KR102193461B1 - Quinoline-based compound and selective androgen receptor agonist comprising the same - Google Patents

Abstract

The present invention relates to a novel quinoline compound, a pharmaceutical composition containing the quinoline compound, and a method for preparing the quinoline compound. The quinoline-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 may be usefully used as a treatment and/or prophylactic agent for disorders and osteoporosis.

Description

Quinoline-based compound and selective androgen receptor agonist comprising the same {Quinoline-based compound and selective androgen receptor agonist comprising the same}

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

[Formula 1]

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

Androgens play a critical role in the establishment and maintenance of the male phenotype (Vitam Horm, 43:145-196, 1986: Endocr Rev 8:1-28, 1987). That is, androgens play a crucial role in the differentiation and growth of male genital organs, initiation and regulation of sperm formation, and regulation of male sexual behavior. In addition, androgens play an important role in development related to masculinization in tissues other than the genitals such as muscles, bones, hair, larynx, skin, adipose tissue, and kidney (J Endocrinol, 126:17-25, 1990). In women, the clear physiological role of androgens has not been fully elucidated, but 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. 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 supplementation therapy, which is currently widely used, has the effect of increasing bone density, real weight and libido in men and women (Menopause, 13:387-396, 2006: J Clin Endocrinol Metab, 85:2839-2853, 2000: J Clin Endocrinol Metab, 85:2670-2677, 2000). However, these treatments are limited in their widespread clinical use due to potential safety issues of androgens (N Engl J Med 350:482-492, 2004). For example, prostate stimulation in men and masculinization in women may cause serious side effects as well as hepatotoxicity.

Selective androgen receptor agonists (SARM agonists) are androgen receptor ligands that have a tissue-selective effect, and can exhibit a positive therapeutic effect of androgen without irritation to the prostate and skin, and can be administered orally (J Clin Endocrinol Metab, 84:3459-3462, 1999). In other words, although SARM agonists exhibit therapeutic effects, androgen side effects such as enlarged prostate, hirsutism, and virilization are not generally present. These compounds tissue-selectively act on androgen receptors to increase 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 quinoline-based compound.

Another example provides a composition for selective androgen activity increase comprising the quinoline-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 quinoline compound as an active ingredient.

Another example provides a health functional food composition for the prevention and/or improvement of a disease or condition that may be improved or respond to treatment due to an increase in androgen activity containing the quinoline-based compound.

Another example provides a method for preparing the quinoline-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 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 can be seen in the following experimental examples, it has an excellent stimulating effect on the androgen receptor, so that symptoms are caused by increased androgen activity. It can be effectively used for the treatment, prevention, and/or amelioration of a disease or condition that 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 "aryl" as used herein refers to a carbocyclic group (eg, phenyl) group having a shared pi electron system and having at least one ring. The term includes groups of monocyclic or fused ring polycyclic (ie, rings that share adjacent pairs of carbon atoms).

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

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

As used herein, the term "alkoxy" unless otherwise defined means an alkyloxy having 1 to 10 carbon atoms.

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

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

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

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

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

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

[Formula 1]

In Formula 1,

R ₁ is unsubstituted or substituted amino, or unsubstituted or substituted pyrrolidinyl;

R ₂ is unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms;

R ₃ is -N(R ₄ )NR ₅ R ₆ or -N(R ₄ )OR ₅ ;

R ₄ and R ₅ are each independently hydrogen or alkyl having 1 to 3 carbon atoms;

R ₆ is selected from the group consisting of hydrogen, -C(O)(CH ₂ )nR ₇ , -C(S)(CH ₂ )nR ₇ , and -S(O) ₂ (CH ₂ )nR ₇ ;

n is 0 or an integer from 1 to 3;

R ₇ is hydrogen, halogen, hydroxy, cyano, unsubstituted or substituted amino, unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms, alkoxy having 1 to 3 carbon atoms, -C(O )R ₈ , -NHC(O)R ₈ , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle; And

R ₈ may be selected from the group consisting of hydroxy, alkyl having 1 to 3 carbon atoms, and alkoxy having 1 to 3 carbon atoms.

Preferably, in the definition of R ₁ ,

The substituted amino is amino in which one or more of the hydrogens contained in amino are each independently substituted with an unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms, and the substituted alkyl is included in the alkyl. At least one of the hydrogens is each independently a linear, branched or cyclic alkyl having 1 to 3 carbon atoms substituted with hydroxy or halogen,

The substituted pyrrolidinyl is pyrrolidinyl wherein at least one of the hydrogens contained in pyrrolidinyl is each independently substituted with unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms, and the substituted Alkyl may be a linear, branched or cyclic alkyl having 1 to 3 carbon atoms in which one or more of the hydrogens contained in the alkyl are each independently substituted with hydroxy or halogen.

In addition, in the definition of R ₂ , the substituted alkyl may be a linear, branched or cyclic alkyl having 1 to 3 carbon atoms in which at least one of the hydrogens contained in the alkyl is independently substituted with halogen.

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

In one embodiment, R ₇ is amino wherein one or more hydrogens are each independently substituted with unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 6 carbon atoms, and one or more hydrogens are each independently halogen or hydrogen Linear, branched or cyclic alkyl having 1 to 3 carbon atoms substituted with oxy, halogen, cyano, alkoxy having 1 to 3 carbon atoms, -C(O)R ₉ , -C(O)NHR ₉ , or -NHC( O) from the group consisting of aryl substituted with R ₉ , heteroaryl in which one or more hydrogens are each independently substituted with halogen or linear, branched or cyclic alkyl having 1 to 3 carbon atoms, and heterocycle in which one or more hydrogens are substituted with oxo It may be selected.

In another embodiment, R ₈ and R ₉ may each independently be selected from the group consisting of hydroxy, alkyl having 1 to 3 carbon atoms, and alkoxy having 1 to 3 carbon atoms.

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

1) 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine;

2) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methyloxazole-5-carbohi Drazide;

3) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)isoxazole-5-carbohydrazide;

4) N-(2-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)-2 -Oxoethyl)acetamide;

5) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-oxooxazolidine-4-carbo Hydrazide;

6) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1H-pyrrole-2-carbohydrazide ;

7) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1-methyl-1H-pyrrole-2- Carbohydrazide;

8) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1H-pyrrole-3-carbohydrazide ;

9) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)benzohydrazide;

10) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2,4,5-trifluorobenzo Hydrazide;

11) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)nicotinohydrazide;

12) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)pyrazine-2-carbohydrazide;

13) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1H-imidazole-4-carbohydra Zayed;

14) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methyl-1H-imidazole-5 -Carbohydrazide;

15) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)furan-3-carbohydrazide;

16) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-6-methylnicotinohydrazide;

17) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)thiazole-4-carbohydrazide;

18) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)picolinohydrazide;

19) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)isonicotinohydrazide;

20) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methylisoxazole-3-carbo Hydrazide;

21) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)furan-2-carbohydrazide;

22) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-5-methylfuran-2-carbohydra Zayed;

23) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-5-fluoronicotinohydrazide;

24) 3-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinecarbonyl)-N-methylbenza mid;

25) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)pivalohydrazide;

26) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-cyanoacetohydrazide;

27) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-chloroacetohydrazide;

28) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)acetohydrazide;

29) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-hydroxyacetohydrazide;

30) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-methoxyacetohydrazide;

31) (R)-N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-hydroxypropane high Drazide;

32) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)tetrahydrofuran-2-carbohydrazide;

33) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)tetrahydrofuran-3-carbohydrazide;

34) Methyl 2-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)-2-oxo acetate;

35) 2-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)-2-oxoacetic acid ;

36) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-3-hydroxybutanehydrazide;

37) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-(pyrrolidin-1-yl ) Acetohydrazide;

38) methyl 2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinecarboxylate;

39) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2,2,2-trifluoroaceto Hydrazide;

40) N-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N,N'-dimethylacetohydrazide;

41) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N-methylacetohydrazide;

42) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N'-methylacetohydrazide;

43) 2-(methoxyamino)-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine;

44) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)propionohydrazide;

45) N'-(6-bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)isobutyrohydrazide;

46) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methoxybenzenesulfonylhydrazide ;

47) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-cyanobenzenesulfonylhydrazide ;

48) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methylbenzenesulfonylhydrazide;

49) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-fluorobenzenesulfonylhydrazide ;

50) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-3-cyanobenzenesulfonylhydrazide ;

51) 2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N,N-diethylhydrazinesulfonamide;

52) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)pyrrolidine-1-sulfonohydrazide ;

53) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)methanesulfonohydrazide;

54) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)propane-1-sulfonohydrazide;

55) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)ethanesulfonohydrazide;

56) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)propane-2-sulfonohydrazide;

57) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)benzenesulfonylhydrazide;

58) 2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N,N-dimethylhydrazinesulfonamide;

59) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2,4-difluorobenzenesulfonyl Hydrazide;

60) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2,5-dichlorothiophene-3- Sulphonohydrazide;

61) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1-methyl-1H-imidazole-2 -Sulfonohydrazide;

62) 3-((2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)sulfonyl)benzoic acid ;

63) 3-((2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)sulfonyl)- N-methylbenzamide;

64) N-(4-((2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)sulfur Phonyl)phenyl)acetamide;

65) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methylpiperazine-1-sulfono Hydrazide;

66) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)piperidine-1-sulfonohydrazide ;

67) 2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N-ethyl-N-methylhydrazinesulfonamide;

68) N'-(6-((2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl) -4-(trifluoromethyl)quinolin-2-yl)acetohydrazide;

69) N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)morpholine-4-sulfonohydrazide;

70) 2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N,N-dimethylhydrazinecarboxamide;

71) N-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)formohydrazide;

72) 2-(6-bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N-ethylhydrazinecarbothioamide.

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 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 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 solid preparations 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, for example, starch, calcium carbonate, 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, lyophilized formulations, suppositories, and the like. As a non-aqueous solvent for preparing a non-aqueous solution or a suspension for preparing a suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like may be used.

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

(a) preparing a compound of Formula 3 by halogenating the compound of Formula 2 below; And

(b) introducing R ₃ to the prepared compound of Formula 3 above.

[Formula 2]

[Formula 3]

In Formulas 2 and 3, R ₁ and R ₂ are as defined in Formula 1, and Hal is halogen.

In the step (a), 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).

In the step (b), the compound of Formula 1 may be prepared by reacting the compound of Formula 3 with hydrazine or hydroxylamine and then reacting acyl chloride or sulfonyl chloride.

The reaction step is illustrated in Scheme 1 below:

[Scheme 1]

In Reaction Scheme 1, R ₁ , R ₂ , R ₃ are the same as defined in Formula 1, and Hal means halogen, such as chlorine or bromine.

In addition, the production method of the present invention is reacted under an organic solvent such as methanol, ethanol, isopropyl alcohol, 1,4-dioxane N,N-dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile, or a mixture of two or more organic solvents. You can get it.

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

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

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

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

50 g (0.22 mol) of 6-amino-4-(trifluoromethyl)quinoline-2(1H)-one was added to a 3 L three-neck flask, and 1.5 L of trifluoroacetic acid was added and stirred. NaBH ₄ 22.4g (23 pellets, 0.59mol, 3eq.) was added over 2 hours and stirred at room temperature for 16 hours. The 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 reaction solution was slowly added to 10 L of a mixed solution of water: methanol = 9:1 and stirred. After stirring for about 3 hours, it was filtered and washed twice with 500 ml of water. The filtrate was dried in vacuo to give 85 g (99%) of the title compound.

¹ H NMR (DMSO-d ₆ , 400MHz): δ 12.10 (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

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

In a 1 L flask, 50 g of compound 6-N,N-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2(1H)-one obtained in Preparation Example 1 ( 0.12mol) was added, and 150ml (13.3eq) of POCl ₃ was added and stirred. The reaction solution was refluxed at 120° C. for about 2 hours, cooled to room temperature, and concentrated under reduced pressure. The concentrate was diluted in 500 ml of ethyl acetate and washed with 500 ml of 2N NaOH aqueous solution. The 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) δ 8.02 (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 brought to room temperature and stirred 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 brought to room temperature and stirred 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 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 brought to room temperature and stirred 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) δ 5.77 (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) δ 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-(trifluoromethyl)quinolin-6-yl) 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 brought to room temperature, 100 mL of ethyl acetate and 100 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=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): δ 7.86 (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- Methylpyrrolidine Preparation of -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 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 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): δ 7.73 (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- Methylpyrrolidine -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 ) 1.9 g (5.16 mmol) 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 brought to room temperature and stirred 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): δ 9.48 (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-( tree Fluoromethyl)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 gradually brought to room temperature and stirred 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): δ 7.75 (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): δ 7.29 (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): δ 8.10(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°C. 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): δ 7.92 (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

[ Example 1] 2- Hydrazinyl -N,N- Vis (2,2,2- Trifluoroethyl )-4-( Triple Lu Oromethyl)quinoline-6- Amine Produce

Compound 2-chloro-N,N-bis (2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 52 g (0.127 mol) obtained in Preparation Example 2 was added to a 1 L flask. Then, 150 ml of ethanol was added and stirred at room temperature. After adding hydrazine monohydrate 94ml (1.9mol, 15eq) dropwise to the reaction solution, the mixture was refluxed at 80°C for 14 hours. After the reaction solution was concentrated under reduced pressure, 500 ml of water was added to the residue to be dispersed. The mixture was filtered, and the filtrate was washed with 500 ml of water and dried in vacuo to give 46 g (93%) of the title compound.

¹ H NMR (400MHz, DMSO-d ₄ ): δ 8.24(s, 1H), 7.58(q, 1H), 7.29(s, 1H), 7.17(s, 1H), 4.40(q, 4H)

Mass[M+H]: 407.25

[ Example 2] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluorome Tyl)quinolin-2-yl)-4- Methyloxazole -5- Carbohydrazide Produce

To a 10 ml flask was added 31.4 mg (0.247 mmol) of 4-methyl-1,3-oxazole-5-carboxylic acid, and 2 ml of N,N-dimethylformamide was added and stirred to dissolve. Example after adding 1-hydroxybenzotriazole (HOBt) 40mg (0.296mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) 47.3mg (0.247mmol) 100 mg (0.247 mmol) of the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in 1 was added. 60ul (0.345mmol) of N,N-diisopropylethylamine was added to the reaction solution and stirred at room temperature for about 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column to obtain 20mg (16%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 8.27 (s, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 4.29 (q , 4H), 2.48(s, 3H)

Mass[M+H]: 516.10

[ Example 3] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluorome Tyl) quinolin-2-yl) Isoxazole -5- Carbohydrazide Produce

In a 10 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.247 mmol) obtained in Example 1 ) 4-methyl-1,3-oxazole-5-carboxylic acid 31.4mg (0.247mmol) was added, dichloromethane 2ml was added and stirred to dissolve. After adding 42ul (0.296mmol) of triethylamine, 24ul (0.247mmol) of isoxazole-5-carbonyl chloride was added, followed by stirring at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column to obtain 25 mg (20%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 8.58 (s, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 7.09 (d , 1H), 4.29 (q, 4H)

Mass[M+H]: 502.08

[ Example 4] N-(2-(2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Triple Lu Oromethyl)quinolin-2-yl) Hydrazinyl )-2- Oxoethyl ) Acetamide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and N-acetylglycine obtained in Example 1 Then, in the same manner as in Example 2, 41 mg (33%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 7.76 (d, 1H), 7.58 (d, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 4.29 (q, 4H), 4.03 (s , 2H), 2.03(s, 3H)

Mass[M+H]: 506.12

[ Example 5] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluorome Tyl)quinolin-2-yl)-2- Oxoxazolidine -4- Carbohydrazide Produce

[Step 1] Benzyl 2- Oxoxazolidine -4- Carboxylate Produce

500 mg of L-serine benzyl ester hydrochloride was dissolved in 10 ml of water, 2N NaOH aqueous solution was added, stirred, extracted with 20 ml of ethyl acetate, and concentrated under reduced pressure. The concentrate was dissolved in 2 ml of tetrahydrofuran, 500 mg (2 eq) of 1,1'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for about 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and separated by column to give 95 mg (28%) of the title compound.

[Step 2] 2- Oxoxazolidine -4- Carboxylic acid Produce

95 mg of the compound benzyl 2-oxooxazolidine-4-carboxylate obtained in step 1 was dissolved in 2 ml of methanol, and 9.5 mg of Pd/C (10%) was added thereto, followed by bubbling hydrogen gas. After about 30 minutes, the reaction solution was filtered and the filtrate was concentrated to give 63 mg (98%) of the title compound.

[Step 3] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2- Oxoxazolidine -4- Carbohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in Example 1 and Compound 2 obtained in Step 2 -Oxooxazolidine-4-carboxylic acid was used in the same manner as in Example 2 to obtain 30 mg (12%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 7.75 (d, 1H), 7.59 (d, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 4.72 (t, 1H), 4.59 (m , 2H), 4.29 (q, 4H)

Mass[M+H]: 520.10

[ Example 6] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluorome Tyl)quinolin-2-yl)-1H-pyrrole-2- Carbohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and pyrrole-2-carboxylic acid obtained in Example 1 Using the same method as in Example 2, 64mg (52%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 7.74 (d, 1H), 7.55 (d, 1H), 7.35 (s, 1H), 7.29 (s, 1H), 6.98 (dd, 2H), 6.23 (t , 1H), 4.28(q, 4H)

Mass[M+H]: 500.11

[ Example 7] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluorome Tyl)quinolin-2-yl)-1- methyl -1H-pyrrole-2- Carbohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and N-methylpyrrole-2 obtained in Example 1 -Using a carboxylic acid, proceeded in the same manner as in Example 2 to obtain 80 mg (63%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 7.75 (d, 1H), 7.55 (d, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 6.98 (t, 1H), 6.92 (s , 1H), 6.13(m, 1H), 4.28(q, 4H), 3.89(s, 3H)

Mass[M+H]: 514.12

[ Example 8] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluorome Tyl)quinolin-2-yl)-1H-pyrrole-3- Carbohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and pyrrole-3-carboxylic acid obtained in Example 1 Using the same method as in Example 2, 85mg (69%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 7.75 (d, 1H), 7.55 (dd, 1H), 7.49 (d, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 6.82 (s , 1H), 6.66(s, 1H), 4.27(q, 4H)

Mass[M+H]: 500.11

[ Example 9] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluorome Tyl) quinolin-2-yl) Of benzohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and benzoic acid obtained in Example 1 Proceeding in the same manner as in 2, 56 mg (44%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 7.97 (d, 1H), 7.75 (d, 1H), 7.57 (m, 5H), 7.36 (s, 1H), 7.33 (s, 1H), 4.29 (q , 4H)

Mass[M+H]: 511.11

[ Example 10] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoro Methyl)quinolin-2-yl)-2,4,5- Of trifluorobenzohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 2,4,5- obtained in Example 1 Trifluorobenzoic acid was used in the same manner as in Example 2 to obtain 70 mg (50%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 7.82 (m, 1H), 7.75 (d, 1H), 7.57 (d, 1H), 7.41 (m, 3H), 4.29 (q, 4H)

Mass[M+H]: 565.08

[ Example 11] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of nicotinohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and nicotinic acid obtained in Example 1 Proceeding in the same manner as in 2, 46mg (36%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 9.14 (d, 1H), 8.76 (t, 1H), 8.40 (d, 1H), 7.75 (d, 1H), 7.76 (m, 2H), 7.36 (s , 1H), 7.35(s, 1H), 4.29(q, 4H)

Mass[M+H]: 512.11

[ Example 12] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)pyrazine-2- Carbohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 2-pyrazine carboxylic acid obtained in Example 1 Then, in the same manner as in Example 2, 88 mg (69%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 9.27 (s, 1H), 8.85 (d, 1H), 8.76 (d, 1H), 7.73 (d, 1H), 7.55 (d, 1H), 7.35 (s , 2H), 4.29 (q, 4H)

Mass[M+H]: 513.10

[ Example 13] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-1H- Imidazole -4- Carbohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 4-imidazole carboxylic acid obtained in Example 1 Using the same method as in Example 2, 75mg (61%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 8.03(s, 1H), 7.86(s, 1H), 7.75(d, 1H), 7.56(d, 1H), 7.35(s, 1H), 7.34(s , 1H), 4.30(q, 4H)

Mass[M+H]: 501.10

[ Example 14] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- methyl -1H- Imidazole -5- Carbohydrazide Produce

[Step 1] 4- methyl -1H- Imidazole -5- Carboxylic acid Produce

After dissolving 0.5g (2.4mmol) of ethyl-4-methyl 5-imidazole carboxylate in 2ml of ethanol, 2.2ml of 3N LiOH aqueous solution was added and stirred at 80℃ for 1 hour, followed by stirring at 40℃ for 16 hours. The reaction temperature was raised to 80° C. and stirred for 5.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the title compound.

[Step 2] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- methyl -1H- Imidazole -5- Carbohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in Example 1 and Compound 4 obtained in Step 1 Proceeding in the same manner as in Example 2 using -methyl-1H-imidazole-5-carboxylic acid, 69 mg (54%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 7.74(d, 1H), 7.63(s, 1H), 7.55(d, 1H), 7.35(s, 1H), 7.33(s, 1H), 4.28(q , 4H), 2.52(s, 3H)

Mass[M+H]: 515.12

[ Example 15] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Furan -3- Carbohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 3-furan carboxylic acid obtained in Example 1 Then, proceeding in the same manner as in Example 2 to give the title compound 62mg (50%).

¹ H NMR (400MHz, CD ₃ OD): δ 8.22(s, 1H), 7.75(d, 1H), 7.76(t, 1H), 7.56(dd, 1H), 7.35(s, 1H), 7.30(s , 1H), 6.91(s, 1H), 4.28(q, 4H)

Mass[M+H]: 501.09

[ Example 16] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-6- Of methylnicotinohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 6-methyl nicotinic acid obtained in Example 1 were used. Then, in the same manner as in Example 2, 90mg (69%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 7.92 (d, 1H), 7.87 (t, 1H), 7.74 (d, 1H), 7.56 (d, 1H), 7.749 (d, 1H), 7.36 (s , 1H), 7.34(s, 1H), 4.28(q, 4H), 2.65(s, 3H)

Mass[M+H]: 526.12

[ Example 17] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)thiazole-4- Carbohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 4-thiazole carboxylic acid obtained in Example 1 Using the same method as in Example 2, 63mg (49%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 9.09 (d, 1H), 8.39 (d, 1H), 7.74 (d, 1H), 7.54 (dd, 1H), 7.36 (s, 1H), 7.33 (s , 1H), 4.28(q, 4H)

Mass[M+H]: 518.06

[ Example 18] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Picolinohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and picolinic acid obtained in Example 1 Proceeding in the same manner as in Example 2, 77 mg (61%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 8.70 (d, 1H), 8.13 (d, 1H), 8.00 (t, 1H), 7.73 (d, 1H), 7.61 (q, 1H), 7.56 (dd , 1H), 7.35(s, 1H), 7.34(s, 1H), 4.28(q, 4H)

Mass[M+H]: 512.11

[ Example 19] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of isonicotinohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and isonicotinic acid obtained in Example 1 Proceeding in the same manner as in Example 2, 90mg (71%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 8.81 (d, 2H), 7.94 (d, 2H), 7.75 (d, 1H), 7.56 (dd, 1H), 7.36 (s, 1H), 7.35 (s , 1H), 4.29 (q, 4H)

Mass[M+H]: 512.11

[ Example 20] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- Methylisoxazole -3- Carbohydrazide Produce

Compounds obtained in Example 1 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 5-methyl isoxazole- Proceeding in the same manner as in Example 2 using 4-carboxylic acid, 20 mg (16%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 8.79 (s, 1H), 7.74 (d, 1H), 7.56 (d, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 4.28 (q , 4H), 2.71(s, 3H)

Mass[M+H]: 516.10

[ Example 21] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Furan -2- Carbohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 2-furoic acid obtained in Example 1 Then, it proceeded in the same manner as in Example 2 to obtain 55mg (44%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 7.76 (s, 1H), 7.75 (d, 1H), 7.55 (dd, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 7.25 (d , 1H), 6.66(q, 1H), 4.28(q, 4H)

Mass[M+H]: 501.09

[ Example 22] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-5- Methylfuran -2- Carbohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 5-methyl 2-furo obtained in Example 1 Proceeding in the same manner as in Example 2 using an acid, 37 mg (29%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 7.75 (d, 1H), 7.55 (dd, 1H), 7.35 (s, 1H), 7.29 (s, 1H), 7.14 (d, 1H), 6.27 (d , 1H), 4.30(q, 4H), 2.42(s, 3H)

Mass[M+H]: 515.11

[Example 23] N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-5-fluoronicotinohigh Preparation of drazide

The compound obtained in Example 1 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 5-fluoro-3 -Using pyridine carboxylic acid, proceeded in the same manner as in Example 2 to obtain 27 mg (21%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 9.01 (s, 1H), 8.70 (d, 1H), 8.18 (dd, 1H), 7.75 (d, 1H), 7.56 (dd, 1H), 7.36 (s , 1H), 7.35(s, 1H), 4.30(q, 4H)

Mass[M+H]: 530.10

[ Example 24] 3-(2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Hydrazinecarbonyl )-N- Of methylbenzamide Produce

[Step 1] methyl 3-( Methylcarbamoyl ) Benzoate Produce

Mono-methyl phthalate 300mg (1.66mmol) was added to a 50ml flask, and N,N-dimethylformamide 20ml was added and stirred. 1-hydroxybenzotriazole (HOBt) 270mg (1.99mmol, 1.2eq), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCL) 320mg (1.66mmol, 1eq) was added. After the addition, 1.7ml (3.33mmol, 2eq) of a 2M methylamine solution was added. To the reaction solution, 405ul (2.33mmol, 1.4eq) of N,N-diisopropylethylamine was added and stirred at room temperature for about 2 hours. After completion of the reaction, it was concentrated under reduced pressure to obtain 300mg (93%) of the title compound.

[Step 2] 3-( Methylcarbamoyl ) Preparation of benzoic acid

After dissolving 60 mg of the compound methyl 3-(methylcarbamoyl)benzoate obtained in step 1 in 2 ml of ethanol, 280 ul of 3N LiOH aqueous solution was added, stirred at room temperature for 1.5 hours, and concentrated under reduced pressure to give 46 mg (83%) of the title compound.

[Step 3] 3-(2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Hydrazinecarbonyl )-N- Of methylbenzamide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in Example 1 and Compound 3 obtained in Step 2 Proceeding in the same manner as in Example 2 using -(methylcarbamoyl)benzoic acid, 45mg (32%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 8.43 (s, 1H), 8.13 (d, 1H), 8.03 (d, 1H), 7.74 (t, 1H), 7.63 (t, 1H), 7.56 (dd , 1H), 7.36(s, 1H), 7.34(s, 1H), 4.28(q, 4H), 2.99(s, 3H)

Mass[M+H]: 568.13

[ Example 25] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of pivalohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and pivaloyl chloride obtained in Example 1 Then, it proceeded in the same manner as in Example 3 to obtain 85mg (70%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.71 (d, 1H), 7.55 (dd, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 4.28 (q, 4H), 1.31 (s, 9H)

Mass[M+H]: 491.14

[ Example 26] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2- Of cyanoacetohydrazide Produce

Using the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and cyanoacetic acid obtained in Example 1 Proceeding in the same manner as in Example 2, 45mg (38%) of the title compound was obtained.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.77 (d, 1H), 7.59 (dd, 1H), 7.36 (s, 1H), 7.27 (s, 1H), 4.30 (q, 4H),

Mass[M+H]: 474.09

[ Example 27] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2- Of chloroacetohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And dissolve in 2 ml of benzene, triethylamine 35μl (1.0eq), chloroacetyl chloride

After adding 25 μl (1.25eq), reflux at 80°C 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 obtain 36 mg (30%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 8.38 (d, 1H), 8.37 (s, 1H), 7.81 (d, 1H), 7.41 (s, 1H), 5.69 (s, 2H), 4.58 (q , 4H)

Mass[M+H]: 483.06

[ Example 28] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of acetohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And acetyl chloride 34.5 μl (1.0 eq), and proceeded in the same manner as in Example 3 to obtain 23 mg (21%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 9.94(s, 1H), 8.97(s, 1H), 7.64(s, 2H), 7.22(d, 2H), 4.44(q, 4H), 1.95(s , 3H)

μMass[M+H]: 449.09

[ Example 29] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2- Of hydroxyacetohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 200 mg (0.492 mmol) obtained in Example 1 ), dissolved in 5 ml of dichloromethane, 80 μl (1.5 eq) of acetoxyacetyl chloride, 0.1 ml (1.5 eq) of triethylamine, and stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, 5 ml of methanol was added, and 5 ml of 2N NaOH aqueous solution was added, followed by stirring. 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 30 mg (13%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.76 (d, 1H), 7.57 (dd, 1H), 7.36 (s, 1H), 7.28 (s, 1H), 4.29 (q, 4H), 4.21 (s, 2H)

Mass[M+H]: 465.09

[ Example 30] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2- Of methoxyacetohydrazide Produce

[Step 1] Acetic 2- Methoxyacetic Anhydride Produce

0.1ml (1.3mmol) of methoxyacetic acid was added to a 25ml flask, dissolved in 4ml of dichloromethane, 0.55ml (3.0eq) of triethylamine and 0.14ml (1.5eq) of acetyl chloride were added, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 174 mg (99%) of the title compound.

Mass[M+H]: 134.09

[Step 2] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2- Of methoxyacetohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in Example 1 and compound Ace obtained in step 1 9.4mg (5%) of the title compound was obtained by proceeding in the same manner as in Example 2 using tic 2-methoxyacetic anhydride.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.75 (d, 1H), 7.56 (dd, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 4,26 (q, 4H), 4.13 ( s, 2H), 3.53(s, 3H)

Mass[M+H]: 479.11

[ Example 31] (R)- N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2- Of hydroxypropane hydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 200 mg (0.492 mmol) obtained in Example 1 ) And 62 μl (1.0 eq) of (S)-(-)-2-acetoxypropionyl chloride were used in the same manner as in Example 29 to obtain 62 mg (26%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.74(d, 1H), 7.57(dd, 1H), 7.35(s, 1H), 7.27(s, 1H), 4.37~4.25(m, 5H), 1.47( d, 3H)

Mass[M+H]: 479.11

[ Example 32] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Tetrahydrofuran -2- Carbohydrazide Produce

[Step 1] Tetrahydrofuran -2- Carbonyl Preparation of chloride

Tetrahydrofuran-2-carboxylic acid 40 μl (0.416 mmol) was added to a 25 ml flask, dissolved in 1 ml of dichloromethane, and 5 μl of N,N-dimethylformamide and 0.141 ml (4 eq) of oxalyl chloride were added. The reaction solution was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain the title compound.

[Step 2] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Tetrahydrofuran -2- Carbohydrazide Produce

In a 25 ml flask, compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 150 mg (0.369 mmol) obtained in Example 1 ) And the tetrahydrofuran-2-carbonyl chloride obtained in step 1 were carried out in the same manner as in Example 29 to obtain 46 mg (30%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.73 (d, 1H), 7.56 (dd, 1H), 7.35 (s, 1H), 7.24 (s, 1H), 4.52 (dd, 1H), 4.28 (q, 4H), 4.14(dd, 1H), 3.93(dd, 1H), 2.37~2.28(m, 1H), 2.19~1.96(m, 3H)

Mass[M+H]: 505.12

[ Example 33] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Tetrahydrofuran -3- Carbohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 184 mg (0.453 mmol) obtained in Example 1 ) And tetrahydro-3-furoic acid 43.3 μl (1.0 eq) were used in the same manner as in Example 2 to obtain 50 mg (22%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.73(d, 1H), 7.56(dd, 1H), 7.34(s, 1H), 7.23(s, 1H), 4.29(q, 4H), 4.08~4.04( m, 1H), 3.96~3.84(m, 3H), 3.23~3.20(m, 1H), 2.26~2.21(m, 2H)

Mass[M+H]: 505.12

[ Example 34] methyl 2-(2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Hydrazinyl )-2- Of oxoacetate Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And methyl chlorooxoacetate 23 μl (1.0 eq) were used in the same manner as in Example 3 to obtain 69 mg (57%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.75 (d, 1H), 7.57 (dd, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 4.30 (q, 4H), 3.94 (s, 3H)

Mass[M+H]: 493.08

[ Example 35] 2-(2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Hydrazinyl )-2- Oxoacetic acid Produce

The compound obtained in Example 34 methyl 2-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl) 42 mg (85 μmol) of -2-oxoacetate was dissolved in 3 ml of 1,4-dioxane, 0.1 ml (1.2 eq) of 1N LiOH aqueous solution was added, followed by stirring at room temperature for 1 hour. 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 with MgSO ₄ , dried under reduced pressure, and 38 mg (94%) of the title compound was obtained.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.75 (d, 1H), 7.55 (d, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 4.28 (q, 4H)

Mass[M+H]: 479.07

[ Example 36] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-3- Of hydroxybutane hydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And 23 μl (1.0 eq) of 3-hydroxybutyric acid were used in the same manner as in Example 2 to obtain 9.4 mg (5%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 9.95(s, 1H), 9.04(s, 1H), 7.67~7.60(m, 2H), 7.29(s, 1H), 7.21(s, 1H), 4.88 (d, 1H), 4.45(q, 4H), 4.03(s, 1H), 2.36~2.22(m, 2H), 1.17(d, 3H)

Mass[M+H]: 493.12

[ Example 37] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2-( Pyrrolidine -1 day) Of acetohydrazide Produce

[Step 1] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2- Of chloroacetohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And 18 μl (1.0 eq) of chloroacetyl chloride were carried out in the same manner as in Example 3 to obtain 51 mg (43%) of the title compound.

[Step 2] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2-( Pyrrolidine -1 day) Of acetohydrazide Produce

In a 25 ml flask, compound N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-chloroaceto obtained in step 1 Hydrazide 51mg (0.105mmol) was added and dissolved in 2ml of acetonitrile. K ₂ CO ₃ 29 mg (2.0 eq) and pyrrolidine 44 μl (5.0 eq) were added to the reaction solution, followed by stirring at room temperature for 1 hour. 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 36 mg (30%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.72 (d, 1H), 7.56 (dd, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 4.29 (q, 4H), 3.45 (s, 2H), 2.92(s, 4H), 1.89(s, 4H)

Mass[M+H]: 518.15

[ Example 38] methyl 2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of hydrazine carboxylate Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And methyl chloroformate 34.5 μl (1.0 eq) were used in the same manner as in Example 3 to obtain 11 mg (10%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 9.31(s, 1H), 8.97(s, 1H), 7.65(s, 2H), 7.20(s, 2H), 4.45(q, 4H), 3.63(s , 3H)

Mass[M+H]: 465.09

[ Example 39] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2,2,2- Of trifluoroacetohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And trifluoroacetic anhydride 29 μl (1.0 eq) were used in the same manner as in Example 3 to obtain 11 mg (10%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 7.67 (m, 2H, 7.21 (s, 2H), 4.47 (q, 4H)

Mass[M+H]: 503.07

[ Example 40] N-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N, N' - Of dimethylacetohydrazide Produce

N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)acetohydrazide 300mg (0.66mmol) obtained in Example 28 ) Was dissolved in tetrahydrofuran, NaH (2.5eq) was added and stirred at room temperature for 30 minutes. Methyl iodide (2.5 eq) was added, stirred at room temperature for 30 minutes, and extracted with ethyl acetate and NH ₄ Cl aqueous solution. The organic layer was separated, dried over MgSO ₄ , filtered, and purified by column chromatography to give 235 mg (75%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.83 (d, 1H), 7.65-7.62 (dd, 1H), 7.38 (s, 1H), 7.17 (s, 1H), 4.35-4,29 (m, 4H) ), 3.43(s, 3H), 3.10(s, 3H), 2.08(s, 3H)

Mass[M+H]: 477.13

[ Example 41] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N- Of methylacetohydrazide Produce

100 mg (0.246 mmol) of the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in Example 1 was dichloro After dissolving in methane and adding triethylamine 125mg (1.23mmol, 5 equivalents), acetyl chloride 48mg (0.615mmol, 2.5 equivalents) was added and stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, extracted with water and ethyl acetate, the organic layer was dried with MgSO ₄ , the filtrate was concentrated under reduced pressure and the resulting mixture was dissolved in tetrahydrofuran, NaH 5.9 mg (0.246 mmol, 1 equivalent) was added, and methyl iodide 35 mg (0.246 mmol) , 1 equivalent) was added and stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, 10 ml of methanol and 2 ml of 2N-NaOH aqueous solution were added, followed by stirring at room temperature for 1 hour. The solution was concentrated under reduced pressure, extracted with water and ethyl acetate, the organic layer was dried over MgSO ₄ , the filtrate was concentrated under reduced pressure and purified by column chromatography to give 35 mg (35%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ 7.77 (d, 1H), 7.42-7.40 (dd, 1H), 7.36 (s, 1H), 7.06 (s, 1H), 6.76 (s, 1H), 4.16-4.10 (m, 4H), 3.22(s, 3H), 2.20(s, 3H)

Mass[M+H]: 463.11

[ Example 42] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)- N' - Of methylacetohydrazide Produce

N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)acetohydrazide 300mg (0.66mmol) obtained in Example 28 ) Was dissolved in N,N-dimethylformamide, and 91.2 mg (0.66 mmol, 1 equivalent) of K ₂ CO _{3 and} 93.7 mg (0.66 mmol, 1 equivalent) of methyl iodide were added and stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, extracted with water and ethyl acetate, the organic layer was dried over MgSO ₄ , the filtrate was concentrated under reduced pressure and purified by column chromatography to give 250 mg (82%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ 7.79 (d, 1H), 7.60 (s, 1H), 7.34-7.26 (m, 2H), 4.16-4.07 (m, 4H), 3.48 (s, 3H), 2.12 (s, 3H)

Mass[M+H]: 463.11

[ Example 43] 2-( Methoxyamino )-N,N- Vis (2,2,2- Trifluoroethyl )-4-( Trifluoromethyl ) Quinoline-6- Amine Produce

Compound 2-chloro-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 300 mg (0.73 mmol) obtained in Preparation Example 2 was added to 20 ml of ethanol After dissolving, 61 mg (0.73 mmol) of methoxyamine hydrochloride was added and refluxed for 2 days. The reaction solution was concentrated under reduced pressure, extracted with water and ethyl acetate, the filtrate was dried over MgSO ₄ , concentrated under reduced pressure, and purified by column chromatography to give 110 mg (36%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ 7.07 (s, 1H), 6.99-6.96 (dd, 1H), 6.83 (d, 1H), 6.77 (s, 1H), 3.98-3.91 (m, 4H), 3.90 (s, 3H)

Mass[M+H]: 422.08

[ Example 44] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of propionohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100mg (0.246mmol) and acetyl obtained in Example 1 Proceeding in the same manner as in Example 3 using propionyl chloride, 40 mg (35%) of the title compound was obtained.

Mass[M+H]: 463.11

[ Example 45] N' -(6- bis (2,2,2- Trifluoroethyl )Amino)-4-( Trifluoromethyl ) Quinolin-2-yl) Of isobutyrohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100mg (0.246mmol) and acetyl obtained in Example 1 52 mg (44%) of the title compound was obtained by proceeding in the same manner as in Example 3 using isobutyryl chloride.

Mass[M+H]: 476.13

[ Example 46] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- Of methoxybenzenesulfonylhydrazide Produce

In a 10 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.247 mmol) obtained in Example 1 ) And 2.5ml of dichloromethane were added and stirred. 51mg (0.247 mmol, 1eq) of 4-methoxybenzenesulfonyl chloride was added to the reaction solution, and 20ul (0.247mmol, 1eq) of pyridine was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and then separated by column to give 80mg (56%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 7.80 (d, 2H), 7.55 (q, 2H), 7.26 (s, 1H), 7.21 (s, 1H), 6.89 (d, 2H), 4.28 (q , 4H), 3.70(s, 3H)

Mass[M+H]: 577.09

[ Example 47] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- Of cyanobenzenesulfonylhydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 4-cyanobenzenesulfur obtained in Example 1 Using phonyl chloride, 75mg (53%) of the title compound was obtained in the same manner as in Example 46.

¹ H NMR (400MHz, CD ₃ OD): δ 8.05(d, 2H), 7.77(d, 2H), 7.47(q, 2H), 7.27(s, 1H), 7.21(s, 1H), 4.28(q , 4H)

Mass[M+H]: 572.07

[ Example 48] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- Of methylbenzenesulfonylhydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and p-toluenesulfonyl chloride obtained in Example 1 Using the same method as in Example 46, 60mg (43%) of the title compound was obtained.

¹ H NMR (400MHz, CD ₃ OD): δ 7.76 (d, 2H), 7.53 (q, 2H), 7.22 (m, 4H), 4.28 (q, 4H), 2.01 (s, 3H)

Mass[M+H]: 561.09

[ Example 49] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- Of fluorobenzenesulfonylhydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 4-fluorobenzenesulfur obtained in Example 1 Using fonyl chloride, 88 mg (63%) of the title compound was obtained in the same manner as in Example 46.

¹ H NMR (400MHz, CD ₃ OD): δ 7.96(q, 2H), 7.55(q, 2H), 7.28(s, 1H), 7.25(s, 1H), 7.15(t, 2H), 4.27(q , 4H), 2.01(s, 3H)

Mass[M+H]: 565.07

[ Example 50] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-3- Of cyanobenzenesulfonylhydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine and 3-cyanobenzenesulfur obtained in Example 1 Using fonyl chloride, 83 mg (59%) of the title compound was obtained in the same manner as in Example 46.

¹ H NMR (400MHz, CD ₃ OD): δ 8.30(s, 1H), 8.13(d, 1H), 7.74(d, 1H), 7.55(t, 1H), 7.52(s, 2H), 7.25(s , 1H), 7.19(s, 1H), 4.28(q, 4H)

Mass[M+H]: 572.07

[ Example 51] 2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N,N- Of diethylhydrazinesulfonamide Produce

[Step 1] Of diethylsulfamoyl chloride Produce

Sulfuryl chloride 7ml (87mmol, 3eq) was added to a 100ml flask, and acetonitrile 30ml was added, followed by stirring at 0°C for 30 minutes. Diethylamine 3ml (29mmol, 1eq) was added dropwise to the reaction solution, the temperature was raised to room temperature, and the reaction solution was refluxed at 80°C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure to give 4.5 g (90%) of the title compound.

¹ H NMR (400MHz, CDCl ₃ ): δ 3.40 (q, 4H), 1.29 (s, 6H)

[Step 2] 2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N,N- Of diethylhydrazinesulfonamide Produce

In a 10 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.247 mmol) obtained in Example 1 ) Was added and 3 ml of N,N-dimethylformamide was added and stirred. Diethylsulfamoyl chloride 42.4mg (0.247mmol, 1eq) and triethylamine 38ul (0.272mmol, 1.1eq) obtained in step 1 were added to the reaction solution, followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and separated by column to give 13 mg (10%) of the title compound.

¹ H NMR (400MHz, CD ₃ OD): δ 7.75 (d, 1H), 7.57 (dd, 1H), 7.43 (s, 1H), 7.34 (s, 1H), 4.29 (q, 4H), 3.30 (m , 4H), 1.06 (t, 6H)

Mass[M+H]: 542.12

[ Example 52] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Pyrrolidine -One- Of sulphonohydrazide Produce

[Step 1] Pyrrolidine -One- Of sulfonyl chloride Produce

Using pyrrolidine instead of diethylamine, 4 g (90%) of the title compound was obtained in the same manner as in Step 1 of Example 51.

¹ H NMR (400MHz, CDCl ₃ ): δ 3.48 (m, 4H), 2.00 (m, 4H)

[Step 2] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Pyrrolidine -One- Of sulphonohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine obtained in Example 1 and compound obtained in Step 1 20 mg (9%) of the title compound was obtained in the same manner as in Step 2 of Example 51 using rollidine-1-sulfonyl chloride.

¹ H NMR (400MHz, CDCl ₃ ): δ 7.77 (d, 1H), 7.39 (dd, 1H), 7.33 (s, 2H), 4.12 (q, 4H), 3.35 (t, 2H), 1.56 (m, 4H), 1.24 (m, 2H)

Mass[M+H]: 540.10

[ Example 53] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of methanesulfonohydrazide Produce

In a 25 ml flask, compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 50mg (0.123mmol) obtained in Example 1 ) And 17.2 μl (1.0 eq) of methanesulfonyl chloride were used to obtain 21 mg (35%) of the title compound in the same manner as in Example 46.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 9.41(d, 2H), 7.70(m, 2H), 7.38(s, 1H), 7.22(s, 1H), 4.47(q, 4H), 3.32(s , 3H)

Mass[M+H]: 485.06

[ Example 54] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)propane-1- Of sulphonohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 145 mg (0.357 mmol) obtained in Example 1 ) And 1-propanesulfonyl chloride 40μl (1.0eq) were used in the same manner as in Example 46 to obtain 73mg (40%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 9.45(s, 1H), 9.37(s, 1H), 7.68(s, 2H), 7.40(s, 1H), 7.23(s, 1H), 4.46(q , 4H), 3.15~3.11(m, 2H), 1.86~1.80(m, 2H), 0.97(t, 3H)

Mass[M+H] :513.09

[ Example 55] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of ethanesulfonohydrazide Produce

In a 25 ml flask, compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 104 mg (0.255 mmol) obtained in Example 1 ) And 40 μl (1.0 eq) of ethanesulfonyl chloride were used to obtain 71 mg (56%) of the title compound in the same manner as in Example 46.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 9.46(s, 1H), 9.36(s, 1H), 7.67(s, 2H), 7.39(s, 1H), 7.22(s, 1H), 4.46(q , 4H), 3.16(q, 2H), 1.31(t, 3H)

Mass[M+H]: 499.08

[ Example 56] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)propane-2- Of sulphonohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And 2-propanesulfonyl chloride 27.6μl (1.0eq) were used in the same manner as in Example 46 to obtain 73mg (40%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 7.78(d, 1H), 7.40(dd, 1H), 7.35(s, 1H), 7.21(s, 1H), 4.13(q, 4H), 3.27~3.24 (m, 1H), 1.45 (d, 6H)

Mass[M+H]: 513.09

[ Example 57] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Of benzenesulfonylhydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And 31.4 μl (1.0 eq) of benzenesulfonyl chloride were used in the same manner as in Example 46 to obtain 39 mg (29%) of the title compound.

¹ H NMR (DMSO-d ₄ , 400MHz) δ 7.83(d, 2H), 7.59~7.47(m, 5H), 7.20(s, 1H), 7.14(s, 1H), 3.33(q, 4H)

Mass[M+H]: 547.08

[ Example 58] 2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N,N- Of dimethylhydrazinesulfonamide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And 26.4 μl (1.0 eq) of N,N-dimethylsulfamoyl chloride were used in the same manner as in Example 46 to obtain 39 mg (29%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ 7.79 (d, 1H), 7.40 (dd, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 4.13 (q, 4H), 2.83 (s, 6H) )

Mass[M+H]: 514.09

[ Example 59] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2,4- Of difluorobenzenesulfonylhydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And 36 μl (1.0 eq) of 2,4-difluorobenzenesulfonyl chloride were used to obtain 26 mg (18%) of the title compound in the same manner as in Example 46.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.89~7.83(m, 1H), 7.58~7.51(m, 2H), 7.27(s, 1H), 7.23(s, 1H), 7.13(t, 1H), 6.91(t, 1H), 4.28(q, 4H)

Mass[M+H]: 583.06

[ Example 60] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-2,5- Dichlorothiophene -3- Of sulphonohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And 2,5-dichlorothiophene-3-sulfonyl chloride 36.5 μl (1.0 eq) were used in the same manner as in Example 46 to obtain 85 mg (56%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.65 (d, 1H), 7.54 (dd, 1H), 7.30 (s, 1H), 7.21 (d, 2H), 4.29 (q, 4H)

Mass[M+H]: 620.96

[ Example 61] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-1- methyl -1H- Imidazole -2- Of sulphonohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) obtained in Example 1 ) And 1-methyl-1H-imidazole-2-sulfonyl chloride 36.5 μl (1.0 eq) were used in the same manner as in Example 46 to give 85 mg (56%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.57 (d, 1H), 7.51 (dd, 1H), 7.26 (s, 1H), 7.14 (d, 2H), 6.82 (s, 1H), 4.28 (q, 4H), 4.10(s, 3H)

Mass[M+H]: 551.08

[ Example 62] 3-((2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Hydrazinyl ) Sulfonyl ) Preparation of benzoic acid

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 300 mg (0.738 mmol) obtained in Example 1 ) And 3-(chlorosulfonyl)benzoic acid 163mg (1.0eq) were used in the same manner as in Example 46 to obtain 400mg (92%) of the title compound.

¹ H NMR (CDCl ₃ , 400MHz) δ 8.57(s, 1H), 8.18(dd, 2H), 7.83(d, 1H), 7.67~7.63(m, 2H), 7.32(d, 2H), 4.35(q , 4H)

Mass[M+H]: 591.07

[ Example 63] 3-((2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Hydrazinyl ) Sulfonyl )-N- Of methylbenzamide Produce

Compound 3-((2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl) obtained in Example 62) Sulfonyl) benzoic acid 100mg (0.169mmol) and methylamine 0.254ml (3.0eq) was carried out in the same manner as in Example 2 to obtain 70mg (69%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 8.04(d, 1H), 7.86(d, 1H), 7.52~7.45(m, 4H), 7.22(d, 2H), 4.27(q, 4H), 2.93( s, 3H)

Mass[M+H]: 604.10

[ Example 64] N-(4-((2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Hydrazinyl ) Sulfonyl ) Phenyl ) Acetamide Produce

Compound 3-((2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl) obtained in Example 62) Sulfonyl) benzoic acid 100mg (0.246mmol) and N-acetylsulfanilyl chloride 34.3μl (1.0eq) was carried out in the same manner as in Example 51 to obtain 56mg (38%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.80~7.78(m, 2H), 7.57~7.47(m, 4H), 7.27(s, 1H), 7.24(s, 1H), 4.27(q, 4H), 2.07(s, 3H)

Mass[M+H]: 604.10

[ Example 65] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- Methylpiperazine -One- Of sulphonohydrazide Produce

[Step 1] 4- Methylpiperazine -One- Of sulfonyl chloride Produce

In a 100 ml flask, using 2.2 ml (27.1 mmol, 3 eq) of sulfuryl chloride and 1 ml (9.0 mmol, 1 eq) of 1-methylpiperazine, proceeded in the same manner as in Step 1 of Example 51, and 5.0 g (93%) of the title compound Was obtained.

[Step 2] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-4- Methylpiperazine -One- Of sulphonohydrazide Produce

In a 100 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 500 mg (1.23 mmol) obtained in Example 1 ) And 244.6 mg (1.0 eq) of the compound 4-methylpiperazine-1-sulfonyl chloride obtained in step 1 were used in the same manner as in Example 51 to obtain 357 mg (51%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.80 (d, 1H), 7.32 (dd, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 4.31 (q, 4H), 3.37 (t, 4H), 2.38(t, 4H), 2.19(s, 3H)

Mass[M+H]: 569.13

[ Example 66] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)piperidin-1- Of sulphonohydrazide Produce

In a 25 ml flask, compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 150 mg (0.369 mmol) obtained in Example 1 ) And 1-piperidinesulfonyl chloride 67.8mg (1.0eq) were used in the same manner as in Example 51 to obtain 38mg (19%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.79 (d, 1H), 7.41 (d, 1H), 3.37 (s, 1H), 6.86 (s, 1H), 4.15 (q, 4H), 3.24 (t, 4H), 1.49-0.96 (m, 6H)

Mass[M+H]: 554.12

[ Example 67] 2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N-ethyl-N- Of methylhydrazinesulfonamide Produce

[Step 1] Of ethylmethylsulfamoyl chloride Produce

In a 100 ml flask, 2.83 ml (34.9 mmol, 3 eq) of sulfuryl chloride and 1 ml (11.6 mmol, 1 eq) of ethylmethylamine were used to obtain 5.0 g (93%) of the title compound in the same manner as in Step 1 of Example 51. I did.

[Step 2] 2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N-ethyl-N- Of methylhydrazinesulfonamide Produce

In a 25 ml flask, compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 150 mg (0.369 mmol) obtained in Example 1 ) And 58.2 mg (1.0 eq) of the compound ethylmethylsulfamoyl chloride obtained in step 1 were used in the same manner as in Example 51 to obtain 357 mg (51%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.80 (d, 1H), 7.32 (dd, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 4.31 (q, 4H), 3.37 (t, 4H), 2.38(t, 4H), 2.19(s, 3H)

Mass[M+H]: 569.13

¹ H NMR (CDCl ₃ , 400MHz) δ 7.78(d, 1H), 7.59(dd, 1H), 7.43(s, 1H), 7.36(s, 1H), 4.31(q, 4H), 3.30~3.24(m , 2H), 2.87(s, 3H), 1.09(t, 3H)

Mass[M+H]: 528.10

[ Example 68] N' -(6-((2R,5R)-2- methyl -5-((R)-2,2,2- Trifluoro -1-hydroxyethyl) Pyrrolidine -1-yl)-4-( Trifluoromethyl ) Quinolin-2-yl) Of acetohydrazide Produce

[Step 1] (R)-2,2,2- Trifluoro -1-((2R,5R)-1-(2- Hydrazinyl -4-( Trifluoromethyl ) Quinoline-6- yl )-5- Methylpyrrolidine Preparation of -2-yl)ethanol

(R)-1-((2R,5R)-1-(2-chloro-4-(trifluoromethyl)quinolin-6-yl)-5-methylpyrrolidin-2-yl obtained in Preparation Example 12 )-2,2,2-trifluoroethanol 300mg (0.73mmol) was dissolved in ethanol, and 232mg (78%) of the title compound was obtained using the same method as in Example 1.

Mass[M+H]: 409.14

[Step 2] N' -(6-((2R,5R)-2- methyl -5-((R)-2,2,2- Trifluoro -1-hydroxyethyl) Pyrrolidine -1-yl)-4-( Trifluoromethyl ) Quinolin-2-yl) Of acetohydrazide Produce

(R)-2,2,2-trifluoro-1-((2R,5R)-1-(2-hydrazinyl-4-(trifluoromethyl)quinoline-6-yl) obtained in step 1 166mg (65%) of the title compound was obtained in the same manner as in Example 3 using -5-methylpyrrolidin-2-yl)ethanol 232mg (0.57mmol) and acetyl chloride 44.7mg (0.57mmol).

Mass[M+H]: 451.15

[ Example 69] N' -(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Morpholine -4- Of sulphonohydrazide Produce

In a 25 ml flask, the compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 500 mg (1.23 mmol) obtained in Example 1 ) And morpholine-4-sulfonyl chloride 228.5mg (1.0eq) was carried out in the same manner as in Example 46 to obtain 277mg (56%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.80 (d, 1H), 7.59 (dd, 1H), 7.37 (d, 2H), 4.30 (q, 4H), 3.60 (t, 4H), 3.34 (t, 4H)

Mass[M+H]: 556.10

[ Example 70] 2-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N,N- Of dimethylhydrazinecarboxamide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100mg (0.246mmol) and dimethyl obtained in Example 1 Carbamoyl chloride was used in the same manner as in Example 3 to obtain 62 mg (53%) of the title compound.

¹ H NMR (CD ₃ OD, 400MHz) δ 7.76-7.73 (dd, 1H), 7.55 (d, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 4.30-4.25 (m, 4H), 3.00(s, 6H)

Mass[M+H]: 478.12

[ Example 71] N-(6-( Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl ) Quinolin-2-yl) Formohydrazide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) and formic acid obtained in Example 1 Using the same method as in Example 2, 62mg (58%) of the title compound was obtained.

¹ H NMR (CDCl ₃ , 400MHz) δ 8.32 (s, 1H), 7.76 (d, 1H), 7.38-7.35 (dd, 1H), 7.17 (s, 1H), 4.17-4.09 (m, 4H)

Mass[M+H]: 435.08

[ Example 72] 2-(6- Bis(2,2,2-trifluoroethyl)amino )-4-( Trifluoromethyl )Quinolin-2-yl)-N- Of ethylhydrazinecarbothioamide Produce

Compound 2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine 100 mg (0.246 mmol) and ethyl obtained in Example 1 82mg (68%) of the title compound was obtained by proceeding in the same manner as in Example 3 using isothiocyanate.

¹ H NMR (DMSO-d ₆ , 400MHz) δ 9.40(s, 1H), 9.03(s, 1H), 8.25(s, 1H), 7.70-7.65(m, 2H), 7.22(s, 1H), 7.01 (s, 1H), 4.49-4.45 (m, 4H), 3.47-3.44 (q, 2H), 1.04-1.00 (t, 3H)

Mass[M+H]: 494.10

[ Experimental example 1] Ability test for androgen receptor

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

compound IC ₅₀ [nM]
(mean±SE) compound IC ₅₀ [nM]
(mean±SE) Example 1 10.0 Example 37 363.0 Example 2 13.2±4.4 Example 38 38.6 Example 3 3.7±1.4 Example 39 15.1 Example 4 21.9 Example 40 156 Example 5 11.8 Example 41 684.3 Example 6 140.6 Example 42 123.3 Example 7 233.4 Example 43 116.4 Example 8 129.3 Example 44 6.7 Example 9 64.8 Example 45 4.6 Example 10 23.8±11.1 Example 46 5.2±2.3 Example 11 10.6±1.2 Example 47 2.9±1.5 Example 12 30.8±9.7 Example 48 4.3 Example 13 278.9±101.5 Example 49 4.2 Example 14 623.3±165.0 Example 50 2.9 Example 15 77.7±11.4 Example 51 70.2±6.5 Example 16 113.4±30.7 Example 52 64.1±7.6 Example 17 39.4±7.4 Example 53 3.9±1.1 Example 18 62.3±37.2 Example 54 2.7±0.3 Example 19 16.4±2.0 Example 55 1.9±0.6 Example 20 20.8±10.7 Example 56 1.9±0.2 Example 21 34.1±23.9 Example 57 1.6±0.2 Example 22 30.3 Example 58 5.4±0.6 Example 23 11.9±1.4 Example 59 2.6±0.3 Example 24 3.2±0.1 Example 60 2.0±0.1 Example 25 71.4 Example 61 1.7±0.5 Example 26 18.7 Example 62 2.4±0.7 Example 27 52.6±24.8 Example 63 2.3±0.3 Example 28 7.8±1.1 Example 64 4.6±1.8 Example 29 8.6±0.3 Example 65 5.4±1.0 Example 30 9.8±0.2 Example 66 7.8 Example 31 8.5±1.6 Example 67 9.7 Example 32 7.4±1.2 Example 68 19.4±3.8 Example 33 6.6±4.1 Example 69 2.4 Example 34 12.5 Example 70 84 Example 35 17.5±2.4 Example 71 13.1±5.4 Example 36 36.7 Example 72 33.6

As shown in Table 1, it was confirmed that the novel SARM derivatives of Examples 1 to 72 bind to the androgen receptor. These results mean that the SARM derivatives of Examples 1 to 72 may bind to the androgen receptor and affect the action of the androgen receptor.

[ Experimental example 2] Transcription activity test

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

CHO (Chinese hamster ovary) cell line (ATCC, #CCL-61) was inoculated into a 96 well plate at 1.5×10 ⁴ cells/well, incubated at 37°C for 24 hours, and then plasmid hAR(ORIGENE, #RC215316) 5ng and A transformed cell line into which a human androgen receptor gene and a luciferase gene were introduced was prepared by adding OPTI-MEM medium (Gibco, #31985) mixed with 100 ng of plasmid ARE-Luc (QIAGEN, #CCS-1019L). The transformed cell line was treated with SARM derivatives (Examples 1 to 72) at a concentration of 0.1 to 10,000 nM and reacted for 24 hours. Thereafter, 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 1 124 Example 37 278.7 Example 2 11.0±0.3 Example 38 160.3 Example 3 10 Example 39 76.17 Example 4 32.9 Example 41 274.7 Example 5 44.3 Example 42 40.9 Example 6 213.5 Example 44 10.4±1.6 Example 7 429.7 Example 45 13.9±6.8 Example 9 26 Example 46 18.3 Example 10 18.4±6.9 Example 47 7.2 Example 11 16.7±7.1 Example 48 96.1 Example 12 13.3±3.9 Example 49 8.3 Example 13 34.1 Example 50 12.7 Example 14 113.1 Example 51 16 Example 15 163 Example 52 12.1 Example 16 8.8 Example 53 1.6±0.7 Example 17 13.6 Example 54 2.1±1.4 Example 18 19.2 Example 55 1.6±1.1 Example 19 90.5 Example 56 5.8±3.9 Example 20 30 Example 57 4.7±2.9 Example 21 105.7 Example 58 1.6±0.1 Example 22 245.6 Example 59 9.6 Example 23 406.4 Example 60 6.1 Example 24 32.4±6.2 Example 61 2.8 Example 25 160.3 Example 62 3.9 Example 26 43.3 Example 63 5.3±1.5 Example 27 8.1±0.7 Example 64 10.3 Example 28 6.6±1.3 Example 65 1.6±0.2 Example 29 4.7 Example 66 20.6 Example 30 20.5±6.7 Example 67 9.8 Example 31 16.2 Example 68 11.1 Example 32 12.8 Example 69 2.4 Example 33 9.6 Example 70 84 Example 34 44.75 Example 71 13.1±5.4 Example 35 29.3 Example 72 33.6 Example 36 76.6

As shown in Table 2, it was confirmed that the compounds of Examples 1 to 72 acted on the androgen receptor, thereby increasing the androgen activity.

[ Experimental example 3] castrated male In rat Efficacy test

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

Results of the efficacy test in castrated male rats designation Dose (mg/kg) Big anal prostate Seminal vesicle Intact control 100±4.2 100.0±5.8 100.0±3.2 Example 11 0.1 1.9±0.1 1.1±0.0 0.6±0.1 0.3 3.6±0.1 0.4±0.0 1.7±0.1 One 8.5±0.6 4.1±0.7 2.6±0.2 3 20.1±0.7 4.8±0.2 2.9±0.2 10 37.3±2.1 8.4±0.6 3.9±0.3 30 64.8±2.9 16.5±2.7 5.8±0.7 100 116.1±3.3 34.0±4.7 20.3±2.4 Example 28 0.3 22.7±0.7 3.5±0.3 3.7±0.3 One 26.4±1.3 8.2±1.2 1.8±0.3 3 44.3±1.8 12.5±2.3 5.7±0.6 10 88.0±6.8 34.4±1.8 14.6±2.6 30 113.8±3.4 41.8±2.6 32.1±2.5 100 114.5±8.6 52.4±1.4 51.6±5.7 Example 53 0 6.5±0.5 3.0±0.8 -0.6±-0.1 One 16.7±0.8 5.7±0.3 1.3±0.1 3 33.9±2.1 10.7±2.2 5.1±0.6 10 73.2±3.0 21.0±2.3 9.9±1.1 30 90.7±4.3 34.0±2.4 17.5±2.9 100 124.3±4.0 53.8±5.8 41.5±4.2 Example 58 0.1 12.7±0.8 2.7±0.3 1.0±0.1 0.3 22.0±0.9 3.9±0.4 1.9±0.1 One 21.8±1.3 7.6±0.8 3.5±0.4 3 41.4±11.3 8.4±1.4 5.5±0.5 10 50.4±3.0 12.5±1.3 8.5±1.7 30 86.3±5.2 14.5±0.8 4.4±1.1 100 114.6±5.3 35.3±4.5 30.8±4.9 Example 61 0.1 -0.3±0.0 -0.1±0.0 -0.6±0.0 One 5.7±0.4 1.6±0.1 0.3±0.0 10 52.9±3.2 8.6±2.4 4.4±0.6 100 74.6±1.9 27.9±7.2 31.9±3.6 Example 69 0.1 -3.2±0.3 0.6±0.0 -1.0±0.1 One 0.4±0.0 2.2±0.3 -0.9±0.1 10 32.0±2.6 7.6±0.9 4.9±0.6 100 95.2±2.0 33.8±3.3 42.5±5.3

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

Claims (10)

A compound of formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
R ₁ is unsubstituted or substituted amino, or unsubstituted or substituted pyrrolidinyl;
In the definition of R ₁ ,
The substituted amino is amino in which one or more of the hydrogens contained in amino are each independently substituted with an unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms, and the substituted alkyl is included in the alkyl. At least one of the hydrogens is each independently a linear, branched or cyclic alkyl having 1 to 3 carbon atoms substituted with hydroxy or halogen,
The substituted pyrrolidinyl is pyrrolidinyl wherein at least one of the hydrogens contained in pyrrolidinyl is each independently substituted with unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms, and the substituted Alkyl is a linear, branched or cyclic alkyl having 1 to 3 carbon atoms in which at least one of the hydrogens contained in the alkyl is independently substituted with hydroxy or halogen,
R ₂ is unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms;
In the definition of R ₂ ,
The substituted alkyl is a linear, branched or cyclic alkyl having 1 to 3 carbon atoms in which at least one of the hydrogens contained in the alkyl is independently substituted with halogen,
R ₃ is -N(R ₄ )NR ₅ R ₆ ;
R ₄ and R ₅ are each independently hydrogen or alkyl having 1 to 3 carbon atoms;
R ₆ is selected from the group consisting of hydrogen, -C(O)(CH ₂ )nR ₇ , -C(S)(CH ₂ )nR ₇ , and -S(O) ₂ (CH ₂ )nR ₇ ;
n is 0 or an integer from 1 to 3;
R ₇ is hydrogen, halogen, hydroxy, cyano, unsubstituted or substituted amino, unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms, alkoxy having 1 to 3 carbon atoms, -C(O )R ₈ , -NHC(O)R ₈ , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocycle; And
R ₈ is selected from the group consisting of hydroxy, alkyl having 1 to 3 carbon atoms, and alkoxy having 1 to 3 carbon atoms;
In the definition of R ₇ above,
The substituted amino is amino in which one or more hydrogens are each independently substituted with unsubstituted or substituted linear, branched or cyclic alkyl having 1 to 6 carbon atoms, and in the substituted alkyl, one or more hydrogens are each independently halogen or Hydroxy substituted linear, branched or cyclic alkyl having 1 to 3 carbon atoms, and the substituted aryl is halogen, cyano, alkoxy having 1 to 3 carbon atoms, -C(O)R ₉ , -C(O) NHR ₉ or -NHC(O)R ₉ substituted aryl, wherein the substituted heteroaryl is a heteroaryl in which one or more hydrogens are each independently substituted with halogen or linear, branched or cyclic alkyl having 1 to 3 carbon atoms And, the substituted heterocycle is a heterocycle in which at least one hydrogen is substituted with oxo; And
R ₉ is selected from the group consisting of hydroxy, alkyl having 1 to 3 carbon atoms, and alkoxy having 1 to 3 carbon atoms. delete delete delete delete The method of claim 1,
The compound is selected from the group consisting of,
A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
2-hydrazinyl-N,N-bis(2,2,2-trifluoroethyl)-4-(trifluoromethyl)quinolin-6-amine;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methyloxazole-5-carbohydrazide ;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)isoxazole-5-carbohydrazide;
N-(2-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)-2-oxo Ethyl)acetamide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-oxooxazolidine-4-carbohydra Zayed;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1H-pyrrole-2-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1-methyl-1H-pyrrole-2-carbohigh Drazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1H-pyrrole-3-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)benzohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2,4,5-trifluorobenzohydra Zayed;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)nicotinohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)pyrazine-2-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1H-imidazole-4-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methyl-1H-imidazole-5-carbo Hydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)furan-3-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-6-methylnicotinohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)thiazole-4-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)picolinohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)isonicotinohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methylisoxazole-3-carbohydra Zayed;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)furan-2-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-5-methylfuran-2-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-5-fluoronicotinohydrazide;
3-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinecarbonyl)-N-methylbenzamide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)pivalohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-cyanoacetohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-chloroacetohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)acetohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-hydroxyacetohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-methoxyacetohydrazide;
(R)-N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-hydroxypropanehydrazide ;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)tetrahydrofuran-2-carbohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)tetrahydrofuran-3-carbohydrazide;
Methyl 2-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)-2-oxoacetate;
2-(2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)-2-oxoacetic acid;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-3-hydroxybutanehydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2-(pyrrolidin-1-yl)aceto Hydrazide;
Methyl 2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinecarboxylate;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2,2,2-trifluoroacetohydra Zayed;
N-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N,N'-dimethylacetohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N-methylacetohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N'-methylacetohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)propionohydrazide;
N'-(6-bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)isobutyrohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methoxybenzenesulfonylhydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-cyanobenzenesulfonylhydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methylbenzenesulfonylhydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-fluorobenzenesulfonylhydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-3-cyanobenzenesulfonylhydrazide;
2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N,N-diethylhydrazinesulfonamide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)pyrrolidine-1-sulfonohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)methanesulfonohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)propane-1-sulfonohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)ethanesulfonohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)propane-2-sulfonohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)benzenesulfonylhydrazide;
2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N,N-dimethylhydrazinesulfonamide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2,4-difluorobenzenesulfonylhydra Zayed;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-2,5-dichlorothiophene-3-sulfono Hydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-1-methyl-1H-imidazole-2-sul Phonohydrazide;
3-((2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)sulfonyl)benzoic acid;
3-((2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)sulfonyl)-N- Methylbenzamide;
N-(4-((2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)hydrazinyl)sulfonyl) Phenyl)acetamide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-4-methylpiperazine-1-sulfonohydra Zayed;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)piperidine-1-sulfonohydrazide;
2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N-ethyl-N-methylhydrazinesulfonamide;
N'-(6-((2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-4 -(Trifluoromethyl)quinolin-2-yl)acetohydrazide;
N'-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)morpholine-4-sulfonohydrazide;
2-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N,N-dimethylhydrazinecarboxamide;
N-(6-(bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)formohydrazide; And
2-(6-bis(2,2,2-trifluoroethyl)amino)-4-(trifluoromethyl)quinolin-2-yl)-N-ethylhydrazinecarbothioamide.
Comprising the compound of any one of claims 1 and 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,
As a pharmaceutical composition for the prevention or treatment of diseases or symptoms that can respond to treatment or improve symptoms due to increased androgen activity,
The above diseases or symptoms include sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, muscle dystropy, cachexia, muscular dystrophy, postoperative muscle loss, neurotransmitter 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 Comprising the compound of any one of claims 1 and 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
As a health functional food composition for the prevention or improvement of a disease or symptom that improves symptoms due to increased androgen activity or responds to treatment,
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) preparing a compound of Formula 3 by halogenating the compound of Formula 2 below; And
(b) comprising the step of introducing R ₃ to the prepared compound of Formula 3,
A method of preparing the compound of formula 1 of claim 1:
[Formula 2]

[Formula 3]

In Formulas 2 and 3, R ₁ , R ₂ and R ₃ are as defined in claim 1, and Hal is halogen.