KR20100110532A - A compound for inhibiting soluble epoxide hydrolase, a method for producing the same and a pharmaceutical composition comprising the same - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing a novel compound or pharmaceutically acceptable salt thereof for suppressing epoxide hydrolase(sEH) is provided to treat obstructive poulmonary disease or obstructive lung disease. CONSTITUTION: A compound suppressing human soluble epoxide hydrolase is denoted by chemical formula 1. A method for preparing the compound of chemical formula 1 comprises: a step of reacting a compound of chemical formula 3 and compound of chemical formula 4 to generate amine intermediate; and a step of reacting amine intermediate with dialkyl phosphate, dihaloalkyl phosphate, diarylphosphite or cyclic alkyl phosphate. A pharmaceutical composition for suppressing the human soluble epoxide hydrolase contains the compound of chemical formula 1 or pharmaceutically acceptable salt as an active ingredient.

Description

COMPOUND FOR INHIBITING SOLUBLE EPOXIDE HYDROLASE, A METHOD FOR PRODUCING THE SAME AND A PHARMACEUTICAL COMPOSITION COMPRISING THE THESE COMPOSITION SAME}

The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for inhibiting human soluble epoxide hydrolase (sEH) comprising the same.

Epoxide hydrolase (EH, EC 3.3.2.3.) Is a catalyst for the hydrolysis of epoxides or arene oxides to diols by addition of water (Oesch, F., et al., Xenobiotica 1973, 3 , 305-340). EH plays an important role in the metabolism of harmful foreign compounds such as hormones, chemotherapy drugs, calcinegens, environmental pollutants and mycotoxins.

EH includes microsomal epoxide hydrolase (mEH) and soluble epoxide hydrolase (sEH). They show significant differences in intracellular location, substrate selectivity, etc., and have a complementary effect on the degradation of plant natural products (Hammock, BD, et al., COMPERHENSIVE TOXICOLOGY. Oxford: Pergamon Press 1977, 283-305; Fretland, AJ, et al., Chem. Bio.Interact 2000,129,41-59). sEH is primarily involved in the metabolism of lipid oxides such as arachidonic acid and linoleic acid (Zeldin, DC, et al., J. Bio. Chem. 1993, 268 , 6402-6407; Moghaddam, MF, et al., Nat. Med. 1997, 3, 562-567). Hydrolysis of the epoxyeicosatrienoic acid (EET) of arachidonic acid shows that they can regulate endothelial function by sEH by controlling their fusion to coronary endothelial phospholipids. Recently, treatment of spontaneous hypertensive rats (SHR) with selective sEH inhibitors has been shown to significantly lower blood pressure (Yu, Z., et al., Circ. Res. 2000, 87, 992-998). ] Reference). In addition, male knockout sEH mice showed significantly lower blood pressure than wild-type mice, indicating that sEH can regulate blood pressure (Sinal, CJ, et al., J. Bio . Chem . 2000, 275 , 40504-405010 ] Reference).

EET also exhibits anti-inflammatory effects in endothelial cells (Node, K. et al., Science 1999, 285, 1276-1279; Campbell, WB, Trends Pharmarcol . Sci. 2000, 21, 125-127). In contrast, diols derived from epoxy linoleate, ie leukotoxin, perturb membrane permeability and calcium homeostasis, leading to inflammation controlled by nitric oxide synthase and endothelin-1 (see literature). [(; see Moghaddam, MF, et al, Nat Med 1997, 3, 562-567...... Ishizaki, T., et al, Am .J Physiol 1995,269, L65-70]) leuco toxin Micromolar levels of are associated with anti-inflammatory and hypoxia and are known to reduce mitochondrial respiration in vitro and to induce mammalian CPR in vivo (Dudda, A, et al., Chem , Phys . Lipids 1996, 82, 39-51; Sakai, T. et al., Am. J. Physiol. 1995, 269, L326-331). Symptoms of Distress Syndrome (ARDS) appear (see Ozawa, T. et al., Am. Rev. Respir. Dis. 1988, 137,535-540). In both cell and individual models, Leukotoxin-mediated toxicity is dependent on epoxide hydrolysis (Moghaddam, MF, et al., Nat. Med. 1997, 3, 562-567; Morisseau, C., et al., Proc. Natl. Acad Sci. USA 1999, 96, 8849-8854), and it was shown that sEH modulates inflammation and vascular permeability. Show that you can be an enemy target.

Recently, 1,3-disubstituted ureas, carbamates and amides have been reported as novel potent and stable sEH inhibitors (US Patent No. 6,150,415). These are competitive strong binding inhibitors with nanomolar K _I values that quantitatively react with purified recombinant sEH (Morisseau, C. et al., Proc. Natl. Acad. Sci. USA 1999, 96, 8849-8854).

According to the X-ray crystal structure, the urea inhibitor forms a hydrogen bond and a salt bridge between the functional group of the urea inhibitor and the sEH active site residue, thereby forming a structure similar to the reaction site of the epoxide ring opened by the enzyme (Argiriadi, MAk et al., Proc. Natl. Acad. Sci. USA 1999, 96, 10637-10642). These inhibitors effectively inhibit epoxide hydrolysis in some in vivo and in vitro models (Yu, Z., et al., Circ. Res. 2000, 87, 992-998; Morisseau, C., et al. , Proc. Natl. Acad. Sci. USA 1999, 96, 8849-8854; Newman, JW, et al, Environ. Health Perspect. 2001, 109, 61-66). However, despite the high activity of these inhibitors, there is a need for compounds with improved pharmacokinetic properties.

The present invention provides a compound having a better activity and solubility and more efficient in formulation and delivery, and sEH inhibition pharmaceutical composition comprising them.

The present invention provides a novel compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for inhibiting human soluble epoxide hydrolase (sEH) comprising the same.

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

In Chemical Formula 1,

R ¹ is any one selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl and substituted or unsubstituted C ₆ -C ₁₀ aromatic groups, wherein said cycloalkyl is monocyclic or polycyclic Wherein the substituted C ₆ -C ₁₀ aromatic group is substituted with one or more substituents selected from the group consisting of —CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ alkyl ester Become;

P ¹ is any one selected from the group consisting of -C (X) NH-, -NHC (X)-, -NHC (X) NH-, -C (X) O-, and -OC (X)-, X is O or S;

P ² is represented by the following formula (2);

In Chemical Formula 2,

,

및 직쇄형 또는 분지형 C₁ - C₆ 알킬로 구성된 군으로부터 선택되며;R ² is

,

And straight or branched C ₁ -C ₆ alkyl;

R ³ is selected from straight or branched C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, or a substituted or unsubstituted C ₆ -C ₁₀ aromatic group,

Wherein the carbon of the C ₆ -C ₁₀ aromatic group may be substituted with one or more atoms selected from the group consisting of N, O, and S, wherein the substituted C ₆ -C ₁₀ aromatic group is —CN, halogen, C ₁ − C ₆ alkyl, C ₁ - C ₆ alkoxy, C ₁ - C ₆ carbon constituting the alkyl ester and a ring N, O, and that that one or more atoms selected from the group consisting of S to Feature C ₃ - C ₈ Substituted with one or more substituents selected from the group consisting of heterocyclo alkyl;

Y is any one selected from the group consisting of dialkylphosphonates, dihaloalkylphosphonates, diarylphosphonates and cyclicalkylphosphonates.

Preferably, R ¹ of the compound is a compound characterized by C ₃ -C ₁₂ cycloalkyl, more preferably R ¹ of the compound is a compound characterized by being an adamantanyl group.

Preferably, P ¹ of the compound is a compound characterized in that -C (O) NH- or -NHC (O) NH-.

임을 특징으로 하는 화합물이다.Preferably, R ² of the compound

It is a compound characterized by.

Preferably, R ³ of the compound is a compound characterized in that it is selected from the group consisting of isobutyl, phenyl, and pyridine.

Preferably, the compound Y is diethylphosphonate.

이며, R³은 이소부틸, 페닐, 및 피리딘으로 구성된 군으로부터 선택된 것을 특징으로 하는 화합물이다.Preferably, R ¹ of the compound is an adamantanyl group, P ¹ is -C (O) NH- or -NHC (O) NH-, and R ² is

R ³ is a compound selected from the group consisting of isobutyl, phenyl, and pyridine.

The present invention comprises the steps of (A) reacting a compound of formula 3 and a compound of formula 4 to generate an imine intermediate; And

(B) reacting the imine intermediate with any one selected from the group consisting of dialkyl phosphites, dihaloalkyl phosphites, diaryl phosphites and cyclic alkyl phosphites It provides a method of preparing:

In the above formula,

R ¹ , R ² , R ³ and P ¹ are as defined in claim 1.

Preferably, the compound of formula 3 is produced by reacting R ¹ -COOH or R ¹ -NCO with NH ₂ -R ² -NH ₂ , wherein R ¹ and R ² are as defined in claim 1 It provides a way to.

The present invention is a pharmaceutical composition for inhibiting human soluble epoxide hydrolase, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention includes the compound or a pharmaceutically acceptable salt thereof as an active ingredient, hypertension, inflammation, adult respiratory distress syndrome, diabetic complications, kidney disease, Raynaud syndrome, obstructive pulmonary disease, interstitial lung A pharmaceutical composition for the treatment or prevention of any one disease selected from the group consisting of diseases, asthma, stroke and arthritis. Preferably, the composition is a pharmaceutical composition, characterized in that it is selected from the group consisting of renal hypertension, pulmonary arterial hypertension and hepatic hypertension, and is a pharmaceutical composition, characterized in that selected from the group consisting of kidney inflammation, vascular inflammation and lung inflammation, Pharmaceutical composition, characterized in that it is selected from the group consisting of chronic obstructive pulmonary disease, emphysema and chronic bronchitis.

As used herein, the term "soluble epoxide hydrolase" ("sEH") refers to a dihydroxy in which endothelial cells, smooth muscle and other cell types are referred to as hydroxyeicosatoenoic acid ("DHET"). It is an enzyme that converts to derivatives. Cloning and sequences of murine sEH are described in Grant et al., J. Biol. Chem. 268 (23): 17628-17633 (1993). Cloning of human sEH sequences, and sequences and accession numbers are described in Beetham et al., Arch. Biochem. Biophys. 305 (1): 197-201 (1993). The amino acid sequence of human sEH is described as SEQ ID NO: 2 of US Pat. No. 5,445,956, and the nucleic acid sequence encoding human sEH is described as the nucleotides 42-1-1703 of the patent sequence 1. Soluble epoxide hydrolases represent a single highly conserved gene product with at least 90% homology between rodents and humans (Arand et al., FEBS Lett., 335: 251-256 (1994)).

As used herein, the term “compound” refers to the entirety of a specified molecule, as well as, but not limited to, salts, prodrug conjugates such as esters and amides, metabolites, hydrates, solvates, and the like. Permittedly, it is intended to include pharmacologically active derivatives.

As used herein, the term "composition" is intended to include not only products that contain specified components in specified amounts, but also any products that are produced directly or indirectly from combinations of specified components in specified amounts. The term "pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to its recipient.

The term "alkyl" as used herein denotes a saturated hydrocarbon radical, which may be straight or branched. This definition applies both when the term is used alone and when used as part of a compound term, such as "arylalkyl", "alkylamino" and similar terms. All numerical ranges in the specification and claims are intended to include their upper and lower limits.

The terms "cycloalkyl" and "cycloalkylene" refer to saturated hydrocarbon rings and include acyclic and polycyclic rings. Similarly, cycloalkyl and cycloalkylene groups having heteroatoms (eg, N, O or S) instead of carbon ring atoms may be referred to as "heterocycloalkyl" and "heterocycloalkylene", respectively. Cycloalkyl and heterocycloalkyl moieties may also be unsubstituted or substituted with halogen atoms or other groups such as nitro, alkyl, alkylamino, carboxyl, alkoxy, aryloxy and the like.

The term "halo" or "halogen" means fluorine, chlorine, bromine or iodine atoms unless otherwise specified.

The term "hetero" refers to a molecule in which one or more carbon atoms are replaced with one atom other than carbon, such as nitrogen, oxygen, sulfur, phosphorus or silicon, generally nitrogen, oxygen or sulfur or more than one non-carbon atom , A bonding group or a substituent. Similarly, the term “heteroalkyl” refers to an alkyl substituent that is heteroatom containing, and the term “heterocyclic”, “heterocycle” or “heterocyclyl” refers to a cyclic substituent or group that is heteroatom containing or aromatic or nonaromatic. Indicates. The terms "heteroaryl" and "heteroaromatic" refer to "aryl" and "aromatic" substituents, each containing heteroatoms. The terms "heterocyclic" and "heterocyclyl" include the terms "heteroaryl" and "heteroaromatic".

The term “substituted” denotes that an atom or group of atoms in one compound is replaced with another atom or group of atoms. For example, an atom or group of atoms may be substituted by one or more of the following substituents or groups: halo, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylamino, hydroxyC ₁ -C ₈ alkyl, haloC ₁ -C ₈ alkyl, carboxyl, hydroxyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkoxyC ₁ -C ₈ alkoxy, thioC ₁ -C ₈ alkyl, aryl, aryl Oxy, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl C ₁ -C ₈ alkyl, heteroaryl, arylC ₁ -C ₈ alkyl, heteroarylC ₁ -C ₈ alkyl, 1 to 2 double bonds C ₂ -C ₈ alkenyl containing, C ₂ -C ₈ alkynyl containing 1 to 2 triple bonds, C ₄ -C ₈ alk (en) (phosphoryl) yl group, cyano, formyl, C ₁ -C ₈ alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C ₁ -C ₈ alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, C ₁ -C ₈ alkylcarbonyl, C ₁ -C ₈ dialkyl Aminocarbonyl, arylaminocarbonyl, diarylaminocar Carbonyl, aryl C ₁ -C ₈ alkyl, aminocarbonyl, halo-C ₁ -C ₈ alkoxy, C ₂ -C ₈ alkenyloxy, C ₂ -C ₈ alkynyloxy, aryl C ₁ -C ₈ alkoxy, amino, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl, C ₁ -C ₈ dialkylaminoC ₁ -C ₈ alkyl, arylaminoC ₁ -C ₈ alkyl, amino, C ₁ -C ₈ Dialkylamino, arylamino, arylC ₁ -C ₈ alkylamino, C ₁ -C ₈ alkylcarbonylamino, arylcarbonylamino, azido, mercapto, C ₁ -C ₈ alkylthio, arylthio, halo C ₁ -C ₈ alkylthio, thiocyano, isothiocyano, C ₁ -C ₈ alkylsulfinyl, C ₁ -C ₈ alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, C ₁ -C ₈ alkylaminosulfonyl, C ₁ -C ₈ dialkylaminosulfonyl and arylaminosulfonyl. When the term "substituted" is in front of a possible substituent description, it is intended that the term apply to all members of that group.

The term "unsubstituted" means the original compound in which no atom or atom group has been replaced.

The compounds of the present invention are effective in obstructive pulmonary disease. Obstructive poulmonary disease and obstructuve lung disease refer to obstructive diseases as opposed to restrictive diseases. These diseases include especially COPD, bronchial asthma and small airway diseases. "Chronic obstructive pulmonary disease" or "COPD" is also known as "chronic obstructive airway disease", "chronic obstructive pulmonary disease" and "chronic airway disease". COPD is generally defined as a disease characterized by reduced maximal expiratory flow and slow forced emptying of the lungs. COPD includes two related conditions, emphysema and chronic bronchitis (Honig and Ingram, in Harrison's Principles of Internal Medicine, (Fauci et al., Eds.), 14th Ed., 1998, McGraw-Hill, New York, pp. 1451-1460).

The compounds of the present invention may reduce the severity or progression of chronic restrictive airway disease. Although chronic airway disease tends to result from destruction of the lung parenchyma, and in particular, the limiting disease is likely to result from excessive collagen deposition in the parenchyma. Such restrictive diseases are generally referred to as "interstitial lung disease" or "ILD" and include diseases such as idiopathic pulmonary fibrosis. The methods, compositions and uses of the present invention are useful for reducing the severity or progression of ILD, such as idiopathic pulmonary fibrosis.

Compounds of the invention can inhibit sEH and stabilize epoxy lipids both in vitro and in vivo. This activity results in a decrease in hypertension in four separate rodent models. It has already been pointed out that inhibitors of sEH can reduce hypertension (see US Pat. No. 6,351,506).

Moreover, inhibitors show a reduction in kidney inflammation associated with and without associated hypertension models. The present invention can be used in connection with diabetes associated with gradual impairment of kidney or kidney function. Chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and breakdown of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Long-term complications of diabetes include retinopathy associated with potential vision loss; Nephropathy leading to kidney failure; Peripheral neuropathy at risk of foot ulcers, amputations and neuroarthritis.

In addition, people with metabolic syndrome have a higher risk of developing type 2 diabetes and are therefore at a higher risk than the average for diabetic nephropathy. Thus, such subjects can be monitored for microproteinuria and administered as an intervention to reduce the incidence of nephropathy with an sEH inhibitor and optionally one or more EETs.

Diseases of dyslipidemia or lipid metabolism are another risk factor for heart disease. Such diseases include increased levels of LDL cholesterol, decreased levels of HDL cholesterol, and increased levels of triglycerides. Increased levels of serum cholesterol, and in particular LDL cholesterol, are associated with increased heart disease risk. Kidneys are also damaged by these high levels. High levels of triglycerides are believed to be associated with kidney damage. In particular, levels of cholesterol exceeding 200 mg / dL, and especially levels exceeding 225 mg / dL, may be administered sEH inhibitors and, optionally, EET.

Compounds of the invention inhibit the proliferation of vascular smooth muscle (VSM) cells without significant cytotoxicity (eg, specific to VSM cells). Since VSM cell proliferation is an essential process in the pathophysiology of atherosclerosis, these compounds are suitable for slowing or inhibiting atherosclerosis.

Compounds of the invention can be used to reduce the severity or progression of asthma. Asthma usually results in mucin oversecretion, which results in partial airway obstruction. That is, irritation of the airways causes the release of mediators that lead to airway obstruction. Lymphocytes and other immunomodulatory cells recruited to the lung from asthma may be different from those mobilized as a result of obstructive poulmonary disease and obstructuve lung disease, COPD or interstitial lung disease (ILD), Airway obstruction due to asthma can be reduced by reducing the influx of immunoregulatory cells such as eosinophils and improving the degree of obstruction.

Compounds of the invention have been shown to reduce brain damage from stroke. Based on these results, we found that sEH inhibitors absorbed prior to ischemic stroke can reduce brain injury area and recover more quickly from stroke effects.

The compounds of the present invention can be used with other therapeutic agents depending on the purpose. The choice of additional agents will largely depend on the desired target therapy (Turner, N. et al. Prog. Drug Res . (1998) 51: 33-94; Haffher, S. Diabetes Care (1998) 21: 160-178; and DeFronzo, R. et al. (Eds.), Diabetes Reviews (1997) Vol. 5 No. 4). Numerous studies have investigated the benefits of combination therapy with oral agonists (Mahler, R., J. Clin. Endocrinol. Metab . (1999) 84: 1 165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, CW, (ed.), Current Therapy In Endocrinology And Metabolism, 6th Edition (Mosby-Year Book, Inc., St. Louis, MO 1997)] Chiasson, J. et al, Ann. Intern. Med . (1994) 121: 928-935; Coniff, R. et al, Clin. Ther . (1997) 19: 16-26; Coniff, R. et al, Am. J. Med . (1995) 98: 443-451; and Iwamoto, Y. et al, Diabet. Med . (1996) 13 365-370; Kwiterovich, P. Am. J. Cardiol (1998) 82 (12A): 3U-17U]. Combination treatment includes the administration of a compound having the general structure of Formula 1 and a single pharmaceutical dose formulation containing one or more additional active agents, as well as the administration of the compound of Formula 1 and each activator in its own separate pharmaceutical dose formulation. Include.

The total daily dose to be administered to the host in a single dose or in separate doses when administering the compound of the present invention, which has been confirmed to be effective as described above, is preferably in the range of 1 to 100 mg per kg of body weight, in the range of 3 to 10 mg. Particularly preferred is the specific dose level for an individual patient, depending on the particular compound to be used, the patient's weight, sex, health condition, diet, time of administration of the drug, method of administration, rate of excretion, drug mixing and the severity of the disease. have.

The compounds of the present invention may be administered by any route as desired, but injection and oral administration are preferred. 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 present invention with a carrier such as one or more inert diluents such as sucrose, lactose, starch and the like, lubricants such as magnesium stearate, disintegrants, binders and the like. .

In the use of the compound of the present invention for therapeutic purposes, the present invention will be described in more detail based on the following Examples and Experimental Examples. However, these Examples and Experimental Examples are only for helping understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Example 1

Preparation Example 1 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyll) phenylamino)-(phenyl) methylphosphonate (Compound NO.1)

In anhydrous dichloromethane (40 mL) in the presence of nitrogen, adamantanecarboxylic acid (2.95 g, 0.016 mol), dimethylaminopyridine (2.00 g, 0.016 mol DMAP), 4-aminobenzylamine (2.00 g, 0.016 mol) ) Was added and stirred. To the reaction mixture was added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (3.14 g, 0.016 mol; EDCI) at room temperature and then stirred for one day under the same conditions. After completion of the reaction, the mixture was extracted with diethyl ether (100 mL), washed with distilled water (100 mL X 2), stirred with anhydrous magnesium sulfate, filtered and dried. The impure mixture was purified by column chromatography (hexane: ethyl acetate = 1: 1), to obtain a white N- (4-aminobenzyl) (1-adamantane) carboxamide in 95% yield. The intermediate (N- (4-aminobenzyl) (1-adamantane) carboxamide (0.70 g, 2.46 mmol) and benzaldehyde were dissolved in anhydrous dichloromethane (15 mL) and stirred for one day in the presence of anhydrous magnesium sulfate. After completion of the reaction, the mixture was extracted with diethyl ether (40 mL X 2), the reaction mixture was washed with distilled water (50 mL X 2), dried and stirred with 20 ml of diethyl ether to prepare imine intermediate at 70% yield. The reaction mixture was dissolved in anhydrous dichloromethane in an imine intermediate, and an excess amount of diethyl phosphite was added, and the reaction mixture was stirred at 100 ° C. for 2 hours, and then extracted with diethyl ether. The solvent was washed with a saturated aqueous solution of sodium carbonate (30 mL X 4), and then washed once more with 50 ml of distilled water, and purified using column chromatography (hexane: ethyl acetate = 1: 2) to obtain diethyl (4-((1 Adamantinka Copy shown) l-methyl) phenylamino) to (l-phenyl) methyl phosphonate to 67 could be the tank to the 90% yield.

¹ H-NMR (CDCl ₃ ): 1.10 (3H, t, J = 6.9 Hz), 1.27 (3H, t, J = 6.9 Hz), 1.67 (6H, s), 1.82 (6H, s), 2.01 (3H , s), 3.60-3.66 (1H, m), 3.88-3.96 (1H, m), 4.09-4.14 (2H, m), 4.24 (2H, s), 4.74 (1H, d, J = 18 Hz), 4.82 (1H, s), 5.65 (1H, s), 6.54 (2H, d, J = 7.5 Hz), 7.01 (2H, d, J = 7.5 Hz), 7.25-7.34 (3H, m), 7.45-7.47 (2H, m)

Preparation Example 2 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-methoxyphenyl) methylphosphonate (Compound NO.2)

Under the same conditions as in Preparation Example 1, 4-methoxybenzaldehyde (0.24 g, 0.0017 mol) was used to obtain the target compound in 70% yield.

¹ H-NMR (CDCl ₃ )): 1.12 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.68 (6H, s), 1.82 (6H, s), 2.01 ( 3H, s), 3.60-3.66 (1H, m), 3.78 (3H, s), 3.90-3.98 (1H, m), 4.09-4.14 (2H, m), 4.24 (2H, s), 4.74 (1H, d, J = 18 Hz), 4.80 (1H, s), 5.65 (1H, s), 6.54 (2H, d, J = 7.5 Hz), 6.86 (2H, d, J = 7.5 Hz), 7.00 (2H, d, J = 7.5 Hz), 7.37 (2H, d, J = 7.5 Hz)

Preparation Example 3 Synthesis of Diethyl (4- (methoxycarbonyl) phenyl) (4-((1-adamantanecarboxamido) methyl) phenylamino) -methylphosphonate (Compound NO. 3)

Under the same conditions as in Preparation Example 1, 4- (methoxycarbonyl) benzaldehyde (0.29 g, 0.0017 mol) was used to obtain the target compound in 40% yield.

¹ H-NMR (CDCl ₃ ) 1.12 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.68 (6H, s), 1.82 (6H, s), 2.01 (3H, s), 3.60-3.66 (1H, m), 3.78 (3H, s), 3.90 (3H, s), 3.93-3.98 (1H, m), 4.09-4.14 (2H, m), 4.24 (2H, s) , 4.80 (1H, d, J = 18 Hz), 4.84 (1H, s), 5.65 (1H, s), 6.50 (2H, d, J = 7.5 Hz), 6.99 (2H, d, J = 7.5 Hz) , 7.54 (2H, d, J = 7.5 Hz), 8.00 (2H, d, J = 7.5 Hz)

Preparation Example 4 Synthesis of Diethyl 1- (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO. 4)

It was carried out under the same conditions as in Preparation Example 1, using the pivalaldehyde (0.32 g, 0.0036 mol) was able to obtain the target compound in 86% yield.

¹ H-NMR (CDCl ₃ ) 1.12 (9H, s), 1.13 (3H, t, J = 6.9 Hz), 1.27 (3H, t, J = 6.9 Hz), 1.71 (6H, s), 1.86 (6H, s), 2.03 (3H, s), 3.47 (1H, dd, J = 18 Hz, 8 Hz), 3.90-4.00 (2H, m), 4.07-4.14 (3H, m), 4.29 (2H, s), 5.72 (1H, s), 6.59 (2H, d, J = 7.5 Hz), 7.05 (2H, d, J = 7.5 Hz)

Preparation Example 5 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (pyridin-4-yl) methylphosphonate (Compound NO. 5)

Under the same conditions as in Preparation Example 1, 4-pyridylaldehyde (0.27 g, 0.0024 mol) was used to obtain the target compound in 80% yield.

¹ H-NMR (CDCl ₃ ) 1.18 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.68 (6H, s), 1.83 (6H, s), 2.01 (3H, s), 3.80-3.90 (1H, m), 4.01-4.06 (1H, m), 4.10-4.15 (2H, m), 4.25 (2H, s), 4.78 (1H, d, J = 18 Hz), 4.80 (1H, s), 5.65 (1H, s), 6.49 (2H, d, J = 7.5 Hz), 7.00 (2H, d, J = 7.5 Hz), 7.39 (2H, d, J = 6.0 Hz), 7.85 (2H, d, J = 6.0 Hz)

Preparation Example 6 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-cyanophenyl) methylphosphonate (Compound NO. 6)

Under the same conditions as in Preparation Example 1, 4-cyanoaldehyde (0.32 g, 0.0024 mol) was used to obtain the target compound in 55% yield.

¹ H-NMR (CDCl ₃ ) 1.17 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.68 (6H, s), 1.83 (6H, s), 2.04 (3H, s), 3.83-3.88 (1H, m), 4.03-4.07 (1H, m), 4.08-4.15 (2H, m), 4.25 (2H, s), 4.77 (1H, d, J = 18 Hz), 4.89 (1H, s), 5.84 (1H, s), 6.49 (2H, d, J = 7.5 Hz), 7.00 (2H, d, J = 7.5 Hz), 7.62 (4H, m)

Preparation Example 7 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-fluorophenyl) methylphosphonate (Compound NO.7)

Performing the same conditions as in Preparation Example 1, using 4- pullo aldehyde (0.31 g, 0.0024 mol) was able to obtain the target compound in 50% yield.

¹ H-NMR (CDCl ₃ ): 1.14 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.69 (6H, s), 1.83 (6H, s), 2.03 (3H , s), 3.72-3.75 (1H, m), 3.93-3.97 (1H, m), 4.08-4.14 (2H, m), 4.25 (2H, s), 4.69-4.75 (2H, m), 5.74 (1H , s), 6.52 (2H, d, J = 7.5 Hz), 6.99-7.05 (4H, m), 7.41-7.44 (2H, m)

Preparation Example 8 Diethyl 1- (4-((1-adamantanecarboxamido) methyl) phenylamino) (2-methoxynaphthalen-6-yl) -dimethylpropylphosphonate (Compound NO. 8) Synthesis of

Under the same conditions as in Preparation Example 1, 6-methoxy-2-naphthylaldehyde (0.46 g, 0.0024 mol) was used to obtain the target compound in 85% yield.

¹ H-NMR (CDCl ₃ ): 1.07 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.66 (6H, s), 1.80 (6H, s), 1.99 (3H , s), 3.59-3.68 (1H, m), 3.78 (3H, s), 3.89-3.92 (1H, m), 3.90 (3H, s), 4.09-4.14 (2H, m), 4.22 (2H, s ), 4.86 (1H, d, J = 18 Hz), 4.89 (1H, s), 5.63 (1H, s), 6.58 (2H, d, J = 7.5 Hz), 6.97 (2H, d, J = 7.5 Hz ), 7.10-7.12 (2H, m), 7.55 (1H, s), 7.69-7.73 (2H, m), 7.83 (1H, s)

Preparation Example 9 Synthesis of Dibutyl (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO. 9)

It was carried out under the same conditions as in Preparation Example 1, using the pivalaldehyde (0.32 g, 0.0036 mol) and excess dibutyl phosphite to obtain the target compound in 85% yield.

¹ H-NMR (CDCl ₃ ): 0.82 (3H, t, J = 6.9 Hz), 0.88 (3H, t, J = 6.9 Hz), 1.12 (9H, s), 1.23-1.30 (4H, m), 1.41 -1.48 (2H, m), 1.52-1.59 (2H, m), 1.71 (6H, s), 1.86 (6H, s), 2.03 (3H, s), 3.48 (1H, dd, J = 18 Hz, 8 Hz), 3.85-3.89 (1H, m), 4.00-4.14 (4H, m), 4.29 (2H, s), 5.71 (1H, s), 6.58 (2H, d, J = 7.5 Hz), 7.05 (2H , d, J = 7.5 Hz)

Preparation Example 10 Synthesis of Diisobutyl (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO.10)

It was carried out under the same conditions as in Preparation Example 1, using the pivalaldehyde (0.32 g, 0.0036 mol) and an excess of diisobutyl phosphite to obtain the target compound in 85% yield.

¹ H-NMR (CDCl ₃ ): 0.78-0.80 (6H, m), 0.85-0.87 (6H, m), 1.13 (9H, s), 1.69-1.85 (8H, m), 1.86 (6H, s), 2.04 (3H, s), 3.48 (1H, dd, J = 18 Hz, 8 Hz), 3.60-3.64 (1H, m), 3.74-3.82 (3H, m), 4.01-4.03 (1H, m), 4.28 (2H, s), 5.70 (1H, s), 6.58 (2H, d, J = 7.5 Hz), 7.05 (2H, d, J = 7.5 Hz)

Preparation Example 11 Synthesis of Diisopropyl (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO. 11)

Under the same conditions as in Preparation Example 1, the target compound was obtained in 85% yield using pivalaldehyde (0.32 g, 0.0036 mol) and an excess of diisopropyl phosphite.

¹ H-NMR (CDCl ₃ ): 1.02 (3H, d, J = 6.9 Hz), 1.11 (9H, s), 1.21 (3H, d, J = 6.9 Hz), 1.72 (6H, s), 1.86 (6H , s), 2.04 (3H, s), 3.41 (1H, dd, J = 18 Hz, 8 Hz), 3.99-4.01 (1H, m), 4.28 (2H, s), 4.63-4.68 (2H, m) , 5.70 (1H, s), 6.58 (2H, d, J = 7.5 Hz), 7.03 (2H, d, J = 7.5 Hz)

Preparation Example 12 Synthesis of Dibenzyl (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO. 12)

Under the same conditions as in Preparation Example 1, the target compound was obtained in 75% yield using pivalaldehyde (0.32 g, 0.0036 mol) and an excess of dibenzyl phosphite.

¹ H-NMR (CDCl ₃ ): 1.12 (9H, s), 1.72 (6H, s), 1.86 (6H, s), 2.04 (3H, s), 3.56 (1H, dd, J = 18 Hz, 8 Hz ), 3.99-4.01 (1H, m), 4.28 (2H, s), 4.80-4.82 (1H, m), 4.95-5.03 (3H, m), 5.70 (1H, s), 6.55 (2H, d, J = 7.5 Hz), 7.03 (2H, d, J = 7.5 Hz), 7.11-7.13 (2H, m), 7.22-7.24 (2H, m), 7.26-7.29 (3H, m), 7.35-7.37 (3H, m)

Preparation Example 13. (4,4-Dimethyl-2-oxo-1,3,2-dioxy) 2- (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2- Synthesis of Dimethylpropyl) Phosphoran (Compound NO.13)

The target compound was prepared under the same conditions as in Preparation Example 1, using pivalaldehyde (0.32 g, 0.0036 mol) and an excess of 4,4-dimethyl-1,3,2-dioxaphosphorane-2-oxide. Obtained at 80% yield.

¹ H-NMR (CDCl ₃ ): 1.01 (6H, s), 1.15 (9H, s), 1.72 (6H, s), 1.86 (6H, s), 2.04 (3H, s), 3.57 (1H, dd, J = 18 Hz, 8 Hz), 3.78-3.79 (2H, m), 3.97-3.98 (1H, m), 4.08-4.11 (2H, m), 4.30 (2H, s), 5.75 (1H, s), 6.61 (2H, d, J = 7.5 Hz), 7.06 (2H, d, J = 7.5 Hz)

Preparation Example 14 Di- (2,2,2, -trifluoroethyl) (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (compound Synthesis of NO.14)

It was carried out under the same conditions as in Preparation Example 1, using the pivalaldehyde (0.32 g, 0.0036 mol) and an excess of di-2,2,2-trifluoro phosphite to obtain the target compound in 75% yield.

¹ H-NMR (CDCl ₃ ): 1.12 (9H, s), 1.72 (6H, s), 1.86 (6H, s), 2.03 (3H, s), 3.67 (1H, dd, J = 18 Hz, 8 Hz ), 3.84-3.90 (2H, m), 4.30-4.45 (5H, m), 5.76 (1H, s), 6.63 (2H, d, J = 7.5 Hz), 7.10 (2H, d, J = 7.5 Hz)

Preparation Example 15 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (p-tolyl) methylphosphonate (Compound NO. 15)

Under the same conditions as in Preparation Example 1, 4-methylbenzaldehyde (0.30 g, 0.0024 mol) was used to obtain the target compound in 35% yield.

¹ H-NMR (CDCl ₃ ): 1.12 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.66 (6H, s), 1.83 (6H, s), 2.01 (3H , s), 2.31 (3H, s), 3.64-3.68 (1H, m), 3.90-3.94 (1H, m), 4.08-4.13 (2H, m), 4.23 (2H, s), 4.66-4.79 (2H , m), 5.67 (1H, s), 6.54 (2H, d, J = 7.5 Hz), 7.11 (2H, d, J = 7.5 Hz), 7.21 (2H, d, J = 7.5 Hz), 7.33 (2H , d, J = 7.5 Hz)

Preparation Example 16 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (naphthalen-2-yl) methylphosphonate (Compound NO. 16)

Under the same conditions as in Preparation Example 1, 2-naphthylaldehyde (0.38 g, 0.0024 mol) was used to obtain the target compound in 35% yield.

¹ H-NMR (CDCl ₃ ): 1.07 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.66 (6H, s), 1.80 (6H, s), 1.99 (3H , s), 3.67-3.71 (1H, m), 3.90-3.94 (1H, m), 4.10-4.15 (2H, m), 4.24 (2H, s), 4.92 (1H, d, J = 18 Hz), 4.93 (1H, s), 5.68 (1H, s), 6.58 (2H, d, J = 7.5 Hz), 6.97 (2H, d, J = 7.5 Hz), 7.45-7.48 (2H, m), 7.59 (1H , d, J = 7.5 Hz), 7.80-7.84 (3H, m), 7.92 (1H, s)

Preparation Example 17 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-tert-butylphenyl) methylphosphonate (Compound NO.17)

Under the same conditions as in Preparation Example 1, 4-t-butylaldehyde (0.40 g, 0.0024 mol) was used to obtain the target compound in 40% yield.

¹ H-NMR (CDCl ₃ ): 1.06 (3H, t, J = 6.9 Hz), 1.24-1.30 (12H, m), 1.66 (6H, s), 1.83 (6H, s), 2.03 (3H, s) , 3.64-3.67 (1H, m), 3.90-3.93 (1H, m), 4.07-4.14 (2H, m), 4.25 (2H, s), 4.92 (1H, d, J = 18 Hz), 4.93 (1H , s), 5.72 (1H, s), 6.56 (2H, d, J = 7.5 Hz), 7.00 (2H, d, J = 7.5 Hz), 7.32-7.36 (4H, m)

Preparation Example 18 Diethyl 1- (4-((1,2,3,4-tetrahydronaphthalene-2-carboxamido) methyl) phenylamino) -2,2-dimethylpropyl-phosphonate (Compound NO 18) Synthesis

Under the same conditions as in Preparation Example 1, 1,2,3,3-tetrahydronaphthalene (0.80 g, 0.0045 mol) and pivalaldehyde (0.36 g, 0.0042 mol) were used to obtain the target compound in 70% yield. Could.

¹ H-NMR (CDCl ₃ ): 1.12 (9H, s), 1.13 (3H, t, J = 6.9 Hz), 1.27 (3H, t, J = 6.9 Hz), 1.92-1.94 (1H, m), 2.10 -2.17 (1H, m), 2.48-2.50 (1H, m), 2.86-3.05 (4H, m), 3.47 (1H, dd, J = 18 Hz, 8 Hz), 3.94-4.08 (5H, m), 4.34 (2H, s), 5.71 (1H, s), 6.60 (2H, d, J = 7.5 Hz), 7.06-7.12 (6H, m)

Preparation Example 19 Synthesis of Diethyl 1- (4-((1-adamantanecarboxamido) methyl) phenylamino) butylphosphonate (Compound NO.19)

Under the same conditions as in Preparation Example 1, using the butyl aldehyde (0.18 g, 0.0024 mol) was able to obtain the target compound in 40% yield.

¹ H-NMR (CDCl ₃ ): 0.91 (3H, t, J = 6.9 Hz), 1.18-1.30 (8H, m), 1.67 (6H, s), 1.85 (6H, s), 2.05 (3H, s) , 3.68 (1H, s), 4.00-4.01 (1H, m), 4.07-4.14 (6H, m), 4.30 (2H, s), 5.73 (1H, s), 6.60 (2H, d, J = 7.5 Hz ), 7.06 (2H, d, J = 7.5 Hz)

Preparation Example 20 Synthesis of Diethyl 1- (4-((cyclohexanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO. 20)

Under the same conditions as in Preparation Example 1, using the cyclohexyl carboxylic acid (0.89 g, 0.0069 mol) and pivalaldehyde (0.74 g, 0.0086 mol) to obtain the target compound in 80% yield.

¹ H-NMR (CDCl ₃ ): 1.11 (9H, s), 1.13 (3H, t, J = 6.9 Hz), 1.24 (5H, t, J = 6.9 Hz), 1.40-1.48 (2H, m), 1.64 -1.66 (2H, m), 1.77-1.78 (2H, m), 1.85-1.88 (2H, m), 2.05-2.07 (2H, m), 3.47 (1H, dd, J = 18 Hz, 8 Hz), 3.88-3.94 (2H, m), 3.99-4.04 (3H, m), 4.29 (2H, s), 5.57 (1H, s), 6.59 (2H, d, J = 7.5 Hz), 7.06-7.12 (6H, m)

Preparation Example 21 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (naphthalen-1-yl) methylphosphonate (Compound NO.21)

Under the same conditions as in Preparation Example 1, 1-naphthylaldehyde (0.38 g, 0.0024 mol) was used to obtain the target compound in 35% yield.

¹ H-NMR (CDCl ₃ ): 0.71 (3H, t, J = 6.9 Hz), 1.32 (3H, t, J = 6.9 Hz), 1.65 (6H, s), 1.80 (6H, s), 2.04 (3H , s), 3.17-3.20 (1H, m), 3.72-3.69 (1H, m), 4.16-4.21 (4H, m), 5.12 (1H, m), 5.57-5.65 (2H, m), 6.49 (2H , d, J = 7.5 Hz), 6.93 (2H, d, J = 7.5 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.56 (1H, t, J = 7.5 Hz), 7.62 (1H, t , J = 7.5 Hz), 7.74-7.80 (2H, m), 7.90 (1H, d, J = 7.5 Hz), 8.24 (1H, d, J = 7.5 Hz),

Preparation Example 22 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-morpholinophenyl) methylphosphonate (Compound NO. 22)

Under the same conditions as in Preparation Example 1, 4- (4-morpholinyl) benzaldehyde (0.47 g, 0.0024 mol) was used to obtain the target compound in 75% yield.

¹ H-NMR (CDCl ₃ ): 1.13 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.68 (6H, s), 1.83 (6H, s), 2.04 (3H , s), 3.13 (4H, s), 3.78-3.80 (1H, m), 3.84 (4H, s), 3.97-3.99 (1H, m), 4.10-4.13 (2H, m), 4.24 (2H, s ), 4.74 (1H, d, J = 18 Hz), 4.78 (1H, s), 5.69 (1H, s), 6.54 (2H, d, J = 7.5 Hz), 6.86 (2H, d, J = 7.5 Hz ), 6.99 (2H, d, J = 7.5 Hz), 7.35 (2H, d, J = 7.5 Hz)

Preparation Example 23 Synthesis of Diethyl 1- (4-((4- (trifluoromethoxy) benzamide) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO. 23)

Under the same conditions as in Preparation Example 1, 4-trittleromethoxybenzyl acid (1.0 g, 0.0048 mol) and pivalaldehyde (0.84 g, 0.0097 mol) were used to obtain the target compound in 78% yield. .

¹ H-NMR (CDCl ₃ ): 1.12 (9H, s), 1.15 (3H, t, J = 6.9 Hz), 1.37 (5H, t, J = 6.9 Hz), 3.48 (1H, dd, J = 18 Hz , 8 Hz), 3.92-9.94 (1H, m), 3.99-4.04 (4H, m), 4.50 (2H, s), 6.23 (1H, s), 6.62 (2H, d, J = 7.5 Hz), 7.15 (2H, d, J = 7.5 Hz), 7.26 (2H, d, J = 7.5 Hz), 7.82 (2H, d, J = 7.5 Hz)

Preparation Example 24 Synthesis of Diethyl 1- (4-((2- (naphthalen-1-yl) acetamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO. 24)

Example Compound The compound was prepared under the same conditions as the synthesis method of 074-183, but 2-naphthaleneacetyl acid (1.0 g, 0.0053 mol) and pivalaldehyde (0.93 g, 0.010 mol) were used to obtain the target compound in 80% yield. .

¹ H-NMR (CDCl ₃ ): 1.06-1.10 (12H, m), 1.20 (3H, t, J = 6.9 Hz), 3.45 (1H, dd, J = 18 Hz, 8 Hz), 3.77 (2H, s ), 3.87-9.94 (2H, m), 4.01-4.05 (3H, m), 4.28 (2H, s), 5.57 (1H, s), 6.53 (2H, d, J = 7.5 Hz), 6.96 (2H, d, J = 7.5 Hz), 7.38 (1H, d, J = 7.5 Hz), 7.47-7.49 (2H, m), 7.71 (1H, s), 7.81-7.83 (2H, m)

Preparation Example 25 Synthesis of Diethyl 1- (4-((2-adamantane-1-ylacetamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate (Compound NO. 25)

Under the same conditions as in Preparation Example 1, 1-adamantaneacetyl acid (1.0 g, 0.0051 mol) and pivalaldehyde (0.89 g, 0.010 mol) were used to obtain the target compound in 90% yield.

¹ H-NMR (CDCl ₃ ): 1.11 (9H, s), 1.13 (3H, t, J = 6.9 Hz), 1.25 (3H, t, J = 6.9 Hz), 1.61 (6H, s), 1.71 (6H , s), 1.93 (2H, s), 1.96 (3H, s), 3.45 (1H, dd, J = 18 Hz, 8 Hz), 3.89-3.96 (2H, m), 4.01-4.05 (3H, m) , 4.29 (2H, s), 5.47 (1H, s), 6.59 (2H, d, J = 7.5 Hz), 7.08 (2H, d, J = 7.5 Hz)

Preparation Example 26 Synthesis of Diethyl 1- (4-((adamantane-1-ylacetamido) methyl) phenylamino) -3,3-dimethylbutylphosphonate (Compound NO. 26)

Under the same conditions as in Preparation Example 1, using the 3,3-dimethyl butyraldehyde (0.25 g, 0.0024 mol) it was possible to obtain the target compound in 25% yield.

¹ H-NMR (CDCl ₃ ): 0.93 (9H, s), 1.14 (3H, t, J = 6.9 Hz), 1.26 (3H, t, J = 6.9 Hz), 1.75 (6H, s), 1.87 (6H , s), 2.05 (3H, s), 3.50 (1H, d, J = 8.0 Hz), 3.81-3.83 (2H, m), 4.06-4.11 (3H, m), 4.30 (2H, s), 5.72 ( 1H, s), 6.59 (2H, d, J = 7.5 Hz), 7.05 (2H, d, J = 7.5 Hz)

Preparation Example 27 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (2-methoxyphenyl) methylpropylphosphonate (Compound NO. 27)

Under the same conditions as in Preparation Example 1, using 2-methoxybenzaldehyde (0.33 g, 0.0024 mol) was able to obtain the target compound in 80% yield.

¹ H-NMR (CDCl ₃ ): 1.02 (3H, t, J = 6.9 Hz), 1.31 (3H, t, J = 6.9 Hz), 1.67 (6H, s), 1.82 (6H, s), 2.03 (3H , s), 3.57-3.60 (1H, m), 3,87-3.89 (1H, m), 3.94 (3H, s), 4.15-4.23 (4H, m), 4.24 (2H, s), 4.87 (1H , t, J = 7.5 Hz), 5.38 (1H, dd, J = 18 Hz, 8.0 Hz), 5.71 (1H, s), 6.56 (2H, d, J = 7.5 Hz), 6.88-6.93 (2H, m ), 6.99 (2H, d, J = 7.5 Hz), 7.23 (1H, d, J = 7.5 Hz), 7.44 (1H, d, J = 7.5 Hz)

Preparation Example 28 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (cyclopropyl) methylpropylphosphonate (Compound NO. 28)

Under the same conditions as in Preparation Example 1, cyclopropanecarboxaldehyde (0.17 g, 0.0024 mol) was used to obtain the target compound in 55% yield.

¹ H-NMR (CDCl ₃ ): 0.38-0.42 (2H, m), 0.59-0.63 (2H, m), 1.21 (3H, t, J = 6.9 Hz), 1.32 (3H, t, J = 6.9 Hz) , 1.72 (6H, s), 1.86 (6H, s), 2.05 (2H, s), 3.29-3.31 (1H, m), 3.80-3.82 (1H, m), 4.03-4.05 (1H, m), 4.11 -4.18 (3H, m), 4.30 (2H, s), 5.74 (1H, s), 6.60 (2H, d, J = 7.5 Hz), 7.05 (2H, d, J = 7.5 Hz)

Preparation Example 29 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (cyclohexyl) methylpropylphosphonate (Compound NO. 29)

Carrying out under the same conditions as in Preparation Example 1, using the cyclonucleic acid carboxaldehyde (0.28 g, 0.0024 mol) it was possible to obtain the target compound in 55% yield.

¹ H-NMR (CDCl ₃ ): 1.18 (3H, t, J = 6.9 Hz), 1.23-1.30 (7H, m), 1.71 (11H, s), 1.86 (7H, s), 2.04 (4H, s) , 3.61-3.64 (1H, m), 3.89-3.99 (2H, m), 4.03-4.05 (1H, m), 4.06-4.13 (3H, m), 4.29 (2H, s), 5.74 (1H, s) , 6.60 (2H, d, J = 7.5 Hz), 7.04 (2H, d, J = 7.5 Hz)

Preparation Example 30 Synthesis of Diethyl 1- (4-((1-adamantanecarboxamido) methyl) phenylamino) -2-oxo-2-phenylethylpropylphosphonate (Compound NO. 30)

Under the same conditions as in Preparation Example 1, using the phenylglyoxal monohydrate (0.33 g, 0.0024 mol) it was possible to obtain the target compound in 25% yield.

¹ H-NMR (CDCl ₃ ): 1.12-1.19 (6H, m), 1.68 (6H, s), 1.86 (6H, s), 2.03 (2H, s), 4.06-4.12 (4H, m), 4.28 ( 2H, s), 5.02 (1H, s), 5.52 (1H, dd, J = 18 Hz, 8 Hz), 5.75 (1H, s), 6.72 (2H, d, J = 7.5 Hz), 7.07 (2H, d, J = 7.5 Hz), 7.49 (2H, d, J = 7.5 Hz), 7.61 (2H, d, J = 7.5 Hz), 8.06 (2H, d, J = 7.5 Hz)

Preparation Example 31 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (anthracene-10-yl) methylpropylphosphonate (Compound NO.31)

Under the same conditions as in Preparation Example 1, 9-anthracenecarboxaldehyde (0.51 g, 0.0024 mol) was used to obtain the target compound in 30% yield.

¹ H-NMR (CDCl ₃ ): 0.71 (3H, t, J = 6.9 Hz), 1.32 (3H, t, J = 6.9 Hz), 1.65 (6H, s), 1.80 (6H s), 2.04 (3H, s), 3.24-3.27 (1H, m), 3.68-3.70 (1H, m), 4.09-4.14 (3H, m), 4.21-4.25 (2H, m), 5.18 (1H, m), 5.62 (1H, s), 6.42 (2H, d, J = 7.5 Hz), 6.83 (2H, d, J = 7.5 Hz), 7.43 (1H, t, J = 6.0 Hz), 7.54 (2H, t, J = 6.0 Hz) , 7.72 (1H, t, J = 6.0 Hz), 7.97 (1H, d, J = 7.5 Hz), 8.06 (2H, d, J = 7.5 Hz), 8.44 (2H, s), 9.02 (1H, d, J = 7.5 Hz)

Preparation Example 32 Synthesis of Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (2-hydroxynaphthalen-6-yl) methylpropylphosphonate (Compound NO. 32)

Under the same conditions as in Preparation Example 1, 6-hydroxy-2-naphthylaldehyde (0.42 g, 0.0024 mol) was used to obtain the target compound in 55% yield.

¹ H-NMR (CDCl ₃ ): 1.11 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.67 (6H, s), 1.81 (6H, s), 1.98 (3H , s), 3.70-3.72 (1H, m), 3.92-3.95 (1H, m), 4.09-4.17 (4H, m), 4.22 (2H, s), 4.89 (1H, d, J = 18 Hz), 4.91 (1H, s), 5.81 (1H, s), 6.58 (2H, d, J = 7.5 Hz), 6.95-7.01 (3H, m), 7.05 (1H, s), 7.41-7.46 (3H, m) , 7.74 (1H, s), 8.68 (1H, s)

Preparation Example 33 of diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (2-acetoxynaphthalen-6-yl)) methylpropylphosphonate (compound NO.33) synthesis

It was carried out under the same conditions as in Preparation Example 1, using 6- atethoxy-2-naphthylaldehyde (0.53 g, 0.0024 mol) to obtain the target compound in 85% yield.

¹ H-NMR (CDCl ₃ ): 1.10 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.67 (6H, s), 1.81 (6H, s), 2.04 (3H , s), 2.35 (3H, s), 3.74-3.76 (1H, m), 3.91-3.93 (1H, m), 4.09-4.15 (2H, m), 4.23 (2H, s), 4.89 (1H, d , J = 18 Hz), 4.91 (1H, s), 5.68 (1H, s), 6.55 (2H, d, J = 7.5 Hz), 6.97 (2H, d, J = 7.5 Hz), 7.23 (1H, d , J = 7.5 Hz), 7.52 (1H, s), 7.61 (2H, d, J = 7.5 Hz), 7.77-7.83 (2H, m), 7.91 (1H, s)

Example 2

Preparation Example 1 Synthesis of Diethyl (4-((3-adamantan-1-yl ureido) methyl) phenylamino) (phenyl) methylphosphonate (Compound NO. 34)

Dissolve 4-aminobenzyl amine (0.50 g, 4.09 mmol) in dimethylformamide (15 mL DMF) in the presence of nitrogen, and then dissolve 1-adamantanyl isocyanate in N, N-dimethylformamide (DMF; 10 mL). 0.73 g, 4.09 mmol) was slowly added dropwise and stirred at room temperature for one day. After completion of the reaction, diethyl ether (60 ml) was added, and then washed twice with distilled water (60 ml). After stirring with anhydrous magnesium sulfate, filtration and drying, 40 ml of ethyl acetate was added to obtain a urea imine compound at a yield of 100%. Urea imine intermediate was synthesized using benzaldehyde (0.11 g, 0.0010 mol) to obtain the target compound in 85% yield in the same manner as in Preparation Example 1 of Example 1 using this urea imine and excess diethyl phosphide. Could.

¹ H-NMR (CDCl ₃ ): 1.09 (3H, t, J = 6.9 Hz), 1.29 (3H, t, J = 6.9 Hz), 1.64 (6H, s), 1.90 (6H, s), 2.03 (3H , s), 3.51-3.61 (1H, m), 3.82-3.89 (1H, m), 4.04-4.11 (4H, m), 4.23 (1H, s), 4.48 (1H, s), 4.67-4.72 (2H , m), 6.53 (2H, d, J = 7.5 Hz), 7.03 (2H, d, J = 7.5 Hz), 7.25-7.31 (3H, m), 7.37-7.39 (2H, m)

Preparation Example 2 Synthesis of Diethyl 1- (4-((3-adamantan-1-yl-ureido) methyl) phenylamino) -2-2-dimethylpropylphosphonate (Compound NO. 35)

It was carried out under the same conditions as in Preparation Example 1 of Example 2, using the pivalaldehyde (0.17 g, 0.0020 mol) to obtain the target compound in 85% yield.

¹ H-NMR (CDCl ₃ ): 1.10 (9H, s), 1.13 (3H, t, J = 6.9 Hz), 1.27 (3H, t, J = 6.9 Hz), 1.64 (6H, s), 1.93 (6H , s), 2.04 (3H, s), 3.47 (1H, dd, J = 18 Hz, 8 Hz), 3.90-4.00 (2H, m), 4.12-4.18 (6H, m), 4.38 (2H, s) , 6.58 (2H, d, J = 7.5 Hz), 7.08 (2H, d, J = 7.5 Hz)

Preparation Example 3 Synthesis of Diethyl 1- (4-((3-adamantan-1-yl-ureido) methyl) phenylamino) (4-morpholinophenyl) methylphosphonate (Compound NO.36)

The preparation was carried out under the same conditions as in Preparation Example 1, except that 4- (4-morpholinyl) benzaldehyde (0.38 g, 0.0020 mol) was used to obtain a target compound in 85% yield.

¹ H-NMR (CDCl ₃ ): 1.11 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.64 (6H, s), 1.89 (6H, s), 2.04 (3H , s), 3.12 (4H, s), 3.78-3.80 (1H, m), 3.84 (4H, s), 3.96-3.97 (1H, m), 3.98 (1H, s), 4.10-4.13 (4H, m ), 4.30 (1H, s), 4.69 (1H, d, J = 18 Hz), 4.71 (1H, s), 6.54 (2H, d, J = 7.5 Hz), 6.85 (2H, d, J = 7.5 Hz ), 7.02 (2H, d, J = 7.5 Hz), 7.33 (2H, d, J = 7.5 Hz)

Preparation Example 4 of diethyl 1- (4-((3-adamantan-1-yl-ureido) methyl) phenylamino) (pyridin-4-yl) methylphosphonate (compound NO.37) synthesis

Under the same conditions as in Preparation Example 1 of Example 2, using 4-pyritylaldehyde (0.21, 0.0020 mol) was able to obtain the target compound in 75% yield.

¹ H-NMR (CDCl ₃ ): 1.18 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 1.64 (6H, s), 1.91 (6H, s), 2.05 (3H , s), 3.83-3.85 (1H, m), 3.98-4.01 (2H, m), 4.09-4.14 (4H, m), 4.25 (1H, s), 4.75 (1H, d, J = 18 Hz), 4.80 (1H, s), 5.65 (1H, s), 6.48 (2H, d, J = 7.5 Hz), 7.05 (2H, d, J = 7.5 Hz), 7.36 (2H, d, J = 6.0 Hz), 8.55 (2H, doublet, J = 6.0 Hz)

Example 3

Preparation Example 1 Synthesis of Diethyl 1- (4- (4- (trifluoromethoxy) phenylcarbamoyl) phenylamino) -2,2-dimethylpropyl-phosphonate (Compound NO. 38)

4-amino benzoic acid ethyl ester (2.00 g, 12.1 mmol) and pivalaldehyde (2.09 g, 24.2 mmol) were added to anhydrous dichloromethane (30 mL) in the presence of anhydrous magnesium sulfate, followed by stirring at room temperature for one day. After completion of the reaction was filtered and extracted twice with diethyl ether (50 mL). The organic solvent was washed twice with distilled water (50 mL) and then vacuum dried at 50 degrees. The obtained residue was dissolved in anhydrous dichloromethane (10 mL), and an excess of diethyl phosphite was added and stirred. After stirring at 100 ° C. for 3 hours, the mixture was extracted with diethyl ether (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (30 mL × 4) and distilled water (50 mL). Purification by column chromatography after anhydrous magnesium sulfate (hexane: ethyl acetate = 2: 1) was able to prepare a phosphonate intermediate in 40% yield. The phosphonate intermediate was dissolved in ethanol (10 mL), and 1N NaOH aqueous solution (10 mL) was added thereto, followed by stirring at room temperature for one day. The reaction mixture was neutralized with 1N hydrochloric acid solution, extracted with diethyl ether, washed with distilled water, treated with anhydrous magnesium sulfate, and dried in vacuo to obtain 95% yield. An acid (0.30 g, 0.87 mmol) was reacted with 4-fluoromethoxyaniline under the same conditions as in Preparation Example 1 of Example 1 using EDCI (0.17 g, 0.87 mmol) and DMAP (0.11 g, 0.87 mmol). The compound could be prepared in 85% yield.

¹ H-NMR (CDCl ₃ ): 1.13 (9H, s), 1.14 (3H, t, J = 6.9 Hz), 1.28 (3H, t, J = 6.9 Hz), 3.59 (1H, dd, J = 18 Hz , 8 Hz), 3.93-3.96 (1H, m), 4.06-4.12 (3H, m), 4.42-4.44 (1H, m), 6.69 (2H, d, J = 7.5 Hz), 7.21 (2H, d, J = 7.5 Hz), 7.64 (2H, d, J = 7.5 Hz), 7.71-7.73 (3H, m)

Example 4. Analysis of Inhibitory Effects of Human sEH

Human sEH inhibitor screening kit (Cayman) using fluorescent substrate ((3-phenyl-oxiranyl) -acetic acid cyano- (6-methoxy-naphthalen-2-yl) -methyl ester; PHOME) to screen for inhibitors of human sEH activity Chemical Company, MI, USA) was purchased and analyzed according to the method of use. Fluorometer was used SpectraMax M2e (Molecular Devices). Compounds of the present invention were dissolved in DMSO at a concentration of 0.05-10,000 nM and used for analysis. IC ₅₀ , a concentration that inhibits human sEH activity by 50%, was obtained to determine the degree of enzyme inhibition of the compound. IC ₅₀ results of the compounds of the present invention are shown in Table 1 below.

TABLE 1

Claims (16)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof. [Formula 1]

In Chemical Formula 1, R ¹ is any one selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl and substituted or unsubstituted C ₆ -C ₁₀ aromatic groups, wherein said cycloalkyl is monocyclic or polycyclic Wherein the substituted C ₆ -C ₁₀ aromatic group is substituted with one or more substituents selected from the group consisting of —CN, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ alkyl ester Become; P ¹ is any one selected from the group consisting of -C (X) NH-, -NHC (X)-, -NHC (X) NH-, -C (X) O-, and -OC (X)-, wherein X is O or S; P ² is represented by the following formula (2); [Formula 2]

In Chemical Formula 2, R ² is

,

And straight or branched C ₁ -C ₆ alkyl; R ³ is straight or branched C ₁ C ₆ alkyl, C ₃ C ₈ cycloalkyl or substituted or unsubstituted C ₆ -Selected from C ₁₀ aromatic groups, Wherein the carbon of the C ₆ -C ₁₀ aromatic group may be substituted with one or more atoms selected from the group consisting of N, O, and S, wherein the substituted C ₆ -C ₁₀ aromatic group is —CN, halogen, C ₁ − C ₃ -C ₈ hetero, characterized in that the carbon constituting the C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl ester and the ring is substituted with one or more atoms selected from the group consisting of N, O and S Substituted with one or more substituents selected from the group consisting of cycloalkyl; Y is any one selected from the group consisting of dialkylphosphonates, dihaloalkylphosphonates, diarylphosphonates and cyclicalkylphosphonates. The method of claim 1, R ¹ is C ₃ -C ₁₂ cycloalkyl. 3. The method of claim 2, R ¹ is an adamantanyl group.  The method of claim 1, P ¹ is -C (O) NH- or -NHC (O) NH-.  The method of claim 1, R ² is

Compound characterized in that. The method of claim 1, R ³ is selected from the group consisting of isobutyl, phenyl, and pyridine. The method of claim 1, Y is diethylphosphonate. The method of claim 1, R ¹ is an adamantanyl group, P ¹ is -C (O) NH- or -NHC (O) NH-, and R ² is

R ³ is selected from the group consisting of isobutyl, phenyl, and pyridine. The method of claim 1, A compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: Diethyl (4-((1-adamantanecarboxamido) methyll) phenylamino)-(phenyl) methylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-methoxyphenyl) methylphosphonate; Diethyl (4- (methoxycarbonyl) phenyl) (4-((1-adamantanecarboxamido) methyl) phenylamino) -methylphosphonate; Diethyl 1- (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2- Dimethylpropylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (pyridin-4-yl) methylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-cyanophenyl) methylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-fluorophenyl) methylphosphonate; Diethyl 1- (4-((1-adamantanecarboxamido) methyl) phenylamino) (2-methoxynaphthalen-6-yl) -dimethylpropylphosphonate; Dibutyl (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate; Diisobutyl (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate; Diisopropyl (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate; Dibenzyl (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate; (4,4-dimethyl-2-oxo-1,3,2-dioxy) 2- (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropyl) Phosphoran; Di- (2,2,2, -trifluoroethyl) (4-((1-adamantanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (p-tolyl) methylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (naphthalen-2-yl) methylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-tert-butylphenyl) methylphosphonate; Diethyl 1- (4-((1,2,3,4-tetrahydronaphthalene-2-carboxamido) methyl) phenylamino) -2,2-dimethylpropyl-phosphonate; Diethyl 1- (4-((1-adamantanecarboxamido) methyl) phenylamino) butylphosphonate; Diethyl 1- (4-((cyclohexanecarboxamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (naphthalen-1-yl) methylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (4-morpholinophenyl) methylphosphonate; Diethyl 1- (4-((4- (trifluoromethoxy) benzamide) methyl) phenylamino) -2,2-dimethylpropylphosphonate; Diethyl 1- (4-((2- (naphthalen-1-yl) acetamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate; Diethyl 1- (4-((2-adamantane-1-ylacetamido) methyl) phenylamino) -2,2-dimethylpropylphosphonate; Diethyl 1- (4-((adamantane-1-ylacetamido) methyl) phenylamino) -3,3-dimethylbutylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (2-methoxyphenyl) methylpropylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (cyclopropyl) methylpropylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (cyclohexyl) methylpropylphosphonate; Diethyl 1- (4-((1-adamantanecarboxamido) methyl) phenylamino) -2-oxo-2-phenylethylpropylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (anthracene-10-yl) methylpropylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (2-hydroxynaphthalen-6-yl) methylpropylphosphonate; Diethyl (4-((1-adamantanecarboxamido) methyl) phenylamino) (2-acetoxynaphthalen-6-yl)) methylpropylphosphonate; Diethyl (4-((3-adamantan-1-yl ureido) methyl) phenylamino) (phenyl) methylphosphonate; Diethyl 1- (4-((3-adamantan-1-yl-ureido) methyl) phenylamino) -2-2-dimethylpropylphosphonate; Diethyl 1- (4-((3-adamantan-1-yl-ureido) methyl) phenylamino) (4-morpholinophenyl) methylphosphonate; Diethyl 1- (4-((3-adamantan-1-yl-ureido) methyl) phenylamino) (pyridin-4-yl) methylphosphonate; And Diethyl1- (4- (4- (trifluoromethoxy) phenylcarbamoyl) phenylamino) -2,2-dimethylpropyl-phosphonate. (A) reacting a compound of Formula 3 and a compound of Formula 4 to generate an imine intermediate; And (B) reacting the imine intermediate with any one selected from the group consisting of dialkyl phosphites, dihaloalkyl phosphites, diaryl phosphites and cyclic alkyl phosphites How to manufacture: (3)

[Formula 4]

In the above formula, R ¹ , R ² , R ³ and P ¹ are as defined in claim 1. The method of claim 10, The compound of formula 3 is produced by reacting R ¹ -COOH or R ¹ -NCO with NH ₂ -R ² -NH ₂ , wherein R ¹ and R ² are as defined in claim 1. 10. A pharmaceutical composition for inhibiting human soluble epoxide hydrolase comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. A compound comprising any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient, hypertension, inflammation, adult respiratory distress syndrome, diabetic complications, metabolic syndrome, lipid metabolism abnormality, kidney disease, A pharmaceutical composition for treating or preventing any one disease selected from the group consisting of Raynaud syndrome, obstructive pulmonary disease, interstitial lung disease, asthma, stroke and arthritis. The method of claim 13, Hypertension is selected from the group consisting of renal hypertension, pulmonary arterial hypertension and hepatic hypertension. The method of claim 13, Inflammation is selected from the group consisting of kidney inflammation, vascular inflammation and lung inflammation. The method of claim 13, Pharmaceutical composition, characterized in that the obstructive pulmonary disease is selected from the group consisting of chronic obstructive pulmonary disease, emphysema and chronic bronchitis.