RU2798336C2 - New compounds for the treatment of mammalian infections - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions includes a compound of formula (I), in which X is either absent or is a bond; in cases where X is absent, the four-membered ring is directly attached to the 6-membered piperidine ring, forming a spirocyclic system; Q is either O or S(O)_p; p = integer in the range 0–2; Y is selected from NR₂R₃, NHC(O)R₄; R₁ is selected from H, F; m = an integer in the range 1–4; one of R₂ and R₃ is H and the other is isoxazolyl; or R₂ and R₃, taken together with the nitrogen to which they are attached, can form a 5-membered heteroaryl with 2 additional heteroatoms representing N; R₄ is independently selected from (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, heteroaryl which is thienyl or furyl, and (C₁-C₆)alkoxy. The group of inventions also includes specific intermediates for the preparation of a compound of formula (I), which are (S)-5-(aminomethyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1- yl)-3,5-difluorophenyl)oxazolidin-2-one; (R)-3-(4-(4-(1,1-dioxythitan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one; (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)oxazolidin-2-one; (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)oxazolidin-2-one; (S)-5-(aminomethyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)oxazolidin-2-one ; (R)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one.

EFFECT: compound of formula (I) with activity against Mycobacterium tuberculosis.

4 cl, 2 tbl, 11 ex

Formula (I)

Description

The field to which the invention relates

The present invention relates to new compounds of formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation. These compounds show activity against Mycobacterium tuberculosis infection.

Prerequisites for the creation of the invention

Tuberculosis (TB) is one of the leading causes of death from infectious diseases in the world. About 33% of the world's population is believed to be infected with Mycobacterium tuberculosis (Mtb), the pathogen that causes TB disease (WHO “Global Tuberculosis Report 2016”, World Health Organization, 2017). Current treatments have the potential to cure drug-susceptible TB, but treatment of drug-resistant or multidrug-resistant TB (MDR-TB) is challenging and requires a two-year course of combination chemotherapy (WHO “Multidrug-Resistant Tuberculosis (MDR-TB) 2016 Update”, World Health Organization, 2016). Resistance to current therapies for MDR-TB and extensively resistant TB (XDR-TB) highlights the need for new drugs with a new mechanism of action.

Linezolid is an approved antibiotic for the treatment of Gram-positive bacterial infections. It has also shown antibacterial activity against the pathogens of mycobacterium tuberculosis . Linezolid and other drugs of the oxazolidinone class inhibit bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosome subunit and interfering with the placement of aminoacyl-tRNA. They do not bind to mammalian cytoplasmic ribosomes, but bind to mitochondrial ribosomes, which are responsible for bone marrow toxicity associated with linezolid and other oxazolidinones. Treatment for TB is long, so linezolid is not suitable for its treatment. Therefore, new oxazolidinones with an improved safety profile are needed that can be used to treat TB. WO 2017015106 describes substituted phenyloxazolidinones for the treatment of tuberculosis. KR 101271224 describes oxazolidinone derivatives containing a bicyclic group having antibacterial activity against Gram-positive bacteria, including various resistant strains. WO 2005054234 describes novel substituted piperidinophenyloxazolidinone derivatives as active ingredients and methods for treating bacterial infection. Other documents are also disclosed that describe the class of oxazolidone inhibitors, including WO 9323384, WO 2002080841, WO 2001042242, WO 2003064415, WO 2009020616, WO 2017070024, WO 2005054234, WO 20020 51819, WO 2017156519, WO 2013044865 and WO 2006059221.

The essence of the invention

The present invention discloses new compounds of formula (I). The compounds of the present invention are useful for treating a human or animal by regulating bacterial protein synthesis. Therefore, the compounds of the present invention are suitable for the treatment of tuberculosis or Mycobacterium infection.

Embodiments of the invention

The main object of the present invention is to provide new compounds of general formula (I), their tautomeric forms, new intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or mixtures thereof, suitable for the treatment of tuberculosis or Mycobacterium infections.

In another embodiment, pharmaceutical compositions are provided containing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, solvates and mixtures thereof, containing pharmaceutically acceptable carriers, solvents, diluents, excipients and other media commonly used in their manufacture.

In yet another embodiment, the use of the novel compounds of the present invention is provided for the treatment of infections in a mammal, such as tuberculosis, by administering to the mammal a therapeutically effective and non-toxic amount of a compound of formula (I) or pharmaceutically acceptable compositions thereof.

In yet another embodiment, a method of treating an infection in a mammal, such as tuberculosis, is provided using a compound of formula (I) or pharmaceutically acceptable compositions thereof in a mammal.

In the latter embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) and a second therapeutic agent for the treatment of infections in a mammal, such as tuberculosis.

Description of the invention

Accordingly, the present invention relates to compounds of formula (I),

Where

X is either absent or is a link; in cases where X is absent, the four-membered ring is directly attached to the 6-membered piperidine ring, forming a spirocyclic system;

Q is either O or S(O) _p ; p = integer in the range 0-2;

Y represents OH, NR ₂ R ₃ , NHC(O)R ₄ ;

R ₁ is selected from H, F, Cl, CH ₃ , CN and OCH ₃ ; m = an integer in the range 1-4;

R₂ and R₃ independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, heterocyclyl and heteroaryl, each of which may be further optionally substituted; R₂ and R₃, taken together with the nitrogen to which they are attached, may form a 4-8 membered heterocyclyl or heteroaryl with 1-3 additional heteroatoms selected from O, S or N and may be further optionally substituted;

R ₄ is independently selected from (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, aryl, heteroaryl, and (C ₁ -C ₆ )alkoxy, each of which may be further optionally substituted;

In an embodiment where any of (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, aryl, heterocyclyl, and heteroaryl groups is optionally substituted, the groups are selected from halo, hydroxyl, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )acyloxy, haloalkyl, NO ₂ , CN and NH ₂ ;

In another embodiment, the groups described above may be selected from the following groups:

- "alkyl" group, used alone or in combination with other radicals, means a linear or branched radical containing from one to six carbon atoms, selected from methyl, ethyl, n- propyl, isopropyl , n- butyl, sec- butyl, t- butyl, amyl, t- amyl, n- pentyl, n-hexyl, etc.;

- "alkoxy" group, used alone or in combination with other radicals, means a linear or branched radical containing from one to six carbon atoms attached to an oxygen atom, selected from methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy , sec- butoxy, iso -butoxy, pentyloxy, hexyloxy, and the like;

- "cycloalkyl" or "alicyclic" group, used alone or in combination with other radicals, is selected from a cyclic radical containing from three to six carbon atoms, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;

the "haloalkyl" group is selected from an alkyl radical as defined above suitably substituted with one or more halogens; for example, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono- or polyhalogenated methyl, ethyl, propyl, butyl, pentyl or hexyl groups;

- the “aryl” or “aromatic” group, used alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings, where such rings can be connected together in the form of pendant pendant groups or can be condensed, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, etc.;

- "heterocyclyl" or "heterocyclic" group, used alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono-, bi- or tricyclic radicals containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2-oxo-piperazinyl, 3-oxo-piperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl , oxapinil, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinone silt, benzothiazinyl, benzothiazinonyl, thienopiperidinyl and the like; In one embodiment, the heterocyclyl group, where applicable, may consist of a suitable number of carbon atoms and include from 1 to 4 heteroatoms selected from the group consisting of N, O and S(O) _p , p = 0-2;

- "heteroaryl" or "heteroaromatic" group, used alone or in combination with other radicals, is selected from suitable single or fused mono-, bi- or tricyclic aromatic heterocyclic radicals containing one or more heteroatoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azachinazole inil, pyridofuranil, pyridothienyl , thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazinyl, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, and the like;

- the "aralkyl" group, used alone or in combination with other radicals, is selected from groups containing an aryl radical as defined above attached directly to an alkyl radical as defined above, more preferably the groups are selected from benzyl, phenethyl, etc. ;

- the "heterocyclylalkyl" group, used alone or in combination with other radicals, is selected from groups containing a heterocyclyl radical, as defined above, attached directly to an alkyl radical, as defined above;

- "spirocyclic system" is a group in which one cyclic ring is attached to another cyclic ring through one carbon atom, which is a common carbon atom for both cyclic rings.

Other preferred embodiments are disclosed below.

Preferred "(C ₁ -C ₆ )alkyl" group R ₂ , R ₃ and R ₄ is selected from methyl, ethyl, n-propyl, isopropyl;

The preferred "(C ₁ -C ₆ )alkoxy" group R ₂ , R ₃ and R ₄ is selected from methoxy and ethoxy;

Preferred "(C ₃ -C ₆ )cycloalkyl" group R ₂ , R ₃ and R ₄ is selected from cyclopropyl and cyclobutyl;

The preferred "heteroaryl" group R ₂ and R ₃ is selected from triazolyl, isoxazolyl, thienyl, furyl.

Suitable groups and substituents on the groups may be selected from those described elsewhere in the present description.

Preferred compounds according to the present invention include, but are not limited to:

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7 -yl)-3,5-difluorophenyl)oxazolidin-2-one;

(S)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-5-((isoxazol-3-ylamino) methyl)oxazolidin-2-one;

(S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide;

(S)-methyl ((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl )methyl)carbamate;

(S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide;

(S)-N-((3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide ;

(S)-N-((3-(3-fluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide;

(S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )acetamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide ;

methyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl ) carbamate;

(S)-5-(aminomethyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)oxazolidin-2-one;

(R)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one;

(S)-5-(aminomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)oxazolidin-2-one;

(S)-5-(aminomethyl)-3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)oxazolidin-2-one;

(S)-5-(aminomethyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)oxazolidin-2-one ;

(R)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one ;

(S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)thiophene-2-carboxamide;

(S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)thiophene-2-carboxamide;

(S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)furan-2-carboxamide;

(S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)furan-2-carboxamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )thiophene-2-carboxamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)thiophene -2-carboxamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )furan-2-carboxamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)furan -2-carboxamide;

(S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)butyramide;

(S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)butyramide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )butyramide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide ;

ethyl-(S)-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)carbamate;

ethyl-(S)-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl) carbamate;

ethyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl ) carbamate;

ethyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)carbamate ;

(S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)cyclopropanecarboxamide;

(S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)cyclopropanecarboxamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )cyclopropanecarboxamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)cyclopropanecarboxamide ;

(S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)cyclobutanecarboxamide;

(S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)cyclobutanecarboxamide;

(S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )cyclobutanecarboxamide;

(S)-N-((3-(4-(4-(1,1-dioxythitan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)cyclobutanecarboxamide ;

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7 -yl)-3-fluorophenyl)oxazolidin-2-one;

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl) -3,5-difluorophenyl)oxazolidin-2-one;

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl) -3-fluorophenyl)oxazolidin-2-one;

(R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7 -yl)-3,5-difluorophenyl)oxazolidin-2-one;

(R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7 -yl)-3-fluorophenyl)oxazolidin-2-one;

(S)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-5-((isoxazol-3-ylamino)methyl) oxazolidin-2-one;

(S)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-5-((isoxazol-3-ylamino)methyl)oxazolidine -2-he;

methyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)carbamate ;

methyl-(S)-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl) carbamate;

methyl-(S)-((3-(3-fluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)carbamate;

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl )phenyl)oxazolidin-2-one;

methyl-(S)-((3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)carbamate ;

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7 -yl)phenyl)oxazolidin-2-one;

(R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1- yl)phenyl)oxazolidin-2-one.

The novel compounds of the present invention can be prepared using the reactions and procedures shown in the scheme below and described in this section. The reactions are carried out in solvents suitable for the reagents and substances used and suitable for the respective transformations. It will be appreciated by those skilled in the art that the nature and order of the synthetic steps presented may be altered in order to optimize the formation of the compounds of the present invention. It is also well known that one or more reactants can be protected and deprotected to facilitate synthesis by methods known to those skilled in the art. It should also be understood that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms. Such stereoisomers and/or diastereoisomers, as well as their optical counterparts, are to be considered as being within the scope of the present invention. It should also be clear that one or more of these compounds can be converted to their salts and other derivatives, based on specific groups present in the compounds, which may be well known to specialists in this field. Such salts and/or other derivatives, as the case may be, should also be considered to be within the scope of the present invention.

Scheme 1: Synthesis of compounds of general formula (I)

Compound(IV) can be obtained by reacting compounds of the formula(II) With (III) in the presence of a base such as sodium carbonate, K₂CO₃, sodium hydride, etc., in solvents such as THF, DMF, MeOH, etc. Compounds of the general formula(v) can be obtained by reduction using stannous chloride dihydrate in ethyl acetate. Compounds of the general formula(VI)can be obtained through interaction(V) with benzyloxycarbonyl chloride, using sodium carbonate as the base, in solvents such as water, ethyl acetate, acetonitrile, or a mixture thereof. Compound formula (I,when Y=OH) can be obtained by treatment with n-butyl lithium and R-glycidyl butyrate in THF. It was then converted to mesylate derivatives(VII)using methanesulfonyl chloride and TEA in solvents such as THF, ACN, etc., which are then reacted with appropriately substituted amines to give the desired compounds (I,when Y=NR ₂ R ₃ ). Connections (I when Y=NH ₂ ) is further reacted with the appropriate acid chloride or anhydride in the presence of a base such as TEA or pyridine to give compounds of the formula(I)with an amide or carbamate bond.

Scheme 2: Synthesis of compounds of general formula (I)

Alternatively, a compound of general formula (V) can be reacted with compounds of formula ( VIII) (prepared according to the procedure described in Tetrahedron: Asymmetry, 7(6) , 1641-1648; 1996 ) in solvents such as MeOH, EtOH and etc., to obtain compounds (IX) . Compounds of general formula (X) can be obtained by cyclization of (X) using CDI in a solvent such as DCM, CHCl ₃ , etc. Compounds ( I) (when Y=NH ₂ ) are prepared by removing the phthalimide protection using aq. methylamine in protic solvents such as MeOH, EtOH, etc. Compounds ( I when Y=NH ₂ ) are further reacted with the appropriate acid chloride or anhydride in the presence of a base such as TEA or pyridine to give compounds of formula (I) with an amide or carbamate linkage.

List of abbreviations

ACN: Acetonitrile

CDI: 1,1'-Carbonyldiimidazole

CHCl ₃ : Chloroform

DCM: Dichloromethane

DMAP: 4-dimethylaminopyridine

DMF: Dimethylformamide

DMSO: Dimethyl Sulfoxide

EtOAc: Ethyl acetate

EtOH: Ethanol

K ₂ CO ₃ : Potassium carbonate

LiAlH ₄ : Lithium aluminum hydride

MeOH: Methanol

NaHCO ₃ : Sodium bicarbonate

Na ₂ SO ₄ : Sodium sulfate

NaOH: Sodium hydroxide

Pd-C: palladium on carbon

TEA: Triethylamine

TFA: Trifluoroacetic acid

THF: Tetrahydrofuran

¹ H NMR: proton nuclear magnetic resonance

h: hour(hours)

min: minute(minutes)

J: Interaction constant in Hz

Hz: Hertz

MABA: microplate assay using alamar blue stain.

Getting connections

EXAMPLE 1

Preparation of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan- 7-yl)-3,5-difluorophenyl)oxazolidin-2-one

Stage 1: N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine

Bis(2-chloroethyl)amine (208 g, 1462 mmol) was added to DCM (200 ml), then a 2M NaOH solution was added and stirred for 30 min. at 25-30°C. The separated DCM layer was dried over Na ₂ SO ₄ and evaporated to give an oil (free amine). To this was added ACN (500 ml), then benzyl bromide (69.5 ml, 585 mmol) and K ₂ CO ₃ (242 g, 1754 mmol) at 25-30°C and stirred for 16 hours at 80°C. The reaction mixture was filtered and the filtrate was evaporated to give a crude oil which was purified by column chromatography using hexane/EtOAc. ESI-MS (m/z): 232.05 [M+H] ⁺ .

Stage 2: diethyl 1-benzylpiperidine-4,4-dicarboxylate

To a stirred solution of the product of step 1 (17 g, 73.2 mmol) in DMF were added K ₂ CO ₃ (30.4 g, 220 mmol), diethyl malonate (11.17 ml, 73.2 mmol) and tetrabutylammonium bromide (2.361 g, 7.32 mmol) at 25-30°C. The reaction mixture was stirred for 16 hours at 90°C. After completion of the reaction, the mixture was diluted with EtOAc and washed with water. The EtOAc layer was dried over Na ₂ SO ₄ and evaporated to give a crude product which was purified by column chromatography using hexane/EtOAc. ESI-MS (m/z): 320.22 [M+H] ⁺ .

Stage 3: (1-benzylpiperidine-4,4-diyl)dimethanol

To a stirred solution of the product of step 2 (26 g, 81 mmol) in THF was added LiAlH ₄ (9.27 g, 244 mmol) at 0°C and the mixture was stirred for 16 hours at 25-30°C. After completion of the reaction, the mixture was cooled to 0°C and diluted with 10 ml of water, then 10 ml of 10% NaOH aqueous solution and filtered through a Hyflow pad. The residue was washed with 10% MeOH in EtOAc. The filtrate was evaporated to give the title product. ESI-MS (m/z): 236.15 [M+H] ⁺ .

Stage 4: piperidine-4,4-diyldimethanol

To a stirred solution of the product of step 3 (4.50 g, 19.12 mmol) in MeOH was added Pd-C (0.407 g, 3.82 mmol) followed by ammonium formate (3.62 g, 57.4 mmol). The reaction mixture was refluxed for 6 hours. After completion of the reaction, the mixture was passed through a hyflow pad and washed with 20% MeOH in EtOAc. The organic layer was distilled off to give the title product. ESI-MS (m/z): 146.10 [M+H] ⁺ .

Stage 5: tert-butyl-4,4-bis(hydroxymethyl)piperidine-1-carboxylate

To a stirred solution of the product of step 4 (9.4 g, 64.7 mmol) in DMF was added TEA (13.54 ml, 97 mmol) and di-tert-butyl dicarbonate (15.03 ml, 64.7 mmol). The reaction mixture was stirred for 3 hours at 25-30°C. After completion of the reaction, the reaction mixture was diluted with EtOAc (150 ml) and washed with water (30 ml). The organic layer was distilled off to give the title product.

Stage 6: tert-butyl-4,4-bis(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

To a stirred solution of the product of step 5 (10 g, 40.8 mmol) in DCM was added TEA (22.92 ml, 163 mmol), then methanesulfonyl chloride (9.46 ml, 122 mmol) was added at 0-5°C and the reaction mixture stirred for 2 hours at 25-30°C. After completion of the reaction, the mixture was diluted with DCM (50 ml) and water (25 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title product.

Stage 7: tert-butyl-2-thia-7-azaspiro[3.5]nonane-7-carboxylate

To a stirred solution of the product of step 6 (4.90 g, 12.20 mmol) in EtOH was added sodium sulfide nonahydrate (3.52 g, 14.65 mmol) and the reaction mixture was refluxed for 16 hours. After completion of the reaction, the mixture was diluted with EtOAc (100 ml). The organic layer was separated, dried over Na ₂ SO ₄ and evaporated to give the crude product, which was purified by column chromatography using hexane/EtOAc to give the title product.

Stage 8: tert-butyl-2-thia-7-azaspiro[3.5]nonane-7-carboxylate 2,2-dioxide

To a round bottom flask was added oxone (9.60 g, 15.61 mmol) in water (45 ml) at 0-5°C. Then the product of step 7 (1.90 g, 7.81 mmol) dissolved in MeOH at 0-5°C was added dropwise. The reaction mixture was stirred at 15-20°C for 4 hours. The reaction mixture was filtered and washed with MeOH (30 ml). MeOH was evaporated and the residue was extracted with DCM. The organic layer was dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the title product as a solid.

Step 9: 7-(2,6-difluoro-4-nitrophenyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide

To a stirred solution of the product of step 8 (0.650 g, 2.361 mmol) in DCM was added TFA (0.903 ml, 11.80 mmol) at 0-5°C and stirred for 3 hours at 25-30°C. After completion of the reaction, DCM was evaporated under reduced pressure to give a crude product which was diluted with DMF (10 ml). To this was added K ₂ CO ₃ (0.946 g, 6.85 mmol) and 1,2,3-trifluoro-5-nitrobenzene (0.404 g, 2.283 mmol) and stirred for 4 hours at 80°C. The reaction mixture was then diluted with water, the resulting solid was filtered to give the title product. ESI-MS (m/z): 333.14 [M+H] ⁺ .

Step 10: 7-(4-Amino-2,6-difluorophenyl)-2-thia-7-azaspiro[3.5]nonane 2,2-dioxide

To a stirred solution of the product of step 9 (0.690 g, 2.076 mmol) in EtOAc was added tin(II) chloride dihydrate (2.342 g, 10.38 mmol) and stirred for 1.5 hours at 80°C. After completion of the reaction, the mixture was cooled to 25°C and made basic with an aqueous solution of ammonia. The EtOAc was decanted off and the residue was re-extracted with EtOAc. The combined EtOAc layer was dried over Na ₂ SO ₄ and concentrated to give the title product. ESI-MS (m/z): 303.15 [M+H] ⁺ .

Step 11: Benzyl (4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)carbamate

To a stirred solution of the product of step 10 (0.535 g, 1.770 mmol) in THF was added NaHCO ₃ (0.223 g, 2.65 mmol) and benzyl chloroformate (0.785 g, 2.300 mmol) at 0-5°C. The reaction mixture was stirred at 25-30°C for 7 hours. After completion of the reaction, the mixture was diluted with EtOAC and water. The organic layer was separated, dried and evaporated under reduced pressure to give a crude product which was purified by column chromatography using hexane/EtOAc to give a pure product. ESI-MS (m/z): 437.16 [M+H] ⁺ .

Step 12: (R)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin- 2nd

To a stirred solution of the product of step 11 (830 mg, 1.902 mmol) in anhydrous THF was added n-butyllithium (2.282 ml (2.5 M), 5.70 mmol) at -78°C. The resulting light yellow solution was stirred at -78°C for 1 hour and then (R)-glycidyl butyrate (685 mg, 4.75 mmol) was added dropwise at -70-75°C. The reaction mixture was stirred for another 1 hour at -78°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with water and EtOAc. The organic layer was separated, dried over Na₂SO₄ and concentrated to give the crude product as an oil. The crude product was purified by column chromatography to obtain the product specified in the header. ESI-MS (m/z): 403.14 [M+H]⁺.

Step 13: (R)-(3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl methanesulfonate

To a stirred solution of the product of step 12 (220 mg, 0.547 mmol) in DCM was added TEA (0.133 ml, 0.957 mmol) and methanesulfonyl chloride (0.047 ml, 0.601 mmol) at 0-5°C. The reaction mixture was stirred for 2 hours at 25-30°C. After completion of the reaction, the mixture was diluted with DCM and washed with water. The DCM layer was separated, dried over Na ₂ SO ₄ and evaporated to give the title product. ESI-MS (m/z): 481.16 [M+H] ⁺ .

Step 14: (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5] nonan-7-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of the product of step 13 (100 mg, 0.208 mmol) in DMF was added 1H-1,2,3-triazole (0.024 mL, 0.416 mmol) and K₂CO₃ (57.5 mg, 0.416 mmol). The reaction mixture was heated to 80°C. After completion of the reaction, the mixture was diluted with EtOAc and water. The EtOAc layer was separated, washed with water, dried over Na₂SO₄ and concentrated to give the crude product. The crude product was purified by column chromatography to obtain the product specified in the header.¹H NMR (DMSO-d ₆): 8.16 (s, 1H), 7.77 (s, 1H), 7.22 (d,J= 8.4 Hz, 2H), 5.23 (m, 1H), 5.17-5.11(m, 2H), 4.83-4.81(m, 1H), 4.21-4.17(m, 1H), 4.03(s, 4H) , 3.87-3.84 (m, 1H), 3.01 (s, 4H), 1.95 (s, 4H). ESI-MS (m/z): 454.12 [M+H]⁺.

EXAMPLE 2

Preparation of (S)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-5-((isoxazol-3-ylamino )methyl)oxazolidin-2-one

Step 1: (R)-tert-butyl((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2- oxooxazolidin-5-yl)methyl)(isoxazol-3-yl)carbamate

To a stirred solution of (R)-(3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl methanesulfonate (100 mg, 0.208 mmol) in DMF was added tert-butylisoxazol-3-ylcarbamate (57.5 mg, 0.312 mmol) and K₂CO₃ (57.5 mg, 0.416 mmol). The reaction mixture was stirred at 80°C for 3 hours. After completion of the reaction, the mixture was diluted with EtOAc and water. The EtOAc layer was separated, dried over Na₂SO₄ And concentrated to give the crude product, which was purified by column chromatography using EtOAc:hexane to give the title product. ESI-MS (m/z): 569.16 [M+H]⁺.

Step 2: (S)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-5-((isoxazol-3 -ylamino)methyl)oxazolidin-2-one

To a stirred solution of step 1 (70 mg, 0.123 mmol) in DCM (10 ml) was added TFA (0.047 ml, 0.616 mmol) at 0-5° C. and stirred for 2 hours. After completion of the reaction, the mixture was diluted with EtOAc and washed with saturated NaHCO₃. The organic layer was separated, dried over Na₂SO₄ and concentrated to give the crude product. The crude product was purified by column chromatography using EtOAc:hexane to give the title product.¹H NMR (DMSO): 8.39 (d,J=1.6 Hz, 1H), 7.25 (d,J=11.6 Hz, 2H), 6.52 (t, 1H), 5.99 (d,J=2.0 Hz, 1H), 5.89 (m, 1H), 4.11 (m, 1H), 4.02 (s, 4H), 3.79-3.77 (s, 1H), 3.44-3.41 (m, 2H), 3.03-3.00 (m, 4H), 1.90-1.88 (m, 4H). ESI-MS (m/z): 469.12 [M+H]⁺.

EXAMPLE 3

Preparation of (S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5 -yl)methyl)acetamide

Step 1: (R)-5-(azidomethyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)oxazolidin- 2nd

To a stirred solution of (R)-(3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl methanesulfonate (380 mg, 0.791 mmol) in DMF was added sodium azide (257 mg, 3.95 mmol) and stirred for 16 hours at 60-65°C. After completion of the reaction, the mixture was diluted with EtOAc and water. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give the title product. ESI-MS (m/z): 428.05 [M+H] ⁺ .

Step 2: (S)-5-(aminomethyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)oxazolidin- 2nd

To a stirred solution of the product of step 1 (0.330 g, 0.772 mmol) in MeOH (5 ml) was added Pd-C (0.016 g, 0.154 mmol) at 0°C. Sodium borohydride (0.088 g, 2.316 mmol) was then added in portions and stirred for 3 hours at 25-30°C. After completion of the reaction, the mixture was passed through a hyflow pad and washed with EtOAc (50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give the title product. ESI-MS (m/z): 402.09 [M+H] ⁺ .

Step 3: (S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidine -5-yl)methyl)acetamide

To a stirred solution of the product of step 2 (150 mg, 0.374 mmol) in DCM were added pyridine (0.030 ml, 0.374 mmol) and acetic anhydride (0.035 ml, 0.374 mmol) and stirred for 3 hours at 25-30°C. After completion of the reaction, the mixture was diluted with water and the product was extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated to give the crude product, which was purified by column chromatography to give the title product.¹H NMR (DMSO-d ₆): 8.24 (t,J=5.8 Hz, 1H), 7.23 (dd,J=5.2 and 16.8 Hz, 2H), 4.74-4.70 (m, 1H), 4.10-4.05 (m, 1H), 4.03 (s, 4H), 3, 70-3.68 (m, 1H), 3.41-3.38 (m, 2H), 3.01-3.00 (m, 4H), 1.91-1.87 (m, 4H), 1.83 (s, 4H). ESI-MS (m/z): 444.20 [M+H]⁺.

EXAMPLE 4

Preparation of (S)-methyl((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)carbamate

To a stirred solution of (S)-5-(aminomethyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)oxazolidin- 2-one (100 mg, 0.249 mmol) in DCM was added pyridine (0.030 ml, 0.374 mmol) followed by methyl chloroformate (0.023 ml, 0.299 mmol) and stirred for 3 hours at 25-30°C. After completion of the reaction, the mixture was diluted with water and the product was extracted with DCM (20 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give the crude product, which was purified by column chromatography to give the title product. ¹ H NMR (DMSO- d ₆ ): 7.53 (br. s, 1H), 7.24 (d, J=12 Hz, 2H), 4.73 (s, 1H), 4.10-4, 06 (m, 2H), 4.02 (s, 4H), 3.741-3.61 (m, 2H), 3.40 (s, 3H), 3.19-3.13 (m, 4H), 1 .89 (m, 4H). ESI-MS (m/z): 460.17 (M+H) ⁺ .

EXAMPLE 5

Preparation of (S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl )methyl)acetamide

Prepared using a method similar to that described in Example 3. ¹ H NMR (DMSO- d ₆ ): 8.24 (t, 1H), 7.49-7.45 (m, 1H), 7.18-7.16 (m, 1H), 7.07-7.03 (m, 1H), 4.72 (m, 1H), 4.10-4.05 (m, 1H), 4.02 (s, 4H), 2.94-2.91 (m, 4H), 1.95-1.92 (m, 4H), 1.24 (s, 3H). ESI-MS (m/z): 426.14 [M+H] ⁺ .

EXAMPLE 6

Preparation of (S)-N-((3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl) acetamide

Stage 1: tert-butyl-2-oxa-7-azaspiro[3.5]nonane-7-carboxylate

To a stirred solution of tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate (880 mg, 3.59 mmol) in THF was added n-butyllithium (1.435 ml, 3.59 mmol) dropwise at 0-5 °C The reaction mixture was stirred at 0-5°C for 30 min. To the mixture was added a solution of p-toluenesulfonyl chloride (684 mg, 3.59 mmol) in THF dropwise at 0-5°C. The reaction mixture was stirred at 0-5°C for 30 min. To this was added n-butyllithium (1.435 ml, 3.59 mmol) at 0-5°C. The reaction mixture was heated at 60°C for 2 hours. The reaction mixture was poured into water and the product was extracted with EtOAC. The organic layer was distilled off to give a crude product, which was purified by column chromatography using hexane/EtOAc to give a pure product.

Stage 2: 7-(2,6-difluoro-4-nitrophenyl)-2-oxa-7-azaspiro[3.5]nonane

To a stirred solution of the product of step 1 (840 mg, 3.70 mmol) in DCM was added TFA (1.4 ml, 18.48 mmol) at 0-5°C and stirred for 3 hours at 25-30°C. After completion of the reaction, DCM was evaporated under reduced pressure to give a crude product which was diluted with DMF. To this was added K ₂ CO ₃ (1.17 g, 8.47 mmol) and 1,2,3-trifluoro-5-nitrobenzene (600 mg, 3.39 mmol) and stirred for 4 hours at 80°C. The reaction mixture was diluted with water to give a solid product. ESI-MS (m/z): 285.08 [M+H] ⁺ .

Step 3: 3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)aniline

To a stirred solution of the product of step 2 (720 mg, 2.53 mmol) in THF (10 ml) was added Pd-C (27 mg) and stirred under hydrogen pressure for 16 hours at 25°C. After completion of the reaction, the mixture was passed through a hyflow pad and the solvent was evaporated to give the title product. ESI-MS (m/z): 255.10 [M+H] ⁺ .

Stage 4: benzyl(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)carbamate

To a stirred solution of the product of step 3 (700 mg, 2.75 mmol) in THF (10 ml) was added NaHCO ₃ (925 mg, 11.01 mmol) and benzyl chloroformate (0.865 ml, 3.03 mmol) at 0°C. The reaction mixture was stirred at 25-30°C for 16 hours. After completion of the reaction, the mixture was diluted with EtOAc and water. The organic layer was evaporated under reduced pressure to give a crude product. The crude product was purified by column chromatography using hexane/EtOAc to give the title product. ESI-MS (m/z): 389.16 [M+H] ⁺ .

Stage 5: (R)-3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

To a stirred solution of the product of step 4 (540 mg, 1.390 mmol) in anhydrous THF was added n-butyllithium (0.612 ml, 1.529 mmol) at -78°C. The resulting light yellow solution was stirred at -78°C for 1 hour and then (R)-glycidyl butyrate (220 mg, 1.529 mmol) was added dropwise at -70°C. The reaction mixture was stirred for another 1 hour at -78°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction, the mixture was poured into an aqueous ammonium chloride solution and the crude product was extracted with EtOAc, then purified by column chromatography to give the title product. ESI-MS (m/z): 355.14 [M+H] ⁺ .

Stage 6: (R)-(3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate

To a stirred solution of the product of step 5 (316 mg, 0.892 mmol) in DCM was added TEA (0.162 ml, 1.159 mmol) and methanesulfonyl chloride (0.07 ml, 0.936 mmol) at 0°C. The reaction mixture was stirred for 2 hours at 25-30°C. After completion of the reaction, the mixture was diluted with DCM (10 ml) and washed with water. The DCM layer was dried over Na ₂ SO ₄ and distilled off to give the title product. ESI-MS (m/z): 433.12 [M+H] ⁺ .

Stage 7: (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)oxazolidin-2-one

To a stirred solution of the product of step 6 (397 mg, 0.918 mmol) in DMF was added sodium azide (298 mg, 4.59 mmol) and stirred for 3 hours at 60-65°C. After completion of the reaction, the mixture was diluted with water and filtered to give the title product. ESI-MS (m/z): 380.14 [M+H] ⁺ .

Stage 8: (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)oxazolidin-2-one

To a stirred solution of the product of step 7 (242 mg, 0.638 mmol) in MeOH was added Pd-C at 0-5°C. Sodium borohydride (72.4 mg, 1.914 mmol) was then added in portions and stirred for 3 hours at 25-30°C. After completion of the reaction, the mixture was passed through a hyflow pad and washed with EtOAc (20 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give the title product. ESI-MS (m/z): 354.15 [M+H] ⁺ .

Stage 9: (S)-N-((3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide

To a stirred solution of the product of step 8 (100 mg, 0.283 mmol) in DCM was added pyridine (0.034 ml, 0.424 mmol) and acetic anhydride (0.037 ml, 0.396 mmol). The reaction mixture was stirred for 1 hour at 25-30°C. After completion of the reaction, the mixture was diluted with DCM and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give the title product. ¹ H NMR (DMSO- d ₆ ): 8.22 (t, J =5.8 Hz, 1H), 7.23 (d, J =11.6 Hz, 2H), 4.73-4.70 ( m, 1H), 4.34 (s, 4H), 4.09-4.05 (m, 1H), 3.70-3.66 (m, 1H), 3.40-3.37 (m, 2H), 2.96-2.93(m, 4H), 1.99-1.86(m, 4H), 1.83(s, 3H). ESI-MS (m/z): 396.16 (M+H) ⁺ .

EXAMPLE 7

Preparation of (S)-N-((3-(3-fluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide

Received in accordance with the procedure similar to that described in example 6, using appropriate modifications. ¹ H NMR (CDCl ₃ ): 7.41 (dd, J =2.4 and 14.0 Hz, 1H), 7.08-7.06 (m, 1H), 6.95-6.90 (m , 1H), 5.99 (m, 1H), 4.78-4.77 (m, 1H), 4.50 (s, 4H), 4.05-4.01 (m, 1H), 3, 77-3.75 (m, 2H), 3.73-3.70 (m, 1H), 2.96-2.93 (m, 4H), 2.07-2.04 (m, 7H). ESI-MS (m/z): 378.15 (M+H) ⁺

EXAMPLE 8

Preparation of (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide

Step 1: (R)-2-(3-((3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)amino)-2-hydroxypropyl)isoindoline-1 ,3-dione

A stirred solution of (S)-2-(oxiran-2-ylmethyl)isoindolin-1,3-dione (1.988 g, 9.78 mmol) and 3,5-difluoro-4-(4-(oxetan-3-yl) piperidin-1-yl)aniline (1.50 g, 5.59 mmol) in aq. EtOH was heated at 100°C for 4 hours. At 80° C., another portion of (S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (1.988 g, 9.78 mmol) was added and stirring was continued for 16 hours. The reaction mixture was filtered to give the title product. ESI-MS (m/z): 472.16 [M+H] ⁺ .

Step 2: (S)-2-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl )isoindoline-1,3-dione

To a stirred solution of the product of step 1 (2.0 g, 4.24 mmol) in CHCl ₃ was added CDI (2.75 g, 16.97 mmol) at 25-30°C. The reaction mixture was stirred at 70°C for 5 hours. The solvent was distilled off and the reaction mixture was acidified with 35% hydrochloric acid to pH=2. The product was extracted with DCM. The organic layer was separated, dried over Na ₂ SO ₄ and distilled off to give the title product. ESI-MS (m/z): 498.14 [M+H] ⁺ .

Step 3: (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)oxazolidin-2-one

To a stirred solution of the product of step 2 (1.90 g, 3.82 mmol) in EtOH was added an aqueous solution of methylamine (2.97 g, 38.2 mmol) at 25-30°C. The reaction mixture was stirred at 80°C for 3 hours. After complete conversion of the starting material, the reaction mixture was diluted with DCM (100 ml) and washed with cold water. The organic layer was dried over Na₂SO₄ and distilled off by distillation to give the title product as a solid. ESI-MS (m/z): 368.15 [M+H]⁺.

Step 4: (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl )acetamide

To a stirred solution of the product of step 3 (1.00 g, 2.72 mmol) in DCM were added pyridine (0.330 ml, 4.08 mmol) and acetic anhydride (0.360 ml, 3.81 mmol) and stirred for 2 hours at 25 -30°C. After complete conversion of the starting material, the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried over Na₂SO₄ and distilled off to give the crude product, which was purified by preparative HPLC to give the title product as a white solid.¹H NMR (DMSO): 8.23 (t, 1H), 7.28-7.21 (m, 2H), 4.75-4.69 (m, 1H), 4.63-4.60 (m , 2H), 4.38-4.35 (m, 2H), 4.10-4.05 (m, 1H), 3.70-3.66 (m, 1H), 3.43-3.38 (m,1H), 3.11-2.97(m, 4H), 2.78-2.72(m, 1H), 1.83(s, 3H), 1.76-1.71(m, 1H) , 1.68-1.60 (m, 2H), 1.19-1.06 (m, 2H). ESI-MS (m/z): 410.16 [M+H]⁺.

EXAMPLE 9

Preparation of (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide

Stage 1: tert-butyl-4-oxo-piperidine-1-carboxylate

To a stirred suspension of piperidin-4-one hydrochloride (30 g, 221 mmol) in anhydrous DCM was added TEA (83 mL, 597 mmol) followed by di-tert-butyl dicarbonate (64.2 mL, 277 mmol) dropwise over 15 minutes at 10-15°C. The resulting mixture was stirred at 25-30°C for 16 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the title product.

Stage 2: diethyl 2-(1-(tert-butoxycarbonyl)piperidine-4-ylidene)malonate

Stirred TiCl solution₄ (52.0 ml, 472 mmol) in carbon tetrachloride (40 ml) was added to THF (150 ml) at 0°C. A solution of the product of step 1 (37.3 g, 187 mmol) and diethyl malonate (25.7 ml, 168 mmol) in THF (150 ml) was then added at 0° C. and stirred for 15 min. To this was added pyridine (98 ml, 1217 mmol) and stirred for 16 hours at 25-30°C. The reaction mixture was poured into 10% citric acid solution and the product was extracted with EtOAc. The organic layer was separated, dried over Na₂SO₄And evaporated under reduced pressure to give the title product.

Step 3: diethyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)malonate

To a stirred solution of the product of step 2 (63 g, 185 mmol) in EtOH was added sodium borohydride (6.98 g, 185 mmol) and stirred for 2 hours at 25-30°C. After complete conversion of the starting material, the reaction mixture was poured into ice water and extracted with DCM. The organic layer was separated, dried over Na₂SO₄And evaporated under reduced pressure to give the title product.

Stage 4: tert-Butyl-4-(1,3-dihydroxypropan-2-yl)piperidine-1-carboxylate

To a stirred solution of the product of step 3 (63 g, 183 mmol) in EtOH (315 ml) was added sodium borohydride (69.4 g, 1834 mmol) at 25-30°C and the resulting mixture was stirred at 70°C for 3 hours. After complete conversion of the starting material, the reaction mixture was diluted with cold water and extracted with EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the title product.

Stage 5: tert-Butyl-4-(1,3-bis(tosyloxy)propan-2-yl)piperidine-1-carboxylate

To a stirred solution of the product of step 4 (10 g, 38.6 mmol) in DCM was added TEA (21.50 ml, 154 mmol) and DMAP (9.42 g, 77 mmol). Then p-toluenesulfonyl chloride (22.05 g, 116 mmol) was added portionwise at 0-5°C. The reaction mixture was stirred at 25-30°C for 3 hours. After completion of the reaction, the reaction mixture was diluted with DCM and washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the title product.

Stage 6: tert-Butyl-4-(thietan-3-yl)piperidine-1-carboxylate

To a stirred solution of the product of step 5 (12.1 g, 21.31 mmol) in DMF was added sodium sulfide nonahydrate (6.14 g, 25.6 mmol) and the reaction mixture was heated at 80-85°C for 16 hours. After completion of the reaction, the mixture was diluted with EtOAc and water. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give an oily product. The crude product was purified by column chromatography using hexane/EtOAc to give the title product.

Stage 7: tert-Butyl-4-(1,1-dioxidothietan-3-yl)piperidine-1-carboxylate

To a stirred solution of the product of step 6 (5.5 g, 21.371 mmol) in DCM was added meta-chloroperbenzoic acid (18.44 g, 107 mmol) and stirred for 4 hours at 25-30°C. After completion of the reaction, the mixture was diluted with DCM and washed with an aqueous solution of NaHCO ₃ . The DCM layer was separated, dried over Na ₂ SO ₄ and concentrated to give the title product. ¹ H NMR (CDCl ₃ ): 4.19-3.99 (m, 4H), 3.88-3.85 (m, 2H), 2.70-2.60 (m, 2H), 2.45 -2.41(m, 1H), 2.35-2.22(m, 1H), 1.87-1.86(m, 2H), 1.55(s, 9H), 1.21-1 ,1 (m, 2H).

Stage 8: 3-(1-(2,6-difluoro-4-nitrophenyl)piperidin-4-yl)thietan-1,1-dioxide

To a stirred solution of the product of step 7 (5.5 g, 19.01 mmol) in DCM was added TFA (2.93 ml, 38.0 mmol) at 0°C and stirred for 3 hours at 25-30°C. After completion of the reaction, the DCM was evaporated to give a crude product which was diluted with DMF. To this was added K ₂ CO ₃ (5.39 g, 39.0 mmol) and 1,2,3-trifluoro-5-nitrobenzene (2.3 g, 12.99 mmol) and stirred for 4 hours at 80° C. The reaction mixture was diluted with water to give the product as a solid. ESI-MS (m/z): 347.07 [M+H] ⁺ .

Stage 9: 3-(1-(4-Amino-2,6-difluorophenyl)piperidin-4-yl)thietan-1,1-dioxide

To a stirred solution of the product of step 8 (2.3 g, 6.64 mmol) in THF was added Pd-C (71 mg) and stirred under hydrogen pressure for 3 hours at 25-30°C. After completion of the reaction, the mixture was passed through a hyflow pad and the solvent was evaporated to give the title product. ESI-MS (m/z): 317.10 [M+H] ⁺ .

Stage 10: benzyl (4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)carbamate

To a stirred solution of the product of step 9 (2.14 g, 6.76 mmol) in THF was added NaHCO ₃ (2.27 g, 27.1 mmol) and benzyl chloroformate (2.124 ml, 7.44 mmol) at 0-5°C . The reaction mixture was stirred at 25-30°C for 7 hours. After completion of the reaction, the mixture was diluted with EtOAc and water. The organic layer was separated and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography using hexane/EtOAc to give the title product. ESI-MS (m/z): 451.10 [M+H] ⁺ .

Stage 11: (R)-3-(4-(4-(1,1-Dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one

To a stirred solution of the product of step 10 (2.47 g, 5.48 mmol) in anhydrous THF was added n-butyllithium (2.41 ml, 6.03 mmol) at -78°C. The resulting light yellow solution was stirred at -78°C for 1 hour and then (R)-glycidyl butyrate (0.869 g, 6.03 mmol) was added dropwise at -70°C. The reaction mixture was stirred for another 1 hour at -78°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction, the mixture was poured into an aqueous ammonium chloride solution and the crude product was extracted with EtOAc, then purified by column chromatography to give the title product. ESI-MS (m/z): 439.10 [M+Na] ⁺ .

Stage 12: (R)-(3-(4-(4-(1,1-Dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate

To a stirred solution of the product of step 11 (590 mg, 1.417 mmol) in DCM was added TEA (0.257 ml, 1.842 mmol) and methanesulfonyl chloride (0.116 ml, 1.488 mmol) at 0-5°C. The reaction mixture was stirred for 2 hours at 25-30°C. After completion of the reaction, the mixture was diluted with DCM and washed with water. The DCM layer was dried over Na ₂ SO ₄ and distilled off to give the title product. ESI-MS (m/z): 495.10 [M+H] ⁺ .

Stage 13: (R)-5-(azidomethyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of the product of step 12 (650 mg, 1.314 mmol) in DMF was added sodium azide (427 mg, 6.57 mmol) and stirred for 3 hours at 60-65°C. After completion of the reaction, the mixture was diluted with water and filtered to give the title product. ESI-MS (m/z): 442.17 [M+H] ⁺ .

Stage 14: (S)-5-(aminomethyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)oxazolidin-2-one

To a stirred solution of the product of step 13 (500 mg, 1.133 mmol) in MeOH was added Pd-C (12 mg) at 0-5°C. Then sodium borohydride (129 mg, 3.40 mmol) was added in portions and stirred for 3 hours at 25-30°C. After completion of the reaction, the mixture was passed through a hyflow pad and washed with EtOAc (50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give the title product. ESI-MS (m/z): 416.15 [M+H] ⁺ .

Stage 15: (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )acetamide

To a stirred solution of the product of step 14 (200 mg, 0.481 mmol) in DCM (5 mL) were added pyridine (0.058 mL, 0.722 mmol) and acetic anhydride (0.064 mL, 0.674 mmol). The reaction mixture was stirred for 1 hour at 25-30°C. After completion of the reaction, the mixture was diluted with DCM and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give the title product. ¹ H NMR (DMSO- d ₆ ): 8.23 (t, J =5.8 Hz, 1H), 7.28-7.23 (m, 2H), 4.74-4.70 (m, 1H ), 4.19-4.15 (m, 2H), 4.13-1.05 (m, 1H), 4.01-3.96 (m, 2H), 3.70-3.66 (m , 1H), 3.41-3.39 (m, 2H), 3.12-3.10 (m, 2H), 2.99-2.94 (m, 2H), 2.30-2.27 (m, 1H), 1.83 (s, 3H), 1.71-1.68 (m, 2H), 1.57-1.54 (m, 1H), 1.27-1.21 (m , 2H). ESI-MS (m/z): 458.18 (M+H) ⁺

EXAMPLE 10

Preparation of (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide

Received in accordance with the procedure similar to that described in example 9, using appropriate modifications. ¹ H NMR (DMSO- d ₆ ): 8.24 (t, 1H), 7.44 (dd, J =2.4 and 14.8 Hz, 1H), 7.16-7.14 (m, 1H ), 7.09-7.06 (m, 1H), 4.72 (m, 1H), 4.20-4.10 (m, 2H), 4.07-4.02 (m, 1H), 4.01-3.97 (m, 2H), 3.71-3.67 (m, 1H), 3.40 (t, 2H), 3.29 (br. s, 2H), 2.62- 2.59 (m, 2H), 2.35-2.28 (m, 1H), 1.83 (s, 3H), 1.70-1.82 (m, 2H), 1.51-1, 62 (m, 1H), 1.23-1.34 (m, 2H). ESI-MS (m/z): 440.12 (M+H) ⁺ .

EXAMPLE 11

Preparation of methyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl) methyl) carbamate

To a stirred solution of (S)-5-(aminomethyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)oxazolidin-2-one (100 mg, 0.241 mmol) pyridine (0.029 ml, 0.361 mmol) and methyl chloroformate (0.026 ml, 0.337 mmol) were added to DCM. The reaction mixture was stirred for 1 hour at 25-30°C. After completion of the reaction, the mixture was diluted with DCM. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give the title product. ¹ H NMR (CDCl ₃ ): 7.53 (t, 1H), 7.50 (d, J =5.6 Hz, 2H), 4.73-4.70 (m, 1H), 4.19- 4.15 (m, 2H), 4.13-4.10 (m, 1H), 4.08-3.96 (m, 2H), 3.74-3.70 (m, 1H), 3. 54 (s, 3H), 3.12-3.00 (m, 2H), 2.97-2.94 (m, 2H), 2.30-2.26 (m, 1H), 1.71- 1.68 (m, 2H), 1.57-1.55 (m, 1H), 1.24-1.21 (m, 4H). ESI-MS (m/z): 474.151 (M+H) ⁺ .

Using suitable starting materials and suitable modifications to the process described in the examples above, including the appropriate addition and/or deletion of steps as necessary, which is within the skill of the art, the following compounds were prepared in a similar manner.

Table 1 Ex. No. Name according to IUPAC ESI-MS (m/z) (M+H) ⁺ 12 (S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)thiophene-2-carboxamide 512.17 13 (S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)thiophene-2-carboxamide 494.15 14 (S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)furan-2-carboxamide 496.12 15 (S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)furan-2-carboxamide 478.15 16 (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )thiophene-2-carboxamide 526.13 17 (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)thiophene -2-carboxamide 508.16 18 (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )furan-2-carboxamide 510.17 19 (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)furan -2-carboxamide 492.11 20 (S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)butyramide 472.14 21 (S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)butyramide 544.2 22 (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )butyramide 486.14 23 (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)butyramide 468.16 24 ethyl-(s)-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)carbamate 474.15 25 ethyl-(s)-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl) carbamate 456.13 26 ethyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl ) carbamate 488.14 27 ethyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)carbamate 470.16 28 (S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)cyclopropanecarboxamide 470.12 29 (S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)cyclopropanecarboxamide 452.14 thirty (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )cyclopropanecarboxamide 484.18 31 (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)cyclopropanecarboxamide 466.15 32 (S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)cyclobutanecarboxamide 484.18 33 (S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)cyclobutanecarboxamide 466.15 34 (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )cyclobutanecarboxamide 498.16 35 (S)-N-((3-(4-(4-(1,1-dioxythitan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)cyclobutanecarboxamide 480.2 36 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7 -yl)-3-fluorophenyl)oxazolidin-2-one 436.12 37 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl) -3,5-difluorophenyl)oxazolidin-2-one 468.13 38 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl) -3-fluorophenyl)oxazolidin-2-one 450.14 39 (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7 -yl)-3,5-difluorophenyl)oxazolidin-2-one 454.12 40 (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7 -yl)-3-fluorophenyl)oxazolidin-2-one 436.12 41 (S)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-5-((isoxazol-3-ylamino)methyl) oxazolidin-2-one 451.12 42 (S)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-5-((isoxazol-3-ylamino)methyl)oxazolidine -2-he 483.16 43 methyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)carbamate 456.18 44 methyl-(S)-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl) carbamate 442.15 45 methyl-(S)-((3-(3-fluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)carbamate 394.11 46 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl )phenyl)oxazolidin-2-one 388.18 47 methyl-(S)-((3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)carbamate 412.14 48 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7 -yl)phenyl)oxazolidin-2-one 406.15 49 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1- yl)phenyl)oxazolidin-2-one 420.17

Biological assessment:

Determination of minimum inhibitory concentration (MIC)

To evaluate the inhibitory effect of the compounds of the invention on bacterial growth, a MABA assay was performed using a culture of Mycobacterium tuberculosis H37Rv in the logarithmic growth phase. A bacterial culture with an optical density of 0.6-0.8 was diluted to a final density of 0.02 in 7H9 medium. 100 μl of diluted Mycobacterium tuberculosis H37Rv was incubated with test compounds in a microtiter plate. A drug-free control containing DMSO was also prepared. After the compound was incubated with the culture for 7 days at 37° C., 20 µl of 0.02% Alamar Blue solution (freshly prepared) was added to each well. The color was allowed to develop for 16 hours at 37°C. A blue color in the well indicated no growth, while a pink color indicated growth in the well. The MIC value was defined as the lowest concentration that prevents a color change from blue to pink. Fluorescence was measured with excitation at 530 nm and emission at 590 nm. The MIC values of the selected compounds are shown in Table 2 .

table 2 Example Mtb MIC (µM) 1 1.25 2 1.25 3 1.25 4 1.25 5 1.25 6 1.25-2.5 7 2.5 8 2.5 9 1.25 10 2.5

The novel compounds of the present invention may be formulated into suitable pharmaceutically acceptable compositions by combination with suitable excipients using well known procedures, methods and concentrations. A pharmaceutical composition containing the compounds of the present invention may contain a suitable binder, a suitable excipient and/or diluent, and any other suitable agents that may be necessary.

The novel compounds of the present invention can be used to treat infections such as tuberculosis in mammals by administering a therapeutically active and non-toxic amount of the compounds of formula (I) or pharmaceutically acceptable compositions thereof.

A method of treating a tuberculosis infection in a subject, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a suitable pharmaceutical composition thereof.

Pharmaceutical compositions of the present invention may exist in various forms. In some embodiments, the pharmaceutical composition is for topical, oral, or parenteral administration.

One or more additional pharmaceutical agents or treatments may be used in combination with the compounds of the present invention to treat or prevent infection in a mammal. Therapeutic agents may be combined with the compounds of the present invention in a single dosage form, or the agents may be administered simultaneously or sequentially in separate dosage forms. The compound of formula (I) can be administered in combination with other therapeutic agents such as isoniazid, rifampin, rifapentine, rifabutin, ethambutol, pyrazinamide, streptomycin, amikacin, levofloxacin, ofloxacin, para-aminosalicylic acid.

Although the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims (31)

1. Compounds of general formula (I),

formula (I) Where X is either missing or is a link; in cases where X is absent, the four-membered ring is directly attached to the 6-membered piperidine ring, forming a spirocyclic system; Q is either O or S(O) _p ; p = integer in the range 0-2; Y is selected from NR ₂ R ₃ , NHC(O)R ₄ ; R ₁ is selected from H, F; m = an integer in the range 1-4; one of R ₂ and R ₃ is H and the other is isoxazolyl; or R ₂ and R ₃ taken together with the nitrogen to which they are attached may form a 5-membered heteroaryl with 2 additional heteroatoms representing N; R ₄ is independently selected from (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, heteroaryl which is thienyl or furyl, and (C ₁ -C ₆ )alkoxy. 2. Compounds of formula (I) according to claim 1, wherein R ₄ is selected from methyl or methoxy. 3. The compound of formula (I) according to claim 1, which is selected from: (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7 -yl)-3,5-difluorophenyl)oxazolidin-2-one; (S)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-5-((isoxazol-3-ylamino) methyl)oxazolidin-2-one; (S)-N-((3-(4-(2,2-dioxido-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide; (S)-methyl ((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl )methyl)carbamate; (S)-N-((3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide; (S)-N-((3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide ; (S)-N-((3-(3-fluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide; (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide; (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl )acetamide; (S)-N-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide ; methyl-(S)-((3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl ) carbamate; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1- yl)phenyl)oxazolidin-2-one. 4. An intermediate compound for obtaining a compound according to claim 1, selected from: (S)-5-(aminomethyl)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)oxazolidin-2-one; (R)-3-(4-(4-(1,1-dioxidothietan-3-yl)piperidin-1-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one; (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperidin-1-yl)phenyl)oxazolidin-2-one; (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)oxazolidin-2-one; (S)-5-(aminomethyl)-3-(4-(2,2-dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)oxazolidin-2-one ; (R)-3-(4-(2,2-Dioxydo-2-thia-7-azaspiro[3.5]nonan-7-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one .