KR100774728B1 - A new n-formyl hydroxylamine derivative as inhibitor of peptide deformylase and preparation method thereof - Google Patents

Abstract

Novel N-formyl hydroxylamine derivatives are provided to inhibit growth of Streptococcus pneumoniae and antibiotic-resistant bacteria by inhibiting activity of peptide deformylase(PDF) associated with protein biosynthesis and polypeptide maturation, thereby treating respiratory disease. The N-formyl hydroxylamine derivatives represented by the formula(I) are provided, wherein A is -C(=O)NHOH or -N(CHO)OH; R1 is hydrogen, C1-3 alkyl, C4-6 cycloalkyl, halogen or hydroxyl; R2 is hydrogen, linear or branched C1-6 alkyl, linear or branched C2-6 alkenyl, C4-6 cycloalkyl, N or O-containing C4-6 heterocycle or benzyl; R3 is hydrogen, linear or branched C1-6 alkyl, linear or branched C2-6 alkenyl, C4-6 cycloalkyl, phenyl or benzyl; Y is a compound represented by the formula(IIa) or formula(IIb). In the formula(IIa) or formula(IIb), R4 is hydrogen, linear or branched C1-6 alkyl, linear or branched C2-6 alkenyl, C4-6 cycloalkyl, phenyl or benzyl; and R5 is hydrogen, halogen, amino, C1-6 alkyl substituted amino, aryl substituted amino, furan or a compound represented by the formula(III). In the formula(III), R6-R10 is independently hydrogen, linear or branched C1-3 alkyl, linear or branched halogen substituted C1-4 alkyl, hydroxy, acyl, acyloxy, halogen(fluoro, chloro, bromo, iodo), cyano, nitro, amino, N,N-dimethylamino, phenyl, morpholinyl or formyl.

Description

A new N-formyl hydroxylamine derivative as inhibitor of peptide deformylase and preparation method

Since the introduction of penicillin in the 1940s, Staphylococcus aureus family of bacteria that are resistant to penicillin appeared and spread rapidly. Since methicillin was modified to modify the structure of penicillin was effectively used in strains showing penicillin resistance, but new methicillin resistant strains appeared.

Because microorganisms have a short replication period, they are rapidly evolving and adapting to environmental changes such as light intensity, oxygen levels, acidity, and antibiotic administration. (Russell and Chopra, 1996, Understanding antibacterial action and resistance, 2nd ed.Ellis Horwood, New York, NY; Jacobs, 1994, Clin . Infect . Dis ., 19: 1-10; Hooper and Wolfson, 1993, Am . Soc . Microbiol, 1993:. 97-118)

In recent literature, vancomycin ( Staphylococcus) aureus resistant to vancomycin-United States, 2002.MMWR (2002) 51 (26): 565-567), including the well-known antibiotics as the only as linezolid (Linezolid resistance in a clinical isolate of Staphylococcus aureus Lancet (2001) 358 (9277): 207-208), bacteria are known to acquire rapid resistance to new classes of antibacterial agents.

Therefore, there is an urgent need for the development of antibiotics with new mechanisms of action.

Antimicrobials such as aminoglycosides, macrolides, tetracyclines and oxazolidinones inhibit the early and / or complex stages of protein synthesis.

The protein synthesis process is similar to bacteria and mammals in general, but there is a step that can selectively inhibit only metabolism of bacteria, and transformylation and deformylation are one of these important differences.

Peptide deformylase (PDF) is an essential enzyme involved in bacterial protein biosynthesis and polypeptide maturation and is one of the new targets in the field of antibiotic development. Formyl peptides to claim Millar (PDF) catalyzes the hydrolysis of the amide bond as the metal-containing enzyme (metalloprotease) containing iron (Fe ^{+ 2).} Protein synthesis in prokaryotes N -.-Formyl-methionine is disclosed by (fMet, N-formylmethionine), as a result the newly synthesized polypeptide has a formylating the N- terminus [Meinnel et al, Biochimie, vol . 75, pp. 1061-1075 (1993). Polypeptide deformillase (PDF) then catalyzes the removal of formyl groups from this formylated polypeptide, followed by further processing of the N -terminus by methionine aminopeptidase (MAP) Form protein.

However, the initiation of protein synthesis in eukaryotes is N - is formyl methionine when developing the PDF inhibitor does not rely on (fMet, N-formylmethionine) expected to be useful as a new class of antibacterial agents. Recently many PDF inhibitors have been developed and many of them may have a metal chelator structure, greatly thiol (thiol), hydroxyl samik acid (hydroxamic acid), N - three such formyl hydroxylamine (N-formyl hydroxylamine) It can be classified into branches.

Prior art related to PDF inhibitors is as follows.

Hydroxamic acid derivatives: WO 99/59568, WO 00/44373, WO 01/44178, WO 01/44179, WO 02/28829, WO 02/081426

N-formyl hydroxyl amine derivatives: WO 01/85160, WO 01/85170, WO 02/070540, WO 02/070541, WO 02/070653, WO 02/070654, WO 02/098901, WO 03/101442, WO 0035440, WO 99/39704, WO 00/35440, WO 00/58294, WO 00/61134, WO 01/10834, WO 01/10835, WO 03/089412

Prior arts described in this document have been studied as PDF inhibitors, but until now, no clinically applicable medicines have been developed.

In view of the development of bacterial resistance to existing antibiotics, the development of antibiotics and antimicrobials with new mechanisms of action is urgently needed.

Accordingly, the present invention is expected to meet this need.

The present invention relates to compounds having good antimicrobial activity and especially to deformillase inhibitors containing novel hydroxylxamic acids or N -formyl hydroxylamine. The present invention also relates to methods for their preparation, intermediates useful for their preparation and pharmaceutical compositions containing them.

The present invention relates to a compound represented by the following formula (I), a racemate, an optical isomer or a diastereomer or a pharmacologically acceptable salt thereof.

In Chemical Formula I,

A is selected from the group of -C (= 0) NHOH or -N (CHO) OH;

R ₁ is hydrogen, C _{1 -3} alkyl, C _{4 -6-cycloalkyl,} halogen or hydroxy;

R ₂ is hydrogen, straight or branched C _1-6 alkyl, straight or branched C _2-6 alkenyl, C _4-6 cycloalkyl, C _4-6 heterocycle comprising N or O atoms Benzyl;

R ₃ is hydrogen, straight or branched C _1-6 alkyl, straight or branched C _2-6 alkenyl, C _4-6 cyclo alkyl, phenyl, benzyl;

Y is selected from formula IIa or formula IIb;

From here,

R ₄ is hydrogen, straight or branched C _1-6 alkyl, straight or branched C _2-6 alkenyl, C _3-6 cyclo alkyl, phenyl, benzyl;

R ₅ is hydrogen, halogen, amino, C _{1 -6} alkyl substituted amino, aryl substituted amino, furan) or (Ⅲ gt;

From here,

_{R 6, R 7, R 8} , R 9 and R ₁₀ are each independently hydrogen, straight or branched C _{1 -3} alkyl, a linear or branched halogen-substituted C ₁ of the ground _-3 alkyl, hydroxy, acyl , Acyloxy, halogen (fluoro, chloro, bromo, iodo), cyano, nitro, amino, N , N -dimethylamino, phenyl, morpholinyl or formyl.

The compounds of the present invention may be in the form of racemic or optical isomers or diastereomers by containing the absent carbon. Accordingly, the compounds of the present invention include all such racemates, optical isomers and diastereomers.

The compounds of the invention may also be in the form of pharmacologically acceptable salts, hydrates, or solvates. Examples of pharmacologically acceptable salts applicable to the compounds of the present invention include hydrochloride, bromate, sulfate, nitrate, methylsulfonate, p -toluenesulfonate, phosphate, acetate, pyruvate, citrate, succinate, lactate, Tartarate, fumarate, maleate, stearate, salicylate, sodium salt, potassium salt, magnesium salt, calcium salt and the like.

The present invention includes a process for preparing the compound of formula (I) or a pharmacologically acceptable salt thereof.

That is, a compound wherein A is —C (═O) NHOH is a compound of formula (I) comprising the step of removing a protecting group after reaction of a compound of formula (IV) with hydroxylamine or N- or O -protected hydroxylamine It includes a method for preparing a pharmaceutically acceptable salt.

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

The reaction of the compound of formula IV with hydroxylamine or N- or O -protected hydroxylamine is carried out using conventional amide synthesis methods such as penta-fluorophenol, N , O -dimethylhydroxylamine, DMAP- It can be carried out in the presence of amide bonding reagents such as EDCI or EDCI-HOBt-NMM, and the usable solvents include solvents such as tetrahydrofuran, dichloromethane, N , N -dimethylformamide and the like. A protecting group such as benzyl can be removed by adding a hydrogenation catalyst, preferably a palladium catalyst, to the amide product, stirring for about 2 to about 24 hours under a hydrogen atmosphere.

Protecting groups such as tert -butyl can be removed by adding hydrochloric acid or trifluoroacetic acid to the amide product by stirring for about 2 to about 24 hours.

Compounds of formula (IV) include compounds of formula (V) and compounds of formula (VIa) (or formula (VIb)) or salts thereof in conventional peptide synthesis methods such as penta-fluorophenol, N , O -dimethylhydroxylamine, DMAP-EDCI Or in the presence of a peptide binding reagent such as EDCI-HOBt-NMM, and usable solvents include solvents such as tetrahydrofuran, dichloromethane, N , N -dimethylformamide, and the like.

Wherein R ₁ , R ₂ , R _{3 ,} R ₄ And R ₅ is as defined above and R ₁₁ is a hydroxy protecting group such as methyl, ethyl, tert -butyl, benzyl.

Compounds of formula (V) can be prepared according to methods known in the organic chemistry art.

Further, a compound wherein A is -N (CHO) OH is a compound of formula I and a pharmaceutically acceptable salt thereof comprising reacting a compound of formula VII with a compound of formula VIa (or formula VIb) or a salt thereof It includes a manufacturing method.

Reacting the compound of formula (VIII) with the compound of formula (VIa) (or formula (VIb)) or a salt thereof may be carried out using conventional peptide synthesis methods such as penta-fluorophenol, N , O -dimethylhydroxylamine, DMAP-EDCI Or in the presence of a peptide binding reagent such as EDCI-HOBt-NMM, and usable solvents include solvents such as tetrahydrofuran, dichloromethane, N , N -dimethylformamide, and the like. A protecting group such as benzyl can be carried out by adding a hydrogenation catalyst, preferably a palladium catalyst, to the amide product and stirring for about 2 to about 24 hours under a hydrogen atmosphere.

A protecting group such as tert -butyl can be carried out by adding hydrochloric acid or trifluoroacetic acid to the amide product and stirring for about 2 to about 24 hours.

Wherein R ₁ and R ₂ are as defined above and R ₁₂ is a hydroxy protecting group such as tert -butyl, benzyl.

Compounds of formula (VIII) may be prepared according to methods known in the organic chemistry art.

Compounds of the formula Ⅵa is a compound with a compound of formula Ⅸ of formula Ⅷ tetrahydrofuran, dichloromethane, N, N-pentamethyl a solvent such as dimethylformamide -phenol fluoroalkyl, N, O-dimethyl It can be prepared by removing an amino protecting group after reaction with an amide bonding reagent such as hydroxylamine, DMAP-EDCI or EDCI-HOBt-NMM.

Wherein R ₃ , R ₄ and R ₅ are as defined above and R ₁₃ is an amino protecting group such as tert -butoxycarbonyl, benzyloxycarbonyl, triphenylmethyl.

Compounds of formula (IX) or salts thereof may be prepared by reacting a compound of formula (X) with a compound of formula (XI) or formula (XII) in ethanol or N, N-dimethylformamide solvent and then reducing the nitro group to an amine.

Wherein R ₄ , R ₅ , R _{6 ,} R ₇ , R ₈ , R ₉ And R ₁₀ is as defined above.

Compounds of formula (VIII) may be readily prepared according to methods known in the art of organic chemistry or according to the methods disclosed in the Examples below.

The sulfide of formula VIb or a salt thereof may be prepared by removing an amino protecting group after reaction of a compound of formula XIII with a compound of formula XI or a compound of formula XII in ethanol or N , N -dimethyl formamide solvent.

The compound of formula (XIII) can be prepared by reacting the compound of formula (XIV) with the compound of formula (XV) in a sealed tube in 1-methyl-2-pyrrolidinone solvent for 12 to 24 hours and then reducing the nitro group to an amino group using a palladium catalyst. .

Wherein R ₃ , R ₄ and R ₁₃ are as defined above.

Compounds of formula (XIV) can be readily prepared according to methods known in the art of organic chemistry or according to the methods disclosed in the Examples below.

The present invention will be described with reference to the following examples, but these examples are for illustrative purposes only and should not be construed as limiting the scope of the invention.

General Procedure I: ( S ) -2-Amino- N- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-part Synthesis of Tyramide Hydrochloride (Scheme 1)

Scheme 1

Step 1: N ¹ -methyl-4-nitro-benzene-1,2-diamine ( lb )

1-methyl-2-pyrrolidinone (360 ml), 2-fluoro-5-nitroaniline (45 g, 288 mmol) and potassium carbonate (81 g, 450 mmol) were added to a sealed reaction vessel, followed by methylamine (2M solution in THF, 288 ml, 144 mmol) was added and stirred at 120 ° C. for 16 hours. After cooling to room temperature, the reactant is added dropwise to 3.6 L of water to form a red precipitate. The precipitate formed was washed with water, filtered and dried to give the title compound (38 g, 80%).

¹ H-NMR (CDCl ₃ ): δ 7.87 (dd, 1H), 7.62 (d, 1H), 6.54 (d, 1H), 4.37 (s, 1H), 3.20 (s, 2H), 2.97 (d, 3H )

Step 2: 2- (4-Fluoro-phenyl) -1-methyl-5-nitro-1 H -benzimidazole ( Ic )

To a solution of Compound Ib (800 mg, 4.79 mmol) in ethanol (21 ml) is added 4-fluoro-benzaldehyde sodium metabisulfite adduct (1.42 g, 6.22 mmol) and stirred at reflux for 6 hours. After cooling to room temperature, ethanol was concentrated under reduced pressure, dissolved in N , N -dimethylformamide solution, and added dropwise to water to form a precipitate. The precipitate formed was washed with water, filtered and dried to give the title compound (840 mg, 65%).

¹ H-NMR (CDCl ₃ ): δ 8.71 (d, 1H), 8.28 (dd, 1H), 7.82-7.76 (m, 2H), 7.50 (d, 1H), 7.35-7.20 (m, 2H), 3.94 (s, 3H)

Step 3: 2- (4-Fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-ylamine ( Id )

To a solution of compound Ic (840 mg, 3.10 mmol) in ethanol (30 ml) is added 10% Pd / C (190 mg) and stirred under hydrogen gas for 4 hours. Filtration under celite and concentration gave the title compound (720 mg, 97%) as a solid compound.

¹ H-NMR (CD ₃ OD): δ 7.81-7.04 (m, 2H), 7.32-7.27 (m, 3H), 7.03 (d, 1H), 6.86 (dd, 1H), 3.75 (s, 3H)

Step 4: VII ( S ) -1- [2- (4-Fluoro-phenyl) -1-methyl-1 H -benzimidazole-5-ylcarbamoyl] -2,2-dimethyl-propyl｝ -carba Mic acid tert -butyl ester ( Ⅰ-f )

A solution of compound Ie (R 3 = tert -butyl, 450 mg, 1.95 mmol) in anhydrous dichloromethane (10 ml) was cooled to 0 ° C. and compound Id (560 mg, 2.34 mmol), dimethylaminopyridine (564 mg, 2.34 mmol) ) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 597 mg, 4.88 mmol) are added and stirred at room temperature for 24 hours. The reaction mixture was washed with distilled water, saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, concentrated and purified by silica gel chromatography to obtain the title compound (1.46 g, 56%) as a white solid compound.

¹ H-NMR (CDCl ₃ ): δ 8.28 (s, 1H), 7.90 (s, 1H), 7.71-7.66 (m, 2H), 7.39 (d, 1H), 7.21-7.14 (m, 3H), 5.50 (d, 1H), 4.13 (d, 1H), 3.76 (s, 3H), 1.44 (s, 9H), 1.09 (s, 9H)

Step 5: ( S ) -2-Amino- N- [2- (4-fluoro-phenyl) -1-methyl-1 H benzimidazol-5-yl] -3,3-dimethyl-butyamide hydrochloride ( Ⅰ-g )

Compound If (1.53 g, 3.37 mmol) was dissolved in ethyl acetate and treated with hydrochloric acid gas to obtain the title compound (1.18 g, 91%) as a white solid compound of hydrochloride, which was used in the next reaction without further purification.

General Procedure II: ( S ) -2-Amino-1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butane- Synthesis of 1-one hydrochloride (Scheme 2)

 Scheme 2

Step 1: [( S ) -1- (methoxy-methyl-carbamoyl) -2,2-dimethyl-propyl] -carbamic acid tert -butyl ester ( II-a )

Compound I-e (R ₃ = tert -butyl, 6 g, 25.95 mmol) was dissolved in dichloromethane (60 ml) and then N , O -dimethylhydroxylamine (2.78 g, 28.55 mmol), dimethylaminopyridine at 0 ° C. (7.30 g, 59.68 mmol) and EDCI (5.97 g, 31.14 mmol) are added and stirred at room temperature for 24 hours. The reaction mixture was washed with distilled water, saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, concentrated and purified by silica gel chromatography to obtain the title compound (7.1 g, 99%).

¹ H-NMR (CDCl ₃ ): δ 5.20 (d, 1H), 4.65 (d, 1H), 3.77 (s, 3H), 3.21 (s, 3H), 1.45 (s, 9H), 1.02 (s, 9H )

Step 2: [( S ) -1- (4-Fluoro-benzoyl) -2,2-dimethyl-propyl] -carbamic acid tert -butyl ester ( II-b )

Compound II-a (7.1 g, 25.87 mmol) synthesized in step 1 was dissolved in anhydrous tetrahydrofuran (THF, 34 ml) and then 4-fluoro-phenyl magnesium bromide (2.0 M solution in THF, 90.54 ml) at 0 ° C. , 181.09 mmol) is added and stirred for 30 minutes at room temperature for 20 hours.

The reaction solution was cooled to 0 ° C., added with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with water and brine. The washed organic layer was dried, concentrated and purified by silica gel chromatography to obtain the title compound (5.4 g, 67%) as a white solid compound.

¹ H-NMR (CDCl ₃ ): δ 8.05-8.02 (m, 2H), 7.26-7.12 (m, 2H), 5.30 (d, 1H), 5.12 (d, 1H), 1.43 (s, 9H), 0.91 (s, 9H)

Step 3: ( S ) -2-Amino-1- (4-fluoro-phenyl) -3,3-dimethyl-butan-1-one hydrochloride ( II-c )

Compound II-b (1 g, 3.23 mmol) was dissolved in ethyl acetate and treated with hydrochloric acid gas to give the title compound (730 mg, 93%) as a white solid compound of hydrochloride, which was used in the next reaction without further purification.

Step 4: 2,2,2-Trifluoro- N -[( S ) -1- (4-fluoro-benzoyl) -2,2-dimethyl-propyl] -acetamide ( II-d )

Compound II-c (730 mg, 3.00 mmol) was dissolved in methanol (5 ml), cooled to 0 ° C. and trifluoroacetic acid ethyl ester (0.45 ml, 3.80 mmol) and triethylamine (0.93 ml, 6.70 mmol) Add and stir at room temperature for 12 hours. Methanol was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried, concentrated and purified by silica gel chromatography to obtain the title compound (770 mg, 85 as a white solid). %) Was obtained.

¹ H-NMR (CDCl ₃ ): δ 8.05-8.02 (m, 2H), 7.22-7.15 (m, 2H), 5.52 (d, 1H), 0.98 (s, 9H)

Step 5: 2,2,2-Trifluoro- N -[( S ) -1- (4-fluoro-3-nitro-benzoyl) -2,2-dimethyl-propyl] -acetamide ( II-e )

Concentrated sulfuric acid (10.24 ml) is cooled to -10 ° C and compound II-d (3.2 g, 10.48 mmol) is added. Slowly add a mixed acid of concentrated sulfuric acid (4.16 ml) and 86% nitric acid (2.08 ml) while maintaining the temperature at -10 ° C, and stir the reaction solution at 0 ° C for 1 hour, and then add ice cubes. After extraction with ethyl acetate, the organic layer is washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. Purification by silica gel chromatography gave the title compound (3.5 g, 95%) as a yellow solid.

¹ H-NMR (CDCl ₃ ): δ 8.71 (dd, 1H), 8.33-8.29 (m, 1H), 7.47 (t, 1H), 7.08 (S, 0.9H), 5.50 (d, 1H), 1.03 ( s, 9H)

Step 6: ( S ) -2-Amino-1- (4-fluoro-3-nitro-phenyl) -3,3-dimethyl-butan-1-one ( II-f )

Compound II-e (3.5 g, 9.99 mmol) is dissolved in methanol (230 ml) and then water (140 ml) and potassium carbonate (7.18 g) are added. After stirring the reaction solution under reflux for 2 hours, methanol was removed. The mixture was extracted with chloroform and the organic layer was washed with water and saturated brine, dried and concentrated to obtain the title compound, which was used in the next reaction without further purification.

Step 7: [( S ) -1- (4-Fluoro-3-nitro-benzoyl) -2,2-dimethyl-propyl] -carbamic acid tert -butyl ester ( II-g )

Compound II-f (2.2 g, 0.65 mmol) prepared in step 6 was dissolved in 1,4-dioxane (17 ml) and water (8.6 ml), and 1N-NaOH (20 ml) was added. Di- tert -butyl dicarbonate (2.07 g, 0.71 mmol)) is added slowly at 0 ° C. and stirred at room temperature for 12 hours. Concentrated under reduced pressure to remove 1,4-dioxane, the aqueous layer was acidified to pH 2.5 with 1M aqueous potassium hydrogensulfate solution and extracted with ethyl acetate. Drying with magnesium sulfate, concentration and purification with silica gel chromatography gave the title compound (2.6 g, 74%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ): δ 8.49 (s, 1H), 8.23 (d, 1H), 7.15 (d, 1H), 5.35 (d, 0.9H), 5.07 (d, 0.9H), 1.45 (s , 9H), 0.98 (s, 9H)

Step 8: [( S ) -2,2-Dimethyl-1- (4-methylamino-3-nitro-benzoyl) -propyl] -carbamic acid tert -butyl ester ( II-h )

In a sealed tube, compound II-g (1 g, 2.82 mmol) was dissolved in 1-methyl-2-pyrrolidinone (NMP, 2.81 ml), followed by methylamine (2.0M solution in THF, 3.1 ml, 6.2 mmol) and N. , N -diisopropyl ethylamine (0.32 ml, 10% v / v in NMP) was added and stirred at 70 ° C. for 16 hours. After cooling to room temperature, extracted with ethyl acetate and washed the organic layer with a large amount of water. After drying over magnesium sulfate and concentration, the residue was purified by silica gel chromatography to obtain the title compound (1 g, 97%) as yellow.

¹ H-NMR (CDCl ₃ ): δ 8.90 (s, 1H), 8.44 (s, 1H), 8.12 (d, 1H), 6.90 (d, 1H), 5.40 (d, 1H), 5.08 (d, 1H ), 3.11 (d, 3H), 1.42 (s, 9H), 0.98 (s, 9H)

Step 9: [( S ) -1- (3-Amino-4-methylamino-benzoyl) -2,2-dimethyl-propyl] -carbamic acid tert -butyl ester ( II-i )

Compound II-h (280 mg, 0.76 mmol) is dissolved in ethanol (7 ml), then 10% Pd / C (75 mg) is added and stirred under hydrogen gas for 3 hours. Filtration and concentration under celite afforded the title compound (210 mg, 85%) as a solid compound, which was used in the next reaction without further purification.

Step 10: ｛( S ) -1- [2- (4-Fluoro-phenyl) -1-methyl-1 H -benzimidazole-5-carbonyl] -2,2-dimethyl-propyl｝ -carbamic acid tert -butyl ester ( II-j )

To a solution of compound II-i (210 mg, 0.60 mmol) in ethanol (5 ml) was added sodium metabisulfite adduct of 4-fluoro-benzaldehyde (230 mg, 0.78 mmol) and stirred at reflux for 4 hours. do.

After cooling to room temperature, ethanol was concentrated under reduced pressure, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated. Purification by silica gel chromatography gave the title compound (250 mg, 89%).

¹ H-NMR (CDCl ₃ ): δ 8.51 (s, 9H), 8.05 (d, 1H), 7.80-7.76 (m, 2H), 7.43 (d, 1H), 7.27-7.21 (m, 2H), 5.53 (d, 1H), 5.29 (d, 1H), 3.90 (s, 3H), 1.44 (s, 9H), 0.93 (s, 9H)

Step 11: ( S ) -2-Amino-1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butane-1 -Warm hydrochloride ( II-k )

Compound II-j (250 mg, 0.56 mmol) was dissolved in ethyl acetate and treated with hydrochloric acid gas to obtain the title compound (210 mg, 100%) as a white solid compound of hydrochloride, which was used in the next reaction without further purification.

General Procedure III: ( R ) -2-cyclopentylmethyl- N ¹ -｛( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl Carbamoyl] -2,2-dimethylpropylpropyl- N ⁴ -hydroxy-succinamide (Scheme 3)

Scheme 3

Step 1: ( R ) -3-cyclopentylmethyl- N -VII ( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazole-5-ylcarbamoyl ] -2,2-dimethyl propyl-succinic acid tert -butyl ester ( III-b )

A solution of compound III-a (R ² = cyclopentylmethyl, 1.1 g, 4.29 mmol) in dried dichloromethane (50 ml) was cooled to 0 ° C. and prepared compound I-g (R ₃ = tert − in General Procedure I). Butyl, R ₄ = methyl, R ₅ = 4-fluoro-phenyl, 1.85 g, 4.72 mmol), dimethylaminopyridine (1.31 g, 10.73 mmol), EDCI (1.07 g, 5.57 mmol) was added and at room temperature for 24 hours Stir. The reaction mixture was washed with 0.5N-HCl aqueous solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, concentrated and purified by silica gel chromatography to obtain the title compound (2.54 g, 100%) as a solid compound. .

¹ H-NMR (CDCl ₃ ): δ 8.24 (s, 1H), 7.88 (d, 1H), 7.75-7.71 (m, 2H), 7.50-7.47 (dd, 1H), 7.29-7.26 (m, 1H) , 7.22-7.18 (m, 2H), 6.60 (d, 1H), 3.82 (s, 3H), 2.72-2.62 (m, 2H), 2.38-2.33 (m, 1H), 1.78-1.65 (m, 5H) , 1.51-1.34 (m, 15H), 1.10-1.00 (m, 12H)

Step 2: ( R ) -3-cyclopentylmethyl- N- VII ( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazole-5-ylcarbamoyl ] -2,2-dimethyl propyl-succinic acid ( Ⅲ-c )

Compound III-b (2.43 g, 4.10 mmol) was dissolved in dichloromethane (24 ml), trifluoroacetic acid (9.72 ml) was added, stirred for 1 hour, concentrated under reduced pressure, and dried under vacuum to give the title compound (2.13 g, 97 %) Was obtained.

¹ H-NMR (CDCl ₃ ): δ 9.20 (s, 0.9H), 7.95 (s, 1H), 7.70-7.65 (m, 3H), 7.26-7.13 (m, 3H), 4.65 (d, 1H), 3.80 (s, 3H), 2.87-2.82 (m, 1H), 2.78-2.70 (m, 1H), 2.61-2.58 (m, 1H), 1.80-1.62 (m, 4H), 1.60-1.35 (m, 6H ), 1.10-0.98 (m, 12H)

Step 3: ( R ) -N ⁴ -benzyloxy-2-cyclopentylmethyl- N ¹ -｛( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimi Dazol-5-ylcarbamoyl] -2,2-dimethyl propyl｝ -succinamide ( III-d )

A solution of compound III-c (900 mg, 1.67 mmol) in dried N , N -dimethylformamide (25 ml) was cooled to 0 ° C. and benzylhydroxylamine hydrochloride (320 mg, 2.00 mmol), 1-hydroxybenzo Triazole hydrate (270 mg, 2.17 mmol), EDCI (420 mg, 2.17 mmol), 4-methylmorpholine (0.92 ml, 8.35 mmol) is added and stirred at room temperature for 24 hours. The reaction mixture was washed with 0.5N-HCl aqueous solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, concentrated and purified by silica gel chromatography to obtain the title compound (300 mg, 30%) as a solid compound.

¹ H-NMR (CDCl ₃ ): δ 10.26 (s, 0.7H), 9.29 (s, 0.7H), 8.00 (s, 0.3H), 7.90 (s, 1H), 7.85 (d, 1H), 7.80- 7.72 (m, 2H), 7.38-7.32 (m, 1H), 7.30-7.20 (m, 5H), 7.19-7.10 (m, 2H), 6.90-6.81 (d, 1H), 4.81-4.79 (m, 2H ), 4.68-4.66 (m, 1H), 3.79 (s, 3H), 2.50-2.32 (m, 2H), 1.80-1.25 (m, 10H), 1.10-0.82 (m, 12H)

Step 4: ( R ) -2-cyclopentylmethyl- N ¹ -｛( S ) -1- [2- (4-fluoro-phenyl) -1-methyl- 1H -benzimidazole-5-ylcarbamoyl] -2,2-dimethyl propyl｝ -N ⁴ -hydride Roxy-succinamide ( III-e )

To a solution of compound III-d (150 mg, 0.23 mmol) in ethanol (15 ml) is added 10% -Pd / C (30 mg) and stirred under hydrogen atmosphere for 3 hours. The reaction mixture was filtered under Celite, concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (100 mg, 79%) as a white solid compound.

¹ H-NMR (DMSO-d ₆ ): δ 10.37 (s, 0.9H), 10.01 (s, 1H), 8.70 (s, 0.9H), 8.02 (s, 1H), 7.92-7.87 (m, 3H) , 7.55-7.52 (m, 1H), 7.43-7.39 (m, 3H), 4.47 (d, 1H), 3.84 (s, 3H), 2.92-2.83 (m, 1H), 2.23-2.05 9m, 2H), 1.87-1.72 (m, 1H), 1.70-1.10 (m, 10H), 1.03 (s, 11H)

General procedure IV: ( R ) -2-cyclopentylmethyl- N- N ( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazole-5-carbonyl ] -2,2-Dimethyl-propyl｝ -3- (formyl-hydroxy-amino) -propionamide (Scheme 4)

Scheme 4

Step 1: ( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl- N -VII ( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazole-5-carbonyl] -2,2-dimethyl-propyl｝ -propionamide ( IV-b )

A solution of compound IV-a (R ₂ = cyclopentylmethyl, 410 mg, 1.34 mmol) in dried dichloromethane (5 ml) was cooled to 0 ° C. and prepared compound II-k (R ₃ = tert − in General Procedure III). Butyl, R ₄ = methyl, R ₅ = 4-fluoro-phenyl 650 mg, 1.47 mmol), dimethylaminopyridine (410 mg, 3.35 mmol), EDCI (334 mg, 1.74 mmol) were added and stirred at room temperature for 24 hours do. The reaction mixture was washed with 0.5N-HCl aqueous solution, saturated aqueous sodium bicarbonate solution, saturated brine, dried over magnesium sulfate, concentrated and purified by silica gel chromatography to obtain the title compound (200 mg, 22%) as a white solid compound. .

¹ H-NMR (CDCl ₃ ): δ 8.51 (s, 1H), 8.15 (s, 0.5H), 8.04-8.02 (m, 1H), 7.80 (s, 0.5H), 7.78-7.76 (m, 2H) , 7.46-7.39 (m, 6H), 7.28-7.23 (m, 2H), 6.42 (d, 1H), 5.64 (d, 1H), 5.10-4.81 (m, 2H), 3.90 (s, 3H), 3.90 -3.51 (m, 2H), 2.68-2.50 (m, 1H), 1.90-1.02 (m, 12H), 1.02-0.88 (m, 9H)

Step 2: ( R ) -2-cyclopentylmethyl- N -VII ( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazole-5-carbonyl] -2,2-Dimethyl-propyl｝ -3- (formyl-hydroxy-amino) -propionamide ( IV-c )

To a solution of compound IV-b (200 mg, 0.32 mmol) in ethanol (5 ml) is added 10% -Pd / C (40 mg) and stirred for 4 hours under hydrogen atmosphere. The reaction mixture was filtered under celite, concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (77 mg, 45%) as a white solid compound.

¹ H-NMR (CDCl ₃ ): δ 8.54 (s, 0.3H), 8.50-8.39 (m, 1H), 8.04 (s, 0.4H), 8.02-7.88 (m, 1H), 7.80-7.77 (m, 2H), 7.48-7.45 (m, 1H), 7.29-7.24 (m, 2H), 6.80 (d, 0.3H), 6.61 (d, 0.5H), 5.71-5.67 (m, 1H), 3.91-3.90 ( m, 4H), 3.70-3.48 (m, 1H), 2.90-2.68 (m, 1H), 1.75-1.31 (m, 12H), 1.04-0.92 (m, 10H)

Example 1. ( R ) -2-cyclopentylmethyl- N ¹ -｛( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl Carbamoyl] -2,2-dimethylpropylpropyl- N ⁴ -hydroxy-succinamide

( R ) -2-cyclopentylmethyl-succinic acid-4- tert -butyl ester III-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N- [2- (4 according to General Procedure III. -Fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butyamide hydrochloride I-g (prepared according to general procedure I. R ₃ = tert- Butyl, R ₄ = methyl, R ₅ = 4-fluoro-phenyl) to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 10.37 (s, 0.9H), 10.01 (s, 1H), 8.70 (s, 0.9H), 8.02 (s, 1H), 7.92-7.87 (m, 3H) , 7.55-7.52 (m, 1H), 7.43-7.39 (m, 3H), 4.47 (d, 1H), 3.84 (s, 3H), 2.92-2.83 (m, 1H), 2.23-2.05 (m, 2H) , 1.87-1.72 (m, 1H), 1.70-1.10 (m, 10H), 1.03 (s, 11H)

Example 2. ( R ) -2-cyclopentylmethyl- N ¹ -｛( S ) -2,2-dimethyl-1- (1-methyl-2- p -tolyl-1 H -benzimidazole-5- Yl-carbamoyl) -propyl] -N ⁴ -hydroxy-succinamide

( R ) -2-cyclopentylmethyl-succinic acid-4- tert -butyl ester III-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-3,3-dimethyl- N according to General Procedure III. -(1-methyl-2- p -tolyl-1 H -benzimidazol-5-yl] -butyamide hydrochloride I-g (prepared according to general procedure I. R ₃ = tert -butyl, R ₄ = Methyl, R ₅ = 4-methyl-phenyl) to give the title compound.

¹ H-NMR (DMSO-d ₆ ): δ 10.36 (s, 0.8H), 9.98 (s, 1H), 8.68 (s, 0.8H), 7.99 (s, 1H), 7.85 (d, 0.9H), 7.73 (d, 2H), 7.51 (d, 1H), 7.43-7.37 (m, 3H), 4.46 (d, 1H), 3.84 (s, 3H), 2.90-2.85 (m, 1H), 2.41 (s, 3H), 2.22-2.03 (m, 2H), 1.80-1.73 (m, 1H), 1.70-1.23 (m, 9H), 1.06-0.96 (m, 11H)

Example 3. ( S ) -2-[( R ) -2-cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] -3,3-dimethyl- N- (1-methyl- 1 H -benzimidazol-5-yl] -butyramide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-3 according to General Procedure IV. , 3-dimenyl- N- (1-methyl-1 H -benzimidazol-5-yl) -butyramide hydrochloride I-g (prepared according to general procedure I. R ₃ = tert -butyl, R ₄ = Methyl, R ₅ = H) to give the title compound.

¹ H-NMR (CDCl ₃ ): δ 8.29 (s, 0.3H), 8.09-7.89 (m, 2H), 7.43-7.39 (m, 2H), 4.56-4.29 (m, 0.8H), 3.85 (s, 3H), 3.84-3.58 (m, 1H), 3.32-3.30 (m, 1H), 3.14-2.98 (m, 1H), 2.04-1.27 (m, 9H), 1.09-1.07 (m, 9H)

Example 4. (S) -2 - [( R) -2- cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionyl Ami no] - N - [2- (4-fluoro-phenyl ) -1 H -benzimidazol-5-yl] -3,3-dimethyl-butyrylamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[2- (4-Fluoro-phenyl) -1 H -benzimidazol-5-yl) -butyramide hydrochloride I-g (prepared according to general procedure I. R ₃ = tert -butyl, R ₄ = Hydrogen, R ₅ = 4-fluoro-phenyl) to give the title compound.

¹ H-NMR (CD ₃ OD): δ 8.29 (s, 0.3H), 8.20-7.95 (m, 3H), 7.95-7.84 (m, 0.5H), 7.58-7.45 (m, 1H), 7.43-7.18 (m, 3H), 4.65-4.54 (m, 1H), 3.82-3.75 (m, 1H), 3.65-3.46 (m, 1H), 3.18-2.98 (m, 1H), 2.11-1.18 (m, 7H) , 1.10-0.98 (m, 12H)

Example 5. ( S ) -2-[( R ) -2-cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] -3,3-dimethyl- N- (2- p- Tolyl- 1H -benzimidazol-5-yl) -butyramide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-3 according to General Procedure IV. , 3-dimethyl- N- (2- p -tolyl-1 H -benzimidazol-5-yl] -butyryl hydrochloride I-g (prepared according to general procedure I. R ₃ = tert -butyl, R ₄ = hydrogen, R ₅ = 4-methyl-phenyl) to give the title compound.

¹ H-NMR (CD ₃ OD): δ 8.29 (s, 0.3H), 8.06-8.01 (m, 3H), 7.90-7.87 (m, 0.5H), 7.50-7.48 (m, 1H), 7.32-7.20 (m, 3H), 4.65-4.54 (m, 1H), 3.87-3.80 (m, 1H), 3.62-3.46 (m, 1H), 3.20-2.98 (m, 1H), 2.25-2.04 (m, 7H) , 1.20-1.09 (m, 12H)

Example 6. (S) -2 - [(R) -2-cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] - N - (1- methyl-2-phenyl -1 H -Benzimidazol-5-yl) -3,3-dimethyl-butyramide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-3 according to General Procedure IV. , 3-dimethyl- N- (1-methyl-2-phenyl-1 H -benzimidazol-5-yl) -butyramide hydrochloride I-g (prepared according to general procedure I. R ₃ = tert -butyl , R ₄ = methyl, R ₅ = phenyl) to prepare the title compound.

¹ H-NMR (CDCl ₃ ): δ 9.38 (s, 0.4H), 9.06 (s, 0.3H), 8.27 (s, 0.4H), 7.98-7.96 (m, 1H), 7.96-7.50 (m, 5H ), 726-7.14 (m, 2H), 748-4.69 (m, 1H), 3.79-3.50 (m, 5H), 3.07 (s. 0.8H), 2.04-1.20 (m, 9H), 1.20-0.98 ( m, 11H)

Example 7. (S) -2 - [( R) -2- cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] - N - [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butyrylamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[2- (4-Fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butyamide hydrochloride I-g (prepared according to general procedure I) R ₃ = tert -butyl, R ₄ = methyl, R ₅ = 4-fluoro-phenyl).

¹ H-NMR (CD ₃ OD): δ 8.28 (s, 0.3H), 8.00 (s, 1H), 7.85-7.77 (m, 2H), 7.48-7.44 (m, 2H), 7.34-7.28 (m, 2H), 4.55-4.53 (m, 1H), 3.83 (s, 3H), 3.83-3.79 (m, 1H), 3.60-3.45 (m, 1H), 3.32-3.29 (m, 1H), 313-2.97 ( m, 0.8H), 1.86-1.39 (m, 10H), 1.09-1.08 (m, 10H)

Example 8. ( S ) -2-[( R ) -2-cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] -3,3-dimethyl- N- (1-methyl- 2- p -tolyl-1 H -benzimidazol-5-yl) -butyramide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-3 according to General Procedure IV. , 3-dimethyl- N- (1-methyl-2- p -tolyl- 1H -benzimidazol-5-yl] -butyamide hydrochloride I-g (prepared according to general procedure I. R ₃ = tert -Butyl, R ₄ = methyl, R ₅ = 4-methyl-phenyl) to give the title compound.

¹ H-NMR (CD ₃ OD): δ 8.28 (s, 0.3H), 7.97 (s, 1H), 7.89-7.86 (m, 1H), 7.62 (d, 2H), 7.42-7.35 (m, 4H) , 4.55 (d, 1H), 4.38-3.72 (m, 4H), 3.71-3.58 (m, 1H), 3.31-3.30 (m, 1H), 3.20-2.97 (m, 1H), 2.45 (s, 3H) , 1.95-1.28 (m, 10H), 1.09 (s, 9H)

Example 9. ( S ) -2-[( R ) -2-cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] -3,3-dimethyl- N- [1-methyl- 2- (4-Trifluoromethyl-phenyl) -1 H -benzimidazol-5-yl] -butyramide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-3 according to General Procedure IV. , 3-dimethyl- N -[(1-methyl-2- (4-trifluoro-phenyl) -1 H -benzimidazol-5-yl] -butyramide hydrochloride I-g (according to general procedure I Prepared The title compound is prepared from R ₃ = tert -butyl, R ₄ = methyl, R ₅ = 4-trifluoro-phenyl).

¹ H-NMR (CD ₃ OD): δ 8.27-8.26 (m, 0.3H), 8.04-7.87 (m, 6H), 7.51-7.45 (m, 2H), 4.53-4.51 (m, 1H), 3.89- 3.78 (m, 4H), 3.61-3.42 (m, 1H), 3.11-2.95 (m, 1H), 2.09-1.19 (m, 10H), 1.19-0.98 (m, 10H)

Example 10. (S) -2 - [( R) -2- cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] - N - [2- (4- methoxy-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butyrylamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[2- (4-methoxy-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butyramide hydrochloride I-g (prepared according to general procedure I) R ₃ = tert -butyl, R ₄ = methyl, R ₅ = 4-methoxy-phenyl) to give the title compound.

¹ H-NMR (CDCl ₃ ): δ 9.30 (s, 0.4H), 8.93 (s, 0.3H), 8.29 (s, 0.5H), 7.92 (s, 1H), 7.65-7.62 (m, 2H), 7.26-7.21 (m, 1H), 7.10-7.00 (m, 3H), 4.76-4.67 (m, 1H), 3.87-3.79 (m, 7H), 3.11 (s, 1H), 2.08-1.22 (m, 10H ), 1.20-0.95 (m, 10H)

Example 11. (S) -2 - [(R) -2-cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] - N - (2- furan-2-yl-1 Methyl-1 H -benzimidazol-5-yl) -3,3-dimethyl-butyrylamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -(2-furan-2-yl-1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butyramide hydrochloride I-g (prepared according to general procedure I. R ₃ = tert -butyl, R ₄ = methyl, R 5 = ₂ -furan) to give the title compound.

¹ H-NMR (CDCl ₃ ): δ 9.33 (s, 0.3H), 8.94 (s, 0.3H), 8.46 (s, 0.3H), 7.91-7.85 (m, 1H), 7.60-7.50 (m, 2H ), 7.20-7.10 (m, 3H), 6.58-6.57 (m, 1H), 4.74-4.66 (m, 1H), 3.96-3.86 (m, 4H), 3.19-3.10 (m, 1H), 1.83-1.18 (m, 10H), 1.18-0.89 (m, 10H)

Example 12. (S) -2 - [(R) -2-cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] - N - [1- cyclopropyl-2- (4 Fluoro-phenyl) -1 H -benzimidazol-5-yl] -3,3-dimethyl-butyramide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[1-Cyclopropyl-2- (4-fluoro-phenyl) -1 H -benzimidazol-5-yl] -3,3-dimethyl-butyramide hydrochloride I-g (prepared according to general procedure I) R ₃ = tert -butyl, R ₄ = cyclopropyl, R ₅ = 4-fluoro-phenyl).

¹ H-NMR (CDCl ₃ ): δ 9.25 (s, 0.3H), 8.90 (s, 0.3H), 8.35 (s, 0.3H), 7.92-7.85 (m, 3H), 7.72-7.54 (m, 0.5 H), 7.50-7.40 (m, 1H), 7.21-7.10 (m, 3H), 4.71-4.66 (m, 1H), 3.82 (s, 1H), 3.47 (s, 2H), 3.05 (s, 0.8H ), 1.83-1.28 (m, 9H), 1.20-0.75 (m, 13H), 0.69-0.64 (m, 2H)

Example 13. (S) -2 - [(R) -2-cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] - N - [1- cyclopropyl-2- (4 Methoxy-phenyl) -1 H -benzimidazol-5-yl] -3,3-dimethyl-butyrylamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[1-cyclopropyl-2- (4-methoxy-phenyl) -1 H -benzimidazol-5-yl] -3,3-dimethyl-butyramide hydrochloride I-g (in accordance with General Procedure I Prepared The title compound is prepared from R ₃ = tert -butyl, R ₄ = cyclopropyl, R ₅ = 4-methoxy-phenyl).

¹ H-NMR (CDCl ₃ ): δ 9.20 (s, 0.5H), 8.72 (s, 0.4H), 8.32 (s, 0.5H), 7.83-7.76 (m, 4H), 7.44-7.41 (m, 1H ), 7.01-3.91 (m, 2H), 4.75-4.65 (m, 1H), 3.87-3.78 (m, 4H), 3.48-3.47 (m, 1H), 3.22-3.29 (m, 1H), 2.02-1.41 (m, 10H), 1.20-0.95 (m, 10H)

Example 14. (S) - N - [ 1- butyl-2- (4-fluoro-phenyl) -1 H-benzimidazol-5-yl] -2 - [(R) -2-cyclopentylmethyl -3- (formyl-hydroxy-amino) -propionylamino] -3,3-dimethyl-butyramide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[1-Butyl-2- (4-fluoro-phenyl) -1 H -benzimidazol-5-yl] -3,3-dimethyl-butyamide hydrochloride I-g (prepared according to general procedure I) R ₃ = tert -butyl, R ₄ = n-butyl, R ₅ = 4-fluoro-phenyl).

¹ H-NMR (CD ₃ OD): δ 8.27 (s, 0.3H), 7.99 (s, 1H), 7.85 (s, 0.6H), 7.76-7.72 (m, 2H), 7.54-7.51 (m, 1H ), 7.45-7.42 (m, 1H), 7.35-7.30 (m, 2H), 4.52 (d, 1H), 4.28 (t, 2H), 3.83-3.28 (m, 1H), 3.20-2.90 (m, 1H ), 1.98-1.33 (m, 9H), 1.20-0.98 (m, 13H), 0.80 (t, 3H)

Example 15. (S) - N - [ 1- cyclohexyl-2- (4-fluorophenyl) -1 H-benzimidazol-5-yl] -2 - [(R) -2-cyclopentyl- Methyl-3- (formyl-hydroxy-amino) -propionylamino] -3,3-dimethyl-butyrylamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[1-cyclohexyl-2- (4-fluoro-phenyl) -1 H -benzimidazol-5-yl] -3,3-dimethyl-butyramide hydrochloride I-g (prepared according to general procedure I) The title compound was prepared from R ₃ = tert -butyl, R ₄ = cyclohexyl, R ₅ = 4-fluoro-phenyl).

¹ H-NMR (CD ₃ OD): δ 8.05 (s, 0.3H), 7.99 (d, 1H), 7.77 (d, 1H), 7.68-7.64 (m, 2H), 7.44-7.41 (m, 1H) , 7.36-7.30 (m, 2H), 4.50-4.48 (m, 1H), 4.32-4.20 (m, 1H), 3.31-3.29 (m, 1H), 3.10-2.90 (m, 1H), 2.82-2.75 ( m, 1H), 2.40-2.29 (m, 2H), 2.05-1.1.62 (m, 7H), 1.57-1.20 (m, 10H), 1.20-0.98 (m, 11H)

Example 16. (S) - N - [ 1- benzyl-2- (4-fluorophenyl) -1 H-benzimidazol-5-yl] -2 - [(R) -2-cyclopentylmethyl -3- (formyl-hydroxy-amino) -propionylamino] -3,3-dimethyl-butyramide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[1-benzyl-2- (4-fluoro-phenyl) -1 H -benzimidazol-5-yl] -3,3-dibutyl-butyramide hydrochloride I-g (prepared according to general procedure I) R ₃ = tert -butyl, R ₄ = benzyl, R ₅ = 4-fluoro-phenyl).

¹ H-NMR (CD ₃ OD): δ 8.28 (s, 0.5H), 8.08-8.00 (m, 5H), 7.85 (s, 1H), 7.51-7.50 (m, 1H), 7.29-7.24 (m, 5H), 4.61-4.54 (m, 2H), 3.86-3.81 (m, 1H), 3.50-3.42 (m, 1H), 3.20-2.85 (m, 1H), 1.87-1.27 (m, 10H), 1.20- 0.8 (m, 10H)

Example 17. (S) - N - [ 1- benzyl-2- (4-trifluoromethyl-phenyl) -1 H-benzimidazol-5-yl] -2 - [(R) -2- cyclopropyl Pentylmethyl-3- (formyl-hydroxy-amino) -propionylamino] -3,3-dimethyl-butyrylamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino- N according to General Procedure IV. -[1-benzyl-2- (4-trifluoromethyl-phenyl) -1 H -benzimidazol-5-yl] -3,3-dibutyl-butyramide hydrochloride I-g (in General Procedure I Prepared according to The title compound is prepared from R ₃ = tert -butyl, R ₄ = benzyl, R ₅ = 4-trifluoro-phenyl).

¹ H-NMR (CD ₃ OD): δ 8.32-8.20 (m, 4H), 8.06 (s, 2H), 7.86-7.80 (m, 5H), 7.60-7.51 (m, 1H), 7.32-7.27 (m , 1H), 4.67-4.55 (m, 2H), 4.90-4.78 (m, 1H), 3.50-340 (m, 1H), 3.21-2.89 (m, 1H), 1.98-1.23 (m, 10H), 1.20 -0.98 (m, 11H)

Example 18. ( R ) -N -[( S ) -1- (2-amino-1-methyl-1 H -benzimidazole-5-carbonyl) -2,2-dimethyl-propyl] -2- Cyclopentylmethyl-3- (formyl-hydroxy-amino) -propionamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-1 according to General Procedure IV. -(2-amino-1-methyl-1 H -benzimidazol-5-yl) -3,3-dimethyl-butan-1-one hydrochloride II-k (prepared according to general procedure II. R ₃ = tert -Butyl, R ₄ = methyl, R ₅ = amino) to prepare the title compound.

¹ H-NMR (CDCl ₃ ): δ 8.54 (s, 0.3H), 8.10-7.92 (m, 2H), 7.20-7.1 (m, 2H), 4.32-4.00 (m, 0.7H), 3.78 (s, 3H), 3.60-3.45 (m, 1H), 3.15-3.10 (m, 1H), 2.32-1.35 (m, 9H), 1.07-0.98 (m, 9H)

Example 19. ( R ) -2-cyclopentylmethyl- N -VII ( S ) -1- [2- (4-fluoro-phenyl) -1-methyl-1 H -benzimidazole-5-carbonyl ] -2,2-dimethyl-propyl｝ -3- (formyl-hydroxy-amino) -propionamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-1 according to General Procedure IV. -[2- (4-Fluoro-phenyl) -1-methyl-1 H -benzimidazol-5-yl] -3,3-dimethyl-butan-1-one hydrochloride II-k (in accordance with General Procedure II) Prepared The title compound is prepared from R ₃ = tert -butyl, R ₄ = methyl, R ₅ = 4-fluoro-phenyl).

¹ H-NMR (CDCl ₃ ): δ 8.54 (s, 0.3H), 8.50-8.39 (m, 1H), 8.04 (s, 0.4H), 8.02-7.88 (m, 1H), 7.80-7.77 (m, 2H), 7.48-7.45 (m, 1H), 7.29-7.24 (m, 2H), 6.80 (d, 0.3H), 6.61 (d, 0.5H), 5.71-5.67 (m, 1H), 3.91-3.90 ( m, 4H), 3.70-3.48 (m, 1H), 2.90-2.68 (m, 1H), 1.75-1.31 (m, 12H), 1.04-0.92 (m, 10H)

Example 20. ( R ) -2-cyclopentylmethyl- N -[( S ) -2,2-dimethyl-1- (1-methyl-2-p-tolyl-1 H -benzimidazole-5-car Bonyl) -propyl] -3- (formyl-hydroxy-amino) -propionamide

( R ) -3- (benzyloxy-formyl-amino) -2-cyclopentylmethyl-propanoic acid IV-a (R ₂ = cyclopentylmethyl) and ( S ) -2-amino-3 according to General Procedure IV. , 3-dimethyl-1- (1-methyl-2- p -tolyl-1 H -benzimidazol-5-yl] -butan-1-one hydrochloride II-k (prepared according to General Procedure II. R ₃ = tert -butyl, R ₄ = methyl, R ₅ = 4-methyl-phenyl).

¹ H-NMR (CDCl ₃ ): δ 9.67 (s, 0.2H), 8.63 (s, 0.3H), 8.52 (s, 0.6H), 8.35 (s, 0.3H), 8.00 (d, 1H), 7.87 (s, 0.7H), 7.68 (d, 2H), 7.52-7.35 (m, 3H), 6.87 (s, 0.4H), 6.65 (s, 0.7H), 4.10-3.80 (m, 4H), 3.68- 3.50 (m, 1H), 2.90-2.89 (m, 1H), 2.50 (s, 3H), 2.00-1.22 (m, 12H), 1.06-0.92 (m, 10H)

Formulation Example

The following are representative pharmaceutical preparations comprising a compound of formula (I).

Formulation Example 1 Tablet Formulation

The following ingredients were mixed well to make a tablet.

Formulation Example 2: Capsule Formulation

The following ingredients were mixed well and placed in capsules.

Formulation Example 3 Injectable Formulations

The following ingredients were mixed to form an injectable preparation.

Experimental Example

Experimental Example 1. Enzyme Activity Test

PDF / FDH coupled assay was used to measure the activity of compounds against PDF enzymes of E. coli and S. aureus . In the PDF / FDH coupled assay, after reacting the PDF substrate formyl-Methionine-Alanine-Serine (fMAS) with PDF, the reacted formate is reacted with formate dehydrogenase (FDH) enzyme and NAD +. Is generated. The amount of NADH produced as a byproduct was measured by absorbance at 340 nm to quantify the amount of NADH indirectly to determine the activity of PDF.

Table 1 shows the IC ₅₀ values of representative compounds obtained using the assay, in nM.

  Table 1

Experimental Example 2. Antimicrobial Activity Test

The minimum inhibitory concentration (MIC) was determined using the microdilution method in 96-well plates.

The compound prepared in Example and the standard antibiotics linezolide and vancomycin were dissolved in dimethyl sulfoxide, prepared at a concentration of 2 mg / ml, and stored at 4 ° C. until use. It was diluted with Miller-Hinton Broth (MHB) and used for MIC determination. The range of concentrations tested was 64-0.0625 μg / ml final concentration using a 2-fold dilution system. Inoculated on Mueller-Hinton Agar plate and placed in 37 degree incubator. The minimum growth inhibition concentration was determined to be the lowest antibiotic concentration with visual inhibition of bacterial growth on Agar after 24 hours of inoculation.

MIC is defined as the minimum concentration of a compound of the invention that does not cause visible growth after culture.

Minimum inhibitory concentrations for the compounds of the present invention are shown in Table 2 below.

TABLE 2

Experimental Example 3. Acute Toxicity Test

In order to make the usefulness of the compounds according to the invention more useful as a drug, an acute toxicity test was conducted using mice.

The compounds of the present invention were dissolved in 50% PEG and orally administered for 2 weeks, and the results are shown in Table 3.

Table 3.

The compounds represented by the general formula (I), the racemates, the optical isomers or the diastereomers thereof, or the pharmacologically acceptable salts thereof of the present invention have excellent safety, are effective against pneumococci, and are useful for treating respiratory diseases and resistant to conventional antibiotics. It can be used as a therapeutic agent for resistant bacteria through future development by showing activity on bacteria having.

Claims (7)

A compound of formula (I), its racemates, optical isomers or diastereomers or pharmacologically acceptable salts thereof:

A in formula I is selected from the group of -C (= 0) NHOH or -N (CHO) OH; R ₁ is hydrogen, C _1-3 alkyl, C _4-6 cyclo alkyl, halogen or hydroxy; R ₂ is hydrogen, straight or branched C _1-6 alkyl, straight or branched C _2-6 alkenyl, C _4-6 cycloalkyl, C _4-6 heterocycle comprising N or O atoms Benzyl; R ₃ is hydrogen, straight or branched C _1-6 alkyl, straight or branched C _2-6 alkenyl, C _4-6 cyclo alkyl, phenyl, benzyl; Y is selected from formula IIa or formula IIb;

Wherein R ₄ is hydrogen, straight or branched C _1-6 alkyl, straight or branched C _2-6 alkenyl, C _3-6 cyclo alkyl, phenyl, benzyl; R ₅ is hydrogen, halogen, amino, C _1-6 alkyl substituted amino, aryl substituted amino, furan or formula III;

Wherein R ₆ , R ₇ , R _8, R ₉ and R ₁₀ are each independently hydrogen, linear or branched C _1-3 alkyl, linear or branched halogen substituted C _1-3 alkyl, hydrate Hydroxy, acyl, acyloxy, halogen (fluoro, chloro, bromo, iodo), cyano, nitro, amino, N , N -dimethylamino, phenyl, morpholinyl or formyl. The compound of claim 1, wherein A is —C (═O) NHOH, R ₁ is hydrogen, R ₂ is isobutyl, n-butyl, n-pentyl, benzyl, or cyclopentylmethyl, and R ₃ is tert − Butyl, isopropyl, phenyl or benzyl, R ₄ is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, phenyl, benzyl, R ₅ is hydrogen, methyl, ethyl, propyl, halogen, amino, amino Phenyl, amino-4-fluoro-phenyl, amino- p -tolyl, 2-furan-2-yl or formula III;

Wherein R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are each independently hydrogen, methyl, fluoro, chloro, bromo, trifluoromethyl, methoxy, nitro, cyano or amino, Racemic, optical isomers or diastereomers or pharmacologically acceptable salts thereof. The compound of claim 1, wherein A is —N (CHO) OH, R ₁ is hydrogen, R ₂ is isobutyl, n-butyl, n-pentyl, benzyl, or cyclopentylmethyl, and R ₃ is tert -butyl Isopropyl, phenyl or benzyl, R ₄ is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, phenyl, benzyl, R ₅ is hydrogen, methyl, ethyl, propyl, halogen, amino, aminophenyl , Amino-4-fluoro-phenyl, amino- p -tolyl, 2-furan-2-yl or formula III;

Wherein R ₆ , R ₇ , R ₈ , R ₉ and R ₁₀ are each independently hydrogen, methyl, fluoro, chloro, bromo, trifluoromethyl, methoxy, nitro, cyano or amino, The racemates, optical isomers or diastereomers or pharmacologically acceptable salts thereof. A compound of formula (I), a racemate, an optical isomer or a diastereomer thereof, or a pharmacology thereof, comprising the step of removing a protecting group after reaction with a compound of formula (IV) with hydroxylamine or an N- or O -protected hydroxylamine Method for preparing an acceptable salt.

Wherein A, R ₁ , R ₂ , R ₃ and Y are as defined in claim 1 above. The method of claim 4, wherein the compound of Formula IV is prepared by reacting a compound of Formula V with Formula VIa (or Formula VIb) or a salt thereof.

Wherein R ₁ , R ₂ , R _{3 ,} R ₄ And R ₅ is as defined in claim 1 and R ₁₁ is a hydroxy protecting group such as methyl, ethyl, tert -butyl, benzyl. A process for preparing a compound of formula (I) and a pharmaceutically acceptable salt thereof comprising reacting a compound of formula (VII) with formula (VIa) (or formula (VIb)) or a salt thereof after removing the protecting group:

Wherein R ₁ , R ₂ , R ₃ R ₄ and R ₅ are as defined in claim 1 and R ₁₂ is a hydroxy protecting group such as tert -butyl, benzyl. An antimicrobial composition comprising a therapeutically effective amount of a compound according to claim 1, a racemate, an optical isomer or a diastereomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.