KR101103503B1 - New nicotinamide derivatives with anti-androgen effect, process for preparing and anti-androgens comprising the same - Google Patents

Abstract

The present invention relates to a novel substance having anti-androgen activity represented by the following formula (1), nicotinamide derivatives and pharmaceutically acceptable salts thereof, a preparation method thereof, and an anti-androgen agent containing the same as an active ingredient. More specifically, the nicotinamide derivatives of the present invention have anti-androgen activity and can be used as a prophylactic or therapeutic agent for androgen diseases such as prostate disease, androgenetic alopecia and acne.

[Formula 1]

In Formula 1, R ₁ , R ₂ , R ₃ , R ₄ , Ar and a are as defined in the detailed description of the invention, respectively.

Anti-androgens, prostate cancer, DIMN, DHT, AR, PSA protein

Description

Nicotinamide derivatives having anti-androgen activity, preparation method thereof, and anti-androgen containing the same as an active ingredient {New nicotinamide derivatives with anti-androgen effect, process for preparing and anti-androgens comprising the same}

The present invention relates to a novel nicotinamide derivative having anti-androgen activity, a pharmaceutically acceptable salt thereof, a preparation method thereof, and an anti-androgen agent containing the same as an active ingredient. More specifically, the nicotinamide derivatives of the present invention have anti-androgen activity and can be used as a prophylactic or therapeutic agent for androgen diseases such as prostate disease, androgenetic alopecia and acne.

Anti-androgen therapy is commonly used for men with prostate cancer or prostatic hyperplasia in men, as well as other alopecia and acne treatment. Since anti-androgen therapy inhibits the action of hormones, the side effects of treatment should be noted.

Anti-androgens currently used in prostate cancer include bicalutamide, flutamide, nilutamide, and cyproterone acetate, among others. Unlike the other three, steroidal anti-androgens are competitively inhibited in the androgen receptor.

The known side effects of cyproterone acetate have been reported to be sexual dysfunction due to lethargy and decreased male hormones, rarely female breasts, and cardiovascular disease and liver cancer. Liver cancer is a fatal side effect.

Side effects from taking nilutamide have been reported with decreased vision, alcohol sensitization, nausea, lethargy, epilepsy and liver cancer. Liver cancer has been reported rarely, but it can cause fatal side effects like cyproterone acetate.

Side effects from taking flutamide include diarrhea and lethargy gynecomastia. It has been reported that liver cancer is more likely than other antiandrogens when taking flutamide.

Bicalutamide (Bicalutamide) is the most widely used anti-androgen, and it is a prostate cancer treatment that overcomes the disadvantages such as decreased sexual function and bone density caused by male hormone decline when taking other anti-androgens. However, bicalutamide has also been reported to have side effects. Side effects of taking bicalutamide include diarrhea, lethargy, nausea, blushing, gynecomastia and breast pain, and rarely side effects from taking medication. have.

The bicalutamide, flutamide, nilutamide, cyproterone acetate, and the like were administered to inactivate the metastatic activity of the human androgen receptor, but eventually treatment During prostate carcinoma, it is resistant to hormone deficiency and begins to regrow. Despite treatment, it has been found that androgen receptors are present and still remain active.

Although bicalutamide is widely used as an anti-androgen substance in the treatment of prostate cancer, there is a lack of effective anti-androgens specifically acting on prostate cancer.

Accordingly, the present invention seeks to develop an anti-androgen substance useful for the prevention and treatment of androgenic diseases such as prostate disease, androgenetic alopecia and acne.

It is an object of the present invention to provide novel nicotinamide derivatives or pharmaceutically acceptable salts thereof having anti-androgen activity.

Another object of the present invention is to provide a pharmaceutical composition having an anti-androgen activity comprising the novel nicotinamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of androgen diseases, including the nicotinamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a novel substance having anti-androgen activity represented by the following formula (1), nicotinamide derivatives and pharmaceutically acceptable salts thereof, a preparation method thereof, and an anti-androgen agent containing the same as an active ingredient. More specifically, the nicotinamide derivatives of the present invention have anti-androgen activity and can be used as a prophylactic or therapeutic agent for androgen diseases such as prostate disease, androgenetic alopecia and acne.

[Formula 1]

[Wherein Ar is (C6-C20) aryl or (C3-C20) heteroaryl, and aryl and heteroaryl of Ar may be further substituted with halogen, (C1-C20) alkyl or (C1-C20) alkoxy There is;

R ₁ is halogen, 5- to 7-membered N-heterocycloalkyl, 5- to 7-membered N-heterocycloalkyl fused with an aromatic ring, and the N-heterocycloalkyl and aromatic rings of R ₁ are fused. N-heterocycloalkyl may be further substituted with (C1-C20) alkyl or (C1-C20) alkoxy;

R ₂ to R ₄ are, independently from each other, hydrogen or (C1-C20) alkyl;

a is an integer of 0 to 10.]

Nicotine amide derivative of Formula 1 according to the present invention can be exemplified by the compound of formula 2 to 7 below.

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Wherein R ₁ is halogen, 5- to 7-membered N-heterocycloalkyl, 5- to 7-membered N-heterocycloalkyl fused with an aromatic ring, and N-heterocycloalkyl and aromatic of R ₁ Ring-fused N-heterocycloalkyl may be further substituted with (C1-C20) alkyl or (C1-C20) alkoxy; R ₁₁ to R ₁₅ are independently of each other hydrogen, halogen, (C 1 -C 20) alkyl or (C 1 -C 20) alkoxy; X is O or S; R ₂ is hydrogen or (C 1 -C 20) alkyl.]

,

,

또는

이고, R₂₁ 및 R₂₂는 서로 독립적으로 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, 펜틸, 헥실, 헵틸, 옥틸, 노닐, 데실, 메톡시, 에톡시, n-프로폭시, i-포로폭시, n-부톡시, i-부톡시, t-부톡시, 펜톡시, 헥실옥시, 헵틸옥시 또는 옥틸옥시이고, R₁₁ 내지 R₁₅는 수소, 플루오르, 클로로, 브로모, 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, 펜틸, 헥실, 헵틸, 옥틸, 노닐, 데실, 메톡시, 에톡시, n-프로폭시, i-포로폭시, n-부톡시, i-부톡시, t-부톡시, 펜톡시, 헥실옥시, 헵틸옥시 또는 옥틸옥시이고, X는 O 또는 S이고, R₂는 수소 또는 메틸인 것을 특징으로 한다.R ₁ is Cl, F, Br,

,

,

or

R ₂₁ and R ₂₂ are each independently of the other methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, methoxy, Ethoxy, n-propoxy, i-popoxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, hexyloxy, heptyloxy or octyloxy, R ₁₁ to R ₁₅ are hydrogen, Fluorine, chloro, bromo, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, methoxy, ethoxy, n -Propoxy, i-pooxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, hexyloxy, heptyloxy or octyloxy, X is O or S, R ₂ is hydrogen or It is characterized by being methyl.

Nicotinamide derivatives according to the present invention may be specifically exemplified as the following compounds, but the following compounds do not limit the present invention:

6-chloro-N- (6-methylpyridin-2-yl) nicotinamide; 6-chloro-N- (5-methylpyridin-2-yl) nicotinamide; 6-chloro-N- (4-methylpyridin-2-yl) nicotinamide; 6-chloro-N- (3-methylpyridin-2-yl) nicotinamide; 6-chloro-N-pyridin-2-yl-nicotinamide; 6-chloro-N- (6-methoxypyridin-3-yl) nicotinamide; 6-chloro-N-pyrimidin-2-yl-nicotinamide; 6-chloro-N-thiazol-2-yl-nicotinamide; 6-chloro-N-phenylnicotinamide; 6-chloro-N-O-tolylnicotinamide; 6-chloro-N- (3-methoxyphenyl) nicotinamide; 6-chloro-N- (2-methoxyphenyl) nicotinamide; 6-chloro-N- (4-fluorophenyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (5-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (4-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methylpyridin-2-yl) nicotinamide; 6- (3,4-Dihydro-1H-isoquinolin-2-yl) -N-pyridin-2-yl-nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methoxypyridine-3-) nicotinamide; 6- (3,4-Dihydro-1H-isoquinolin-2-yl) -N-pyrimidin-2-yl-nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-thiazol-2-yl-nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-phenylnicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-O-tolylnicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxyphenyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (2-methoxyphenyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (4-fluorophenyl) nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methylpyridin2-yl) -nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (5-methylpyridin-2-yl) -nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (4-methylpyridin-2-yl) -nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methylpyridin-2-yl) -nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N-pyridin-2-yl-nicotinamide; 6- (piperidin-1-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (4-ethylpiperazin-1-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (4-methylpiperazin-1-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (4-methyl-1,4-diazepan-1-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methoxypyridin-3-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-methyl-N- (4-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxybenzyl) nicotinamide; 6- (piperidin-1-yl) -N- (3-methoxybenzyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-methyl-N- (3-methoxyphenyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-methyl-N- (2-methylphenyl) nicotinamide; 6- (3,4-Dihydro-1H-isoquinolin-2-yl) -N-methyl-N- (2-methoxyphenyl) nicotinamide.

Nicotinamide derivatives according to the present invention may be prepared as shown in Schemes 1 and 2 according to the type of substituents of R1. The following preparation method does not limit the method for preparing the nicotinamide derivative of Formula 1 according to the present invention, and modifications of the following preparation method will be apparent to those skilled in the art.

Scheme 1 is a case in which R ₁ is halogen, and a carboxylic acid derivative (a) is refluxed with thionyl chloride to prepare an acid chloride (b), and then reacted with various amine compounds (c) to make R ₁ halogen. The nicotinamide derivative of 1 can be prepared.

Scheme 1

[Wherein Ar is (C6-C20) aryl or (C3-C20) heteroaryl, and aryl and heteroaryl of Ar may be further substituted with halogen, (C1-C20) alkyl or (C1-C20) alkoxy There is; R ₁ is halogen; R ₂ to R ₄ are, independently from each other, hydrogen or (C1-C20) alkyl; a is an integer of 0 to 10.]

Scheme 2 is a halogen compound (d) and an N-heterocycloalkyl compound when R ₁ is a 5- to 7-membered N-heterocycloalkyl or a 5- to 7-membered N-heterocycloalkyl fused with an aromatic ring. (e) may be reacted to prepare a nicotinamide derivative of Formula 1 wherein R ₁ is a 5- to 7-membered N-heterocycloalkyl or an aromatic ring is a 5- to 7-membered N-heterocycloalkyl fused. .

Scheme 2

[Wherein Y is halogen; Ar is (C6-C20) aryl or (C3-C20) heteroaryl, wherein the aryl and heteroaryl of Ar may be further substituted with halogen, (C1-C20) alkyl or (C1-C20) alkoxy; R ₁ is a 5- to 7-membered N-heterocycloalkyl or a 5- to 7-membered N-heterocycloalkyl fused with an aromatic ring, and the N-heterocycloalkyl and an aromatic ring of R ₁ are fused to N- Heterocycloalkyl may be further substituted with (C1-C20) alkyl or (C1-C20) alkoxy; Halogen; R ₂ to R ₄ are, independently from each other, hydrogen or (C1-C20) alkyl; a is an integer of 0 to 10.]

Nicotinamide derivatives of the formula (1) according to the present invention is a substance acting as an anti-androgen, the present invention is an agent having an anti-androgen activity comprising the nicotinamide derivative of the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient To provide a pharmaceutical composition. In addition, the present invention provides a composition for the prevention or treatment of androgen disorders, comprising an effective amount of the nicotinamide derivative of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. All. Androgenetic diseases that can be prevented or treated by the pharmaceutical composition of the present invention include prostate diseases such as prostate cancer, prostatic hyperplasia, prostatitis, prostatic seminal vesicles, prostatic vaginitis, and male alopecia and acne, in particular the present invention. The pharmaceutical composition of the present invention is used to prevent or treat prostate cancer by inhibiting prostate cancer cell line proliferation.

Salts suitable for use in the medicament may include organic and inorganic acids, solvates and hydrates of the salt compounds are also included in the present invention. Pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy al Obtained from non-toxic organic acids such as canoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Nate, Xylene Sulfonate, Phenyl Acetate, Phenyl Propionate, Phenyl Butyrate, Citrate, Lactate, β-hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1 Sulfonates, naphthalene-2-sulfonates or mandelate.

The amount of nicotinamide derivative of formula (1) or a pharmaceutically acceptable salt thereof used to achieve a therapeutic effect according to the present invention, as well as the specific compound, the method of administration, the subject to be treated and the disease to be treated, Nicotine amide derivatives and the pharmaceutically acceptable salts thereof are usually 50mg / Kg to 150mg / Kg, can be administered once or several times a day, the dosage is the weight, age, sex, health status, diet of the patient Depending on the administration time, administration method, excretion rate and severity of the disease, etc., the administration method can be administered orally or parenterally (for example, intravenously) in the form of pills, capsules, powders and solutions. can do.

Oral administration of the pharmaceutical composition according to the present invention can be prepared in all the various forms, for example tablets, powders, dry syrups, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills It can exist in many forms, such as drinks, sublingual tablets, etc.

Tablets according to the present invention may be administered to a patient in any form or manner in which an effective amount is bioavailable, ie, by oral route, and is suitable for administration depending on the nature of the disease state to be treated, the stage of the disease, and other relevant circumstances. The form or manner can be easily selected and the composition according to the invention can comprise one or more pharmaceutically acceptable excipients, wherein the proportions and properties of such excipients are dependent on the solubility and chemical properties of the selected tablets, the chosen administration Determined by the route and standard pharmaceutical practice.

The composition according to the invention may comprise a pharmaceutically acceptable excipient, in addition to the nicotinamide derivatives of formula 1 and pharmaceutically acceptable salts thereof, and any one or more therapeutic ingredients. Excipient materials can be solid or semisolid materials that can function as a vehicle or replacement of the active ingredient, and suitable excipients are well known in the art. Excipient materials may be selected in connection with the intended dosage form, specifically for tablets, powders, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills, sublingual tablets or syrup forms, The therapeutically active drug component can be combined with any non-toxic pharmaceutically acceptable inert excipients such as lactose or starch. Optionally, the pharmaceutical tablets of the present invention may contain a binder such as amorphous cellulose, gum tragacanth or gelatin, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, and a glidant such as colloidal silicon dioxide. It may also contain sweetening agents such as sucrose or saccharin, colorants or flavoring agents such as peppermint or methyl salicylate. Because of their ease of administration, tablets may be the most advantageous oral unit dosage form, and if desired, tablets may be coated with sugar, shellac or other enteric coatings in standard aqueous or non-aqueous techniques.

The novel nicotinamide derivatives of the present invention compete with androgen receptor (AR) and by binding to androgen receptor (AR; Androgen Receptor) by competing with the dihydrotestosterone (DHT) agonist of androgen receptor (AR; Androgen Receptor), transcriptional activity (AR) ) And the anti-androgen effect. In addition, the androgen receptor is an important factor in prostate cancer, by inhibiting the prostate cancer cell line (LNCaP) by treating the prostate cancer cell line (LNCaP) by treating the nicotinamide derivative of the present invention, as a target protein in prostate cancer It also inhibits the expression of known PSA proteins, suggesting that they have an effective antiandrogen effect in prostate cancer cell lines. That is, the nicotinamide derivative of the present invention has an anti-androgen effect and is useful for the prevention and treatment of androgen diseases such as prostate disease, androgenetic alopecia and acne.

Hereinafter, the present invention will be described in detail by Examples and Experimental Examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.

Example  1-13

Example 1 Preparation of 6-chloro-N- (6-methylpyridin-2-yl) nicotinamide [4a]

6-Chloronicotinic acid 1 (1.57 g, 10 mmol) and SOCl ₂ were mixed and refluxed overnight. Excess SOCl ₂ was removed by vacuum distillation. The residue 2 was dissolved in CH ₂ Cl ₂ , and a solution of 2-amino-methylpyridine 3a (5.4 g, 50 mmol), triethylamine (1.71 g, 17 mmol) and CH ₂ Cl ₂ was carefully added. . The reaction mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was extracted with CH ₂ Cl ₂ , washed with water and brine, and dried over Na ₂ SO ₄ . The organic layer was concentrated in vacuo and the residue was recrystallized from 2-propanol to give the compound 4a as a white solid (2.05 g, 83%). IR (cm- ¹ ): 3309 (NH), 1665 (CO). ¹ H NMR (300 MHz, CDCl ₃ ): 8.95 (1H, m, -N = CH), 8.73 (1H, s, NH), 8.2 8.19 (1H, m, Aromatic-H), 8.13 (1H, d, J = 8.3 Hz, Aromatic-H), 7.76 (1H, m, Aromatic-H), 7.46 (1H, d, J = 8.3 Hz, Aromatic-H), 6.98 (1H, d, J = 7.4 Hz, Aromatic- H), 2.46 (3H, s, -CH ₃ ). ESI-MS: m / z (248, MH ⁺ ).

Example 2 Preparation of 6-chloro-N- (5-methylpyridin-2-yl) nicotinamide [4b]

Compound 4b was obtained by the same method as the synthesis of compound 4a using compound 1 (1.57 g, 10 mmol) and compound 3b (5.4 g, 50 mmol) in the presence of triethylamine (1.71 g, 17 mmol) (white solid, 1.6 g, 65%). IR (cm- ¹ ): 3237 (NH), 1687 (CO). ¹ H NMR (300 MHz, CDCl ₃ ): 8.94 8.92 (2H, m, -N = CH, NH), 8.24 8.18 (2H, m, Aromatic-H), 8.04 (1H, s, -N = CH), 7.61 7.58 (1H, m, Aromatic-H), 7.46 (1H, d, J = 8.3 Hz, Aromatic-H), 2.32 (3H, s, -CH ₃ ). ESI-MS: m / z (248, MH ⁺ ).

Example 3 Preparation of 6-chloro-N- (4-methylpyridin-2-yl) nicotinamide [4c]

Compound 4c was obtained by the same method as the synthesis of compound 4a, using compound 1 (2.36 g, 15 mmol) and compound 3c (8.1 g, 75 mmol) in the presence of triethylamine (2.57 g, 25.5 mmol) (yellow solid). , 1.6 g, 65%). IR (cm- ¹ ): 3237 (NH), 1687 (CO). ¹ H NMR (300 MHz, CDCl ₃ ): 8.94 8.92 (2H, m, -N = CH, NH), 8.24 8.18 (2H, m, Aromatic-H), 8.04 (1H, s, -N = CH), 7.61 7.58 (1H, m, Aromatic-H), 7.46 (1H, d, J = 8.3 Hz, Aromatic-H), 2.32 (3H, s, -CH ₃ ). ESI-MS: m / z (248, MH ⁺ ).

Example 4 Preparation of 6-chloro-N- (3-methylpyridin-2-yl) nicotinamide [4d]

Compound 4d was obtained by the same method as the synthesis of compound 4a, using compound 1 (2.35 g, 15 mmol) and compound 3d (0.81 g, 7.5 mmol) in the presence of triethylamine (2.58 g, 25.5 mmol) (white solid) , 950 mg, 25%). ¹ H NMR (300 MHz, CDCl ₃ ): 9.03 (1H, s, -N = CH), 8.30 (1H, d, J = 7.2 Hz, -N = CH), 8.11 (1H, m, Aromatic-H) , 7.69 (1H, d, J = 7.5 Hz, Aromatic-H), 7.36 (1H, d, J = 8.1 Hz, Aromatic-H), 7.13 (1H, s, Aromatic-H), 2.37 (3H, s, -CH ₃ ). ESI-MS: m / z (248, MH ⁺ ).

Example 5 Preparation of 6-Chloro-N-pyridin-2-yl-nicotinamide [4e]

Compound 4e was obtained by the same method as the synthesis of compound 4a using compound 1 (2.36 g, 15 mmol) and compound 3e (7.05 g, 75 mmol) in the presence of triethylamine (2.57 g, 25.5 mmol) (yellow solid) , 2.4 g, 68%). ¹ H NMR (300 MHz, CDCl ₃ ): 9.33 (1H, s, NH), 8.95 (1H, d, J = 2.4 Hz, -N = CH), 8.36 8.33 (1H, m, -N = CH), 8.22 8.19 (2H, m, Aromatic-H), 7.81 7.75 (1H, m, Aromatic-H), 7.45 (1H, d, J = 8.1 Hz, Aromatic-H), 7.10 (1H, t, J = 5.1 Hz , Aromatic-H). ESI-MS: m / z (234, MH ⁺ ).

Example 6 Preparation of 6-chloro-N- (6-methoxypyridin-3-yl) nicotinamide [4f]

In the presence of triethylamine (0.49 g, 4.83 mmol), Compound 2 (440 mg, 2.5 mmol) and Compound 3f (352 mg, 2.8 mmol) were reacted at 0 ° C. for 90 minutes in the same manner as in the synthesis of Compound 4a. Obtained compound 4f (reddish solid, 172 mg, 26%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.87 (1H, d, J = 2.4 Hz, -N = CH), 8.28 (1H, d, J = 2.7 Hz, -N = CH), 8.18 (1H, dd , J = 8.1, 2.4 Hz, Aromatic-H), 7.98 (1H, dd, J = 8.7, 2.7 Hz, Aromatic-H), 7.65 (1H, s, NH), 7.49 (1H, d, J = 8.1 Hz , Aromatic-H), 6.81 (1H, d, J = 8.7 Hz, Aromatic-H), 3.95 (3H, s, -CH ₃ ). ESI-MS: m / z (262, MH ⁻ ).

Example 7 Preparation of 6-Chloro-N-pyridin-2-yl-nicotinamide [4 g]

Compound 4g was obtained by the same method as the synthesis of compound 4a, using compound 1 (1.58 g, 10 mmol) and compound 3g (1.90 g, 20 mmol) in the presence of triethylamine (1.72 g, 17 mmol) (yellow solid). , 0.66 g, 28%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.71 (1H, d, J = 1.8 Hz, -N = CH), 8.66 (1H, d, J = 5.1 Hz, -N = CH), 8.05 (1H, d , J = 2.7 Hz, -N = CH), 8.02 (1H, d, J = 2.4 Hz, Aromatic-H), 7.41 (1H, dd, J = 8.4, 0.6 Hz, Aromatic-H), 7.27 7.21 (1H , m, Aromatic-H). ESI-MS: m / z (233, MH ⁻ ).

Example 8 Preparation of 6-chloro-N-thiazol-2-yl-nicotinamide [4h]

Compound 4h was obtained by the same method as the synthesis of compound 4a using compound 1 (1.58 g, 10 mmol) and compound 3h (2.06 g, 20 mmol) in the presence of triethylamine (1.72 g, 17 mmol) (white solid) , 0.67 g, 28%). ¹ H NMR (300 MHz, CDCl ₃ ): 9.02 (1H, d, J = 2.4 Hz, -N = CH), 8.27 (1H, dd, J = 8.4, 2.7 Hz, Aromatic-H), 7.26 (1H, dd, J = 7.5, 0.6 Hz, Aromatic-H), 7.33 7.26 (2H, m, NH, -N = CH), 7.06 (1H, d, J = 3.6 Hz, -S-CH). ESI-MS: m / z (238, MH ⁻ ).

[ Example  9] 6- Chloro -N- Of phenylnicotinamide [4i]  Produce

Compound 4i was obtained by the same method as the synthesis of compound 4a using compound 1 (1.71 g, 17 mmol) and compound 3i (4.65 g, 50 mmol) in the presence of triethylamine (1.71 g, 17 mmol) (white solid) , 1.39 g, 60%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.85 (1H, d, J = 2.4 Hz, -N = CH), 8.16 (1H, dd, J = 8.4, 2.4 Hz, Aromatic-H), 7.83 (1H, s, NH), 7.62-7.16 (6H, m, Aromatic-H). ESI-MS: m / z (231, MH ⁻ ).

[ Example  10] 6- Chloro -N- O - Of tolylnicotinamide [4j]  Produce

Compound 4j was obtained by the same method as the synthesis of compound 4a, using compound 1 (1.00 g, 6.3 mmol) and compound 3j (3.38 g, 31.5 mmol) in the presence of triethylamine (1.08 g, 10.7 mmol) (off-white solid) , 0.76 g, 49%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.85 (1H, d, J = 2.1 Hz, -N = CH), 8.15 (1H, dd, J = 8.1, 2.4 Hz, Aromatic-H), 7.78 (1 H, d, J = 7.5 Hz, Aromatic-H), 7.68 (1H, s, NH), 7.46-7.13 (4H, m, Aromatic-H), 2.31 (3H, s, -CH ₃ ). ESI-MS: m / z (245, MH ⁻ ).

[ Example  11] 6- Chloro -N- (3- Methoxyphenyl ) Nicotinamide Preparation of [4k]

Compound 4k was obtained in the same manner as the synthesis of Compound 4a using compound 1 (1.00 g, 6.3 mmol) and compound 3k (3.88 g, 31.5 mmol) in the presence of triethylamine (1.08 g, 10.7 mmol) (light red). Color solid, 1.23 g, 75%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.85 (1H, d, J = 1.8 Hz, -N = CH), 8.16 (1H, dd, J = 8.1, 2.4 Hz, Aromatic-H), 7.72 (1H, s, NH), 7.47 (1H, d, J = 7.5 Hz, Aromatic-H), 7.38-6.73 (4H, m, Aromatic-H), 3.84 (3H, s, -OCH ₃ ). ESI-MS: m / z (261, MH ⁻ ).

[ Example  12] 6- Chloro -N- (2- Methoxyphenyl ) Nicotinamide Preparation of [4l]

Compound 4l was obtained by the same method as the synthesis of compound 4a, using compound 1 (1.00 g, 6.3 mmol) and compound 3l (3.88 g, 31.5 mmol) in the presence of triethylamine (1.08 g, 10.7 mmol) (off-white solid) , 0.92 g, 56%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.88 (1H, d, J = 2.1 Hz, -N = CH), 8.46 (1H, dd, J = 7.8, 1.5 Hz, Aromatic-H), 8.18 (1H, dd, J = 8.4, 2.7 Hz, Aromatic-H), 7.49-6.92 (4H, m, Aromatic-H), 3.94 (3H, s, -OCH ₃ ). ESI-MS: m / z (261, MH ⁻ ).

[ Example  13] 6- Chloro -N- (4- Fluorophenyl ) Nicotinamide [4m] Preparation

Compound 4m was obtained by the same method as the synthesis of compound 4a using compound 1 (1.00 g, 6.3 mmol) and compound 3m (3.50 g, 31.5 mmol) in the presence of triethylamine (1.08 g, 10.7 mmol) (light black). Solid, 0.88 g, 56%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.85 (1H, d, J = 2.4 Hz, -N = CH), 8.17 (1H, dd, J = 8.4, 2.7 Hz, Aromatic-H), 7.76 (1H, s, NH), 7.60-7.06 (5H, m, Aromatic-H). ESI-MS: m / z (249, MH ⁻ ).

Example  14-26

Example 14 Preparation of 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methylpyridin-2-yl) nicotinamide [6a]

Compound 4a (1.0 g, 4.04 mmol) and 1,2,3,4-tetrahydroisoquinoline 5 (1.08 g, 8.08 mmol) were mixed with 2-propanol and refluxed for 48 hours. After removing the solvent, the residue was recrystallized from 2-propanol to give the target compound 6a (off-white solid, 1.0 g, 72%). IR (cm- ¹ ): 3435 (NH), 1671 (CO). ¹ H NMR (300 MHz, CDCl ₃ ): 8.81 (1H, dd, J = 2.6, 0.6 Hz, -N = CH), 8.41 (1H, s, NH), 8.16 (1H, d, J = 8.3 Hz, Aromatic-H), 8.02 (1H, dd, J = 9.0, 2.6 Hz, Aromatic-H), 7.62 (1H, t, J = 7.7 Hz, Aromatic-H), 7.22 7.20 (4H, m, Aromatic-H) , 6.90 (1H, d, J = 7.4 Hz, Aromatic-H), 6.66 (1H, d, J = 9.0 Hz, Aromatic-H), 4.80 (2H, s, -CH ₂ -N-), 3.94 3.90 ( 2H, m, -N- CH ₂ -CH _2- ), 2.99 (2H, t, J = 5.9 Hz, -N-CH ₂ -CH _2- ), 2.46 (3H, s, -CH ₃ ). ESI-MS: m / z (345, MH ⁺ ).

Example 15 Preparation of 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (5-methylpyridin-2-yl) nicotinamide [6b]

Using compound 4b (1.0 g, 4.04 mmol), compound 5 (1.08g, 8.08 mmol) and 2-propanol, the desired compound 6b was obtained by the same method as the preparation of compound 6a (light yellow solid, 904 mg, 65%). ). IR (cm- ¹ ): 3307 (NH), 1670 (CO). ¹ H NMR (300 MHz, CDCl ₃ ): 8.79 (1H, d, J = 2.1 Hz, -N = CH), 8.49 (1H, s, NH), 8.26 (1H, d, J = 8.5 Hz, Aromatic- H), 8.09 (1H, s, -N = CH), 8.03 (1H, dd, J = 8.9, 2.3 Hz, Aromatic-H), 7.55 (1H, d, J = 8.4 Hz, Aromatic-H), 7.23 7.15 (4H, m, Aromatic-H), 6.67 (1H, d, J = 9.0 Hz, Aromatic-H), 4.80 (2H, s, -CH ₂ -N-), 3.92 (2H, t, J = 5.8 Hz, -N- CH ₂ -CH _2- ), 2.99 (2H, t, J = 5.8 Hz, -N-CH ₂ -CH _2- ), 2.30 (3H, s, -CH ₃ ). ESI-MS: m / z (345, MH ⁺ ).

Example 16 Preparation of 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (4-methylpyridin-2-yl) nicotinamide [6c]

Using compound 4c (1.7 g, 6.86 mmol), compound 5 (1.82g, 13.7 mmol), and 2-propanol, the target compound 6c was obtained by the same method as the preparation of compound 6a (white solid, 1.8 g, 76%). . IR (cm- ¹ ): 3314 (NH), 1676 (CO). ¹ H NMR (300 MHz, CDCl ₃ ): 8.81 (1H, d, J = 2.1 Hz, -N = CH), 8.59 (1H, s, NH), 8.22 8.18 (1H, m, -N = CH), 8.11 (1H, d, J = 5.1 Hz, Aromatic-H), 8.03 (1H, dd, J = 8.7, 2.4 Hz, Aromatic-H), 7.23 7.11 (4H, m, Aromatic-H), 6.87 (1H, d, J = 5.1 Hz, Aromatic-H), 6.67 (1H, d, J = 8.7 Hz, Aromatic-H), 4.80 (2H, s, -CH ₂ -N-), 3.92 (2H, t, J = 5.7 Hz, -N- CH ₂ -CH _2- ), 2.99 (2H, t, J = 6.0 Hz, -N-CH ₂ -CH _2- ), 2.39 (3H, s, -CH ₃ ). ESI-MS: m / z (345, MH ⁺ ).

Example 17 Preparation of 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methylpyridin-2-yl) nicotinamide [6d]

Using compound 4d (520 mg, 2.1 mmol), compound 5 (560 mg, 4.2 mmol) and 2-propanol, the desired compound 6d was obtained by the same method as the preparation of compound 6a (yellow solid, 290 mg, 41%). . ¹ H NMR (300 MHz, CDCl ₃ ): 8.81 (1H, d, J = 1.8 Hz, -N = CH), 8.27 8.22 (2H, m, -N = CH, NH), 8.06 (1H, dd, J = 9.0, 2.4 Hz, Aromatic-H), 7.66 7.60 (1H, m, Aromatic-H), 7.35 7.10 (5H, m, Aromatic-H), 6.68 (1H, d, J = 8.7 Hz, Aromatic-H) , 4.81 (2H, s, -CH ₂ -N-), 3.93 (2H, t, J = 5.7 Hz, -N- CH ₂ -CH _2- ), 2.99 (2H, t, J = 6.0 Hz, -N -CH ₂ - CH _2- ), 2.33 (3H, s, -CH ₃ ). ESI-MS: m / z (345, MH ⁺ ).

Example 18 Preparation of 6- (3,4-Dihydro-1H-isoquinolin-2-yl) -N-pyridin-2-yl-nicotinamide [6e]

Using compound 4e (600 mg, 2.6 mmol), compound 5 (692 mg, 5.2 mmol) and 2-propanol, the desired compound 6e was obtained by the same method as the preparation of compound 6a (brown solid, 201 mg, 23%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.80 (1H, d, J = 2.4 Hz, -N = CH), 8.55 (1H, s, NH), 8.38 8.18 (2H, m, Aromatic-H), 8.03 (1H, dd, J = 9.3, 2.7 Hz, Aromatic-H), 7.81 7.70 (1H, m, Aromatic-H), 7.23 7.20 (4H, m, Aromatic-H), 7.06 7.02 (1H, m, Aromatic- H), 6.68 (1H, d, J = 9.0 Hz, Aromatic-H), 4.81 (2H, s, -CH ₂ -N-), 3.92 (2H, t, J = 6.0 Hz, -N- CH _2- CH _2- ), 2.99 (2H, t, J = 6.0 Hz, -N-CH ₂ -CH _2- ). ESI-MS: m / z (330, MH ⁺ ).

Example 19 Preparation of 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methoxypyridin-3-yl) nicotinamide [6f]

Using compound 4f (100 mg, 0.38 mmol), compound 5 (100 mg, 0.76 mmol), and 2-propanol, the target compound 6f was obtained by the same method as the preparation of compound 6a (light yellow solid, 50 mg, 37). %). ¹ H NMR (300 MHz, CDCl ₃ ): 8.72 (1H, d, J = 2.1 Hz, -N = CH), 8.24 (1H, d, J = 2.4 Hz, -N = CH), 8.01 (2H, dd , J = 9.0, 2.7 Hz, Aromatic-H), 7.54 (1H, s, NH), 7.26 7.19 (4H, m, Aromatic-H), 6.73 (2H, dd, J = 25, 9.0 Hz, Aromatic-H ), 4.81 (2H, s, -CH ₂ -N-), 3.94 3.90 (5H, m, -N- CH ₂ -CH _2- , -OCH ₃ ), 2.99 (2H, t, J = 6.0 Hz,- N-CH ₂ - CH _2- ). ESI-MS: m / z (359, MH ⁻ ).

Example 20 Preparation of 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-pyrimidin-2-yl-nicotinamide [6 g]

Compound 4g (0.60 g, 2.6 mmol), compound 5 (0.69 g, 5.1 mmol) and 2-propanol were reacted in the same manner as in the preparation of compound 6a, and then the solvent was removed, and then the residue was n-hexane-EA. Purification by column chromatography (2: 1) afforded 6 g of the target compound (white solid, 0.28 g, 32%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.51 (1H, d, J = 2.1 Hz, -N = CH), 7.79 (1H, dd, J = 8.1, 2.1 Hz, Aromatic-H), 7.43 (1H, d, J = 8.1 Hz, -N = CH), 7.26 7.20 (7H, m, -N = CH, Aromatic-H), 6.95 (1H, s, NH), 4.89 (1H, s, -CH ₂ -N 4.60 (1H, s, -CH ₂ -N-), 3.99 (1H, s, -N- CH ₂ -CH _2- ), 3.66 (1H, s, -N- CH ₂ -CH _2- ) , 2.92 (2H, s, -N-CH ₂ -CH _2- ).

Example 21 Preparation of 6- (3,4-Dihydro-1H-isoquinolin-2-yl) -N-thiazol-2-yl-nicotinamide [6h]

Using compound 4h (100 mg, 0.42 mmol), compound 5 (111 mg, 0.83 mmol), and 2-propanol, the desired compound 6h was obtained by the same method as the preparation of compound 6a (brown solid, 23 mg, 16%). . ¹ H NMR (300 MHz, DMSO-d ₆ ): 12.4 (1H, s, NH), 8.88 (1H, d, J = 2.1 Hz, -N = CH), 8.23 (1H, dd, J = 9.0, 2.4 Hz, Aromatic-H), 7.52 (1H, d, J = 3.6 Hz, -N = CH), 7.29 7.20 (5H, m, -S-CH, Aromatic-H), 6.94 (1H, d, J = 9.0 Hz, Aromatic-H), 4.82 (2H, s, -CH ₂ -N-), 3.90 (2H, t, J = 6.0 Hz, -N- CH ₂ -CH _2- ), 2.92 (2H, t, J = 5.7 Hz, -N-CH ₂ - CH _2- ). ESI-MS: m / z (337, MH ⁺ ).

[ Example  22] 6- (3,4- Dihydro -1H- Isoquinoline 2-yl) -N- Of phenylnicotinamide [6i]  Produce

Using compound 4i (500 mg, 2.15 mmol), compound 5 (573 mg, 4.30 mmol) and 2-propanol, the desired compound 6i was obtained by the same method as the preparation of compound 6a (white solid, 100 mg, 14%). . ¹ H NMR (300 MHz, CDCl ₃ ): 8.72 (1H, d, J = 2.1 Hz, -N = CH), 8.02 (1H, dd, J = 9.3, 2.5 Hz, Aromatic-H), 7.64-7.10 ( 9H, m, Aromatic-H), 6.69 (1H, d, J = 9.0 Hz, Aromatic-H), 4.81 (2H, s, -CH ₂ -N-), 3.92 (2H, t, J = 6.3 Hz, -N- CH ₂ -CH _2- ), 2.99 (2H, t, J = 6.0 Hz, -N-CH ₂ -CH _2- ), 1.57 (1H, s, NH). ESI-MS: m / z (328, MH ⁻ ).

[ Example  23] 6- (3,4- Dihydro -1H- Isoquinoline 2-yl) -N-O- Of tolylnicotinamide [6j]  Produce

Using compound 4j (500 mg, 2.03 mmol), compound 5 (541 mg, 4.06 mmol) and 2-propanol, the desired compound 6j was obtained by the same method as the preparation of compound 6a (white solid, 267 mg, 39%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.73 (1H, d, J = 1.8 Hz, -N = CH), 8.05 (1H, dd, J = 9.0, 2.7 Hz, Aromatic-H), 7.97 (1H, d, J = 7.5 Hz, Aromatic-H), 7.51 (1H, s, NH), 7.27-6.70 (8H, m, Aromatic-H), 4.81 (2H, s, -CH ₂ -N-), 3.92 ( 2H, t, J = 5.7 Hz, -N- CH ₂ -CH _2- ), 3.00 (2H, t, J = 6.0 Hz, -N-CH ₂ - CH _2- ), 2.33 (3H, s, -CH ₃ ). ESI-MS: m / z (342, MH ⁻ ).

[ Example  24] 6- (3,4- Dihydro -1H- Isoquinoline -2-yl) -N- (3- Methoxyphenyl ) Nicotinamide Preparation of [6k]

Using compound 4k (500 mg, 1.90 mmol), compound 5 (506 mg, 3.80 mmol), and 2-propanol, the target compound 6k was obtained by the same method as the preparation of compound 6a (white solid, 305 mg, 45%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.71 (1H, d, J = 2.1 Hz, -N = CH), 8.01 (1H, dd, J = 9.0, 2.4 Hz, Aromatic-H), 7.62 (1H, s, NH), 7.44-6.67 (9H, m, Aromatic-H), 4.80 (2H, s, -CH ₂ -N-), 3.92 (2H, t, J = 5.7 Hz, -N- CH ₂ -CH _2- ), 3.84 (3H, s, -OCH ₃ ), 3.00 (2H, t, J = 5.7 Hz, -N-CH ₂ -CH _2- ). ESI-MS: m / z (358, MH ⁻ ).

[ Example  25] 6- (3,4- Dihydro -1H- Isoquinoline -2-yl) -N- (2- Methoxyphenyl ) Nicotinamide Preparation of [6l]

Compound 4l (450 mg, 1.70 mmol), compound 5 (453 mg, 3.40 mmol), and 2-propanol were used to obtain the title compound 6l in the same manner as the preparation of compound 6a (yellow solid, 354 mg, 58%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.75 (1H, d, J = 2.4 Hz, -N = CH), 8.50 (1H, dd, J = 7.8, 1.8 Hz, Aromatic-H), 8.44 (1H, s, NH), 8.06 (1H, dd, J = 9.0, 2.4 Hz, Aromatic-H), 7.25-6.70 (8H, m, 8H, Aromatic-H), 4.81 (2H, s, -CH ₂ -N- ), 3.92 (2H, t, J = 6.9 Hz, -N- CH ₂ -CH _2- ), 3.90 (3H, s, -OCH ₃ ), 3.00 (2H, t, J = 6.0 Hz, -N-CH ₂ - CH _2- ). ESI-MS: m / z (360, MH ⁺ ).

[ Example  26] 6- (3,4- Dihydro -1H- Isoquinoline -2-yl) -N- (4- Fluorophenyl ) Nicotinamide Preparation of [6m]

Using compound 4m (500 mg, 2.00 mmol), compound 5 (536 mg, 4.00 mmol), and 2-propanol, the target compound 6m was obtained by the same method as the preparation of compound 6a (white solid, 378 mg, 54%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.70 (1H, d, J = 2.7 Hz, -N = CH), 8.00 (1H, dd, J = 9.0, 2.7 Hz, Aromatic-H), 7.60 (1H, s, NH), 7.59-7.02 (8H, m, Aromatic-H), 6.68 (1H, d, J = 9.0 Hz, Aromatic-H), 4.80 (2H, s, -CH ₂ -N-), 3.92 ( 2H, t, J = 6.0 Hz, -N- CH ₂ -CH _2- ), 2.99 (2H, t, J = 6.0 Hz, -N-CH ₂ -CH _2- ). ESI-MS: m / z (346, MH ⁻ ).

Example  27-31

Example 27 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methylpyridin-2-yl) nicotinamide [8a] Manufacture

Compound 4a (450 mg, 1.8 mmol) and compound 7 (420 mg, 2.2 mmol) were mixed with 2-propanol and refluxed for 48 hours. After the solvent was removed, water was mixed into the residue, extracted with EA, washed with brine and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography to give the target compound 8a (yellow solid, 150 mg, 20%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.80 (1H, d, J = 2.1 Hz, -N = CH), 8.38 (1H, s, NH), 8.16 (1H, dd, J = 7.8, 5.1 Hz, Aromatic-H), 8.02 (1H, dd, J = 9.0, 2.7 Hz, Aromatic-H), 7.68-6.66 (5H, m, Aromatic-H), 4.73 (2H, s, -CH ₂ -N-), 3.96-3.79 (8H, m, -OMe, -N- CH ₂ -CH _2- ), 2.91 (2H, t, J = 6.0 Hz, -N-CH ₂ -CH _2- ), 2.47 (3H, s, -CH ₃ ). ESI-MS: m / z (405, MH ⁺ ).

Example 28 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (5-methylpyridin-2-yl) nicotinamide [8b] Manufacture

Using compound 4b (500 mg, 2.02 mmol), compound 7 (782 mg, 4.05 mmol) and 2-propanol, target compound 8b was obtained in the same manner as in the preparation of compound 8a (light yellow solid, 800 mg). , 97%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.78 (1H, d, J = 1.8 Hz, -N = CH), 8.44 (1H, s, NH), 8.25 (1H, d, J = 8.4 Hz, Aromatic- H), 8.10 (1H, s, -N = CH), 8.02 (1H, dd, J = 9.0, 2.4 Hz, Aromatic-H), 7.55 (1H, dd, J = 8.4, 1.8 Hz, Aromatic-H) , 6.72-6.60 (3H, m, Aromatic-H), 4.73 (2H, s, -CH ₂ -N-), 3.94-3.84 (8H, m, -OMe, -N- CH ₂ -CH _2- ), 2.90 (2H, t, J = 5.7 Hz, -N-CH ₂ -CH _2- ), 2.30 (3H, s, -CH ₃ ). ESI-MS: m / z (405, MH ⁺ ).

Example 29 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (4-methylpyridin-2-yl) nicotinamide [8c] Manufacture

Using compound 4c (250 mg, 1.01 mmol), compound 7 (390 mg, 2.02 mmol), and 2-propanol, the target compound 8c was obtained by the same method as the preparation of compound 8a (yellow solid, 229 mg, 56%). . ¹ H NMR (300 MHz, CDCl ₃ ): 8.87 (1H, s, NH), 8. 80 (1H, d, J = 2.1 Hz, -N = CH), 8.22 (1H, d, J = 1.5 Hz, -N = CH), 8.07-8.00 (2H, m, Aromatic-H), 6.83 (1H, d, J = 4.8 Hz, Aromatic-H), 6.70-6.63 (3H, m, Aromatic-H), 4.71 ( 2H, s, -CH ₂ -N-), 3.92-3.86 (8H, m, -OMe, -N- CH ₂ -CH _2- ), 2.89 (2H, t, J = 5.7 Hz, -N-CH ₂ CH _2- ), 2.37 (3H, s, -CH ₃ ).

Example 30 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methylpyridin-2-yl) nicotinamide [8d] Manufacture

Using compound 4d (344 mg, 1.39 mmol), compound 7 (537 mg, 2.78 mmol) and 2-propanol, the desired compound 8d was obtained by the same method as the preparation of compound 8a (yellow solid, 130 mg, 23%). . ¹ H NMR (300 MHz, CDCl ₃ ): 9.17 (1H, s, NH), 8.81 (1H, d, J = 2.1 Hz, -N = CH), 8.21 (1H, d, J = 3.6 Hz, -N = CH), 8.04 (1H, dd, J = 8.7, 2.1 Hz, Aromatic-H), 7.57 (1H, d, J = 7.5 Hz, Aromatic-H), 7.09 (1H, dd, J = 7.2, 5.1 Hz , Aromatic-H), 6.69-6.55 (3H, m, Aromatic-H), 4.69 (2H, s, -CH ₂ -N-), 4.09-3.76 (8H, m, -OMe, -N- CH _2- CH _2- ), 2.87 (2H, t, J = 5.7 Hz, -N-CH ₂ -CH _2- ), 2.30 (3H, s, -CH ₃ ). Anal. Calcd for C ₂₃ H ₂₄ N ₄ O ₃ .

Example 31 Preparation of 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N-pyridin-2-yl-nicotinamide [8e]

Using compound 4e (500 mg, 2.15 mmol), compound 7 (830 mg, 4.3 mmol) and 2-propanol, the desired compound 8e was obtained by the same method as the preparation of compound 8a (yellow solid, 553 mg, 66%). . ¹ H NMR (300 MHz, CDCl ₃ ): 8.79 (1H, d, J = 2.4 Hz, -N = CH), 8.46 (1H, s, NH), 8.35 (1H, d, J = 7.5 Hz, -N = CH), 8.03 (1H, dd, J = 9.3, 2.7 Hz, Aromatic-H), 7.74 (1H, m, Aromatic-H), 7.05 (1H, m, Aromatic-H), 6.72-6.67 (3H, m, Aromatic-H), 4.74 (2H, s, -CH ₂ -N-), 4.15-3.79 (8H, m, -OMe, -N- CH ₂ -CH _2- ), 2.91 (2H, t, J = 6.0 Hz, -N-CH ₂ - CH _2- ).

Example  32-35

[ Example  32] 6- (piperidin-1-yl) -N- (6- Methylpyridine -2 days) Nicotinamide Preparation of [9a]

Compound 4a (112 mg, 0.5 mmol) and piperidine (85 mg, 1 mmol) were mixed with DMSO and stirred at 100 ° C. for 18 hours. The reaction mixture was extracted with EA, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by column chromatography to obtain the target compound 9a (colorless oil, 90 mg, 60%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.74 (1H, d, J = 2.4 Hz, -N = CH), 8.55 (1H, s, NH), 8.15 (1H, d, J = 8.4 Hz, Aromatic- H), 7.95 (1H, dd, J = 9.0, 2.7 Hz, Aromatic-H), 7.60 (1H, t, J = 7.5 Hz, Aromatic-H), 6.88 (1H, d, J = 7.5 Hz, Aromatic- H), 6.60 (1H, d, J = 8.4 Hz, Aromatic-H), 3.65 (4H, t, J = 5.7 Hz, -CH ₂ -N-CH _2- ), 2.44 (3H, s, CH ₃ ) , 1.73-1.59 (6H, m, aliphatic-H).

[ Example  33] 6- (4- Ethyl piperazine -1-yl) -N- (6- Methylpyridine -2 days) Nicotinamide [ 9b]  Produce

Using compound 4a (248 mg, 1 mmol) and N -ethylpiperazine (228 mg, 2 mmol), target compound 9b was obtained by the same method as the preparation of compound 9a (yellow sticky oil, 179 mg, 52%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.80 (1H, s, NH), 8.77 (1H, d, J = 2.4 Hz, -N = CH), 8.15 (1H, d, J = 8.4 Hz, Aromatic- H), 7.99 (1H, dd, J = 9.0, 2.4 Hz, Aromatic-H), 7.59 (1H, t, J = 7.8 Hz, Aromatic-H), 6.87 (1H, d, J = 6.9 Hz, Aromatic- H), 6.60 (1H, d, J = 9.6 Hz, Aromatic-H), 3.68 (5H, t, J = 5.1 Hz, -NC ₂ H _5- ), 2.60-2.33 (8H, m, -NC ₂ H _4- ), 1.12 (3H, s, CH ₃ ).

[ Example  34] 6- (4- Methylpyrazine -1-yl) -N- (6- Methylpyridine -2 days) Nicotinamide Preparation of [9c]

Using compound 4a (248 mg, 1 mmol) and N -methylpiperazine (200 mg, 2mmol), target compound 9c was obtained by the same method as the preparation of compound 9a (yellow sticky oil, 176 mg, 57%). ¹ H NMR (300 MHz, CDCl ₃ ): 9.04 (1H, s, NH), 8.78 (1H, d, J = 2.1 Hz, -N = CH), 8.16 (1H, d, J = 8.1 Hz, Aromatic- H), 8.00 (1H, dd, J = 9.0, 2.7 Hz, Aromatic-H), 7.59 (1H, t, J = 7.5 Hz, Aromatic-H), 6.87 (1H, d, J = 7.5 Hz, Aromatic- H), 6.59 (1H, d, J = 9.0 Hz, Aromatic-H), 3.68 (4H, t, J = 5.1 Hz, -NC ₂ H _4- ), 2.50 (4H, t, J = 5.1 Hz,- NC ₂ H _4- ), 2.40 (3H, s, -N-CH ₃ ), 2.33 (3H, s, -CH ₃ ).

[ Example  35] 6- (4- methyl -1,4- Diazepan -1-yl) -N- (6- Methylpyridine -2 days) Nicotinamide [ 9d]  Produce

Using compound 4a (248 mg, 1 mmol) and N -methyl homopiperazine (200 mg, 2 mmol), target compound 9d was obtained by the same method as the preparation of compound 9a (yellow oil, 165 mg, 48%). ¹ H NMR (300 MHz, CDCl ₃ ): 8.89 (1H, s, NH), 8.75 (1H, d, J = 2.1 Hz, -N = CH), 8.15 (1H, d, J = 8.1 Hz, Aromatic- H), 7.96 (1H, dd, J = 9.0, 2.4 Hz, Aromatic-H), 7.59 (1H, t, J = 7.8 Hz, Aromatic-H), 6.86 (1H, d, J = 7.2 Hz, Aromatic- H), 6.46 (1H, d, J = 9.3 Hz, Aromatic-H), 3.87 (2H, d, J = 3.9 Hz, -N- CH ₂ -CH ₂ -N-CH ₃ ), 3.66 (2H, t , J = 6.0 Hz, -N- CH ₂ -CH ₂ -CH ₂ -N-CH ₃ ), 2.73 (2H, t, J = 4.8 Hz, -N-CH ₂ -CH ₂ -N-CH ₃ ), 2.60 (2H, t, J = 5.1Hz, -N-CH 2 -CH 2 - CH 2 -N-CH 3), 2.39 (6H, s, CH 3), 2.04 (2H, m, -N-CH 2 CH ₂ -CH ₂ -N-CH ₃ ).

Preparation Example 1 Preparation of 6,7-dimethoxy 1,2,3,4-tetrahydroisoquinoline [7]

NaHCO ₃ was added while stirring the aqueous solution of 6,7-dimethoxy 1,2,3,4-tetrahydroisoquinoline hydrochloride, and after 30 minutes, the degree of neutralization was confirmed using a pH paper. The reaction mixture was extracted with CH ₂ Cl ₂ , washed with brine and dried over Na ₂ SO ₄ . The organic layer was concentrated in vacuo to afford white solid compound 7. ¹ H NMR (300 MHz, CDCl ₃ ): 6.57 (1H, s, Aromatic-H), 6.49 (1H, s, Aromatic-H), 3.93 (2H, s, -CH ₂ -NH), 3.11 (2H, t, J = 6.0 Hz, -N- CH ₂ -CH _2- ), 2.70 (2H, t, J = 6.0 Hz, -N-CH ₂ -CH _2- ), 2.37 (1H, s, NH).

[ Experimental Example  1] according to the present invention Nicotinamide  Androgen receptors of derivatives ( AR ; androgen receptor Specific transcriptional activity transcriptional activity ) Inhibition  Experiment

1. Experimental Method

Luciferase assay was performed to determine transcriptional activity of androgen receptor (AR), glucocorticoid receptor (GR), and estrogen receptor (ER). PARE2-TATA-luc was used for reporter luc for AR, MMTV-luc for reporter luc for GR (glucocorticoid receptor), and ERE-luc for reporter luc for ER (estrogen receptor). A transfection assay was performed.

* Terminology

Luciferase assay (Luciferase assay) is a method of 'promote the activation of the promoter' is a test method using the principle of ligation of the promoter portion of a specific gene to the luciferase-containing vector (luciferase) and emit the light when the promoter is activated By cloning the promoter or regulatory element of a specific gene into the 5 'upstream of the reporter gene to produce a reporter vector, introducing the vector into the appropriate cell (using transfection) and treating it with various substances (Anti-androgen substance, ligand, etc.), and then the activity of the reporter enzyme (luciferase) transcribed and translated by the change in promoter activity is measured.

pARE2-TATA-luc is a DNA used in the luciferase assay, which is a clone of a DNA sequence capable of binding to androgen receptors into a luciferase vector.

MMTV-luc is a DNA used in the luciferase assay, which is a clone of a DNA sequence capable of binding to a glucocorticoid receptor into a luciferase vector.

ERE-luc is a DNA used in the luciferase assay, which clones a DNA sequence capable of binding to an estrogen receptor into a luciferase vector.

Transient transfection assay is a method of transforming foreign plasmid DNA into animal cells. Transient transfection assay is used to transform foreign DNA not originally possessed by the cell line into the cell line and introduce it transiently. Is the way.

Dihydortestosterone (DHT) is an agonist for AR, Hydroxyflutamide (OHF) is an antagonist for AR, BIC (Bicalutamide) is an antagonist for AR, and CPA (Cyproterone acetate) is AR Is an antagonist for, DXM (Dexamethason) is a ligand for GR, E2 (Estradiol) is a ligand for ER, and DIMN (6- (3,4-dihydro-) 1H-isoquinolin-2-yl) -N- ( 6 -methylpyridin-2-yl) nicotinamide; compound 6a prepared in Example 14.

2. Experimental results

Treatment with DIMN (Compound 6a ) did not affect the transcriptional activity on GR and ER, but showed the effect of inhibiting transcriptional activity by treating DIMN (Compound 6a ) with AR. (See Figure 1).

[ Experimental Example  2] according to the present invention Nicotinamide  According to the concentration of derivatives AR ( androgen receptor Specific transcriptional activity transcriptional activity ) Degree of inhibition  Experiment

1. Experimental Method

Transient transfection was performed using reporter luc (pARE2-TATA-luc) for AR, and then luciferase assay was performed.

2. Experimental results

Treatment of DIMN (Compound 6a ) with 0.01 uM to 50 uM resulted in inhibition of transcriptional activity against AR in a concentration-dependent manner. In addition, the inhibition of transcriptional activity of OHF (hydroxyflutamide) and CPA (cyproterone acetate), which are AR antagonists, showed similar transcriptional activity inhibition when DIMN (Compound 6a ) was used at about 10uM. (See FIG. 2).

[ Experimental Example  3] according to the present invention Nicotinamide  Derivatives AR ( androgen  transcriptional activity against receptors transcriptional activity ) Confirmation experiment

1. Experimental Method

The effect of nicotinamide derivatives (30 compounds in total) according to the present invention on transcriptional activity against AR was confirmed by luciferase assay.

2. Experimental results

10uM OHF (hydroxyflutamide), BIC (bicalutamide) and DIMN (Compound 6a ) showed similar inhibition of transcriptional activity.

17 derivatives were found to inhibit about 50% of the transcriptional activity increased by DHT, an agonist of AR, in the nicotinamide inducers according to the present invention when treated with the same concentration (2 in FIG. 3). 4,6,7,9,10,11,12,13,15,16,17,19,20,21,22,23). Among them, derivatives 2,7,9,11,13,20,21 were found to inhibit transcriptional activity similar to or more effectively than AR antagonists OHF (hydroxyflutamide) or BIC (bicalutamide) (see FIG. 3).

Experimental Example 4 Whether the nicotinamide derivatives according to the present invention competitively inhibit the binding of DHT, an agonist to AR (androgen receptor)

1. Experimental Method

To determine whether the nicotinamide derivatives according to the present invention bind AR with DHT, a antagonistic steroid binding assay was performed. Wild type AR was transiently transfected into COS-7 cell line and isotopically labeled with 5nM [ ³ H] 5α-DHT 2 hours before the next day antagonistic steroid binding assay. unlabeled (labeling) isotopically 5nM ~ 5uM DHT, 5nM ~ 50uM BIC, 5nM ~ 50uM OHF, 5nM ~ 50uM of compound 6a (DIMN) and 5nM ~ 50uM nicotinamide nicotinamide derivative Derivative d-7 was treated.

* Terminology

The antagonistic steroid binding assay inserts DHT, a ligand of the androgen receptor labeled with tritium, and puts the anti-androgens unlabeled with radioisotopes in different concentrations. The experiment is to determine whether androgen substances bind to androgen receptors in a competitive relationship with the ligand DHT. In this case, in order to find out whether the anti-androgen substance binds to the ligand DHT competitively to the androgen receptor, a method of measuring the level of the remaining isotope tritium (tritium) is used.

2. Experimental results

After 2 hours of reaction, radioactivity was measured, and nicotinamide derivative 6a (DIMN) did not bind more effectively than OHF (hydroxyflutamide) and BIC (bicalutamide), which are known as antagonists of AR, but combined in a similar manner. Thereby inhibiting the binding of DHT to AR. Concentrations that inhibit DHT binding to AR by 50% (IC ₅₀ ) were 1 to 2 nM for DHT, 0.4 to 0.5 uM for OHF, 0.9 uM for BIC, and 1 to 2 uM for Nicotinamide Derivative Compound 6a (DIMN). Amide derivative d-7 was identified as 10 uM, respectively. Binding to AR was shown to nicotine amide derivative compound 6a (DIMN) is 2 to 4 times lower than OHF, and 1 to 2 times lower than BIC (see Fig. 4). Therefore, it can be seen that the nicotinamide derivatives according to the present invention bind to AR, which is an important factor in prostate cancer, by competing with DHT, which is an agonist of AR.

[ Experimental Example  5] according to the present invention Nicotinamide  Derivatives are prostate cancer cell line ( LNCaP Inhibition of cell proliferation

1. Experimental Method

To determine the effect of nicotinamide derivatives according to the present invention on the proliferation of prostate cancer cell line (LNCaP), MTS assay was performed. LNCaP cells, a prostate cancer cell line, were dispensed in a 96 well plate at 2000 cells / well, followed by treatment with DHT, which is an agonist of AR, with DHT, and 10 μM of chemicals with DHT on LNCaP cells for 5 days. Growth of LNCaP, a prostate cancer cell line, was confirmed at absorbance 490 nm. MTS assay (assay) is one of the experimental methods to determine the cell proliferation, in the experimental example of the present invention was tested using the MTS assay kit (Promega, Cat. No. G1112) sold by Promega.

2. Experimental results

On the 5th day, LNCaP cell growth increased by DHT, an agonist of AR, was treated with OHF (hydroxyflutamide) and BIC (bicalutamide), 10-uM of AR, and the growth of LNCaP cells was 15-17%. The decrease was confirmed. In comparison, nicotinamide Treatment with Derivative Compound 6a (DIMN) showed 20% growth inhibition and nicotinamide Inhibition of growth of about 30% when the derivative d-7 was treated, the nicotinamide derivative of the present invention was found to inhibit the proliferation of LNCaP, a prostate cancer cell line more effectively than the conventional AR antagonist (Fig. 5).

Experimental Example 6 Whether Nicotinamide Derivatives According to the Present Inhibition Proliferation of Prostate Cancer Cell Line (LNCaP) Experiment II

1. Experimental Method

A thymidine incorporation assay was performed to investigate the effect of DIMN on proliferation of prostate cancer cell line (LNCaP). The thymidine incorporation assay uses the principle of thymidine incorporation into the DNA of proliferating cells, using isotope-labeled thymidine to obtain isotope levels. You can check with LNCaP, a prostate cancer cell line, was dispensed in a 96 well plate at 2000 cells / well, and then grown for 2 days, followed by antagonists BIC (hydroxyflutamide), OHF (hydorxyflutamide), and nicotinamide with AR agonist DHT. Derivative Compound 6a (DIMN) and Nicotinamide Each of the derivatives d-7 was treated and incubated for 3 days. Four hours before the thymidine incorporation assay, the cells in culture were treated with thymidine at a concentration of 10 uCi / ml.

2. Experimental results

When the cell proliferation of the treatment with DHT, which is an agonist for AR, was 100%, the change in cell proliferation was confirmed when each chemical and AR antagonist were treated with agonist DHT. Nicotinamide at 1 uM Concentration Nicotine amide with cell proliferation of 20% and 10 uM when treated with derivative compound 6a (DIMN) Treatment of the derivative compound 6a (DIMN) inhibited cell proliferation by 60%. Nicotinamide Treatment of derivative d-7 with 1 uM concentration inhibited cell proliferation by 40% and 10 uM concentration. When treated with 1uM and 10uM of BIC (bicalutamide), an AR antagonist, the effect of proliferation of prostate cancer cell lines (LNCaP) was about 10% and 20%, respectively. In addition, when treated with 1uM, 10uM concentration of OHF (hydroxyflutamide) did not show a difference in each concentration showed inhibition of cell proliferation within 15%. These results suggest that nicotinamide Derivative Compound 6a (DIMN) or Nicotinamide Derivative d-7 was found to effectively inhibit the proliferation of prostate cancer cell line (LNCaP) compared to AR antagonists BIC (bicalutamide) and OHF (hydroxyflutamide) (see Figure 6).

Experimental Example 7 Whether the nicotinamide derivatives according to the present invention inhibit the expression of PSA (prostate specific antigen), a target protein of DHT in prostate cancer cell line (LNCaP)

1. Experimental Method

It was confirmed by Western blotting that DIMN inhibits the expression of PSA like OHF (hydroxyflutamide) and BIC (bicalutamide), which are other AR antagonists. Western blotting or immunoblotting is an immunochemical method that finds only a protein (antigen) in a protein mixture bound to a membrane using an antibody that recognizes a specific protein (antigen). to be. Prostate cancer cell line LNCaP cells were treated with DHT, which is not treated with AR antagonist (first line) and DHT alone (second line), and treated with DHT and other compounds (third to seventh lines) for 2 days. Expression of the target proteins of AR and PSA protein was confirmed. In addition, tubulin (tubulin) was confirmed as to quantify the protein.

2. Experimental results

Experimental results showed that the protein expression of AR and PSA increased when DHT was treated, compared with that of DHT, which is an agonist of AR, and treated with OHF (hydroxyflutamide) or BIC (bicalutamide), which are AR antagonists, together with DHT. When the protein expression of AR and PSA increased by DHT was reduced.

Nicotinamide When the derivative compound 6a (DIMN) was treated to cells at different concentrations, it was confirmed that the protein expression of AR and PSA decreased in a concentration-dependent manner, and compared with the expression level of the protein when treated with the same concentration of the AR antagonist. Nicotinamide treated at 10 uM compared to one AR antagonist OHF or BIC Derivative compound 6a (DIMN) was confirmed that the protein expression of AR and PSA was further reduced. Nicotinamide Derivative compound 6a (DIMN) has been shown to be able to effectively control the expression of AR and PSA compared to the conventional AR antagonists OHF or BIC can be used as an effective prostate cancer treatment (see Figure 7).

1 shows experimental results of inhibiting AR (androgen receptor) specific transcriptional activity of nicotinamide derivatives according to the present invention [AR: androgen receptor, GR: glucocorticoid receptor, ER: estrogen receptor, DHT: Dihydortestosterone, OHF: Hydroxyflutamide, BIC: Bicalutamide, CPA: Cyproterone acetate, DXM: Dexamethason, E2: Estradiol, DIMN: Compound 6a prepared in Example 14].

Figure 2 shows the experimental results of the degree of inhibition of AR (androgen receptor) specific transcriptional activity according to the concentration of nicotinamide derivatives according to the present invention [DHT: Dihydortestosterone, OHF: Hydroxyflutamide, CPA: Cyproterone acetate, DIMN: Compound 6a prepared in Example 14].

Figure 3 shows the results of the transcriptional activity of the nicotinamide derivatives according to the present invention confirmed the transcriptional activity (androscription receptor) [OHF: Hydroxyflutamide, BIC: Bicalutamide, DIMN: Compound 6a prepared in Example 14, DIMN -d #: d-1 to d-29].

Figure 4 shows the experimental results of whether the nicotinamide derivatives according to the present invention competitively inhibit the binding of DHT, an agonist to AR [DHT: Dihydortestosterone, OHF: Hydroxyflutamide, BIC: Bicalutamide, DIMN: prepared in Example 14 Compound 6a , DIMN-d7].

5 shows experimental results of whether nicotinamide derivatives according to the present invention by MTS assay inhibit the proliferation of prostate cancer cell line (LNCaP) [DHT: Dihydortestosterone, OHF: Hydroxyflutamide, BIC: Bicalutamide, DIMN: 14 Compound 6a , DIMN-d7].

Figure 6 shows the experimental results of whether the nicotinamide derivatives according to the present invention by Thymidine incorporation assay inhibits proliferation of prostate cancer cell line (LNCaP) [DHT: Dihydortestosterone, OHF: Hydroxyflutamide, BIC: Bicalutamide, DIMN: implementation Compound 6a prepared in Example 14, DIMN-d7].

7 shows experimental results of whether DIMN inhibits the expression of prostate specific antigen (PSA), a target protein of DHT in prostate cancer cell line (LNCaP) [OHF: Hydroxyflutamide, BIC: Bicalutamide, DIMN: Preparation in Example 14 Compound 6a ].

Claims (9)

Nicotine amide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. [Formula 1]

[Wherein Ar is (C6-C20) aryl or (C3-C20) heteroaryl, and aryl and heteroaryl of Ar may be further substituted with halogen, (C1-C20) alkyl or (C1-C20) alkoxy There is; R ₁ is halogen,

,

,

,

or

ego; R ₂₁ and R ₂₂ are independently of each other (C1-C20) alkyl or (C1-C20) alkoxy; R ₂ is hydrogen or (C 1 -C 20) alkyl; R ₃ and R ₄ are hydrogen; a is an integer of 0 or 1.] The method of claim 1, Nicotine amide derivative represented by the following formula (2) to 7 or a pharmaceutically acceptable salt thereof. [Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Wherein, R ₁ is Cl, F, Br,

,

,

,

or

R ₂₁ and R ₂₂ are each independently of the other methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, methoxy, Ethoxy, n-propoxy, i-pooxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, hexyloxy, heptyloxy or octyloxy; R ₁₁ to R ₁₅ independently of one another are hydrogen, fluorine, chloro, bromo, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, Nonyl, decyl, methoxy, ethoxy, n-propoxy, i-pooxy, n-butoxy, i-butoxy, t-butoxy, pentoxy, hexyloxy, heptyloxy or octyloxy; X is S; R ₂ is hydrogen or methyl.] delete 3. The method of claim 2, Nicotinamide derivatives or pharmaceutically acceptable salts thereof, which are selected from the following compounds. 6-chloro-N- (6-methylpyridin-2-yl) nicotinamide; 6-chloro-N- (5-methylpyridin-2-yl) nicotinamide; 6-chloro-N- (4-methylpyridin-2-yl) nicotinamide; 6-chloro-N- (3-methylpyridin-2-yl) nicotinamide; 6-chloro-N-pyridin-2-yl-nicotinamide; 6-chloro-N- (6-methoxypyridin-3-yl) nicotinamide; 6-chloro-N-pyrimidin-2-yl-nicotinamide; 6-chloro-N-thiazol-2-yl-nicotinamide; 6-chloro-N-phenylnicotinamide; 6-chloro-N-O-tolylnicotinamide; 6-chloro-N- (3-methoxyphenyl) nicotinamide; 6-chloro-N- (2-methoxyphenyl) nicotinamide; 6-chloro-N- (4-fluorophenyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (5-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (4-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methylpyridin-2-yl) nicotinamide; 6- (3,4-Dihydro-1H-isoquinolin-2-yl) -N-pyridin-2-yl-nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methoxypyridine-3-) nicotinamide; 6- (3,4-Dihydro-1H-isoquinolin-2-yl) -N-pyrimidin-2-yl-nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-thiazol-2-yl-nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-phenylnicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-O-tolylnicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxyphenyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (2-methoxyphenyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (4-fluorophenyl) nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (6-methylpyridin-2-yl) -nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (5-methylpyridin-2-yl) -nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (4-methylpyridin-2-yl) -nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methylpyridin-2-yl) -nicotinamide; 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl) -N-pyridin-2-yl-nicotinamide; 6- (piperidin-1-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (4-ethylpiperazin-1-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (4-methylpiperazin-1-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (4-methyl-1,4-diazepan-1-yl) -N- (6-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-methyl-N- (4-methylpyridin-2-yl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N- (3-methoxybenzyl) nicotinamide; 6- (piperidin-1-yl) -N- (3-methoxybenzyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-methyl-N- (3-methoxyphenyl) nicotinamide; 6- (3,4-dihydro-1H-isoquinolin-2-yl) -N-methyl-N- (2-methylphenyl) nicotinamide; 6- (3,4-Dihydro-1H-isoquinolin-2-yl) -N-methyl-N- (2-methoxyphenyl) nicotinamide. A method for preparing the nicotinamide derivative of formula 1 according to claim 1, wherein the carboxylic acid derivative of formula a is reacted with thionyl chloride to produce an acid chloride of formula b, and then reacted with an amine compound of formula c. [Formula 1]

(A)

[Formula b]

[Formula c]

[Wherein Ar, R ₂ to R ₄ and a are the same as defined in claim 1, R ₁ is halogen.] A method for preparing the nicotinamide derivative of formula 1 according to claim 1 by reacting a compound of formula d with a compound of formula e. [Formula 1]

[Formula d]

[Formula e]

[Wherein Y is halogen; Ar, R ₂ to R ₄ and a are the same as defined in claim 1 and R ₁ is

,

,

,

or

ego; R ₂₁ and R ₂₂ are independently of each other (C1-C20) alkyl or (C1-C20) alkoxy.] delete Alopecia, acne, characterized in that it comprises a nicotinamide derivative according to any one of claims 1, 2 and 4 or a pharmaceutically acceptable salt effective amount thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for the prophylaxis or treatment of prostate cancer, prostatic hyperplasia, prostatitis, prostatitis or prostatic vasculitis. delete

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