KR20080007046A - Melanocortin receptor agonists - Google Patents

Abstract

A novel compound is provided which is an excellent selective agonist of the human melanocortin-4 receptor(MC-4R), thereby being useful for preventing and treating obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction, and inflammation. A compound as a melanocortin receptor agonist is represented by the formula(1), wherein R^1 is H, C1-10 alkyl, C3-7 cycloalkyl, C1-6 alkylcarbonyl, carbamoyl, thiocarbamoyl, C1-4 alkyl carbamoyl, or C1-4 alkylthiocarbamoyl; R^2 is a C6-10 aryl which is mono- or di-substituted or non-substituted by a substituent selected from the group consisting of halogen, hydroxy, C1-4 alkyl and C1-4 alkoxy; R^3 is C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, monocyclic heterocycle, monocyclic heteroaryl, carboxy, C1-4 alkyloxycarbonyl, C1-4 alkylcarbonyl, cyano, carbamoyl, thiocarbamoyl, C1-4 alkylcarbamoyl, (C1-4 alkyl)(C1-4 alkyl)carbamoyl, C1-4 alkylthiocarbamoyl or (C1-4 alkyl)(C1-4 alkyl)thiocarbamoyl; R^4 is C3-8 cycloalkyl, C6-10 aryl or heterocycle; and R^5 is C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, heteroaryl or heterocycle. A method for preparing the compound of the formula(1) comprises a step of amide-coupling a compound represented by the formula(2) with a compound represented by the formula(3). A functional agonist composition of melanocortin receptor comprises a pharmaceutically acceptable carrier, the compound of the formula(1), a pharmaceutically acceptable salt thereof or an isomer thereof.

Description

Melanocortin receptor agonists

The present invention relates to a compound of the formula (1), a pharmaceutically acceptable salt or isomer thereof, which has excellent anti-inflammatory activity against the melanocortin receptor:

[Formula 1]

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in the specification.

The present invention also relates to a method for preparing the compound of Formula 1.

The present invention also relates to a composition for inhibiting melanchotin receptors, characterized in that it contains the compound of Formula 1 as an active ingredient, in particular, a composition for preventing and treating obesity, diabetes, inflammation and erectile dysfunction. .

Pro-opiomelanocortin (POMC) is derived from the POMC gene and is mainly expressed in the hypothalamus, pituitary gland, brain stem, etc. , MSH), β-MSH, γ-MSH, adrenal cortical stimulating hormone (adrenocorticotrophic hormone), such as neuropeptides exhibit a physiological effect. Melanocortin peptides regulate a variety of physiological phenomena according to affinity for each of the MCRs, such as skin pigmentation, body temperature, inflammation, appetite, behavioral control is known (Mountjoy KG, et al. , Mol Cell Endocrinol 1997, 128, 171; Haskell-Luevano C. et al., Drug News Perspect 1999, 12, 197; Wikberg, JES, et al., Pharmacol Res 2000, 42, 393).

Melanocortin receptors (MCRs) belong to the G-protein mating receptor and all five types have been identified to date. MC1R is expressed in melanocytes and macrophages, and in melanocytes, the color of skin and hair is determined by regulating melanin pigment. MC2R is expressed in the adrenal and adipose tissues and is well known for the mediating function of parasignal secretion by adrenal cortical stimulating hormone in the adrenal glands. MC3R, 4R and 5R are thought to mediate the central nervous system action by melanocotin peptides, which are expressed not only in nerve endings but also in the brain, resulting in effects on behavior, learning, memory, appetite, nerve development and regeneration. To date, MC3R is known to be involved in erectile dysfunction and inflammatory response, MC4R is involved in obesity and diabetes, and studies on the specificity of action of each receptor have been actively conducted (see MacNeil DJ, et al., Eur J Pharmacol 2002, 450, 93). As a result, genetic studies in active obese people found that MC4R was deeply involved, and that MC4R-free knockout mice developed obesity by overeating, indicating that this receptor is important for appetite control. (Lud, Willard D, et al., Nature 1994, 371 (6500), 799; Huszar D et al., Cell 1997, 88 (1), 131; Hinney A, et. al., J Clin Endocrinol Metab 1990, 84 (4), 1483; O 'Rahilly, SO et al., Nature Medicine 2004, 10, 351; Coll, AP et al., Curr opin Endocrinol Diabetes 2005, 12, 205) .

As the MCRs were found to be involved in the regulation of several important physiological phenomena, the search for anti-inflammatory or antagonists was actively conducted, mainly through the structural activity correlation of peptides that changed the combination of amino acids. Representative MCR agonist peptides include NDP-MSH (Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Po-Val-NH ₂ ) and MTII (Ac-Nle-c [ Asp-His-DPhe-Arg-Trp-Lys] -NH ₂ ), these are alpha-MSH (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe) for MC1R, 3R, 4R, R5 -Arg-Trp-Gly-Lys-Po-Val-NH ₂ ) (see Haskell-Luevano C, et al., J Med Chem 1997, 40, 1738). In particular, the MCR anti-peptide peptide MTII was absorbed by the subcutaneous injection route and then passed through the Blood Brain Barrier (BBB) to show effects on the central nervous system (Dorr RT, et al., Life Sci 1996, 58 (20), 1777), as well as its ability to cause erections, have recently been reported to be efficacious in clinical trials in men suffering from erectile dysfunction (Wessels, et al. Urology, 2000, 56, 641: Wessels, et al. J. Urol., 1998, 160, 389). In recent years, small molecule peptides have also been shown to have good antitumor efficacy against MC4R, and this substance has been reported to have an appetite suppressant effect in animal experiments (Benoit, SC, et al. J. Neuroscience 2000, 20, 3442). .

The discovery of various structures and their physiological studies of nonpeptidyl small molecule MCR agonists have also been recently reported. (Review: Expert Opin Ther Patents 2004, 14, 327, Curr Opin Investig Drugs 2004, 5, 1063, Peptides 2005, 26, 2026). In particular, Merck reported for the first time an excellent anti-inflammatory agent selective for MC4R, which was discovered through appropriate structural change studies from small molecule materials with activity as growth hormone promoters (WO 99/64002, WO 00/74679). Animal testing of rats injected with this substance in rats has demonstrated efficacy in inducing erection (Sebhat, IK, et al., J Med Chem 2002, 45, 4589). Merck then uncovered superior small molecule MC4R agonists of similar structure and reported that they had anorexia and weight loss effects in rats (see Bioorg Med Chem Lett 2004, 15, 171, Bioorg Med Chem Lett 2005, 15, 3501). ). In addition, Merck has filed patents for MCR agonists of various compounds (see WO 01/55109, WO 01/70337, WO 01/70708, WO 02/081443, WO 02/15909, WO 02/067869, WO 02/068387). , WO 02/068388, WO 2004/087159, WO 2004/078716, WO 2004/078717). Various small molecule MCR adjuvants have also recently been reported in patents by several other research groups (see WO 02/059095, WO 02/059107, WO 02/059117, WO 02/059108, WO 02/085925, WO 03/009847). , WO 03/009850, WO 02/018327, WO 2005/040109, WO 2005/047251, WO 2005/077935). In addition, small molecule antiviral agents selected for MC1R have been reported to exhibit anti-infective efficacy in animal studies using mice (Herpin, TF, et al., J Med Chem 2003, 46, 1123).

The peptidic MCR agonists described above have great limitations due to their molecular properties that cannot be used as oral preparations. In addition, most of the small molecule MCR agonists reported to date, as well as from Merck, will have value for use as a medicament only if they are improved in oral absorption, brain permeability, and efficacy. It is therefore an object of the present invention to provide new molecule small molecule MCR agonists, which can be used for the prevention and treatment of obesity, diabetes and sexual dysfunction.

In particular, it is an object of the present invention to provide a compound of formula (1), a pharmaceutically acceptable salt or isomer thereof, which is excellent in antimicrobial potency against MCRs, in particular selective antigenic potency against MC4R.

Another object of the present invention is to provide a method for preparing the compound of Formula 1.

It is also an object of the present invention to provide a melanocortin receptor hyperfunctional agent composition comprising a compound of formula 1, a pharmaceutically acceptable salt or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. .

In particular, the compositions according to the invention exhibit excellent effects in the prevention and treatment of obesity, erectile dysfunction, diabetes, and inflammation.

The present invention provides a compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof:

[Formula 1]

In the above formula

R ¹ is hydrogen, C ₁ -C ₁₀ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylcarbonyl, carbamoyl, thiocarbamoyl, C ₁ -C ₄ -alkylcarbamoyl or C _1- C ₄ -alkylthiocarbamoyl,

Wherein alkyl or cycloalkyl is substituted by one or more substituents independently selected from the group consisting of halogen, amino, C ₁ -C ₄ -alkyl, trifluoromethyl, hydroxy, C ₁ -C ₄ -alkoxy and oxo Unsubstituted,

R ² represents C ₆ -C ₁₀ -aryl unsubstituted or substituted or unsubstituted by a substituent selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

R ³ is C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₂ -C ₆ -alkenyl, monocyclic heterocycle, monocyclic heteroaryl, carboxy, C ₁ -C ₄ -alkyl Oxycarbonyl, C ₁ -C ₄ -alkylcarbonyl, cyano, carbamoyl, thiocarbamoyl, C ₁ -C ₄ -alkylcarbamoyl, (C ₁ -C ₄ -alkyl) (C ₁ -C _4- Alkyl) carbamoyl, C ₁ -C ₄ -alkylthiocarbamoyl or (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) thiocarbamoyl,

Wherein alkyl, cycloalkyl, heterocycle or heteroaryl is methyl, trifluoromethyl, hydroxy, hydroxyimino, amino, (C ₁ -C ₄ -alkyl) amino and (C ₁ -C ₄ -alkyl) ( Unsubstituted or substituted by a substituent selected from the group consisting of C ₁ -C ₄ -alkyl) amino,

R ⁴ represents C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl or heterocycle,

Wherein C ₆ -C ₁₀ -aryl is mono- or di-substituted by a substituent selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ -alkyl, trifluoromethyl, C ₁ -C ₄ -alkoxy and amino Unsubstituted,

Cycloalkyl or heterocycle is mono-substituted or di-substituted or unsubstituted by a substituent selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ -alkyl, trifluoromethyl, C ₁ -C ₄ -alkoxy and oxo,

R ⁵ represents C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ -C ₆ -cycloalkyl, heteroaryl or heterocycle,

Wherein alkyl or cycloalkyl is unsubstituted or substituted by a substituent selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ -alkoxy, amino, carbamoyl, hydroxyimino and oxo,

Here, heteroaryl represents an aromatic 3-6 membered ring which contains 1 to 2 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, and which can be fused with benzo or C ₃ -C ₈ -cycloalkyl ,

Heterocycle includes 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and may be fused with benzo or C ₃ -C ₈ -cycloalkyl, and may be saturated or contain 1 or 2 double bonds. The containing 4-8 membered ring is shown.

In the definition for the substituents of the compounds of the formula (1) according to the invention the term alkyl, when used alone or in combination with alkyloxy, respectively means a straight or branched chain hydrocarbon radical, the term cycloalkyl being unsaturated including cyclohexyl It means an aliphatic ring.

The term aryl means a 6- to 10-membered aromatic group including phenyl, naphthyl and the like.

The term heteroaryl means an aromatic 3-6 membered ring containing 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and capable of being fused with benzo or C ₃ -C ₈ -cycloalkyl Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine , Pyrimidine, pyrazine and similar groups, but is not limited thereto. Examples of bicyclic heteroaryl include indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthia Sol, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furypyridine and similar groups, but is not limited thereto.

The term heterocycle includes one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, which may be fused with benzo or C ₃ -C ₈ -cycloalkyl, saturated or with one or two double bonds It means a 4 to 8 membered ring containing, examples thereof include piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine and similar groups It is not limited to.

Preferred compounds in the compound of Formula 1 according to the present invention are also

Iii) R ¹ is hydrogen, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -alkylcarbonyl, carbamoyl, thiocarbamoyl, C ₁ -C ₄ -alkylcarbamoyl Or C ₁ -C ₄ -alkylthiocarbamoyl, or

Particularly preferably hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, acetyl, propionyl, isobutylyl, pivaloyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, t- A compound representing butylcarbamoyl, methylthiocarbamoyl or ethylthiocarbamoyl,

Ii) R ² represents phenyl mono- or di-substituted or unsubstituted by a substituent selected from the group consisting of fluorine, chlorine and methyl,

Particularly preferably phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl or 2,4-difluorophenyl;

Iii) R ³ is C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, oxazolyl, thiazolyl, oxazolinyl, thiazolinyl, carboxy, C ₁ -C ₄ -alkyloxycarbonyl, acetyl , Cyano, carbamoyl, thiocarbamoyl, C ₁ -C ₄ -alkylcarbamoyl, (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) carbamoyl, C ₁ -C ₄ -alkylthio Carbamoyl or (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) thiocarbamoyl, wherein alkyl is hydroxy, hydroxyimino, amino, (C ₁ -C ₄ -alkyl) amino and Unsubstituted or substituted by a substituent selected from the group consisting of (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) amino,

Iii) C ₅ -C ₆ -cycloalkyl or hetero, wherein R ⁴ is mono- or di-substituted or unsubstituted by a substituent selected from the group consisting of fluorine, chlorine, hydroxy, methyl, trifluoromethyl, methoxy and oxo Cycle or phenyl mono- or di-substituted or unsubstituted by a substituent selected from the group consisting of fluorine, chlorine, hydroxy, methyl, trifluoromethyl, methoxy and amino, or

Particularly preferably mono- or di-substituted or unsubstituted by a substituent selected from the group consisting of cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, tetrahydropyranyl, or fluorine, chlorine and methyl A compound representing phenyl,

v) R ⁵ represents propen-2-yl, furanyl, thiophenyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl or fluorine, hydroxy, methoxy, ethoxy, C ₁ -C ₄ -alkyl unsubstituted or substituted by a substituent selected from the group consisting of amino and oxo, or

Particularly preferably methyl, trifluoromethyl, ethyl, propen-2-yl, isopropyl, t-butyl, hydroxybutyl, furanyl, thiophenyl, dihydrofuranyl, tetrahydrofuranyl or tetrahydro It is a compound which shows pyranyl.

The compounds according to the invention can also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbonic acid such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Acid addition salts formed by, and the like, particularly preferably acid addition salts formed by sulfuric acid, methanesulfonic acid or hydrochloric acid and the like. The compound of formula 1 according to the present invention can be converted to its salts by conventional methods.

On the other hand, the compounds according to the invention may have an asymmetric carbon center and therefore may exist as R or S isomers, racemates, diastereomeric mixtures and individual diastereomers, all of these isomers and mixtures being included in the scope of the invention. do.

Meanwhile, the present invention relates to a method for preparing a compound of formula 1 by amide coupling a compound of formula 2 with a compound of formula 3:

[Formula 2]

[Formula 3]

[Formula 1]

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.

The present invention also provides a method of preparing a compound of formula 1 comprising amide coupling a compound of formula 2 'with a compound of formula 3 to form a compound of formula 1 and deprotecting the formed compound of formula 1'. It is about:

[Formula 2 ']

[Formula 1 ']

[Formula 1]

Wherein R ¹ is hydrogen, R ² , R ³ , R ⁴ and R ⁵ are as defined above, P is an aminoprotecting group, preferably t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc).

In addition, in the above process, the present invention provides a method for preparing a compound of formula (I '), followed by (i) amide coupling with C ₁ -C ₆ -alkyl-CO ₂ H, or (ii) isocyanate, C ₁ -C ₄ To a process for preparing a compound of formula (I) comprising reacting with an -alkylisocyanate, isothiocyanate or C ₁ -C ₄ -alkylisothiocyanate:

[Formula 1 ']

[Formula 1]

Wherein R ¹ is C ₁ -C ₆ -alkylcarbonyl, carbamoyl, thiocarbamoyl, C ₁ -C ₄ -alkylcarbamoyl or C ₁ -C ₄ -thiocarbamoyl, wherein alkyl is halogen, Unsubstituted or substituted by a substituent selected from the group consisting of amino, C ₁ -C ₄ -alkyl, trifluoromethyl, hydroxy, C ₁ -C ₄ -alkoxy and oxo; R ² , R ³ , R ⁴ and R ⁵ are as defined above.

The reaction may preferably be carried out in conventional solvents which do not adversely affect the reaction, particularly preferably using at least one solvent selected from dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride and chloroform. However, it is not limited to these.

The deprotection reaction of the amino group is carried out in the presence of a strong acid such as hydrochloric acid (HCl), trifluoroacetic acid (TFA) or the like, or in the presence of an amine base such as triethylamine, diisopropylethylamine (DIPEA), or the like. It can be carried out using a hydrogenation reaction. Specific reaction conditions may be referred to those described in T.W. Green & G. M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp 309-405.

In addition, known coupling agents that can be used in the coupling reaction include dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1,1'- Carbonimides, such as dicarbonyldiimidazole (CDI), are used in a mixed state with 1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT), or bis- ( 2-oxo-3-oxazolidinyl) -phosphinic chloride (BOP-Cl), diphenylphosphoryl azide (DPPA), N- [dimethylamino-1H-1,2,3-triazole [4,5 -b] pyridin-1-ylmethylene] -N-methylmethanealuminum (HATU) or the like may be used, but is not limited thereto.

Compounds of formula (1) prepared according to the process of the invention can be converted to their salts by conventional methods.

After completion of the reaction according to the process of the invention described above, the product can be separated and purified by conventional post-treatment methods such as chromatography, recrystallization and the like.

Since the compound of the present invention exhibits excellent anticancer activity against the melanocortin receptor, the present invention also contains a compound of formula (1) as an active ingredient with a pharmaceutically acceptable carrier. To provide. In particular, the compositions according to the invention show excellent effects in the prevention and treatment of obesity, erectile dysfunction, diabetes and inflammation, but are not limited to these diseases.

The total daily dose to be administered to the host in a single dose or in separate doses when administering a compound of the present invention for clinical purposes is preferably in the range of 0.01 to 10 mg / kg body weight, but specific dose levels for individual patients may be used. It may vary depending on the specific compound, the weight of the patient, sex, health condition, diet, the time of administration of the drug, the method of administration, the rate of excretion, the mixing of the drug and the severity of the disease.

The compounds of the present invention can be administered by any route as desired. Injection, oral and nasal administration are preferred, but can also be administered through the skin, abdominal cavity, larynx and rectum.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared using suitable dispersing agents, wetting agents or suspending agents according to known techniques. Solvents that can be used for this are water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are also commonly used as solvents or suspending media. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may also be used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Particularly, capsules and tablets are useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms can be prepared by mixing the active compound of formula 1 according to the invention with one or more inert diluents such as sucrose, lactose, starch and the like and a carrier such as a lubricant, disintegrant, binder, etc., such as magnesium stearate .

Representative compounds of Formula 1 according to the present invention include compounds as shown in Table 1 below.

The invention is illustrated in more detail by the following example compounds, but is not limited thereto.

Explanation of abbreviations and terms used in the names of the compounds in the following Preparation Examples and Examples are as follows.

Ac: Acetyl

AcOH: acetic acid

Bn: Benzyl

BOP: (benzotriazol-1-yl-oxy) tris (dimethylamino_phosphonium hexafluoro phosphate

Bu: Butyl

CBZ (Cbz): benzyloxycarbonyl

BOC (Boc): t-butoxycarbonyl

CDI: N, N`-carbonyldiimidazole

c-Hex: cyclohexyl

c-Pen: cyclopentyl

c-Pr: cyclopropyl

DAST: diethylaminosulfur trifluoride

DCC: dicyclohexylcarbodiimide

DCE: Dichloroethane

DCM: Dichloromethane

DIPEA: Diisopropylethylamine

DMAP: 4-dimethylaminopyridine

DMF: N, N-dimethylformamide

DMSO: Dimethylsulfoxide

DPPA: diphenylphosphoryl azide

EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EDTA: ethylene diaminetetraacetic acid

Et: ethyl

EtOAc: ethyl acetate

Fmoc: 9 - fluorenylmethoxycarbonyl

Hex: normal hexane

HATU: N-[(dimethylamino) (3H-1,2,3-triazolo [4,5-b] pyridin-3-yloxy) methylene] -N-methylenemethane ammonium hexafluorophosphate

HOAT: 1-hydroxy-7-azabenzotriazole

HOBT: hydroxybenzotriazole

HBTU: 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluoro phosphate.

i-Pr: Isopropyl

i-Bu: isobutyl

KOCN: Potassium Cyanate

LiBH ₄ : lithium borohydride

Me: methyl

MTBE: Methyl t-butyl ether

MgSO ₄ : Magnesium Sulfate

NaBH ₄ : Sodium Borohydride

NaBH (OAc) ₃ : sodium triacetoxyborohydride

NaOH: Sodium Hydroxide

NaN ₃ : Sodium Azide

Ph: Phenyl

Pr: Profile

TEA: triethylamine

TFA: trifluoroacetic acid

TFAA: trifluoro anhydride

THF: Tetrahydrofuran

t-Bu: tertiary butyl

The following preparations more specifically illustrate the preparation of intermediates required for the synthesis of the example compounds according to the invention.

Production Example  One: methyl  (2S, 4S) -1- Boc -4- Aminopyrrolidine -2- Carboxylate

Step A: (4R) -1- Boc -4- Hydroxy -L-proline

(4R) -hydroxy-L-proline (5.08 g, 38.77 mmol) was dissolved in 40 ml of 1N NaOH and 40 ml of 1,4-dioxane, followed by di-t-butyl dicarbonate (9.3 g, 42.6 mmol). Dropwise at 0 ° C. The reaction was stirred at room temperature for 8 hours, concentrated under reduced pressure, acidified with 1N hydrochloric acid and extracted with EtOAc. The extracted organic solution was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain the title compound (8.8 g, 99%). MS [M + H] = 232 (M + 1)

Step B: Methyl (2S, 4R) -1- Boc -4- Hydroxypyrrolidine -2- Carboxylate

(4R) -1-Boc-4-hydroxy-L-proline (8 g, 34.63 mmol) obtained in step A was dissolved in DMF, and methyl iodide (2.6 ml, 51.9 mmol) was added thereto. The reaction was stirred at room temperature for 5 hours, concentrated under reduced pressure and extracted with EtOAc. The extracted organic solution was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound (8.0 g, 95%). MS [M + H] = 246 (M + 1)

Step C: methyl  (2S, 4R) -1- Boc -4-[( Methylsulfonyl ) Oxy ] Pyrrolidine -2- Carboxylate

Methyl (2S, 4R) -1-Boc-4-hydroxypyrrolidine-2-carboxylate (8 g, 32.65 mmol) obtained in step B was dissolved in DCM, followed by TEA (11.99 ml, 81.56 mmol) and methanesulphate. Phonine chloride (3.77 ml, 48.9 mmol) was added dropwise at 0 ° C. After the reaction was stirred at room temperature for 3 hours, the organic solution was washed with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound (9.4 g, 90%). . MS [M + H] = 324 (M + 1)

Step D: methyl  (2S, 4S) -1- Boc -4- Azidopyrrolidine -2- Carboxylate

Methyl (2S, 4R) -1-Boc-4-[(methylsulfonyl) oxy] pyrrolidine-2-carboxylate (9 g, 27.86 mmol) obtained in step C was dissolved in DMF, followed by NaN ₃ (2.7 g). , 41.79 mmol) was added and stirred at 90 ° C. for 10 hours. The reaction mixture was concentrated under reduced pressure, extracted with EtOAc, and the extracted organic solution was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, EtOAc / Hex = 1/4) to give the title compound (6 g, 80%). MS [M + H] = 271 (M + 1)

Step E: methyl  (2S, 4S) -1- Boc -4- Aminopyrrolidine -2- Carboxylate

Obtained in step D Methyl (2S, 4S) -1-Boc-4-azidopyrrolidine-2-carboxylate (6 g, 22.22 mmol) was dissolved in dioxane (10 mL) and Pd / C (800 mg) was added dropwise. The reaction was stirred under hydrogen conditions for 24 h, filtered through celite and concentrated under reduced pressure to give the title compound (5.34 g, 98.5%) in oil form. MS [M + H] = 245 (M + 1)

Preparation Example 2 (2S, 4S) -1- Boc -2-allyl-4- Aminopyrrolidine

Step A: (2S, 4R) -1-Boc-2-allyl-4-hydroxypyrrolidine

(3R) -1-BOC-3-hydroxypyrrolidine (1 g, 5.34 mmol) is dissolved in 50 ml of diethyl ether and charged with nitrogen. After the reaction temperature was lowered to -78 ° C, N, N, N ', N'tetramethylethylenediamine (620 mg, 5.34 mmol) was added thereto, and then sec-butyllithium (4.45 ml of 1.4M cyclohexane solution, 6.23 mmol) was slowly added dropwise thereto. . After maintaining the temperature for 30 minutes, dimethyl sulfate (1.44 g, 10.68 mmol) was dissolved in 10 ml of diethyl ether. After slowly raising the temperature to room temperature, 12 ml of water was added thereto, and the mixture was diluted with diethyl ether. The organic solution was dried with K ₂ CO ₃ and the residue was purified by column chromatography (eluent, EtOAc / Hex = 1/4) to give the title compound (840 mg, 70%). MS [M + H] = 228 (M + 1)

Step B: (2S, 4S) -1-Boc-2-allyl-4-azidopyrrolidine

From (2S, 4S) -1-Boc-2-allyl-4-hydroxypyrrolidine obtained in step A, a compound was prepared in the same manner as in steps C to D of Preparation Example 1. MS [M + H] = 253 (M + 1)

Step C: (2S, 4R) -1-Boc-2-allyl-4-aminopyrrolidine

(2S, 4R) -1-Boc-2-allyl-4-azidopyrrolidine (450 mg, 1.78 mmol) obtained in step B was dissolved in THF with water (0.03 ml) and then triphenylphosphine (0.46 mg, 1.78 mmol) was added dropwise. After stirring for 18 hours at room temperature, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography (eluent, MeOH / DCM = 1/9) to give the title compound (280 mg, 70%). MS [M + H] = 227 (M + 1)

Preparation Example 3 (2S, 4S) -1- Boc -2-propyl-4- Aminopyrrolidine

(2S, 4S) -1-Boc-2-allyl-4-aminopyrrolidine (450 mg, 1.78 mmol) prepared in Preparation Example 2 was dissolved in dioxane (5 mL), and then Pd / C (40 mg) was added dropwise. It was. The reaction was stirred under hydrogen conditions for 24 hours, filtered through celite and concentrated under reduced pressure to give the title compound (390 mg, 98.5%) in oil form. MS [M + H] = 229 (M + 1)

Preparation Example 4 (2R, 4S) -1- Boc -2-propyl-4- Aminopyrrolidine

Using (2R, 4R) -1-Boc-2-allyl-4-hydroxypyrrolidine, the title compound was obtained using the same method as Preparation Example 2-3. MS [M + H] = 229 (M + 1)

Preparation Example 5 (2S, 4S) -1- Boc -4-( Cyclohexylamino )-2- Propylpyrrolidine

(2S, 4S) -1-Boc-4-amino-2-propylpyrrolidine (1 g, 4.38 mmol) dissolved in DCE (20 mL) and NaBH (OAc) ₃ (1.39 g, 6.57 mmol) in cyclohexanone ) Was added dropwise at room temperature. After the reaction was stirred at room temperature for 4 hours, saturated aqueous sodium hydrogen carbonate solution was added and the organics were extracted with DCM (50 mL X 2) and EtOAc. The extracted organic solution was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, EtOAc / Hex = 1/2) to give the title compound (1 g, 75%). MS [M + H] = 311 (M + 1)

Preparation Example 6 4,4-dimethyl- Cyclohexanone

4,4-dimethyl-cyclohexen-1-one (5 g, 52 mmol) was added to a hydrogen reaction vessel, methanol (50 mL) was added, followed by Pd / C (300 mg). The hydrogen reactor was pressurized with hydrogen (45 psi) and reacted for 12 hours. Upon completion of the reaction, the solid material was removed using celite to afford the title compound. MS [M + H] = 127 (M + 1)

Preparation Example 7 Methyl (2S, 4S) -1-Boc-4-[(2,4-difluorophenyl) amino] pyrrolidine-2-carboxylate

Methyl (2S, 4S) -1-Boc-4-aminopyrrolidine-2-carboxylate (1.3 g, 5.36 mmol) obtained in Preparation Example 1 was dissolved in toluene (20 ml) and sodium t-butyloxide (618 mg). , 6.43 mmol) and 2- (di-t-butylphosphino) biphenyl (144 mg, 0.48 mmol), tris (dibenzylideneacetone) -dipalladium (0) (293 mg, 0.32 mmol), 1-bro Mo-2,4-difluorobenzene (1.24 g, 6.43 mmol) was added thereto, and the mixture was stirred at 110 ° C. for 10 hours. After completion of the reaction, the solid material was removed using Celite, extracted with water and EtOAc. The organic layer was dried over MgSO ₄ , concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc / Hex = 1/4) to obtain the title compound. (1.48 g, 78%) was obtained. MS [M + H] = 357 (M + 1)

Preparation Example 8 Methyl (2S, 4S) -1-CBZ-4-[(4,4-difluorocyclohexyl) amino] pyrrolidine-2-carboxylate

Step A: (4R) -1-CBZ-4-hydroxy-L-proline

(4R) -hydroxy-L-proline (3.87 g, 26.9 mmol) and TEA (7.54 mL, 53.8 mmol) were dissolved in 60 mL of DCM and CbzCl (5.50 g, 29.6 mmol) was added dropwise at room temperature. After the reaction was stirred at room temperature for 4 hours, saturated aqueous ammonium chloride solution was added, and the organics were extracted with DCM and EtOAc. The extracted organic solution was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, EtOAc / n-hexane = 1/2) to give the title compound (9.06 g, 96.1%). MS [M + H] = 266 (M + 1)

Step B: Methyl (2S, 4S) -1- CBZ -4- Azidopyrrolidine -2- Carboxylate

(4R) -1-CBZ-4-hydroxy-L-proline obtained in step A was reacted in the same manner as in Steps C to D of Preparation Example 1 to obtain the title compound. MS [M + H] = 305 (M + 1)

Step C: Methyl (2S, 4S) -1- CBZ -4- Aminopyrrolidine -2- Carboxylate

Obtained in step B Methyl (2S, 4S) -1-CBZ-4-azidopyrrolidine-2-carboxylate was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound. MS [M + H] = 279 (M + 1)

Step D: Methyl (2S, 4S) -1-CBZ-4- (1,4-dioxaspiro [4,5] dec-8-ylamino) pyrrolidine-2-carboxylate

Methyl (2S, 4S) -1-CBZ-4-aminopyrrolidine-2-carboxylate (4.44 g, 16.0 mmol) and 1,4-cyclohexadione monoethylene ketal (2.99 g, 19.2 mmol) obtained in step C. ) Was dissolved in DCE (50 mL) and NaBH (OAc) ₃ (6.78 g, 32.0 mmol) was added dropwise at room temperature. After the reaction was stirred at room temperature for 4 hours, saturated aqueous NaHCO ₃ solution was added, and the organics were extracted with DCM (50 mL X 2) and EtOAc. The extracted organic solution was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, MeOH / DCM = 5/95) to give the title compound (5.8 g, 87%). MS [M + H] = 419 (M + 1)

Step E: Methyl (2S, 4S) -1-CBZ-4-[(4-oxocyclohexyl) amino] pyrrolidine-2-carboxylate

Methyl (2S, 4S) -1-CBZ-4- (1,4-dioxaspiro [4,5] dec-8-ylamino) pyrrolidine-2-carboxylate (1.48 g, obtained in step D, 3.55 mmol) was dissolved in 6 ml of THF, and 6 ml of 3N HCl was added dropwise at room temperature. After the reaction was completed, the mixture was stirred at 70 ° C., added with 3N NaOH, basified, and extracted with EtOAc. The extracted organic solution was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, MeOH / DCM = 5/95) to give the title compound (1.1 g, 85.1%). MS [M + H] = 375 (M + 1)

Step F: Methyl (2S, 4S) -1-CBZ-4-[(4,4-difluorocyclohexyl) amino] pyrrolidine-2-carboxylate

The methyl (2S, 4S) -1-CBZ-4-[(4-oxocyclohexyl) amino] pyrrolidine-2-carboxylate (1.1 g, 2.91 mmol) obtained in step E was dissolved in DCM, and then DAST ( 0.29 g, 1.8 mmol) was added dropwise at -78 deg. The reaction temperature was slowly raised to room temperature and stirred until the reaction was completed. After confirming that all the reaction disappeared, the reaction was terminated with saturated ammonium bicarbonate solution and extracted with DCM. The extracted organics were washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent, MeOH / DCM = 5/95) to give the title compound (0.59 g, 60%). MS [M + H] = 339 (M + 1)

Preparation Example 9-19

From the preparation examples above, the following compounds were obtained in the same manner as in Preparation Example 5 from the aminopyrrolidine compound and the commercially available ketone compounds.

Preparation Example 20 2,2-dimethyl-3- Acetyloxypropionic acid

2,2-dimethyl-3-hydroxypropionic acid (11.8 g, 100 mmol) was dissolved in pyridine (30 mL) and the temperature of the reaction solution was lowered to 0 ° C. Acetyl chloride (11.8 g, 15.0 mmol) was slowly added dropwise, and then the temperature of the reaction solution was raised to room temperature, followed by stirring at room temperature for 3 hours. After the reaction was completed, 1N hydrochloric acid (30 mL) was added to adjust the pH to about 3-4, and the organics were extracted with EtOAc. The extracted organics were washed 4-5 times with 1N hydrochloric acid, dried over MgSO _4, and concentrated under reduced pressure to obtain the title compound (15.2 g, 95.0%). MS [M + H] = 161 (M + 1)

Preparation Example 21 2,2-dimethyl-3- Acetyloxypropionyl  Chloride

Dissolve 2,2-dimethyl-3-acetyloxypropionic acid (11.76 g, 80 mmol) obtained in Preparation Example 20 in benzene (100 mL), lower the temperature of the reaction solution to 0 ° C, and then oxalyl chloride (15.0 g, 120). mmol) was slowly added dropwise. After 3 hours the solvent was removed under reduced pressure and distilled under reduced pressure to afford the title compound. MS [M + H] = 179 (M + 1)

Production Examples 22-27

Using the commercially available carboxylic acid in the same manner as in Preparation Example 21 to synthesize the following acyl chloride.

Preparation Example 28: (2S, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-propylpyrrolidine

Acetylchloride in DCM (20 mL) dissolved (2S, 4S) -1-Boc-4- (cyclohexylamino) -2-propylpyrrolidine (1 g, 2.84 mmol) and TEA (1.67 mL, 11.36 mmol) (0.2 mL, 2.84 mmol) was added slowly dropwise at 0 ° C. After completion of the reaction, the solvent was removed under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to the remaining filtrate, and the organics were extracted with EtOAc. The extracted organic solution was washed with 1N hydrochloric acid, dried over MgSO ₄ , concentrated under reduced pressure, and purified by column chromatography (eluent: EtOAc / Hex = 1/2) to obtain the title compound (0.69 g, 70%). MS [M + H] = 353 (M + 1)

Manufacture example 29-42

The amine obtained in Production Examples 5, 7, 8, and 9 to 19 and acyl chloride obtained or prepared in Production Examples 21 to 27 were reacted in the same manner as in Production Example 28 to obtain the following compound.

Preparation Example 43: (2S, 4S) -1-Boc-4- {3-acetyloxy-2,2-dimethylpropanoyl} (cyclohexyl) amino} -2-propylpyrrolidine

(2S, 4S) -1-Boc-4- (cyclohexylamino) -2-propylpyrrolidine (1.28 g, 2.84 mmol) was dissolved in THF (5 mL), TEA (5 mL) and DMAP (0.34 g, 2.84 mmol) was added dropwise and then 2,2-dimethyl-3-acetyloxypropionyl chloride (1.01 g, 5.68 mmol) obtained in Preparation Example 21 was added. The reaction temperature was raised to 90 ° C and stirred for 48 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to the remaining filtrate, and the organics were extracted with EtOAc. The extracted organic solution was washed with 1N hydrochloric acid, dried over MgSO ₄ , concentrated under reduced pressure, and purified by column chromatography (eluent: EtOAc / Hex = 1/4) to obtain the title compound (0.81 g, 62.9%). MS [M + H] = 453 (M + 1)

Preparation Example 44-50

The amine obtained in Production Examples 5, 7, 8, and 9 to 19 and acyl chloride obtained or prepared in Production Examples 21 to 27 were reacted in the same manner as in Production Example 28 to obtain the following compound.

Preparation Example 61 (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (aminocarbonyl) pyrrolidine

Step A: (4R) -4- [acetyl (cyclohexyl) amino] -1- (Boc) -L-proline

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] pyrrolidine-2-carboxylate (1.5 g, 2.71 mmol) was dissolved in methanol (10 ml) and water (10 ml) and LiOH (0.19 mg, 8.13 mmol) was added. After stirring for 3 hours at room temperature, it was concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with brine, dried over MgSO _4, and concentrated under reduced pressure to obtain the title compound (0.91 g, 95%). MS [M + H] = 453 (M + 1)

Step B: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (aminocarbonyl) pyrrolidine

(4R) -4- [acetyl (cyclohexyl) amino] -1-Boc-L-proline (0.91 g, 2.57 mmol) obtained in step A was dissolved in THF and TEA (0.41 ml, 2.84 mmol) was added dropwise. Ethylchloroformate (0.3 g, 2.84 mmol) was slowly added dropwise at 0 ° C., followed by stirring for 1 hour while maintaining the temperature. 1 equivalent of 28% aqueous ammonia was slowly added dropwise at 0 ° C., and stirred for 1 hour while maintaining the temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with brine, dried over MgSO ₄ , concentrated under reduced pressure, and purified by column chromatography (eluent: EtOAc / Hex = 1/1) to obtain the title compound (0.72 g, 80%). MS [M + H] = 354 (M + 1)

Preparation Example 62: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-[(dimethylamino) carbonyl] pyrrolidine

(4R) -4- [acetyl (cyclohexyl) amino] -1-Boc-L-proline (0.91 g, 2.57 mmol) was dissolved in DMF (10 mL) and DIPEA (1.15 mL, 6.70 mmol) was added dropwise and 2M Dimethylamine-THF solution (1.5 ml, 3 mmol), HOBT (399 mg, 3 mmol) and EDC (588 mg, 3 mmol) were added dropwise sequentially. After the reaction was stirred at room temperature for 12 hours, the solution was concentrated under reduced pressure. EtOAc was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and 1N hydrochloric acid. The remaining organic solution was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc: Hex = 1/2) to give the title compound (910 mg, 93%). MS [M + H] = 382 (M + 1)

Preparation Example 63: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-[(ethylamino) carbonyl] pyrrolidine

The title compound was prepared in the same manner as in Preparation 62, except that ethylamine was used instead of dimethylamine. MS [M + H] = 382 (M + 1)

Preparation Example 64: (2S, 4S) -1-Boc-2-{[(2- {cbz-amino} ethyl) amino] carbonyl} -4-[(2,2-dimethylpropanoyl) ( cis -4-methylcyclohexyl) amino] pyrrolidine

The title compound was prepared in the same manner as in Preparation 62, except that 1-cbz-ethylenediamine was used instead of dimethylamine. MS [M + H] = 587 (M + 1)

Preparation 65: (2R, 4S) -1-Boc- [acetyl (cyclohexyl) amino] -2-[(t-butylamino) carbonyl] pyrrolidine

The title compound was prepared in the same manner as in Preparation 62, except that t-butyl amine was used instead of dimethylamine. MS [M + H] = 410 (M + 1)

Preparation Example 66: (2S, 4S) -1-Boc-2- (4,5-dihydro-1,3-oxazol-2-yl) -4- [isobutyryl (cis-4-methylcyclohexyl ) Amino] pyrrolidine

Step A: (2S, 4S) -1-Boc-2-{[(2-hydroxyethyl) amino] carbonyl} -4- [isobutyryl (cis-4-methylcyclohexyl) amino] pyrrolidine

The title compound was synthesized in the same manner as in Preparation 62, except that hydroxy ethyl amine was used instead of dimethylamine. MS [M + H] = 440 (M + 1)

Step B: (2S, 4S) -1-Boc-2- (4,5-dihydro-1,3-oxazol-2-yl) -4- [isobutyryl (cis-4-methylcyclohexyl) amino] pi Lollidine

(2S, 4S) -1-Boc-2-{[(2-hydroxyethyl) amino] carbonyl} -4- [isobutyryl (cis-4-methylcyclohexyl) amino] pyrroli obtained in step A Dean (176 mg, 0.4 mmol) was dissolved in toluene (3 ml) with DMAP (48.8 mg, 0.4 mmol) and DIPEA (0.27 ml, 1.6 mmol) and then 20% phosgene / toluene solution (0.31 ml, 0.60 mmol) Was added drop wise. After stirring for 48 hours at 30 ~ 40 ℃ the solution was concentrated under reduced pressure. EtOAc was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and 1N hydrochloric acid. The remaining organic solution was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc) to give the title compound (130 mg, 78%). MS [M + H] = 422 (M + 1)

Preparation Example 67 (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (aminothiocarbonyl) pyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (aminocarbonyl) pyrrolidine (500 mg, 1.41 mmol) was dissolved in benzene (3 ml) and then Lawsons Reagent (570 mg, 1.47 mmol) was added. The temperature was raised to 80 ° C. and stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure. EtOAc was added to the residue, and the mixture was washed with brine. The remaining organic solution was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc: Hex = 1/2) to give the title compound (480 mg, 93%). MS [M + H] = 370 (M + 1)

Preparation Example 68: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (hydroxymethyl) pyrrolidine

(2R, 4R) -1-Boc-4- [acetyl (cyclohexyl) amino] pyrrolidine-2-carboxylate (1.5 g, 2.71 mmol) was dissolved in THF (10 ml) and LiBH ₄ (177 mg, 8.13 mmol) was added. After stirring for 2 hours at 70 ℃ concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over MgSO _4, and concentrated under reduced pressure to obtain the title compound (0.74 g, 81%). MS [M + H] = 341 (M + 1)

Preparation Example 69: (2S, 4S) -1- Boc -4- [acetyl ( Cyclohexyl ) Amino] -2- Methylpyrrolidine

Step A: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (hydroxymethyl) pyrrolidine

(2R, 4S) -4- [acetyl (cyclohexyl) amino] pyrrolidine-2-carboxylate (1 g, 2.71 mmol) was dissolved in THF (5 ml) and LiBH ₄ (172 mg, 8.15 mmol) was added dropwise. It was. After stirring for 5 hours at room temperature, it was concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc: Hex = 1/2) to obtain the title compound (755m g, 82). %) Was obtained. MS [M + H] = 341 (M + 1)

Step B: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-{[(methylsulfonyl) oxy] methyl} pyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (hydroxymethyl) pyrrolidine obtained in step A was reacted in the same manner as in step C of Preparation Example 1 to obtain the title compound. Obtained. MS [M + H] = 419 (M + 1)

Step C: (2S, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-methylpyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-{[(methylsulfonyl) oxy] methyl} pyrrolidine (500 mg, 1.19 mmol) obtained in step B was diluted with THF. (5 ml) and LiBH ₄ (77 mg, 3.57 mmol) was added dropwise at 70 ° C. After stirring for 5 hours at 70 ℃ concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc: Hex = 1/4) to give the title compound (204 mg, 53 %) Was obtained. MS [M + H] = 325 (M + 1)

Preparation Example 70: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-[( E )-(Hydroxyamino) methyl] pyrrolidine

Step A: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-formylpyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (hydroxymethyl) pyrrolidine (500 mg, 1.47 mmol) was dissolved in DCM (5 ml) and 15 wt% Death Martin / DCM reagent (2.2 mmol) was added dropwise at 70 ° C. After stirring for 3 hours at room temperature, it was concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc: Hex = 1/4) to obtain the title compound (298 mg, 60%). It was. MS [M + H] = 354 (M + 1)

Step B: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-[( E )-(Hydroxyamino) methyl] pyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-formylpyrrolidine (298 mg, 0.88 mmol) obtained in step A was dissolved in methanol with TEA (0.64 ml, 4.4 mmol). Dissolved in (5 ml) and added hydroxylamine hydrochloride (305 mg, 4.4 mmol) and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc: Hex = 1/2) to obtain the title compound (240 mg, 78%). It was. MS [M + H] = 354 (M + 1)

Preparation Example 71: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (aminomethyl) pyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (hydroxymethyl) pyrrolidine was obtained in the same manner as in the steps C through E of Preparation Example 1 to obtain the title compound. . MS [M + H] = 340 (M + 1)

Preparation Example 72: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-[(dimethylamino) methyl) pyrrolidine

      Reductive amination in the same manner as in Preparation Example 5, with (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (aminomethyl) pyrrolidine and formaldehyde obtained in Preparation Example 71. Reaction was synthesized. MS [M + H] = 368 (M + 1)

Preparation Example 73 (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-cyanopyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (aminocarbonyl) pyrrolidine (500 mg, 1.41 mmol) obtained in Preparation Example 61 was added to DCM (5 ml). After thawing, TFAA (0.2 ml, 1.41 mmol) was added dropwise and stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure. EtOAc was added to the residue, and the mixture was washed with brine. The remaining organic solution was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc: Hex = 1/2) to give the title compound (439 mg, 93%). MS [M + H] = 336 (M + 1)

Preparation Example 74: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (1,3-thiazol-2-yl) pyrrolidine

Step A: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (4-hydroxy-4,5-dihydro-1,3-thiazol-2-yl) Pyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (aminothiocarbonyl) pyrrolidine (740 mg, 2 mmol) was dissolved in dimethoxyethane (10 ml) 50 wt% chloroacetaldehyde (0.38 ml, 3 mmol) and sodium hydrogen carbonate (504 mg, 6 mmol) were added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc: Hex = 1/1) to obtain the title compound (509 mg, 62%). It was. MS [M + H] = 412 (M + 1)

Step B: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (1,3-thiazol-2-yl) pyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (4-hydroxy-4,5-dihydro-1,3-thiazol-2-yl obtained in step A Pyrrolidine (509 mg, 1.24 mmol) was dissolved in pyridine (0.9 ml, 11.1 mmol) and TFAA (1.0 g, 4.96 mmol) was added dropwise at 0 ° C. After stirring for 1.5 hours while maintaining the temperature, the mixture was concentrated under reduced pressure and the organics were extracted with EtOAc. The extracted organic solution was washed with 0.5N hydrochloric acid solution and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / Hex = 2/1) to give the title compound (249 mg, 51.0%). MS [M + H] = 394 (M + 1)

Preparation Example 75: (2R, 4S) -1-Boc-2-acetyl-4- [acetyl (cyclohexyl) amino] pyrrolidine

Step A: (2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-{[methoxy (methyl) amino] carbonyl} pyrrolidine

(4R) -4- [acetyl (cyclohexyl) amino] -1- (Boc) -L-proline (0.91 g, 2.57 mmol) was dissolved in DMF (10 mL) and DIPEA (1.15 mL, 6.70 mmol) was added dropwise. Then, N, O-dimethylhydroxylamine hydrochloride (292 mg, 3 mmol) and HBTU (1.1 g, 3 mmol) were added dropwise sequentially. After the reaction was stirred at room temperature for 1 hour, the solution was concentrated under reduced pressure. EtOAc was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and 1N hydrochloric acid. The remaining organic solution was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc: Hex = 3/1) to give the title compound (510 mg, 50%). MS [M + H] = 398 (M + 1)

Step B: (2R, 4S) -1-Boc-2-acetyl-4- [acetyl (cyclohexyl) amino] -pyrrolidine

(2R, 4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2-{[methoxy (methyl) amino] carbonyl} pyrrolidine (510 mg, 1.44 mmol) obtained in step A was prepared. It was dissolved in THF (5 ml) and ether solution (1.2 ml, 3.66 mmol) of methylmagnesium bromide 3M was added thereto and stirred for 3 hours. After the reaction was terminated, the solution was concentrated under reduced pressure, diluted with EtOAc in the residue, washed with water and brine. The remaining organic solution was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc: Hex = 3/1) to give the title compound (233 mg, 46%). ] = 353 (M + 1)

Preparation Example 76: (4S) -1-Boc-4- [acetyl (cyclohexyl) amino] -2- (1-hydroxyethyl) pyrrolidine

(2R, 4S) -1-Boc-acetyl-4- [acetyl (cyclohexyl) amino] -pyrrolidine (233 mg, 0.66 mmol) was dissolved in methanol (5 ml) and NaBH ₄ (49.9 mg, 1.32 mmol) Put it. After stirring for 2 hours at room temperature, it was concentrated under reduced pressure and extracted with EtOAC. The extracted organic solution was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure to obtain the title compound (185 mg, 80%). MS [M + H] = 355 (M + 1)

Preparation Example 77-125

Compounds obtained in Production Examples 46 to 60 and 30 to 42 were obtained using the same method as in Preparation Examples 61 to 76 above.

Preparation Example 126: (3S, 4R) -1-t-Butyl-4- (2,4- Difluorophenyl ) Pyrrolidine -3- Carboxylic acid

These compounds were prepared by patent number WO 2004/09126.

Preparation Example 132: (3S, 4R) -1- Boc -4- (2,4- Difluorophenyl ) Pyrrolidine -3- Carboxylic acid

Step A: (4R) -4- (2,4-difluorophenyl) pyrrolidine-3-carbonitrile

(4R) -1-t-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carbonitrile (4 g, 15.15 mmol) was dissolved in DCE (10 ml) and then 1-chloroethyl Chloroformate (2.45 ml, 22.68 mmol) was added dropwise at 0 ° C. The reaction temperature was raised to 70 ° C. and maintained at this temperature. 1.8-bis (dimethylamino) naphthalene (4.87 g, 22.72 mmol) was dissolved in DCE (10 ml) and added dropwise for 2 hours. After the reaction was terminated, methanol (10 ml) was added thereto, the temperature was maintained for 1 hour, and the reaction mixture was concentrated under reduced pressure to obtain the title compound without further purification. MS [M + 1] = 209 (M + 1)

Step B: (4R) -1-BOC-4- (2,4-difluorophenyl) pyrrolidine-3-carbonitrile

(4R) -4- (2,4-difluorophenyl) pyrrolidine-3-carbonitrile, DMAP (1.8 g, 15.15 mmol) and TEA (5.56 ml, 15.15 mmol) obtained in step A were diluted with DCM (10). ml), then di-t-butyl dicarbonate (4.9 g, 22.7 mmol) was added dropwise at 0 ° C. The reaction was stirred at room temperature for 8 hours, concentrated under reduced pressure and extracted with EtOAc. The extracted organic solution was washed with 1N hydrochloric acid and brine, dried over MgSO ₄ , concentrated under reduced pressure, and purified by column chromatography (eluent: EtOAc / Hex = 1/6) to obtain the title compound (3.3 g, steps A and B two-step yield). 72%) was obtained. MS [M + H] = 309 (M + 1)

Step C: (3S, 4R) -1-Boc-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid

(4R) -1-BOC-4- (2,4-difluorophenyl) pyrrolidine-3-carbonitrile (3.3 g, 10.6 mmol) obtained in step B was dissolved in ethanol (10 ml) and 6N NaOH 5 ml of solution was added and stirred at 70 ° C. for 4 hours. After the reaction was completed, the solvent was removed, diluted with ether, and the organic solution was washed with 6 N hydrochloric acid sufficiently acidic. The organic solution was washed with brine, dried over MgSO ₄ , and concentrated under reduced pressure to obtain the title compound (3.43 g, 99.0%). MS [M + 1] = 328 (M + 1)

Manufacture example 133-136

The compounds obtained in Production Examples 127 to 130 were reacted in the same manner as in Production Example 132 to obtain the following compounds.

Preparation Example 137-139

The compound obtained in Preparation Examples 13,17 and 18 was reacted in the same manner as in Preparation Example 28 to obtain the following compound.

Manufacture example 140-157

Compounds up to Production Examples 29 to 60 and the compounds obtained in Production Examples 137 to 139 were reacted in the same manner as in Production Examples 61 to 76 to obtain the following compounds.

Example  1: (4S) -1-{[(3S, 4R) -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -4-[(2,2-di Methylprop Panoyl) ( cis -4- Methylcyclohexyl ) Amino] -L- Prolineamide TFA salt

Step A: (4S) -4-[(2,2- Dimethylpropanoyl ) (cis-4- Methylcyclohexyl ) Amino] -L-prolineamide TFA salt

1-BOC- (4S) -4-[(2,2-dimethylpropanoyl) (cis-4-methylcyclohexyl) amino] -L-prolineamide (500 mg, 1.22 mmol) in DCM (5 mL) Was dissolved in and TFA (5 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was concentrated under reduced pressure to give the title compound (420 mg, 99.9%). MS [M + H] = 310 (M + 1)

Step B: N- Boc -(2S, 4S) -2- ( Aminocarbonyl ) -4-[(2,2- Dimethylpropanoyl ) ( cis -4-methylcyclohexyl) amino]- Pyrrolidine

(4S) -4-[(2,2-dimethylpropanoyl) (cis-4-methylcyclohexyl) amino] -L-prolineamide TFA salt (420 mg, 1.21 mmol) obtained in step A was purified by DMF (5 ML), and the solution was basified by dropwise addition of DIPEA (0.84 mL, 4.84 mmol), followed by (3S, 4R) -1-Boc-4- (4-chlorophenyl) pyrrolidine-3-carboxylic acid (390 mg). , 1.21 mmol) and HBTU (459 mg, 1.21 mmol) were added dropwise. After the reaction was stirred at room temperature for 2 hours, the solution was concentrated under reduced pressure. EtOAc was diluted with the residue and washed with saturated aqueous sodium hydrogen carbonate solution, water and 1N hydrochloric acid. The remaining organic solution was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: EtOAc: Hex = 1/1) to give the title compound (586 mg, 93.9%). MS [M + H] = 617 (M + 1)

Step C: (4S) -1-{[(3S, 4R) -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -4-[(2,2-dimethylpropanoyl) ( cis -4- Methylcyclohexyl ) Amino] -L- Prolineamide TFA salt

N-Boc- (2S, 4S) -2- (aminocarbonyl) -4-[(2,2-dimethylpropanoyl) ( cis -4-methylcyclohexyl) amino] -pyrroli obtained in step B Dean (586 mg, 1.13 mmol) was reacted in the same manner as Step A, and the residue concentrated under reduced pressure was purified by HPLC to obtain the title compound (677 mg, 95.0%). MS [M + H] = 517 (M + 1)

Example  2 ~ 21

By using the protected pyrrolidine compound synthesized in Preparation Examples 28-125 and the carboxylic acid obtained in Preparation Examples 132-136 in the same manner as in Example 1, the following compounds were obtained.

Example  22: (4S) -1-{[(3S, 4R) -4- (4- Chlorophenyl )-One- Methylpyrrolidine -3 days] Cabo Nil} -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L- Prolineamide  TFA salt

(4S) -1-{[(3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4-[(2,2-dimethylprop) obtained in Example 1 Panoyl) ( cis -4-methylcyclohexyl) amino] -L-prolineamide TFA salt (100 mg, 0.15 mmol) was dissolved in DMF (3 mL) and then reduced amino reaction in the same manner as in Preparation Example 5 with formalin. Was run. Purification by HPLC gave the title compound (82 mg, 85.3%). MS [M + H] = 531 (M + 1)

Example  23-27

The compounds obtained in Examples 1 to 21 were reacted in the same manner as in Example 22, to obtain the following compounds .

Example  28: (4S) -1-{[(3S, 4R) -1-t-butyl-4- (4- Chlorophenyl )- Pyrrolidine -3 days] Carbonyl } -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L- Prolineamide  TFA salt

(4S) -1-BOC-4-[(2,2-dimethylpropanoyl) (cis-4-methylcyclohexyl) amino] -L-prolineamide obtained in Preparation Example 89 and Step B of Example 1; The compound obtained using the same method was purified by HPLC to give the title compound. MS [M + H] = 574 (M + 1)

Example  29: N-[(3S, 5S) -1-{[(3S, 4R) -1-t-Butyl-4- (4- Chlorophenyl )- Pyrrolidine -3 days] Carbonyl } -5- Propylpyrrolidine -3-yl] -3- Hydroxy -2,2-dimethyl-N- (cis-4- Methyl cycle Lohexyl) Propanamide TFA salt

Step A: 3-{[(3S, 5S) -1-{[(3S, 4R) -1-t-butyl-4- (4- Chlorophenyl )- Pyrrolidine -3 days] Carbonyl } -5- Propylpyrrolidine -3-yl] (cis-4- Methylcyclohexyl ) Amino} -2,2-dimethyl-3-jade Sopro Pill acetate

(2S, 4S) -1-Boc-4-{[3- (acetyloxy) -2,2-dimethylpropanoyl] (cis-4-methylcyclohexyl) amino} -2-propyl obtained in Preparation Example 44. The title compound was obtained by repeating the same method as Example 1 using pyrrolidine-1-carboxylate. MS [M + H] = 630 (M + 1)

Step B: N-[(3S, 5S) -1-{[(3S, 4R) -1-t-Butyl-4- (4- Chlorophenyl )- Pyrrolidine -3-yl] carbonyl} -5- Propylpyrrolidine -3-yl] -3- Hydroxy -2,2-dimethyl-N- (cis-4- Methylcyclohexyl ) Propanamide TFA salt

3-{[(3S, 5S) -1-{[(3S, 4R) -1-t-butyl-4- (4-chlorophenyl) -pyrrolidin-3-yl] carbonyl} obtained in step A} -5-propylpyrrolidin-3-yl] (cis-4-methylcyclohexyl) amino} -2,2-dimethyl-3-oxopropyl acetate (200 mg, 0.31 mmol) in methanol (5 ml) and water After dissolving in (5ml) LiOH (22 mg, 0.93 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, dissolved in methanol, and purified by HPLC to obtain the title compound. MS [M + H] = 588 (M + 1)

Example  30: N-[(3S, 5S) -1-{[(3S, 4R) -1-t-Butyl-4- (4- Chlorophenyl )- Pyrrolidine -3 days] Carbonyl } -5- Propylpyrrolidine -3-yl] -N- Cyclohexyl -3- Hydroxy -2,2- Dimethyl Pro Panamide TFA salt

(2S, 4S) -1-Boc-4- {3-acetyloxy-2,2-dimethylpropanoyl} (cyclohexyl) amino} -2-propylpyrrolidine obtained in Preparation Example 43 was used in Example 29 and Reaction was carried out in the same manner to obtain the title compound. MS [M + H] = 575 (M + 1)

Example  31: (4S) -1-{[(3S, 4R) -1-t-butyl-4- (2,4- Difluorophenyl )-One- Methylpyrrolidine -3 days] Carbonyl }-4-[( Isobutyryl ) (4,4- Difluorocyclohexyl ) Amino] -L- Proline amides TFA salt

Step A: (2S, 4S) -2- ( Aminocarbonyl ) -4-[(4,4- Difluorocyclohexyl ) ( Isobutyryl ) Amino] Pyrrolidine -One- Carboxylate

1-cbz- (2S, 4S) -2- (aminocarbonyl) -4-[(4,4-difluorocyclohexyl) (isobutyryl) amino] pyrrolidine (450 mg) obtained in Preparation Example 81. , 0.99 mmol) was dissolved in 1,4-dioxane (10 ml) and Pd / C (40 mg) was added dropwise. The reaction was stirred under hydrogen conditions for 8 hours, filtered through celite and concentrated under reduced pressure to give the title compound (310 mg, 99.5%) in oil form. MS [M + H] = 318 (M + 1)

Step B: (4S) -1-{[(3S, 4R) -1-T-Butyl-4- (2,4- Difluorophenyl )-One- Methylpyrrolidine -3 days] Carbonyl }-4-[( Isobutyryl ) (4,4- Difluorocyclohexyl ) Amino] -L- Prolineamide TFA salt

Example of (2S, 4S) -2- (aminocarbonyl) -4-[(4,4-difluorocyclohexyl) (isobutyryl) amino] pyrrolidine-1-carboxylate obtained in step A Reaction was carried out in the same manner as 1 to obtain the title compound. MS [M + H] = 583 (M + 1)

Example  32-77

The following compounds were obtained by reacting the protected pyrrolidine compound synthesized in Preparation Examples 28 to 125 with the carboxylic acid obtained in Preparation Examples 132 to 136 in the same manner as in Example 28.

Example  78: (4S) -1-{[(3S, 4R) -1- ( Aminocarbonyl ) -4- (4- Chlorophenyl )-One- Pyrrolidine -3 days] Carbonyl } -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L- F Rollinamide

(4S) -1-{[(3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4-[(2,2-dimethylpropano) obtained in Example 1 I) ( cis -4-methylcyclohexyl) amino] -L-prolineamide TFA salt (100 mg, 0.15 mmol) was dissolved in DMF, followed by dropwise addition of KOCN (24 mg, 0.3 mmol) and catalytic amount of acetic acid. After stirring for 1 hour at room temperature, the reaction was extracted with EtOAc, washed with excess water and brine and the organic solution was dried over MgSO ₄ . The residue was purified by HPLC to give the title compound. MS [M + H] = 560 (M + 1)

Example  79: (4S) -1-{[(3S, 4R) -1- ( Aminocarbonyl ) -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L-proline

Step A: methyl (4S) -1-{[(3S, 4R) -1- ( Aminocarbonyl ) -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -4-[(2,2- Dimethylpropanoyl ) (cis-4- Methylcyclohexyl ) Amino] -L-prolol Renate

The title compound was obtained in the same manner as in Example 78, using the compound obtained in Preparation Example 47. MS [M + H] = 575 (M + 1)

Step B: (4S) -1-{[(3S, 4R) -1- ( Aminocarbonyl ) -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L- Prolineamide

Methyl (4S) -1-{[(3S, 4R) -1- (aminocarbonyl) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4- [obtained in step A (2,2-dimethylpropanoyl) (cis-4-methylcyclohexyl) amino] -L-prolinate (100 mg, 0.17 mmol) was dissolved in methanol (5 ml) and water (5 ml), followed by LiOH (12.2). mg, 0.51 mmol) was added. After stirring for 1 hour at room temperature, the reaction was concentrated under reduced pressure, acidified with 1N hydrochloric acid and extracted with EtOAc. After washing with excess water and brine and drying the organic solution with MgSO ₄ , the residue was purified by HPLC to give the title compound. MS [M + H] = 561 (M + 1)

Example  80-86

The compounds obtained in Examples 2 to 21 were reacted in the same manner as in Example 78, to obtain the following compounds.

Example  87: (4S) -1-{[(3S, 4R) -1- ( Aminocarbonyl ) -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -N- (2- Aminoethyl ) -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohex Amino) -L- Prolineamide TFA salt

Step A: (4S) -1-{[(3S, 4R) -1- ( Aminocarbonyl ) -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -N- (2- CBZ - Aminoethyl ) -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L- Prolineamide

(2S, 4S) -1-Boc-2-{[(2- {cbz-amino} ethyl) amino] carbonyl} -4-[(2,2-dimethylpropanoyl) obtained in Production Example 64 ( cis The title compound was obtained by reaction with -4-methylcyclohexyl) amino] pyrrolidine in the same manner as in Example 78. MS [M + H] = 737 (M + 1)

Step B: (4S) -1-{[(3S, 4R) -1- ( Aminocarbonyl ) -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -N- (2- Aminoethyl ) -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L- Prolineamide TFA salt

(4S) -1-{[(3S, 4R) -1- (aminocarbonyl) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -N- (2 obtained in step A -CBZ-aminoethyl) -4-[(2,2-dimethylpropanoyl) ( cis -4-methylcyclohexyl) amino] -L-prolineamide (150 mg, 0.20 mmol) in 6N hydrochloric acid (5 ml) After melting, the mixture was stirred at 100 ° C. for 30 minutes. After the reaction was completed, the reaction solution was distilled under reduced pressure and purified by HPLC to obtain the title compound. MS [M + H] = 603 (M + 1)

Example  88 and 89

Reaction was carried out in the same manner as in Example 87 using Preparation Examples 64 and 110 to obtain the following compound.

Example  90: (4S) -1-{[(3S, 4R) -1- ( Ethylaminocarbonyl ) -4- (4- Chlorophenyl )-One- Pyrrolidine -3 days] Carbonyl } -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L-pre Rollinami De

(4S) -1-{[(3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4-[(2,2-dimethylpropano) obtained in Example 1 I) ( cis -4-methylcyclohexyl) amino] -L-prolineamide TFA salt (100 mg, 0.15 mmol) was dissolved in DCM with TEA (0.04 ml, 0.3 mmol) and then ethylisocyanate (16 mg, 0.22) mmol) was added dropwise. After stirring for 1 hour at room temperature, the reaction was extracted with EtOAc, washed with excess water and brine and the organic solution was dried over MgSO ₄ . The residue was purified by HPLC to give the title compound. MS [M + H] = 588 (M + 1)

Example 91-101

Using the compounds obtained in Examples 2 to 21, and commercially available isocyanates and isothiocyanates, the following compounds were synthesized in the same manner as in Example 90.

Example  102: (4S) -1-{[(3S, 4R) -1-acetyl-4- (4- Chlorophenyl ) Pyrrolidine -3 days] Ka Carbonyl} -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L- Prolineamide

(4S) -1-{[(3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4-[(2,2-dimethylpropano) obtained in Example 1 I) ( cis -4-methylcyclohexyl) amino] -L-prolineamide TFA salt (80 mg, 0.12 mmol) and AcOH were subjected to an amide coupling reaction in the same manner as in Example 1 to obtain the title compound. MS [M + H] = 559 (M + 1)

Example  103-105

Using the compounds obtained in Examples 2 to 21 and commercially available carboxylic acid, the following compounds were synthesized in the same manner as in Example 102.

Example  106: (4S) -1-{[(3S, 4R) -1- Cyclopropyl -4- (4- Chlorophenyl ) Pyrrolidine -3 days] Carbonyl } -4-[(2,2- Dimethylpropanoyl ) ( cis -4- Methylcyclohexyl ) Amino] -L-prolineamide TFA salt

(4S) -1-{[(3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4-[(2,2-dimethylpropano) obtained in Example 1 I) ( cis -4-methylcyclohexyl) amino] -L-prolineamide TFA salt (120 mg, 0.18 mmol) was dissolved in DCE (5 ml) and 1-ethoxycyclopropoxytrimethylsilane (47 mg, 0.27 mmol) ) And sodium cyanoborohydride (23 mg, 0.36 mmol) were added, and a catalytic amount of acetic acid was added thereto, followed by stirring at 80 ° C. for 2 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, extracted with saturated aqueous sodium hydrogen carbonate solution and EtOAc, the organic solution was dried over MgSO ₄ , concentrated under reduced pressure, and the residue was purified by HPLC to obtain the title compound. MS [M + H] = 557 (M + 1)

Examples 107-151

Reaction was carried out in the same manner as in Examples 1, 2, 28, 78, 90, 102 and 106, using the protected pyrrolidine compound synthesized in Preparation Examples 140 to 157 and the carboxylic acid obtained in Preparation Examples 132 to 136 selectively. This gave the following compounds.

Compounds of the present invention were evaluated according to the method of A and B described below by measuring the agonistic activity against the activity of the melanocyte inhibitor (MCR) and the binding capacity to the MCR and evaluated the degree of physiological activity.

A. Measurement of Luciferase Expression

As one of the methods for measuring the activity of the compound according to the present invention as an MCR agonist, the amount of expression of a label gene (eg, luciferase) in proportion to the increase in the intracellular cAMP content was measured.

First, a permanently expressed human Embryonic Kidney (HEK) cell line (HEK MC1R-Luc, MC3R-Luc, which expresses the MCR gene of each subtype and the luciferase gene (CRE-LUC) under the control of the CAMP (cAMP Response Element) at the same time. MC4R-Luc or MC5R-Luc) were constructed. The cell lines were treated with a selection medium (10% heat-inactivated fetal bovine serum (Gibco / BRL), 100 units / ml penicillin (Gibco / BRL), 100 units / ml streptomycin (C) in a 37 ° C. incubator with 6% CO _2. Cultured using Dulbecco's Modified Eagles Medium (DMEM) containing Gibco / BRL) and 200 μg / ml Geneticin (G418) (Gibco / BRL), 70% of the total area When rinsed once with 10 ml of Ca ⁺⁺ and Mg ⁺⁺ (Phosphate Buffered Saline; PBS), 3 ml of PBS solution containing 0.05% trypsin and 0.53 mM EDTA was added. The trypsin / EDTA solution was removed, incubated for 1 minute in a 37 ° C. incubator, then resuspended in 10 ml of selective medium and centrifuged for 5 minutes at 1500 rpm After removing the supernatant, the precipitated cells were removed in 5 ml of phenol red ( Phenol Red) was resuspended in a selective medium containing no cell suspension. Was added to each well of a cell culture plate (Costar) for 96-well Luminometer to 5X10 ⁴ cells in 100ul culture medium and incubated for 18 hours in a 37 ℃ incubator containing 6% CO _2. The culture medium was used to treat the MCR adjuvants (Example compound) diluted to each step concentration, so that the final DMSO concentration did not exceed 1%, and then incubated for 5 hours in a 37 ° C. incubator in which 6% CO ₂ was present. Each well was treated with 50 μl of Bright-Glo Luciferase Reagent (Promega), and then allowed to stand at room temperature for 15 minutes. The amount of luminescence induced by the concentration-diluted antidiarrheal agent was converted into% value relative to the amount indicated by 10 μM NDP-MSH treatment. EC ₅₀ was expressed as a concentration that induces 50% of the maximum amount of luminescence that can be induced by each antidiarrheal agent and this measurement was determined using statistical software (Prizm).

B. cAMP measurement

As another method of measuring the activity of the compounds according to the invention as MCR agonists, an increase in the intracellular cAMP content was measured.

First, a permanently expressed HEK (Human Embryonic Kidney) cell line (HEK MC1R, MC3R, MC4R or MC5R) expressing the MCR genes of each subtype was added to 2 × 10 ⁵ in 1 ml of culture medium per well of a 24-well cell culture plate (Costar). Cells were added and then incubated for 24 hours in a 37 ° C. incubator with 6% CO ₂ . The medium of each well was removed and washed once with 0.5 ml of cold DMEM. MCR adjuvants (Example compound) diluted to 200 μl DMEM containing 500 μM IBMX (isobutylmethylxanthine) at a stepwise concentration were treated with a final DMSO concentration of no greater than 1% and then with 6% CO ₂ present. Incubated for 30 minutes in an incubator. The content of cAMP in each cell was measured using an Amersham cAMP measurement kit (TRK432).

In more detail, 14.4 μl of 6M PCA (60%) was added to each well, left on ice for 10 minutes, and then 200 μl of each well was transferred to a microcentrifuge tube. 11 μl of 5M KOH / 1M Tris was added thereto, neutralized, and centrifuged at 12,000 rpm for 1 minute. After taking 50 μl of the supernatant, 50 μl of ³ H-labeled cAMP (0.9 pmol, 0.025 μCi) was added, and 100 μl of binding protein was added thereto, followed by shaking for 5 seconds. After standing on ice for 2 hours, 100 μl of charcoal was added and centrifuged at 12,000 rpm for 3 minutes at 4 ° C. 200 μl of the supernatant was taken and placed in a scintillation vial, 5 ml of scintillant was added, and radioactivity was measured.

The amount of cAMP induced by the antidiarrheal agent diluted at each step concentration was converted to a percentage value relative to the amount indicated by 10 μM NDP-MSH treatment. EC ₅₀ was expressed as a concentration that induces 50% of the maximum amount of cAMP that can be induced by each antidiarrheal agent and this measurement was determined using statistical software (Prizm).

As a result of the measurement according to the method described above, it was confirmed that the example compound of the present invention exhibits antifungal effect on each MCR. They showed particularly good anti-inflammatory and binding effects on MC4R and EC ₅₀ values of 0.001 μM to 10 μM. Specifically, for example, Example Compounds 1, 7, 10, 18, 22, 28, 42, 63, 79, and 121 show good antiviral EC ₅₀ values of 0.005 μM to 0.180 μM for MC4R as shown in the table below. Indicated.

Claims (19)

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

In the above formula R ¹ is hydrogen, C ₁ -C ₁₀ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkylcarbonyl, carbamoyl, thiocarbamoyl, C ₁ -C ₄ -alkylcarbamoyl or C _1- C ₄ -alkylthiocarbamoyl, Wherein alkyl or cycloalkyl is unsubstituted or substituted by a substituent selected from the group consisting of halogen, amino, C ₁ -C ₄ -alkyl, trifluoromethyl, hydroxy, C ₁ -C ₄ -alkoxy and oxo, R ² represents C ₆ -C ₁₀ -aryl unsubstituted or substituted or unsubstituted by a substituent selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy, R ³ is C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₂ -C ₆ -alkenyl, monocyclic heterocycle, monocyclic heteroaryl, carboxy, C ₁ -C ₄ -alkyl Oxycarbonyl, C ₁ -C ₄ -alkylcarbonyl, cyano, carbamoyl, thiocarbamoyl, C ₁ -C ₄ -alkylcarbamoyl, (C ₁ -C ₄ -alkyl) (C ₁ -C _4- Alkyl) carbamoyl, C ₁ -C ₄ -alkylthiocarbamoyl or (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) thiocarbamoyl, Wherein alkyl, cycloalkyl, heterocycle or heteroaryl is methyl, trifluoromethyl, hydroxy, hydroxyimino, amino, (C ₁ -C ₄ -alkyl) amino and (C ₁ -C ₄ -alkyl) ( Unsubstituted or substituted by a substituent selected from the group consisting of C ₁ -C ₄ -alkyl) amino, R ⁴ represents C ₃ -C ₈ -cycloalkyl, C ₆ -C ₁₀ -aryl or heterocycle, Wherein C ₆ -C ₁₀ -aryl is mono- or di-substituted by a substituent selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ -alkyl, trifluoromethyl, C ₁ -C ₄ -alkoxy and amino Unsubstituted, Cycloalkyl or heterocycle is mono- or di-substituted or unsubstituted by a substituent selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ -alkyl, trifluoromethyl, C ₁ -C ₄ -alkoxy and oxo, R ⁵ represents C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₃ -C ₆ -cycloalkyl, heteroaryl or heterocycle, Wherein alkyl, cycloalkyl, heteroaryl or heterocycle is unsubstituted or substituted by a substituent selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ -alkoxy, amino, carbamoyl, hydroxyimino and oxo, Here, heteroaryl represents an aromatic 3-6 membered ring which contains 1 to 2 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, and which can be fused with benzo or C ₃ -C ₈ -cycloalkyl , Heterocycle includes 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and may be fused with benzo or C ₃ -C ₈ -cycloalkyl, and may be saturated or contain 1 or 2 double bonds. The containing 4-8 membered ring is shown. The compound of claim 1, wherein R ¹ is hydrogen, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -alkylcarbonyl, carbamoyl, thiocarbamoyl, C ₁ -C ₄ A compound of formula (1) representing a -alkylcarbamoyl or C ₁ -C ₄ -alkylthiocarbamoyl, a pharmaceutically acceptable salt or isomer thereof. The compound of claim 2, wherein R ¹ is hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclopentyl, acetyl, propionyl, isobutylyl, pivaloyl, carbamoyl, methylcarbamoyl, ethylcarba A compound of formula (1) representing a moyl, propyl carbamoyl, t-butylcarbamoyl, methylthiocarbamoyl or ethylthiocarbamoyl, a pharmaceutically acceptable salt or isomer thereof. 2. A compound of formula (1), a pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R ² represents phenyl mono- or di-substituted or unsubstituted by a substituent selected from the group consisting of fluorine, chlorine and methyl. The compound of formula 1 according to claim 4, wherein R ² represents phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl or 2,4-difluorophenyl, a pharmaceutically acceptable salt or isomer thereof . The compound of claim 1, wherein R ³ is C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, oxazolyl, thiazolyl, oxazolinyl, thiazolinyl, carboxy, C ₁ -C ₄ -alkyloxy Carbonyl, acetyl, cyano, carbamoyl, thio carbamoyl, C ₁ -C ₄ -alkylcarbamoyl, (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) carbamoyl, C ₁ -C ₄ -alkylthiocarbamoyl or (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) thiocarbamoyl, Wherein alkyl is substituted with a substituent selected from the group consisting of hydroxy, hydroxyimino, amino, (C ₁ -C ₄ -alkyl) amino and (C ₁ -C ₄ -alkyl) (C ₁ -C ₄ -alkyl) amino A compound of formula (1), pharmaceutically acceptable salts or isomers thereof, substituted or unsubstituted. C ₅ -C ₆ -according to claim 1, wherein R ⁴ is mono- or di-substituted or unsubstituted by a substituent selected from the group consisting of fluorine, chlorine, hydroxy, methyl, trifluoromethyl, methoxy and oxo. A compound of formula (I) which represents mono-, di- or unsubstituted phenyl by cycloalkyl or heterocycle or by a substituent selected from the group consisting of fluorine, chlorine, hydroxy, methyl, trifluoromethyl, methoxy and amino, Pharmaceutically acceptable salts or isomers thereof. 8. The compound of claim 7 wherein R ⁴ is selected from the group selected from the group consisting of cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, tetrahydropyranyl, or fluorine, chlorine and methyl A compound of formula (1), a pharmaceutically acceptable salt or isomer thereof, representing substituted or disubstituted or unsubstituted phenyl. The compound of claim 1, wherein R ⁵ represents propen-2-yl, furanyl, thiophenyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, or fluorine, hydroxy, methoxy , A compound of formula (I) representing a C ₁ -C ₄ -alkyl unsubstituted or substituted by a substituent selected from the group consisting of ethoxy, amino and oxo, a pharmaceutically acceptable salt or isomer thereof. 10. The compound of claim 9, wherein R ⁵ is methyl, trifluoromethyl, ethyl, propen-2-yl, isopropyl, t-butyl, hydroxybutyl, furanyl, thiophenyl, dihydrofuranyl, tetrahydro A compound of formula 1, a pharmaceutically acceptable salt or isomer thereof, representing furanyl or tetrahydropyranyl. The compound, pharmaceutically acceptable salt or isomer thereof, according to claim 1, which is selected from the following groups: (4 S) -1 - {[ (4 R) -1- methyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4 - [(4,4 Dimethylcyclohexyl) (2,2-dimethylpropanoyl) amino] -L-prolineamide; (4 S) -1 - {[(4 R) -1- tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- [(4, 4dimethylcyclohexyl) (isobutyryl) amino] -L-prolineamide; N - [(3 S, 5 R) -5- ( aminocarbonyl thionyl) -1 - {[(4 R ) -1- tert - butyl-4- (2,4-Oro deployment phenyl) pyrrolidine -3-yl] carbonyl} pyrrolidin-3-yl] -2,2-dimethyl- N- ( cis -4-methylcyclohexyl) propanamide; (4 S) -1 - {[(4 R) -1- tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- [(4, 4-dimethylcyclohexyl) (2,2-dimethylpropanoyl) amino] -N , N -dimethyl-L-prolineamide; (4 S) -1 - {[(4 R) -1- tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- [(4, 4-dimethylcyclohexyl) (isobutyryl) amino] -N , N -dimethyl-L-prolineamide; (4 S) -1 - {[(4 R) -1- tert-butyl-4- (2,4-deployment ruro phenyl) pyrrolidin-3-yl] carbonyl} -4 - [(2,2 -Dimethylpropanoyl) ( cis -4-methylcyclohexyl) amino] -L-prolineamide; N - {(3 S, 5 S) -1 - {[(4 R) -1- tert - butyl-4- (2,4-deployment oro-phenyl) pyrrolidin-3-yl] carbonyl} 5 - [(dimethylamino) carbonyl, thionyl] pyrrolidin-3-yl} - N - (4,4- dimethyl-cyclohexyl) -2-methyl-propanamide; N - {(3 S, 5 S) -1 - {[(4 R) -1- tert - butyl-4- (2,4-deployment oro-phenyl) pyrrolidin-3-yl] carbonyl} 5 - [(dimethylamino) carbonyl, thionyl] pyrrolidin-3-yl} - N - (4,4- dimethyl-cyclohexyl) -2, 2-dimethylpropanamide; (4 S) -1 - {[ (4 R) -1- cyclopropyl-4- (2,4-deployment oro-phenyl) pyrrolidin-3-yl] carbonyl} -4 - [(4,4 -Dimethylcyclohexyl) (2,2-dimethylpropanoyl) amino] -N , N -dimethyl-L-prolineamide; (4 S) -1 - {[ (4 R) -1- cyclopentyl-4- (2,4-deployment oro-phenyl) pyrrolidin-3-yl] carbonyl} -4 - [(4,4 -Dimethylcyclohexyl) (2,2-dimethylpropanoyl) amino] -N , N -dimethyl-L-prolineamide; (4 S) -1 - {[ (4 R) -4- -1- isopropyl-P (2,4-oro-phenyl deployer) pyrrolidine-3-yl] carbonyl} -4 - [(4,4 -Dimethylcyclohexyl) (2,2-dimethylpropanoyl) amino] -N , N -dimethyl-L-prolineamide; N - {(3 S, 5 S) -1 - {[(4 R) -4- (2,4- deployer oro-phenyl) -1-isopropyl-pyrrolidin-3-yl] carbonyl} -5 - [(dimethylamino) carbonyl, thionyl] pyrrolidin-3-yl} - N - (4,4- dimethyl-cyclohexyl) -2, 2-dimethylpropanamide; (4 S) -1 - {[(4 R) -1- tert-butyl-4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4 - [(4,4-dimethyl-bicyclo Hexyl) (tetrahydrofuran-3-ylcarbonyl) amino] -N , N -dimethyllL-prolineamide; (4 S) -1 - {[(4 R) -1- tert-butyl-4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4 - [(4,4-dimethyl-bicyclo Hexyl) (2,2-dimethylpropanoyl) amino] -N -ethyl-L-prolineamide; N - [(3 S, 5 R) -1 - {[(4 R) -1- tert - butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} 5- (1,3-thiazol-2-yl) pyrrolidin-3-yl] - N - (4,4- dimethyl-cyclohexyl) -2, 2-dimethylpropanamide; N - [(3 S, 5 S) -1 - {[(4 R) -1- tert - butyl-4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -5- (4 , 5-dihydro-1,3-oxazol-2-yl) pyrrolidin-3-yl] - N - (4,4- dimethyl-cyclohexyl) -2, 2-dimethylpropanamide; N - [(3 S, 5 R) -5- acetyl -1 - {[(4 R) -1- tert - butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl; carbonyl} pyrrolidin-3-yl] - N - (4,4- dimethyl-cyclohexyl) -2,2-ami de; (4 S) -1 - {[ (4 R) -1- ( aminocarbonyl) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4 - [( 4,4-dimethylcyclohexyl) (2,2-dimethylpropanoyl) amino] -L-prolineamide; (4 S) -1 - ({ (4 R) -4- (4- chlorophenyl) -1 - [(methylamino) carbonyl, thionyl] pyrrolidin-3-yl} carbonyl) -4 - [( 4,4-dimethylcyclohexyl) (2,2-dimethylpropanoyl) amino] -N , N -dimethyl-L-prolineamide; (4 S) -1 - ({ (4 R) -4- (4- chlorophenyl) -1 - [(ethylamino) carbonyl thionyl] pyrrolidin-3-yl} carbonyl) -4 - [( 2,2-dimethylpropanoyl) ( cis -4-methylcyclohexyl) amino] -N , N -dimethyl-L-prolineamide; (4 S) -1 - {[ (4 R) -1- Acetyl-4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4 - [(4,4-dimethyl-cyclohexyl) (2,2-dimethylpropanoylamino] -N , N -dimethyl-L-prolineamide; (4 S) -1 - {[ (4 R) -4- (4- chloro-phenyl) -1-isobutyryl rilpi 3-yl] carbonyl} -4 - [(4,4-dimethyl-cyclohexyl ) (2,2-dimethylpropanoyl) amino] -L-prolineamide; (4 S) -1 - {[(4 R) -1- tert-butyl-4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4 - [(4,4-dimethyl-bicyclo Hexyl) (2,2-dimethylpropanoyl) amino] -N , N -dimethyl-L-prolineamide; (4 S) -1 - {[(4 R) -1- tert-butyl-4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -4 - [(2,2-dimethylpropanoyl Panoyl) ( cis -4-methylcyclohexyl) amino] -N , N -dimethyl-L-prolineamide; N - {(3 S, 5 S) -1 - {[(4 R) -1- tert - butyl-4- (2,4-deployment by oro-phenyl) pyrrolidin-3-yl] carbonyl} car - 5 - [(Z) - (hydroxyimino) methyl-pyrrolidin-3-yl} - N - (4,4- dimethyl-cyclohexyl) -2, 2-dimethylpropanamide; And N - [(3 S, 5S ) - 5- acetyl -1 - {[(4 R) -1- tert - butyl-4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} pyrrolidine 3-yl] - N - (4,4- dimethyl-cyclohexyl) -2,2-dimethylpropanamide. A process for preparing a compound of formula 1 by amide coupling a compound of formula 2 with a compound of formula 3: [Formula 2]

[Formula 3]

[Formula 1]

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1. A method of preparing a compound of Formula 1 comprising amide coupling a compound of Formula 2 'with a compound of Formula 3 to form a compound of Formula 1' and deprotecting the formed compound of Formula 1 ': [Formula 2 ']

[Formula 1 ']

[Formula 1]

Wherein R ¹ is hydrogen, R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1, and P represents an aminoprotecting group. The process of claim 13, wherein the compound of formula 1 'is deprotected and then (i) amide coupled with C ₁ -C ₆ -alkyl-CO ₂ H, or (ii) isocyanate, C ₁ -C ₄ -alkyl A process for preparing a compound of Formula 1 comprising reacting with isocyanate, isothiocyanate or C ₁ -C ₄ -alkylisothiocyanate: [Formula 1]

Wherein R ¹ is C ₁ -C ₆ -alkylcarbonyl, carbamoyl, thiocarbamoyl, C ₁ -C ₄ -alkylcarbamoyl or C ₁ -C ₄ -thiocarbamoyl, wherein alkyl is halogen, Unsubstituted or substituted by a substituent selected from the group consisting of amino, C ₁ -C ₄ -alkyl, trifluoromethyl, hydroxy, C ₁ -C ₄ -alkoxy and oxo; R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1. A functional antidiabetic composition of melanocortin receptor characterized by containing a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof as defined in claim 1 together with a pharmaceutically acceptable carrier. The composition for preventing and treating obesity according to claim 15. The composition of claim 15 for preventing and treating diabetes. The composition of claim 15 for preventing and treating inflammation. The composition for preventing and treating erectile dysfunction according to claim 15.