sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, age-related sarcopenia, osteopenia, osteoporosis, cognitive and emotional changes, depression, anemia, hair loss, obesity. Diseases or symptoms associated with the reduction,

b) Sexual dysfunction, decreased libido, sarcopenia, age-related sarcopenia, osteopenia, osteoporosis, cognitive and emotional changes, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer. Diseases or symptoms related to androgen reduction in women

c) muscle wasting disorder (due to aging, fractures, severe burns, end-stage renal disease, cancer, AIDS, chronic obstructive pulmonary disease, stroke, etc.) May be a muscle wasting disorder), and

d) Osteopenia and osteoporosis (e.g., the osteopenia or osteoporosis may be due to factors other than a decrease in androgen in men or women, for example, it may be due to a decrease in female hormones), due to a decrease in the number or content of muscle cells Muscle dystropy, cachexia related to cancer or chronic diseases, muscular dystrophy, muscle loss after surgery (muscle loss due to muscle incision and extraction), neuromuscular disease due to neurotransmitter system abnormalities, rheumatic disease, hypomuscular obesity ( sarcopenic obesity), etc.

A pharmaceutical composition containing the compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated and used in the form of a conventional pharmaceutical formulation. For example, the pharmaceutical formulation may be prepared in various formulations for oral administration or parenteral administration, and the form of the formulation may be variously determined according to a method of use, an administration method, an administration purpose, and the like.

When manufactured in various formulations for oral administration or parenteral administration, at least one selected from the group consisting of commonly used fillers, extenders, binders, wetting agents, disintegrants, diluents such as surfactants, excipients, etc. It can be formulated.

As a solid preparation for oral administration, tablets, pills, powders, granules, capsules, etc. may be included, and such solid preparations include the active ingredient and at least one excipient, such as starch, calcium carbonate, and sucrose. (sucrose), lactose (lactose), it can be prepared by mixing at least one selected from the group consisting of gelatin. Further, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. In addition, liquid formulations for oral administration may include suspensions, liquid solutions, emulsions, and syrups. When formulated into the liquid formulation, water and/or liquid paraffin, which are commonly used simple diluents, may be used, and optionally, a group consisting of various excipients, for example, wetting agents, sweetening agents, fragrances, preservatives, etc. One or more selected from may be additionally included.

Parenteral administration may be performed by intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, intranasal administration, transdermal administration, or the like. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried formulations, suppositories, and the like. As a non-aqueous solvent for preparing a non-aqueous solution or a suspension for preparing a suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

The content of one or more active ingredients selected from the group consisting of the compound of Formula 1, isomers thereof, and pharmaceutically acceptable salts thereof in the pharmaceutical composition is, for example, 0.001 to 99.9% by weight, 0.01 to 90% by weight, or It may be 0.1 to 50% by weight, but is not limited thereto, and may be appropriately adjusted according to the form of the formulation, administration method, administration purpose, and the like.

In addition, a pharmaceutically effective amount of a pharmaceutical composition containing the compound of Formula 1, isomers thereof, and/or pharmaceutically acceptable salts thereof of the present invention as an active ingredient, based on the amount of the active ingredient, from about 0.1 to It may range from about 1,000 mg/day. The pharmaceutically effective amount may be administered or dosed once or twice a day in consideration of the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease, but is limited thereto. And can be administered in various dosages and methods.

The patient may be a mammal, for example, a primate including a human, a rodent including a mouse, a rat, or the like, and specifically may be a human. For example, the patient may be a mammal, such as a human, in need of increased androgen activity, or in need of prophylaxis and/or treatment of a disease or condition that may ameliorate or respond to treatment due to increased androgen activity.

In another example, a health functional food composition for increasing androgen activity comprising at least one selected from the group consisting of the compound of Formula 1, isomers thereof, and pharmaceutically acceptable salts thereof, or improved due to increased androgen activity There is provided a functional food composition for preventing and/or improving a disease or condition that can respond to treatment. Diseases or conditions that may be improved or respond to treatment due to the increase in androgen activity are as described above.

In another example, a method of making a compound of Formula 1 is provided.

In one embodiment, the present invention provides a step of preparing a compound of Formula 3a by introducing an amino group at position 5 of the compound of Formula 2a; And substituting the amino group of the compound of Formula 3a with R ₁ , R ₂ , or R ₁ and R ₂ , wherein X in Formula 1 is N and R ₅ is oxo, a method of preparing a compound of Formula 1 (Manufacturing method 1).

Preferably, the compound of Formula 3a in the above may be prepared through a reduction reaction after nitrating the position 5 of the compound of Formula 2a.

[Formula 2a]

[Formula 3a]

In Formulas 2a and 3a, R ₃ and R ₄ are each as defined in Formula 1.

In another embodiment, the present invention provides a step of preparing a compound of Formula 3a by introducing an amino group at position 5 of the compound of Formula 2a; Substituting the amino group of the compound of Formula 3a with R ₁ , R ₂ , or R ₁ and R ₂ ; And a cyanation reaction, wherein in Formula 1, X is N and R ₅ is cyano, it provides a method of preparing a compound of Formula 1 (Production Method 2).

Preferably, in the cyanation reaction, a compound in which R ₅ is oxo is halogenated using a reagent such as POCl3 or POBr3 or substituted with a trifluoromethoxy group using a reagent such as trifluoromethanesulphonic anhydride, and then Zn( CN) ₂ , it can be carried out using a cyanide reagent such as CuCN.

In another embodiment, the present invention provides a step of preparing a compound of Formula 3a by introducing an amino group at position 5 of the compound of Formula 2a; Substituting the amino group of the compound of Formula 3a with R ₁ , R ₂ , or R ₁ and R ₂ ; Cyanation reaction; Preparing a compound of formula 4a; And introducing a heteroaryl at position 5, wherein X in Formula 1 is N, and R ₅ is heteroaryl. It provides a method of preparing a compound of Formula 1.

Preferably, the compound of Formula 4a in the above may be prepared using hydroxylamine or the like.

[Formula 4a]

In Formula 4a, R ₁ to R ₄ are each as defined in Formula 1.

In another embodiment, the present invention provides the steps of substituting the amino group of the compound of Formula 3b with R ₁ , R ₂ , or R ₁ and R ₂ ; And substituting a cyano group with heteroaryl, wherein X in Formula 1 is N and R 5 is heteroaryl, providing a method for preparing a compound of Formula 1 (Preparation Method 4).

Preferably, the heteroarylation reaction may be prepared through the intermediate formula 4b using hydroxylamine or the like as in Preparation Method 3.

[Formula 3b]

In Chemical Formula 3b, R ₃ to R ₄ are as defined in Chemical Formula 1.

[Formula 4b]

In Formula 4b, R ₁ to R ₄ are as defined in Formula 1.

Those of ordinary skill in the art to which the present invention pertains will be able to prepare a compound by various methods based on the structure of Formula 1, and all of these methods should be interpreted as being included in the scope of the invention. That is, the compound of Formula 1 may be prepared within the scope of the present invention by arbitrarily combining several synthetic methods described in the present specification or published in the prior art. Therefore, the manufacturing method according to the present invention is not limited to those presented above.

The present invention provides novel androgen receptor agonists and pharmaceutically acceptable salts thereof, wherein the androgen receptor agonists are androgen receptor mediated diseases or conditions, that is, various hormone-related diseases in men and women, muscle It can be usefully used as a treatment and prevention agent for wasting diseases and osteoporosis.

Hereinafter, preferred examples and experimental examples are presented to aid in understanding the present invention. However, the following examples and experimental examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited thereto.

[ Example 1] 5-( Bis(2,2,2-trifluoroethyl)amino )-3-( Trifluoromethyl ) Preparation of pyridin-2(1H)-one

[Step 1] 5-Nitro-3-( Trifluoromethyl ) Preparation of pyridin-2(1H)-one

30 ml of sulfuric acid was added to a 100 ml flask and cooled to 0°C. 3-(trifluoromethyl)-2-pyridinone 5g (30mmol) was added and stirred for 5 minutes. 11.7 ml of nitric acid was added dropwise to the reaction solution for 5 minutes, and the temperature was raised to room temperature over 2 hours. The reaction solution was heated to 50° C. and stirred for 3 hours. After cooling to room temperature, it was gradually added to 340 ml of ice water and diluted. After extraction with 300 ml of ethyl acetate, it was washed with saturated NaCl aqueous solution, and the aqueous layer was removed. After dehydration and drying with MgSO _{4, it} was concentrated under reduced pressure. 300 ml of isopropyl ether was added to the concentrated residue, dispersed, stirred for about 30 minutes, and filtered. The filtrate was washed with 100 ml of isopropyl ether and dried in vacuo to give 4.3 g (67%) of the title compound.

¹ H NMR (400MHz, DMSO-d ₄ ): δ 8.96 (d, 1H), 8.46 (d, 1H)

Mass[M+H]: 209.01

[Step 2] 5-amino-3-( Trifluoromethyl ) Preparation of pyridin-2(1H)-one

After dissolving 5.5 g (2.64 mmol) of the compound 5-nitro-3-(trifluoromethyl) pyridine-2 (1H)-one obtained in step 1 in 50 ml of methanol, 550 mg of Pd/C (10%) was added and hydrogen gas was added. Bubbled. After about 1 hour, the reaction solution was filtered and the filtrate was concentrated to obtain 4 g (2.24 mmol, 85%) of the title compound.

¹ H NMR(400MHz, DMSO-d ₄ ): 7.51(d, 1H), 7.01(s, 1H), 4.54(s, 2H)

Mass[M+H]: 179.04

[Step 3] 5-( Bis(2,2,2-trifluoroethyl)amino )-3-( Trifluoromethyl ) Preparation of pyridin-2(1H)-one

In a 1L flask, 1.3 g (39 mmol) of the compound 5-amino-3-(trifluoromethyl)pyridin-2(1H)-one obtained in step 2 was added, and 50 ml of trifluoroacetic acid was added thereto, followed by stirring. The reaction solution was refluxed at 100° C. and NaBH ₄ (pellet) was added. After refluxing while being added over 2 to 3 days, the reaction was terminated, basified with 2N NaOH, and extracted three times with 50 ml of ethyl acetate. The extracted solvent was concentrated under reduced pressure and separated by column to obtain 500mg (20%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 8.02 (d, 1H), 8.59 (d, 1H), 3.92 (q, 4H)

Mass[M+H]: 343.04

[ Example 2] 5-( Bis(2,2,2-trifluoroethyl)amino )-3-( Trifluoromethyl ) Preparation of picolinonitrile

[Step 1] 6- Bromo -N,N- Vis (2,2,2- Trifluoroethyl )-5-( Trifluoromethyl ) Pyridine-3- Amine Produce

To a 50 ml flask was added 500 mg (1.46 mmol) of the compound 5-(bis(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)pyridin-2(1H)-one obtained in Example 1 Then, 10 ml of N,N-dimethylformamide was added and stirred. POBr ₃ 628mg (2.2mmol, 1.5eq) was added to the reaction solution and stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and separated by column to obtain 200 mg (34%) of the title compound.

¹ H NMR (400MHz, DMSO-d ₄ ): δ 8.53 (d, 1H), 7.87 (d, 1H), 4.60 (q, 4H)

Mass[M+H]: 404.96

[Step 2] 5-( Bis(2,2,2-trifluoroethyl)amino )-3-( Trifluoromethyl ) Picolinonitrile Produce

Compound 6-bromo-N,N-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyridin-3-amine 180 mg (0.44 mmol) obtained in step 1 was added to a 25 ml flask. Then, 5 ml of N,N-dimethylformamide was added and stirred. In the reaction solution, 104mg (0.89mmol, 2.0eq) of Zn(CN) ₂ , 74mg (0.13mmol, 0.3eq) of 1,1'-(diphenylphosphino) ferrocin, Pd ₂ (dba) ₃ 40mg (0.04mmol, 0.1eq) was added and then reacted at 200°C for 10 minutes using a microwave reactor. The reaction was concentrated under reduced pressure and then separated by column to obtain 120 mg (77%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 8.71 (d, 1H), 7.80 (d, 1H), 4.57 (q, 4H)

Mass[M+H]: 352.04

[ Example 3] 6-(1,2,4- Oxadiazole -3-yl)-N,N- Vis (2,2,2- Trifluoroethyl )-5-(t Lifluorome Tyl) pyridine-3- Amine Produce

[Step 1] (Z)-5-( Bis(2,2,2-trifluoroethyl)amino )- N' - Hydroxy -3-( Trifluoromethyl ) Of picoline imidamide Produce

Compound 5-(bis(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile 120mg (0.34mmol) obtained in Example 2 was added, and isopropyl alcohol 5ml was added. Stirred. 48mg (0.37mmol, 1.1eq) of hydroxylamine hydrochloride and 173mg (0.41mmol, 1.2eq) of NaHCO ₃ were added to the reaction solution and refluxed at 80°C. After the reaction for 5 hours, 1 ml of a 50% aqueous solution of hydroxylamine was added and refluxed for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and separated by column to give 117 mg (89%) of the title compound.

¹ H NMR (400MHz, DMSO-d ₄ ): δ 9.64(s, 1H), 8.69(s, 1H), 7.78(s, 1H), 5.75(s, 2H), 4.63(q, 4H)

Mass[M+H]: 385.06

[Step 2] 6-(1,2,4- Oxadiazole -3-yl)-N,N- Vis (2,2,2- Trifluoroethyl )-5-(t Lifluoromethyl ) Pyridine-3- Amine Produce

Compound (Z)-5-(bis(2,2,2-trifluoroethyl)amino)-N'-hydroxy-3-(trifluoromethyl)picolinimidamide 192 mg (0.5) obtained in step 1 mmol) and 5 ml of acetonitrile were added and stirred. Triethyl orthoformate 167ul (1.0mmol, 2eq) and trifluoroacetic acid (ca. 20ul) were added to the reaction solution and refluxed at 60°C for about 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and column-separated to give 169mg (86%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.86 (s, 1H), 8.59 (s, 1H), 7.55 (s, 1H), 4.18 (q, 4H)

Mass[M+H]: 395.05

[ Example 4] 4-(1,2,4- Oxadiazole -3-yl)-N,N- Vis (2,2,2- Trifluoroethyl )-3-(t Lifluorome Teal) Of benzeneamine Produce

[Step 1] 4-( Bis(2,2,2-trifluoroethyl)amino )-2-( Trifluoromethyl ) Benzonitrile Produce

20 g (107 mmol) of 4-amino-2-(trifluoromethyl)benzonitrile was added to a 1 L flask, and 500 ml of trifluoroacetic acid was added and stirred. The reaction solution was refluxed at 100° C. for 1 day, and NaBH ₄ (pellet) was added. The reaction solution was cooled to room temperature, basified with 2N NaOH, and extracted three times with 50 ml of ethyl acetate. The extracted solvent was concentrated under reduced pressure and separated by column to obtain 8 g (21%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.71 (d, 1H), 7.17 (d, 1H), 7.06 (dd, 1H), 4.13 (q, 4H)

Mass[M+H]: 351.05

[Step 2] (Z)-4-( Bis(2,2,2-trifluoroethyl)amino )- N' - Hydroxy -2-( Trifluoromethyl ) Benzimidamide Produce

Example 3 using compound 4-(bis(2,2,2-trifluoroethyl)amino)-2-(trifluoromethyl)benzonitrile 2.0 g (5.71 mmol) obtained in step 1 in a 100 ml flask Proceeding in the same manner as in Step 1 of, 790mg (36%) of the title compound was obtained.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.48 (d, 1H), 7.15 (d, 1H), 7.03 (dd, 1H), 4.80 (s, 1H), 4.09 (q, 4H)

Mass[M+H]: 384.07

[Step 3] 4-(1,2,4- Oxadiazole -3-yl)-N,N- Vis (2,2,2- Trifluoroethyl )-3-(t Lifluoromethyl ) Of benzeneamine Produce

In a 100 ml flask, compound (Z)-4-(bis(2,2,2-trifluoroethyl)amino)-N'-hydroxy-2-(trifluoromethyl)benzimidamide 790 mg ( 2.06mmol) was carried out in the same manner as in Step 2 of Example 3 to obtain 529mg (65%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ 8.78 (s, 1H), 7.78 (d, 1H), 7.29 (d, 1H), 7.12 (dd, 1H), 4.13 (q, 4H)

Mass[M+H]: 394.05

[ Example 5] 3-(4-( Bis(2,2,2-trifluoroethyl)amino )-2-( Trifluoromethyl ) Phenyl )1,2,4- Oxadiazole Preparation of -5(4H)-one

In a 100 ml flask, compound (Z)-4-(bis(2,2,2-trifluoroethyl)amino)-N'-hydroxy-2-(trifluoromethyl)benzyl obtained in step 2 of Example 4 220mg (0.57mmol) of midamide was added and dissolved in 10ml of tetrahydrofuran, and then 92.4mg (0.57mmol) of 1,1-carbonyldiimidazole was added and refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, extracted with 2N-hydrochloric acid aqueous solution and ethyl acetate, and the organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and purified by column chromatography to give 158 mg (68%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ 7.65 (d, 1H), 7.25 (s, 1H), 7.14-7.12 (dd, 1H), 4.17-4.10 (m, 4H)

Mass[M+H]: 410.05

[ Example 6] 4-(2H- Tetrazole -5-yl)-N,N- Vis (2,2,2- Trifluoroethyl )-3-( Trifluoromethyl ) Of benzeneamine Produce

Compound 4-(bis(2,2,2-trifluoroethyl)amino)-2-(trifluoromethyl)benzonitrile 250 mg (0.71 mmol) obtained in step 1 of Example 4 was added to N,N-dimethyl After dissolving in 5 ml of formamide, 92 mg (1,42 mmol) of NaN _{3 and} 3.8 mg (0.07 mmol) of NH ₄ Cl were added, and 1 ml of water was added, followed by stirring at 100° C. for 10 hours. The reaction mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, the organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and purified by column chromatography to give 150 mg (54%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.58 (d, 1H), 7.50 (s, 1H), 7.45-7.42 (dd, 1H), 4.47-4.41 (m, 4H)

Mass[M+H]: 394.06

[ Example 7] 5-((2,2,2- Trifluoroethyl )(1,1,1- Trifluoropropane -2-yl)amino)-3-( Trifluoromethyl ) Picolinonitrile Produce

[Step 1] 3-( Trifluoromethyl )-5-((1,1,1- Trifluoropropane Preparation of -2-yl)amino)pyridin-2(1H)-one

To a 50 ml flask, 500 mg (2.80 mmol) of the compound 5-amino-3-(trifluoromethyl)pyridin-2(1H)-one obtained in step 2 of Example 1 was added, and 5 ml of trifluoroacetic acid was added and stirred. After cooling to 0°C, 1,1,1-trifluoroacetone (5.61mmol, 2eq) was added and stirred for 1 hour, and sodium borohydride (5.61mmol, 2eq) was added, followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, layered with water (10ml) and ethyl acetate (10ml), the aqueous layer was removed, and washed with 2N sodium hydroxide (10ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The concentrate was separated by column chromatography to give 160 mg (16%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.55 (s, 1H), 7.15 (s, 1H), 4.12 (d, 1H), 3.65 (1H), 1.25 (m, 3H)

Mass[M+H]: 275.05

[Step 2] 5-((2,2,2- Trifluoroethyl )(1,1,1- Trifluoropropane -2-yl)amino)-3-( Trifluoromethyl ) Preparation of pyridin-2(1H)-one

In a 25 ml flask, compound 3-(trifluoromethyl)-5-((1,1,1-trifluoropropan-2-yl)amino)pyridin-2(1H)-one 160 mg (0.45 mmol) obtained in step 1 ) And 5 ml of trifluoroacetic acid was added and stirred. The reaction solution was refluxed at 100°C, and 1 g of sodium borohydride was added. After completion of the reaction, the mixture was concentrated under reduced pressure, and the layer was separated with water (10ml) and ethyl acetate (10ml), and the aqueous layer was removed, followed by washing with 2N sodium hydroxide (10ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 30mg (19%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.68 (d, 1H), 7.41 (d, 1H), 3.71 (m, 1H), 3.64 (m, 2H), 1.28 (d, 3H)

Mass[M+H]: 357.06

[Step 3] 5-((2,2,2- Trifluoroethyl )(1,1,1- Trifluoropropane -2-yl)amino)-3-( Trifluoromethyl )Pyridin-2-yl Of trifluoromethanesulfonate Produce

In a 25 ml flask, compound 5-((2,2,2-trifluoroethyl)(1,1,1-trifluoropropan-2-yl)amino)-3-(trifluoromethyl) obtained in step 2 Pyridine-2(1H)-one 30mg (0.08mmol) was added and 2ml of pyridine was added and stirred. The reaction solution was cooled to 0° C., trifluoromethanesulphonic anhydride 36u (0.21 mmol, 2.5 eq) was added, followed by stirring at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure, and the layer was separated with water (10ml) and ethyl acetate (10ml), and the aqueous layer was removed, followed by washing with 2N sodium hydroxide (10ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 36 mg (88%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.25 (d, 1H), 7.69 (d, 1H), 4.25 (m, 1H), 4.01 (m, 2H), 1.53 (d, 3H)

Mass[M+H]: 489.01

[Step 4] 5-((2,2,2- Trifluoroethyl )(1,1,1- Trifluoropropane -2-yl)amino)-3-( Trifluoromethyl ) Picolinonitrile Produce

In a 5 ml reaction vessel, compound 5-((2,2,2-trifluoroethyl)(1,1,1-trifluoropropan-2-yl)amino)-3-(trifluoromethyl) obtained in step 3 )Pyridine-2-yl trifluoromethanesulfonate 36mg (0.07mmol) was added and N,N-dimethylformamide 1ml was added and stirred. Zn(CN) ₂ (0.15mmol, 2eq), Pd ₂ (dba) ₃ (0.0007mmol, 0.01eq) and 1,1'-bis(diphenylphosphino)ferrosine (0.002mmol, 0.03eq) were sequentially added and reacted at 200°C for 1 minute using a microwave reactor. After completion of the reaction, the reaction solution was filtered, the filtrate was layered with water (10ml) and ethyl acetate (10ml), the aqueous layer was removed, and washed with a saturated aqueous ammonium chloride solution. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 20mg (74%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.57 (s, 1H), 7.50 (s, 1H), 4.56 (m, 1H), 4.13 (q, 2H), 1.63 (d, 3H)

Mass[M+H]: 366.06

[ Example 8] 5-( Isopropyl (2,2,2-trifluoroethyl) amino )-3-( Trifluoromethyl ) Picolinonitrile Produce

[Step 1] 5-( Isopropylamino )-3-( Trifluoromethyl ) Preparation of pyridin-2(1H)-one

In a 50 ml airtight container, put 500 mg (2.80 mmol) of the compound 5-amino-3-(trifluoromethyl)pyridin-2(1H)-one obtained in step 2 of Example 1, and add 10 ml of 1,2-dichloroethane, and the mixture was stirred. Made it. Acetone (2.80mmol, 1eq), sodium triacetoxyborohydride (5.60mmol, 2eq), and acetic acid (cat.) were added, and the mixture was capped with a stopper and stirred at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the layer was separated with water (20 ml) and ethyl acetate (20 ml) to remove the aqueous layer. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. Separated by column chromatography to obtain 290mg (47%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.45 (s, 1H), 6.93 (s, 1H), 3.30 (m, 1H), 1.16 (d, 6H)

Mass[M+H]: 221.08

[Step 2] 5-( Isopropyl (2,2,2-trifluoroethyl) amino )-3-( Trifluoromethyl ) Preparation of pyridin-2(1H)-one

In a 25 ml flask, use the compound 5-(isopropylamino)-3-(trifluoromethyl)pyridin-2(1H)-one obtained in Step 1, and use the same method as in Step 2 of Example 7 to prepare 280 mg (70) of the title compound. %).

¹ H NMR (400MHz, CDCl ₃ ): δ 7.72 (s, 1H), 7.42 (s, 1H), 3.47 (q, 2H), 3.35 (m, 1H), 1.07 (d, 6H)

Mass[M+H]: 323.09

[Step 3] 55-( Isopropyl (2,2,2-trifluoroethyl) amino )-3-( Trifluoromethyl )Pyridin-2-yl Of trifluoromethanesulfonate Produce

In a 25 ml flask, use the compound 5-(isopropyl(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)pyridin-2(1H)-one obtained in Step 2 as the step of Example 7 Using the same method as in 3, 300mg (74%) of the title compound was obtained.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.07 (d, 1H), 7.47 (d, 1H), 4.07 (m, 1H), 3.86 (q, 2H), 1.28 (d, 6H)

Mass[M+H]: 435.03

[Step 4] 5-( Isopropyl (2,2,2-trifluoroethyl) amino )-3-( Trifluoromethyl ) Picolinonitrile Produce

In a 5 ml reaction vessel, compound 5-(isopropyl(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)pyridin-2-yl trifluoromethanesulfonate obtained in step 3 was used. 200mg (93%) of the title compound was obtained using the same method as in Step 4 of Example 7.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.45 (d, 1H), 7.34 (d, 1H), 4.22 (m, 1H), 3.99 (q, 2H), 1.35 (d, 6H)

Mass[M+H]: 312.09

[ Example 9] 5-(( Cyclopropylmethyl )(2,2,2- Trifluoroethyl )Amino)-3-( Trifluoromethyl ) Picolinonitrile Produce

[Step 1] 5-((2,2,2- Trifluoroethyl )Amino)-3-( Trifluoromethyl ) Preparation of pyridin-2(1H)-one

To a 500 ml flask, 5 g (28.0 mmol) of the compound 5-amino-3-(trifluoromethyl)pyridin-2(1H)-one obtained in step 2 of Example 1 was added, and 100 ml of trifluoroacetic acid was added thereto, followed by stirring. 5 g of sodium borohydride was added and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the layer was separated with water (200ml) and ethyl acetate (200ml), the aqueous layer was removed, and the mixture was washed with 2N sodium hydroxide (100ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 7 g (90%) of the title compound.

¹ H NMR (400MHz, DMSO): δ 7.67 (d, 1H), 7.15 (s, 1H), 5.671 (t, 1H), 3.86 (m, 2H)

Mass[M+H]: 261.04

[Step 2] 5-((2,2,2- Trifluoroethyl )Amino)-3-( Trifluoromethyl )Pyridin-2-yl Of trifluoromethanesulfonate Produce

In a 50 ml flask, the compound 5-((2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)pyridin-2(1H)-one obtained in Step 2 was used as in Step 3 of Example 7 Using the same method, 7.8g (74%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 8.36 (d, 1H), 7.92 (d, 1H), 4.22 (m, 1H), 3.47 (q, 2H)

Mass[M+H]: 392.99

[Step 3] 5-((2,2,2- Trifluoroethyl )Amino)-3-( Trifluoromethyl ) Picolinonitrile Produce

Example with 3 g of compound 5-((2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)pyridin-2-yl trifluoromethanesulfonate obtained in step 2 in a 50 ml reaction vessel Using the same method as in Step 4 of 7, 1.5 g (74%) of the title compound was obtained.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.30 (d, 1H), 7.22 (d, 1H), 4.87 (m, 1H), 3.93 (m, 2H)

Mass[M+H]: 270.04

[Step 4] 5-(( Cyclopropylmethyl )(2,2,2- Trifluoroethyl )Amino)-3-( Trifluoromethyl ) Picolinonitrile Produce

In a 50 ml reaction vessel, compound 5-((2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile 60mg (0.223mmol) obtained in step 3 was added and N,N- 3 ml of dimethylformamide was added and stirred. 65ul of (bromomethyl)cyclopropane (0.669mmol, 3eq) and sodium hydride (0.669mmol, 3eq) were added and stirred at room temperature. The reaction solution was layered with water (10ml) and ethyl acetate (10ml), the aqueous layer was removed, and washed with a saturated aqueous ammonium chloride solution. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 20mg (28%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.41 (d, 1H), 7.30 (d, 1H), 4.12 (q, 2H), 3.41 (d, 2H), 1.03 (m, 1H), 0.69 (m, 2H), 0.33 (m, 2H)

Mass[M+H]: 324.09

[ Example 10] 5-( Isobutyl (2,2,2-trifluoroethyl) amino )-3-( Trifluoromethyl ) Picolinonitrile Produce

In a 50 ml reaction vessel, compound 5-((2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile 60 mg (0.223 mmol) and 1 obtained in step 3 of Example 9 -Using iodo-2-methylpropane, 150mg (62%) of the title compound was obtained using the same method as in Step 4 of Example 9.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.37 (d, 1H), 7.26 (d, 1H), 4.09 (q, 2H), 3.40 (d, 2H), 2.14 (m, 1H), 1.01 (d, 6H)

Mass[M+H]: 326.10

[ Example 11] 5-(cyclobutyl (2,2,2- Trifluoroethyl )Amino)-3-( Trifluoromethyl ) Picolinonitrile Produce

[Step 1] 6- Bromo -5-( Trifluoromethyl ) Pyridine-3- Amine Produce

In a 500ml flask, 2-bromo-5-nitro-3-(trifluoromethyl)pyridine 2g (7.38mmol) was added, acetic acid (143ml) and ethyl acetate (143ml) were added, and stirred at 65℃, followed by Fe 2.07g ( 36.9mmol, 5eq) was added and stirred for about 4 to 5 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain 800mg (45%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.90 (d, 1H), 7.35 (d, 1H), 6.12 (br, 2H)

Mass[M+H]: 240.95

[Step 2] 6- Bromo -N- Cyclobutyl -5-( Trifluoromethyl ) Pyridine-3- Amine Produce

In a 50 ml flask, 84 mg (0.35 mmol) of compound 6-bromo-5-(trifluoromethyl)pyridin-3-amine obtained in step 1 was added, followed by adding 5 ml of 1,2-dichloroethane, followed by stirring. After adding 26ul of cyclobutanone (0.35mmol, 1eq) and 148mg (0.70mmol, 2eq) of sodium triacetoxyborohydride, 40ul of acetic acid (0.70mmol, 2eq) was added and stirred at room temperature for 16 hours. The reaction solution was stirred at 50° C. for about 4 hours. The reaction solution was concentrated under reduced pressure, layered with water (20ml) and ethyl acetate (20ml), the aqueous layer was removed, the organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. Separated by column chromatography to give the title compound 26mg (25%).

¹ H NMR (400MHz, CDCl ₃ ): δ 7.80 (s, 1H), 7.03 (d, 1H), 3.87 (m, 1H), 2.43 (m, 2H), 1.85 (m, 4H)

Mass[M+H]: 295.00

[Step 3] 6- Bromo -N- Cyclobutyl -N-(2,2,2- Trifluoroethyl )-5-( Trifluoromethyl ) Pyridine-3- Amine Produce

In a 25 ml flask, use the compound 6-bromo-N-cyclobutyl-5-(trifluoromethyl)pyridin-3-amine obtained in step 2, using the same method as in step 2 of Example 7, and 30 mg (90% of the title compound). ).

¹ H NMR (400MHz, CDCl ₃ ): δ 8.08 (d, 1H), 7.35 (d, 1H), 4.09 (m, 1H), 3.93 (q, 2H), 2.38 (m, 2H), 2.01 (m, 2H), 1.80 (m, 2H)

Mass[M+H]: 377.00

[Step 4] 5-(cyclobutyl (2,2,2- Trifluoroethyl )Amino)-3-( Trifluoromethyl ) Picolinonitrile Produce

Example of compound 6-bromo-N-cyclobutyl-N-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyridin-3-amine obtained in step 3 in a 5 ml reaction vessel Using the same method as in Step 4 of 7, 15 mg (58%) of the title compound was obtained.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.38 (d, 1H), 7.78 (d, 1H), 4.19 (m, 1H), 4.07 (q, 2H), 2.45 (m, 2H), 2.10 (m, 2H), 1.86 (m, 2H)

Mass[M+H]: 324.09

[ Example 12] 3- Chloro -2- methyl -4-(1,2,4- Oxadiazole -3-yl)-N,N-bis(2,2,2- Trifluoroethyl ) Preparation of aniline

[Step 1] 4- Bromo -3- Chloro -2- Methylaniline Produce

Into a 100 ml flask, 10 g (38.09 mmol) of N-(4-bromo-3-chloro-2-methylphenyl)acetamide was added, followed by stirring in 38 ml of ethanol. After adding 38ml (27eq) of 12N HCl to the reaction solution, it was refluxed at 80°C for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give 8.5 g (95%) of the title compound.

¹ H NMR (400MHz, DMSO-d ₄ ): δ 7.20(d, 1H), 6.53(d, 1H), 5.36(s, 2H), 2.16(s, 3H)

Mass[M+H]: 219.95

[Step 2] 4- Bromo -3- Chloro -2- methyl -N,N- Of bis(2,2,2-trifluoroethyl)aniline Produce

To a 1 L flask, 8.54 g (39 mmol) of the compound 4-bromo-3-chloro-2-methylaniline obtained in step 1 was added, and 250 ml of trifluoroacetic acid was added, followed by stirring. While stirring at room temperature, 9g (9 pellets) of NaBH ₄ was added over 4 hours and stirred at room temperature for 16 hours. The reaction solution was refluxed at 100° C. and ₄ g (4 pellets) of NaBH ₄ was added thereto. After completion of the reaction, the mixture was concentrated under reduced pressure, and the layer was separated with water (300ml) and ethyl acetate (300ml), and the aqueous layer was removed and washed with 2N NaOH (300ml). The organic layer was washed with water and a saturated NaCl aqueous solution, dried over MgSO _4, and then concentrated under reduced pressure. The concentrate was separated by column to obtain 6 g (40%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.46 (d, 1H), 7.00 (d, 1H), 3.71 (q, 4H), 2.40 (s, 3H)

Mass[M+H]: 383.95

[Step 3] 4-( Bis(2,2,2-trifluoroethyl)amino )-2- Chloro -3- Of methylbenzonitrile Produce

In a 100 ml flask, add 1 g (2.6 mmol) of the compound 4-bromo-3-chloro-2-methyl-N,N-bis(2,2,2-trifluoroethyl)aniline obtained in step 2 and N,N- 25 ml of dimethylformamide was added and stirred. To the reaction solution, 350mg (3.9mmol, 1.5eq) of CuCN(I) and 743mg (3.9mmol, 1.5eq) of CuI were added and refluxed at 160-170°C. After the reaction for 4 hours, 495mg (2.6mmol, 1eq) of CuI was added and refluxed for 16 hours. The reaction was concentrated under reduced pressure and then separated by column to obtain 570mg (66%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.52 (d, 1H), 7.20 (d, 1H), 3.79 (q, 4H), 2.38 (s, 3H)

Mass[M+H]: 331.04

[Step 4] (Z)-4-( Bis(2,2,2-trifluoroethyl)amino )-2- Chloro - N' - Hydroxy -3- Of methylbenzimidamide Produce

In a 50 ml flask, the compound 4-(bis(2,2,2-trifluoroethyl)amino)-2-chloro-3-methylbenzonitrile obtained in step 3 was used in the same manner as in step 1 of Example 3. 180mg (30%) of the compound was obtained.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.31 (d, 1H), 7.15 (d, 1H), 4.93 (s, 2H) 3.75 (q, 4H), 2.37 (s, 3H)

Mass[M+H]: 364.06

[Step 5] 3- Chloro -2- methyl -4-(1,2,4- Oxadiazole -3-yl)-N,N-bis(2,2,2- Trifluoroethyl ) Preparation of aniline

In a 10 ml flask, compound (Z)-4-(bis(2,2,2-trifluoroethyl)amino)-2-chloro-N'-hydroxy-3-methylbenzimidamide 180 mg (0.5) obtained in step 4 mmol) and 5 ml of acenonitril were added and stirred. Triethyl orthoformate 167ul (1.0mmol, 2eq) and trifluoroacetic acid (ca. 20ul) were added to the reaction solution and refluxed at 60°C for about 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and separated by column to obtain 90 mg (48%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 8.80 (s, 1H), 7.71 (d, 1H), 7.26 (s, 1H), 3.80 (q, 4H), 2.44 (s, 3H)

Mass[M+H]: 374.04

[ Experimental example 1] Ability test for androgen receptor

In order to determine the androgen receptor binding ability of the agonists of the present invention, the following in vitro experiment was performed. COS-7 cell line (ATCC, #CRL-1651), an African green monkey kidney fibroblast-like cell line, was seeded in a 48-well plate at 2.5 x 10 ⁴ cells/well, and 37℃ After incubation for 24 hours at, OPTI-MEM medium (Gibco, #31985) mixed with 5 ng of plasmid hAR (ORIGENE, #RC215316) containing human androgen receptor gene was added to transform the human androgen receptor gene ( transfection) cell line was prepared. The obtained transformed cell line was treated with [3H]MIB (Mibolerone) at a concentration of 1 nM and compounds at a concentration of 0.1 to 10,000 nM and reacted for 2 hours. Thereafter, the cells were lysed and the amount of [3H]MIB bound to the intracellular androgen receptor was measured using a radiometer (Packard, #Topcount NXT C9904V1), and the result was 50% inhibitory concentration (IC ₅₀ ) As shown in Table 1.

compound IC ₅₀ [nM]
(mean±SE) compound IC ₅₀ [nM]
(mean±SE) Example 1 8037.1±1334.8 Example 7 8.9±2.8 Example 2 24.4±2.9 Example 8 9.4±0.0 Example 3 471.9 Example 9 11.0 Example 4 23.9±1.2 Example 10 10.8 Example 5 1250.6 Example 11 1.7 Example 6 3412.6±274.5

As shown in Table 1, it was confirmed that the novel SARM derivatives of Examples 1 to 11 bind to the androgen receptor. These results mean that the SARM derivatives of Examples 1 to 11 may bind to the androgen receptor and affect the action of the androgen receptor.

[ Experimental example 2] Transcription activity test

In order to determine the transcriptional activity of the agonists of the present invention, the following in vitro experiment was performed.

CHO (Chinese hamster ovary) cell line (ATCC, #CCL-61) was inoculated into a 96 well plate at 1.5×10 ⁴ cells/well, incubated at 37°C for 24 hours, and then plasmid hAR(ORIGENE, #RC215316) 5ng and A transformed cell line into which a human androgen receptor gene and a luciferase gene were introduced was prepared by adding OPTI-MEM medium (Gibco, #31985) mixed with 100 ng of plasmid ARE-Luc (QIAGEN, #CCS-1019L). The transformed cell line was treated with SARM derivatives (Examples 1 to 11) at a concentration of 0.1 to 10,000 nM and reacted for 24 hours. After that, a dual-luciferase assay (Promega, #E2940) was performed, and luminescence in the culture medium was measured using a luminometer (Molecular Devices, #SpectraMax L). The obtained results were converted to 100% of the SARM derivative untreated control activity and the positive control dihydrotestosterone (dihydrotestosterone, DHT; Sigma Aldrich, #A8380) 10nM treatment group activity to 100%, indicating 50% transcriptional activity. It is shown in Table 2 as (EC ₅₀ ).

compound EC ₅₀ [nM]
(mean±SE) compound EC ₅₀ [nM]
(mean±SE) Example 2 3.4±1.5 Example 8 0.03±0.01 Example 3 8.4±3.4 Example 9 1.9 Example 4 0.2±0.1 Example 10 1.5 Example 6 18.7±9.7 Example 11 1.2 Example 7 0.06

As shown in Table 2, it was confirmed that the compounds of Examples 1 to 11 acted on androgen receptors, thereby increasing androgen activity.

[ Experimental example 3] castrated male In rat Efficacy test

SD (Sprague-Dawley) male rats (7 weeks old) were castrated with ketamine/xylazine under anesthesia, and then randomly separated 5 rats per group. From the next day, the agonists were dissolved in a vehicle solution and administered orally at 5 ml per kg once a day for 14 days. For the vehicle, DMSO, Co-solvent, and DW were prepared in a ratio of 4: 80: 16 (v/v/v), respectively, and the Co-solvent used PEG400, Ethanol, and Tween 80, respectively, 85: 10: 5 (v/ v/v) was mixed and used. 24 hours after the last drug administration, the body weight was measured and killed. Thereafter, levator ani muscle, ventral prostate, and seminal vesicles were excised and weighed (Hershberger assay). The results are shown in Table 3 below as a relative weight% relative to the organ weight of the intact control group.

Results of efficacy test in castrated male rats designation Dose (mg/kg) Big anal prostate Seminal vesicle Intact control 100±4.2 100.0±5.8 100.0±3.2 Example 2 0.003 12.8±1.0 2.8±0.5 2.3±0.2 0.01 45.5±3.3 7.1±0.6 6.5±0.7 0.03 72.0±2.5 13.6±0.9 11.9±1.1 0.1 123.1±4.1 44.6±2.1 53.8±3.4 0.3 125.1±5.6 64.5±3.4 74.3±4.8 One 147.7±4.2 96.1±3.1 101.9±10.2 Example 4 0.1 14.3±0.6 6.5±1.1 0.9±0.1 0.3 48.2±2.5 15.6±1.5 24.3±2.4 One 55.1±2.0 18.0±1.8 5.9±0.8 3 98.8±4.0 40.5±3.6 33.5±4.5 10 116.5±7.7 58.0±6.8 73.9±3.2 30 134.3±6.9 78.3±5.3 83.2±5.3 100 114.5±5.2 55.2±5.7 60.2±6.1

As a result of the test, it was confirmed that the castrated rats as shown in Table 3 had reduced levator ani muscles, prostate and seminal vesicles compared to intact rats. However, it was confirmed that the levator ani muscle was statistically significantly increased in the rats repeatedly administered orally for 14 days with SARM agonists compared to the castrated group. In addition, the increase in the levator ani muscle was more pronounced than that of the prostate or seminal vesicles, indicating that the SARM derivative compounds of the present invention not only increase androgen activity by acting on the androgen receptor, but also have excellent tissue-selective pharmacological effects.

Claims (17)

delete delete delete delete delete delete Which is selected from the group consisting of,
A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
5-(bis(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)pyridin-2(1H)-one;
5-(bis(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;
6-(1,2,4-oxadiazol-3-yl)-N,N-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyridin-3-amine;
4-(1,2,4-oxadiazol-3-yl)-N,N-bis(2,2,2-trifluoroethyl)-3-(trifluoromethyl)benzeneamine;
3-(4-(bis(2,2,2-trifluoroethyl)amino)-2-(trifluoromethyl)phenyl)1,2,4-oxadiazole-5(4H)-one;
4-(2H-tetrazol-5-yl)-N,N-bis(2,2,2-trifluoroethyl)-3-(trifluoromethyl)benzeneamine;
5-((2,2,2-trifluoroethyl)(1,1,1-trifluoropropan-2-yl)amino)-3-(trifluoromethyl)picolinonitrile;
5-(isopropyl(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;
5-((cyclopropylmethyl)(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;
5-(isobutyl(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile;
5-(cyclobutyl(2,2,2-trifluoroethyl)amino)-3-(trifluoromethyl)picolinonitrile. Comprising the compound according to claim 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
As a pharmaceutical composition for the prevention or treatment of diseases or symptoms that can respond to treatment or improve symptoms due to increased androgen activity,
The above diseases or symptoms include sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, muscle dystropy, cachexia, muscular dystrophy, postoperative muscle loss, neurotransmitter disorders. Neuromuscular disease caused by, rheumatic disease, sarcopenic obesity, cognitive and emotional changes, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer, ovarian cancer, muscle wasting disorder, osteopenia And that is selected from the group consisting of osteoporosis, the pharmaceutical composition. delete Comprising the compound according to claim 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
As a health functional food composition for preventing or ameliorating diseases or symptoms that can respond to treatment or improve symptoms due to increased androgen activity,
The above diseases or symptoms include sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, muscle dystropy, cachexia, muscular dystrophy, postoperative muscle loss, neurotransmitter disorders. Neuromuscular disease caused by, rheumatic disease, sarcopenic obesity, cognitive and emotional changes, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer, ovarian cancer, muscle wasting disorder, osteopenia And one selected from the group consisting of osteoporosis, health functional food composition. delete delete delete delete delete delete delete