KR101447641B1 - Novel peptide deformylase inhibitor compounds and a method for producing the same - Google Patents

Abstract

The present invention relates to a novel peptide deformylase inhibitor or a pharmaceutically acceptable salt thereof having excellent antimicrobial activity, a process for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.

Description

[0001] The present invention relates to a novel peptide deforma- lase inhibitor compound and a method for producing the same,

Various antibiotics have been developed for the treatment of infectious diseases caused by germs, which cause millions of deaths each year. The main classes include macrolide, quinolone, vancomycin such as beta-lactam, aminoglycoside, tetracycline, sulphonamide and erythromycin, including penicillin, cephalosporin, monobactam and carbapenem Glycopeptide series, oxazolidinone series, etc. ( J. Med . Chem ., 1996 , 39 , 3853-3874, Curr . Opin . Microbiol ., 2004 , 7 , 466-476).

However, super-resistant bacteria, which are increasing at a steep rate, are emerging and show serious resistance to existing antibiotics. Staphylococcus which is resistant to penicillin after the introduction of penicillin in the 1940s aureus Bacteria of the family appeared and spread rapidly. Methicillin, a modification of the structure of penicillin, has been developed and used effectively for penicillin-resistant strains, but new methicillin-resistant strains have emerged.

In recent literature, vancomycin ( Staphylococcus a lineage resistance in a clinical isolate of Staphylococcus , as well as the well-known antibiotics, including aureus resistant to vancomycin - United States, 2002. MMWR , 2002 , 51 (26), 565-567 aureus Lancet , 2001 , 358 (9277), 207-208), the bacteria are known to exhibit rapid resistance. Therefore, development of antibiotics with new mechanism of action is urgent.

Protein synthesis has been an important target in the development of antibiotics. Many well - known antibiotics act to inhibit one or more of these complex protein synthesis processes. Peptide deformylase (PDF, peptide deformylase) is an essential enzyme involved in bacterial protein biosynthesis and polypeptide maturation, and is one of the new targets in the field of recent antibiotic development research. Peptide depharmilase (PDF) catalyzes the hydrolysis of amide bonds as a metal-containing enzyme containing iron ions (Fe ^{2 +} ). Protein synthesis in prokaryotes N - formyl-methionine is disclosed by (fMet, N -formylmethionine), as a result the newly synthesized polypeptide is a capsule milhwa N - has the terminal (Biochimie, 1993, 75, 1061-1075 ). Then the polypeptide depharmilase (PDF) catalyzes the removal of the formyl from the formylated polypeptide, followed by N -terminal progression by methionine aminopeptidase (MAP) to form the mature protein .

The structural features of the PDF inhibitors reported so far have bactericidal effects and actinonine-like skeletons from natural products.

A metal chelate structure is significantly thiol (thiol), hydroxyl samik acid (hydroxamic acid), N - can be classified into three types such as formyl hydroxylamine (N -formyl hydroxylamine).

In terms of the development of antibiotics, the role of these PDFs in bacterial protein synthesis may be an optional and important target.

The prior art associated with the PDF inhibitor 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 -formylhydroxylamine 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 00 / 35440, WO 99/39704, WO 00/35440, WO 00/58294, WO 00/61134, WO 01/10834, WO 01/10835, WO 03/089412, WO 06/115353, WO 08/150089.

Although the prior art described in the above literature has been studied, there is no example of clinical use of a deforamylase inhibitor as an antibiotic. Compounds targeting PDF are expected to prevent cross resistance with currently used antibiotics do.

From the point of view that the rate of emergence of resistant bacteria showing serious resistance to existing antibiotics is rapid, development of antibiotics and antimicrobial agents having new mechanism of action is urgently required. Therefore, the present invention is expected to meet such a demand.

WO 99/59568, WO 00/44373, WO 01/44178, WO 01/44179, WO 02/28829, WO 02/081426, 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 00/35440, WO 99/39704, WO 00/35440, WO 00/58294, WO 00/61134, WO 01/10834, WO 01/10835, WO 03/089412, WO 06/115353, WO 08/150089

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The present invention relates to a peptide depharmilase inhibitor containing a compound having excellent antimicrobial activity, particularly a novel hydroxamic acid or N -formylhydroxylamine.

The present invention also relates to processes for their preparation, to intermediates useful for their preparation and to pharmaceutical compositions containing them.

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

In the above formula (I)

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

R ₂ is selected from the group consisting of hydrogen, straight or branched C _{1 -6} alkyl substituted or unsubstituted with C _{4 -6} cycloalkyl, straight or branched C _{2 -6} alkenyl, C _{4 -6} cycloalkyl, N Or C _{4 -6} heterocycle containing 0 atoms or benzyl;

R ₃ is hydrogen, straight or branched C _{1 -6} alkyl, linear or branched C _{2 -6} alkenyl, C _{4 -6} cycloalkyl, phenyl or benzyl;

k and l are 0 or 1;

A is selected from formulas IIa, IIb and IIc;

In the above formulas IIa, IIb and IIc,

R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently hydrogen, straight or branched C _{1 -3} alkyl, linear or branched C _{1 -3} alkenyl, linear or branched a C _{1 -3-alkynyl,} straight or branched C _{1 -3} alkyl amines, C _{3 -6} cycloalkyl, C _{4 -6} heterocyclyl, C _{1 -3} alkoxy, C _{1 -3} acyl, C _{1 - 3} acyloxy, hydroxyl, amide, halogen, a C _{1 -3} halogen-substituted alkyl, cyano, nitro, or morpholinyl, and;

Q ₁ is carbon or nitrogen;

Q ₂ is carbon or nitrogen or oxygen;

m and n are 0 or 1.

The present invention also relates to compounds of formula I wherein R ₁ is hydrogen and R ₂ is isobutyl, n -butyl, n -pentyl, benzyl or cyclopentylmethyl and R ₃ is tert -butyl, isopropyl, phenyl or benzyl ;

A is, R _4, R _5, R _6, R ₇ or R ₈ is hydrogen, methyl, ethyl, fluoro, chloro, bromo, -C (= O) trifluoromethyl, methoxy, ethynyl OMe , -NH (C = O) Me, cyano, hydroxy, nitro and morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl , 5,6,7,8-tetrahydro-1,6-naphthyridin Lee each optionally substituted, isoindole the one, 6,7-dihydro -5 H - pyrrolo [3,4- b] pyridinyl, piperidinyl , piperazinyl, morpholinyl, pyrrolidinyl, imidazolidinyl optionally substituted, optionally substituted oxazolidine, decahydro-isoquinolin-yl, octahydro -1 H - cyclopenta [c] pyridinyl, octahydro -1 H - iso of turning one or octahydro-cyclopenta [c] pyrrol-yl, and La mikche, enantiomer, or diastereomer, or directed to a pharmaceutically acceptable salt thereof.

The compounds of the present invention may be in the form of racemics, optical isomers or diastereomers by containing absent carbons. Thus, the compounds of the present invention include both racemics, optical isomers and diastereomers.

The compounds of the present invention may also be in the form of pharmaceutically acceptable salts, hydrates or solvates. Examples of pharmaceutically acceptable salts which can be applied to the compounds of the present invention include pharmaceutically acceptable salts such as hydrochloride, bromate, sulfate, nitrate, methanesulfonate, p -toluenesulfonate, phosphate, acetate, pyruvate, citrate, Maleate, malate, stearate, salicylate, sodium salt, potassium salt, magnesium salt and calcium salt, and the like.

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

That is, the step of reacting the compound of the formula (IIa) or (IIb) or (IIc) or the salt thereof with the compound of the formula (III) or the step of reacting the compound of the formula (IV) with the compound of the formula Lt; RTI ID = 0.0 > I < / RTI > and pharmaceutically acceptable salts thereof.

With a compound of formula (IIa) or (IIb) or (IIc) or a salt thereof with a compound of formula (III) in the presence of a conventional reductive amination reaction such as sodium borohydride or sodium triacetoxyborohydride or sodium cyanoborohydride Examples of usable solvents include methanol, ethanol, dichloromethane, 1,2-dichloroethane, 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 and stirring under a hydrogen atmosphere for about 2 to about 24 hours.

Protecting groups such as tetrahydro- 2H -pyranyl can be performed by adding acetic acid or trifluoroacetic acid to the amide product and stirring for about 1 to about 24 hours.

The step of reacting the compound of the formula (IV) with the compound of the formula (VIa), the compound of the formula (VIb) or the compound of the formula (VIc) or a salt thereof can be carried out by a conventional peptide synthesis method such as penta-fluorophenol, N , O -dimethylhydroxylamine, DMAP-EDCI or EDCI-HOBt-NMM. Examples of usable solvents include 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 under a hydrogen atmosphere for about 2 to about 24 hours.

Protecting groups such as tetrahydro- 2H -pyranyl can be performed by adding acetic acid or trifluoroacetic acid to the amide product and stirring for about 1 to about 24 hours.

In the above formula _{R 1, R 2, R 3} , R 4, R 5, R 6, R 7, R 8, Q 1, Q 2 and k, l, m, n are as defined above, R ₉ is Is a hydroxy protecting group such as methyl, ethyl, tert -butyl, benzyl or tetrahydro- 2H -pyranyl.

Compounds of formula (IIa) or (IIb) or (IIc) and compounds of formula (IV) may be prepared according to methods known in the art of organic chemistry.

The compound of Formula Ⅲ is tetrahydrofuran, the compound and the compounds of formula Ⅵ of Formula Ⅳ, dichloromethane, N, N-a solvent such as dimethylformamide penta-dimethyl-hydroxy-fluoro-phenol, N, O in And then removing the amino protecting group after reacting with an amide coupling reagent such as hydroxylamine, DMAP-EDCI or EDCI-HOBt-NMM.

The compound of the above formula (Va) or (Vb) or (Vc) can be obtained by reacting the compound of the above formula (IIa) or (IIb) or (IIc) or a salt thereof with a compound of the formula (VI) Followed by removal of the amino protecting group after reaction with a reductive amination reagent such as borohydride or sodium triacetoxyborohydride or sodium cyanoborohydride.

Or a compound of the formula (VII) with a compound of the formula (VIIIa) or (VIIIb) or (VIIIc) or a salt thereof in the presence of a solvent such as tetrahydrofuran, dichloromethane or N , N -dimethylformamide, pentafluorophenol, N , O- Amine, DMAP-EDCI or EDCI-HOBt-NMM, and then removing the amino protecting group.

In the formula _{R 3, R 4, R 5} , R 6, R 7, R 8, Q 1, Q 2 and k, l, m, n are as defined above, R ₁₀ is hydrogen, tert - butoxy Carbonyl, benzyloxycarbonyl or triphenylmethyl.

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

The compound of Formula Ⅵ is tetrahydrofuran, the compound and the compounds of formula Ⅸ of Formula Ⅶ, dichloromethane, N, N-a solvent such as dimethylformamide penta-dimethyl-hydroxy-fluoro-phenol, N, O in And then removing the amino protecting group after reacting with an amide coupling reagent such as hydroxylamine, DMAP-EDCI or EDCI-HOBt-NMM.

The compound of formula (VIIIa) or (VIIIb) or (VIIIc) can be prepared by reacting a compound of formula (IIa) or (IIb) or (IIc) or a salt thereof with a compound of formula (IX) in a solvent such as methanol, ethanol, dichloromethane, 1,2- Followed by removal of the amino protecting group after reaction with a reductive amination reagent such as borohydride or sodium triacetoxyborohydride or sodium cyanoborohydride.

Or a compound of the formula (VIIIa) can be prepared by reacting the compound of the formula (X) with the compound of the formula (XI) in a solvent such as acetonitrile, N , N -dimethylformamide or the like using triethylamine, N , N -diisopropylethylamine, potassium carbonate or the like And then removing the amino protecting group after the reaction with the reaction reagent.

Wherein R ₄ , R ₅ , R ₆ , R ₇ , Q ₁ and k, l, m are as defined above and R ₁₁ is hydrogen, tert -butoxycarbonyl, benzyloxycarbonyl or triphenylmethyl And Y is halogen, methanesulfonyl or p -toluenesulfonyl.

The compounds of formula IX and the compounds of formula X may be prepared according to methods known in the art of organic chemistry.

The compound of formula (XI) can also be easily prepared according to methods known in the art of organic chemistry or methods described in the following examples.

In a preferred embodiment, the compound of formula (I)

(R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- ( isoindoline-2-yl) -piperidin -1 -Yl) -3,3-dimethyl-1-oxobutan-2-yl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (3,4- dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3, Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (pyrrolidin- 1 -yl) piperidin- 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1- (4-morpholinopiperidin- (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (6,7- dimethoxy-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine- 1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (7,8- dihydro-1,6-naphthyridine -6 (5 H) - yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;

(R) - N - (( S) -1- (4- (3,4- dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3,3-dimethyl -1 - oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;

(2 R) -3- cyclopentyl - N - ((2 S) -3,3- dimethyl-1- (4- (octahydro-isoquinolin -2 (1 H) - yl) piperidin-1-yl ) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- ( 6-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- (6- methoxy-3,4-dihydro-isoquinoline -2 (1 H ) -yl) piperidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) propanamide;

(R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- (7- methoxy-3,4-dihydro-isoquinoline -2 (1 H ) -yl) piperidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) propanamide;

(R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1 - ((R) -3- ( isoindoline-2-yl) blood L-yl) -3,3-dimethyl-l-oxobutan-2-yl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1- (4- (5- Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (5- fluoro Roy stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1 Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) - N - (( S) -1- (4- (5- chloroisatin stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane-2-one ) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (5- ethyl sweep turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1 Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1 - ((R) -3- (3,4- dihydro-isoquinoline -2 (1 H) - yl) pyrrolidin-1-yl ) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1- (4- (4-methylisisoindolin-2-yl) piperidin- Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (4,5,6,7-tetrafluoroisisoindolin- Piperidin-1-yl) butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (4- fluoro Roy stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1 Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (5,8- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (6,8- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (5,6,8- trifluoro-3,4-dihydroisoquinoline -2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) propanamide;

(R) - N - (( S) -1- (4- (8- chloro-6-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl ) -3,3-dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- ( 5-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (-3,4- dihydro-isoquinoline -2 (1 H) ethynyl-7-yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (6,7- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) - N - (( S) -1- (4- (4- chloroisatin stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane-2-one ) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (-3,4- dihydro-isoquinoline -2 (1 H) 7-Fluoro-yl) piperidin-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (4,7- difluoro-Roy stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) - N - (( S) -1- (4- (7- cyano-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3, Dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (5,7,8-trifluoro- -2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (4- (6,8- dichloro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1 -Yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (8- (trifluoromethyl) -3, 4-dihydroisoquinoline- 2 (1 H ) -yl) piperidin-1-yl) butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (6- (trifluoromethyl) -3,4-dihydroisoquinoline- 2 (1 H ) -yl) piperidin-1-yl) butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1 - ((R) -3- (6,7- dimethyl-3,4-dihydro-isoquinoline -2 (1 H) - yl) blood L -yl) -3,3-dimethyl-l-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) - N - (( S) -1- (3- (3,4- dihydro-isoquinoline -2 (1 H) - yl) azetidin-1-yl) -3,3-dimethyl-1 Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;

( S ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- Butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -1- (3- (4,7- difluoro-Roy stamp turned-2-yl) azetidin-1-yl) -3,3-dimethyl- 1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) - N - (( S) -1- (3- (5,6- difluoro-2-yl) azetidine turned stamp Roy-yl) -3,3-dimethyl-1-oxo-butane- 2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;

(R) -3- cyclopentyl - N - ((S) -1- (3- (7,8- dihydro-1,6-naphthyridine -6 (5 H) - yl) azetidin-1-yl ) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1-oxo-1 - (( R ) -3- (5,6,8-trifluoro- Dihydroisoquinolin-2 ( 1H ) -yl) pyrrolidin-1-yl) butan-2-yl) -2 - (( N -hydoxyformoamido) methyl) propanamide;

(R) - N - (( S) -1- (4- (6- cyano-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3, Dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;

( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (piperazin- 1 -yl) piperidin- - yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -3,3- dimethyl-1- (4- (6-morpholino-3,4-dihydro-isoquinoline -2 (1 H) - one ) Piperidin-1-yl) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) - N - (( S) -1- (4- (6- Acetamido-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) 3, Dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;

(R) -3- cyclopentyl - N - ((S) -3,3- dimethyl-1- (4- (6-nitro-3,4-dihydro-isoquinoline -2 (1 H) - yl) blood Yl) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;

(R) - N - (( S) -3,3- dimethyl-1-oxo-1- (4- (5,6,8- trifluoro-3,4-dihydro-isoquinoline -2 (1 H ) -Yl) piperidin-1-yl) butan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;

(R) - N - (( S) -1- (4- (6,8- dichloro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3 , 3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;

(R) - N - (( S) -1- (4- (6,7- dimethoxy-3,4-dihydro-isoquinoline -2 (1 H) - blood-yl) piperidine-1-yl) - 3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;

(R) - N - (( S) -1- (4- (6,7- dimethyl-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3 , 3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;

(2 R) -3- cyclopentyl - N - ((2 S) -1- (4- -hexahydro -1 H - cyclopenta [c] pyridine -2 (3 H) - yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide; And

(2 R) -3- cyclopentyl - N - ((2 S) -1- (4- ( hexahydro-cyclopenta [c] pyrrolo -2 (1 H) - yl) piperidin-1-yl) -3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide, racemate, optical isomer or diastereomer Isomer or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may be administered alone (or in combination with one or more other compounds of the invention or one or more other drugs) (or any combination thereof). In general, they will be administered as a pharmaceutical composition or formulation with one or more pharmaceutically acceptable carriers or excipients. The term "carrier" or "excipient" is used herein to describe any ingredient other than the compound (s) of the present invention. The choice of carrier or excipient will depend to a large extent on factors such as the manner of administration, the effect of the excipient on solubility and stability, and the type of formulation.

Suitable pharmaceutical compositions of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences ', 19th Edition (Mack Publishing Company, 1995 ).

Oral administration

The compounds of the present invention can be administered orally. Oral administration may involve swallowing, whereby the compound enters the gastrointestinal tract, or oral or sublingual administration may be used whereby the compound enters the blood stream directly from the oral cavity.

Formulations suitable for oral administration include, for example, tablets, microparticles, capsules containing liquid or powder, suspensions (including liquid-filled), chews, multi- and nano-microparticles, gels, solid solutions , Liposomes, films (including mucosal adhesives), ovules, solid formulations such as sprays, and liquid formulations. Liquid form preparations include, for example, suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and / . Liquid formulations may also be prepared, for example, by reconstitution of the solids from the sachet. Compounds of the present invention may also be prepared by the methods described in Expert Opinion in Therapeutic Patents , 11 (6), 981-986 by Liang and Chen ( 2001 ), all of which are incorporated herein by reference.

In the case of tablet formulations, depending on the dose, the drug may contain up to about 1 wt. % To about 80 wt. %, More typically about 5 wt.% Of the dosage form. % To about 60 wt. %. In addition to drugs, tablets generally contain a disintegrant. Examples of disintegrants are sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, Starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will contain about 1 wt. % To about 25 wt. %, Preferably about 5 wt. % To about 20 wt. %. Binders are generally used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate can do.

Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant is present in an amount of from about 0.2 wt. % To about 5 wt. % Of the tablet, and the lubricant can comprise about 0.2 wt.% Of the tablet. % To about 1 wt. % Can be configured.

The tablets also generally contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant generally contains about 0.25 wt.% Of the tablet. % To about 10 wt. %, Preferably about 0.5 wt. % To about 3 wt. %. Other possible ingredients include antioxidants, colorants, flavors, preservatives and taste-masking agents.

Typical tablets contain up to about 80% drug, about 10 wt. % To about 90 wt. % Binder, about 0 wt. % To about 85 wt. % Diluent, about 2 wt. % To about 10 wt. % Disintegrant, and about 0.25 wt. % To about 10 wt. % Of lubricant. The tablet mixture can be tableted directly or by tableting with a roller. Alternatively, the tablet mixture or a portion of the mixture may be wet-, dry- or melt-granulated, melt-congealed, or extruded prior to tableting. The final formulation may include one or more layers, may be coated or non-coated, and may even be encapsulated.

Formulations of the tablets are discussed in the following references: " Pharmaceutical Dosage Forms : Tablets , Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated to be immediate and / or controlled release. Controlled release formulations include delay-, sustained-, pulsed-, control-, targeting and programmed release.

Suitable modified release formulations for the purposes of the present invention are described in U.S. Pat. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in the following references: Verma et al., Pharmaceutical Technology On - line . 25 (2), 1-14 ( 2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Parenteral  administration

The compounds of the present invention may also be administered directly into the blood stream, muscle, or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intraspinal, intrathecal, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needles (including deep-draw) syringes, needle-less syringes, and infusion techniques.

Parenteral formulations are typically aqueous solutions, which may contain, for example, excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from about 3 to about 9), but in some applications they are more suitably May be formulated as a sterile non-aqueous solution or as a dry form for use with suitable vehicles such as sterile pyrogen-free water.

For example, the preparation of parenteral formulations under sterile conditions by lyophilization can be readily accomplished using standard pharmaceutical techniques known to those skilled in the art.

The solubility of the compounds of formula I used in the preparation of the parenteral solutions may be increased by employing suitable formulation techniques such as incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and / or controlled release. The controlled release formulations include delay-, sustained-, pulse-, control-, targeting and programmed release. Thus, the compounds of the invention may be formulated as solid, semi-solid, or thixotropic liquids for administration as an implanted depot providing controlled release of the active compound. Examples of such formulations include drug-coated stents and PLGA microspheres.

Topical administration

The compounds of the present invention may also be administered topically to the skin or mucosa, i. E., Dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dispersants, dressings, foams, films, skin patches, foils, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated - see, for example, J. Pharm . Sci . , 88 (10), 955-958 by Finnin and Morgan (October 1999 ).

Other means of topical administration include delivery by electroporation, electrophoresis, sonophoresis, sonography and injection by ultrafiltration or immersion (e.g., Powderject ^™ , Bioject ^™ , etc.).

Formulations for topical administration may be formulated to be immediate and / or controlled release. The controlled release formulations include delay-, sustained-, pulse-, control-, targeting and programmed release.

inhale/ Intranasal  administration

The compounds of the present invention may also be administered intranasally or by inhalation and are typically administered in the form of a dry powder (either alone, as a mixture, for example, as a dry mixture with lactose, Such as phosphatidylcholine) or a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane May be administered as a pressurized container, pump, spray, sprayer (preferably a sprayer using electrohydrodynamics to produce fine mist), or aerosol spray from a sprayer, with or without use. For intranasal use, the powder may comprise a biocide, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer or nebulizer may be, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersion, solubilization or extending release of the active ingredient, propellant (s) Or a solution or suspension of the compound (s) of the present invention, including any surfactant such as oleic acid, oleic acid, or oleic lactic acid. Prior to use in dry powder or suspension formulations, the drug product is micronised to a size suitable for inhalation delivery (typically less than 5 microns). Such micronization can be achieved by any suitable milling method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (e.g., gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated with a compound of the present invention, a suitable powder base such as lactose or starch, and a suitable powder base such as L-leucine, mannitol or magnesium stearate, May be formulated to contain a powder mix of the same performance modifier. The lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A solution formulation suitable for use in an atomizer utilizing electrohydrodynamics to produce fine mist can contain from about 1 μg to about 20 mg of the compound of the present invention per actuation and a working volume of from about 1 μL to about Lt; RTI ID = 0.0 > uL. ≪ / RTI > Typical formulations may include a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavors such as menthol and levomenthol, or sweeteners such as saccharin or saccharin sodium may be added to such formulations of the invention intended for inhaled / intranasal administration. Formulations for inhaled / intranasal administration can be formulated to be immediate and / or controlled release using, for example, poly (DL-lactic-coglycolic acid (PGLA) -, control-, targeting and program emission.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. The unit according to the invention is typically arranged to administer a "puff " containing a metered dose or about 1 to about 100 mg of a compound of formula (I). The total daily dose will typically be within a single dose, or, more generally, from about 50 mg to about 20 mg, which may be administered in divided doses over that day.

rectal/ Vagina  administration

The compounds of the present invention may be administered to the rectum or vagina, for example, in the form of suppositories, pessaries or enema. Although cocoa butter is a traditional suppository base, various substitutes can be used as needed, as appropriate.

Formulations for rectal / vaginal administration may be formulated to be immediate and / or controlled release. The controlled release formulations include delay-, sustained-, pulse-, control-, targeting and programmed release.

Eye / ear administration

The compounds of the present invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for eye and ear administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicon) implants, wafers, lenses and particulates or vesicular systems, For example, niosomes or liposomes. A polymer such as a crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer such as hydroxypropyl methylcellulose, hydroxyethyl cellulose or methyl cellulose, or a heteropolysaccharide polymer such as gellan gum For example, a preservative such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for eye / ear administration may be formulated to be immediate and / or controlled release. The controlled release formulations include delay-, sustained-, pulse-, control-, targeting and programmed release.

Other Technologies

The compounds of the present invention may also be formulated as cyclodextrins and suitable derivatives or polyethylene glycol-containing polymers thereof, for their use in any of the abovementioned modes of administration, to improve their solubility, dissolution rate, taste concealment, bioavailability and / It can be combined with macromolecular entities.

For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizer. The most commonly used for this purpose are alpha-, beta- and gamma-cyclodextrins, examples of which are found in WO 91/11172, WO 94/02518 and WO 98/55148.

part Kit

For example, as long as it may be desirable to administer a combination of active compounds for the treatment of a particular disease or condition, two or more pharmaceutical compositions (at least one containing a compound according to the invention) Are within the scope of the invention which can be conveniently combined in kit form suitable for administration.

Thus, the kit of the present invention comprises at least one separate pharmaceutical composition comprising at least one compound of formula I according to the present invention, and a pharmaceutical composition comprising the composition as described above, Means. An example of such a kit is a common blister pack used for packaging tablets, capsules, and the like.

The kits of the invention are particularly suitable for the administration of different dosage forms, for example oral and parenteral administration, in order to administer the individual compositions at different dosage intervals, or to titrate the individual compositions against each other. To aid in compliance, the kit typically includes an instruction for administration and may be provided with so-called memory aiding means.

The compound represented by the formula (I) of the present invention, a racemic or diastereomer thereof or a pharmaceutically acceptable salt thereof is excellent in safety and can be used as a conventional antibiotic such as methicillin resistant Staphylococcus aureus, vancomycin resistant enterococci and penicillin resistant pneumococci And thus it is useful as a therapeutic agent for resistant bacteria through future development.

The invention will now be described with reference to the following examples which are intended to be illustrative only and should not be construed as limiting the scope of the invention.

General Procedure Ⅰ: (R) -3- cyclopentyl - N - ((S) -1- (4- (5,8- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - one (Reaction Scheme 1) Synthesis of 3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido)

Step 1: tert - butyl 4- (5,8-difluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine-1-carboxylate (1-b)

To a solution of compound 1-a (R ₄ = R ₇ = fluoro, R ₅ = R ₆ = hydrogen, Q ₁ = carbon, m = 1, 7.60 g, 44.92 mmol) in 1,2-dichloroethane (250 mL) Compound 1-h (R ₁₁ = tert -butoxycarbonyl, k = 1 = 9.49 g, 47.17 mmol, 1.05 eq.) Was added and cooled to 0 ° C. Acetic acid (2.60 mL, 44.29 mmol) and sodium triacetoxyborohydride (20.00 g, 89.85 mmol, 2.00 eq.) Were added and stirred at room temperature for 18 hours. The reaction mixture was concentrated, diluted with dichloromethane, and washed with aqueous sodium hydroxide solution and distilled water. Dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (15.83 g, 99%) as a pale yellow solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 6.80 (m, 2H), 4.19 (brs, 2H), 3.75 (s, 2H), 2.85-2.61 (m, 7H), 1.87 (d, 2H, J = 12.4 Hz ), 1.60-1.51 (m, 2H), 1.50-1.42 (m, 9H).

Step 2: 5,8-Difluoro-2- (piperidin-4-yl) -1,2,3,4-tetrahydroisoquinoline ( 1-

To a solution of compound 1-b (15.83 g, 44.91 mmol) in ethyl acetate (82 mL) was added a 6 N aqueous hydrochloric acid solution (82 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered, and concentrated to give the title compound (11.00 g, 95%) as a pale yellow liquid, which was used in the next step without further purification.

_{^{1 H-NMR (CDCl 3)}} : δ 6.80 (m, 2H), 3.77 (s, 2H), 3.19 (dd, 2H, J = 2.4 Hz, 10.0 Hz), 2.82 (s, 4H), 2.68-2.57 ( m, 3H), 1.90 (d, 2H, J = 13.2Hz), 1.59-1.47 (m, 3H).

Step 3: ( S ) -tert -butyl (1- (4- (5,8-difluoro-3,4-dihydroisoquinolin-2 ( 1H ) -yl) piperidin- Dimethyl-1-oxobutan-2-yl) carbamate ( 1-d )

Dichloromethane (220 mL) = solution of compound 1-c (11.00 g, 43.60 mmol) to a compound 1-i solution (R ₃ tert - butyl, R ₁₀ = tert - butoxycarbonyl, 10.70 g, 45.77 mmol, 1.05 eq (10.80 g, 87.20 mmol, 2.00 eq.) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (9.30 g, 47.96 mmol, 1.10 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate and distilled water. Dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (13.70 g, 68%) as a pale yellow solid compound.

¹ H-NMR (CDCl ₃ ): δ 6.81 (m, 2H), 5.35 (d, 1H, J = 9.2 Hz), 4.76-4.62 2H), 3.75 (d, 2H, J = 4.8 Hz), 3.21-3.05 (m, 1H), 2.88-2.59 (m, 6H), 2.05-1.90 1.44 (d, 9H, J = 5.6 Hz), 0.98 (d, 9H, J = 11.2 Hz).

Step 4: ( S ) -2-Amino-1- (4- (5,8-difluoro-3,4-dihydroisoquinolin-2 ( 1H ) -yl) piperidin- -3-dimethylbutan- 1- one ( 1-e )

To a solution of compound 1-d (13.70 g, 29.42 mmol) in ethyl acetate (100 mL) was added 6 N aqueous hydrochloric acid (100 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered and concentrated to give the title compound (10.75 g, 99%) as a pale yellow liquid, which was used in the next step without further purification.

_{^{1 H-NMR (CDCl 3)}} : δ 6.80 (m, 2H), 4.78 (m, 1H), 4.14 (m, 1H), 3.75 (s, 2H), 3.57 (d, 1H, J = 10.0 Hz), (M, 2H), 1.67-1.42 (m, 4H), 0.98 (d, 9H, J = 13.6 Hz), 3.17-3.01 (m, 1H), 2.88-2.58 (m, 6H).

Step 5: (R) -3- (N - ( benzyloxy) formamido) -2- (cyclopentylmethyl) - N - ((S) -1- (4- (5,8-difluoro-a - 3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane-2-yl) propanamide (1-f)

To a solution of compound 1-e (10.75 g, 29.42 mmol) in dichloromethane (150 mL) was added compound 1-j (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₉ = benzyl, 9.43 g, 30.88 mmol, 1.05 eq (7.26 g, 58.83 mmol, 2.00 eq.) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.30 g, 32.35 mmol, 1.10 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate and distilled water. The extract was dried with magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (15.70 g, 82%) as a pale yellow solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 8.13 (brs, 0.5H), 7.88 (brs, 0.5H), 7.48-7.32 (m, 5H), 6.80 (m, 2H), 6.33 (dd, 2H, J = (M, 1H), 2.82-2.58 (m, 7H), 3.80-3.52 (m, ), 2.03-1.88 (m, 2H), 1.66-1.42 (m, 11H), 0.97-0.90 (m, 11H).

Step 6: (R) -3- cyclopentyl - N - ((S) to 1- (4- (5,8-difluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide ( 1-g )

To a solution of compound 1-f (10.88 g, 16.67 mmol) in ethanol (213 mL) was added 10 wt. % Pd / C (1.40 g) was added and stirred for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered, concentrated, and then purified by silica gel chromatography to obtain the title compound (7.80 g, 83%) as an off-white solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 8.22 (s, 0.5H), 7.82 (s, 0.5H), 6.90 (m, 2H), 6.72-6.52 (m, 1H), 5.05-4.94 (m, 1H) 2H), 3.60-3.46 (m, 1H), 3.22-3.12 (m, 1H), 2.92-2.59 (m, m, 7H), 2.08-1.94 (m, 2H), 1.81-1.37 (m, 11H), 1.07-0.89 (m, 11H).

General Procedure II: Preparation of ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (pyrrolidin- 1 -yl) piperidin- Yl) -2 - (( N -hydroxyformamido) methyl) propanamide (Reaction Scheme 2)

Step 1: tert -Butyl 4- (pyrrolidin-1-yl) piperidine-1-carboxylate ( 2-b )

1, 2-dichloroethane (5 mL) solution of compound 2-a (R ₈ = hydrogen, Q = ₂ carbon, m = 0, 0.09 mL, 1.00 mmol) 1-h to the solution of compound (R ₁₁ = tert - butoxy Carbonyl, k = 1, 0.20 g, 1.00 mmol) was added and the mixture was cooled to 0 < 0 > C. Acetic acid (3 drops) and sodium triacetoxyborohydride (0.42 g, 2.00 mmol, 2.00 eq.) Were added and stirred at room temperature for 18 hours. The reaction mixture was concentrated, diluted with dichloromethane, and washed with aqueous sodium hydroxide solution and distilled water. Dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (0.25 g, 100%) as a pale yellow solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 4.11 (brs, 2H), 2.77 (m, 2H), 2.60 (m, 4H), 2.15 (m, 1H), 1.87 (d, 2H, J = 13.2 Hz), 1.80 (m, 4H), 1.51 - 1.38 (m, 2H), 1.45 (s, 9H).

Step 2: 4- (Pyrrolidin-1-yl) piperidine ( 2-c )

To a solution of 2-b (0.25 g, 1.00 mmol) in ethyl acetate (2 mL) was added a 6 N aqueous hydrochloric acid solution (1.7 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered and concentrated to give the title compound (0.14 g, 88%) as a pale yellow liquid, which was used in the next step without further purification.

_{^{1 H-NMR (CDCl 3)}} : δ 4.01 (m, 2H), 2.76 (m, 2H), 2.60 (m, 4H), 2.14 (m, 1H), 1.86 (m, 2H), 1.78 (m, 4H ), 1.45 (m, 2H).

Step 3: ( S ) -tert -Butyl (3,3-dimethyl-1-oxo-1- (4-pyrrolidin- 1 -yl) piperidin- 1 -yl) butan- ( 2-d )

To a solution of compound 2-c (0.14 g, 0.88 mmol) in dichloromethane (4.4 mL) was added compound 1-i (R ₃ = tert -butyl, R ₁₀ = tert -butoxycarbonyl, 0.22 g, 0.97 mmol, 1.10 eq (0.27 g, 2.20 mmol, 2.50 eq.) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.25 g, 1.32 mmol, 1.50 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate and distilled water. The extract was dried with magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (0.11 g, 31%) as a pale yellow solid compound.

¹ H-NMR (CDCl ₃ ):? 5.33 (m, 1H), 4.52 (m, 2H), 4.14 ), 2.24 (m, 1H), 1.96 (m, 2H), 1.81 (m, 4H), 1.51 (m, 2H), 1.42 (s, 9H), 0.97 (d, 9H, J = 7.2 Hz).

Step 4: (S) -2- amino-3,3-dimethyl-1- (4- (pyrrolidin-1-yl) piperidin-1-yl) butane-1-one (2-e)

Ethyl acetate (1 mL) was stirred solution of compound 2-d (0.11 g, 0.29 mmol) followed by the addition of 6 N hydrochloric acid solution (0.48 mL) was added at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered and concentrated to give the title compound (0.06 g, 78%) as a pale yellow liquid, which was used in the next step without further purification.

¹ H-NMR (CDCl ₃ ):? 4.60 (m, 1 H), 4.01 (d, 1 H, J = 14.4 Hz), 3.10 2H), 2.07-1.90 (m, 2H), 1.79 (m, 4H), 1.57-1.35 (m, 2H), 0.97 (d, 9H, J = 5.2 Hz).

Step 5: ( R ) -3- ( N - (Benzyloxy) formamido) -2- (cyclopentylmethyl) - N - (( S ) -3,3- Yl) butan- 2- yl) propanamide ( 2-f )

In dichloromethane (1 mL) solution of compound 2-e (0.06 g, 0.22mmol ) R ( the compound 1-j solution ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₉ = benzyl, 0.07 g, 0.24 mmol, 1.10 eq ), 4-dimethylaminopyridine (0.07 g, 0.55 mmol, 2.50 eq.) And 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (0.11 g, 0.55 mmol, 2.50 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate and distilled water. Dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (0.08 g, 60%) as a pale yellow solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 8.13 (brs, 0.5H), 7.87 (brs, 0.5H), 7.38 (m, 5H), 6.33 (m, 1H), 4.99 (m, 1H), 4.86 (m (M, 1H), 4.80 (m, 1H), 4.11 (m, 1H), 3.69 1H), 2.02-1.40 (m, 19H), 1.02 (m, 2H), 0.94 (d, 9H, J = 8.0 Hz).

Step 6: ( R ) -3-Cyclopentyl- N - (( S ) -3,3-dimethyl-1-oxo-1- (4- (pyrrolidin- 1 -yl) piperidin- ) But-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide ( 2-g )

To a solution of 2-f (0.08 g, 0.14 mmol) in ethanol (2 mL) was added 10 wt. % Pd / C (0.01 g) was added, and the mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered, concentrated, and then purified by silica gel chromatography to obtain the title compound (0.06 g, 94%) as a pale orange solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 8.39 (d, 0.4H, J = 6.0 Hz), 7.83 (d, 0.6H, J = 5.6 Hz), 6.66 (m, 0.4H), 6.55 (m, 0.6H ), 4.88 (m, 1H), 4.60 (m, 0.5H), 4.44 (m, 0.5H), 4.21-4.00 ), 3.28-3.07 (m, 2H), 2.82 (m, 2H), 2.77-2.60 (m, 4H) ), 1.06 (m, 2H), 0.97 (dd, 9H, J = 5.6 Hz, 19.2 Hz).

General Procedure Ⅲ: (2 R) -3- cyclopentyl - N - ((2 S) -3,3- dimethyl-1- (4- (octahydro-isoquinolin -2 (1 H) - yl) piperidine Yl) -2 - (( N -hydroxyformamido) methyl) propanamide (Reaction Scheme 3)

Step 1: tert -Butyl 4- (octahydroisoquinolin-2 (1 H ) -yl) piperidine-1-carboxylate ( 3-b )

1, 2-dichloroethane (20 mL) of compound 3-a (m = n = 1, 0.58 g, 4.07 mmol) to the compound 1-h (R ₁₁ = tert solution-butoxycarbonyl, k = l = 1 , 0.81 g, 4.07 mmol) was added and the mixture was cooled to 0 < 0 > C. After adding acetic acid (0.23 mL, 4.07 mmol) and sodium triacetoxyborohydride (1.81 g, 8.13 mmol, 2.00 eq.), The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, diluted with dichloromethane, and washed with aqueous sodium hydroxide solution and distilled water. Dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (1.05 g, 81%) as a pale yellow solid compound.

¹ H-NMR (CDCl ₃ ):? 4.26 (brs, 2H), 3.37 (brs, 1H), 3.15 m, 8H), 1.52-1.41 (m, 9H), 1.40-0.98 (m, 4H), 0.98-0.85 (m, 1H).

Step 2: 2- (Piperidin-4-yl) decahydroisoquinoline ( 3-c )

To a solution of compound 3-b (1.05 g, 3.26 mmol) in ethyl acetate (16 mL) was added a 6 N aqueous hydrochloric acid solution (16 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered, and concentrated to give the title compound (0.80 g, 95%) as a pale yellow liquid, which was used in the next step without further purification.

_{^{1 H-NMR (CDCl 3)}} : δ 4.23 (brs, 2H), 3.36 (brs, 1H), 3.15 (brs, 1H), 2.71 (brs, 4H), 2.26 (brs, 4H), 1.82-1.51 (m , 8H), 1.40-1.01 (m, 4H), 0.98-0.89 (m, 1H).

Step 3: tert - butyl ((2 S) -3,3- dimethyl-1- (4- (octahydro-isoquinolin -2 (1 H) - yl) piperidin-1-yl) -1-oxo-butane Yl) carbamate ( 3-d ) < RTI ID = 0.0 >

To a solution of compound 3-c (0.80 g, 3.09 mmol) in dichloromethane (19 mL) was added compound 1-i (R ₃ = tert -butyl, R ₁₀ = tert -butoxycarbonyl, 0.76 g, 3.24 mmol, 1.05 eq (0.76 g, 3.24 mmol, 1.05 eq.) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.66 g, 3.40 mmol, 1.10 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate and distilled water. Dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (0.60 g, 45%) as a pale yellow solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 4.72-4.50 (m, 1H), 4.23-4.08 (m, 1H), 3.16-2.92 (m, 1H), 2.88-2.62 (m, 1H), 2.61-2.46 ( m, 1 H), 2.02-1.10 (m, 23H), 1.07-0.78 (m, 16H).

Step 4: (2 S) -2- amino-3,3-dimethyl-1- (4- (octahydro-isoquinolin -2 (1 H) - yl) piperidin-1-yl) butane-1-one ( 3-e )

To a solution of 3-d (0.60 g, 1.38 mmol) in ethyl acetate (6.5 mL) was added a 6 N aqueous hydrochloric acid solution (6.5 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered, and concentrated to give the title compound (0.43 g, 85%) as a pale yellow liquid, which was used in the next step without further purification.

_{^{1 H-NMR (CDCl 3)}} : δ 4.72-4.50 (m, 1H), 4.23-4.08 (m, 1H), 3.16-2.92 (m, 1H), 2.88-2.62 (m, 1H), 2.61-2.46 ( m, 1 H), 2.02-1.10 (m, 14H), 1.07-0.78 (m, 16H).

Step 5: (2 R) -3- ( N - ( benzyloxy) formamido) -2- (cyclopentylmethyl) - N - ((2 S ) -3,3- dimethyl-1- (4- ( octahydro-isoquinolin -2 (1 H) - yl) piperidin-1-yl) butane-1-oxo-2-yl) propanamide (3-f)

Dichloromethane (150 mL) of the compound 3-e (0.43 g, 1.17 mmol) to the compound _1-j (R 1 solution = H, R ₂ = cyclopentylmethyl, R ₉ = benzyl, 0.39 g, 1.28 mmol, 1.10 eq (0.29 g, 2.33 mmol, 2.00 eq.) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.25 g, 1.28 mmol, 1.10 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate and distilled water. Dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (0.11 g, 15%) as a pale yellow solid compound.

¹ H-NMR (CDCl ₃ ):? 8.12 (s, 0.5H), 7.88 (s, 0.5H), 7.48-7.32 (m, 5H), 6.41-6.27 2H), 4.79 (s, 1H), 4.72-4.55 (dd, 1H, J = 12.4 Hz, 28.4 Hz), 4.25-4.01 (m, 2H), 3.81-3.52 1H), 2.85-2.74 (m, 1H), 2.67-2.37 (m, 4H), 1.95-1.13 (m, 27H), 1.08-0.80 (m, 9H).

Step 6: (2 R) -3- cyclopentyl-N - ((2 S) -3,3- dimethyl-1- (4- (octahydro-isoquinolin -2 (1 H) - yl) piperidine- Yl) -2 - (( N -hydroxyformamido) methyl) propanamide ( 3-g )

To a solution of 3-f (0.11 g, 0.18 mmol) in ethanol (2 mL) was added 10 wt. % Pd / C (0.005 g) was added and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, concentrated, and then purified by silica gel chromatography to obtain the title compound (0.06 g, 65%) as an off-white solid compound.

¹ H-NMR (CDCl ₃ ):? 8.40 (s, 0.4H), 7.83 (s, 0.6H), 6.68-6.45 2H), 3.81-3.52 (m, 2H), 3.09-2.92 (m, 1H), 2.85-2.74 1.13 (m, 26H), 1.09-0.79 (m, 10H).

General Procedure Ⅳ: (R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- (6- methoxy-3,4 Synthesis of dihydroisoquinolin-2 ( 1H ) -yl) piperidin-1-yl) -3,3-dimethyl-1-oxobutan-

Step 1: Piperidin-4-one ( 4-a )

Ethyl acetate (200 mL) solution of compound _{1-h (R 11 = tert} - butoxycarbonyl, k = l = 1, 8.00 g, 40.15 mmol) solution in 6 N hydrochloric acid aqueous solution at room temperature followed by the addition (100 mL) Stir for 20 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. Washed with distilled water, dried over magnesium sulfate, filtered and concentrated to give the title compound (9.20 g, 97%) as a pale yellow liquid, which was used in the next step without further purification.

¹ H-NMR (CDCl ₃ ):? 3.72 (t, 4H, J = 6.1 Hz), 2.45 (t, 4H, J = 6.1 Hz).

Step 2: (S) - tert - butyl (3,3-dimethyl-1-oxo-1- (4-oxopiperidine-1-yl) butane-2-yl) carbamate (4-b)

Dichloromethane (140 mL) Compound 4-a (9.20 g, 40.15 mmol) to a compound 1-i solution of (R ₃ = tert - butyl, R ₁₀ = tert - butoxycarbonyl, 11.20 g, 48.18 mmol, 1.20 eq (12.26 g, 100.37 mmol, 2.50 eq.) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11.50 g, 60.22 mmol, 1.50 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with aqueous hydrochloric acid solution, sodium hydrogencarbonate aqueous solution and distilled water. Dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (12.62 g, 97%) as a pale yellow solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 5.28 (d, 1H, J = 10.8 Hz), 4.56 (d, 1H, J = 10.0 Hz), 4.28-4.11 (m, 1H), 3.74-3.49 (m, 1H ), 2.66-2.41 (m, 4H), 1.42 (s, 9H), 1.01 (s, 9H).

Step 3: (S) -1- (2- amino-3,3-dimethylbutanoyl) piperidin-4-one (4-c)

To a solution of 4-b (7.52 g, 24.07 mmol) in ethyl acetate (120 mL) was added 6 N aqueous hydrochloric acid (60 mL) and the mixture was stirred at room temperature for 20 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered and concentrated to give the title compound (4.70 g, 79%) as a pale yellow liquid, which was used in the next step without further purification.

¹ H-NMR (CDCl ₃ ):? 4.14-4.11 (m, 1H), 4.01-3.97 (m, 1H), 3.83-3.53 (m, 3H), 2.57-2.44 2H), 1.01 (s, 9H).

Step 4: ( R ) -3- ( N - (Benzyloxy) formamido) -2- (cyclopentylmethyl) - N - (( S ) -3,3- Yl) butan-2-yl) propanamide ( 4-d )

To a solution of 4-c (4.70 g, 18.89 mmol) in dichloromethane (94 mL) was added compound 1-j (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₉ = benzyl, 6.92 g, 22.67 mmol, 1.20 eq (5.78 g, 47.23 mmol, 2.50 eq.) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.42 g, 28.34 mmol, 1.50 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with aqueous hydrochloric acid solution, sodium hydrogencarbonate aqueous solution and distilled water. Dried over magnesium sulfate, filtered, concentrated and purified by silica gel chromatography to obtain the title compound (5.31 g, 59%) as a white solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 8.14 (brs, 0.6H), 7.86 (brs, 0.4H), 7.43-7.35 (m, 5H), 6.25 (d, 1H, J = 9.20 Hz), 5.01-4.89 (m, 2H), 2.64-2.56 (m, 2H), 2.52 (m, 2H), 4.79 -2.41 (m, 3H), 1.75-1.40 (m, 10H), 0.97 (s, 9H).

Step 5: ( R ) -3- ( N - (Benzyloxy) formamido) -2- (cyclopentylmethyl) - N - (( S ) -1- (4- (6-methoxy- -dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane-2-yl) propanamide (4-e)

1, 2-dichloroethane (4.5 mL) of compound 4-d (0.45 g, 0.91 mmol) solution of the compound in _{1-a (R 4 = R} 5 = R 7 = hydrogen, R = _6-methoxy, Q ₁ = carbon , m = 1, 0.15 g, 0.91 mmol) and sodium triacetoxyborohydride (0.38 g, 1.81 mmol, 2.00 eq.) were added and stirred at room temperature for 12 hours. The reaction mixture was diluted with distilled water, extracted with ethyl acetate and washed with ammonium chloride aqueous solution. Dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (0.41 g, 70%) as a pale yellow solid compound.

¹ H-NMR (CDCl ₃ ):? 8.13 (brs, 0.6H), 7.86 (brs, 0.4H), 7.43-7.35 (m, 5H), 6.71-6.61 (M, 1H), 3.77 (s, 3H), 3.71-3.60 (m, 2H), 3.14-2.96 (m, 1H), 2.85-2.66 (m, 2H), 2.63-2.59 (m, 0.98 (m, 2 H), 0.94 (s, 9 H).

Step 6: (R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- (6- methoxy-3,4- dihydro-isoquinolin -2 (1 H) - yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane-2-yl) propanamide (4-f)

To a solution of 4-e (0.22 g, 0.33 mmol) in ethanol (2 mL) was added 10 wt. % Pd / C (0.02 g) was added and stirred for 8 hours under a hydrogen atmosphere. The reaction mixture was filtered, concentrated, and then purified by silica gel chromatography to obtain the title compound (0.02 g, 17%) as an off-white solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 8.37 (brs, 0.3H), 7.76 (brs, 0.7H), 6.95-6.87 (m, 1H), 6.71-6.62 (m, 2H), 5.01-4.89 (m, 2H), 4.77-4.56 (m, 1H), 4.25-4.16 (m, 1H), 3.83-3.68 (m, 5H), 3.47-3.41 2.69 (m, 7H), 2.04-1.92 (m, 2H), 1.77-1.36 (m, 11H), 1.02-0.98 (m, 2H), 0.94 (s, 9H).

General procedure V: Preparation of ( R ) -3-cyclopentyl- N - (( S ) -1- (4- (4,7-difluoroisoindolin-2-yl) piperidin- , (3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

Step 1: 2,3-Bis (bromomethyl) -1,4-difluorobenzene ( 5-b )

To a solution of compound 5-a (R ₄ = R ₇ = fluoro, R ₅ = R ₆ = hydrogen, Q ₁ = carbon, m = 0, 1.95 g, 11.20 mmol) in dichloromethane (56 mL) was added tetrabromomethane (Y = bromo, 9.30 g, 28.00 mmol, 2.50 eq.) Was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 ° C, triphenylphosphine (7.34 g, 28.00 mmol, 2.50 eq.) Was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by silica gel chromatography to give the title compound (3.36 g, 100%) as an off-white solid compound.

¹ H-NMR (CD ₃ OD):? 7.17 (dd, 2H, J = 6.8 Hz, 13.6 Hz), 4.72 (s, 4H).

Step 2: tert -Butyl 4- (4,7-difluoroisoindolin-2-yl) piperidine-1-carboxylate ( 5-c )

In acetonitrile (120 mL) 5-b ( 3.65 g, 12.17 mmol) compound in a solution of potassium carbonate (. 5.01 g, 36.51 mmol, 3.00 eq) and compound _{5-i (R 11 = tert} - butoxycarbonyl, k = l = 1, 1.10 g, 12.17 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. Washed with distilled water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (1.09 g, 26%) as an off-white solid compound.

_{^{1 H-NMR (CD 3 OD}} ): δ 6.97 (dd, 2H, J = 6.0 Hz, 11.6 Hz), 4.10-4.03 (m, 6H), 2.91 (brs, 2H), 2.72-2.67 (m, 1H) , 1.99 (d, 2H, J = 14.4Hz), 1.49-1.22 (m, 11H).

Step 3: 4,7-Difluoro-2- (piperidin-4-yl) isoindoline ( 5-d )

To a solution of compound 5-c (1.09 g, 3.22 mmol) in ethyl acetate (6 mL) was added 6 N aqueous hydrochloric acid (6 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered and concentrated to give the title compound (0.84 g, 95%) as a pale yellow liquid, which was used in the next step without further purification.

_{^{1 H-NMR (CD 3 OD}} ): δ 6.97 (dd, 2H, J = 6.0 Hz, 11.6 Hz), 4.20-4.00 (m, 6H), 2.87 (brs, 2H), 2.70-2.61 (m, 1H) , 1.80 (m, 2H), 1.49-1. 22 (m, 2H).

Step 4: ( S ) -tert -Butyl (1- (4- (4,7-difluoroisoindolin-2-yl) piperidin- 1 -yl) -3,3-dimethyl- Yl) carbamate ( 5-e ) < RTI ID = 0.0 >

To a solution of compound 5-d (0.84 g, 3.53 mmol) in dichloromethane (60 mL) was added 1-i (R ₃ = tert -butyl, R ₁₀ = tert -butoxycarbonyl, 0.86 g, 3.71 mmol, 1.05 eq. ) And 4-dimethylaminopyridine (0.86 g, 7.06 mmol, 2.00 eq.) And 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (0.74 g, 3.88 mmol, 1.10 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and then washed with an aqueous solution of ammonium chloride, an aqueous solution of sodium hydrogen carbonate and distilled water. Dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (1.00 g, 63%) as a pale yellow solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 6.88-6.84 (m, 2H), 5.36 (t, 1H, J = 10.4 Hz), 4.66 (dd, 1H, J = 4.0 Hz, 6.4 Hz), 4.63-4.28 ( (m, 1H), 4.04 (d, 4H, J = 4.8 Hz), 3.39-3.21 (m, 1H), 3.13-2.91 2H), 1.69-1.50 (m, 2H), 1.43 (d, 10H, J = 4.4 Hz), 0.98 (d, 9H, J = 1.6 Hz).

Step 5: ( S ) -2-Amino-1- (4- (4,7-difluoroisoindolin-2-yl) piperidin- 1 -yl) -3,3-dimethylbutan- ( 5-f )

To a solution of compound 5-e (0.84 g, 1.86 mmol) in ethyl acetate (6 mL) was added 6 N aqueous hydrochloric acid (6 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 deg. C, the pH was adjusted with aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane. Washed with distilled water, dried over magnesium sulfate, filtered and concentrated to give the title compound (0.43 g, 85%) as a pale yellow liquid, which was used in the next step without further purification.

¹ H-NMR (CDCl ₃ ):? 6.88-6.85 (m, 2H), 4.48-4.37 (m, 1H), 4.04-3.97 1H), 3.08-2.94 (m, 1H ), 2.76-2.70 (m, 1H), 2.05-1.97 (m, 4H), 1.66-1.52 (m, 2H), 0.99 (d, 9H, J = 2.0 Hz) .

Step 6: (R) -3- of ((S) -1- (4- (4,7-di-iso-a-fluoro - (N - (benzyloxy) formamido) -2- (cyclopentylmethyl) - N Yl) piperidin-1-yl) -3,3-dimethyl-1-oxobutan-2- yl) propanamide ( 5-g )

To a solution of compound 5-f (0.65 g, 1.85 mmol) in dichloromethane (20 mL) was added compound 1-j (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₉ = benzyl, 0.95 g, 1.95 mmol, 1.05 eq (0.57 g, 4.64 mmol, 2.50 eq.) And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.37 g, 1.95 mmol, 1.05 eq. And the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with aqueous ammonium chloride, sodium hydroxide aqueous solution and distilled water. The extract was dried with magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (0.92 g, 78%) as a pale yellow solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 8.13 (brs, 0.5H), 7.87 (brs, 0.5H), 7.44-7.38 (m, 5H), 6.86 (dd, 2H, J = 6.0 Hz, 11.6 Hz), (M, 2H), 4.80 (brs, 1H), 4.50 (d, 0.5H, J = 13.2 Hz), 4.15-4.11 (m, 4H), 3.76-3.71 (m, 1.5H), 3.38 (m, 0.5H), 3.25-3.19 , 2.59-2.57 (m, 1H), 2.56-2.53 (m, 1.5H), 1.98-1.84 (m, 2H), 1.74-1.40 (m, 9H).

Step 7: ( R ) -3-Cyclopentyl- N - (( S ) -1- (4- (4,7-difluoroisoindolin-2-yl) piperidin- 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide ( 5-h )

To a solution of 5-g (0.72 g, 1.12 mmol) in ethanol (22 mL) was added 10 wt. % Pd / C (0.10 g) was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, concentrated, and then purified by silica gel chromatography to obtain the title compound (0.36 g, 59%) as an off-white solid compound.

_{^{1 H-NMR (CDCl 3)}} : δ 8.41 (d, 0.4H, J = 7.6 Hz), 7.82 (d, 0.6H, J = 2.0 Hz), 6.90-6.86 (m, 2H), 6.75-6.62 (m (M, 1H), 4.95-4.89 (m, 1H), 4.50-4.47 (m, 0.4H), 4.15-4.11 (M, 2H), 3.50-3.54 (m, 0.5H), 3.50-3.40 (m, 1H), 3.26-3.20 1.95 (m, 2H), 1.79-1.36 (m, 11H), 1.07-1.03 (m, 2H), 0.99-0.95 (m, 9H).

Example 1. (R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- ( isoindoline-2-yl) blood 1-yl) -3,3-dimethyl-1-oxobutan-2-yl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₅ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₁ = = 1, m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.39 (d, 0.4H, J = 15.6 Hz), 7.85 (s, 0.6H), 7.21 (d, 4H, J = 5.2 Hz), 6.73 (m, 0.4H) 2H), 3.97 (d, 4H, J = 8.4Hz), 6.61 (m, 0.6H), 4.94 J = 8.0 Hz), 3.79 (m, 1H), 3.61-3.36 (m, 2H), 3.26 (m, ), 2.03 (d, 1H, J = 8.4 Hz), 1.96 (m, 1H), 1.83-1.44 (m, 11H), 1.07 (m, 2H), 0.97 (d, 9H, J = 19.6 Hz).

Example 2. (R) -3- cyclopentyl - N - ((S) -1- (4- (3,4- dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl ) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₅ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₁ = = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.40 (d, 0.4H, J = 3.6 Hz), 7.82 (s, 0.6H), 7.11 , 4.95 (m, 1H), 4.70 (d, 0.6H, J = 12.0 Hz), 4.55 (m, 2H), 3.56 (d, 0.5H, J = 13.6 Hz), 3.46 (d, 0.5H, J = 16.0 Hz), 3.25-3.06 , 2.06-1.93 (m, 2H), 1.85-1.36 (m, 11H), 1.07 (m, 2H), 0.98 (dd, 9H, J = 9.6 Hz, 18.0 Hz).

Example 3 Synthesis of ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo- 1- (4- (pyrrolidin- 1 -yl) piperidin- Yl) -2 - (( N -hydroxyformamido) methyl) propanamide

Preparation of the title compound 2-g (R ₁ = R ₈ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₂ = carbon, k = 1 = 1, m = 0) according to general procedure II Respectively.

_{^{1 H-NMR (CDCl 3)}} : δ 8.39 (d, 0.4H, J = 6.0 Hz), 7.83 (d, 0.6H, J = 5.6 Hz), 6.66 (m, 0.4H), 6.55 (m, 0.6H ), 4.88 (m, 1H), 4.60 (m, 0.5H), 4.44 (m, 0.5H), 4.21-4.00 ), 3.28-3.07 (m, 2H), 2.82 (m, 2H), 2.77-2.60 (m, 4H) ), 1.06 (m, 2H), 0.97 (dd, 9H, J = 5.6 Hz, 19.2 Hz).

Example 4. Synthesis of ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1- (4 -morpholinopiperidin- ) -2 - (( N -hydroxyformamido) methyl) propanamide

The title compound 2-g (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₂ = oxygen, k = 1 = m = 1) was prepared according to general procedure II.

_{^{1 H-NMR (CDCl 3)}} : δ 8.41 (d, 0.4H, J = 3.4 Hz), 7.83 (d, 0.6H, J = 2.4 Hz), 6.63 (t, 0.4H, J = 8.4 Hz, 8.4 Hz ), 6.49 (dd, 0.6H, J = 9.6 Hz, 16.4 Hz), 4.89 (m, 1H), 4.63 (m, 0.6H), 4.50 (m, 0.4H), 4.18-4.00 (m, 1.5H) , 3.80 (m, 0.5H), 3.71 (m, 4H), 3.59 (m, 0.5H), 3.49 (m, 0.5H), 3.22-3.02 2H), 1.82-1.30 (m, 11H), 1.04 (m, 2H), 0.97 (dd, 9H, J = 8.8 (m, Hz, 20.4 Hz).

Example 5. (R) -3- cyclopentyl - N - ((S) -1- (4- (6,7- dimethoxy-3,4-dihydro-isoquinoline -2 (1 H) - yl) Yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₅ = R ₆ = methoxy, Q ₁ = k = l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.40 (s, 0.4H), 7.82 (s, 0.6H), 6.58 (d, 1H , J = 3.2 Hz), 6.51 (d, 1H, J = 10.4 Hz), 5.37 (d, 1H, J = 9.2 Hz), 4.73-4.60 (m, 1H), 4.19 (m, 1H), 3.84 ( t, 6H, J = 1.6Hz, 1.6 Hz) 3.67 (m, 1H), 3.52 (dd, 1H, J = 14.8Hz, 40.8 Hz), 2.88-2.57 (m, 7H) , 2.06-1.90 (m, 2H), 1.89-1.34 (m, 15H), 1.17-0.88 (m, 11H).

Example 6. (R) -3- cyclopentyl - N - ((S) -1- (4- (7,8- dihydro-1,6-naphthyridine -6 (5 H) - yl) piperidine 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure IV the title compound 4-f (R ₁ = R ₄ = R ₅ = R ₆ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₁ = nitrogen, 1).

¹ H-NMR (CDCl ₃ ):? 8.40-8.39 (m, 1H), 8.38 (m, 0.4H), 7.82 (s, 0.6H), 7.35-7.30 1H), 6.84 (m, 0.3H), 6.73-6.69 (m, 0.7H), 4.99-4.93 2H), 3.17-3.01 (m, 3H), 2.95-2.70 (m, 5H), 2.04-1.93 (m, , 2H), 1.79-1.42 (m, 12H), 1.07-1.03 (m, 2H), 1.00-0.94 (m, 9H).

Example 7. (R) - N - ( (S) -1- (4- (3,4- dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) 3,3 - dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide

According to general procedure IV the title compound 4-f (R ₁ = R ₄ = R ₅ = R ₆ = R ₇ = hydrogen, R ₂ = n -butyl, R ₃ = tert -butyl, Q ₁ = = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.39 (d, 0.4H, J = 5.2 Hz), 7.84 (d, 0.6H, J = 2.4 Hz), 7.12 (m, 3H), 7.01 (m, 1H), (M, 2H), 3.63-3.47 (m, 1H), 4.67-4.68 (m, 1H), 3.25-3.07 (m, 1H), 2.92-2.59 (m, 7H), 2.08-1.91 (m, 1H), 1.80-1.16 (m, 10H), 1.06-0.80 (m, 12H).

Example 8. (2 R) -3- cyclopentyl - N - ((2 S) -3,3- dimethyl-1- (4- (octahydro-isoquinolin -2 (1 H) - yl) piperidine -1-yl) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

The title compound 3-g (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, k = 1 = m = n = 1) was prepared according to general procedure III.

¹ H-NMR (CDCl ₃ ):? 8.40 (s, 0.4H), 7.83 (s, 0.6H), 6.68-6.45 2H), 3.81-3.52 (m, 2H), 3.09-2.92 (m, 1H), 2.85-2.74 1.13 (m, 26H), 1.09-0.79 (m, 10H).

Example 9. (R) -3- cyclopentyl - N - ((S) -1- (4- (6- fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure IV the title compound 4-f (R ₁ = R ₄ = R ₅ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₆ = fluoro, Q ₁ = k = l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.41 (s, 0.5H), 7.83 (s, 0.5H), 6.96 (m, 2H), 3.65-3.43 (m, 1H), 3.21-3.07 (m, 1H), 4.82-4.68 (m, 1H), 2.88-2.58 (m, 7H), 2.04-1.91 (m, 2H), 1.86-1.32 (m, 13H), 1.12-0.91 (m, 11H).

Example 10. (R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- (6- methoxy-3,4 Dihydroisoquinolin-2 (1 H ) -yl) piperidin-1-yl) -3,3-dimethyl- 1 -oxobutan- 2- yl) propanamide

Title compound was prepared according to general procedure _{Ⅳ 4-f (R 1 =} R 4 = R 5 = R 7 = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert - butyl, R ₆ = methoxy, Q ₁ = carbon, k = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.38 (s, 0.3H), 7.76 (s, 0.7H), 7.03-6.89 (m, 1H), 6.71-6.23 (m, 2H), 5.02-4.89 (m, 1H), 3.94-3.64 (m, 1H), 3.23-3.05 (m, 1H), 4.94-4.56 2.60 (m, 7H), 2.07-1.87 (m, 2H), 1.77-1.36 (m, 11H), 1.09-0.96 (m, 11H).

Example 11. (R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- (7- methoxy-3,4 Dihydroisoquinolin-2 (1 H ) -yl) piperidin-1-yl) -3,3-dimethyl- 1 -oxobutan- 2- yl) propanamide

Title compound was prepared according to general procedure _{Ⅳ 4-f (R 1 =} R 4 = R 6 = R 7 = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert - butyl, R ₅ = methoxy, Q ₁ = carbon, k = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.39 (s, 0.3H), 8.16 (s, 0.1H), 7.77 (s, 0.6H), 7.02-6.98 (m, 1H), 6.72-6.69 (m, 1H ), 6.57-6.52 (m, 1 H), 5.01-4.88 (m, 1 H), 4.76-4.52 (m, 1 H), 4.25-4.14 (m, 2H), 3.26-3.02 (m, 2H), 2.91-2.58 (m, 6H), 2.04-1.88 (m, 2H), 1.78-1.33 .

Example 12. (R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1 - ((R) -3- ( isoindoline -2 Yl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2- yl) propanamide

According to general procedure V, the title compound 5-h (R ₁ = R ₄ = R ₅ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₁ = = 0, l = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.52 (s, 0.4H), 7.81 (s, 0.7H), 7.68-7.61 (m, 1H), 7.33-7.27 (m, 2H), 7.21-7.15 (m, 2H), 3.57-3.40 (m, 1H), 3.17-2.94 (m, 1H), 4.97-4.88 m, 1H), 2.89-2.65 (m, 3H), 2.04-1.20 (m, 14H), 1.13-0.88 (m, 11H).

Example 13. Synthesis of ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- ) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

Title compound was prepared according to general procedure _{Ⅴ 5-h (R 1 =} R 4 = R 6 = R 7 = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert - butyl, R ₅ = methyl, Q ₁ = carbon, k = l = 1, m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.35 (d, 0.3H, J = 8.0 Hz), 7.79 (s, 0.7H), 7.11-7.07 (m, 1H), 7.03-7.01 (m, 2H), 6.88 -6.83 (m, 1H), 4.97 (t, 1H, J = 7.6 Hz), 4.47-4.43 (m, 0.5H), 4.19-4.00 (m, 1.5H), 3.92 (d, 4H, J = 6.8 Hz ), 3.77-3.71 (m, 1H), 3.43-3.41 (m, 1.5H), 3.25-3.16 (m, 1H), 2.91-2.86 s, 3H), 2.02-1.93 (m, 2H), 1.74-1.32 (m, 12H), 1.01-0.94 (m, 11H).

Example 14. ( R ) -3-Cyclopentyl- N - (( S ) -1- (4- (5-fluoroisoindolin- 2- yl) piperidin- Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure V, the title compound 5-h (R ₁ = R ₄ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₅ = fluoro, Q ₁ = k = l = 1, m = 0).

_{^{1 H-NMR (CD 3 OD}} ): δ 8.25 (s, 0.3H), 7.82 (s, 0.7H), 7.25-7.20 (m, 1H), 7.01-6.91 (m, 2H), 5.01-4.94 (m (M, 4H), 3.78-3.73 (m, 1H), 3.59 (m, 0.4H) 2H), 2.07-2.30 (m, 2H), 3.73-3.39 (m, 0.6H), 3.34-3.20 (m, 1.4H), 3.06-3.02 1.99 (m, 2H), 1.84 (m, 1H), 1.69-1.28 (m, 10H), 1.05-0.98 (m, 11H).

Example 15. (R) - N - ( (S) -1- (4- (5- chloroisatin stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane Yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide

The title compound 5-h (R ₁ = R ₄ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₅ = chloro, Q ₁ = carbon, k = l = 1, m = 0).

¹ H-NMR (CDCl ₃ ):? 8.40 (d, 0.3H, J = 8.4 Hz), 7.82 (s, 0.7H), 7.20-7.11 (m, 3H), 6.84-6.82 (M, 1H), 4.64-4.43 (m, 0.5H), 4.32-4.26 (m, 0.5H), 4.17-4.05 (m, 1H), 3.94-3.91 (m, 2H), 3.82-3.76 (m, 1H), 3.56-3.35 (m, 1.5H), 3.25-3.18 (m, 1H), 2.95-2.69 ), 1.76-1.47 (m, 12H), 1.03-0.94 (m, 11H).

Example 16. ( R ) -3-Cyclopentyl- N - (( S ) -1- (4- (5-ethylisisoindolin-2-yl) piperidin- Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure V, the title compound 5-h (R ₁ = R ₄ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₅ = ethyl, Q ₁ = = l = 1, m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.40 (d, 0.4H, J = 17.6 Hz), 7.84 (s, 0.6H), 7.13 (t, 1H, J = 7.2 Hz), 7.04 (m, 2H), (M, 1H), 4.64 (m, 0.4H), 6.51 (d, 0.6H, J = 8.0 Hz), 4.92 4H), 3.81 (d, 0.5H, J = 9.6 Hz, 14.0 Hz), 3.59 (m, 0.5H), 3.49 2H), 2.92 (m, 0.6H), 2.75-2.60 (m, 3.5H), 2.06-1.85 (m, 2.5H), 1.84-1.44 , J = 7.6 Hz), 1.06 (m, 2H), 0.97 (d, 9H, J = 20.4 Hz).

Example 17. (R) -3- cyclopentyl - N - ((S) -1 - ((R) -3- (3,4- dihydro-isoquinoline -2 (1 H) - yl) pyrrolidine Yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure V, the title compound 5-h (R ₁ = R ₄ = R ₅ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₁ = , l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.40 (s, 0.3H), 7.76 (s, 0.7H), 7.14-6.99 (m, 4H), 6.93-6.67 (M, 2H), 2.34-2. 17 (m, 3H), 2.04- 1.99 (m, 1H), 1.82-1.38 (m, 9H), 1.02-0.97 (m, 9H).

Example 18. Synthesis of ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- ) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

Title compound was prepared according to general procedure _{Ⅴ 5-h (R 1 =} R 5 = R 6 = R 7 = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert - butyl, R ₄ = methyl, Q ₁ = carbon, k = l = 1, m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.39 (d, 0.4H, J = 15.2 Hz), 7.83 (s, 0.6H), 7.37 (m, 1H), 7.13 (m, 1H), 7.02 (m, 1H ), 6.71 (d, 0.4H, J = 14.0 Hz), 6.58 (m, 0.6H), 4.93 (m, 1H), 4.45 (d, 0.4H, J = 14.0 Hz), 4.32-4.02 (M, 1H), 3.43 (m, 2H), 3.94 (m, (m, 1H), 2.70 ( m, 2H), 2.25 (d, 3H, J = 6.4 Hz), 2.01 (m, 2H), 1.88-1.38 (m, 11H), 1.04 (m, 2H), 0.97 ( d, 9H, J = 19.6 Hz).

Example 19. Synthesis of ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (4,5,6,7-tetrafluoroisisoindoline- Yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure V, the title compound 5-h (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₅ = R ₆ = R ₇ = fluoro, Q ₁ = k = l = 1, m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.40 (d, 0.4H, J = 3.6 Hz), 7.83 (s, 0.6H), 6.77 (m, 0.4H), 6.62 (m, 0.6H), 4.93 (m (M, 1H), 4.46 (d, 0.5H, J = 10.0 Hz), 4.15-3.93 (m, 5.5H), 3.80 2H), 1.92 (m, 2H), 1.83-1.37 (m, 11H), 1.06 (m, 2H), 0.98 (d, 9H, J = .

Example 20. ( R ) -3-Cyclopentyl- N - (( S ) -1- (4- (4-fluoroisoindolin-2-yl) piperidin- Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure V, the title compound 5-h (R ₁ = R ₅ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = fluoro, Q ₁ = k = l = 1, m = 0).

_{^{1 H-NMR (CD 3 OD}} ): δ 8.23 (s, 0.3H), 7.75 (s, 0.7H), 7.27-7.20 (m, 1H), 7.06 (t, 1H, J = 8.8 Hz), 6.95- (M, 1H), 4.51-4.96 (m, 1H), 4.54-4.51 (m, 0.6H), 4.33-4.25 (M, 1H), 3.75-3.69 (m, 1H), 3.59 (m, 0.4H), 3.39-3.32 (M, 2H), 3.02-2.76 (m, 3.5H), 2.07-1.94 (m, 2H), 1.89-1.27 (m, 11H), 1.23-1.12 (m, 2H), 1.02-0.99 (m, 9H).

Example 21. (R) -3- cyclopentyl - N - ((S) -1- (4- (5,8- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - one ) Piperidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₅ = R ₆ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₇ = fluoro, Q ₁ = k = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.22 (s, 0.5H), 7.82 (s, 0.5H), 6.90 (m, 2H), 6.72-6.52 (m, 1H), 5.05-4.94 (m, 1H) 2H), 3.60-3.46 (m, 1H), 3.22-3.12 (m, 1H), 2.92-2.59 (m, m, 8H), 2.08-1.94 (m, 2H), 1.81-1.37 (m, 11H), 1.07-0.89 (m, 11H).

Example 22. (R) -3- cyclopentyl - N - ((S) -1- (4- (6,8- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - one ) Piperidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure IV the title compound 4-f (R ₁ = R ₅ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₆ = fluoro, Q ₁ = k = l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.40 (s, 0.4H), 7.82 (s, 0.6H), 6.95 2H), 3.62-3.43 (m, IH), 4.06 (m, IH) , 3.15-3.05 (m, 1H), 2.98-2.58 (m, 7H), 2.06-1.90 (m, 2H), 1.85-1.33 (m, 11H), 1.11-0.89 (m, 11H).

Example 23. ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (5,6,8-trifluoro- dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₅ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₆ = R ₇ = fluoro, Q ₁ = k = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.25 (s, 0.3H), 7.53 (s, 0.7H), 6.79-6.73 (m, 1H), 4.99-4.63 (m, 2H), 4.29-4.21 (m, 1H), 3.67-3.35 (m, 5H), 3.11-2.96 (m, 1H), 2.81-2.51 (m, 7H), 2.04-1.43 (m, 13H), 1.37-1.15 (m,

Example 24. (R) - N - ( (S) -1- (4- (8- chloro-6-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine Yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₅ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = chloro, R ₆ = fluoro, Q ₁ = Carbon, k = 1 = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.41 (s, 0.4H), 7.83 (s, 0.6H), 6.93 (m, 1H), 6.89 (m, 0.4H), 6.75 (m, 1H), 6.60 ( m, 0.6H), 4.95 (m , 1H), 4.73 (d, 0.6H, J = 12.8 Hz), 4.59 (m, 0.4H), 4.21 (m, 1H), 4.08 (m, 0.5H), 3.89 (m, 2H), 3.71 (d, 2H, J = 7.2 Hz), 3.52 (dd, 1H, J = 14.0 Hz, 1.98 (m, 2H), 1.83-1.36 (m, 11H), 1.07 (m, 2H), 0.98 (dd, 9H, J = 10.4 Hz, 18.0 Hz).

Example 25. (R) -3- cyclopentyl - N - ((S) -1- (4- ( 5-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₅ = R ₆ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₇ = fluoro, Q ₁ = k = l = m = 1).

_{^{1 H-NMR (CD 3 OD}} ): δ 8.20 (s, 0.3H), 7.68 (s, 0.7H), 7.19-7.09 (m, 1H), 6.92-6.82 (m, 1H), 5.05-4.95 (m (M, 2H), 3.75-3.62 (m, 1H), 3.60-3.32 (m, 1H), 3.20 2H), 1.93-1.79 (m, 1H), 1.79-1.21 (m, 2H), 3.00-2.80 (m, 6H), 3.78-3.60 11H), 1.20-0.96 (m, 11H).

Example 26. (R) -3- cyclopentyl - N - ((S) -1- (4- (-3,4- dihydro-isoquinoline -2 (1 H) ethynyl-7-yl) piperidine 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₅ = ethynyl, Q ₁ = k = l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.41 (s, 0.4H), 7.81 (s, 0.6H), 7.24-6.86 (m, 3H), 5.00-4.94 1H), 4.26-4.07 (m, 1H), 3.84-3.76 (m, 2H), 3.53-3.44 m, 5H), 2.06-1.93 (m, 5H), 1.77-1.37 (m, 12H), 1.08-1.03 (m, 2H), 1.00-0.93 (m, 9H).

Example 27. (R) -3- cyclopentyl - N - ((S) -1- (4- (6,7- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - one ) Piperidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₅ = R ₆ = fluoro, Q ₁ = k = l = m = 1).

_{^{1 H-NMR (CD 3 OD}} ): δ 8.22 (s, 0.3H), 7.76 (s, 0.7H), 7.00-6.88 (m, 2H), 5.00-4.94 (m, 1H), 4.64-4.50 (m (M, 3H), 3.60-3.32 (m, 1H), 3.20-2.97 (m, 1H), 2.95-2.74 (m, 6H), 2.70 -2.59 (m, 1H), 2.09-1.90 (m, 2H), 1.90-1.76 (m, 1H), 1.76-1.30 (m, 11H), 1.14-0.90 (m, 11H).

Example 28. (R) - N - ( (S) -1- (4- (4- chloroisatin stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane Yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide

Title compound was prepared according to general procedure _{Ⅴ 5-h (R 1 =} R 5 = R 6 = R 7 = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert - butyl, R ₄ = chloro, Q ₁ = carbon, k = l = 1, m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.41 (d, 0.4H, J = 1.08 Hz), 7.84 (s, 0.6H), 7.17 (m, 2H), 7.10 (m, 1H), 6.60 (t, 0.5 H, J = 9.2 Hz), 6.47 (d, 0.5H, J = 9.2 Hz), 4.92 (m, 1H), 4.43 (m, 0.5H), 4.16-3.93 (m, 5.5H), 3.82 (dd, 1H, J = 9.6 Hz, 14.4 Hz), 3.61 (m, 0.5H), 3.51 (m, 0.5H), 3.41 2H), 1.95 (m, 2H), 1.83-1.42 (m, 11H), 1.07 (m, 2H), 0.98 (d, 9H, J = 22.0 Hz).

Example 29. (R) -3- cyclopentyl - N - ((S) -1- (4- ( 7-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₅ = fluoro, Q ₁ = k = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.41 (s, 0.4H), 7.84 (s, 0.6H), 7.03 (m, 1H), 6.83 (m, 1H), 6.71 (m, 1H), 6.62 (m , 0.4H), 6.50 (m, 0.6H), 4.92 (m, 1H), 4.71 (d, 0.5H, J = 14.4 Hz), 4.57 1H, J = 14.4 Hz, 41.2 Hz), 3.12 (m, 1H), 2.88-2.70 (m, 5.5H), 3.74 H), 2.64 (m, 1.5H), 1.96 (m, 2H), 1.37-1.84 (m, 11H), 1.08 (m, 2H), 0.98 (dd, 9H, J = 9.6 Hz, 20.4 Hz).

Example 30. ( R ) -3-cyclopentyl- N - (( S ) -1- (4- (4,7-difluoroisoindolin-2-yl) piperidin- , 3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure V, the title compound 5-h (R ₁ = R ₅ = R ₆ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₇ = fluoro, Q ₁ = k = l = 1, m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.41 (d, 0.4H, J = 7.6 Hz), 7.82 (d, 0.6H, J = 2.0 Hz), 6.90-6.86 (m, 2H), 6.75-6.62 (m (M, 1H), 4.95-4.89 (m, 1H), 4.50-4.47 (m, 0.4H), 4.15-4.11 , 3.83-3.76 (m, 2H), 3.50-3.40 (m, 1H), 3.26-3.20 (m, 1H), 2.90-2.70 (m, 2H), 2.02-1.95 m, 11H), 1.07-1.03 (m, 2H), 0.99-0.95 (m, 9H).

Example 31. (R) - N - ( (S) -1- (4- (7- cyano-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl Yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure IV the title compound 4-f (R ₁ = R ₄ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₅ = cyano, Q ₁ = k = l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.40 (s, 0.4H), 7.82 (s, 0.6H), 7.41-7.39 (m, 1H), 7.34-7.29 1H), 4.95-4.86 (m, 1H), 4.30-4.16 (m, 1H), 4.07-4.01 (m, (M, 2H), 1.79-1.32 (m, 12H), 1.07-0.83 (m, 1H), 3.07 (m, 1H), 3.00-2.91 ).

Example 32. ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo- 1- (4- (5,7,8-trifluoro- dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₆ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₅ = R ₇ = fluoro, Q ₁ = k = l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.41 (s, 0.5H), 7.83 (s, 0.5H), 6.74 (m, 2H), 3.61-3.44 (m, 1H), 3.22-3.05 (m, 1H), 2.87-2.58 (m, 7H), 2.02-1.90 (m, , 1.85-1.35 (m, 12H), 1.12-0.92 (m, 12H).

Example 33. (R) -3- cyclopentyl - N - ((S) -1- (4- (6,8- dichloro-3,4-dihydro-isoquinoline -2 (1 H) - yl) blood 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₅ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₆ = chloro, Q ₁ = = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.41 (s, 0.4H), 7.82 (s, 0.6H), 7.19 (d, 1H, J = 3.2 Hz), 7.13 (m, 0.4H), 7.03 (d, 1H, J = 3.2 Hz), 6.86 (dd, 0.6H, J = 8.8 Hz, 24.4 Hz), 4.97 (m, 1H), 4.74 (d, 0.6H, J = 12.4 Hz), 4.60 (d, 0.4H , J = 13.2 Hz), 4.23 (m, 1H), 4.10 (m, 0.5H), 3.81 (m, 0.5H), 3.72 (d, 2H, J = 8.4 Hz), 3.49 (m, 1H), 3.12 (m, 1H), 2.90-2.59 ( m, 6H), 2.00 (m, 2H), 1.82-1.36 (m, 11H), 1.06 (m, 2H), 0.98 (dd, 9H, J = 10.4 Hz, 17.2 Hz).

Example 34. ( R ) -3-Cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (8- (trifluoromethyl) dihydro-isoquinolin -2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₅ = R ₆ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = trifluoromethyl, Q ₁ = Carbon, k = 1 = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.28 (s, 0.4H), 7.84 (s, 0.6H), 7.51 (m, 1H), 7.37 (m, 1H), 7.33 (m, 1H), 5.04 (m 2H), 3.43 (m, 1H), 3.08 (m, 1H), 3.02-2.64 (m, 7H) 2.10-1.92 (m, 2H), 1.88-1.44 (m, 12H), 1.17-0.95 (m, 12H).

Example 35. Synthesis of ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (6- (trifluoromethyl) dihydro-isoquinolin -2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₅ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₆ = trifluoromethyl, Q ₁ = Carbon, k = 1 = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.37 (s, 0.4H), 7.66 (s, 0.6H), 7.35 (d, 2H, J = 6.4 Hz), 7.11 (dd, 1H, J = 8.8 Hz, 16.0 2H), 3.68-3.41 (m, 2H), 3.17-4.28 (m, 1H) (M, 2H), 1.01-0.88 (m, 9H), 3.08 (m, 2H), 2.92-2.57 (m, 6H), 1.97-1.88 ).

Example 36. (R) -3- cyclopentyl - N - ((S) -1 - ((R) -3- (6,7- dimethyl-3,4-dihydro-isoquinoline -2 (1 H) 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

Title compound was prepared according to general procedure _{Ⅴ 5-h (R 1 =} R 4 = R 7 = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert - butyl, R ₅ = R ₆ = methyl, Q ₁ = carbon, k = 0, l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.40 (s, 0.4H), 7.84 (s, 0.6H), 7.11-7.03 (m, 2H), 6.93-6.67 (m, 1H), 4.56-4.34 (m, 2H), 2.50 (s, 6H), 2.39-2.25 (m, 2H), 3.95-3.80 (m, m, 1H), 2.08-2.03 (m, 1H), 1.82-1.29 (m, 11H), 1.02-0.97 (m, 9H).

Example 37. (R) - N - ( (S) -1- (3- (3,4- dihydro-isoquinoline -2 (1 H) - yl) azetidin-1-yl) -3,3- Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₅ = R ₆ = R ₇ = hydrogen, R ₂ = n -butyl, R ₃ = tert -butyl, Q ₁ = = 0, m = 1).

¹ H-NMR (CDCl ₃ ):? 8.40 (s, 0.3H), 7.76 (s, 0.7H), 7.14-6.99 (m, 4H), 6.65-6.41 2H), 3.63-3.47 (m, IH), 3.25-3.07 (m, IH), 2.92-2.30 (m, 2.59 (m, 5H), 1.97-1.91 (m, 1H), 1.84-1.18 (m, 11H), 1.13-0.94 (m, 10H).

Example 38. ( R ) -3-Cyclopentyl- N - (( S ) -3,3-dimethyl- 1- (4- (4- methylpiperazin- 1 -yl) piperidin- -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

Preparation of the title compound 2-g (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₈ = methyl, Q ₂ = nitrogen, k = 1 = m = 1) according to general procedure II Respectively.

_{^{1 H-NMR (CDCl 3)}} : δ 8.43 (s, 0.4H), 7.84 (s, 0.6H), 6.64 (m, 0.4H), 6.50 (m, 0.6H), 4.88 (m, 1H), 4.62 (m, 0.6H), 4.51 (m, 0.4H), 4.19-4.01 (m, 1.5H), 3.81 2H), 1.81 (m, 4H), 2.48-2.30 (m, 6H), 2.15 (s, 3H), 1.95-1.82 -1.33 (m, 11H), 1.05 (m, 2H), 0.96 (dd, 9H, J = 8.8 Hz, 20.4 Hz).

Example 39. Synthesis of ( R ) -3-cyclopentyl- N - (( S ) -1- (3- (4,7-difluoroisoindolin- Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₅ = R ₆ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₇ = fluoro, Q ₁ = k = 1 = m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.31 (s, 0.4H), 7.86 (s, 0.6H), 6.94-6.82 (m, 2H), 6.42-6.12 (m, 1H), 5.01-4.88 (m, 1H), 3.81-3.54 (m, 1H), 4.81-4.52 (m, 1H), 4.32-4.13 2.62 (m, 4H), 1.99-1.92 (m, 1H), 1.89-1.21 (m, 11H), 1.18-0.87 (m, 10H).

Example 40. (R) - N - ( (S) -1- (3- (5,6- -2- yl) azetidine turned difluoro Roy stamp-yl) -3,3-dimethyl -1 - oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₇ = hydrogen, R ₂ = n -butyl, R ₃ = tert -butyl, R ₅ = R ₆ = fluoro, Q ₁ = k = 1 = m = 0).

_{^{1 H-NMR (CDCl 3)}} : δ 8.24 (s, 0.3H), 7.78 (s, 0.7H), 7.02-6.86 (m, 2H), 6.65-6.41 (m, 1H), 5.01-4.62 (m, 2H), 4.26-4.10 (m, 1H), 3.88-3.72 (m, 2H), 3.63-3.47 1.91 (m, 1H), 1.84-1.18 (m, 10H), 1.13-0.94 (m, 9H).

Example 41. (R) -3- cyclopentyl - N - ((S) -1- (3- (7,8- dihydro-1,6-naphthyridine -6 (5 H) - yl) azetidine Yl) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure IV the title compound 4-f (R ₁ = R ₄ = R ₅ = R ₆ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₁ = nitrogen, m = 1).

¹ H-NMR (CDCl ₃ ):? 8.41-8.38 (m, 1H), 8.37 (m, 0.4H), 7.83 (s, 0.6H), 7.36-7.29 1H), 6.84 (m, 0.3H), 6.74-6.70 (m, 0.7H), 4.98-4.94 2H), 3.17-3.02 (m, 1H), 2.95-2.70 (m, 3H), 2.04-1.93 (m, , 2H), 1.80-1.42 (m, 11H), 1.07-1.03 (m, 2H), 1.00-0.95 (m, 9H).

Example 42. (R) -3-cyclopentyl-N - ((S) -3,3- dimethyl-1-oxo -1 - ((R) -3- (5,6,8- trifluoro- 3,4-dihydro-isoquinoline -2 (1 H) - yl) pyrrolidin-1-yl) butane-2-yl) -2 - ((N - hidi hydroxy-formamido) methyl) propanamide

According to general procedure V, the title compound 5-h (R ₁ = R ₅ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₄ = R ₆ = R ₇ = fluoro, Q ₁ = k = 0, l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.25 (s, 0.3H), 7.53 (s, 0.7H), 6.90-6.72 (m, 1H), 6.71 (m, 1H), 4.73-4.60 (m, 1H) , 4.04-3.88 (m, 2H), 3.74-3.59 (m, 4H), 3.41-3.26 (m, 2H), 3.03-2.60 (m, 6H), 2.42-2.17 m, 1H), 1.78-1.18 (m, 11H), 1.08-0.87 (m, 9H).

Example 43. (R) - N - ( (S) -1- (4- (6- cyano-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl Yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 4-g (R ₁ = R ₄ = R ₅ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₆ = cyano, Q ₁ = k = l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.42 (s, 0.4H), 7.83 (s, 0.6H), 7.21-7.19 2H), 3.23-3. 07 (m, 1H), 3.00-3. 18 (m, 2H) 2.91 (m, 2H), 2.85-2.65 (m, 5H), 1.98-1.91 (m, 2H), 1.79-1.32 (m, 12H), 1.07-0.83 (m, 11H).

Example 44. ( R ) -3-Cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (piperazin- 1 -yl) piperidin- ) Butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

The title compound 2-g (R ₁ = R ₈ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, Q ₂ = nitrogen, k = 1 = m = 1) was prepared according to general procedure II.

_{^{1 H-NMR (CDCl 3)}} : δ 8.41 (s, 0.4H), 7.83 (s, 0.6H), 6.66 (m, 0.4H), 6.54 (m, 0.6H), 4.89 (m, 1H), 4.61 (M, 2H), 3.57-3.47 (m, 1H), 3.24-3.03 (m, 1H), 2.86-2.59 (m, 6H), 2.58-2.41 5H), 1.97-1.83 (m, 2H), 1.72-1.33 (m, 11H), 1.04 (m, 2H), 0.97 (m, 9H).

Example 45. Synthesis of ( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1- (4- (6-morpholino-3,4-dihydroisoquinolin- Yl ) -2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₅ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₆ = morpholinyl, Q ₁ = carbon , k = 1 = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.43 (s, 0.4H), 7.84 (s, 0.6H), 7.10-6.93 (M, 2H), 2.89 (m, 2H), 3.89-3.40 (m, 2.60 (m, 5H), 1.98-1.90 (m, 2H), 1.83-1.41 (m, 12H), 1.07-0.86 (m, 11H).

Example 46. (R) - N - ( (S) -1- (4- (6- Acetamido-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine-1 Dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₅ = R ₇ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, R ₆ = acetamido, Q ₁ = carbon , k = 1 = m = 1).

¹ H-NMR (CDCl ₃ ): 隆 8.43 (s, 0.4H), 7.84 (s, 0.6H), 7.61-7.50 (m, 1H), 7.48-7.35 1H), 4.99-4.90 (m, 1H), 4.31-4.21 (m, 1H), 3.75-3.66 (m, 3H), 3.65-3.47 2.60 (m, 5H), 2.05 (s, 3H), 1.98-1.90 (m, 2H), 1.83-1.41 (m, 12H), 1.08-0.87 (m, 11H).

Example 47. (R) -3- cyclopentyl - N - ((S) -3,3- dimethyl-1- (4- (6-nitro-3,4-dihydro-isoquinoline -2 (1 H) Yl) -2 - (( N -hydroxyformamido) methyl) propanamide

The title compound _1-g (R 1 in accordance with the general procedure _{Ⅰ = R 4 = R 5 =} R 7 = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert - butyl, R ₆ = nitro, Q ₁ = carbon, k = l = m = 1).

¹ H-NMR (CDCl ₃ ):? 8.43 (s, 0.4H), 7.84 (s, 0.6H), 7.65-7.60 (m, 1H), 7.58-7.43 1H), 4.97-4.92 (m, 1H), 4.33-4.21 (m, 1H), 3.74-3.48 (m, 6H), 3.10-2.99 (m, 2H), 2.79-2.69 1.90 (m, 2H), 1.85-1.47 (m, 12H), 1.09-0.85 (m, 11H).

Example 48. (R) - N - ( (S) -3,3- dimethyl-1-oxo-1- (4- (5,6,8- trifluoro-3,4-dihydro-isoquinoline- 2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) hexanoic amide

According to general procedure I, the title compound 1-g (R ₁ = R ₅ = hydrogen, R ₂ = n -butyl, R ₃ = tert -butyl, R ₄ = R ₆ = R ₇ = fluoro, Q ₁ = k = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.39 (d, 0.4H, J = 5.2 Hz), 7.84 (d, 0.6H, J = 2.4 Hz), 6.91 (s, 1H), 6.72 (m, 1H), 2H), 3.65-3.49 (m, 1H), 3.21-3.06 (m, 1H) , 2.93-2.60 (m, 7H), 2.09-1.98 (m, 1H), 1.81-1.14 (m, 10H), 1.04-0.81 (m, 12H).

Example 49. (R) - N - ( (S) -1- (4- (6,8- dichloro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine-1 Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₅ = R ₇ = hydrogen, R ₂ = n -butyl, R ₃ = tert -butyl, R ₄ = R ₆ = chloro, Q ₁ = = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.40 (d, 0.4H, J = 5.2 Hz), 7.87 (d, 0.6H, J = 2.4 Hz), 7.03 (s, 1H), 6.99 (m, 1H), 1H), 3.83-3.76 (m, 2H), 3.69-3.50 (m, 1H), 4.69-4. ), 3.25-3.10 (m, 1H), 2.94-2.60 (m, 7H), 2.10-1.99 (m, 1H), 1.84-1.21 (m, 10H), 1.07-0.85 (m, 12H).

Example 50. (R) - N - ( (S) -1- (4- (6,7- dimethoxy-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1 Yl) -2 - (( N -hydroxyformamido) methyl) hexanamide

According to general procedure I, the title compound 1-g (R ₁ = R ₄ = R ₇ = hydrogen, R ₂ = n -butyl, R ₃ = tert -butyl, R ₅ = R ₆ = methoxy, Q ₁ = k = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.40 (d, 0.4H, J = 5.2 Hz), 7.88 (d, 0.6H, J = 2.4 Hz), 6.58 (m, 1H), 6.53 (m, 1H), (M, 2H), 3.83 (s, 6H), 3.81-3.72 (m, 2H), 4.83-4. (M, 1H), 2.93-2.61 (m, 1H), 2.19-1.88 (m, 1H), 1.85-1.22 , 12H).

Example 51. (R) - N - ( (S) -1- (4- (6,7- dimethyl-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine-1 Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide

The title compound _1-g (R 1 in accordance with the general procedure Ⅰ = R ₄ = R ₇ = hydrogen, R ₂ = n - butyl, R ₃ = tert - butyl, R ₅ = R ₆ = methyl, Q ₁ = carbon, k = l = m = 1).

_{^{1 H-NMR (CDCl 3)}} : δ 8.40 (d, 0.4H, J = 5.2 Hz), 7.88 (d, 0.6H, J = 2.4 Hz), 6.55 (m, 1H), 6.48 (m, 1H), 2H), 3.70-3.55 (m, IH), 4.65-4. 45 (m, ), 3.23-3.14 (m, 1H), 2.93-2.64 (m, 7H), 2.35 (s, 6H), 2.14-1.99 , 12H).

Example 52. (2 R) -3- cyclopentyl - N - ((2 S) -1- (4- -hexahydro -1 H - cyclopenta [c] pyridine -2 (3 H) - yl) piperidine 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

The title compound 3-g (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, k = 1 = m = 1, n = 0) was prepared according to general procedure III.

¹ H-NMR (CDCl ₃ ):? 8.40 (s, 0.4H), 7.83 (s, 0.6H), 6.69-6.49 (m, 1H), 2.84-2.69 (m, 1H), 2.65-2.33 (m, 4H), 1.94-3.30 (m, 1.21 (m, 24H), 1.07-0.84 (m, 10H).

Example 53. (2 R) -3- cyclopentyl - N - ((2 S) -1- (4- ( hexahydro-cyclopenta [c] pyrrolo -2 (1 H) - yl) piperidine- 1 - yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide

The title compound 3-g (R ₁ = hydrogen, R ₂ = cyclopentylmethyl, R ₃ = tert -butyl, k = 1 = 1, m = n = 0) was prepared according to general procedure III.

¹ H-NMR (CDCl ₃ ):? 8.42 (s, 0.4H), 7.82 (s, 0.6H), 6.69-6.43 1H), 2.84-2.77 (m, 1H), 2.62-2.32 (m, 4H), 1.91- 1.12 (m, 22H), 1.08-0.77 (m, 10H).

Formulation Example

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

Formulation Example 1: Tablet formulation

The following ingredients were mixed well to make tablets.

ingredient content The compound of the present invention 400 mg Corn starch 40 mg Microcrystalline cellulose NF 10 mg Croscarmellose sodium 25 mg Lactose 110 mg Magnesium stearate 5 mg

Formulation Example 2: Capsule preparation

The following ingredients were mixed well and placed in a capsule.

ingredient content The compound of the present invention 250 mg Lactose, spray-dried 148 mg Magnesium stearate 2 mg

Formulation Example 3: Formulation for injection

The following ingredients were mixed to form the injectable formulation.

ingredient content The compound of the present invention 0.2-20 mg Sodium acetate buffer, 0.4 M 20 mL HCl (1 N ) or NaOH (1 N ) A sufficient amount to make a proper pH Water (distilled water, sterilization) A sufficient amount to make a total of 20 mL

Experimental Example

Experimental Example 1. Enzyme activity test

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

Table 4 shows the IC ₅₀ values of the representative compounds obtained using the assay method, and the unit is nM.

compound Escherichia coli Streptococcus Pneumoniae Streptococcus pyogenes Example 1 150 65 70 Example 2 132 77 86 Example 5 102 42 84 Example 9 122 55 83 Example 18 133 46 88 Example 20 102 63 61 Example 22 113 25 42 Example 27 117 42 63 Example 29 155 43 54 Example 30 160 50 62

Experimental Example 2. Antibacterial activity test

The lowest inhibitory concentration (MIC) was determined using a microdilution method in a 96-well plate.

The compounds prepared in the examples and the standard antibiotics linzolide and vancomycin were dissolved in dimethyl sulfoxide at a concentration of 2 mg / mL and stored at 4 ° C until use. This was diluted with Miller-Hinton broth (MHB) and used for MIC determination. The range of concentrations tested was 64-0.0625 μg / mL using a 2-fold dilution system at final concentration. Mueller-Hinton agar plates were inoculated and placed in a 37 ° C incubator. The minimum development inhibition concentration was determined as the lowest antibiotic concentration on the agar after 24 hours of inoculation.

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

The minimum inhibitory concentrations for the compounds of the present invention are shown in Table 5 below.

compound MIC (μg / mL) Methicillin-
resistant Staphylococcus aureus Vancomycin-
resistant
Enterococcus faecalis Vancomycin-
resistant
Enterococcus faecium Penicillin-
resistant Streptococcus
Pneumoniae Example 2 One 2 0.25 0.06 Example 3 16 16 16 2 Example 4 4 16 4 One Example 5 16 16 2 0.5 Example 6 2 8 4 0.5 Example 7 8 16 4 0.5 Example 9 2 One 0.25 0.25 Example 12 4 4 One 0.5 Example 14 2 8 2 0.5 Example 15 4 8 2 0.5 Example 16 8 4 2 0.25 Example 21 One 2 One 0.12 Example 25 One 16 One 0.12 Example 28 One 8 One 0.12 Example 32 One 2 0.5 0.12 Example 34 One 4 0.5 0.12 Linezolid 2 2 2 One Vancomycin 2 > 64 > 64 0.25

Experimental Example 3. Acute Toxicity Test

In order to further clarify the usefulness of the compounds of the present invention as drugs, acute toxicity tests using mice were conducted.

The compounds of the present invention were dissolved in 50% PEG and orally administered for 2 weeks. The results are shown in Table 6.

compound LD ₅₀ (mg / kg) Example 2 > 1,000 Example 18 > 1,000 Example 27 > 1,000

Claims (8)

A compound of formula (I), a racemic mixture, an optical isomer, or a diastereomer or a pharmaceutically acceptable salt thereof:

In the above formulas,
R < ₁ > is hydrogen;
R < _{2 >} is hydrogen or a linear or branched, substituted or unsubstituted C _4-6 cycloalkyl,
C _1-6 alkyl which is branched;
R ₃ is hydrogen or straight or branched C _1-6 alkyl;
k and l are 0 or 1;
A is selected from formulas IIa, IIb and IIc;

Wherein R ₄ , R ₅ , R ₆ , and R ₇ are each independently selected from the group consisting of hydrogen, straight or branched C _1-3 alkyl, straight or branched C _1-3 alkynyl, fluoro , chloro, bromo, C _1-3 alkoxy, and halogen may be selected from the C _1-3 alkyl, cyano, nitro, morpholinyl, and the group consisting of -NH (C = O) Me-substituted,
In the above formula (IIb), R ₈ may be selected from the group consisting of hydrogen, straight or branched C _1-3 alkyl,
Q ₁ can be carbon or nitrogen; Q ₂ can be carbon or nitrogen or oxygen;
m and n are 0 or 1. A compound of formula (I), a racemic mixture, an optical isomer, or a diastereomer or a pharmaceutically acceptable salt thereof:

In the above formulas,
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;
k and l are 0 or 1;
A is selected from formulas IIa, IIb and IIc;

Wherein the R ₄ , R ₅ , R ₆ , R ₇ or R ₈ group is selected from the group consisting of hydrogen, methyl, ethyl, ethynyl, fluoro, chloro, bromo, trifluoromethyl, methoxy, -C , -NH (C = O) Me, cyano, hydroxy, nitro and morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl , 5,6,7,8-tetrahydro-1,6-naphthyridin Lee each optionally substituted, one turn of isobutane, 6,7-dihydro -5 H - pyrrolo [3,4- b] pyridinyl, piperidinyl , piperazinyl, morpholinyl, pyrrolidinyl, imidazolidinyl optionally substituted, optionally substituted oxazolidine, decahydro-isoquinolin-yl, octahydro -1 H - cyclopenta [c] pyridinyl, octahydro -1 H - iso of Lt; / RTI > cyclopenta [ c ] pyrroyl,
Q ₁ can be carbon or nitrogen, Q ₂ can be carbon or nitrogen or oxygen,
m and n are 0 or 1. 2. Compounds of formula I according to claim 1, wherein < RTI ID = 0.0 >
(R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- ( isoindoline-2-yl) -piperidin -1 -Yl) -3,3-dimethyl-1-oxobutan-2-yl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (3,4- dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3, Dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (pyrrolidin- 1 -yl) piperidin- 2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1- (4-morpholinopiperidin- (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (6,7- dimethoxy-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine- 1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (7,8- dihydro-1,6-naphthyridine -6 (5 H) - yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;
(R) - N - (( S) -1- (4- (3,4- dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3,3-dimethyl -1 - oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;
(2 R) -3- cyclopentyl - N - ((2 S) -3,3- dimethyl-1- (4- (octahydro-isoquinolin -2 (1 H) - yl) piperidin-1-yl ) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- ( 6-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- (6- methoxy-3,4-dihydro-isoquinoline -2 (1 H ) -yl) piperidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) propanamide;
(R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1- (4- (7- methoxy-3,4-dihydro-isoquinoline -2 (1 H ) -yl) piperidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) propanamide;
(R) -3- cyclopentyl--2 - ((N - hydroxy-formamido) methyl) - N - ((S) -1 - ((R) -3- ( isoindoline-2-yl) blood L-yl) -3,3-dimethyl-l-oxobutan-2-yl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1- (4- (5- Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (5- fluoro Roy stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1 Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) - N - (( S) -1- (4- (5- chloroisatin stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane-2-one ) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (5- ethyl sweep turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1 Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1 - ((R) -3- (3,4- dihydro-isoquinoline -2 (1 H) - yl) pyrrolidin-1-yl ) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1- (4- (4-methylisisoindolin-2-yl) piperidin- Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (4,5,6,7-tetrafluoroisisoindolin- Piperidin-1-yl) butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (4- fluoro Roy stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1 Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (5,8- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (6,8- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (5,6,8- trifluoro-3,4-dihydroisoquinoline -2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) propanamide;
(R) - N - (( S) -1- (4- (8- chloro-6-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl ) -3,3-dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- ( 5-fluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (-3,4- dihydro-isoquinoline -2 (1 H) ethynyl-7-yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (6,7- difluoro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1-yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) - N - (( S) -1- (4- (4- chloroisatin stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl-1-oxo-butane-2-one ) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (-3,4- dihydro-isoquinoline -2 (1 H) 7-Fluoro-yl) piperidin-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (4,7- difluoro-Roy stamp turned-2-yl) piperidin-1-yl) -3,3-dimethyl -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) - N - (( S) -1- (4- (7- cyano-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3, Dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (5,7,8-trifluoro- -2 (1 H) - yl) piperidin-1-yl) butane-2-yl) -2 - ((N - hydroxy-formamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (4- (6,8- dichloro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidine -1 -Yl) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (8- (trifluoromethyl) -3, 4-dihydroisoquinoline- 2 (1 H ) -yl) piperidin-1-yl) butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (6- (trifluoromethyl) -3,4-dihydroisoquinoline- 2 (1 H ) -yl) piperidin-1-yl) butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1 - ((R) -3- (6,7- dimethyl-3,4-dihydro-isoquinoline -2 (1 H) - yl) blood L -yl) -3,3-dimethyl-l-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) - N - (( S) -1- (3- (3,4- dihydro-isoquinoline -2 (1 H) - yl) azetidin-1-yl) -3,3-dimethyl-1 Oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;
( S ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- Butan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -1- (3- (4,7- difluoro-Roy stamp turned-2-yl) azetidin-1-yl) -3,3-dimethyl- 1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) - N - (( S) -1- (3- (5,6- difluoro-2-yl) azetidine turned stamp Roy-yl) -3,3-dimethyl-1-oxo-butane- 2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;
(R) -3- cyclopentyl - N - ((S) -1- (3- (7,8- dihydro-1,6-naphthyridine -6 (5 H) - yl) azetidin-1-yl ) -3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl-1-oxo-1 - (( R ) -3- (5,6,8-trifluoro- Dihydroisoquinolin-2 ( 1H ) -yl) pyrrolidin-1-yl) butan-2-yl) -2 - (( N -hydoxyformoamido) methyl) propanamide;
(R) - N - (( S) -1- (4- (6- cyano-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3, Dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;
( R ) -3-cyclopentyl- N - (( S ) -3,3-dimethyl- 1 -oxo-1- (4- (piperazin- 1 -yl) piperidin- - yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -3,3- dimethyl-1- (4- (6-morpholino-3,4-dihydro-isoquinoline -2 (1 H) - one ) Piperidin-1-yl) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) - N - (( S) -1- (4- (6- Acetamido-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) 3, Dimethyl-1-oxobutan-2-yl) -3-cyclopentyl-2 - (( N -hydroxyformamido) methyl) propanamide;
(R) -3- cyclopentyl - N - ((S) -3,3- dimethyl-1- (4- (6-nitro-3,4-dihydro-isoquinoline -2 (1 H) - yl) blood Yl) -1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide;
(R) - N - (( S) -3,3- dimethyl-1-oxo-1- (4- (5,6,8- trifluoro-3,4-dihydro-isoquinoline -2 (1 H ) -Yl) piperidin-1-yl) butan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;
(R) - N - (( S) -1- (4- (6,8- dichloro-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3 , 3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;
(R) - N - (( S) -1- (4- (6,7- dimethoxy-3,4-dihydro-isoquinoline -2 (1 H) - blood-yl) piperidine-1-yl) - 3,3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;
(R) - N - (( S) -1- (4- (6,7- dimethyl-3,4-dihydro-isoquinoline -2 (1 H) - yl) piperidin-1-yl) -3 , 3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) hexanamide;
(2 R) -3- cyclopentyl - N - ((2 S) -1- (4- -hexahydro -1 H - cyclopenta [c] pyridine -2 (3 H) - yl) piperidine-1 Yl) -3 - (( N -hydroxyformamido) methyl) propanamide; And
(2 R) -3- cyclopentyl - N - ((2 S) -1- (4- ( hexahydro-cyclopenta [c] pyrrolo -2 (1 H) - yl) piperidin-1-yl) -3-dimethyl-1-oxobutan-2-yl) -2 - (( N -hydroxyformamido) methyl) propanamide, racemate, optical isomer or diastereomer Isomer or a pharmaceutically acceptable salt thereof. A compound of formula (III), a racemic mixture, an optical isomer, or a diastereomer:

Wherein R ₁ , R ₂ , R ₃ , k and l are as defined in claim 1 and R ₉ is methyl, ethyl, tert -butyl, benzyl or tetrahydro- 2H -pyranyl. A compound of formula Va, formula Vb or formula Vc, racemic mixture, optical isomer, or diastereomer or its salt:

Wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , Q ₁ , Q ₂ , k, l, m and n are as defined in claim 1. Reacting a compound of formula (III) with a compound of formula (II'a) or (II'b) or (II'c) or a salt thereof, or a pharmaceutically acceptable salt thereof:

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , A, Q ₁ , Q ₂ , k, l, m and n are as defined in claim 1 , R < ₉ > is methyl, ethyl, tert -butyl, benzyl or tetrahydro- 2H -pyranyl. Reacting a compound of formula (IV) with a compound of formula (Va) or (Vb) or (Vc) or a salt thereof, or a pharmaceutically acceptable salt thereof:

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , A, Q ₁ , Q ₂ , k, l, m and n are as defined in claim 1 , R < ₉ > is methyl, ethyl, tert -butyl, benzyl or tetrahydro- 2H -pyranyl. An antimicrobial composition comprising a therapeutically effective amount of a compound according to claims 1 or 2, or a salt thereof, and a pharmaceutically acceptable carrier.