KR102164612B1 - Azole-based compound and selective androgen receptor agonist comprising the same - Google Patents

Abstract

A novel azole-based compound, a pharmaceutical composition containing the azole-based compound, and a method for preparing the azole-based compound are provided.
The azole-based compound acts on the androgen receptor to increase the activity of the androgen receptor, thereby improving symptoms or responding to treatment due to the increase in androgen activity, such as various hormone-related diseases in men and women, muscle wasting. It can be usefully used as a treatment and/or prevention agent for disorders, osteopenia, and osteoporosis.

Description

An azole-based compound and a selective androgen receptor agonist comprising the same {Azole-based compound and selective androgen receptor agonist comprising the same}

It relates to a novel azole compound of Formula 1, a pharmaceutical composition containing the azole compound, and a method for preparing the azole 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 genital organs 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 with age, the amount of androgens in the blood decreases, leading to symptoms such as decreased libido and sex life, lack of vitality, decreased euphoria, and decreased bone mineral density after menopause. It is 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, males and females 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 replacement 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 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 prostate enlargement, hirsutism, and virilization, do not generally appear. These compounds tissue-selectively act on androgen receptors to increase their activity, thereby eliminating or reducing the negative or unwanted properties of androgens, while exerting the effects of androgens. Accordingly, the compounds can be effectively used for the treatment and/or prevention and/or amelioration of 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 side effects of androgens. .

An example of the present invention provides a novel azole-based compound.

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

Another example provides a pharmaceutical composition for the prevention and/or treatment of a disease or condition that may be improved or respond to treatment due to an increase in androgen activity containing a pharmaceutically effective amount of the azole compound as an active ingredient.

Another example provides a health functional food composition for preventing and/or improving diseases or conditions that may be improved or respond to treatment due to an increase in androgen activity containing the azole-based compound.

Another example provides a method for preparing the azole-based compound.

The present inventors 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 Formula 1,

R1 is an unsubstituted or substituted amino group, or an unsubstituted or substituted pyrrolidinyl group;

R2 is an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 3 carbon atoms;

X can be N, CH or C(O).

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 isomers. All of the compounds, isomers, and salts should be construed 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 previously known androgen receptor agonist, and, as confirmed in Experimental Examples 1 and 2, 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 may 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 from the viewpoint of pharmaceutical, biological or other properties may be collectively referred to. The pharmaceutically acceptable salts include acids that form 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, it is possible to obtain a salt of each form 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 "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.

The term "alkyl" as used herein refers to an aliphatic hydrocarbon group. The alkyl moiety may be a “saturated alkyl” group containing no alkene or alkyne moieties, or may be a “unsaturated alkyl” group containing 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.

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,

R1 is an unsubstituted or substituted amino group, or an unsubstituted or substituted pyrrolidinyl group;

R2 is an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 3 carbon atoms;

X can be N, CH or C(O).

In the definition of R1,

The substituted amino group is an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (e.g., 1 to 4 carbon atoms or 2 or 3 carbon atoms) each independently of one or more of the hydrogens contained in the amino group. It may be a substituted amino group, wherein the substituted alkyl group is a linear of 1 to 6 carbon atoms (e.g., 1 to 4 carbon atoms or 2 or 3 carbon atoms) in which at least one of the hydrogens contained in the alkyl group is independently substituted with halogen, It may be a branched or cyclic alkyl group;

The substituted pyrrolidinyl group is one or more of the hydrogens contained in the pyrrolidinyl group, each independently an oxo group or an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (eg, 1 to 4 carbon atoms) It may be a pyrrolidinyl group substituted with, wherein the substituted alkyl group has 1 to 6 carbon atoms each independently substituted with a hydroxy group, an oxo group, or a halogen in which at least one of the hydrogens contained in the alkyl group (e.g., 1 to 6 carbon atoms) It may be a linear, branched or cyclic alkyl group of 4).

In the definition of R2, the substituted alkyl group may be a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms (eg, 3 carbon atoms) in which at least one of the hydrogens included in the alkyl group is independently substituted with halogen.

In Formula 1,'(H)' means that hydrogen may or may not be present depending on the type of X. When X is N, hydrogen is present, and X is CH or C(O) If it is, hydrogen does not exist.

The "each independently substituted" means that when the number of substituted hydrogens is 2 or more, each hydrogen may be substituted with the same or different substituents.

In one embodiment, R1 may be the substituted amino group or the substituted pyloridinyl group, and R2 may be the substituted alkyl group.

More specifically, in one embodiment, R1 may be an amino group in which one or more hydrogens, such as two hydrogens, are each independently substituted with an unsubstituted or substituted linear or branched alkyl group having 2 or 3 carbon atoms, wherein the substitution The alkyl group may be a linear or branched alkyl group having 2 or 3 carbon atoms in which one or more hydrogens, such as three hydrogens, are each independently substituted with halogen, such as fluorine. In another embodiment, R1 may be a pyrrolidinyl group in which one or more hydrogens, such as one to three hydrogens, are each independently an oxo group or an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms, Here, the substituted alkyl group may be a linear or branched alkyl group having 1 to 4 carbon atoms in which one or more hydrogens, such as 1 to 4 hydrogens, are each independently substituted with a hydroxy group or halogen (eg, fluorine). Further, R2 may be a linear alkyl group having 1 to 3 carbon atoms, such as 1 carbon number, in which one or more, for example, 3 hydrogens are substituted with halogen (eg, fluorine).

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

1) (R)-2,2,2-trifluoro-1-((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinoline -7-yl)pyrrolidin-2-yl)ethanol;

2) (R)-5-(hydroxymethyl)-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-one;

3) (R)-(1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)methanol;

4) (R)-2,2,2-trifluoro-1-((R)-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pi Rolidin-2-yl)ethanol;

5) (S)-2,2,2-trifluoro-1-((R)-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pi Rolidin-2-yl)ethanol;

6) ((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)methanol;

7) 1-((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)ethanol ;

8) 1-((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)propane -1-ol;

9) 2-Methyl-1-((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidine-2 -Yl)propan-1-ol;

10) N-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-N-(1,1,1-trifluoropropan-2-yl)tetrazolo[1,5 -a]quinolin-7-amine;

11) N,N-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine;

12) N,N-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinolin-7-amine ;

13) 7-(bis(2,2,2-trifluoroethyl)amino)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinoline-1( 2H)-one;

14) N,N-diethyl-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine;

15) N-N-dipropyl-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine;

16) N-ethyl-N-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine;

17) 7-(2,5-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)tetrazolo[1,5-a]quinoline; And

18) N-isopropyl-N-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine.

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. In addition, any asymmetric carbon atom on the compound of the above embodiment may exist in any form of the (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 the increase in 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 a decrease in the number or content of muscle cells, cachexia. (cachexia), muscular dystrophy, postoperative muscle loss, neuromuscular disease due to neurotransmitter system abnormalities, 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 osteoporosis may be selected from the group consisting of.

Diseases or conditions that 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, for example 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, 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, and an administration purpose.

When manufactured in various formulations for oral administration or parenteral administration, use 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 one or more selected from the group consisting of gelatin. In addition, 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, syrups, and the like. When formulated into the liquid formulation, water and/or liquid paraffin, which are commonly used simple diluents, may be used. 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 the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like can 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, the method of administration, the purpose of administration, etc.

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 taken 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 A functional food composition for preventing and/or improving a disease or condition capable of responding to treatment is provided. Diseases or conditions that can 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 manufacturing method comprises the steps of preparing a compound of Formula 1 by introducing an azide compound, a hydrazide compound, or a semicarbazide to the compound of Formula 3 below. Can contain:

[Formula 3]

When X of the compound of Formula 1 is N, the step of preparing the compound of Formula 1 may be performed by reacting the compound of Formula 3 with an azide compound, such as sodium azide (NaN ₃ ). When X of the compound of Formula 1 is CH, the step of preparing the compound of Formula 1 may be performed by reacting the compound of Formula 3 with a hydrazide compound, for example, formic hydrazide. When X in the compound of Formula 1 is carbon (C(O)) substituted with oxo, the step of preparing the compound of Formula 1 may be performed by reacting semicarbazide with the compound of Formula 3 .

In another embodiment, the preparation method is, prior to the step of introducing the azide compound, hydrazide compound, or semicarbazide, by halogenating the compound of formula 2 below to prepare the compound of formula 3 Can contain as:

[Formula 2]

The intermediate compound of Formula 3 may be a compound substituted with halogen, such as chlorine or bromine. To prepare a compound of Formula 3 it may be carried out by a step, such as step of reacting a halogen compound, such as POCl ₃ or POBr ₃ in the compound of Formula 2 to a halogenated compound of the general formula (2).

The reaction step is illustrated in Scheme 1 below:

[Scheme 1]

In Formula 2, Formula 3, and Reaction Formula 1, R1, R2, and X are as defined in Formula 1, and Hal means halogen, such as chlorine or bromine.

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 below.

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.

[ Manufacturing example 1] 6-N,N-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Preparation of quinoline-2 (1H)-one

In a 3L three-neck flask, 50 g (0.22 mol) of 6-amino-4-(trifluoromethyl)quinolin-2(1H)-one and 1.5 L of trifluoroacetic acid were added and stirred. NaBH ₄ 22.4g (23 pellets, 0.59 mol, 3 eq.) was added to the obtained reaction solution over 2 hours, followed by stirring at room temperature for 16 hours. The obtained reaction solution was refluxed at 100°C, and NaBH ₄ (pellet 1g/ea) was continuously added thereto, followed by stirring until the reaction was completed. After completion of the reaction, the obtained reaction solution was slowly added to 10 L of a mixed solution of water:methanol=9:1 (v:v) and stirred. After stirring for about 3 hours, the obtained reaction solution was filtered and washed twice with 500 ml of water. The obtained filtrate was vacuum-dried to give 85 g (99%) of the title compound.

¹ H NMR (DMSO-d ₆ , 400MHz): δ12.10(s, 1H), 7.56(dd, 1H), 7.36(d, 1H), 7.14(s, 1H), 6.95(s, 1H), 4.38 (q, 4H)

Mass[M+H]: 393.06

[Preparation Example 2] 2-Chloro-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinoline-6- Amine Produce

In a 1 L flask, compound 6-N,N-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2(1H)-one obtained in Preparation Example 1 50g (0.12mol) and POCl ₃ 150ml (13.3eq) were added and stirred. The obtained reaction solution was refluxed at 120° C. for about 2 hours, cooled to room temperature, and concentrated under reduced pressure. The obtained concentrate was diluted in 500 ml of ethyl acetate, and then washed with 500 ml of 2N NaOH aqueous solution. The obtained organic layer was washed with 500 ml of water, and then washed with a saturated NaCl aqueous solution, and the aqueous layer was removed. The oil layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure to obtain 52 g (97%) of the title compound.

¹ H NMR (DMSO-d ₆ , 400MHz) δ8.02 (d, 1H), 7.92 (m, 2H), 7.29 (s, 1H), 4.61 (q, 4H)

Mass[M+H]: 411.02

[ Manufacturing example 3] (R)-5-(( tert - Butyldimethylsilyloxy ) methyl ) Pyrrolidine Preparation of -2-one

To a 1L flask, 30 g (232 mmol) of (R)-5-oxopyrrolidine-2-carboxylic acid and 400 mL of methanol were added and cooled to 0°C. Thionyl chloride 16.9 mL (255 mmol, 1.1 eq.) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. 200 mL of methanol was added to the concentrated residue, followed by concentration under reduced pressure. 400 mL of ethanol was added to the concentrated residue and cooled to 0°C. NaBH ₄ 10.5g (278mmol, 1.2eq.) was slowly added to the reaction solution. The reaction solution was stirred at room temperature for 16 hours. 1N-citric acid aqueous solution was added dropwise to the reaction solution. The reaction solution was filtered and washed with ethyl acetate:methanol=3:1 (v:v) solvent. The filtrate was concentrated under reduced pressure, and ethyl acetate:methanol=3:1 was added to the concentrated residue. After dehydration and drying with MgSO _{4, it} was concentrated under reduced pressure. The reaction solution and 400 mL of N,N-dimethylformamide were added to a 1 L flask and cooled to 0°C. To the reaction solution, imidazole 30.2 g (464 mmol, 2.0 eq.) and tert-butyldimethylsilyl chloride 38.5 g (255 mmol, 1.1 eq.) were added. The reaction solution was stirred at room temperature for 16 hours. 400 mL of ethyl acetate and 400 mL of water were added, stirred, and the layers were separated. The aqueous layer was removed, the oil layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography (n-hexane:ethylacetate=2:1 to ethylacetate:methanol=10:1, (v:v)) and then concentrated under reduced pressure to give 12.9g (24%) of the title compound. I did.

¹ H NMR (CDCl ₃ , 400MHz) δ5.77(bs, 1H), 3.73(m, 1H), 3.61(m, 1H), 3.41(m, 1H), 2.38-2.30(m, 2H), 2.16( m, 1H), 1.71(m, 1H), 0.86(s, 9H), 0.04(s, 6H)

Mass[M+H]: 230.10

[ Manufacturing example 4] 6- Bromo -4-( Trifluoromethyl ) Preparation of quinoline-2 (1H)-one

To a 500 mL flask, add 17.2 g (100 mmol) of 4-bromoaniline, 16.2 mL (110 mmol, 1.1 eq.) of 4-bromoaniline, 16.2 mL of ethyl 4,4,4-trifluoroacetoacetate, and 120 mL of toluene, and reflux at 140°C while stirring the reaction solution. I did. After 10 minutes, 1.5 mL of water was added dropwise and the reaction solution was refluxed for 16 hours. After evaporating the reaction solution for 30 minutes, the reaction solution was concentrated under reduced pressure. While the concentrated residue was heated to 80° C., 60 mL of sulfuric acid was added dropwise over 10 minutes. The reaction solution was stirred while warming to 80° C. for 2 days. The reaction solution was cooled to room temperature and the reaction solution was transferred to a 1 L Erlenmeyer flask. The Erlenmeyer flask was cooled to 0°C, and 500 mL of finely ground ice was added to the reaction solution. After stirring for 30 minutes, it was filtered and washed 3 times with a large amount of water. The solid was dried in an oven at 50° C. for one day to obtain 15.98 g (55%) of the title compound.

¹ H NMR (acetone-d ₆ , 400 MHz) ?11.29 (bs, 1H), 7.86 (s, 1H), 7.85 (d, 1H), 7.50 (d, 1H), 7.01 (s, 1H);

Mass[M+H]: 291.95

[ Manufacturing example 5] 6- Bromo -2- Isopropoxy -4-( Trifluoromethyl ) Preparation of quinoline

In a 500 mL flask, compound 6-bromo-4-(trifluoromethyl)quinoline-2(1H)-one 6 g (20.5 mmol) and CsF 12.5 g (82.0 mmol, 4.0 eq.) obtained in Preparation Example 4, N, 80 mL of N-dimethylformamide was added, followed by stirring, while 6.1 mL (61.5 mmol, 3.0 eq.) of 2-iodopropane was added dropwise. After 16 hours, 100 mL of ethyl acetate and 100 mL of water were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, a saturated NaCl aqueous solution was added and shaken, and the aqueous layer was removed (repeated twice). The oil layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography (n-hexane:ethylacetate=20:1 (v:v)), and then concentrated under reduced pressure to obtain 6.67g (97%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ 8.09(s, 1H), 7.73(s, 2H), 7.18(s, 1H), 5.53(m, 1H), 1.39(d, 6H)

Mass[M+H]: 334.00

[ Manufacturing example 6] (R)-5-(( tert - Butyldimethylsilyloxy ) methyl )-1-(2- Isopropoxy -4-(t Lifluoromethyl ) Quinoline-6-day) Pyrrolidine Preparation of -2-one

In a 250 mL flask, 6.67 g (20.0 mmol) of compound 6-bromo-2-isopropoxy-4-(trifluoromethyl)quinoline obtained in Preparation Example 5 and 20 mL of toluene were added and stirred. The reaction solution was replaced with nitrogen, and Cs ₂ CO ₃ 22.8g (70.0mmol, 3.5eq.), Pd ₂ (dba) ₃ 549mg (0.6mmol, 0.03eq.), rac-2,2'-bis( Diphenylphosphino)-1,1'-binapthyl (BINAP) 1.12g (1.8mmol, 0.09eq.) was added. To the reaction solution, a solution of 9.16 g (40.0 mmol, 2.0 eq.) of the compound (R)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one obtained in Preparation Example 3 was dissolved in 20 mL of toluene. Added dropwise. The reaction solution was refluxed at 140° C. for 16 hours. The reaction solution was added to 100 mL of ethyl acetate and 100 mL of water at room temperature, stirred, and the layers were separated. The aqueous layer was removed, the oil layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography (n-hexane:ethylacetate=10:1 to 3:1, (v:v)), and then concentrated under reduced pressure to give 8.32g (86%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.86(s, 3H), 7.17(s, 1H), 5.54(m, 1H), 4.35(m, 1H), 3.65(dd, 1H), 3.58(dd , 1H), 2.75(m, 1H), 2.53(m, 1H), 2.33(m, 1H), 2.15(m, 1H), 1.39(d, 6H), 0.82(s, 9H), -0.12(d , 6H)

Mass[M+H]: 483.22

[ Manufacturing example 7] ((2R,5R)-1-(2- Isopropoxy -4-( Trifluoromethyl )Quinolin-6-yl)-5-me Tilpyrroli Preparation of din-2-yl)methanol

In a 500 mL flask, the compound obtained in Preparation Example 6 (R)-5-((tert-butyldimethylsilyloxy)methyl)-1-(2-isopropoxy-4-(trifluoromethyl)quinolin-6-yl) 6.75g (14.0mmol) of pyrrolidin-2-one and 70 mL of tetrahydrofuran were added and stirred. The reaction solution was purged with nitrogen and cooled to -78°C. 1.6M methyl lithium / diethyl ether 26.2 mL (42.0 mmol, 3.0 eq.) was gradually added dropwise to the reaction solution. After stirring at -78°C for 4 hours, 1.6M methyl lithium / diethyl ether 8.8 mL (14.0 mmol, 1.0 eq.) was slowly added dropwise. After stirring at -78°C for 2 hours, methanol was slowly added dropwise. After 30 mL of methanol:ethyl acetate = 1:1 (v:v) solution was added and stirred, The reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure, and 100 mL of a trifluoroacetic acid:methanol = 1:9 solution was added to the concentrated residue, and while stirring, 1.35 g (20% w/w) of 10% Pd/C was added. The mixture was stirred for 3 days under normal pressure hydrogen gas (hydrogen balloon was replaced frequently. A total of 5 times). After completion of the reaction, the reaction solution was filtered through celite, and washed with methanol and ethyl acetate. The filtrate was concentrated under reduced pressure, and the concentrated residue was separated by column chromatography (n-hexane:ethylacetate=8:1 to 2:1, (v:v)) and concentrated under reduced pressure to obtain 2.85 g (55%) of the title compound. Obtained.

¹ H NMR (CDCl ₃ , 400MHz): δ7.73(d, 1H), 7.29(dd, 1H), 7.10(s, 1H), 7.04(s, 1H), 5.48(m, 1H), 3.94(m , 1H), 3.87(m, 1H), 3.74(dd, 1H), 3.68(dd, 1H), 2.13(m, 1H), 2.02(m, 2H), 1.83(bs, 1H), 1.73(m, 1H), 1.37 (d, 6H), 1.33 (d, 3H)

Mass[M+H]: 369.17

[ Manufacturing example 8] (2R,5R)-1-(2- Isopropoxy -4-( Trifluoromethyl )Quinolin-6-yl)-5-me Tilpyrroli Din-2- Carbaldehyde Produce

In a 100 mL flask, the compound obtained in Preparation Example 7 ((2R,5R)-1-(2-isopropoxy-4-(trifluoromethyl)quinolin-6-yl)-5-methylpyrrolidin-2-yl ) 1.9g (5.16mmol) of methanol and 26 mL of dichloromethane/N,N-dimethylformamide (1/1) were added, substituted with nitrogen while stirring, and the reaction solution was cooled to 0°C. Triethylamine 3.57mL (25.8mmol, 5.0eq.) and SO ₃ -pyridine complex 4.1g (25.8mmol, 5.0eq.) were added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. To the reaction solution, 30 mL of ethyl acetate and 30 mL of 1N-HCl aqueous solution were added, stirred, and the layers were separated. The aqueous layer was removed, the oil layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography (n-hexane:ethylacetate=20:1 to 10:1, (v:v)), and then concentrated under reduced pressure to give 1.51 g (80%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ9.48(d, 1H), 7.72(d, 1H), 7.10(s, 1H), 7.07(d, 1H), 6.95(s, 1H), 5.47(m , 1H), 4.16-4.07 (m, 2H), 2.24-2.14 (m, 3H), 1.80-1.75 (m, 1H), 1.39-1.36 (m, 9H)

Mass[M+H]: 367.16

[ Manufacturing example 9] (R)-2,2,2- Trifluoro -1-((2R,5R)-1-(2- Isopropoxy -4-( Trifluoromethyl )Quinolin-6-yl)-5- Methylpyrrolidine Preparation of -2-yl)ethanol

In a 100 mL flask, the compound obtained in Preparation Example 8 (2R,5R)-1-(2-isopropoxy-4-(trifluoromethyl)quinolin-6-yl)-5-methylpyrrolidine-2-carbaldehyde 1.51g (4.12mmol) and 16 mL of tetrahydrofuran were added, substituted with nitrogen while stirring, and 3.13g (20.6mmol, 5.0 eq.) of CsF was added. The reaction solution was cooled to -78°C, and 0.913 mL (6.18 mmol, 1.5 eq.) of (trifluoromethyl) trimethylsilane was added dropwise to the reaction solution. The reaction solution was slowly stirred at room temperature for 16 hours. 16 mL of ethanol was added to the reaction solution and stirred for 1 hour. 30 mL of ethyl acetate and 30 mL of 1N-HCl aqueous solution were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, the oil layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography (n-hexane:dichloromethane=2:1 to 1:1, (v:v)), and then concentrated under reduced pressure to give 650mg (36%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.75(d, 1H), 7.19(dd, 1H), 7.11(s, 1H), 6.98(s, 1H), 5.48(m, 1H), 4.43(m , 1H), 4.16(m, 1H), 3.91(m, 1H), 2.46(m, 1H), 2.33(m, 1H), 2.06-2.00(m, 2H), 1.78(m, 1H), 1.38- 1.36 (m, 9H)

Mass[M+H]: 437.16

[ Manufacturing example 10] 6-((2R,5R)-2- methyl -5-((R)-2,2,2- Trifluoro -1-hydroxyethyl) Pyrrolidine -1-yl)-4-( Trifluoromethyl ) Preparation of quinoline-2 (1H)-one

In a 100 mL flask, compound (R)-2,2,2-trifluoro-1-((2R,5R)-1-(2-isopropoxy-4-(trifluoromethyl)quinoline obtained in Preparation Example 9) -6-yl)-5-methylpyrrolidin-2-yl)ethanol 650mg (1.49mmol) acetic acid 6ml and conc. Dissolved in 1.5 ml of HCl and refluxed at 60° C. for 4 hours. The reaction solution was cooled to room temperature, neutralized with saturated NaHCO ₃ , water and ethyl acetate were added, stirred, and the layers were separated. The aqueous layer was removed, the oil layer was separated, dehydrated with MgSO ₄ , dried and concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 580 mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.29(d, 1H), 7.05(dd, 1H), 6.98(s, 1H), 6.87(s, 1H), 4.35(q, 1H), 4.07(t , 1H), 3.82-3.79(m, 1H), 3.04(s, 1H), 2.48-2.41(m, 1H), 2.11-1.98(m, 2H), 1.79-1.76(m, 1H),1.31(d , 3H)

Mass[M+H]: 495.11

[ Manufacturing example 11] (R)-1-((2R,5R)-1-(2- Chloro -4-( Trifluoromethyl )Quinolin-6-yl)-5- Methylpyrrolidine -2-yl)-2,2,2- Trifluoroethyl Formate Produce

In a 250 ml flask, compound 6-((2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1 obtained in Preparation Example 10 -Yl)-4-(trifluoromethyl)quinoline-2(1H)-one 580mg (1.47mmol) was dissolved in 7ml of toluene, thionyl chloride 0.214ml (3.0eq) and N,N-dimethylformamide 0.228ml ( 2.0eq) was added and stirred at room temperature for 1 hour and then refluxed at 120°C for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, washed with saturated NaHCO ₃ and brine, the organic layer was separated, dehydrated with MgSO ₄ and concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 370 mg (57%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ8.10(s, 1H), 7.97(d, 1H), 7.30(s, 1H), 7.27(dd, 1H), 6.97(s, 1H), 5.90(q , 1H), 4.35(t, 1H), 4.00-3.97(m, 1H), 2.48-2.44(m, 1H), 2.20-2.06(m, 2H), 1.83-1.77(m, 1H), 1.28(d , 3H)

Mass[M+H]: 441.07

[ Manufacturing example 12] (R)-1-((2R,5R)-1-(2- Chloro -4-( Trifluoromethyl )Quinolin-6-yl)-5- Methylpyrrolidine -2-yl)-2,2,2- Of trifluoroethanol Produce

In a 50 ml flask, the compound (R)-1-((2R,5R)-1-(2-chloro-4-(trifluoromethyl)quinolin-6-yl)-5-methylpyrrolidine obtained in Preparation Example 11 -2-yl)-2,2,2-trifluoroethyl formate 370mg (0.839mmol) was dissolved in tetrahydrofuran:water=6ml:3ml (2:1), and cooled to 0?. LiOH 40mg (2.0eq) was added dropwise to the reaction solution, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to obtain 300mg (87%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.92(d, 1H), 7.54(s, 1H), 7.28(dd, 1H), 6.90(s, 1H), 4.47-4.46(m, 1H), 4.23 (t, 1H), 4.02-4.00 (m, 1H), 2.57-2.51 (m, 2H), 1.88-1.83 (m, 1H), 1.36 (d, 3H)

Mass[M+H]: 413.08

[ Manufacturing example 13] (R)-(5-oxo-1-(2-oxo-4-( Trifluoromethyl )-1,2- Dihydroquinoline -6-days) Pyrrolidine -2 days) Of methyl acetate Produce

Compound (R)-5-((tert-butyldimethylsilyloxy)methyl)-1-(2-isopropoxy-4-(trifluoromethyl)quinolin-6-yl)pyrrolidine obtained in Preparation Example 6 Proceeding in the same manner as in Preparation Example 10 using 2-one, 1.24 g (66%) of the title compound was obtained.

¹ H NMR (CDCl ₃ , 400MHz): δ7.76(s, 1H), 7.67(dd, 1H), 7.48(d, 1H), 7.09(s, 1H), 4.48-4.45(m, 1H), 4.16 -4.05(m, 2H), 2.71-2.60(m, 2H), 2.42-2.41(m, 1H), 2.08-2.39(m, 1H), 1.97(s, 3H)

Mass[M+H]: 369.10

[ Manufacturing example 14] (R)-(1-(2- Chloro -4-( Trifluoromethyl )Quinolin-6-yl)-5- Oxopyrrolidine -2 days) Of methyl acetate Produce

In a 50 ml flask, the compound obtained in Preparation Example 13 (R)-(5-oxo-1-(2-oxo-4-(trifluoromethyl)-1,2-dihydroquinolin-6-yl)pyrrolidine- 2-day) 200mg (0.543mmol) of methyl acetate was added, 2ml of POCl _{3 was} added, and the mixture was refluxed at 80? for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, washed with saturated NaHCO ₃ and brine, the organic layer was separated, dehydrated with MgSO ₄ and concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 160 mg (76%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ8.14-8.03(m, 3H), 7.67(s, 1H), 4.67-4.63(m, 1H), 4.22-4.09(m, 2H), 2.79-2.72( m, 1H), 2.65-2.58 (m, 1H), 2.47-2.41 (m, 1H), 2.13-2.06 (m, 1H), 1.94 (s, 3H)

Mass[M+H]: 387.06

[ Manufacturing example 15] (R)-1-(2- Chloro -4-( Trifluoromethyl )Quinolin-6-yl)-5-( Hydroxymethyl ) Pyrrolidine Preparation of -2-one

In a 50 ml flask, 81 mg of compound (R)-(1-(2-chloro-4-(trifluoromethyl)quinolin-6-yl)-5-oxopyrrolidin-2-yl)methylacetate obtained in Preparation Example 14 (0.210 mmol) was dissolved in 5 ml of methanol, and 5 ml of 2N NaOH was added, followed by stirring at room temperature for 1 hour. After adding ethyl acetate and water and stirring, the organic layer was separated, dehydrated with Na ₂ SO ₄ and concentrated under reduced pressure to obtain 72 mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.92-7.87(m, 3H), 7.22(s, 1H), 4.43-4.38(m, 1H), 3.80-3.75(m, 1H), 3.68-3.64( m, 1H), 2.80-2.72 (m, 1H), 2.62-2.54 (m, 1H), 2.41-2.31 (m, 1H), 2.26-2.06 (m, 1H),

Mass[M+H]: 345.05

[ Manufacturing example 16] (R)- methyl 1-(2- Isopropoxy -4-( Trifluoromethyl )Quinolin-6-yl)pyrrolidine-2- Carboxylate Produce

Preparation Example 6 using 10 g (29.9 mmol) of compound 6-bromo-2-isopropoxy-4-(trifluoromethyl)quinoline and 7.7 g (2 eq) of D-proline methyl ester hydrochloride obtained in Preparation Example 5 Proceeding in the same manner as, 7.8g (68%) of the title compound was obtained.

¹ H NMR (CDCl ₃ , 400MHz): δ7.72(d, 1H), 7.08-7.05(m, 2H), 6.85(s, 1H), 5.49-5.43(m, 1H), 4.36(dd, 1H) , 3.71(s, 3H), 3.70-3.65(m, 1H), 3.53-3.45(m, 1H), 2.39-2.29(m, 1H), 2.27-2.15(m, 2H), 2.13-2.06(m, 1H), 1.36 (d, 6H)

Mass[M+H]: 383.15

[ Manufacturing example 17] (R)-(1-(2- Isopropoxy -4-( Trifluoromethyl ) Quinoline-6-day) Pyrrolidine Preparation of -2-yl) methanol

In a 100 ml flask, the compound (R)-methyl 1-(2-isopropoxy-4-(trifluoromethyl)quinolin-6-yl)pyrrolidine-2-carboxylate 503 mg (1.32 mmol) obtained in Preparation Example 16 Was dissolved in ethanol: tetrahydrofuran = 15ml:10ml (3:2), and cooled to 0?. NaBH ₄ 60mg (1.2eq) and LiCl 196mg (3.5eq) were added to the reaction solution and stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 335 mg (72%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.72(d, 1H), 7.27-7.24(m, 1H), 7.09(s, 1H), 6.97(s, 1H), 5.48-5.45(m, 1H) , 3.99-3.91(m, 1H), 3.71(d, 2H), 3.69-3.56(m, 1H), 3.32-3.21(m, 1H), 2.10-2.03(m, 4H)

Mass[M+H]: 355.16

[ Manufacturing example 18] (R)-(1-(2-oxo-4-( Trifluoromethyl )-1,2- Dihydroquinoline -6-days) Pyrrolidine -2 days) Of methyl acetate Produce

Compound (R)-(1-(2-isopropoxy-4-(trifluoromethyl)quinolin-6-yl)pyrrolidin-2-yl)methanol 335mg (0.946mmol) obtained in Preparation Example 17 was used Then, it proceeded in the same manner as in Preparation Example 10 to obtain 251mg (75%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.38(d, 1H), 7.16(dd, 1H), 7.06(s, 1H), 6.92(s, 1H), 4.36(dd, 1H), 4.08-3.97 (m, 1H), 3.83(dd, 1H), 3.59-3.46(m, 1H), 3.18(q, 1H), 2.05(s, 3H), 2.12-1.97(m, 4H)

Mass[M+H]: 355.12

[ Manufacturing example 19] (R)-(1-(2- Chloro -4-( Trifluoromethyl ) Quinoline-6-day) Pyrrolidine -2 days) Of methyl acetate Produce

Compound (R)-(1-(2-oxo-4-(trifluoromethyl)-1,2-dihydroquinolin-6-yl)pyrrolidin-2-yl)methylacetate obtained in Preparation Example 18 237mg (0.67mmol) was used in the same manner as in Preparation Example 14 to obtain 253mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.92(d, 1H), 7.53(s, 1H), 7.44(dd, 1H), 6.94(s, 1H), 4.31(dd, 1H), 4.29-4.13 (m, 1H), 3.86(dd, 1H), 3.61-3.56(m, 1H), 3.33-3.27(q, 1H), 2.16-2.03(m, 4H), 2.07(s, 3H)

Mass[M+H]: 373.09

[ Manufacturing example 20] (R)-(1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine -2 days) Of methyl acetate Produce

Compound (R)-(1-(2-chloro-4-(trifluoromethyl)quinolin-6-yl)pyrrolidin-2-yl)methylacetate 250mg (0.67mmol) obtained in Preparation Example 19 was added to N, After dissolving in 5ml of N-dimethylformamide, 218mg (3.35mmol, 5.0eq) of NaN ₃ was added and refluxed at 120°C for 2 days. Water and ethyl acetate were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 264 mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ8.59(d, 1H), 8.20(s, 1H), 7.41(dd, 1H), 7.17(s, 1H), 4.32(dd, 1H), 4.21-4.16 (m, 1H), 3.88(dd, 1H), 3.65-3.56(m, 1H), 3.30(q, 1H), 2.22-2.08(m, 4H), 2.06(s, 3H)

Mass[M+H]: 380.13

[ Manufacturing example 21] ((2R,5R)-1-(2- Isopropoxy -4-( Trifluoromethyl )Quinolin-6-yl)-5- Methylpyrrolidine Preparation of -2-yl) methanol

In a 250 ml flask, the compound (R)-5-((tert-butyldimethylsilyloxy)methyl)-1-(2-isopropoxy-4-(trifluoromethyl)quinolin-6-yl) obtained in Preparation Example 6 5.79g (12mmol) of pyrrolidine-2-one was added, and 52ml of tetrahydrofuran was added and stirred. The reaction solution was purged with nitrogen and cooled to -78°C. 1.6M methyl lithium / diethyl ether 26.2 mL (42.0 mmol, 3.0 eq.) was gradually added dropwise to the reaction solution. After stirring at -78°C for 4 hours, 1.6M methyl lithium / diethyl ether 8.8 mL (14.0 mmol, 1.0 eq.) was slowly added dropwise. After stirring at -78°C for 2 hours, methanol was slowly added dropwise. After 30 mL of methanol: ethyl acetate = 1:1 solution was added and stirred, the reaction solution was passed through celite and filtered. The filtrate was concentrated under reduced pressure, and 100 mL of a trifluoroacetic acid:methanol = 1:9 solution was added to the concentrated residue, and while stirring, 1.35 g (20% w/w) of 10% Pd/C was added. The mixture was stirred for 1 day under normal pressure hydrogen gas. The reaction solution was filtered through Celite copper. The filtrate was concentrated under reduced pressure, and the concentrated residue was dissolved in 35 ml of tetrahydrofuran, and 1.0 M in tetrahydrofuran of tetrabutylammonium fluoride was added dropwise, followed by stirring at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to obtain 2.74 g (62%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.72(d, 1H), 7.30(dd, 1H), 7.09(s, 1H), 7.03(s, 1H), 5.49-5.44(m, 1H), 3.98 -3.93(m, 1H), 3.91-3.80(m, 1H), 3.79-3.70(m, 1H), 3.69-3.62(m, 1H), 2.18-2.03(m, 1H), 2.02-1.97(m, 2H), 1.79-1.66 (m, 1H), 1.63-1.60 (m, 1H), 1.37 (d, 6H)

Mass[M+H]: 369.17

[ Manufacturing example 22] ((2R,5R)-5- methyl -1-(2-oxo-4-( Trifluoromethyl )-1,2- Dihydroquinoline -6-days) Pyrrolidine -2 days) Of methyl acetate Produce

The compound obtained in Preparation Example 21 ((2R,5R)-1-(2-isopropoxy-4-(trifluoromethyl)quinolin-6-yl)-5-methylpyrrolidin-2-yl)methanol 1.41 In the same manner as in Preparation Example 10 using g (3.83 mmol), 800 mg (57%) of the title compound was obtained.

¹ H NMR (CDCl ₃ , 400MHz): δ7.32(d, 1H), 7.17(dd, 1H), 7.04(s, 1H), 6.98(s, 1H), 4.32(dd, 1H), 3.97-3.88 (m, 2H), 3.81-3.76 (m, 1H), 2.22-2.11 (m, 1H), 2.07 (s, 3H), 2.03-1.89 (m, 2H), 1.81-1.74 (m, 1H), 1.29 (d, 3H)

Mass[M+H]: 369.13

[ Manufacturing example 23] ((2R,5R)-1-(2- Bromo -4-( Trifluoromethyl )Quinolin-6-yl)-5- Methylpyrrolidine -2 days) Of methyl acetate Produce

In a 100 ml flask, the compound obtained in Preparation Example 22 ((2R,5R)-5-methyl-1-(2-oxo-4-(trifluoromethyl)-1,2-dihydroquinolin-6-yl)pyrroly Din-2-yl) methyl acetate 800mg (0.543mmol) was added, dissolved in 10ml of acetonitrile, and 622.6mg (1.0eq) of POBr ₃ was added, followed by refluxing at 80? for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, washed with saturated NaHCO ₃ and brine, the organic layer was separated, dehydrated with MgSO ₄ and concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 902 mg (96%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ7.94(d, 1H), 7.65(s, 1H), 7.43(dd, 1H), 6.98(s, 1H), 4.36(dd, 1H(, 4.14-4.09 (m, 1H), 3.97-3.91 (m, 2H), 2.26-2.23 (m, 1H), 2.07 (s, 3H), 2.04-1.97 (m, 2H), 1.85-1.80 (m, 1H), 1.34 (d, 3H)

Mass[M+H]: 431.05

[ Manufacturing example 24] ((2R,5R)-5- methyl -1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine -2 days) Of methyl acetate Produce

In a 100 ml flask, the compound obtained in Preparation Example 23 ((2R,5R)-1-(2-bromo-4-(trifluoromethyl)quinolin-6-yl)-5-methylpyrrolidin-2-yl) Proceeding in the same manner as in Preparation Example 20 using 901mg (2.09mmol) of methyl acetate to obtain 720mg (88%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ8.59(d, 1H), 8.20(s, 1H), 7.43(d, 2H), 4.39-4.36(m, 1H), 4.11(br, 1H), 3.99 -3.93(m, 2H), 2.38-2.26(m, 1H), 2.09(s, 3H), 2.06-1.93(m, 2H), 1.90-1.84(m, 1H), 1.36(d, 3H)

Mass[M+H]: 394.14

[ Manufacturing example 25] 6-((1,1,1- Trifluorobutane -2-yl)amino)-4-( Trifluoromethyl ) Preparation of quinoline-2 (1H)-one

6-amino-4-(trifluoromethyl)quinoline-2(1H)-one 1g (4.38mmol) was added to a 100ml flask, dissolved in trifluoroacetic acid, and cooled to 0?. 1.2ml (2.0eq) of 1,1,1-trifluoro-2-butanone was added to the reaction solution, followed by stirring at room temperature for 1 hour. After cooling the reaction solution to 0?, NaBH ₄ was slowly added thereto, followed by stirring at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate and 2N NaOH aqueous solution were added and stirred. The reaction solution was separated by layer to remove the aqueous layer, and the organic layer was separated, dehydrated and dried with Na ₂ SO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 420 mg (28%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz): δ7.26-7.15(m, 2H), 6.97(s, 1H), 6.88(s, 1H), 6.19(d, 1H), 4.02(m, 1H) , 1.83-1.75(m, 1H), 1.62-1.54(m,1H), 0.95(t, 3H)

Mass[M+H]: 339.09

[ Manufacturing example 26] 6-((1,1,1- Trifluorobutane -2-yl)(2,2,2- Trifluoroethyl )Amino)-4-( Trifluoromethyl ) Preparation of quinoline-2 (1H)-one

In a 100 ml flask, compound 6-((1,1,1-trifluorobutan-2-yl)amino)-4-(trifluoromethyl)quinolin-2(1H)-one 420 mg (1.24) obtained in Preparation Example 25 mmol), dissolved in 10 ml of trifluoroacetic acid, refluxed at 100° C., and NaBH ₄ caplet was added every 2 hours. After 16 hours, the reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, and stirred with a saturated NaHCO ₃ aqueous solution. The reaction solution was separated by layer to remove the aqueous layer, and the organic layer was separated, dehydrated and dried with Na ₂ SO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 253 mg (49%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz): δ7.67(d, 1H), 7.38(d, 1H), 7.32(s, 1H), 6.97(s, 1H), 4.42-4.30(m, 1H) , 4.21-4.04(m, 1H), 1.83-1.77(m, 1H), 1.73-1.69(m, 1H), 0.97(t, 3H)

Mass[M+H]: 421.09

[ Manufacturing example 27] 2- Chloro -N-(1,1,1- Trifluorobutane -2-yl)-N-(2,2,2- Trifluoroethyl )-4-( Trifluoromethyl ) Quinoline-6- Amine Produce

In a 100 ml flask, compound 6-((1,1,1-trifluorobutan-2-yl)(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl obtained in Preparation Example 26 )Quinoline-2(1H)-one 212mg (0.504mmol) was carried out in the same manner as in Preparation Example 14 to obtain 210mg (95%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz): δ8.04(s, 2H), 7.97(s, 1H), 7.47(s, 1H), 4.64-4.51(m, 2H), 4.46-4.34(m, 1H), 2.50-1.97(m, 1H), 1.87-1.81(m, 1H), 0.91(t, 3H)

Mass[M+H]: 439.05

[ Manufacturing example 28] 6- Bromo -2- Chloro -4-( Trifluoromethyl ) Preparation of quinoline

Using the compound 6-bromo-4-(trifluoromethyl)quinolin-2(1H)-one 2g (6.85mmol) obtained in Preparation Example 4 in a 100ml flask, proceed in the same manner as in Preparation Example 14, and the title compound 2g (94%) was obtained.

¹ H NMR (Acetone-d ₆ , 400MHz): δ8.28-8.25(m, 1H), 8.13-8.05(m, 2H), 8.00(s, 1H)

Mass[M+H]: 309.92

[ Manufacturing example 29] 7- Bromo -5-( Trifluoromethyl ) Tetrazolo Preparation of [1,5-a]quinoline

In a 100 ml flask, using 2 g (6.44 mmol) of compound 6-bromo-2-chloro-4- (trifluoromethyl) quinoline obtained in Preparation Example 28, dissolved in N,N-dimethylformamide: water = 10 ml: 3 ml. NaN ₃ 2.09g (5.0eq) was added and refluxed at 100? for 16 hours. Water and ethyl acetate were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to obtain 1.2 g (55%) of the title compound.

¹ H NMR (Acetone-d ₆ , 400MHz): δ8.79(d, 1H), 8.68(s, 1H), 8.37(t, 1H), 8.30(dd, 1H)

Mass[M+H]: 316.96

[ Manufacturing example 30] 6-( Dipropylamino )-4-( Trifluoromethyl ) Preparation of quinoline-2 (1H)-one

1 g (4.38 mmol) of 6-amino-4-(trifluoromethyl)quinoline-2(1H)-one was added to a 100 ml flask, and then dissolved in dichloromethane. Propionaldehyde 635mg (2.5eq) was added to this solution, stirred at room temperature for 30 minutes, NaBH ₄ was slowly added, and stirred at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate and 2N NaOH aqueous solution were added and stirred. The reaction solution was separated by layer to remove the aqueous layer, and the organic layer was separated, dehydrated and dried with Na ₂ SO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 1.02 g (75%) of the title compound.

Mass[M+H]: 313.14

[ Manufacturing example 31] 2- Chloro -N,N- Dipropyl -4-( Trifluoromethyl ) Quinoline-6- Amine Produce

Using 500 mg (1.6 mmol) of compound 6-(dipropylamino)-4-(trifluoromethyl)quinolin-2(1H)-one obtained in Preparation Example 30 in a 100 ml flask, proceed in the same manner as in Preparation Example 14. 486mg (92%) of the title compound was obtained.

¹ H NMR (CDCl ₃ , 400MHz): δ7.86(d, 1H), 7.50(s, 1H), 7.31-7.24(dd, 1H), 6.88(s, 1H), 3.36(t, 4H), 1.69 -1.61(m, 4H), 0.94(t, 6H)

Mass[M+H]: 331.11

[ Example 1] (R)-2,2,2- Trifluoro -1-((2R,5R)-5- methyl -1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine Preparation of -2-yl)ethanol

In a 25 ml flask, the compound (R)-1-((2R,5R)-1-(2-chloro-4-(trifluoromethyl)quinolin-6-yl)-5-methylpyrrolidine obtained in Preparation Example 12 -2-yl)-2,2,2-trifluoroethanol 300mg (0.727mmol) was used to give the title compound 198mg (65%) in the same manner as in Preparation Example 20.

¹ H NMR (CDCl ₃ , 400MHz): δ8.37(d, 1H), 8.04(s, 1H), 7.13(dd, 1H), 6.88(s, 1H), 4.51-4.47(m, 1H), 4.18 (t, 1H), 3.95-3.92 (m, 1H), 3.71 (d, 1H), 2.70-2.68 (m, 1H), 2.11-2.03 (m, 2H), 1.89-1.84 (m, 1H), 1.45 (d, 3H)

Mass[M+H]: 420.12

[ Example 2] (R)-5-( Hydroxymethyl )-1-(5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7 days) Pyrrolidine Preparation of -2-one

In a 25 ml flask, 100 mg of compound (R)-1-(2-chloro-4-(trifluoromethyl)quinolin-6-yl)-5-(hydroxymethyl)pyrrolidin-2-one obtained in Preparation Example 15 (0.29mmol) was dissolved in N,N-dimethylformamide:water=10ml:3ml, and 94.3mg (5.0eq) of NaN ₃ was added, followed by refluxing at 100°C for 16 hours. Water and ethyl acetate were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 198 mg (65%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ8.80(d, 1H), 8.32~8.26(m, 3H), 4.55~4.52(m, 1H), 3.83~3.75(m, 2H), 2.85~2.79(m) , 1H), 2.65~2.58(m, 1H), 2.41~2.39(m, 1H), 2.27~2.21(m, 1H)

Mass[M+H]: 352.09

[ Example 3] (R)-(1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine Preparation of -2-yl) methanol

Compound (R)-(1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)methylacetate obtained in Preparation Example 20 264 mg (0.696) mmol) in the same manner as in Preparation Example 15 to obtain 170mg (72%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ 8.56 (d, 1H), 8.19 (s, 1H), 7.34 (dd, 1H), 7.16 (s, 1H), 4.05 (s, 1H), 3.75 (s, 2H), 3.62(t, 1H), 3.31(q, 1H), 2.20~2.10(m, 4H)

Mass[M+H]: 338.12

[ Example 4] (R)-2,2,2- Trifluoro -1-((R)-1-(5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7 days) Pyrrolidine Preparation of -2-yl)ethanol

[Step 1] (R)-1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine -2- Carbaldehyde Produce

In a 25 ml flask, 152 mg of the compound (R)-(1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)methanol obtained in Example 3 (0.45mmol) was added, dissolved in 3ml of pyridine, cooled to 0°C, 287mg (1.5eq) of Dess-Martin periodinane was added, followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate and saturated Na ₂ S ₂ O ₃ aqueous solution were added, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over Na ₂ SO ₄ and concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 150 mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ9.61(d, 1H), 8.60(d, 1H), 8.22(s, 1H), 7.17(dd, 1H), 7.11(s, 1H), 4.33-4.30 (m, 1H), 3.80-3.74 (m, 1H), 3.53 (q, 1H), 2.37-2.28 (m, 2H), 2.24-2.07 (m, 2H)

Mass[M+H]: 336.10

[Step 2] (R)-2,2,2- Trifluoro -1-((R)-1-(5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7 days) Pyrrolidine Preparation of -2-yl)ethanol

Compound (R)-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidine-2-carbaldehyde 100 mg (0.298) obtained in step 1 of Example 4 mmol), followed by separating the (R)-isomer using column chromatography to obtain 20mg (17%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ8.17(d, 1H), 7.92(s, 1H), 6.97(dd, 1H), 6.61(s, 1H), 4.58(s, 1H), 4.49(s, 1H), 4.13~3.08(m, 1H), 3.62~3.58(m, 1H), 3.27~3.22(m, 1H), 2.56~2.42(m, 2H), 2.13~2.02(m, 2H)

Mass[M+H]: 406.10

[ Example 5] (S)-2,2,2- Trifluoro -1-((R)-1-(5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7 days) Pyrrolidine Preparation of -2-yl)ethanol

Compound (R)-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidine-2-carbaldehyde 100 mg (0.298) obtained in step 1 of Example 4 mmol) was used in the same manner as in Preparation Example 9, and then (S)-isomer was separated using column chromatography to obtain 32mg (26%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ8.30(d, 1H), 8.02(s, 1H), 7.32(dd, 1H), 7.07(s, 1H), 4.23~4.20(m, 1H), 4.0~ 3.96(m, 1H), 3.69~3.61(m, 1H), 3.22~3.18(m, 1H), 2.21~2.02(m, 4H)

Mass[M+H]: 406.10

[ Example 6] ((2R,5R)-5- methyl -1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine Preparation of -2-yl) methanol

Compound obtained in Preparation Example 24 ((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl ) Proceed in the same manner as in Preparation Example 15 using 720 mg (1.83 mmol) of methyl acetate to obtain 642 mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ8.55(d, 1H), 8.19(s, 1H), 7.39(d, 2H), 4.07-3.98(m, 1H), 3.96-3.88(m, 1H) , 3.84-3.75(m, 2H), 2.23-2.16(m, 1H), 2.14-2.02(m, 2H), 1.84-1.76(m, 1H), 1.75-1.67(m, 1H), 1.38(d, 3H)

Mass[M+H]: 352.13

[ Example 7] 1-((2R,5R)-5- methyl -1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine Preparation of -2-yl)ethanol

[Step 1] (2R,5R)-5- methyl -1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine -2- Carbaldehyde Produce

In a 50 ml flask, the compound obtained in Example 6 ((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidine- 2-day) Using 100mg (0.285mmol) of methanol, the procedure was carried out in the same manner as in Step 1 of Example 4 to obtain 100mg (99%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ9.50(d, 1H), 8.59(d, 1H), 8.22(s, 1H), 7.198(dd, 1H), 7.14(s, 1H), 4.28-4.18 (m, 1H), 4.17-4.13 (m, 1H), 2.34-2.21 (m, 3H), 1.89-1.83 (m, 1H), 1.41 (d, 3H)

Mass[M+H]: 350.12

[Step 2] 1-((2R,5R)-5- methyl -1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine Preparation of -2-yl)ethanol

In a 25 ml flask, the compound (2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrroly obtained in step 1 of Example 7 Din-2-carbaldehyde 100mg (0.286mmol) was added, dissolved in tetrahydrofuran, charged with nitrogen, and cooled to -78°C. 1.4 M methylmagnesium bromide 0.225ml (1.1eq) was added dropwise to the reaction solution, and the temperature was gradually raised to room temperature, followed by stirring for 4 hours. Water and ethyl acetate were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 35mg (35%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ8.46(dd, 2H), 8.14(d, 2H), 7.55(dd, 1H), 7.35(s, 1H), 7.21(dd, 1H), 7.04(s , 1H), 4.31~4.30(m, 1H), 3.94~3.73(m, 6H), 2.36~2.27(m, 3H), 2.11~1.91(m, 3H), 1.90~1.76(m, 3H), 1.42 (t, 6H), 1.36 (d, 3H), 1.29 (d, 3H)

Mass[M+H]: 366.15

[ Example 8] 1-((2R,5R)-5- methyl -1-(5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinolin-7-yl) Pyrrolidine Preparation of -2-yl)propan-1-ol

In a 25 ml flask, the compound (2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrroly obtained in step 1 of Example 7 Using din-2-carbaldehyde 80mg (0.23mmol) and ethylmagnesium bromide 3.0M in diethyl ether 0.153ml (2.0eq), proceed in the same manner as in Step 2 of Example 7 to obtain 30mg (34%) of the title compound. Obtained.

¹ H NMR (CDCl ₃ , 400MHz): δ8.49(dd, 2H), 8.32(s, 1H), 7.59(dd, 1H), 7.39(dd, 1H), 7.31(s, 1H), 7.07(s , 1H), 3.96-3.86 (m, 5H), 3.68-3.64 (m, 1H), 2.24-2.20 (m, 2H), 2.19-2.12 (m, 1H), 2.01-1.91 (m, 3H), 1.87 -1.79 (m, 2H), 1.71-1.58 (m, 4H), 1.40 (dd, 6H), 1.11-1.04 (m, 6H)

Mass[M+H]: 380.16

[ Example 9] 2- methyl -1-((2R,5R)-5- methyl -1-(5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7 days) Pyrrolidine Preparation of -2-yl)propan-1-ol

In a 25 ml flask, the compound (2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrroly obtained in step 1 of Example 7 Using din-2-carbaldehyde 80mg (0.23mmol) and isopropylmagnesium bromide 2.0M in tetrahydrofuran 0.35ml (3.0eq) in the same manner as in Example 7 step 2, the title compound 12mg (13%) Was obtained.

¹ H NMR (CDCl ₃ , 400MHz): δ8.50(d, 1H), 8.15(s, 1H), 7.10(s, 2H), 4.08(s, 1H), 3.96(s, 1H), 3.71(d , 1H), 2.37~2.33(m, 1H), 2.03~1.97(m, 2H), 1.79~1.77(m. 2H), 1.42(d, 3H), 1.09(s, 6H)

Mass[M+H]: 394.18

[ Example 10] N-(2,2,2- Trifluoroethyl )-5-( Trifluoromethyl )-N-(1,1,1- Trifluoropropane -2 days) Tetrazolo [1,5-a]quinoline-7- Amine Produce

In a 50 ml flask, the compound 2-chloro-N-(1,1,1-trifluorobutan-2-yl)-N-(2,2,2-trifluoroethyl)-4-( Trifluoromethyl) quinolin-6-amine 210 mg (0.479 mmol) was used in the same manner as in Example 1 to obtain 170 mg (80%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz): δ8.71(s, 1H), 8.68(d, 1H), 8.11(dd, 1H), 7.65(s, 1H), 4.67~4.61(m, 1H) , 4.57~4.52(m, 1H), 4.43~4.37(m, 1H), 2.05~2.00(m, 1H), 1.87~1.82(m, 1H), 0.94(t, 3H)

Mass[M+H]: 432.08

[ Example 11] N,N- Vis (2,2,2- Trifluoroethyl )-5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7- Amine Produce

Using the compound 2-chloro-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 2.32 g (5.64 mmol) obtained in Preparation Example 2 Proceeding in the same manner as in Example 1, 2.05g (87%) of the title compound was obtained.

¹ H NMR (DMSO-d ₄ , 400MHz): δ8.74(s, 1H), 8.65(d, 1H), 7.95(d, 1H), 7.48(s, 1H), 4.62(q, 4H)

Mass[M+H]: 418.06

[ Example 12] N,N- Vis (2,2,2- Trifluoroethyl )-5-( Trifluoromethyl )-[1,2,4]triazolo[4,3-a]quinoline-7- Amine Produce

In a 25 ml flask, 70 mg (0.17 mmol) of the compound 2-chloro-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in Preparation Example 2 was added. After dissolving in 2ml of benzyl alcohol, 123mg (12eq) of formic hydrazide was added, the mixture was refluxed at 140°C for 16 hours. The reaction solution was cooled to room temperature, water and ethyl acetate were added, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 35 mg (49%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz): δ9.23(s, 1H), 8.14(s, 1H), 7.98(d, 1H), 7.53(s, 1H), 7.37(dd, 1H), 4.16(q , 4H)

Mass[M+H]: 417.07

[ Example 13] 7-( Bis(2,2,2-trifluoroethyl)amino )-5-( Trifluoromethyl )-[1,2,4] Triazolo Preparation of [4,3-a]quinolin-1(2H)-one

To a 25 ml flask was added 100 mg (0.244 mmol) of the compound 2-chloro-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in Preparation Example 2 Then, it was dissolved in 3ml of 2-ethoxyethanol, and 55mg (2.0eq) of semicarbazide was added, followed by refluxing at 130°C for 16 hours. The reaction solution was cooled to room temperature, water and ethyl acetate were added, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 15 mg (14%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz): δ8.90(d, 1H), 7.77(s, 1H), 7.57(dd, 1H), 7.21(s, 1H), 4.45(q, 4H)

Mass[M+H]: 433.06

[ Example 14] N,N- Diethyl -5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinoline-7- Amine Produce

Compound 7-bromo-5-(trifluoromethyl) tetrazolo[1,5-a]quinoline 20 mg (63 μmol) obtained in Preparation Example 29 was added to a 25 ml flask, dissolved in 2 ml of toluene, and diethylamine 8 μl (1.2 eq) , Pd ₂ (dba) ₃ 0.6mg (0.01eq), sodium t-butoxide 12mg (2.0eq), 2-dicyclohexylphosphino-2'6'-dimethoxybiphenyl 1mg (0.04eq) and nitrogen Charged. The reaction solution was refluxed at 110°C for 16 hours. The reaction solution was cooled to room temperature, water and ethyl acetate were added, stirred, and the layers were separated. The aqueous layer was removed, the organic layer was separated, dehydrated and dried over MgSO _4, and then concentrated under reduced pressure. The concentrated residue was separated by column chromatography and concentrated under reduced pressure to give 3.7 mg (19%) of the title compound.

¹ H NMR (Acetone-d ₆ , 400MHz): δ8.56(d, 1H), 8.42(s, 1H), 7.57(dd, 1H), 7.18(s, 1H), 3.60(q, 4H), 1.26 (t, 6H)

Mass[M+H]: 310.12

[ Example 15] N-N- Dipropyl -5-( Trifluoromethyl ) Tetrazolo Preparation of [1,5-a]quinoline-7-amine

Using 486 mg (1.44 mmol) of the compound 22-chloro-N,N-dipropyl-4-(trifluoromethyl)quinolin-6-amine obtained in Preparation Example 31 in a 50 ml flask, proceed in the same manner as in Example 1. 398mg (82%) of the title compound was obtained.

¹ H NMR (CDCl ₃ , 400MHz) δ 8.53 (d, 1H), 8.18 (s, 1H), 7.26 (d, 1H), 7.16 (s, 1H), 3.38 (t, 4H), 1.70-1.65 ( m, 4H), 0.98 (t, 6H)

Mass[M+H]: 432.08

[ Example 16] N-ethyl-N-(2,2,2- Trifluoroethyl )-5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7- Amine Produce

[Step 1] 6- Ethylamino -4- Trifluoromethylquinoline Preparation of -2(1H)-one

Using 1 g (4.38 mmol) of 6-amino-4- (trifluoromethyl) quinoline-2 (1H)-one and 193 mg (4.38 mmol) of acetaldehyde, the title compound 730 mg (2.85 mmol, 65%) was obtained.

Mass[M+H]: 257.08

[Step 2] 6-( Ethyl (2,2,2-trifluoroethyl) amino )-4-( Trifluoromethyl ) Preparation of quinoline-2 (1H)-one

Using 730 mg (2.85 mmol) of 6-ethylamino-4-trifluoromethylquinoline-2 (1H)-one obtained in step 1 of Example 16, the title compound 915 mg (2.57 mmol, 95) in the same manner as in Preparation Example 26. %) was obtained.

Mass[M+H]: 339.09

[Step 3] 2- Chloro -N-ethyl-N-(2,2,2- Trifluoroethyl )-4-( Trifluoromethyl ) Quinoline-6- Amine Produce

Using 915 mg (2.57 mmol) of 6-(ethyl(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2(1H)-one obtained in step 2 of Example 16 Thus, 695 mg (1.95 mmol, 76%) of the title compound was obtained in the same manner as in Preparation Example 14,

Mass[M+H]: 357.05

[Step 4] N-ethyl-N-(2,2,2- Trifluoroethyl )-5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7- Amine Produce

2-Chloro-N-ethyl-N-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 280 mg (0.79 mmol) obtained in step 3 of Example 16 Using the same method as in Example 1 to obtain the title compound 240mg (0.66mmol, 84%).

¹ H NMR (Acetone-d ₆ , 400MHz): δ8.63(d, 1H), 8.49(s, 1H), 7.79-7.76(dd, 1H), 7.41(s, 1H), 4.44-4.37(q, 2H), 3.80-3.75 (q, 2H), 1.31 (t, 3H)

Mass[M+H]: 364.09

[ Example 17] 7-(2,5- Dimethylpyrrolidine -1-yl)-5-( Trifluoromethyl ) Tetrazolo [ Of 1,5-a] quinoline Produce

[Step 1] 6-(2,5- Dimethylpyrrolidine -1-yl)-4-( Trifluoromethyl ) Preparation of quinolin-2-(1H)-one

Using 6-amino-4-(trifluoromethyl)quinoline-2(1H)-one 1 g (4.38 mmol) and 2,5-hexanedione 500 mg (4.38 mmol), the title compound 1.12 was carried out in the same manner as in Preparation Example 30. g (3.63 mmol, 83%) was obtained.

Mass[M+H]: 311.13

[Step 2] 2- Chloro -6-(2,5- Dimethylpyrrolidine -1-yl)-4-( Trifluoromethyl ) Preparation of quinoline

Using 1.12 g (3.63 mmol) of 6-(2,5-dimethylpyrrolidin-1-yl)-4-(trifluoromethyl)quinolin-2-(1H)-one obtained in step 1 of Example 17 Thus, the title compound (2.54 mmol, 70%) was obtained in the same manner as in Preparation Example 14.

Mass[M+H]: 329.76

[Step 3] 7-(2,5- Dimethylpyrrolidine -1-yl)-5-( Trifluoromethyl ) Tetrazolo [ Of 1,5-a] quinoline Produce

Using 400 mg (1.22 mmol) of 2-chloro-6-(2,5-dimethylpyrrolidin-1-yl)-4-(trifluoromethyl)quinoline obtained in step 2 of Example 17, 330mg (81%) of the title compound was obtained by the same method.

¹ H NMR (CDCl ₃ , 400MHz): δ8.54(d, 1H), 8.18(s, 1H), 7.23-7.20(m, 1H), 7.08(s, 0.34H), 7.04(s, 0.66H) , 4.19-4.09 (m, 1.32H), 3.98-3.90 (m, 0.68H), 2.38-2.25 (m, 1.32H), 2.22-2.12 (m, 0.68H), 1.89-1.79 (m, 0.68H) , 1.79-1.68(m, 1.32H), 1.50(d, 0.68H), 1.17(d, 1.32H)

Mass[M+H]: 336.14

[ Example 18] N-isopropyl-N-(2,2,2- Trifluoroethyl )-5-( Trifluoromethyl ) Tetrazolo [1,5-a]quinoline-7- Amine Produce

[Step 1] 6-( Isopropylamino )-4-( Trifluoromethyl ) Preparation of quinoline-2(H)-one

Using 1 g (4.38 mmol) of 6-amino-4- (trifluoromethyl) quinoline-2 (1H)-one and 254 mg (4.38 mmol) of acetone, the title compound 923 mg (3.42 mmol, 78) in the same manner as in Preparation Example 30. %) was obtained.

Mass[M+H]: 271.25

[Step 2] 6-( Isopropyl (2,2,2-trifluoroethyl) amino )-4-( Trifluoromethyl ) Preparation of quinoline-2(H)-one

Using 923 mg (3.42 mmol) of compound 6-(isopropylamino)-4-(trifluoromethyl)quinolin-2(H)-one obtained in step 1 of Example 18, the title compound 1.12g (3.18mmol, 93%) was obtained.

Mass[M+H]: 353.27

[Step 3] 2- Chloro -N-isopropyl-N-(2,2,2- Trifluoroethyl )-4-( Trifluoromethyl ) Quinoline-6- Amine Produce

Compound 6-(isopropyl(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2(H)-one obtained in step 2 of Example 18 1.12 g (3.18 mmol) ) To obtain 883mg (2.38mmol, 75%) of the title compound in the same manner as in Preparation Example 14.

Mass[M+H]: 371.72

[Step 4] N-isopropyl-N-(2,2,2- Trifluoroethyl )-5-( Trifluoromethyl ) Tetrazolo [ 1,5-a]quinoline -7- Amine Produce

Compound 2-chloro-N-isopropyl-N-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 300 mg (0.81 mmol) obtained in step 3 of Example 18 ) To obtain 240mg (0.64mmol, 79%) of the title compound in the same manner as in Example 1.

¹ H NMR (Acetone-d ₆ , 400MHz): δ8.64(d, 1H), 8.49(s, 1H), 7.90-7.87(dd, 1H), 7.57(s, 1H), 4.42-4.27(m, 3H), 1.36 (d, 6H)

Mass[M+H]: 378.11

[ Experimental example 1] androgen receptor binding test

In order to examine the androgen receptor binding ability of the prepared compound (SARM derivative), the following in vitro experiment was performed. COS-7 cell line (ATCC, #CRL-1651), an African green monkey kidney fibroblast-like cell line, was inoculated into a 48-well plate at 2.5×10 ⁴ cells/well, and at 37°C. After incubation for 24 hours, plasmid hAR containing human androgen receptor gene (ORIGENE, #RC215316) 5ng mixed OPTI-MEM medium (Gibco, #31985 ) was added to prepare a transformed cell line into which the human androgen receptor gene was introduced. The obtained transformed cell line was treated with [3H]MIB (Mibolerone) at a concentration of 1 nM and SARM derivatives (Examples 1 to 18) 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 ) shown in Table 1.

compound IC ₅₀ [nM]
(mean±SE) compound IC ₅₀ [nM]
(mean±SE) Example 1 2.1±0.4 Example 10 12.9±1.0 Example 2 448.1±71.0 Example 11 2.8±0.4 Example 3 9.4±1.8 Example 12 37.5 Example 4 3.0 Example 13 790.8 Example 5 17.8±2.3 Example 14 5.6±2.0 Example 6 11.0±0.4 Example 15 10.1±3.9 Example 7 6.2±0.4 Example 16 5.7±2.0 Example 8 7.2±2.6 Example 17 9.7±2.4 Example 9 60.9 Example 18 5.0±1.6

As shown in Table 1, it was confirmed that the novel SARM derivatives of Examples 1 to 18 bind to the androgen receptor. These results mean that the SARM derivatives of Examples 1 to 18 may bind to the androgen receptor and affect the action of the androgen receptor.

[ Experimental example 2] Transfer activity test

In order to determine the transcriptional activity of the prepared compound (SARM derivative), the following in vitro experiment was performed.

CHO (Chinese hamster ovary) cell line (ATCC, #CCL-61) was inoculated into a 96 well plate at 1.5x10 ⁴ cells/well, incubated at 37°C for 24 hours, and then 5ng of plasmid hAR (ORIGENE, #RC215316) and plasmid ARE-Luc (QIAGEN, #CCS-1019L) 100 ng of OPTI-MEM medium (Gibco, #31985) was added to prepare a transformed cell line into which a human androgen receptor gene and a luciferase gene were introduced. The transformed cell line was treated with SARM derivatives (Examples 1 to 18) 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) 10 nM 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 1 1.2±0.2 Example 9 28.3 Example 2 0.6±0.7 Example 10 34.1±2.6 Example 3 13.6±3.5 Example 11 1.2±0.4 Example 4 1.1±0.4 Example 14 12.3±7.2 Example 5 16.6±1.2 Example 15 6.0±1.1 Example 6 7.2 Example 16 10.4±0.6 Example 7 3.8 Example 17 14.3±5.0 Example 8 5.1±0.2 Example 18 5.0±0.6

As shown in Table 2, it was confirmed that the compounds according to the examples of the present invention act on androgen receptors to increase androgen activity.

Claims (10)

A compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R1 is an unsubstituted or substituted amino group, or an unsubstituted or substituted pyrrolidinyl group,
R2 is an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 3 carbon atoms,
X is N, CH or C(O),
In the definition of R1,
The substituted amino group is an amino group wherein at least one of the hydrogens included in the amino group is independently substituted with an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and the substituted alkyl group is included in the alkyl group. At least one of hydrogen is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms each independently substituted with halogen,
The substituted pyrrolidinyl group is a pyrrolidinyl group in which at least one of the hydrogens contained in the pyrrolidinyl group is independently an oxo group or an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 6 carbon atoms , The substituted alkyl group is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms in which at least one of the hydrogens contained in the alkyl group is each independently substituted with a hydroxy group, an oxo group, or a halogen,
In the definition of R2,
The substituted alkyl group is a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms in which at least one of the hydrogens contained in the alkyl group is independently substituted with halogen.
The method of claim 1,
R1 is an amino group in which at least one hydrogen is independently substituted with an unsubstituted or substituted linear or branched alkyl group having 2 or 3 carbon atoms, wherein the substituted alkyl group has 2 carbon atoms each independently substituted with halogen Or a linear or branched alkyl group of 3,
A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R1 is a pyrrolidinyl group in which one or more hydrogens are each independently an oxo group or an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms, and the substituted alkyl group is one or more hydrogens each independently hydride A linear or branched alkyl group having 1 to 4 carbon atoms substituted with a lock group or halogen,
A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R2 is a linear alkyl group having 1 to 3 carbon atoms in which at least one hydrogen is substituted with halogen,
A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
The method of claim 1,
The following compounds are selected from the group consisting of,
Compounds, isomers thereof, or pharmaceutically acceptable salts thereof:
(R)-2,2,2-trifluoro-1-((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinoline-7 -Yl)pyrrolidin-2-yl)ethanol;
(R)-5-(hydroxymethyl)-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-one;
(R)-(1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)methanol;
(R)-2,2,2-trifluoro-1-((R)-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidine -2-yl)ethanol;
(S)-2,2,2-trifluoro-1-((R)-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidine -2-yl)ethanol;
((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)methanol;
1-((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)ethanol;
1-((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl)propane-1 -Come;
2-Methyl-1-((2R,5R)-5-methyl-1-(5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-yl)pyrrolidin-2-yl ) Propan-1-ol;
N-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-N-(1,1,1-trifluoropropan-2-yl)tetrazolo[1,5-a ]Quinolin-7-amine;
N,N-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine;
N,N-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinolin-7-amine;
7-(bis(2,2,2-trifluoroethyl)amino)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinoline-1(2H) -On;
N,N-diethyl-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine;
NN-dipropyl-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine;
N-ethyl-N-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine;
7-(2,5-dimethylpyrrolidin-1-yl)-5-(trifluoromethyl)tetrazolo[1,5-a]quinoline; And
N-isopropyl-N-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)tetrazolo[1,5-a]quinolin-7-amine.
A disease or symptom that contains the compound of any one of claims 1 to 5, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, which improves symptoms or responds to treatment due to increased androgen activity. As a pharmaceutical composition for the prevention or treatment of,
The above diseases or symptoms include sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, muscle dystropy, cachexia, muscular dystrophy, postoperative muscle loss, neurotransmitter abnormalities. 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 osteoporosis will be selected from the group consisting of, a pharmaceutical composition.
delete The prevention or amelioration of a disease or symptom that improves symptoms or responds to treatment due to increased androgen activity containing the compound of any one of claims 1 to 5, isomers thereof, or pharmaceutically acceptable salts thereof. As a functional food composition for health,
The above diseases or symptoms include sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, muscle dystropy, cachexia, muscular dystrophy, postoperative muscle loss, neurotransmitter abnormalities. 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.
A method for preparing a compound of Formula 1, comprising the step of introducing an azide compound, a hydrazide compound, or semicarbazide to the compound of Formula 3:
[Formula 1]

[Formula 3]

In Formula 1 or Formula 3,
R1 is an unsubstituted or substituted amino group, or an unsubstituted or substituted pyrrolidinyl group,
R2 is an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 3 carbon atoms,
X is N, CH or C(O),
Hal is a halogen,
In the definition of R1,
The substituted amino group is an amino group wherein at least one of the hydrogens included in the amino group is independently substituted with an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and the substituted alkyl group is included in the alkyl group. At least one of hydrogen is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms each independently substituted with halogen,
The substituted pyrrolidinyl group is a pyrrolidinyl group in which at least one of the hydrogens contained in the pyrrolidinyl group is independently an oxo group or an unsubstituted or substituted linear, branched or cyclic alkyl group having 1 to 6 carbon atoms , The substituted alkyl group is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms in which at least one of the hydrogens contained in the alkyl group is each independently substituted with a hydroxy group, an oxo group, or a halogen,
In the definition of R2,
The substituted alkyl group is a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms in which at least one of the hydrogens contained in the alkyl group is independently substituted with halogen.
The method of claim 9,
Before the step of introducing an azide compound, a hydrazide compound, or semicarbazide to the compound of Formula 3,
The preparation method further comprises the step of preparing the compound of Formula 3 by halogenating the compound of Formula 2 below:
[Formula 2]

In Chemical Formula 2, R1 and R2 are as defined in claim 9.