Piperazinyl sulfonyl aryl compounds for the treatment of bacterial infections - Patents.com

Abstract

The present invention relates to a compound of formula (I): TIFF2024540008000257.tif4299 (In the formula, R 1 , R 2 , R 3 , R 4 , Y, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 The present invention relates to the compounds of formula (I) and phenylalanine, as defined herein, and pharma- ceutically acceptable salts thereof, and compositions comprising said compounds, and methods of using said compounds.

Description

[Background technology]

[0001] The present invention relates to organic compounds useful for the treatment and / or prevention of bacterial infections in mammals. In particular, these molecules are capable of inhibiting the LPS synthesis pathway, in particular inhibiting LpxH, and are useful for the treatment of bacterial infections.

[0002] The intensive use of antibiotics has exerted selective evolutionary pressure on microorganisms to generate gene-based resistance mechanisms. Modern medicine and socio-economic behavior exacerbate the problem of resistance development, for example by creating conditions for slow growth of pathogenic microorganisms in artificial joints, and by favoring long-term host reservoirs, for example in immunocompromised patients. In the hospital environment, the main sources of infection, Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., Enterobacteriaceae (e.g. Klebsiella pneumonia, Acinetobacter baumannii and Pseudomonas aeruginosa), are increasing in number and becoming multidrug resistant and therefore difficult to treat. This is especially true in the case of Gram-negative organisms, where the situation is becoming worrying, since no novel agents with differentiated mechanisms of action have been approved for decades. Thus, there is a significant medical need for novel antibacterial compounds that address Gram-negative resistant bacteria, especially third-generation cephalosporin- and carbapenem-resistant Enterobacteriaceae as well as multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. One way to address the problem of cross-resistance to established classes of antibiotics is to inhibit essential proteins or functions that are not targeted by current antibiotics.

[0003] Gram-negative bacteria are unique in that their outer membrane contains lipopolysaccharide (LPS), which is important for maintaining membrane integrity and essential for bacterial viability (reviewed in Ann. Rev. Biochem 76:295-329, 2007). The major lipid component of LPS is lipid A, and inhibition of lipid A biosynthesis is lethal to the bacteria. Lipid A is synthesized at the cytoplasmic surface of the bacterial inner membrane via a pathway consisting of nine different enzymes. These enzymes are highly conserved in most Gram-negative bacteria. LpxH, a calcineurin-like phosphatase (CLP), catalyzes the hydrolysis of UDP-2,3-diacyl-glucosamine (UDP-DAGn) to generate lipid X and UMP (22,24,25). LpxH has no mammalian homolog, making it a good target for the development of novel antibiotics targeting Gram-negative bacteria. Summary of the Invention

[0004] The present invention relates to novel compounds of formula (I): [ka] (In the formula, R 1 is unsubstituted or amino C 1-6 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl substituted by alkyl; 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, Amino C 1-6 Alkyl or C 1-6 Alkylamino C 1-6 2-oxo-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepinyl substituted with alkyl; Hydroxy and Hydroxy C 1-6 2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl substituted twice with substituents independently selected from alkyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, Hydroxy and Hydroxy C 1-6 2-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d]oxazolyl substituted three times by substituents independently selected from alkyl; 3-oxo-2,6,9-triazaspiro[4.5]decanyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 3-oxo-2,8-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl, oxoazetidinyl substituted by amino; ((Amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, (C 1-6 Alkyl)2AminoC 1-6 Alkyl, (dihydroxypyrrolidinyl)C 1-6 Alkyl, (pyrrolidinylamino)C 1-6 Alkyl, 2,6-diazaspiro[3.3]heptanyl C 1-6 Alkyl, dihydroxy (C 1-6 Alkoxy)tetrahydrofuranyl, aminoazetidinyl C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, C 1-6 Alkylcarbonylamino C 1-6 Alkyl, Hydroxy C 1-6 Alkyl and piperazinyl C 1-6oxooxazolidinyl substituted once or twice by substituents independently selected from alkyl, or (((C 1-6 Alkyl)2AminoC 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, ((amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, ((amino C 3-7 Cycloalkyl)azetidinyl)C 1-6 Alkyl, ((C 1-6 Alkylamino)azetidinyl)C 1-6 Alkyl, (aminoazetidinyl)C 1-6 Alkyl, (amino C 1-6 Alkyl)azetidinyl, (azetidinyl C 1-6 Alkylamino)C 1-6 Alkyl, (C 1-6 Alkylpiperazinyl)C 1-6 Alkyl, (hydroxy C 1-6 Alkyl)piperazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, amino, amino(hydroxy)piperidinyl, amino, amino(hydroxy)pyrrolidinyl, aminoazetidinyl, amino C 1-6 Alkyl, (amino C 1-6 Alkyl)amino, aminopyrrolidinyl, azetidinylamino, C 1-6 Alkyl, C 1-6 Alkylamino, dihydroxypyrrolidinyl, (hydroxy C 1-6 Alkyl)amino, piperazinyl, piperazinyl C 1-6 oxopyrrolidinyl substituted once, twice or three times by substituents independently selected from alkyl, piperidinylamino and pyrrolidinylamino; R 2 is H or cyano, R 3 Benzyl, C 3-7 cycloalkylsulfonyl, Cyano C 3-7 Cycloalkyl, Phenoxy, Phenyl C 3-7 Cycloalkyl, tetrahydropyranylsulfonyl, or Halogen, (amino C 1-6 Alkyl)C 3-7 Cycloalkyl, (hydroxy C 1-6 Alkyl)C 3-7 Cycloalkyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dioxanyl, 3,6-dihydro-2H-pyranyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 8-oxabicyclo[3.2.1]octanyl, azetidinyl, C 1-6 Alkylhalopyrazinyl, C 1-6 Alkylmorpholinyl, C 1-6 Alkylpyrazinyl, Carbamoyl C 3-7 Cycloalkyl, Hydroxy C 3-7 C substituted twice or three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, and pyridinyl; 1-6 is alkyl, R 4 is a halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy or C 2-6 is alkynyl, Q 1 is N or CR a and R a is H or a halogen, Q 2 is N or CR b and R b is H or a halogen, Q 3 is N or CH, Q 4 is N or CH, Q 5 is N or CH, Y is O or NH. or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] definition "C 1-6 The term "alkyl" refers to saturated straight or branched chain alkyl groups containing 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 1-6 "Alkyl" groups are methyl, ethyl, and n-propyl.

[0006] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.

[0007] The term "halopyrazinyl" refers to a pyrazinyl group in which at least one of the hydrogen atoms of the pyrazinyl group has been replaced by the same or different halogen atom, in particular a fluoro atom. Examples of halopiperidinyl include fluoropyrazinyl, difluoropyrazinyl, and the like.

[0008] "C 2-6 The term "alkynyl" refers to a monovalent linear or branched saturated hydrocarbon group of 2 to 6 carbon atoms containing one, two or three triple bonds. In certain embodiments, alkynyl has 2 to 4 carbon atoms containing one or two triple bonds. 2-6 Examples of alkynyl include ethynyl, propynyl, prop-2-ynyl, isopropynyl, n-butynyl, and the like.

[0009] "Haro C 1-6 The term "alkyl" refers to 1-6 At least one of the hydrogen atoms of the alkyl group is replaced by the same or different halogen atom, in particular a fluoro atom. 1-6 Indicates an alkyl group. HaloC 1-6Examples of alkyl include monofluoromethyl, difluoromethyl, or trifluoromethyl, monofluoroethyl, difluoroethyl, or trifluoroethyl, or monofluoropropyl, difluoropropyl, or trifluoropropyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, trifluoroethyl, fluoromethyl, difluoromethyl, difluoroethyl, or trifluoromethyl.

[0010] "C 3-7 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical containing 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl.

[0011] The term "oxo" refers to a divalent oxygen atom, ═O.

[0012] The terms "cis isomer" and "trans isomer" refer to the relative stereochemistry of a molecule or moiety. For example: tert-butyl cis-1-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (compound 116a) of Example 116 as the "cis isomer" [ka] teeth, [ka] and [ka] Similarly, the trans-ethyl 2-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclopropanecarboxylate (compound 117c) of Example 117 as the "trans isomer" refers to a mixture of the above. [ka] teeth, [ka] The method of indicating relative stereochemistry also applies to the final compound.

[0013] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0014] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from the aliphatic, alicyclic, aromatic, aryl-containing aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0015] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, piperidine, N-ethylpiperidine, and polyamine resins.

[0016] The term "pharmacologically active metabolite" refers to a pharmacologically active product produced through metabolism in the body of a particular compound or its salt. After entering the body, most drugs become substrates for chemical reactions that can change their physical properties and biological effects. These metabolic transformations usually affect the polarity of the compounds of the present invention and change the way the drug is distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect.

[0017] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. The therapeutically effective amount may vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0018] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharma- ceutically acceptable excipients, for administration to a mammal, e.g., a human in need thereof.

[0019] Inhibitors of UDP-2,3-diacylglucosamine hydrolase (LpxH) The present invention relates to a compound of formula (I): [ka] (In the formula, R 1 is unsubstituted or amino C 1-6 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl substituted by alkyl; 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, Amino C 1-6 Alkyl or C 1-6 Alkylamino C 1-6 2-oxo-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepinyl substituted with alkyl; Hydroxy and Hydroxy C 1-62-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl substituted twice with substituents independently selected from alkyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, Hydroxy and Hydroxy C 1-6 2-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d]oxazolyl substituted three times by substituents independently selected from alkyl; 3-oxo-2,6,9-triazaspiro[4.5]decanyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 3-oxo-2,8-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl, oxoazetidinyl substituted by amino; ((Amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, (C 1-6 Alkyl)2AminoC 1-6 Alkyl, (dihydroxypyrrolidinyl)C 1-6 Alkyl, (pyrrolidinylamino)C 1-6 Alkyl, 2,6-diazaspiro[3.3]heptanyl C 1-6 Alkyl, dihydroxy (C 1-6 Alkoxy)tetrahydrofuranyl, aminoazetidinyl C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, C 1-6 Alkylcarbonylamino C 1-6 Alkyl, Hydroxy C1-6 Alkyl and piperazinyl C 1-6 oxooxazolidinyl substituted once or twice by substituents independently selected from alkyl, or (((C 1-6 Alkyl)2AminoC 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, ((amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, ((amino C 3-7 Cycloalkyl)azetidinyl)C 1-6 Alkyl, ((C 1-6 Alkylamino)azetidinyl)C 1-6 Alkyl, (aminoazetidinyl)C 1-6 Alkyl, (amino C 1-6 Alkyl)azetidinyl, (azetidinyl C 1-6 Alkylamino)C 1-6 Alkyl, (C 1-6 Alkylpiperazinyl)C 1-6 Alkyl, (hydroxy C 1-6 Alkyl)piperazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, amino, amino(hydroxy)piperidinyl, amino(hydroxy)pyrrolidinyl, aminoazetidinyl, amino C 1-6 Alkyl, (amino C 1-6 Alkyl)amino, aminopyrrolidinyl, azetidinylamino, C 1-6 Alkyl, C 1-6 Alkylamino, dihydroxypyrrolidinyl, (hydroxy C 1-6 Alkyl)amino, piperazinyl, piperazinyl C 1-6 oxopyrrolidinyl substituted once, twice or three times by substituents independently selected from alkyl, piperidinylamino and pyrrolidinylamino; R 2 is H or cyano, R 3 Benzyl, C 3-7 cycloalkylsulfonyl, Cyano C 3-7Cycloalkyl, Phenoxy, Phenyl C 3-7 Cycloalkyl, tetrahydropyranylsulfonyl, or Halogen, (amino C 1-6 Alkyl)C 3-7 Cycloalkyl, (hydroxy C 1-6 Alkyl)C 3-7 Cycloalkyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dioxanyl, 3,6-dihydro-2H-pyranyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 8-oxabicyclo[3.2.1]octanyl, azetidinyl, C 1-6 Alkylhalopyrazinyl, C 1-6 Alkylmorpholinyl, C 1-6 Alkylpyrazinyl, Carbamoyl C 3-7 Cycloalkyl, Hydroxy C 3-7 C substituted twice or three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, and pyridinyl; 1-6 is alkyl, R 4 is a halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy or C 2-6 is alkynyl, Q 1 is N or CR a and R a is H or a halogen, Q 2 is N or CR b and R b is H or a halogen, Q 3 is N or CH, Q 4 is N or CH, Q 5 is N or CH, Y is O or NH. or a pharma- ceutically acceptable salt thereof.

[0020] Another embodiment of the present invention is a compound of formula (Ia): [ka] (In the formula, R 1 is unsubstituted or amino C 1-6 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl substituted by alkyl; 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, Amino C 1-6 Alkyl or C 1-6 Alkylamino C 1-6 2-oxo-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepinyl substituted with alkyl; Hydroxy and Hydroxy C 1-6 2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl substituted twice with substituents independently selected from alkyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, Hydroxy and Hydroxy C 1-6 2-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d]oxazolyl substituted three times by substituents independently selected from alkyl; 3-oxo-2,6,9-triazaspiro[4.5]decanyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 3-oxo-2,8-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl, oxoazetidinyl substituted by amino; ((Amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, (C 1-6 Alkyl)2AminoC 1-6 Alkyl, (dihydroxypyrrolidinyl)C 1-6 Alkyl, (pyrrolidinylamino)C 1-6 Alkyl, 2,6-diazaspiro[3.3]heptanyl C 1-6 Alkyl, dihydroxy (C 1-6 Alkoxy)tetrahydrofuranyl, aminoazetidinyl C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, C 1-6 Alkylcarbonylamino C 1-6 Alkyl, Hydroxy C 1-6 Alkyl and piperazinyl C 1-6 oxooxazolidinyl substituted once or twice by substituents independently selected from alkyl, or (((C 1-6 Alkyl)2AminoC 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, ((amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, ((amino C 3-7 Cycloalkyl)azetidinyl)C 1-6 Alkyl, ((C 1-6 Alkylamino)azetidinyl)C 1-6 Alkyl, (aminoazetidinyl)C 1-6 Alkyl, (amino C 1-6 Alkyl)azetidinyl, (azetidinyl C 1-6 Alkylamino)C1-6 Alkyl, (C 1-6 Alkylpiperazinyl)C 1-6 Alkyl, (hydroxy C 1-6 Alkyl)piperazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, amino, amino(hydroxy)piperidinyl, amino(hydroxy)pyrrolidinyl, aminoazetidinyl, amino C 1-6 Alkyl, (amino C 1-6 Alkyl)amino, aminopyrrolidinyl, azetidinylamino, C 1-6 Alkyl, C 1-6 Alkylamino, dihydroxypyrrolidinyl, (hydroxy C 1-6 Alkyl)amino, piperazinyl, piperazinyl C 1-6 oxopyrrolidinyl substituted once, twice or three times by substituents independently selected from alkyl, piperidinylamino and pyrrolidinylamino; R 2 is H or cyano, R 3 Benzyl, C 3-7 cycloalkylsulfonyl, Cyano C 3-7 Cycloalkyl, Phenoxy, Phenyl C 3-7 Cycloalkyl, tetrahydropyranylsulfonyl, or Halogen, (amino C 1-6 Alkyl)C 3-7 Cycloalkyl, (hydroxy C 1-6 Alkyl)C 3-7 Cycloalkyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dioxanyl, 3,6-dihydro-2H-pyranyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 8-oxabicyclo[3.2.1]octanyl, azetidinyl, C 1-6 Alkylhalopyrazinyl, C 1-6 Alkylmorpholinyl, C 1-6 Alkylpyrazinyl, Carbamoyl C3-7 Cycloalkyl, Hydroxy C 3-7 C substituted twice or three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, and pyridinyl; 1-6 is alkyl, R 4 is a halogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy or C 2-6 is alkynyl, Q 1 is N or CR a and R a is H or a halogen, Q 2 CR b and R b is H or a halogen, Q 3 is N, Q 4 is N or CH, Q 5 is N or CH, Y is O or a pharma- ceutically acceptable salt thereof.

[0021] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to (iii)(i) or (ii) or a pharma- ceutically acceptable salt thereof, wherein R 1 is 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, Hydroxy and Hydroxy C 1-62-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl substituted twice with substituents independently selected from alkyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, ((Amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, (C 1-6 Alkyl)2AminoC 1-6 Alkyl, dihydroxy (C 1-6 Alkoxy)tetrahydrofuranyl, amino C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkylamino C 1-6 Alkyl, Hydroxy C 1-6 Alkyl and piperazinyl C 1-6 oxooxazolidinyl substituted once or twice by substituents independently selected from alkyl, or ((Amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, ((amino C 3-7 Cycloalkyl)azetidinyl)C 1-6 Alkyl, (aminoazetidinyl)C 1-6 Alkyl, (C 1-6 Alkylpiperazinyl)C 1-6 Alkyl, (hydroxy C 1-6 Alkyl)piperazinyl, amino, amino(hydroxy)piperidinyl, amino(hydroxy)pyrrolidinyl, amino C 1-6 Alkyl, aminopyrrolidinyl, C 1-6 Alkylamino, dihydroxypyrrolidinyl, (hydroxy C 1-6Alkyl)amino, piperazinyl, piperazinyl C 1-6 and oxopyrrolidinyl substituted with a substituent selected from alkyl and piperidinylamino.

[0022] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (iv)(i) to (iii), or a pharma- ceutically acceptable salt thereof, wherein R 1 is 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, 2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl, substituted twice with substituents independently selected from hydroxy and hydroxymethyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, oxooxazolidinyl substituted once or twice by substituents independently selected from (3-(aminomethyl)azetidin-1-yl)methyl, (dimethylamino)methyl, 3,4-dihydroxy-5-methoxy-tetrahydrofuran-2-yl, aminomethyl, aminomethyl, hydroxymethyl, methyl, (methylamino)methyl and piperazin-1-ylmethyl, or and oxopyrrolidinyl substituted by a substituent selected from (3-(1-aminocyclopropyl)azetidin-1-yl)methyl, (3-(aminomethyl)azetidin-1-yl)methyl, (3-aminoazetidin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl, 3-(hydroxymethyl)piperazin-1-yl, 3,4-dihydroxypyrrolidin-1-yl, 3-amino-4-hydroxypiperidin-1-yl, 3-amino-4-hydroxypyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 4-piperidinylamino, amino, aminomethyl, (hydroxyethyl)amino, methylamino, piperazin-1-yl and piperazin-1-ylmethyl.

[0023] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (v)(i) to (iv), wherein R 12-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-3-yl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridin-1-yl, 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-3-yl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepine- 3-yl, 3-oxo-2,6-diazaspiro[4.5]decan-2-yl, 4-((3-(1-aminocyclopropyl)azetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-((3-aminoazetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-((4-methylpiperazin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-(2-hydroxyethylamino)-2-oxo-pyrrolidin-1-yl, 4-(3-(aminomethyl)azetidin-1-yl )methyl)-2-oxo-pyrrolidin-1-yl, 4-(3-(hydroxymethyl)piperazin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3,4-dihydroxypyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino-4-hydroxypiperidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino-4-hydroxy-pyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino-4-hydroxy-pyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-aminopyrrolidin-1-yl)-2-oxo-pyrrolidin 4-(4-piperidinylamino)-2-oxo-pyrrolidin-1-yl, 4-(methylamino)-2-oxo-pyrrolidin-1-yl, 4-(piperazin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(piperazin-1-ylmethyl)-2-oxo-pyrrolidin-1-yl, 4-amino-2-oxo-pyrrolidin-1-yl, 4-aminomethyl-2-oxo-oxazolidin-3-yl, 4-aminomethyl-2-oxo-pyrrolidin-1-yl, 4-methyl-2-oxo-5-(3,4-Dihydroxy-5-methoxy-tetrahydrofuran-2-yl)oxazolidin-3-yl, 5-((3-(aminomethyl)azetidin-1-yl)methyl)-2-oxo-oxazolidin-3-yl, 5-((dimethylamino)methyl)-2-oxo-oxazolidin-3-yl, 5-(2-aminoethyl)-2-oxo-oxazolidin-3-yl, 5-(methylaminomethyl)-2-oxo-oxazolidin-3-yl, 5-(piperazin-1-ylmethyl)-2-oxo-oxazolidin-3-yl oxazolidin-3-yl, 5-aminomethyl-2-oxo-oxazolidin-3-yl, 5-hydroxymethyl-2-oxo-oxazolidin-3-yl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-4-yl, 6-hydroxy-5-hydroxymethyl-2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazol-3-yl or 6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl.

[0024] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (i) to (v) or a pharma- ceutically acceptable salt thereof, wherein R 1 However, ((Amino C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, ((amino C 3-7 Cycloalkyl)azetidinyl)C 1-6 Alkyl, (aminoazetidinyl)C 1-6 Alkyl, (C 1-6 Alkylpiperazinyl)C 1-6 Alkyl, (hydroxy C 1-6 Alkyl)piperazinyl, amino, amino(hydroxy)piperidinyl, amino, amino(hydroxy)pyrrolidinyl, amino C 1-6 Alkyl, aminopyrrolidinyl, C 1-6 Alkylamino, dihydroxypyrrolidinyl, (hydroxy C 1-6 Alkyl)amino, piperazinyl, piperazinyl C 1-6 and oxopyrrolidinyl substituted with a substituent selected from alkyl and piperidinylamino.

[0025] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (i) to (vi) or a pharma- ceutically acceptable salt thereof, wherein R 1 4-((3-(1-aminocyclopropyl)azetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-((3-aminoazetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-((4-methylpiperazin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-(2-hydroxyethylamino)-2-oxo-pyrrolidin-1-yl, 4-(3-(aminomethyl)azetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-(3-(hydroxymethyl)piperazin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3,4-dihydroxypyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4- (3-amino-4-hydroxypiperidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino-4-hydroxy-pyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-aminopyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(4-piperidinylamino)-2-oxo-pyrrolidin-1-yl, 4-(methylamino)-2-oxo-pyrrolidin-1-yl, 4-(piperazin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(piperazin-1-ylmethyl)-2-oxo-pyrrolidin-1-yl, 4-amino-2-oxo-pyrrolidin-1-yl or 4-aminomethyl-2-oxo-pyrrolidin-1-yl.

[0026] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (i) to (vii) or a pharma- ceutically acceptable salt thereof, wherein R 3 Benzyl, phenyl C 3-7 Cycloalkyl, or halogen, (hydroxy C 1-6 Alkyl)C 3-7Cycloalkyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dioxanyl, 3,6-dihydro-2H-pyranyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 8-oxabicyclo[3.2.1]octanyl, C 1-6 Alkylhalopyrazinyl, C 1-6 Alkylpyrazinyl, Carbamoyl C 3-7 Cycloalkyl, Hydroxy C 3-7 C substituted three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, pyrazinyl, pyridinyl, tetrahydropyranyl, and phenyl 1-6 It is an alkyl.

[0027] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (ix)(i) to (viii) or a pharma- ceutically acceptable salt thereof, wherein R 3 However, halogen, (hydroxy C 1-6 Alkyl)C 3-7 Cycloalkyl, 1,4-dioxanyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, C 1-6 Alkylhalopyrazinyl, C 1-6 Alkylpyrazinyl, Hydroxy C 3-7 C substituted three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, phenyl, pyridinyl and tetrahydropyranyl 1-6 It is an alkyl.

[0028] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (x)(i) to (ix) or a pharma- ceutically acceptable salt thereof, wherein R 3is difluoro(1,4-dioxan-2-yl)methyl, difluoro(2-(hydroxymethyl)cyclopropyl)methyl, difluoro(2-pyridinyl)methyl, difluoro(3-hydroxycyclobutyl)methyl, difluoro(3-oxabicyclo[3.1.0]hexan-6-yl)methyl, difluoro(5-chloro-6-methyl-pyrazin-2-yl)methyl, difluoro(6-methylpyrazin-2-yl)methyl, difluoro(morpholin-2-yl)methyl, difluoro(oxetan-3-yl)methyl, difluoro(phenyl)methyl, difluoro(tetrahydropyran-4-yl)methyl or difluoro[3-azabicyclo[3.1.0]hexan-1-yl]methyl.

[0029] A further embodiment of the present invention is a compound of formula (xi) wherein R 2 is H; or a pharma- ceutically acceptable salt thereof.

[0030] A further embodiment of the present invention is a compound of formula (xii) in which R 4 But halogen or C 1~6 or a pharma- ceutically acceptable salt thereof.

[0031] A further embodiment of the present invention is a compound of formula (xiii) wherein R 4 is chloro or methyl; or a pharma- ceutically acceptable salt thereof.

[0032] A further embodiment of the present invention is a compound of formula (xiv), wherein Q 1 But, CR a and R a is H or a halogen; or a compound of formula (I) or (Ia) as defined in any one of (i) to (xiii), or a pharma- ceutically acceptable salt thereof.

[0033] A further embodiment of the present invention is a compound of formula (xv), wherein Q1 But, CR a and R a is H or fluoro; or a pharma- ceutically acceptable salt thereof.

[0034] A further embodiment of the present invention is a compound of formula (xvi), wherein Q 2 is CH; or a pharma- ceutically acceptable salt thereof.

[0035] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (xvii)(i) to (xvi), or a pharma- ceutically acceptable salt thereof, wherein: R 1 But amino or amino C 1-6 is an oxopyrrolidinyl substituted by alkyl; R 2 But H, R 3 However, halogen, (hydroxy C 1-6 Alkyl)C 3-7 Cycloalkyl, 1,4-dioxanyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, C 1-6 Alkylhalopyrazinyl, C 1-6 Alkylpyrazinyl, Hydroxy C 3-7 C substituted three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, phenyl, pyridinyl and tetrahydropyranyl 1-6 is alkyl, R 4 But halogen or C 1-6 is alkyl, Q 1 But, CR a and R a is H or a halogen, Q 2 is CH, Q 3 is N, Q4 is N or CH; Q 5 is N or CH; Y is O.

[0036] A further embodiment of the present invention is a compound of formula (I) or (Ia) as defined in any one of (xviii)(i) to (xvii), or a pharma- ceutically acceptable salt thereof, wherein: R 1 is oxopyrrolidinyl substituted by amino or aminomethyl; R 2 But H, R 3 is difluoro(1,4-dioxan-2-yl)methyl, difluoro(2-(hydroxymethyl)cyclopropyl)methyl, difluoro(2-pyridinyl)methyl, difluoro(3-hydroxycyclobutyl)methyl, difluoro(3-oxabicyclo[3.1.0]hexan-6-yl)methyl, difluoro(5-chloro-6-methyl-pyrazin-2-yl)methyl, difluoro(6-methylpyrazin-2-yl)methyl, difluoro(morpholin-2-yl)methyl, difluoro(oxetan-3-yl)methyl, difluoro(phenyl)methyl, difluoro(tetrahydropyran-4-yl)methyl or difluoro[3-azabicyclo[3.1.0]hexan-1-yl]methyl, R 4 is chloro or methyl; Q 1 But, CR a and R a is H or fluoro; Q 2 is CH, Q 3 is N, Q 4 is N or CH; Q 5 is N or CH; Y is O.

[0037] Another embodiment of the present invention is a compound of formula (I) or (Ia), or a pharma- ceutically acceptable salt thereof, selected from: 4-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-(aminomethyl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-phenyl]pyrrolidin-2-one; 5-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; N-[[3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide; 4-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3,3-dimethyl-pyrrolidin-2-one; 4-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; (3S)-3-amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]azetidin-2-one; 3-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 5-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; 2-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6-diazaspiro[4.5]decan-3-one; 2-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,8-diazaspiro[4.5]decan-3-one; 6-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6-diazaspiro[3.4]octan-7-one; 7-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxa-2,7-diazaspiro[3.4]octan-6-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; (3aR,6aS)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-one; (3aR,7aS)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one; (3aR,7aS)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridin-2-one; (3aS,7aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one; (3aS,8aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepin-2-one; 4-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-5-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-6-hydroxy-5-(hydroxymethyl)-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazol-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(3S,4R,5R)-3,4-dihydroxy-5[-methoxy-tetrahydrofuran-2-yl]-4-methyl-oxazolidin-2-one; (3aS,5S,6S,7S,7aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5,7-dihydroxy-6-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d]oxazol-2-one; 8-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; (3aS,8aR)-5-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepin-2-one; (3aS,8aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[2-(methylamino)ethyl]-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(methylaminomethyl)oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(dimethylamino)methyl]oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(piperazin-1-ylmethyl)oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[[cis-3,4-dihydroxypyrrolidin-1-yl]methyl]oxazolidin-2-one; 5-[(3-aminoazetidin-1-yl)methyl]-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(2,6-diazaspiro[3.3]heptan-2-ylmethyl)oxazolidin-2-one; 5-[[3-(aminomethyl)azetidin-1-yl]methyl]-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(pyrrolidin-3-ylamino)methyl]oxazolidin-2-one; 4-[[3-(aminomethyl)azetidin-1-yl]methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(4-methylpiperazin-1-yl)methyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-[(dimethylamino)methyl]azetidin-1-yl]methyl]pyrrolidin-2-one; 4-[(azetidin-3-ylmethylamino)methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-[[3-(1-aminocyclopropyl)azetidin-1-yl]methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-[(3-aminoazetidin-1-yl)methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(piperazin-1-ylmethyl)pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-(dimethylamino)azetidin-1-yl]methyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-(methylamino)azetidin-1-yl]methyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(methylamino)pyrrolidin-2-one; 4-(2-aminoethylamino)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(2-hydroxyethylamino)pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-piperazin-1-yl-pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3S,4R)-3,4-dihydroxypyrrolidin-1-yl]pyrrolidin-2-one; 4-[3-(aminomethyl)azetidin-1-yl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-(3-aminopyrrolidin-1-yl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-(3-aminoazetidin-1-yl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3S)-3-(hydroxymethyl)piperazin-1-yl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3R)-3-(hydroxymethyl)piperazin-1-yl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]]heptan-2-yl]pyrrolidin-2-one; 4-[(3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-1-(4-((4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)pyrrolidin-2-one; 4-(azetidin-3-ylamino)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(pyrrolidin-3-ylamino)pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(4-piperidylamino)pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-methyl-pyrrolidin-2-one; 4-Amino-1-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]pyrrolidin-2-one; 5-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-fluoro-phenyl]oxazolidin-2-one; 5-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-fluorophenyl]oxazolidin-2-one; 4-Amino-1-[4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[4-(trideuteriomethyl)-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonyl-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-2-carbonitrile; 4-Amino-1-[4-[4-[6-chloro-4-(difluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-(6-chloro-4-cyclopropylsulfonyl-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-(6-chloro-4-tetrahydropyran-4-ylsulfonyl-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]cyclopropanecarbonitrile; 4-Amino-1-[4-[4-(6-chloro-4-phenoxy-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-(4-benzyl-6-chloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-(1-phenylcyclopropyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[4-[difluoro(phenyl)methyl]-6-methyl-pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[2-chloro-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[4-chloro-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[2-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[4-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-methoxy-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[4-[difluoro(phenyl)methyl]-6-methoxy-pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-vinyl-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 2-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6,9-triazaspiro[4.5]decan-3-one; 5-(aminomethyl)-1-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (3aR,7aS)-3-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one; 5-(aminomethyl)-3-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(2-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(3-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(4-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(pyrimidin-5-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(pyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(pyrimidin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydropyran-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydrofuran-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(oxetan-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[3,6-dihydro-2H-pyran-4-yl(difluoro)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydropyran-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(8-oxabicyclo[3.2.1]octan-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro(3-oxabicyclo[3.1.0]hexan-6-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[[(2S)-1,4-dioxan-2-yl]-difluoromethyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[[(2R)-1,4-dioxan-2-yl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(2R)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro(1,2,3,6-tetrahydropyridin-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(3R)-3-piperidyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(3S)-3-piperidyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[4-[azetidin-3-yl(difluoro)methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 3-[4-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(hydroxymethyl)oxazolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-(5-methylpyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-(6-methylpyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[(5-chloro-6-methyl-pyrazin-2-yl)-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[cis-6-methylmorpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; ((4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-(5-methylmorpholin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[4-[[cis-3-azabicyclo[3.1.0]hexan-1-yl]difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[trans-difluoro-[2-(hydroxymethyl)cyclopropyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[4-[[trans-4-(aminomethyl)cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[trans-difluoro-(3-hydroxycyclobutyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; and trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide.

[0038] Pharmaceutical Compositions and Administration Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and therapeutically inert carriers, diluents or excipients, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, the compounds of formula (I) can be formulated into galenical dosage forms by mixing at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably anywhere in the range of about 3 to about 8. In one example, the compounds of formula (I) are formulated in acetate buffer at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0039] The composition is formulated, dosed, and administered in a manner consistent with good medical practice.Factors to be considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the delivery site of the drug, the method of administration, the administration schedule, and other factors known to medical practitioners.The "effective amount" of the compound to be administered is governed by such considerations and is the minimum amount required to reduce bacterial load or improve host survival through the inhibition of lipid A biosynthesis by targeting LpxH enzyme.For example, such amount may be below the amount that is toxic to normal cells, or to the mammal as a whole.

[0040] In one example, a pharma- ceutical effective amount of a compound of the invention administered parenterally per dose will range from about 0.1 to 1000 mg / kg of patient body weight, or alternatively about 1 to 100 mg / kg of patient body weight per day, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 5 to about 5000 mg of a compound of the invention.

[0041] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, where localized treatment is desired, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0042] The compounds of the present invention may be administered in any convenient dosage form, such as, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents and additional active agents.

[0043] Typical preparation is prepared by mixing the compound of the present invention and carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams&Wilkins,2004;Gennaro, Alfonso R., et al.Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams&Wilkins,2000;and Rowe, Raymond C.Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press,2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical composition (i.e., a medicament).

[0044] An example of a suitable oral dosage form is a tablet containing about 10-500 mg of the compound of the present invention, formulated with about 40-400 mg of anhydrous lactose, about 5-50 mg of croscarmellose sodium, about 5-50 mg of polyvinylpyrrolidone (PVP) K30, and about 1-10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving, for example, 5-1000 mg of the compound of the present invention in a suitable buffer solution, for example, phosphate buffer, and adding, if desired, an isotonicity agent, for example, a salt such as sodium chloride. The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0045] Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharma- ceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or excipient.

[0046] Another embodiment includes pharmaceutical compositions comprising a compound of formula (I) for use in the treatment and / or prevention of a bacterial infection.

[0047] The following Compositions A and B illustrate typical compositions of the present invention and serve merely as representative thereof.

[0048] Composition A The compounds of the invention can be used, as active ingredient, in a manner known per se to produce tablets of the following composition: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0049] Composition B The compound of the present invention can be used as an active ingredient in a manner known per se to produce capsules having the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0050] Indications and Treatment Methods The compounds of the invention are inhibitors of the LpxH enzyme, a key enzyme in the LPS synthesis pathway, which is essential in most Gram-negative bacteria. Thus, the compounds of the invention are capable of preventing bacterial growth in susceptible organisms and are effective in treating bacterial infections, preferably Gram-negative bacterial infections (all claimed), such as nosocomial pneumonia, urinary tract infections, systemic infections (bacteremia and septicemia), skin and soft tissue infections, surgical infections, eye infections, intraperitoneal infections, pulmonary infections and Gram-negative bacteria such as third generation cephalosporin-resistant and carbapenem-resistant Klebsiella pneumoniae (e.g., Klebsiella pneumoniae, Escherichia coli) and multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii or Acinetobacter spp., e.g., Neisseria gonorrhoeae, Haemophilus influenzae, Pylori, e.g., Bacteroides spp., e.g., Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides distasonis, Campylobacter jejuni, Campylobacter fetus or Campylobacter coli, Francisella tularensis and Providencia spp., e.g. Providencia stuartii, Providencia rettgeri or Providencia alcalifaciens and Pseudomonas spp.; as well as for cleaning purposes, e.g. to remove pathogenic microorganisms and bacteria from surgical instruments, catheters and artificial implants or to render a room or area sterile.

[0051] The products of the present invention can be administered, for example, parenterally, for example by injection, or orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, for example in the form of suppositories. Pharmaceutical compositions containing these compounds can be prepared using conventional procedures well known to those skilled in the art, for example by combining the ingredients into a dosage form together with suitable non-toxic inert therapeutically compatible solid or liquid carrier materials, and, if necessary, with conventional pharmaceutical adjuvants. It is considered that the compounds will ultimately be embodied into a composition of suitable oral, parenteral or topical dosage form. The compositions of the present invention can contain, as an optional ingredient, any of a variety of adjuvants that are commonly used in the manufacture of pharmaceutical preparations. Thus, for example, when formulating the compositions of the present invention into the desired oral dosage form, optional ingredients may be used, such as fillers, for example, co-precipitated aluminum hydroxide-calcium carbonate, dicalcium phosphate or lactose; disintegrants, such as corn starch; and lubricants, such as talc, calcium stearate, etc. However, it should be fully understood that any components specified herein are given as examples only, and the present invention is not limited to their use. Other such adjuvants known in the art can be used in carrying out the present invention. Suitable as such carrier materials are inorganic carrier materials as well as organic carrier materials. Thus, for tablets, coated tablets, dragees and hard gelatin capsules, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substance. However, for soft gelatin capsules, no carrier is required). Suitable carrier materials for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.As pharmaceutical adjuvants, conventional preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for changing osmotic pressure, buffers, coating agents and antioxidants may be considered.

[0052] synthesis The compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are illustrated in the following schemes and examples. All substituents, particularly R 1 , R 2 , R 3 , R 4 , Y, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is defined above. Further, unless otherwise specified, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to one of ordinary skill in the art of organic chemistry.

[0053] A general synthetic route for preparing compounds of formula (I) is given below. Scheme 1 [ka] X 1 and X 2 is a halogen, e.g., Cl, Br, I. PG is a protecting group, such as a tert-Boc or Cbz group.

[0054] Step (i) may be a sulfonation reaction between a halogenated phenylsulfonyl chloride (II) and a protected piperazine (III) under basic conditions (e.g., in the presence of a suitable base such as trimethylamine) to provide a compound of formula (IV).

[0055] Compounds of formula (V) can be obtained in step (ii) by deprotection of compounds of formula (IV) with a suitable acid, such as trifluoroacetic acid, or with H2 using a reducing agent, such as palladium.

[0056] Step (iii) may be a nucleophilic substitution by reacting intermediate (V) with a halogenated compound of formula (VI) using a suitable base to provide a compound of formula (VII).

[0057] The final compound of formula (I) can be prepared by the reaction of a compound of formula (VII) with a cyclic amide such as a lactam or carbamate and R using a catalyst such as CuI in the presence of a base such as CsCO3. 1 H can be obtained in step (iv) through a coupling reaction.

[0058] The compounds of the present invention may be obtained as mixtures of diastereomers or enantiomers which may be separated by methods well known in the art, for example (chiral) HPLC or SFC.

[0059] The present invention also relates to a process for the preparation of a compound of formula (I) comprising the steps of: a) reacting a compound of formula (VII) in the presence of a catalyst and a base [ka] and lactam or carbamate, R 1 Coupling reaction with H Including, During the ceremony, In step a), the catalyst may be CuI and the base may be Cs2CO3.

[0060] Compounds of formula (I) when prepared by the above process are also an object of the present invention. EXAMPLES

[0061] The present invention may be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0062] Abbreviation The present invention may be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0063] The abbreviations used herein are as follows: ACN Acetonitrile aq.Aqueous solution BAST Bis(2-methoxyethyl)aminosulfur trifluoride DAST Diethylaminosulfur trifluoride DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMEDA 1,2-Dimethylethylenediamine DMF Dimethylformamide DMP Dess-Martin Periodinane DMSO Dimethyl sulfoxide EA Ethyl acetate FA Formic Acid h(s) or hr(s) hours HATU 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High Performance Liquid Chromatography IPA Isopropyl Alcohol m-CPBA meta-chloroperoxybenzoic acid MIC Minimum inhibitory concentration NMP N-Methyl-2-pyrrolidone obsd.actual value PE Petroleum Ether prep-HPLC Preparative High Performance Liquid Chromatography rt room temperature SFC Supercritical Fluid Chromatography TEA Triethylamine TFA Trifluoroacetic acid TLC Thin Layer Chromatography

[0064] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 cartridge module, ii) ISCO combi-flash chromatography instrument. Brand and pore size of silica gel: i) KP-SIL 60 Å, particle size: 40-60 μm; ii) CAS Registry Number: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore size: 200-300 or 300-400.

[0065] Intermediates and final compounds were purified by preparative HPLC on reversed-phase columns using XBridge™ Prep-C18 (5 μm, OBD™ 30×100 mm) columns, SunFire™ Prep-C18 (5 μm, OBD™ 30×100 mm) columns, Phenomenex Synergi-C18 (10 μm, 25×150 mm) or Phenomenex Gemini-C18 (10 μm, 25×150 mm) Waters AutoP purification system (sample manager 2767, pump 2525, detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water, acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water). or Gilson-281 purification system (Pump 322, Detector: UV 156, Solvent system: 0.05% ammonium hydroxide in acetonitrile and water, 0.225% FA in acetonitrile and water, 0.05% HCl in acetonitrile and water, 0.075% TFA in acetonitrile and water, or acetonitrile and water).

[0066] For SFC chiral separations, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm) or AD (10 μm, 30 × 250 mm) using a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure 100 bar, detection UV at 254 or 220 nm.

[0067] LC / MS spectra of the compounds were obtained using an LC / MS (Waters™ Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ). The LC / MS conditions were as follows (run time 3 min or 1.5 min): Acidic conditions I: A: 0.1% TFA in HO, B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H2O, B: 0.01875% TFA in acetonitrile; Basic conditions I: A: 0.1%NH in H2O 3· ·H2O, B: acetonitrile; Basic condition II: A: 0.025% NH3·H2O in H2O, B: acetonitrile; Neutral conditions: A: H2O, B: acetonitrile.

[0068] Mass spectra (MS): Generally, only ions that represent the parent mass are reported; unless otherwise stated, the mass ions quoted are the positive mass ions (M−H). + It is.

[0069] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0070] Microwave-assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise stated.

[0071] Preparation Example The following examples are intended to illustrate the meaning of the invention but do not in any way represent a limitation within the scope of the meaning of the invention.

[0072] Intermediate A 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-4-(4-iodophenyl)sulfonyl-piperazine [ka] The title compound was prepared according to the following procedure.

[0073] Step 1: 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine (Intermediate A1) [ka] To a solution of piperazine (47.86 g, 555.58 mmol) in 1,4-dioxane (150 mL) was added 2,6-dichloro-4-(trifluoromethyl)pyridine (15.0 g, 69.45 mmol) slowly. The mixture was stirred at 60° C. for 1 h, then diluted with water (300 mL) and extracted three times with EA (200 mL). The combined organic layers were washed four times with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated to give intermediate A1 (18 g, 67.76 mmol, 97.6% yield) as a white solid. MS found: 265.8 (MH + ).

[0074] Step 2: 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-4-(4-iodophenyl)sulfonyl-piperazine (Intermediate A) To a solution of intermediate A1 (7.9 g, 29.75 mmol) and TEA (12.44 mL, 89.25 mmol) in THF (100 mL) was added 4-iodobenzenesulfonyl chloride (9.0 g, 29.75 mmol) and the mixture was stirred at 20° C. for 12 h. The mixture was diluted with EA (400 mL) and filtered. The filtrate was washed three times with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was triturated with PE (150 mL) to give intermediate A (14.5 g, 27.27 mmol, 91.7% yield) as a white solid. MS found: 531.8 (MH + ).

[0075] Intermediate B 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2H-pyrrol-5-one [ka] The title compound was prepared according to the following procedure.

[0076] Step 1: 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-hydroxy-pyrrolidin-2-one (Intermediate B1) [ka] To a solution of intermediate A (1.0 g, 1.88 mmol) in DMF (10 mL) was added 4-hydroxy-2-pyrrolidone (209.15 mg, 2.07 mmol), Cs2CO3 (1.23 g, 3.76 mmol), DMEDA (33.16 mg, 0.380 mmol), and CuI (0.01 mL, 0.380 mmol) in one portion. The reaction was stirred under N2 at 70 °C for 2 h. The mixture was diluted with water (50 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA = 10:1 to 0:1) and preparative HPLC to give intermediate B1 (320 mg, 0.630 mmol, 33.7% yield) as a white solid.

[0077] Step 2: 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2H-pyrrol-5-one (Intermediate B) To a solution of Intermediate B1 (320.0 mg, 0.630 mmol) in DCM (4 mL) was added TEA (0.18 mL, 1.27 mmol) in one portion. After cooling to 0° C., methanesulfonyl chloride (0.07 mL, 0.950 mmol) was added and the reaction was then warmed to 20° C. for 1 h. The mixture was diluted with DCM (20 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give Intermediate B (290 mg, 0.60 mmol, 93.98% yield) as a yellow oil.

[0078] Intermediate C tert-Butyl N-[5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate [ka] The title compound was prepared according to the following procedure.

[0079] Step 1: Benzyl 4-(4-iodophenyl)sulfonylpiperazine-1-carboxylate (Intermediate C1) [ka] To a solution of 1-Cbz-piperazine (8.01 g, 36.4 mmol), TEA (6.45 mL, 46.3 mmol) in DCM (200 mL) was added 4-iodobenzenesulfonyl chloride (10.0 g, 33.06 mmol) at 0° C., and the mixture was stirred at 25° C. for 2 h. The mixture was concentrated to give a residue, which was triturated with petroleum ether and washed with water to give intermediate C1 (18.0 g, 37.0 mmol, 95.2% yield) as a white solid. MS found: 487.0 (MH + ). 1 H NMR (400MHz, CDCl3): δ ppm 7.94(br d,J=8.8Hz,2 H),7.89(m,2 H),7.43(m,1 H),7.32-7.33(m,4 H),5.01(s,2 H),3.12-3.14(m,8 H).

[0080] Step 2: Benzyl 4-((4-(4-((tert-butoxycarbonyl)amino)-2-oxopyrrolidin-1-yl)phenyl)sulfonyl)piperazine-1-carboxylate (Intermediate C2) [ka] To a mixture of intermediate C1 (18.0 g, 37.0 mmol), tert-butyl N-(5-oxopyrrolidin-3-yl)carbamate (8.89 g, 44.4 mmol) and K2CO3 (15.4 g, 111 mmol) in NMP (180 mL) was added CuI (7.05 g, 37.0 mmol, 1.00 equiv) and N1,N2-dimethylcyclohexane-1,2-diamine (5.26 g, 37.0 mmol). The mixture was stirred under N2 at 90 °C for 2 h. The mixture was diluted with EA (200 mL) and filtered. The filtrate was washed with NH3·H2O (2% wt, 200 mL), twice with aqueous CaCl2 (150 mL, 2 N) and twice with NaCl (150 mL), dried over Na2SO4, filtered and concentrated to give a yellow oil. The oil was purified by preparative HPLC to give intermediate C2 (13.5 g, 24.2 mmol, 65.3% yield) as a grey solid. MS found: 559.3 (MH + ).

[0081] Step 3: tert-Butyl N-[5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate (Intermediate C) To a solution of intermediate C2 (500.0 mg, 0.90 mmol) in methanol (10 mL) was added Pd / C (10% wt, 100.0 mg). The mixture was stirred under H2 (15 psi) at 25 °C for 2 h. The mixture was diluted with MeOH (100 mL), filtered through a celite pad, and concentrated to give intermediate C (300 mg, 0.710 mmol, 78.96% yield) as a grey solid. MS found: 425.3 (MH + ).

[0082] Intermediate D tert-Butyl N-[(3R)-5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate [ka] The title compound was prepared in a similar manner to the preparation of intermediate C, by using tert-butyl N-[(3R)-5-oxopyrrolidin-3-yl]carbamate instead of tert-butyl N-(5-oxopyrrolidin-3-yl)carbamate. Intermediate D (700 mg) was obtained as a white solid. MS found: 425.2 (MH + ). Intermediate E and Intermediate F 2,6-Dichloro-4-[[(2S)-1,4-dioxan-2-yl]-difluoro-methyl]pyridine and 2,6-Dichloro-4-[[(2R)-1,4-dioxan-2-yl]-difluoro-methyl]pyridine [ka] The title compound was prepared according to the following procedure:

[0083] Step 1: 1,4-Dioxane-2-carbaldehyde (Intermediate E1) [ka] To a mixture of DCM (450 mL) in DMSO (15.75 g, 315.1 mmol) was added dropwise at -60°C. After stirring for 1 h, (1,4-dioxan-2-yl)methanol (15.5 g, 131.3 mmol) was added and the mixture was stirred at -60°C for 2 h. TEA (39.83 g, 393.9 mmol) was added at -60°C and the mixture was slowly warmed to 10°C. The suspension was filtered and the filtrate was concentrated to give the crude product, which was distilled under vacuum pump and collected at 70°C to give intermediate E1 (21.5 g, yield: 70.7%) as a colorless liquid. 1 H NMR (400MHz, CDCl3): δ ppm 9.54-9.64(m,1 H),3.97-4.09(m,1 H)3.82-3.95(m,2 H)3.52-3.79(m,4 H).

[0084] Step 2: (2,6-dichloropyridin-4-yl)(1,4-dioxan-2-yl)methanol (Intermediate E2) [ka] To a mixture of 2,6-dichloro-4-iodopyridine (21.46 g, 78.37 mmol) in THF (70 mL) was added CH3MgCl / LiCl (64.92 mL, 84.4 mmol) under N2 at -50 °C. The mixture was stirred at 25 °C for 2 h, then 1,4-dioxane-2-carbaldehyde (14.0 g, 60.28 mmol) in THF (10 mL) was added at -50 °C. The mixture was stirred at 25 °C for 1 h. The reaction was then poured into saturated aqueous NH4Cl solution and extracted three times with EA (300 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=3:2) to give intermediate E2 (8.3 g, 31.43 mmol, 52.13% yield) as a yellow oil. MS found: 264.1 (MH + ).

[0085] Step 3: (2,6-Dichloropyridin-4-yl)(1,4-dioxan-2-yl)methanone (Intermediate E3) [ka] To a solution of intermediate E2 (6.4 g, 24.23 mmol) in DCM (60 mL) was added DMP (11.31 g, 26.66 mmol) at 0° C. and the reaction was stirred at 20° C. for 0.5 h. The mixture was poured into a mixture of aqueous Na2CO3 (400 mL) and EA:THF=5:1 (500 mL). After stirring for 0.5 h, the reaction was filtered and the organic layer was extracted twice with aqueous Na2CO3 (300 mL), dried over anhydrous Na2SO4, filtered and concentrated to give intermediate E3 (6 g, 22.89 mmol, 94.47% yield) as a pale yellow solid.

[0086] Step 4: 2,6-Dichloro-4-[1,4-dioxan-2-yl(difluoro)methyl]pyridine (Intermediate E4) [ka] To a solution of intermediate E3 (7.0 g, 26.71 mmol) in DCM (150 mL) was added DAST (140.0 mL, 1060 mmol), and the mixture was then stirred at 20° C. for 12 h. The reaction was extracted with EA (400 mL×3), and the organic layer was washed with aqueous NaHCO (200×3 mL), brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC (TFA as admixture) to give intermediate E4 (4 g, 14.08 mmol, 52.72% yield) as a white solid. MS found: 284.0 (MH + ). 1 H NMR (400MHz, CDCl3): δ ppm 7.35(s,2H),3.87-4.00(m,2H),3.79-3.81(m,1H),3.62-3.71(m,2H),3.53-3.60(m,2H).

[0087] Step 5: 2,6-Dichloro-4-[[(2S)-1,4-dioxan-2-yl]-difluoro-methyl]pyridine and 2,6-dichloro-4-[[(2R)-1,4-dioxan-2-yl]-difluoro-methyl]pyridine (Intermediates E and F) 4.0 g of intermediate E4 was purified by SFC using the following conditions to give intermediate E (1.48 g, 36.5% yield, 99% ee, faster elution) and intermediate F (1.5 g, 37.5% yield, 99% ee, slower elution) as white solids. SFC conditions: Column: OJ (250 mm x 50 mm, 10 um); 0.1% NH3H2O ​​EtOH; Start B 15%, End B 15%; Flow rate (ml / min): 180.

[0088] intermediate G tert-Butyl (2R)-2-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]morpholine-4-carboxylate [ka] The title compound was prepared according to the following procedure.

[0089] Step 1: tert-Butyl (2R)-2-formylmorpholine-4-carboxylate (Intermediate G1) [ka] To a solution of (COCl)2 (21.91 g, 172.6 mmol) in DCM (80 mL) was added DMSO (17.97 g, 230.14 mmol) at -60 °C and the mixture was stirred at -60 °C for 0.5 h under N2. A solution of (R)-N-Boc-2-hydroxymethylmorpholine (25.0 g, 115.07 mmol) in DCM (50 mL) was then added and the reaction was stirred at -60 °C for an additional 1 h. DIPEA (59.49 g, 460.28 mmol) was added and the mixture was stirred at -60 to -20 °C for 1 h and then at 0 °C for 1 h. The mixture was diluted with DCM (500 mL), washed three times with aqueous CaCl2 (100 mL) and twice with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column (PE:EA=10:1 to 1:5) to give intermediate G1 (8 g, 37.17 mmol, 32.3% yield) as a colorless oil. MS Found: 115.9 (MH + -100).

[0090] Step 2: tert-Butyl-(2R)-2-[(2,6-dichloro-4-pyridyl)-hydroxymethyl]morpholine-4-carboxylate (Intermediate G2) [ka] To a solution of 2,6-dichloro-4-iodopyridine (9.16 g, 33.45 mmol) in THF (30.0 ml) was added CH3MgCl / LiCl in THF (28.3 mL, 36.79 mmol) under N2 at -40°C and the mixture was stirred at 25°C for 1 h. Then, intermediate G1 (7.2 g, 33.45 mmol) in THF (130 mL) was added at -40°C and the mixture was stirred at 25°C for 1 h. The mixture was poured into water (100 mL) and extracted with EA (600 mL). The organic layer was washed twice with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=100:1 to 1:2) to give intermediate G2 (6 g, 16.52 mmol, 49.38% yield) as a white solid. MS Found: 363.3 (MH + ).

[0091] Step 3: tert-Butyl-(2R)-2-(2,6-dichloropyridine-4-carbonyl)morpholine-4-carboxylate (Intermediate G3) [ka] To a solution of intermediate G2 (5.5 g, 15.14 mmol) in THF (80 mL) was added DMP (7.06 g, 16.66 mmol) slowly at 0° C. under N2, then the mixture was stirred for 2 h. The mixture was poured into aqueous K2CO3 (100 mL) at 0° C., then extracted three times with EA (150 mL). The organic layer was washed three times with aqueous K2CO3 (50 mL) and twice with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give intermediate G3 (5.3 g, 14.67 mmol, 96.9% yield) as a white solid. MS found: 305.2 (MH + -56).

[0092] Step 4: tert-Butyl-(2R)-2-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]morpholine-4-carboxylate (Intermediate G) To a solution of intermediate G3 (5.0 g, 13.84 mmol) in DCM (8 mL) was added DAST (3.0 mL, 207.63 mmol) and stirred at 40 °C for 3 h. The mixture was poured into aqueous NaHCO3 at 0 °C and then extracted three times with EA (200 mL). The combined organic layers were washed twice with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA = 10:1 to 1:1) to give intermediate G (2.2 g, 5.74 mmol, 41.47% yield, 90% ee) as a white solid. MS found: 327.3 (MH + -56).

[0093] Intermediate H tert-Butyl-(2S)-2-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]morpholine-4-carboxylate [ka] The title compound was prepared similarly to the preparation of intermediate G, by using (S)-N-Boc-2-hydroxymethylmorpholine instead of (R)-N-Boc-2-hydroxymethylmorpholine. Intermediate H (1.2 g, 95.5% ee) was obtained as a white solid. MS found: 327.2 (MH + -56).

[0094] Intermediate I tert-Butyl 4-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] The title compound was prepared according to the following procedure.

[0095] Step 1: tert-Butyl 4-(methoxy(methyl)carbamoyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate I1) [ka] To a solution of 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid (4.5 g, 19.80 mmol), HATU (11.29 g, 29.70 mmol) and DIPEA (8.96 g, 69.30 mmol) in DMF (50 mL) was added N,O-dimethylhydroxylamine hydrochloride (4.83 g, 49.50 mmol). The reaction was stirred at 15 °C for 2 h. The mixture was poured into water (30 mL) and extracted twice with EA (40 mL). The organic layer was washed twice with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA = 1:0 to 5:1) to give intermediate I1 (4.7 g, yield: 87.80%) as a white solid. MS measured value: 215.4(MH + -56).

[0096] Step 2: tert-Butyl 4-(2,6-dichloropyridine-4-carbonyl)-3,6-dihydro-2H-pyridine-1-carboxylate (Intermediate I2) [ka] To a solution of 2,6-dichloro-4-iodopyridine (5.07 g, 18.5 mmol) in THF (15.0 ml) was added CH3MgCl / LiCl in THF (14.23 mL, 18.5 mmol) under N2 at -40 °C. After stirring at 25 °C for 1 h, intermediate I1 (2.5 g, 9.25 mmol) in THF (25 mL) was added to the solution at -40 °C. The mixture was poured into water (100 mL) and extracted with EA (600 mL). The organic layer was washed twice with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA = 100:1 to 1:1) to give intermediate I2 (1.5 g, 4.2 mmol, 45.4% yield) as a pale yellow oil. MS measured value: 301.3 (MH + -56).

[0097] Step 3: tert-Butyl 4-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]-3,6-dihydro-2H-pyridine-1-carboxylate (Intermediate I) To a solution of intermediate I2 (1.5 g, 4.2 mmol) in DCM (3 mL) was added DAST (6.77 g, 41.99 mmol) and stirred at 40 °C for 12 h. The mixture was poured into saturated NaHCO3 (aq) at 0 °C and then extracted three times with EA (100 mL). The combined organic layers were washed twice with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA = 10:1 to 1:1) to give intermediate I (1 g, 2.64 mmol, 62.8% yield) as a pale yellow oil. MS found: 323.2 (MH + -56).

[0098] Intermediate J tert-Butyl 3-(2,6-dichloropyridine-4-carbonyl)piperidine-1-carboxylate [ka] The title compound was prepared in a manner similar to the preparation of Intermediate G3, by using tert-butyl 3-formylpiperidine-1-carboxylate instead of Intermediate G1. Intermediate J (3.1 g) was obtained as a yellow oil. MS found: 359.0 (MH + ).

[0099] Intermediate K tert-Butyl 3-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]azetidine-1-carboxylate [ka] The title compound was prepared in a manner similar to that of intermediate G, by using tert-butyl 3-formylazetidine-1-carboxylate instead of intermediate G1. Intermediate K (1.1 g) was obtained as a yellow solid. MS found: 353.1 (MH + ).

[0100] Example 1 4-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0101] Step 1: tert-Butyl N-[1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (Compound 1a) [ka] A mixture of intermediate A (100 mg, 188 μmol), tert-butyl (5-oxopyrrolidin-3-yl)carbamate (75.3 mg, 376 μmol), DMEDA (3.32 mg, 37.6 μmol), CuI (7.17 mg, 37.6 μmol) and Cs2CO3 (122 mg, 376 μmol) in DMF (5 mL) was heated at 75° C. for 1 h. The mixture was then poured into ice water, extracted three times with DCM (10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=5:1) to give compound 1a (97 mg, 85% yield) as a white solid. MS found: 604.2 (MH + ).

[0102] Step 2: 4-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 1) A solution of compound 1a (100 mg, 166 μmol) in TFA (5 mL) was stirred at room temperature for 5 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give Example 1 (10 mg, 12% yield) as a white solid. MS found: 504.2 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.78-7.89(m,2H),7.64-7.75(m,2H),6.81(s,1H),6.72(s,1H),4.29(dd,J=7.2,11.2Hz,1H),3.97-4.16(m,1H),3 .85(dd,J=2.4,11.2Hz,1H),3.56-3.70(m,4H),3.09(dd,J=8.4,18.0Hz,1H),2.95-3.00(m,4H),2.46-2.69(m,1H).

[0103] Example 2 4-(Aminomethyl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-phenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl-N-[(5-oxopyrrolidin-3-yl)carbamate instead of tert-butyl[(5-oxopyrrolidin-3-yl)methyl]carbamate. Example 2 (17.1 mg) was obtained as a white solid. MS found: 518.0 (MH + ). 1H NMR(400MHz,CD3OD):δ ppm 7.75-7.790(m,2H),7.68-7.73(m,2H),6.81(s,1H),6.73(s,1H),4.02(dd,J=8.0,9. 6Hz,1H),3.57-3.73(m,5H),2.92-3.15(m,6H),2.66-2.83(m,2H),2.35-2.55(m,1H).

[0104] Example 3 5-(Aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl N-[(2-oxooxazolidin-5-yl)methyl]carbamate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 3 (30 mg) was obtained as a white solid. MS found: 520.0 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.15(brs,3H),7.53-7.96(m,4H),7.10(s,1H),6.98(s,1H),4.81-5.06(m,1H),4.24(t,J=9. 2Hz,1H),3.87(dd,J=6.4,9.2Hz,1H),3.63-3.77(m,4H),3.27(s,2H),2.96(t,J=4.8Hz,4H).

[0105] Example 4 N-[[3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide [ka] To a solution of Example 3 (50 mg, 96.2 μmol) and DIPEA (62 mg, 481 μmol) in DCM (5 mL) was added acetyl chloride (15.1 mg, 192 μmol) dropwise at room temperature. The mixture was stirred at room temperature for 16 h. The solvent was evaporated and the crude product was purified by preparative HPLC to give Example 4 as a white solid (15 mg, 25% yield). MS found: 561.9 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.23(t,J=6.0Hz,1H),7.78(s,4H),7.09(s,1H),6.97(s,1H),4.58-4.86(m,1H),4.16(t,J=9.2Hz,1H),3 .78(dd,J=6.4,9.12Hz,1H),3.68-3.74(m,4H),3.42(t,J=5.6Hz,2H),2.96(t,J=4.8Hz,4H),1.81(s,3H).

[0106] Example 5 4-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3,3-dimethyl-pyrrolidin-2-one [ka] A mixture of intermediate A (0.060 g, 113 μmol), 4-amino-3,3-dimethylpyrrolidin-2-one (14.5 mg, 113 μmol), DMEDA (1.99 mg, 22.6 μmol), CuI (4.3 mg, 22.6 μmol) and K3PO4 (71.8 mg, 339 μmol) in DMF (1.5 mL) was heated at 80° C. for 1.5 h. The mixture was then poured into water and extracted with DCM. The organic layer was concentrated and the crude product was purified by preparative HPLC to give Example 5 as a white solid (40 mg, 64.4% yield). MS found: 521.1 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 8.31(br s,2H),7.83-7.89(m,2H),7.71-7.76(m,2H),7.02(s,1H),6.90(s,1H),4.22(dd,J=6.4,11.2Hz,1H),3.61-3.80(m,6H),2.90(br t,J=4.8Hz,4H),1.16(s,3H),1.11(s,3H).

[0107] Example 6 4-(Aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 5, by using 4-(aminomethyl)oxazolidin-2-one instead of 4-amino-3,3-dimethylpyrrolidin-2-one. Example 6 (10 mg) was obtained as a white solid. MS found: 520.1 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.95(br s,3H),7.84-7.90(m,2H),7.78-7.83(m,2H),7.10(s,1H),6.98(s,1H),4.81-4.98(m,1H),4. 53-4.60(m,1H),4.45-4.51(m,1H),3.66-3.68(m,4H),3.11-3.22(m,1H),2.91-3.09(m,5H).

[0108] Example 7 (3S)-3-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]azetidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using (3S)-3-aminoazetidin-2-one instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 7 (10 mg) was obtained as a white solid. MS found: 490.0 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.67-7.85(m,2H),7.38-7.61(m,2H),6.82(s,1H),6.74(s,1H),4.62(dd,J=2.8 ,5.6Hz,1H),4.07(dd,J=5.6,7.2Hz,1H),3.53-3.76(m,5H),2.92-3.03(m,4H).

[0109] Example 8 3-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl N-(2-oxopyrrolidin-3-yl)carbamate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 8 (20 mg) was obtained as a white solid. MS found: 504.1 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.82-8.02(m,2H),7.65-7.82(m,2H),6.82(s,1H),6.73(s,1H),4.19(dd,J=8.8,11.2Hz,1H), 3.82-4.04(m,2H),3.59-3.68(m,4H),2.91-3.04(m,4H),2.51-2.69(m,1H),1.95-2.19(m,1H).

[0110] Example 9 5-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl N-[2-(2-oxooxazolidin-5-yl)ethyl]carbamate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 9 (66.4 mg) was obtained as a white solid. MS found: 578.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.02-8.26(m,3 H),7.74-7.84(m,4 H),7.08-7.13(m,1 H),6.95-7.00(m,1 H),4.79-4.92(m,1 H),4.18-4.29(m,1 H),3.67-3.90(m,5 H),2.86-3.07(m,6 H),1.99-2.13(m,2 H).

[0111] Example 10 2-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6-diazaspiro[4.5]decan-3-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl 3-oxo-2,6-diazaspiro[4.5]decane-6-carboxylate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 10 (10 mg) was obtained as a white solid. MS found: 558.2 (MH + ). 1H NMR(400MHz,CD3OD):δ ppm 7.78-7.90(m,2H),7.67-7.78(m,2H),6.81(s,1H),6.73(s,1H),4.07(s,2H),3.51- 3.81(m,4H),3.24-3.33(m,4H),2.95-3.02(m,4H),1.92(s,2H),1.64-1.77(m,4H).

[0112] Example 11 2-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,8-diazaspiro[4.5]decan-3-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 11 (15 mg) was obtained as a white solid. MS found: 558.1 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 8.50(br s,2H),7.93(d,J=8.8Hz,2H),7.77(d,J=8.8Hz,2H),7.09(s,1H),6.97(s,1H),3.79(s,2H), 3.66-3.75(m,4H),3.03-3.22(m,4H),2.96(t,J=4.8Hz,4H),2.61(s,2H),1.65-1.88(m,4H).

[0113] Example 12 6-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6-diazaspiro[3.4]octan-7-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl 6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 11 (10 mg) was obtained as a white solid. MS found: 530.0 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 8.73(br d,J=1.6Hz,2H),7.83-7.91(m,2H),7.74-7.83(m,2H),7.09(s,1H),6.98(s,1H), 4.14(s,2H),4.06(td,J=5.2,10.8Hz,4H),3.65-3.80(m,4H),2.90-3.03(m,6H).

[0114] Example 13 7-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxa-2,7-diazaspiro[3.4]octan-6-one [ka] The title compound was prepared in a similar manner to the preparation of Example 5, by using 5-oxa-2,7-diazaspiro[3.4]octan-6-one instead of 4-amino-3,3-dimethylpyrrolidin-2-one. Example 13 (8 mg) was obtained as a white solid. MS found: 532.2 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.80-7.87(m,2H),7.71-7.79(m,2H),7.10(s,1H),6.98(s,1H),4.19-4.45(m,6H),3.71(t,J=5.2Hz,4H),2.96(br t,J=4.8Hz,4H).

[0115] Example 14 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 5, by using 1-oxa-3,8-diazaspiro[4.5]decan-2-one hydrochloride instead of 4-amino-3,3-dimethylpyrrolidin-2-one. Example 14 (58 mg) was obtained as a white solid. MS found: 560.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.66-7.80(m,4H),6.97-7.04(m,1H),6.84-6.93(m,1H),3.81-3.87(m,2H),3.62-3.6 6(m,4H),2.86-2.91(m,4H),2.72-2.81(m,2H),2.59-2.67(m,2H),1.59-1.80(m,4H).

[0116] Example 15 (3aR,6aS)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 5 by using (3aR,6aS)-3,3a,4,5,6,6a-hexahydropyrrolo[3,4-d]oxazol-2-one instead of 4-amino-3,3-dimethylpyrrolidin-2-one. Example 15 (10 mg) was obtained as a white solid. MS found: 532.1 (MH + ). 1H NMR(400MHz,CD3OD):δ ppm 7.73-8.02(m,4H),6.94(s,1H),6.85(s,1H),5.48(dd,J=4.8,7.6Hz,1H),5.36-5.43(m ,1H),3.90(d,J=13.2Hz,1H),3.73-3.81(m,4H),3.747-3.72(m,3H),3.05-3.19(m,4H).

[0117] Example 16 (3aR,7aS)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl (3aR,7aS)-2-oxo-3,3a,4,6,7,7a-hexahydrooxazolo[4,5-c]pyridine-5-carboxylate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 16 (10 mg) was obtained as a white solid. MS found: 546.1 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.74(d,J=2.4Hz,4H),6.82(s,1H),6.73(s,1H),4.82-4.99(m,2H),3.60-3.70(m,4H), 3.55(dd,J=4.4,14.0Hz,1H),3.10-3.31(m,3H),2.91-3.04(m,4H),2.16-2.30(m,2H).

[0118] Example 17 (3aR,7aS)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl (3aR,7aS)-2-oxo-1,3a,4,6,7,7a-hexahydrooxazolo[5,4-c]pyridine-5-carboxylate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 17 (33 mg) was obtained as a white solid. MS found: 546.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.09-9.67(m,2H),7.83-7.89(m,2H),7.76-7.82(m,2H),7.09(s,1H),6.97(s,1H),4.98(br d,J=7.2Hz,1H),4.78-4.89(m,1H),3.61-3.677(m,5H),3.39-3.45(m,1H),3.06-3.14(m,1H),2.98(br t,J=4.4Hz,5H),2.30-2.41(m,1H),1.66-1.78(m,1H).

[0119] Example 18 (3aS,7aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl (3aS,7aR)-2-oxo-3,3a,4,6,7,7a-hexahydrooxazolo[4,5-c]pyridine-5-carboxylate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 18 (120 mg) was obtained as a white solid. MS found: 546.0 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 9.19-9.31(m,2H),7.80(s,4H),7.10(s,1H),6.98(s,1H),4.09-5.02(m,2H),3.6 8-3.78(m,4H),3.49-3.56(m,1H),3.11-3.22(m,2H),3.02-3.09(m,1H),2.99(br s,4H),2.31(br s,1H),2.09-2.020(m,1H).

[0120] Example 19 (3aS,8aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl (3aS,8aR)-2-oxo-3a,4,6,7,8,8a-hexahydro-3H-oxazolo[4,5-c]azepine-5-carboxylate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 19 (10 mg) was obtained as a white solid. MS found: 560.1 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.67-7.85(m,4H),6.82(s,1H),6.74(s,1H),4.97-5.12(m,2H),3.59-3.72(m,4H),3.41-3.454(m,1H),3.24-3 .30(m,1H),3.13-3.19(m,2H),2.92-3.07(m,4H),2.20(d,J=4.4Hz,2H),1.95-2.11(m,1H),1.69-1.86(m,1H).

[0121] Example 20 4-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-5-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl 5-oxo-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-b]pyrrole-1-carboxylate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 20 (100 mg) was obtained as a white solid. MS found: 530.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.56(br s,2H),7.84-7.93(m,2H),7.74-7.84(m,2H),7.09(s,1H),6.92-7.01(m,1H),5.0 2-5.16(m,1H),4.32-4.47(m,1H),3.68-3.73(m,4H),3.20-3.29(m,2H),2.99(br d,J=5.2Hz,6H),2.29(br s,1H),1.85(br d,J=7.2Hz,1H).

[0122] Example 21 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-6-hydroxy-5-(hydroxymethyl)-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazol-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 5, by using 6-hydroxy-5-(hydroxymethyl)-3a,5,6,6a-tetrahydro-3H-furo[2,3-d]oxazol-2-one instead of 4-amino-3,3-dimethylpyrrolidin-2-one. Example 21 (5 mg) was obtained as a white solid. MS found: 579.1 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.85(d,J=8.8Hz,2H),7.71(d,J=8.8Hz,2H),6.82(s,1H),6.73(s,1H),6.12(d,J=6.0Hz,1H),4.84(d,J=5.2Hz,1H ),4.31(d,J=2.4Hz,1H),4.02(dt,J=2.8,5.2Hz,1H),3.57-3.69(m,4H),3.46(d,J=5.2Hz,2H),2.91-3.05(m,4H).

[0123] Example 22 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(3S,4R,5R)-3,4-dihydroxy-5[-methoxy-tetrahydrofuran-2-yl]-4-methyl-oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 5, by using 5[(3S,4R,5R)-3,4-dihydroxy-5-methoxy-tetrahydrofuran-2-yl]-4-methyl-oxazolidin-2-one instead of 4-amino-3,3-dimethylpyrrolidin-2-one. Example 22 (20 mg) was obtained as a white solid. MS found: 637.1 (MH + ). 1H NMR (400MHz, DMSO-d6): δ ppm 7.92(d,J=8.8Hz,2H),7.77(d,J=8.8Hz,2H),7.09(s,1H),6.97(s,1H),4.94-5. 38(m,1H),4.76-4.89(m,2H),4.74(d,J=1.2Hz,1H),4.51(dd,J=7.32,9.6Hz,1H ),4.17(t,J=5.2Hz,1H),4.03(dd,J=5.2,9.8Hz,1H),3.83(dd,J=1.2,4.8Hz,1H ),3.67-3.75(m,4H),3.27(s,3H),2.99(t,J=4.8Hz,4H),1.26(d,J=6.4Hz,3H).

[0124] Example 23 (3aS,5S,6S,7S,7aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5,7-dihydroxy-6-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d]oxazol-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 5 by using (3aS,5S,6S,7S,7aR)-5,7-dihydroxy-6-(hydroxymethyl)-3,3a,5,6,7,7a-hexahydropyrano[2,3-d]oxazol-2-one in 4-amino-3,3-dimethylpyrrolidin-2-one. Example 23 (10 mg) was obtained as a white solid. MS found: 609.2 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=8.8Hz,2H),7.78(d,J=8.8Hz,2H),7.08(s,1H),6.97(s,1H),6.07(d,J=6.0Hz,1H),5.61(d,J=5.2Hz,1H),5.38(d,J=5.2Hz,1H),4.8 1(t,J=5.6Hz,1H),4.60(dd,J=4.4,6.0Hz,1H),3.80-3.87(m,1H),3.67 -3.75(m,4H),3.57-3.63(m,2H),3.44-3.54(m,2H),2.93-3.04(m,4H).

[0125] Example 24 8-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka] The title compound was prepared according to the following scheme.

[0126] Step 1: tert-Butyl N-[2-[3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl]ethyl]carbamate (compound 24a) [ka] A mixture of Example 11 (0.050 g, 89.3 μmol), tert-butyl (2-oxoethyl)carbamate (28.4 mg, 179 μmol) and NaBH(OAc)3 (75.7 mg, 357 μmol) in DCM (1 mL) was heated at 25° C. overnight. The mixture was then poured into water and extracted with DCM. The organic layer was concentrated to give the crude product, which was used directly in the next step. MS found: 703.2 (MH + ). Step 2: 8-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one (Example 24) A mixture of compound 24a (0.062 g, 88.2 μmol) and TFA (450 mg, 0.3 mL, 3.95 mmol) in DCM (1 mL) was heated at 25° C. for 2 h. The mixture was concentrated and the crude product was purified by HPLC to give Example 24 (15 mg, 26.8% yield) as a white solid. MS found: 603.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.77-7.84(m,4H),7.06-7.11(m,1H),6.93-7.00(m,1H),3.97-4.04(m,2H),3.70-3.7 4(m,4H),3.50-3.56(m,4H),3.07-3.22(m,4H),2.94-2.99(m,4H),1.90-2.23(m,4H).

[0127] Example 25 (3aS,8aR)-5-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepin-2-one [ka] The title compound was prepared according to the following procedure.

[0128] Step 1: tert-Butyl N-[2-[(3aS,8aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-oxo-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepin-5-yl]ethyl]carbamate (compound 25a) [ka] A mixture of Example 19 (50 mg, 74.2 μmol), tert-butyl (2-oxoethyl)carbamate (23.6 mg, 148 μmol) and NaBH(OAc)3 (62.9 mg, 297 μmol) in DCM (2 mL) was stirred at 25° C. overnight. The mixture was then poured into water and extracted with DCM. The organic layer was concentrated to give the crude product, which was used directly in the next step (52 mg, 100% yield). MS found: 703.2 (MH + ). Step 2: (3aS,8aR)-5-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepin-2-one (Example 25) A solution of compound 24a (80 mg, 114 μmol) in TFA (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give Example 25 (15 mg, 21.9% yield). MS found: 603.2 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.85(s,4H),6.92(s,1H),6.84(s,1H),4.99(td,J=6.0,8.8Hz,1H),4.69-4.83(m,1H),3.63-3.87(m,4H),3.07-3.1 6(m,4H),2.95(dd,J=6.8,14.8Hz,1H),2.55-2.84(m,7H),2.08-2.20(m,2H),1.90-2.04(m,1H),1.54-1.72(m,1H).

[0129] Example 26 (3aS,8aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[2-(methylamino)ethyl]-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 25, by using tert-butyl N-methyl-N-(2-oxoethyl)carbamate instead of tert-butyl (2-oxoethyl)carbamate. Example 26 (19 mg) was obtained as a white solid. MS found: 617.2 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.85(s,4H),6.92(s,1H),6.84(s,1H),4.99(td,J=5.6,8.8Hz,1H),4.77-4.84(m,1H),3.69-3.80(m,4H),3.07-3.18(m,4H),2.97( dd,J=6.6,14.8Hz,1H),2.73-2.82(m,3H),2.65-2.72(m,4H),2.60(s,3H),2.08-2.19(m,2H),1.90-2.04(m,1H),1.58-1.70(m,1H).

[0130] Example 27 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(methylaminomethyl)oxazolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0131] Step 1: 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(hydroxymethyl)oxazolidin-2-one (compound 27a) [ka] To a solution of intermediate A (3.4 g, 6.39 mmol), 5-(hydroxymethyl)oxazolidin-2-one (1.12 g, 9.59 mmol) and K2CO3 (2.65 g, 19.18 mmol) in NMP (42.5 mL) was added CuI (243.56 mg, 1.28 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (181.91 mg, 1.28 mmol) under N2. The mixture was stirred at 80 °C under N2 for 5 h. The mixture was diluted with EA (400 mL) and filtered. The filtrate was washed three times with aqueous CaCl2 (100 mL), twice with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=2:1 to 1:5) to give compound 27a (2.7 g, 5.18 mmol, 81.1% yield) as a white solid. MS Found: 520.1 (MH + ).

[0132] Step 2: [3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-oxo-oxazolidin-5-yl]methyl 4-methylbenzenesulfonate (compound 27b) [ka] To a solution of compound 27a (1.4 g, 2.69 mmol), p-toluenesulfonic anhydride (1.75 g, 5.38 mmol) and DIPEA (1.04 g, 8.06 mmol) in THF (8 mL) was added DMAP (65.67 mg, 0.540 mmol) under nitrogen. The mixture was stirred at 45 °C under N for 12 h and then diluted with EA (300 mL). The solution was washed with aqueous K2CO3 (100 mL), 2 times with aqueous 1N HCl (100 mL) and 2 times with brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA = 2:1 to 1:5) to give compound 27b (1.7 g, 2.52 mmol, 93.69% yield) as a white solid. MS measured value: 675.2(MH+ ).

[0133] Step 3: 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(methylaminomethyl)oxazolidin-2-one (Example 27) To a solution of compound 27b (120.0 mg, 0.18 mmol) and KI (88.5 mg, 0.53 mmol) in DMSO (1.5 mL) was added monomethylamine and 18-crown-6 (4.7 mg, 0.02 mmol) in THF (3.0 mL, 6 mmol) under N2. The mixture was stirred at 60 °C under N2 for 3 h. The mixture was diluted with EA (200 mL) and filtered. The filtrate was washed three times with aqueous CaCl2 (50 mL) and twice with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give Example 27 (23.4 mg, 0.040 mmol, 22.64% yield) as a white solid. MS found: 534.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.99-9.90(m,2 H),7.75-7.84(m,4 H),7.06-7.13(m,1 H),6.94-6.99(m,1 H),5.04-5.20(m,1 H),4.20-4.34(m,1 H),3.91-4.03(m,1 H),3.61-3.79(m,4 H),3.30-3.36(m,2 H),2.86-3.06(m,4 H),2.56-2.63(m,3 H).

[0134] Example 28 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(dimethylamino)methyl]oxazolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 27, by using dimethylamine instead of monomethylamine. Example 28 (17.1 mg) was obtained as a white solid. MS found: 548.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 10.77-11.01(m,1 H),7.73-7.86(m,4 H),7.08-7.12(m,1 H),6.95-7.00(m,1 H),5.20-5.35(m,1 H),4.21-4.35(m,1 H),3.84-3.95(m,1 H),3.50-3.75(m,6 H),2.93-3.06(m,4 H),2.80-2.90(m,6 H).

[0135] Example 29 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(piperazin-1-ylmethyl)oxazolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 27, by using piperazine instead of monomethylamine. Example 29 (49.9 mg) was obtained as a white solid. MS found: 589.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.51-10.01(m,2 H),7.72-7.90(m,4 H),7.07-7.14(m,1 H),6.93-7.00(m,1 H),5.16-5.38(m,1 H),4.24-4.34(m,1 H),3.49-3.92(m,14 H),2.90-3.02(m,4 H).

[0136] Example 30 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[[cis-3,4-dihydroxypyrrolidin-1-yl]methyl]oxazolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 27, by using cis-pyrrolidine-3,4-diol hydrochloride instead of monomethylamine. Example 30 (25.5 mg) was obtained as a white solid. MS found: 606.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 10.69-11.44(m,1 H),7.75-7.83(m,4 H),7.08-7.13(m,1 H),6.95-7.01(m,1 H),5.09-5.71(m,3 H),4.03-4.37(m,3 H),3.59-3.94(m,8 H),3.37-3.48(m,2 H),2.92-3.18(m,5 H).

[0137] Example 31 5-[(3-aminoazetidin-1-yl)methyl]-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one [ka] The title compound was prepared according to the following scheme.

[0138] Step 1: tert-Butyl N-[1-[[3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-oxo-oxazolidin-5-yl]methyl]azetidin-3-yl]carbamate (compound 31a) [ka] To a solution of compound 27b (220.0 mg, 0.330 mmol), 3-N-Boc-amino-azetidine (168.37 mg, 0.980 mmol) and KI (0.05 mL, 0.980 mmol) in ACN (5 mL) was added K2CO3 (135.11 mg, 0.980 mmol) under N2. The mixture was stirred at 70 °C for 8 h. The mixture was diluted with EA (200 mL) and filtered. The filtrate was washed twice with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give compound 31a (90 mg, 0.130 mmol, 40.91% yield) as a white solid. MS found: 675.0 (MH + ).

[0139] Step 2: 5-[(3-aminoazetidin-1-yl)methyl]-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one (Example 31) To a solution of compound 31a (90.0 mg, 0.130 mmol) in DCM (2 mL) was added TFA (1.0 mL, 12.98 mmol) and the reaction was stirred at 25° C. for 2 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give Example 31 (40 mg, 0.060 mmol, 43.06% yield) as a white solid. MS found: 575.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.29-8.76(m,2 H),7.74-7.86(m,4 H),7.07-7.14(m,1 H),6.94-7.02(m,1 H),4.86-5.02(m,1 H),3.83-4.31(m,9 H),3.70-3.76(m,4 H),2.89-3.02(m,4 H).

[0140] Example 32 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(2,6-diazaspiro[3.3]heptan-2-ylmethyl)oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31, by using tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate instead of 3-N-Boc-amino-azetidine. Example 32 (95.7 mg) was obtained as a white solid. MS found: 601.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.84-9.07(m,2 H),7.73-7.87(m,4 H),7.07-7.12(m,1 H),6.93-6.99(m,1 H),4.89-5.03(m,1 H),4.31-4.45(m,4 H),4.11-4.28(m,5 H),3.82-3.88(m,1 H),3.70-3.73(m,4 H),3.53-3.62(m,2 H),2.89-3.03(m,4 H).

[0141] Example 33 5-[[3-(aminomethyl)azetidin-1-yl]methyl]-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31, by using tert-butyl N-(azetidin-3-ylmethyl)carbamate instead of 3-N-Boc-amino-azetidine. Example 33 (95.7 mg) was obtained as a white solid. MS found: 589.2 (MH + ). + ). 1H NMR(400MHz,DMSO-d6):δ ppm 10.55-11.53(m,1 H),7.96-8.22(m,3 H),7.72-7.86(m,4 H),7.06-7.14(m,1 H),6.93-6.99(m,1 H),4.89-5.07(m,1 H),3.98-4.34(m,5 H),3.82-3.90(m,1 H),3.72(br d,J=4.4Hz,4 H),3.59-3.67(m,2 H),2.90-3.26(m,7 H).

[0142] Example 34 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(pyrrolidin-3-ylamino)methyl]oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31, by using N-Boc-3-aminopyrrolidine instead of 3-N-Boc-amino-azetidine. Example 34 (57.3 mg) was obtained as a white solid. MS found: 589.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.96-9.61(m,2 H),7.73-7.87(m,4 H),7.06-7.14(m,1 H),6.92-7.00(m,1 H),4.93-5.11(m,1 H),4.20-4.35(m,1 H),3.85-3.96(m,2 H),3.70-3.75(m,4 H),3.56(br dd,J=12.0,7.6Hz,1 H),3.22-3.48(m,5 H),2.91-3.02(m,4 H).

[0143] Example 35 4-[[3-(aminomethyl)azetidin-1-yl]methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31, by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and tert-butyl N-(azetidin-3-ylmethyl)carbamate instead of 3-N-Boc-amino-azetidine. Example 35 (15 mg) was obtained as a white solid. MS found: 587.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.71-11.11(m,1H),7.84-7.95(m,4H),7.73-7.82(m,2H),7.09(s,1H),6.98(s,1H),3.81-4.30(m,5H),3.68-3.75(m,4H),3. 64(dd,J=6.4,9.2Hz,1H),3.16-3.23(m,1H),3.01-3.15(m,2H),2.96(t,J=4.8Hz,4H),2.62-2.82(m,2H),2.39-2.55(m,3H).

[0144] Example 36 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(4-methylpiperazin-1-yl)methyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 27, by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and 1-methylpiperazine instead of monomethylamine. Example 36 (25 mg) was obtained as a white solid. MS found: 600.9 (MH + ). 1H NMR(400MHz,CD3OD):δ ppm 7.88-7.93(m,2H),7.75-7.83(m,J=9.2Hz,2H),6.91(s,1H),6.82(s,1H),4.03(dd,J=7.6,9.6Hz, 1H),3.67-3.77(m,5H),3.01-3.0114(m,4H),2.62-2.87(m,3H),2.39-2.356(m,10H),2.31(s,3H).

[0145] Example 37 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-[(dimethylamino)methyl]azetidin-1-yl]methyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 27, by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and 1-(azetidin-3-yl)-N,N-dimethyl-methanamine instead of monomethylamine. Example 37 (25 mg) was obtained as a white solid. MS found: 614.9 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.86-7.93(m,2H),7.75-7.85(m,2H),6.91(s,1H),6.82(s,1H),4.25-4.41(m,2H),3.95-4.14(m,3H),3.69-3.80(m,5H),3.48(d d,J=1.6,3.2Hz,2H),3.34-3.42(m,2H),3.11-3.16(m,1H),3.03-3.10(m,4H),2.88(s,6H),2.72-2.86(m,2H),2.42-2.55(m,1H).

[0146] Example 38 4-[(azetidin-3-ylmethylamino)methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31, by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate instead of 3-N-Boc-amino-azetidine. Example 38 (23 mg) was obtained as a white solid. MS found: 587.0 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.86-7.92(m,2H),7.77-7.84(m,2H),6.91(s,1H),6.82(s,1H),4.10-4.24(m,3H),3.99-4.07(m,2H),3.67- 3.83(m,5H),3.37-3.39(m,3H),3.16-3.27(m,2H),3.04-3.11(m,4H),2.81-2.94(m,2H),2.47-2.60(m,1H).

[0147] Example 39 4-[[3-(1-aminocyclopropyl)azetidin-1-yl]methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31, by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and tert-butyl N-[1-(azetidin-3-yl)cyclopropyl]carbamate instead of 3-N-Boc-amino-azetidine. Example 39 (25 mg) was obtained as a white solid. MS found: 612.9 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.87-7.94(m,2H),7.76-7.82(m,2H),6.91(s,1H),6.82(s,1H),4.00(dd,J=7.6,9.8Hz,1H),3.61-3.78(m,5H),3.38-3.47(m,2H) ,3.04-3.11(m,4H),2.95(t,J=7.6Hz,2H),2.72(dd,J=8.0,16.8Hz,1H),2.46-2.66(m,4H),2.29-2.44(m,1H),0.47-0.67(m,4H).

[0148] Example 40 4-[(3-aminoazetidin-1-yl)methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31, by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and tert-butyl N-(azetidin-3-yl)carbamate instead of 3-N-Boc-amino-azetidine. Example 40 (25 mg) was obtained as a white solid. MS found: 573.0 (MH + ). 1H NMR(400MHz,CD3OD):δ ppm 7.89(d,J=8.8Hz,2H),7.74-7.83(m,2H),6.91(s,1H),6.82(s,1H),4.00(dd,J=7.6,9.6Hz,1H),3.62-3.77(m,7H) ),3.57(quin,J=6.8Hz,1H),3.03-3.11(m,4H),2.85(dt,J=4.0,7.2Hz,2H),2.50-2.77(m,4H),2.33-2.45(m,1H).

[0149] Example 41 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(piperazin-1-ylmethyl)pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31, by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and tert-butylpiperazine-1-carboxylate instead of 3-N-Boc-amino-azetidine. Example 41 (25 mg) was obtained as a white solid. MS found: 587.0 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.88-7.94(m,2H),7.80(d,J=8.8Hz,2H),6.91(s,1H),6.82(s,1H),4.05(dd,J=7.6,9.8Hz,1H),3.68-3.77( m,5H),3.23(t,J=5.2Hz,4H),3.04-3.11(m,4H),2.65-2.85(m,6H),2.57(d,J=3.2Hz,2H),2.38-2.50(m,1H).

[0150] Example 42 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-(dimethylamino)azetidin-1-yl]methyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 27, by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and N,N-dimethylazetidin-3-amine instead of monomethylamine. Example 42 (25 mg) was obtained as a white solid. MS found: 600.1 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.86-7.892(m,2H),7.77-7.84(m,2H),6.91(s,1H),6.82(s,1H),4.06(t,J=8.8Hz,3H),3.82(d,J=2.8 Hz,3H),3.67-3.76(m,5H),3.11-3.18(m,1H),3.00-3.11(m,5H),2.63-2.85(m,8H),2.41-2.55(m,1H).

[0151] Example 43 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-(methylamino)azetidin-1-yl]methyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 31 by using 4-(hydroxymethyl)pyrrolidin-2-one instead of 5-(hydroxymethyl)oxazolidin-2-one and by using tert-butyl N-(azetidin-3-yl)-N-methyl-carbamate instead of 3-N-Boc-amino-azetidine. Example 43 (25 mg) was obtained as a white solid. MS found: 587.0 (MH +). 1 H NMR(400MHz,CD3OD):δ ppm 7.86-7.93(m,2H),7.75-7.84(m,2H),6.91(s,1H),6.82(s,1H),3.98-4.15(m,4H),3.80-3.97( m,2H),3.68-3.78(m,5H),2.98-3.12(m,6H),2.74-2.85(m,1H),2.70(s,4H),2.41-2.53(m,1H).

[0152] Example 44 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(methylamino)pyrrolidin-2-one [ka] To a solution of Intermediate B (100.0 mg, 0.210 mmol) in THF (3 mL) was added methylamine (1.03 mL, 2.05 mmol) and the mixture was heated to 90° C. for 1 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give Example 44 (25 mg, 0.050 mmol, 23.2% yield) as a white solid. MS found: 518.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.42-9.61(m,2H),7.91(s,2H),7.79(d,J=9.2Hz,2H),7.09(s,1H),6.97 (s,1H),4.21-4.28(m,1H),4.04-4.10(m,1H),3.95-4.03(m,1H),3.71(br s,4H),3.01-3.09(m,1H),2.97(br s,4H),2.80-2.88(m,1H),2.61(br s,3H).

[0153] Example 45 4-(2-Aminoethylamino)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 44, by using ethylenediamine instead of monomethylamine. Example 45 (18 mg) was obtained as a white solid. MS Found: 487.0 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 10.21-10.97(m,1 H),7.58-8.52(m,4 H),6.73-7.31(m,2 H),3.59-4.13(m,4 H),2.91-3.27(m,3 H),1.97-2.24(m,3 H).

[0154] Example 46 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(2-hydroxyethylamino)pyrrolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 44, by using hydroxyethylamine instead of monomethylamine. Example 46 (35 mg) was obtained as a white solid. MS found: 548.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.31-9.47(m,2H),7.90(s,2H),7.81(s,2H),7.09(s,1H),6.97(s,1H),5.27-5.38(m,1H),4.21- 4.29(m,1H),4.03-4.15(m,2H),3.66-3.74(m,6H),3.08-3.13(m,2H),3.01-3.07(m,1H),2.97(br t,J=4.8Hz,4H),2.82-2.90(m,1H).

[0155] Example 47 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-piperazin-1-yl-pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 44, by using piperazine instead of monomethylamine. Example 47 (11 mg) was obtained as a white solid. MS found: 573.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.33-9.50(m,1H),7.90-7.96(m,2H),7.80(s,2H),7.08(s,1H),6.97(s ,1H),4.16-4.25(m,1H),4.00-4.10(m,1H),3.80-3.94(m,2H),3.71(br s,4H),3.29-3.35(m,4H),3.08-3.24(m,4H),3.00-3.01(m,1H),2.95-2.99(m,4H),2.73-2.92(m,2H).

[0156] Example 48 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3S,4R)-3,4-dihydroxypyrrolidin-1-yl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 44, by using -[(3S,4R)-pyrrolidine-3,4-diol instead of monomethylamine. Example 48 (45 mg) was obtained as a white solid. MS found: 590.0 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.90-7.97(m,2H),7.70-7.78(m,2H),7.08(s,1H),6.93-6.99(m,1H),4.56-4.63(m,2H),3.86-3 .99(m,3H),3.66-3.75(m,5H),3.14-3.23(m,1H),2.87-3.00(m,6H),2.68-2.75(m,1H),2.52(br s,1H),2.33-2.40(m,2H).

[0157] Example 49 4-[3-(aminomethyl)azetidin-1-yl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following scheme.

[0158] Step 1: tert-Butyl N-[1-[1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]azetidin-3-yl]carbamate (compound 49a) [ka] To a solution of intermediate B (80.0 mg, 0.16 mmol) in DMF (1 mL) was added tert-butyl N-(azetidin-3-ylmethyl)carbamate (84.89 mg, 0.49 mmol) and the mixture was heated to 90° C. for 1 h. The mixture was diluted with water (20 mL) and then extracted three times with EA (10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give compound 49a (85 mg, 0.130 mmol, 78.49% yield) as a white solid. MS found: 673.2 (MH + ).

[0159] Step 2: 4-[3-(aminomethyl)azetidin-1-yl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 49) To a solution of compound 49a (80.0 mg, 0.12 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.49 mmol) in one portion. The mixture was stirred at 20° C. for 1 h and then concentrated. The crude product was purified by preparative HPLC to give Example 49 (45 mg, 0.070 mmol, 58.2% yield) as a white solid. MS found: 573.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.11-8.16(m,1H),7.89-7.94(m,2H),7.73-7.77(m,2H),7.08(s,1H),6.95-6.98(m,1H),3.90-4.24(m,2H),3. 69-3.73(m,4H),3.58-3.66(m,1H),3.37-3.42(m,4H),3.01-3.07(m,2H),2.94-2.97(m,4H),2.51-2.53(m,2H).

[0160] Example 50 4-(3-aminopyrrolidin-1-yl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 49, by using tert-butyl N-[pyrrolidin-3-yl]carbamate instead of tert-butyl N-(azetidin-3-ylmethyl)carbamate. Example 50 (16 mg) was obtained as a white solid. MS found: 573.3 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 8.49-8.73(m,3H),8.48-8.49(m,1H),7.91-7.97(m,2H),7.77-7.82(m,2H),7.05-7.12(m ,1H),6.95-6.99(m,1H),4.25-4.45(m,2H),4.12-4.24(m,1H),3.79-4.10(m,2H),3.71(br s,4H),3.51-3.59(m,1H),3.03-3.18(m,2H),2.98(br s,4H),2.33(br d,J=1.6Hz,2H).

[0161] Example 51 4-(3-aminoazetidin-1-yl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 49, by using tert-butyl N-(azetidin-3-yl)carbamate instead of tert-butyl N-(azetidin-3-ylmethyl)carbamate. Example 51 (21 mg) was obtained as a white solid. MS found: 559.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.24-8.30(m,1H),7.90(s,2H),7.73(d,J=8.8Hz,2H),7.08(s,1H),6.96(s,1H) ,3.89(s,1H),3.69-3.72(m,4H),3.50-3.52(m,4H),3.05-3.08(m,1H),2.96(br t,J=4.8Hz,4H),2.67-2.75(m,3H),2.16-2.22(m,1H).

[0162] Example 52 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 49, by using tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate instead of tert-butyl N-(azetidin-3-ylmethyl)carbamate. Example 52 (26 mg) was obtained as a white solid. MS found: 585.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.68-8.81(m,2H),7.87(s,2H),7.78(d,J=8.8Hz,2H),7.09(s,1H),6.97(s,1H),4.16-4.40(m,4H),4.12(br s,4H),3.78-3.84(m,1H),3.69-3.74(m,4H),2.98-3.05(m,1H),2.96(br s,4H),2.52-2.61(m,2H).

[0163] Example 53 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3S)-3-(hydroxymethyl)piperazin-1-yl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 49, by using tert-butyl (2S)-2-(hydroxymethyl)piperazine-1-carboxylate instead of tert-butyl N-(azetidin-3-ylmethyl)carbamate. Example 53 (35 mg) was obtained as a white solid. MS found: 603.3 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 9.34-9.58(m,1H),8.93-9.26(m,1H),7.93(d,J=8.8Hz,2H),7.78(d,J=8.8Hz,2H),7.04-7.10(m,1H),6.97(s ,1H),4.11-4.21(m,1H),3.92-4.02(m,1H),3.76-3.64(m,7H),3.55-3.63(m,4H),3.06-3.21(m,2H),2.97(br t,J=4.4Hz,4H),2.85-2.92(m,1H),2.70-2.84(m,2H),2.54-2.69(m,1H).

[0164] Example 54 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3R)-3-(hydroxymethyl)piperazin-1-yl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 49, by using tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate instead of tert-butyl N-(azetidin-3-ylmethyl)carbamate. Example 54 (65 mg) was obtained as a white solid. MS found: 603.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.57-9.69(m,1H),9.18-9.38(m,1H),7.93(s,2H),7.79(d,J=8.8Hz,2H),7.09(s,1H),6.97(s,1H),4.18(br s,1H),3.99-4.06(m,1H),3.67-3.77(m,7H),3.58-3.66(m,4H),3.14-3.25(m,2H),2.98(br t,J=4.4Hz,4H),2.70-2.94(m,4H).

[0165] Example 55 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]]heptan-2-yl]pyrrolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 49, by using (1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane instead of tert-butyl N-(azetidin-3-ylmethyl)carbamate. Example 55 (22 mg) was obtained as a white solid. MS found: 589.0 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.31-10.01(m,2H),7.93(d,J=8.8Hz,2H),7.79(d,J=8.8Hz,2H),7.09(s,1H),6.97(s,1H),4 .34-4.61(m,2H),3.96-4.29(m,3H),3.57-3.75(m,6H),2.86-3.07(m,6H),1.92-2.37(m,2H).

[0166] Example 56 4-[(3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 49, by using tert-butyl N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]carbamate instead of tert-butyl N-(azetidin-3-ylmethyl)carbamate. Example 56 (31 mg) was obtained as a white solid. MS found: 589.1 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 8.54-9.03(m,3H),7.91-7.97(m,2H),7.80(s,2H),7.06-7.10(m,1H),6.94-6.98(m,1H),4.43-4 .53(m,1H),4.23-4.29(m,1H),4.08-4.21(m,1H),3.64-3.86(m,7H),3.00-3.13(m,2H),2.98(br d,J=4.4Hz,4H).

[0167] Example 57 4-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-1-(4-((4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 49, by using tert-butyl N-[(3R,4R)-4-hydroxy-3-piperidyl]carbamate instead of tert-butyl N-(azetidin-3-ylmethyl)carbamate. Example 57 (20.1 mg) was obtained as a white solid. MS found: 603.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.28-8.65(m,3H),7.93(s,2H),7.80(br d,J=1.2Hz,2H),7.08(s,1H),6.96(s,1H),3.89-4.42(m,4H),3.58-3.87(m,7H),3.18-3.25(m,1H),2.94-3.01(m,1H),2.98(br d,J=4.4Hz,7H),1.97-2.12(m,1H),1.70-1.93(m,1H).

[0168] Example 58 4-(azetidin-3-ylamino)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0169] Step 1: tert-Butyl 3-[[1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]amino]azetidine-1-carboxylate (compound 58a) [ka] To a solution of Example 1 (120.0 mg, 0.24 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (203.8 mg, 1.2 mmol) in methanol (0.42 mL) and THF (0.42 mL) was added anhydrous Na2SO4 (85.01 mg, 0.710 mmol). The mixture was stirred at 25° C. for 2 h, then NaBH3CN (104.75 mg, 1.67 mmol) was added, and the mixture was stirred at 45° C. for 6 h. The mixture was diluted with water (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed twice with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (FA as additive) to give compound 58a (90 mg, 0.140 mmol, 57.34% yield) as a white solid. MS measured value: 659.0 (MH + ).

[0170] Step 2: 4-(azetidin-3-ylamino)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 58) To a solution of compound 58a (80.0 mg, 0.12 mmol) in DCM (2 mL) was added TFA (1.0 mL, 12.98 mmol). The mixture was stirred at 25° C. for 2 h and then concentrated. The crude product was dissolved in methanol (3.0 mL) and basified to pH 7.0 with ammonium hydroxide. The solution was purified by preparative HPLC to give Example 58 (29.6 mg, 0.05 mmol, 39.7% yield) as a white solid. MS found: 559.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.87-9.87(m,2 H),7.71-7.99(m,4 H),7.06-7.14(m,1 H),6.93-7.00(m,1 H),3.66-4.42(m,12 H),2.88-3.08(m,5 H),2.56-2.75(m,1 H).

[0171] Example 59 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(pyrrolidin-3-ylamino)pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 58, by using tert-butyl 3-oxopyrrolidine-1-carboxylate instead of tert-butyl 3-oxoazetidine-1-carboxylate. Example 59 (33.5 mg) was obtained as a white solid. MS found: 573.0 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 10.17-10.81(m,2 H),9.29-9.92(m,2 H),7.88-7.96(m,2 H),7.77-7.86(m,2 H),7.08-7.14(m,1 H),6.95-7.01(m,1 H),3.98-4.38(m,4 H),3.68-3.81(m,4 H),3.44-3.64(m,3 H),2.91-3.28(m,7 H),2.13-2.41(m,2 H).

[0172] Example 60 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(4-piperidylamino)pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 58, by using tert-butyl 4-oxopiperidine-1-carboxylate instead of tert-butyl 3-oxoazetidine-1-carboxylate. Example 60 (58 mg) was obtained as a white solid. MS found: 587.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.77-10.68(m,4 H),7.75-7.96(m,4 H),7.05-7.16(m,1 H),6.93-7.01(m,1 H),4.07-4.38(m,3 H),3.65-3.81(m,4 H),3.39-3.61(m,3 H),2.82-3.10(m,8 H),2.14-2.29(m,2 H),1.82-2.02(m,2 H).

[0173] Example 61 4-Amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-methyl-pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl N-(2-methyl-5-oxo-pyrrolidin-3-yl)carbamate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate. Example 61 (20 mg) was obtained as a white solid. MS found: 518.2 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.82-7.93(m,2H),7.70-7.79(m,2H),7.08(s,1H),6.97(s,1H),3.91-4.17(m,3H),3 .65-378(m,6H),2.92-3.04(m,5H),2.22(dd,J=2.8,17.2Hz,1H),1.08-1.24(m,3H).

[0174] Example 62 4-Amino-1-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0175] Step 1: 1-[(6-bromo-3-pyridyl)sulfonyl]-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine (Compound 62a) [ka] A mixture of intermediate 1a (207.14 mg, 0.780 mmol), 6-bromo-pyridine-3-sulfonyl chloride (200.0 mg, 0.780 mmol) and DIPEA (0.27 mL, 1.56 mmol) in DCM (6.67 mL) was stirred at 25° C. for 2 h. After the reaction was completed, the solvent was removed under vacuum and the crude product was purified by silica gel column chromatography (PE:EA=5:2) to give compound 62a (300 mg, 75.25% yield) as a white solid. MS found: 485.0 (MH + ).

[0176] Step 2: tert-Butyl N-[1-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 62b) [ka] A mixture of tert-butyl N-(5-oxopyrrolidin-3-yl)carbamate (41.2 mg, 0.21 mmol), CuI (0.02 mmol), Cs2CO3 (134.2 mg, 0.41 mmol), compound 62a (100.0 mg, 0.21 mmol) in DMF (2 mL) was heated in a microwave reactor at 85° C. for 1 h. The mixture was poured into ice water, extracted twice with DCM (15 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel to give compound 62b (80 mg, 0.130 mmol, 61.01% yield) as a white solid. MS found: 605.2 (MH + ).

[0177] Step 3: 4-Amino-1-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]pyrrolidin-2-one (Example 62) A mixture of compound 62b (60.0 mg, 0.10 mmol) and HCl (0.05 mL, 0.10 mmol) in EA was stirred at 25° C. for 2 h. After the reaction was completed, the solvent was removed under vacuum and the crude product was purified by preparative HPLC to give Example 62 (6 mg, 0.01 mmol, 11.58% yield) as a white solid. MS found: 505.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.73(d,J=2.4Hz,1H),8.50(d,J=9.2Hz,1H),8.18-8.25(m,3H),7.09(s,1H),6.96(s,1H),4.23(dd,J=12.6,7.2Hz,1H),4.11 (dd,J=12.6,2.0Hz,1H),4.03(s,1H),3.66-3.76(m,4H),3.15(dd,J=18.0,8.0Hz,1H),2.97-3.05(m,4H),2.60-2.67(m,1H).

[0178] Example 63 5-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-fluoro-phenyl]oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl N-[(2-oxooxazolidin-5-yl)methyl]carbamate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate and 4-bromo-3-fluorobenzenesulfonyl chloride instead of 4-iodobenzenesulfonyl chloride. Example 63 (35 mg) was obtained as a white solid. MS found: 538.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.17-8.31(m,2H),7.77-7.83(m,1H),7.72(br dd,J=13.2,2.0Hz,1H),7.55(br dd,J=8.8,2.0Hz,1H),7.10(s,1H),6.98(s,1H),4.62-4.72(m,2H),4.11(m,1H),3.90(br dd,J=9.2,6.0Hz,1H),3.67-3.77(m,4H),3.06-3.16(m,4H).

[0179] Example 64 5-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-fluorophenyl]oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using tert-butyl N-[(2-oxooxazolidin-5-yl)methyl]carbamate instead of tert-butyl (5-oxopyrrolidin-3-yl)carbamate and 4-bromo-2-fluorobenzenesulfonyl chloride instead of 4-iodobenzenesulfonyl chloride. Example 64 (45 mg) was obtained as a white solid. MS found: 538.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.82-7.92(m,1H),7.74(dd,1H,J=2.0,10.8Hz),7.67(dd,1H,J=2.0,8.4Hz),7.11(s,1H),6.9 8(s,1H),4.83-4.93(m,1H),4.11-4.34(m,1H),3.93-4.02(m,1H),3.61-3.85(m,4H),3.11(br d,2H,J=6.0Hz),3.03-3.14(m,4H).

[0180] Example 65 4-Amino-1-[4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine instead of 2,6-dichloro-4-(trifluoromethyl)pyridine. Example 65 (14 mg) was obtained as a white solid. MS found: 484.8 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 8.23(br s,2H),7.86-7.99(m,2H),7.72-7.83(m,2H),6.85-7.04(m,1H),4.21-4.3 0(m,1H),4.03-4.10(m,1H),3.74-3.90(m,5H),3.02-3.13(m,1H),2.97(br t,J=4.8Hz,4H),2.53-2.61(m,1H),2.33-2.40(m,3H).

[0181] Example 66 4-Amino-1-[4-[4-[4-(trideuteriomethyl)-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0182] Step 1: tert-Butyl N-[1-[4-[4-[4-chloro-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 66a) [ka] A mixture of intermediate C (0.320 g, 754 μmol), 2,4-dichloro-6-(trifluoromethyl)pyrimidine (164 mg, 754 μmol) and DIPEA (292 mg, 2.26 mmol) in THF (2 mL) was stirred at 90° C. overnight. The mixture was concentrated and the residue was diluted with EA and washed with 1N HCl (10 mL). The organic layer was dried, concentrated and used directly in the next step. MS found: 605.4 (MH + ).

[0183] Step 2: tert-Butyl N-[5-oxo-1-[4-[4-[4-(trideuteriomethyl)-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-3-yl]carbamate (compound 66b) [ka] A mixture of compound 66a (0.15 g, 248 μmol), (methyl-d3)boronic acid (31.2 mg, 496 μmol), K2CO3 (103 mg, 744 μmol), Ag2O (144 mg) and Pd(dppf)Cl2 (18.1 mg) in THF (0.5 mL) was stirred at 80 °C overnight. The organic layer was concentrated and used directly in the next step. MS found: 588.3 (MH + ).

[0184] Step 3: 4-Amino-1-[4-[4-[4-(trideuteriomethyl)-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 66) A mixture of compound 66b (0.120 g, 204 μmol) and TFA (460 mg) in DCM (0.5 mL) was stirred at 25° C. for 1 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give 4.5 mg of example 66. MS found: 488.3 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.92-8.01(m,2H),7.80-7.84(m,2H),6.93(s,1H),4.24(dd,1H,J=6.4,10.4Hz),3.94(br d,1H,J=3.2Hz),3.87(br s,4H),3.74(dd,1H,J=2.8,10.4Hz),3.11-3.15(m,4H),3.02(dd,1H,J=7.6,17.6Hz),2.51(dd,1H,J=3.6,17.6Hz).

[0185] Example 67 1-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonyl-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-2-carbonitrile [ka] The title compound was prepared according to the following procedure.

[0186] Step 1: tert-Butyl N-[1-(4-benzylsulfanylphenyl)-5-oxopyrrolidin-3-yl]carbamate (Compound 67a) [ka] A mixture of tert-butyl N-(5-oxopyrrolidin-3-yl)carbamate (215.15 mg, 1.07 mmol), CuI (0.100 equiv.), Cs2CO3 (700.19 mg, 2.15 mmol), 1-benzylsulfanyl-4-bromo-benzene (300.0 mg, 1.07 mmol) in DMF (10.44 mL) was heated in a microwave reactor at 85° C. for 1 h. The mixture was poured into ice water, extracted twice with DCM (15 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give compound 67a (300 mg, 0.750 mmol, 65.16% yield) as a white solid. MS found: 399.2 (MH + ).

[0187] Step 2: tert-Butyl N-[1-(4-chlorosulfonylphenyl)-5-oxopyrrolidin-3-yl]carbamate (Compound 67b) [ka] To a mixture of compound 67a (200.0 mg, 0.500 mmol) in ACN (7.53 mL), AcOH (0.753 mL) and water (0.753 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (197.75 mg, 1 mmol) at 25° C. for 1 h. After completion, the mixture was poured into brine (25 mL), extracted twice with EA (15 mL) and washed twice with brine (15 mL). The organic layer was concentrated and the crude product was purified by silica gel chromatography (PE:EA=13:3) to give compound 67b (42 mg, 0.110 mmol, 20.09% yield) as a colorless oil. MS Found: 397 (MNa + ).

[0188] Step 3: tert-Butyl 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-cyano-piperazine-1-carboxylate (compound 67c) [ka] A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (239.91 mg, 1.11 mmol) and tert-butyl 2-cyanopiperazine-1-carboxylate (200.0 mg, 1.11 mmol) was stirred at 100° C. for 12 h. Then water (30 mL) was added and the solution was extracted with EA, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give compound 67c (150 mg, 0.380 mmol, 31.1% yield). MS found: 391.1 (MH + ).

[0189] Step 4: 4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-2-carbonitrile (compound 67d) [ka] Compound 67c (150.0 mg, 0.380 mmol) was dissolved in 2M HCl / EA (10 mL) and the mixture was stirred at room temperature for 4 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give compound 67d (75 mg, 0.26 mmol, 60.5% yield). MS found: 291.1 (MH + ).

[0190] Step 5: tert-Butyl N-[1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-cyano-piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 67e) [ka] To a mixture of compound 67b (75.0 mg, 0.200 mmol) and pyridine (0.5 mL) in DCM (4.52 mL) was added compound 67d (42.0 mg, 0.140 mmol) and the reaction was stirred at room temperature for 8 h. Water (10 mL) was added and the mixture was extracted with EA, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give compound 67e (50 mg, 0.080 mmol, 49.51% yield). MS found: 651.1 (MNa + ).

[0191] Step 6: 1-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonyl-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-2-carbonitrile (Example 67) Compound 67e (49.76 mg, 0.080 mmol) was dissolved in 4M HCl / 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 4 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give Example 67 (25 mg, 0.050 mmol, 58.74% yield) as a white solid. MS found: 529.1 (MH + ). 1H NMR (400MHz, DMSO-d6): δ ppm 7.95(d,J=8.8Hz,2H),7.86(d,J=8.8Hz,2H),7.25(s,1H),7.10(s,1H),5.25( s,1H),4.78(d,J=13.6Hz,1H),4.45(d,J=12.8Hz,1H),4.06(d,J=9.6Hz,1H), 3.82(d,J=12.0Hz,1H),3.75(s,1H),3.57(d,J=9.6Hz,1H),3.28(dd,J=13.6, 3.2Hz,1H),3.09(t,J=11.2Hz,1H),2.71-2.90(m,2H),2.33(d,J=16.4Hz,1H).

[0192] Example 68 4-Amino-1-[4-[4-[6-chloro-4-(difluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 1, by using 2,6-dichloro-4-(difluoromethyl)pyridine instead of 2,6-dichloro-4-(trifluoromethyl)pyridine. Example 68 (42.4 mg) was obtained as a white solid. MS found: 486.1 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.90-7.94(m,2 H),7.81-7.86(m,2 H),6.79(s,1 H),6.73(s,1 H),6.56(s,1 H),4.39(dd,J=11.2,6.8Hz,1 H),4.18(m,1 H),3.93(dd,J=11.2,2.4Hz,1 H),3.65-3.75(m,4 H),3.19(dd,J=18.0,8.4Hz,1 H),3.03-3.11(m,4 H),2.67(dd,J=18.0,2.8Hz,1 H).

[0193] Example 69 4-Amino-1-[4-[4-(6-chloro-4-cyclopropylsulfonyl-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0194] Step 1: 2,6-Dichloro-4-cyclopropylsulfanyl-pyridine (Compound 69a) [ka] To a solution of 4-bromo-2,6-dichloro-pyridine (100.0 mg, 0.440 mmol), cyclopropanethiol (32.68 mg, 0.440 mmol) in DMF (2 mL) was added K2CO3 (0.25 mL, 1.32 mmol). The mixture was heated to 80°C for 4 h, then diluted with water (40 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give compound 69a (100 mg, 0.450 mmol, 82.46% yield) as a yellow oil. MS found: 220.0 (MH + ).

[0195] Step 2: 2,6-Dichloro-4-(cyclopropylsulfonyl)pyridine (compound 69b) [ka] To a solution of compound 69a (80.0 mg, 0.360 mmol) in DCM (4 mL) was added m-CPBA (0.15 mL, 1.09 mmol) in one portion. The mixture was stirred at 20° C. for 2 h and then concentrated. The crude product was purified by preparative HPLC to give compound 69b (60 mg, 0.240 mmol, 65.48% yield) as a yellow solid. MS found: 252.9 (MH + ).

[0196] Step 3: tert-Butyl (1-(4-((4-(6-chloro-4-(cyclopropylsulfonyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)-5-oxopyrrolidin-3-yl)carbamate (compound 69c) [ka] To a mixture of intermediate C (80.0 mg, 0.190 mmol), Cs2CO3 (184.19 mg, 0.570 mmol) in DMSO (4 mL) was added compound 69b (61.77 mg, 0.240 mmol) and the mixture was stirred at 80 °C for 2 h. The solvent was evaporated, the residue was dissolved in water and extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give compound 69c (100 mg, 0.160 mmol, 66.31% yield) as a yellow solid. 640.1 (MH + ).

[0197] Step 4: 4-Amino-1-(4-((4-(6-chloro-4-(cyclopropylsulfonyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)pyrrolidin-2-one (Example 69) To a solution of compound 69b (80.0 mg, 0.120 mmol) in DCM (2 mL) was added TFA (1.0 mL, 0.370 mmol). The mixture was stirred at 20° C. for 1 h and then concentrated. The crude product was purified by preparative HPLC to give Example 69 (30.4 mg, 0.060 mmol, 43.67% yield) as a yellow solid. MS found: 540.1 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 8.38-8.51(m,3H),7.87-7.97(m,2H),7.73-7.83(m,2H),7.11(d,J=0.8Hz,1H),7.03(d,J=0.8Hz,1H),4.20-4.32(m,1 H),3.99-4.13(m,1H),3.81-3.894(m,1H),3.64-3.78(m,4H),2.91-3.15(m,6H),2.57-2.67(m,1H),1.03-1.21(m,4H).

[0198] Example 70 4-Amino-1-[4-[4-(6-chloro-4-tetrahydropyran-4-ylsulfonyl-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0199] Step 1: 2,6-Dichloro-4-tetrahydropyran-4-ylsulfanyl-pyridine (Compound 70a) [ka] To a solution of 2,6-dichloropyridine-4-thiol (90.0 mg, 0.500 mmol), K2CO3 (0.08 mL, 1 mmol) in NMP (2 mL) was added 4-bromo-tetrahydropyran (82.49 mg, 0.500 mmol). The mixture was stirred under N2 at 70 °C for 15 h. The mixture was diluted with water (50 mL) and extracted three times with EA (50 mL). The organic layer was washed twice with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give compound 70a (120 mg, 0.450 mmol, 90.88% yield) as a yellow solid. MS found: 490.9 (MH + ).

[0200] Step 2: 4-Amino-1-[4-[4-(6-chloro-4-tetrahydropyran-4-ylsulfonyl-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 70) The title compound was prepared in a similar manner to the preparation of Example 69, by using Compound 69a instead of Compound 70a. Example 70 (33.2 mg) was obtained as a white solid. MS found: 584.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.48-8.64(m,3H),7.87-8.01(m,2H),7.70-7.84(m,2H),7.00-7.12(m,1H),6.89-6.98(m,1H),4.21-4.33(m,1H),4.03-4.10 (m,1H),3.86-3.94(m,3H),3.69-3.78(m,5H),3.22-3.31(m,2H),2.97-3.11(m,5H),2.67(s,1H),1.65-1.74(m,2H),1.51(br s,2H).

[0201] Example 71 1-[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]cyclopropanecarbonitrile [ka] The title compound was prepared according to the following procedure.

[0202] Step 1: tert-Butyl 2-cyano-2-(2,6-dichloropyridin-4-yl)acetate (Compound 71a) [ka] A mixture of 2,4,6-trichloropyridine (1.82 g, 10 mmol), tert-butyl 2-cyanoacetate (1.69 g, 12 mmol) and Cs2CO3 (4.9 g, 15 mmol) in DMF (20 mL) was stirred at 90 °C for 2 h. The mixture was then poured into water (10 mL) and extracted with EA. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA = 20:1 to 10:1) to give compound 71a (2.01 g, 8.4 mmol, 70% yield) as a yellow oil. MS found: 287.0 (MH + ).

[0203] Step 2: 2-(2,6-dichloropyridin-4-yl)acetonitrile (Compound 71b) [ka] A mixture of intermediate 71a (2 g, 6.97 mmol) and TFA (7.94 g, 69.7 mmol) in DCM (3 mL) was stirred at room temperature for 2 h and then concentrated. The crude product was poured into saturated aqueous NaHCO3 and extracted with EA (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=10:1-10:5) to give compound 71b (1.17 g, 6.27 mmol, 90% yield) as a yellow solid. MS found: 187.0 (MH + ).

[0204] Step 3: 1-(2,6-dichloro-4-pyridyl)cyclopropanecarbonitrile (Intermediate 71c) [ka] To a solution of intermediate 71b (0.8 g, 4.28 mmol) and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.86 g, 5.13 mmol) in DMF (10 mL) was added DBU (1.95 g, 12.8 mmol). The mixture was stirred at room temperature for 2 h, then poured into water and extracted with EA. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA=2:1-1:5) to give compound 71c (0.6 g, 2.81 mmol, 65.8% yield) as a white solid. MS found: 214.1 (MH + ).

[0205] Step 4: 1-[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]cyclopropanecarbonitrile (Example 71) The title compound was prepared in a similar manner to the preparation of Example 69, by using Compound 71b instead of Compound 69b. Example 71 (6.0 mg) was obtained as a white solid. MS Found: 501.4 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.89-7.93(m,2 H),7.77-7.82(m,2 H),6.53(d,J=1.2Hz,1 H),6.50(d,J=1.2Hz,1 H),4.58(br s,2 H),4.15(dd,J=10.0,6.4Hz,1 H),3.78(s,1 H),3.61-3.69(m,5 H),3.03-3.08(m,4 H),2.91(dd,J=17.2,7.2Hz,1 H),2.38-2.43(m,1 H),1.74-1.78(m,2 H),1.55-1.59(m,2 H).

[0206] Example 72 4-Amino-1-[4-[4-(6-chloro-4-phenoxy-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0207] Step 1: 2,6-Dichloro-4-phenoxy-pyridine (Compound 72a) [ka] To a solution of 4-bromo-2,6-dichloro-pyridine (100.0 mg, 0.44 mmol) in DMF (1.0 mL) was added phenol (41.48 mg, 0.44 mmol), potassium (51.7 mg, 1.32 mmol) in one portion. The reaction was stirred at 100° C. for 1 h, diluted with water (20 mL) and extracted three times with EA (10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give compound 72a (100 mg, 0.42 mmol, 94.5% yield) as a colorless oil.

[0208] Step 2: 4-Amino-1-[4-[4-(6-chloro-4-phenoxy-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 72) The title compound was prepared in a similar manner to the preparation of Example 69, by using Compound 69a instead of Compound 72a. Example 72 (45 mg) was obtained as a white solid. MS found: 528.2 (MH + ). 1 H NMR (400MHz, DMSO-d6): δ ppm 8.47-8.70(m,3H),8.45-8.72(m,4H),7.88-7.91(m,2H),7.78(s,2H),7. 42-7.48(m,2H),7.24-7.30(m,1H),7.09-7.13(m,2H),6.25-6.28(m,1H), 6.27(s,1H),6.11-6.14(m,1H),4.24-4.29(m,1H),4.05-4.11(m,1H),3. 95-3.99(m,1H),3.53-3.58(m,1H),3.01-3.06(m,5H),2.69-2.75(m,1H).

[0209] Example 73 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0210] Step 1: 2,6-Dichloro-N-methoxy-N-methyl-pyridine-4-carboxamide (Compound 73a) [ka] A mixture of 2,6-dichloroisonicotinic acid (30 g, 156.25 mmol) in SOCl2 was stirred at 90 °C for 16 h and then concentrated. The crude product was dissolved in DCM (300 mL) and a solution of O,N-dimethylhydroxylamine (18288.75 mg, 187.5 mmol) and DIPEA (20 mL) was added. The mixture was stirred at room temperature for 12 h and washed three times with brine (150 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column on silica gel (PE:EA = 100:0 to 0:100) to give compound 73a (30000 mg, 127.62 mmol, 73.51% yield) as a white solid. MS found: 235.1 (MH + ).

[0211] Step 2: (2,6-Dichloro-4-pyridyl)-phenyl-methanone (compound 73b) [ka] To a solution of compound 73a (500.0 mg, 2.13 mmol) in THF (15 mL) was added phenylmagnesium bromide (0.24 mL, 2.13 mmol) at -70 °C under N2, and the mixture was stirred for 2 h. The mixture was quenched with saturated NH4Cl (100 mL) and extracted three times with EA (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0-30%) to give compound 73b (150 mg, 0.600 mmol, 25.2% yield) as a white solid. MS found: 252 (MH + ).

[0212] Step 3: 2,6-Dichloro-4-[difluoro(phenyl)methyl]pyridine (Compound 73c) [ka] A solution of compound 73b (1300.0 mg, 5.16 mmol) and BAST (10.0 mL) was stirred at 25 °C for 12 h. The reaction was quenched with ice water (50 mL) and extracted with EA (30 mL) three times. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column (PE:EA = 1:0 to 1:1) to give compound 73c (800 mg, 2.92 mmol, 50.94% yield) as a pale yellow solid. MS found: 274 (MH + ).

[0213] Step 4: tert-Butyl N-[1-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 73d) [ka] To a solution of intermediate C (309.76 mg, 0.730 mmol) and compound 73c (200.0 mg, 0.730 mmol) in DMSO (0.5 mL), DIPEA (2.0 mL) was added and the reaction was stirred at 115 °C for 12 h. The reaction was quenched with brine (50 mL) and extracted twice with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column (EA in PE = 0-70%) to give compound 73d (400 mg, 0.600 mmol, 82.79% yield) as a white solid. MS found: 662 (MH + ).

[0214] Step 5: 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 73) Compound 73d (400.0 mg, 0.60 mmol) was dissolved in 2M HCl / EA (10 mL) and the reaction was stirred at room temperature for 4 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give Example 73 (300 mg, 0.530 mmol, 86.47% yield) as a white solid. MS found: 562 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=8.8Hz,2H),7.77(d,J=8.8Hz,2H),7.55-7.62(m,2H),7.44-7.54(m,3H),6.95(s,1H),6.76(s,1H), 4.14(dd,J=10.4,6.4Hz,1H),3.88(s,1H),3.64-3.72(m,5H),2.86-3.01(m,5H),2.46(dd,J=17.4,3.2Hz,1H).

[0215] Example 74 4-Amino-1-[4-[4-(4-benzyl-6-chloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0216] Step 1: 4-Benzyl-2,6-dichloro-pyridine (Compound 74a) [ka] A mixture of methyltriphenylphosphonium bromide (1.7 g, 4.76 mmol), potassium t-butoxide (0.45 g, 4.76 mmol) in THF (20 mL) was stirred under N2 for 0.5 h, then compound 73b (1 g, 3.97 mmol) was added. The resulting mixture was stirred at room temperature for 12 h, then poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=20:1 to 10:1) to give compound 74a (0.23 g, 0.99 mmol, 25% yield) as a yellow gum. MS found: 236.0 (MH + ).

[0217] Step 2: 4-Amino-1-[4-[4-(4-benzyl-6-chloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 74) The title compound was prepared in a similar manner to the preparation of Example 73, by using Compound 74a instead of Compound 73c. ​​Example 74 (3.6 mg) was obtained as a white solid. MS found: 526 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.92(d,J=8.8Hz,2 H),7.78-7.82(m,2 H),7.24-7.31(m,2 H),7.15-7.21(m,3 H),6.52(s,1 H),6.45(s,1 H),4.26(m,1 H),3.94-4.00(m,1 H),3.83(s,2 H),3.77(dd,J=10.8,2.8Hz,1 H),3.56-3.63(m,5 H),2.93-3.15(m,8 H),2.51(m,1 H).

[0218] Example 75 4-Amino-1-[4-[4-[6-chloro-4-(1-phenylcyclopropyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0219] Step 1: 2,6-Dichloro-4-(1-phenylvinyl)pyridine (Compound 75a) [ka] A mixture of methyltriphenylphosphonium bromide (1.7 g, 4.76 mmol), potassium t-butoxide (0.45 g, 4.76 mmol) in THF (20 mL) was stirred under N2 for 0.5 h, then compound 73b (1 g, 3.97 mmol) was added. The resulting mixture was stirred at room temperature for 12 h, then poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=20:1 to 10:1) to give compound 75a (0.50 g, 2.38 mmol, 50% yield) as a yellow gum. MS found: 250.2 (MH + ).

[0220] Step 2: 2,6-Dichloro-4-(1-phenylcyclopropyl)pyridine (Compound 75b) [ka] A mixture of trimethylsulfoxonium iodide (2.2 g, 10 mmol), sodium hydride (0.4 g, 10 mmol) in THF (5 mL) was stirred at room temperature for 0.5 h 30, then compound 75a (500 mg, 2 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h, then poured into water and extracted with EA. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE:EA=20:1 to 10:1) to give compound 75b (0.32 g, 1.2 mmol, 60% yield) as a yellow gum. MS found: 264.1 (MH + ).

[0221] Step 3: 4-Amino-1-[4-[4-[6-chloro-4-(1-phenylcyclopropyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 75) The title compound was prepared in a similar manner to the preparation of Example 73, by using Compound 75b instead of Compound 73c. ​​Example 75 (7.4 mg) was obtained as a white solid. MS found: 552 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.92(m,2 H),7.78(m,2 H),7.23-7.31(m,5 H),6.24-6.39(m,2 H),4.18-4.33(m,1 H),3.86-4.00(m,1 H),3.69-3.80(m,1 H),3.48-3.50(m,4 H),2.99-3.03(m,5 H),2.45-2.58(m,1 H),1.31(s,4H).

[0222] Example 76 4-Amino-1-[4-[4-[4-[difluoro(phenyl)methyl]-6-methyl-pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 73, by using 2-chloro-6-methylpyrimidine-4-carboxylate instead of 2,6-dichloro-N-methoxy-N-methyl-pyridine-4-carboxamide. Example 76 (28 mg) was obtained as a white solid. MS found: 543 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.18(br s,2H),7.90(d,J=9.2Hz,2H),7.77(d,J=9.2Hz,2H),7.45-7.56(m,5H),6.89(s,1H),4.25(dd,J=6.8,11.2Hz,1H),4.07(br s,1H),3.79(br s,5H),3.43-3.63(m,1H),3.21-3.31(m,1H),3.17(s,1H),3.07(dd,J=8.4,17.6Hz,1H),2.92(br t,J=4.8Hz,4H),2.67(s,1H),2.53-2.60(m,1H),2.33(s,3H),2.07(s,1H).

[0223] Examples 77 and 78 4-Amino-1-[4-[4-[2-chloro-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] 4-Amino-1-[4-[4-[4-chloro-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure:

[0224] Step 1: (2,6-Dichloropyrimidin-4-yl)-phenyl-methanone (compound 77a) [ka] A solution of methyl 2,6-dichloropyrimidine-4-carboxylate (1.1 g, 5.31 mmol) in THF (1.5 mL) was cooled to -78°C under N2 and treated with PhMgBr (5.31 mL, 5.31 mmol) dropwise over 0.5 h. The reaction was stirred at -78°C for 30 min and then quenched with water (5 mL) and brine (5 mL). The mixture was extracted twice with EA (10 mL) and the organic phase was dried and concentrated to give compound 77a (500 mg, 37.2%). MS found: 253.2 (MH + ).

[0225] Step 2: 2,4-Dichloro-6-[difluoro(phenyl)methyl]pyrimidine (compound 77b) [ka] Compound 77a (0.500 g, 1.98 mmol) and DAST (15.9 g, 13 mL, 98.4 mmol) were stirred at room temperature for 4 h. The mixture was cooled at 0° C. and quenched with water (10 mL). The mixture was extracted with DCM (20 mL). The organic phase was dried and concentrated to give the crude product (545 mg, 100% yield).

[0226] Step 3: tert-Butyl N-[1-[4-[4-[2-chloro-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]-5-oxopyrrolidin-3-yl]carbamate (Compound 77c) [ka] tert-Butyl N-[1-[4-[4-[4-chloro-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 78c) [ka] A mixture of intermediate C (23.1 mg, 54.5 μmol), compound 77a (0.015 g, 54.5 μmol) and DIPEA (21.1 mg, 29.2 μL, 164 μmol) in THF (200 μL) was stirred at 70° C. overnight. The mixture was concentrated to give a mixture of compounds 77c and 78c, which was used directly in the next step. MS found: 663.7 (MH + ).

[0227] Step 4: 4-amino-1-[4-[4-[2-chloro-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 77) and 4-amino-1-[4-[4-[4-chloro-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 78) A mixture of compounds 77c and 78c (0.035 g, 52.8 μmol) and TFA (181 mg) in DCM (1 mL) was stirred for 1 h at 25° C. The mixture was concentrated and purified by preparative HPLC to give Example 77 (24 mg, 80% yield) and Example 78 (5 mg, 16.8% yield) as white solids.

[0228] Example 77: MS measured value: 563.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.88-7.95(m,J=8.8Hz,2H),7.69-7.79(m,J=8.8Hz,2H),7.45-7.58(m,5H),7.19(s,1H),3.88-4.08(m,1H),3.82(br s,4H),3.56-3.74(m,1H),3.45-3.50(m,1H),3.18(br s,1H),3.00(br t,J=4.8Hz,4H),2.76(dd,J=6.8,16.8Hz,1H),2.25(dd,J=4.0,16.8Hz,1H).

[0229] Example 78: MS measured value: 563.6 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.85-7.93(m,J=8.8Hz,2H),7.67-7.77(m,J=8.8Hz,2H),7.43-7.62(m,5H),7.08(s,1H),3.97(br dd,J=6.0,9.6Hz,1H),3.72-3.84(m,4H),3.57-3.71(m,1H),3.44-3.49(m,1H),2.94(br t,J=4.8Hz,4H),2.54-2.581(m,1H),2.24(dd,J=4.0,16.8Hz,1H).

[0230] Examples 79 and 80 4-Amino-1-[4-[4-[2-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] 4-Amino-1-[4-[4-[4-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure:

[0231] Step 1: tert-Butyl 4-[2-chloro-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazine-1-carboxylate (Compound 79a) [ka] tert-Butyl 4-[4-chloro-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazine-1-carboxylate (compound 80a) [ka] A mixture of tert-butyl piperazine-1-carboxylate (339 mg, 1.82 mmol), compound 77b (0.50 g, 1.82 mmol) and K2CO3 (502 mg, 3.64 mmol) in DMSO (10 mL) was stirred at 85 °C overnight. The mixture was diluted with EA (20 mL) and washed with water (20 mL). The organics were dried and concentrated to give a mixture of compounds 79a and 80a (772 mg, 100% yield), which was used in the next step without further purification. MS found: 425.3 (MH + ).

[0232] Step 2: tert-Butyl 4-[2-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazine-1-carboxylate (compound 79b) [ka] tert-Butyl 4-[4-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazine-1-carboxylate (compound 80b) [ka] A mixture of compounds 79a and 80a (0.10 g, 235 μmol), potassium cyclopropyltrifluoroborate (104 mg, 706 μmol), Pd(dppf)Cl2 (17 mg, 23.5 μmol) and K2CO3 (97.4 mg, 706 μmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was stirred at 70 °C overnight. The mixture was diluted with EA and washed with water. The organics were concentrated to give the crude product (100 mg, 100% yield), which was used directly in the next step. MS found: 431.3 (MH + ).

[0233] Step 3: 2-Cyclopropyl-4-[difluoro(phenyl)methyl]-6-piperazin-1-yl-pyrimidine (Compound 79c) [ka] 4-Cyclopropyl-6-[difluoro(phenyl)methyl]-2-piperazin-1-yl-pyrimidine (compound 80c) [ka] A mixture of compounds 79b and 80b (0.100 g, 232 μmol) and TFA (750 mg, 0.5 mL, 6.58 mmol) in DCM (1 mL) was stirred at 25° C. for 1 h. The mixture was concentrated to give the crude product (76 mg, 100% yield), which was used directly in the next step. MS found: 331.2 (MH + ).

[0234] Step 4: 2-Cyclopropyl-4-[difluoro(phenyl)methyl]-6-[4-(4-iodophenyl)sulfonylpiperazin-1-yl]pyrimidine (Compound 79d) [ka] 4-Cyclopropyl-6-[difluoro(phenyl)methyl]-2-[4-(4-iodophenyl)sulfonylpiperazin-1-yl]pyrimidine (compound 80d) [ka] A solution of 4-iodobenzenesulfonyl chloride (104 mg, 345 μmol) and a mixture of compounds 79c and 80c (0.076 g, 230 μmol), TEA (140 mg, 192 μl, 1.38 mmol) was stirred at room temperature for 1 h. The mixture was diluted with EA (20 mL) and washed twice with water (10 mL). The organics were dried and concentrated to give the crude product (137 mg, 100% yield). MS found: 597.3 (MH + ).

[0235] Step 5: tert-Butyl N-[1-[4-[4-[2-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 79e) [ka] tert-Butyl N-[1-[4-[4-[4-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 80e) [ka] A mixture of compounds 79d and 80d (0.137 g, 230 μmol), tert-butyl (5-oxopyrrolidin-3-yl)carbamate (69 mg, 345 μmol), DMEDA (4.05 mg, 45.9 μmol), CuI (8.75 mg, 45.9 μmol) and K3PO4 (122 mg, 574 μmol) in DMF (1.5 mL) was heated at 90° C. overnight. The reaction was diluted with EA (20 mL) and washed twice with water (10 mL). The organics were dried and concentrated to give the crude product (150 mg, 98% yield), which was used directly in the next step. MS found: 669.4 (MH + ).

[0236] Step 6: 4-amino-1-[4-[4-[2-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 79) and 4-amino-1-[4-[4-[4-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 80) A mixture of Compounds 79e and 80e (0.150 g, 224 μmol) and TFA (750 mg, 0.5 mL, 6.58 mmol) in DCM (2 mL) was stirred for 2 h at 25° C. The mixture was concentrated and purified by preparative HPLC to give Example 79 (15 mg, 11.8%) and Example 80 (3.5 mg, 2.7%) as white solids.

[0237] Example 79: MS measured value: 569.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.83(d,J=8.8Hz,2H),7.67(d,J=8.8Hz,2H),7.36-7.49(m,5H),6.83(s,1H),3.93(br dd,J=6.4,9.6Hz,2H),3.69(br s,4H),2.87(br t,J=4.4Hz,4H),2.71(br dd,J=7.2,16.8Hz,1H),2.57-2.64(m,1H),2.212-2.29(m,1H),1.80-1.86(m,1H),0.71-0.84(m,4H).

[0238] Example 80: MS measured value: 569.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.82(d,J=8.8Hz,2H),7.65(d,J=8.8Hz,2H),7.45-7.49(m,2H),7.37-7.45(m,3H),6.87(s,1H),3.92(br dd,J=6.4,9.6Hz,2H),3.67(br s,4H),2.78-2.83(m,4H),2.71(br dd,J=7.2,16.8Hz,2H),2.14-2.26(m,1H),1.91-2.05(m,1H),0.81-1.03(m,4H).

[0239] Examples 81 and 82 4-Amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-methoxy-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] 4-Amino-1-[4-[4-[4-[difluoro(phenyl)methyl]-6-methoxy-pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure:

[0240] Step 1: tert-Butyl 4-[4-[difluoro(phenyl)methyl]-2-methoxy-pyrimidin-2-yl]piperazine-1-carboxylate (compound 81a) [ka] tert-Butyl 4-[6-[difluoro(phenyl)methyl]-6-methoxy-pyrimidin-4-yl]piperazine-1-carboxylate (Intermediate 82a) [ka] A mixture of compounds 79a and 80a (0.10 g, 235 μmol) and sodium methanolate (94.1 μL, 471 μmol) in MeOH (1 mL) was stirred at 80° C. overnight. The mixture was concentrated, diluted with EA (5 mL) and washed with water (10 mL). The organic layer was dried and concentrated to give the crude product (99 mg, 100% yield), which was used directly in the next step. MS found: 421.5 (MH + ).

[0241] Step 2: 4-amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-methoxy-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 81) and 4-amino-1-[4-[4-[4[difluoro(phenyl)methyl]-6-methoxy-pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 82) The title compound was prepared similarly to the preparation of Examples 79 and 80, by using a mixture of compounds 81a and 82a instead of a mixture of compounds 79e and 80e. Examples 81 (28 mg) and 82 (4.2 mg) were obtained as white solids.

[0242] Example 81: MS measured value: 559.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.91(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,2H),7.43-7.57(m,5H),6.82(s,1H),4.00(br dd,J=6.0,9.6Hz,2H),3.79(br s,4H),3.73(s,3H),3.67-3.68(m,1H),2.96(br t,J=4.4Hz,4H),2.79(dd,J=7.2,16.8Hz,1H),2.19-2.36(m,1H).

[0243] Example 82: MS measured value: 559.4 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.82(br d,J=8.8Hz,2H),7.65(d,J=8.8Hz,2H),7.41-7.49(m,5H),6.30(s,1H),3.92(br dd,J=6.0,9.6Hz,2H),3.77(s,3H),3.72(br s,4H),2.83(br s,4H),2.64-2.76(m,1H),2.18(br dd,J=4.0,16.8Hz,1H),2.00(s,1H).

[0244] Example 83 (4R)-4-Amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0245] Step 1: tert-Butyl 4-[6-[difluoro(phenyl)methyl]-2-methyl-pyrimidin-4-yl]piperazine-1-carboxylate (compound 83a) [ka] A mixture of compound 79a (0.100 g, 235 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (202 μL, 706 μmol), Na2CO3 (62.4 mg, 588 μmol) and Pd(PPh3)4 (27 mg) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was stirred at 130 °C overnight. The mixture was concentrated and the residue was used directly in the next step. MS found: 405.3 (MH + ).

[0246] Step 2: (4R)-4-Amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 83) The title compound was prepared in a manner similar to the preparation of Example 79, by using Compound 83a instead of Compound 79e and Intermediate D instead of Intermediate C. Example 83 (12 mg) was obtained as a white solid. MS found: 543.2 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.80-7.87(m,J=8.8Hz,2H),7.62-7.72(m,J=8.8Hz,2H),7.36-7.49(m,5H),6.91(s,1H),3.91(br dd,J=6.0,9.6Hz,2H),3.73(br s,4H),3.57(br s,1H),2.88(br t,J=4.4Hz,4H),2.69(dd,J=6.8,16.8Hz,1H),2.24(s,3H),2.17(dd,J=4.0,16.8Hz,1H).

[0247] Example 84 4-Amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-vinyl-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 79, by using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane instead of potassium cyclopropyltrifluoroborate. Example 84 (2 mg) was obtained as a white solid. MS found: 555.3 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.86-7.97(m,2H),7.80-7.84(m,2H),7.54-7.61(m,2H),7.44-7.53(m,3H),7.00(s,1H),6.58-6.66(m,1H),6.53(d,J=2.0Hz,1H),5.66(br dd,J=2.0,10.2Hz,1H),4.40(br dd,J=7.2,11.2Hz,1H),4.21(br t,J=7.2Hz,1H),3.97(br dd,J=2.0,11.2Hz,1H),3.90(br s,4H),3.20(br dd,J=8.4,18.0Hz,1H),3.06-3.14(m,4H),2.72(br dd,J=2.8,18.0Hz,1H).

[0248] Example 85 2-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6,9-triazaspiro[4.5]decan-3-one [ka] The title compound was prepared according to the following procedure.

[0249] Step 1: tert-Butyl 4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazine-1-carboxylate (Compound 85a) [ka] Compound 73c (150 mg, 547 μmol) and tert-butyl piperazine-1-carboxylate (204 mg, 1.09 mmol) were dissolved in DMSO (5 mL) followed by the addition of K2CO3 (227 mg, 1.64 mmol). The reaction was stirred at 90° C. overnight. The mixture was partitioned between EA (300 mL) and water (300 mL). The organic layers were combined, washed three times with water (100 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product (230 mg, 0.542 mmol, 99.1%) as a yellow oil. MS found 424.6: (MH + ).

[0250] Step 2: 1-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazine (compound 85b) [ka] Compound 85a (0.23 g, 543 μmol) was dissolved in DCM (7.5 mL) followed by the addition of TFA (2.5 mL, 543 μmol). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was redissolved in EA (200 mL), washed with 1M aqueous K2CO3 solution (200 mL), brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product (0.25 g, 543 μmol, 100% yield) as a pale yellow solid. MS found: 324.5 (MH + ).

[0251] Step 3: 1-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]-4-(4-iodophenyl)sulfonyl-piperazine (Compound 85c) [ka] Compound 85b (50 mg, 154 μmol) was dissolved in DCM (5 mL) followed by the addition of TEA (64.6 μL, 463 μmol) and 4-iodobenzenesulfonyl chloride (93.4 mg, 309 μmol) and the reaction was stirred at room temperature for 2 h. The mixture was partitioned between EA (300 mL) and water (300 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product (90 mg, 0.152 mmol, 99% yield) as a pale yellow solid. MS found: 590.1 (MH + ).

[0252] Step 4: Di-tert-butyl 2-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-oxo-2,6,9-triazaspiro[4.5]decane-6,9-dicarboxylate (compound 85d) [ka] A mixture of compound 85c (0.07 g, 119 μmol), di-tert-butyl 3-oxo-2,6,9-triazaspiro[4.5]decane-6,9-dicarboxylate (65 mg, 183 μmol, WuXi AppTec), DMEDA (10.5 mg, 12.8 μL), CuI (6.78 mg, 35.6 μmol) and K3PO4 (78.7 mg, 356 μmol) in DMF (5 mL) was heated at 70° C. for 2 h. The mixture was then poured into water (250 mL) and extracted three times with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0-30%) to give compound 85d (90 mg, 110.2 μmol, 92.8% yield) as a brown oil. MS found: 817.5 (MH + ).

[0253] Step 5: 2-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6,9-triazaspiro[4.5]decan-3-one (Example 85) Compound 85d (90 mg, 110 μmol) was dissolved in DCM (5 mL) followed by the addition of TFA (100 μl, 1.3 mmol). The reaction was stirred at room temperature for 1 h and concentrated. The crude product was purified by preparative HPLC to give Example 85 (4.15 mg, 6.72 μmol, 5% yield) as a light brown solid. MS found: 617.5 (MH + ). 1H NMR(400MHz,CD3OD):δ ppm 7.90(d,J=8.8Hz,2 H),7.81(d,J=8.8Hz,2 H),7.42-7.52(m,5 H),6.78(s,1 H),6.66(s,1 H),4.61-4.67(m,1 H),4.04(d,J=10.4Hz,1 H),3.92(d,J=10.4Hz,1 H),3.63-3.72(m,4 H),3.11-3.19(m,4 H),3.03-3.10(m,4 H),2.89(d,J=17.6Hz,1 H),2.75(d,J=17.6Hz,1 H),2.19(t,J=7.6Hz,1 H),2.03(br d,J=5.6Hz,1 H),1.60(br s,1 H).

[0254] Example 86 5-(Aminomethyl)-1-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] A mixture of compound 85c (91 mg, 154 μmol), 5-(aminomethyl)pyrrolidin-2-one (35.2 mg, 309 μmol), DMEDA (16.6 μL, 154 μmol), CuI (12 mg, 63 μmol) and K3PO4 (102 mg, 463 μmol) in DMF (5 mL) was heated at 70° C. for 2 h. The mixture was then poured into water (200 mL) and extracted three times with DCM (200 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give Example 86 (6 mg, 8.7 μmol, 5.35% yield) as a white solid. MS found: 576.2 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.88(br d,J=9.2Hz,4 H),7.75-7.83(m,2 H),7.46-7.65(m,5 H),6.93-6.97(m,1 H),6.76(s,1 H),4.61-4.67(m,1 H),3.63-3.71(m,4 H),2.93-3.06(m,4 H),2.60-2.80(m,2 H),2.52-2.52(m,1 H),2.39-2.47(m,1 H),2.26-2.36(m,1 H),2.04-2.13(m,1 H).

[0255] Example 87 (3aR,7aS)-3-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 85, by using tert-butyl (3aR,7aS)-2-oxohexahydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate instead of di-tert-butyl 3-oxo-2,6,9-triazaspiro[4.5]decane-6,9-dicarboxylate. Example 87 (23 mg) was obtained as a white solid. MS found: 585.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.78(s,4H),7.52-7.56(m,2H),7.45-7.52(m,2H),7.37-7.60(m,1H),6.90(s,1H),4.99(td,J=4.0,7.6Hz,1H),4.84-4.94(m,1H),3.81(br s,4H),3.50(br dd,J=8.8,13.2Hz,1H),3.15-3.27(m,2H),3.08(br d,J=9.6Hz,1H),2.88-3.01(m,4H),2.17-2.18(m,1H),2.07(s,1H).

[0256] Example 88 5-(Aminomethyl)-3-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 85, by using tert-butyl ((2-oxooxazolidin-5-yl)methyl)carbamate instead of di-tert-butyl 3-oxo-2,6,9-triazaspiro[4.5]decane-6,9-dicarboxylate. Example 88 (21 mg) was obtained as a white solid. MS found: 559.3 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.71-7.85(m,4H),7.45-7.58(m,5H),6.89(s,1H),4.84-4.97(m,1H),4.22(t, J=9.2Hz,1H),3.86-3.88(m,1H),3.78-3.89(m,4H),3.13-3.29(m,2H),2.91(br t,J=4.8Hz,4H),2.33(s,3H).

[0257] Example 89 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(2-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0258] Step 1: (2,6-Dichloro-4-pyridyl)-(2-pyridyl)methanone (compound 89a) [ka] To a solution of 2-bromopyridine (0.41 mL, 4.25 mmol) and 2,6-dichloro-N-methoxy-N-methyl-pyridine-4-carboxamide (1000.0 mg, 4.25 mmol) in THF (20 mL) was added n-BuLi (1.77 mL, 4.25 mmol) under N2 at -70 °C for 40 min. The mixture was stirred at -70 °C for 4 h, then quenched with saturated NH4Cl (50 mL) and extracted with EA (30 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0-30%) to give compound 89a (450 mg, 1.78 mmol, 37.62% yield) as a white solid. MS found: 253 (MH + ).

[0259] Step 2: 2,6-Dichloro-4-[difluoro(2-pyridyl)methyl]pyridine (compound 89b) [ka] Compound 89a (150.0 mg, 0.590 mmol) was dissolved in BAST (2.0 mL) and the reaction was stirred at 25 °C for 12 h. The mixture was quenched with ice water (20 mL) and extracted twice with EA (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0-50%) to give compound 89b (85 mg, 0.310 mmol, 46.9% yield) as a yellow solid. MS found: 275.1 (MH + ).

[0260] Step 3: tert-Butyl N-[1-[4-[4-[6-chloro-4-[difluoro(2-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 89c) [ka] Compound 89b (85.0 mg, 0.310 mmol) and intermediate D (131.17 mg, 0.310 mmol) were dissolved in a mixture of DMSO (0.5 mL) and DIPEA (2.0 mL). The reaction was stirred at 115 °C for 12 h. The reaction was quenched with brine (20 mL) and extracted twice with DCM (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0-70%) to give compound 89c (120 mg, 0.180 mmol, 52.71% yield) as a yellow solid. MS found: 663.2 (MH + ).

[0261] Step 4: 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(2-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 89) Compound 89c (100.0 mg, 0.150 mmol) was dissolved in 2M HCl / EA (5 mL). The reaction mixture was stirred at room temperature for 12 h. The solvent was removed and the crude product was purified by preparative HPLC to give Example 89 (83 mg, 0.150 mmol, 96.8% yield) as a white solid. MS found: 563.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.63(d,J=4.4Hz,1H),8.02(td,J=7.6,1.6Hz,1H),7.92(d,J=8.8Hz,2H),7 .86(d,J=7.8Hz,1H),7.76(d,J=8.8Hz,2H),7.55(dd,J=7.2,5.2Hz,1H),6.9 2(s,1H),6.76(s,1H),4.11(dd,J=10.4,6.4Hz,1H),3.84(dd,J=8.4,5.2Hz, 1H),3.66(d,J=5.2Hz,5H),2.86-3.01(m,5H),2.42(dd,J=17.2,3.2Hz,1H).

[0262] Example 90 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(3-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 89, by using 3-bromopyridine instead of 2-bromopyridine. Example 90 (60 mg) was obtained as a white solid. MS found: 563.1 (MH + ). 1 H NMR (400MHz, DMSO-d6): δ ppm 8.85(s,1H),8.73(d,J=4.4Hz,1H),8.30(s,2H),8.06(d,J=8.0Hz,1H),7.92(d,J =8.8Hz,2H),7.80(d,J=8.8Hz,2H),7.54(dd,J=8.0,4.8Hz,1H),7.01(s,1H),6.8 7(s,1H),4.27(dd,J=11.2,6.9Hz,1H),4.09(s,1H),3.83(d,J=10.0Hz,1H),3.68 (s,4H),3.08(dd,J=18.0,8.0Hz,1H),2.96(s,4H),2.59(dd,J=18.0,2.4Hz,1H).

[0263] Example 91 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(4-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 89, by using 4-bromopyridine instead of 2-bromopyridine. Example 91 (22 mg) was obtained as a white solid. MS found 563.2 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 8.78(s,2H),8.37(s,2H),7.91(d,J=8.8Hz,2H),7.79(d,J=8.8Hz,2H),7.67(s,2H),6.99(s,1H),6.85(s,1H),4.26(dd,J=11.2,6. 8Hz,1H),4.09(s,1H),3.82(s,1H),3.68(d,J=4.0Hz,4H),3.08(dd,J=18.0,8.2Hz,1H),2.96(s,4H),2.60(dd,J=18.0,2.4Hz,1H).

[0264] Example 92 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(pyrimidin-5-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 89, by using 4-bromopyridine instead of 5-bromopyrimidine. Example 92 (19.5 mg) was obtained as a white solid. MS Found: 563.2 (MH + ). 1 H NMR (400MHz, DMSO-d6): δ ppm 1 H NMR(400MHz,DMSO)9.36(s,1H),9.12(s,2H),7.92(d,J=8.8Hz,2H),7.79(d,J =8.8Hz,2H),7.03(s,1H),6.95(s,1H),4.25(dd,J=11.2,6.8Hz,1H),4.07(br s,1H),3.82(br s,1H),3.68(br s,4H),3.31(br s,1H),3.11-3.03(m,1H),2.97(d,J=4.4Hz,4H).

[0265] Example 93 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(pyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 89, by using 2-bromopyrazine instead of 2-bromopyridine. Example 92 (50 mg) was obtained as a white solid. MS found: 564 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.17(t,J=10.0Hz,1H),8.86(d,J=2.4Hz,1H),8.74(s,1H),7.91(d,J=8 .8Hz,2H),7.75(d,J=8.8Hz,2H),6.97(d,J=14.0Hz,1H),6.84(s,1H),4. 03(dd,J=10.0,6.0Hz,1H),3.62-3.68(m,5H),3.52-3.56(m,1H),2.88-3.03(m,4H),2.81(dd,J=17.2,7.2Hz,1H),2.30(dd,J=17.2,3.6Hz,1H).

[0266] Example 94 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(pyrimidin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0267] Step 1: 2,6-Dichloro-4-pyridyl)-pyrimidin-2-yl-methanone (Compound 93a) [ka] To a solution of n-BuLi (2.82 mL, 6.76 mmol) in THF (30 mL) was added 2,6-dichloropyridine (1.0 g, 6.76 mmol) at -78 °C and then stirred under N2 for 30 min. A solution of methylpyrimidine-2-carboxylate (0.26 mL, 6.76 mmol) in THF (15 mL) was added dropwise. The reaction was stirred at -78 °C under N2 for another 5 h. The reaction mixture was quenched with aqueous NH4Cl (100 mL) and extracted three times with EA (40 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (EA in PE = 0-15%) to give compound 93a (450 mg, 1.77 mmol, 23.59% yield) as a colorless oil. MS found: 254 (MH + ).

[0268] Step 2: 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(pyrimidin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 93) The title compound was prepared in a similar manner to the preparation of Example 89, by using Compound 93a instead of Compound 89b. Example 93 (7 mg) was obtained as a white solid. MS found: 564.1 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 8.96(d,J=4.8Hz,2H),7.91(d,J=8.8Hz,2H),7.63-7.78(m,3H),6.90(s,1H),6.76(s,1H),3.95-4.05(m ,1H),3.64(s,5H),3.49(d,J=7.2Hz,1H),2.94(s,4H),2.77(dd,J=16.8,6.8Hz,1H),2.22-2.33(m,1H).

[0269] Example 95 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydropyran-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0270] Step 1: N-Methoxy-N-methyl-tetrahydropyran-4-carboxamide (Compound 95a) [ka] A mixture solution of tetrahydro-2H-pyran-4-carboxylic acid (2000.0 mg, 15.37 mmol), HATU (11688.3 mg, 30.74 mmol) and DIPEA (20 mL) in DCM (60 mL) was stirred at room temperature for 30 min. Then, O,N-dimethylhydroxylamine (1798.8 mg, 18.44 mmol) was added and the reaction was stirred at room temperature for 12 h. The mixture was washed three times with brine (30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0-100%) to give compound 95a (2000 mg, 11.55 mmol, 67.62% yield) as a pale yellow oil. MS found: 174 (MH + ).

[0271] Step 2: (2,6-Dichloro-4-pyridyl)-tetrahydropyran-4-yl-methanone (compound 95b) [ka] To a solution of n-BuLi (1.2 mL, 2.89 mmol) in THF (20 mL) was added 2,6-dichloropyridine (428 mg, 2.89 mmol) at −70° C. under nitrogen for 40 min, and compound 95a (500.0 mg, 2.89 mmol) was added. The mixture was stirred at −70° C. for 4 h, quenched with saturated NH4Cl (50 mL), and extracted with EA (30 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE=0-30%) to give compound 95b (200 mg, 0.770 mmol, 23.97% yield) as a white solid. MS found: 260,262 (MH + ).

[0272] Step 2: 2,6-Dichloro-4-[difluoro(tetrahydropyran-4-yl)methyl]pyridine (Compound 95c) [ka] Compound 95b (200.0 mg, 0.770 mmol) was dissolved in BAST (3.0 mL) and the reaction was stirred at 25 °C for 12 h. The mixture was quenched with ice water (20 mL) and extracted twice with EA (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 0-50%) to give compound 95c (150 mg, 0.530 mmol, 62.24% yield) as a white solid. MS found: 282,284 (MH + ).

[0273] Step 3: tert-Butyl N-[1-[4-[4-[6-chloro-4-[difluoro(tetrahydropyran-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 95d) [ka] Compound 95c (150.0 mg, 0.530 mmol) and intermediate C (92.93 mg, 0.220 mmol) were dissolved in a mixture of DMSO (0.5 mL) and DIPEA (2.0 mL). The reaction was stirred at 115 °C for 12 h. The mixture was quenched with brine (50 mL) and extracted twice with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EA in PE = 10-70%) to give compound 95d (100 mg, 0.150 mmol, 25.26% yield) as a yellow solid. MS found: 670 (MH + ).

[0274] Step 4: 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydropyran-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 95) Compound 95d (100.0 mg, 0.150 mmol) was dissolved in 2M HCl / EA (10 mL) and the reaction was stirred at room temperature for 4 h. The mixture was then concentrated and the crude product was purified by preparative HPLC to give Example 95 (28 mg, 0.05 mmol, 32.6% yield) as a white solid. MS found: 570 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=8.8Hz,2H),7.75(d,J=8.8Hz,2H),6.79(s,1H),6.71(s,1H),3.98(dd,J=9. 6,6.0Hz,1H),3.85(dd,J=11.2,3.2Hz,2H),3.65(dd,J=11.6,7.2Hz,5H),3.48(dd,J=9 .6,3.2Hz,1H),3.24(t,J=10.8Hz,2H),2.92-3.01(m,4H),2.76(dd,J=16.8,6.8Hz,1H) ,2.45(s,1H),2.24(dd,J=16.8,4.0Hz,1H),1.97(s,2H),1.39(dt,J=12.4,8.8Hz,4H).

[0275] Example 96 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydrofuran-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 95, by using tetrahydrofuran-3-carboxylic acid instead of tetrahydro-2H-pyran-4-carboxylic acid. Example 96 (160 mg) was obtained as a white solid. MS found: 556 (MH + ). 1 H NMR(400MHz,CD3OD):δ ppm 7.92(d,J=8.8Hz,2H),7.81(d,J=8.8Hz,2H),6.74(d,J=8.8Hz,2H),4.35(dd,J=11.2,6.8Hz,1H),4.11(s,1H),3.89(dd,J= 11.2,2.8Hz,1H),3.73-3.84(m,3H),3.60-3.73(m,5H),2.99-3.18(m,6H),2.63(dd,J=18.0,3.2Hz,1H),1.88-2.00(m,2H).

[0276] Example 97 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(oxetan-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 95, by using oxetane-3-carboxylic acid instead of tetrahydro-2H-pyran-4-carboxylic acid. Example 97 (22 mg) was obtained as a white solid. MS found: 542 (MH + ). 1H NMR(400MHz,CD3OD):δ ppm 7.91(d,J=8.8Hz,2H),7.79(d,J=8.8Hz,2H),6.73(s,1H),6.67(s,1H), 5.60(s,1H),5.50(s,1H),4.15(dd,J=10.0,6.4Hz,1H),4.07(s,2H),3. 78(td,J=7.2,3.6Hz,1H),3.61-3.72(m,5H),3.26-3.28(m,1H),3.01-3.10(m,4H),2.92(dd,J=17.2,7.6Hz,1H),2.41(dd,J=17.2,4.0Hz,1H).

[0277] Example 98 4-Amino-1-[4-[4-[6-chloro-4-[3,6-dihydro-2H-pyran-4-yl(difluoro)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 95, by using 3,6-dihydro-2H-pyran-4-carboxylic acid instead of tetrahydro-2H-pyran-4-carboxylic acid. Example 98 (60 mg) was obtained as a white solid. MS found: 568 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=8.8Hz,2H),7.76(d,J=8.8Hz,2H),6.78(s,1H),6.67(s,1H),6.09(s,1H),4.09(d,J=16.0Hz,3H),3.80 (s,1H),3.58-3.70(m,7H),2.96(s,4H),2.87(dd,J=17.2,7.2Hz,1H),2.38(dd,J=17.2,2.8Hz,1H),2.04(s,2H).

[0278] Example 99 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydropyran-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 95, by using tetrahydro-2H-pyran-3-carboxylic acid instead of tetrahydro-2H-pyran-4-carboxylic acid. Example 99 (200 mg) was obtained as a white solid. MS found: 570.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=8.8Hz,2H),7.77(d,J=8.8Hz,2H),6.80(s,1H),6.72(s,1H),4.13(dd,J=10.4,6.4Hz,1H),3.73-3.88(m,3H),3.59-3.73(m,5H) ),3.21(ddd,J=11.2,9.2,4.4Hz,2H),2.83-3.03(m,5H),2.45(dd,J=17.4,3.2Hz,2H),1.61(dd,J=31.4,12.4Hz,2H),1.29-1.52(m,2H).

[0279] Example 100 4-Amino-1-[4-[4-[6-chloro-4-[difluoro(8-oxabicyclo[3.2.1]octan-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a manner similar to that of Example 95, by using 8-oxabicyclo[3.2.1]octane-3-carboxylic acid instead of tetrahydro-2H-pyran-4-carboxylic acid. Example 100 (70.4 mg) was obtained as a white solid. MS found: 596.3 (MH + ). 1H NMR(400MHz,CD3OD):δ ppm 7.95(d,J=8.8Hz,2H),7.85(d,J=8.8Hz,2H),6.70(d,J=5.2Hz,2H),4.42(dd,J=11. 4,6.8Hz,3H),4.21(t,J=7.6Hz,1H),3.97(dd,J=11.4,2.0Hz,1H),3.66-3.78(m,4H ),3.21(dd,J=18.0,8.4Hz,1H),3.14-3.03(m,4H),2.71(dd,J=18.0,2.8Hz,1H),2. 46-2.64(m,1H),1.86-1.99(m,2H),1.60-1.81(m,4H),1.40(dd,J=13.2,4.4Hz,2H).

[0280] Example 101 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro(3-oxabicyclo[3.1.0]hexan-6-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 95, by using 8-oxabicyclo[3.2.1]octane-3-carboxylic acid instead of tetrahydro-2H-pyran-4-carboxylic acid and intermediate D instead of intermediate C. Example 101 (300 mg) was obtained as a white solid. MS found: 568.3 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=8.8Hz,2 H),7.75(m,J=8.8Hz,2 H),6.85(s,1 H),6.79(s,1 H),3.99(br dd,J=9.6,6.0Hz,1 H),3.75(d,J=8.8Hz,2 H),3.56(br d,J=8.4Hz,2 H),3.48(br dd,J=9.6,3.2Hz,2 H),3.33(br s,4 H),2.96(br s,4 H),2.76(dd,J=16.8,6.8Hz,1 H),2.24(br dd,J=16.8,4.0Hz,2 H),2.03(br s,2 H), 1.43-1.56(m,1 H).

[0281] Example 102 and Example 103 (4R)-4-amino-1-[4-[4-[6-chloro-4-[[(2S)-1,4-dioxan-2-yl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (4R)-4-amino-1-[4-[4-[6-chloro-4-[[(2R)-1,4-dioxan-2-yl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a manner similar to the preparation of Example 95, by using Intermediate E or Intermediate F in place of Compound 95b, and Intermediate D in place of Intermediate C.

[0282] Example 102 (40.4 mg) was obtained as a white solid. MS measured value: 572 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=9.2Hz,2 H),7.72-7.77(m,2 H),6.84(s,1 H),6.76(s,1 H),4.11-4.27(m,1 H),3.99(dd,J=9.6,6.0Hz,1 H),3.71-3.85(m,2 H),3.41-3.68(m,8 H),2.96(br t,J=4.8Hz,4 H),2.76(dd,J=16.8,6.8Hz,1 H),2.11-2.38(m,2 H),1.97-2.05(m,1 H),1.23(br s,1 H).

[0283] Example 103 (35.8 mg) was obtained as a white solid. MS measured value: 572 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=9.2Hz,2 H),7.72-7.77(m,2 H),6.84(s,1 H),6.76(s,1 H),4.11-4.27(m,1 H),3.99(dd,J=9.6,6.0Hz,1 H),3.71-3.85(m,2 H),3.41-3.68(m,8 H),2.96(br t,J=4.8Hz,4 H),2.76(dd,J=16.8,6.8Hz,1 H),2.11-2.38(m,2 H),1.97-2.05(m,1 H),1.23(br s,1 H).

[0284] Example 104 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0285] Step 1: tert-Butyl (2S)-2-[[2-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]morpholine-4-carboxylate (compound 104a) [ka] To a solution of intermediate G (59.58 mg, 0.160 mmol) and intermediate D (60.0 mg, 0.140 mmol) in DMSO (2 mL) was added DIPEA (36.47 mg, 0.280 mmol). The mixture was stirred at 100° C. for 12 h. To the mixture was added water (50 mL) and EA (50 mL). The organic phase was washed with aqueous solution of CaCl2 (30 mL), brine (30 mL), dried over Na2SO4 and concentrated. The crude product was purified by preparative TLC to give compound 104a (90 mg, 0.120 mmol, 82.56% yield) as a white solid. MS found: 771.1 (MH + ).

[0286] Step 2: (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 104) A mixture of compound 104a (80.0 mg, 0.10 mmol) in TFA (1.33 mL, 18.01 mmol) was stirred at 15° C. for 2 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give Example 104 (56 mg, 0.090 mmol, 83.54% yield) as a white solid. MS found: 571.1 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 7.89-7.95(m,2 H),7.80(d,J=8.8Hz,3 H),6.85(s,1 H),6.76(s,1 H),4.33-4.44(m,1 H),4.26(dd,J=11.2,7.2Hz,1 H),3.99-4.11(m,2 H),3.87(d,J=12.8Hz,1 H),3.77(t,J=12.8Hz,1 H),3.64-3.71(m,4 H),3.18(d,J=12.4Hz,3 H),3.02-3.12(m,2 H),2.94-3.02(m,5 H).

[0287] Example 105 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro-[(2R)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 104, by using Intermediate H instead of Intermediate G. Example 105 (35.5 mg) was obtained as a white solid. MS found: 571.1 (MH + ). 1 H NMR (400MHz, DMSO-d6): δ ppm 8.38(br s,3 H)7.92(d,J=8.8Hz,2 H),7.80(d,J=9.2Hz,2 H),6.86(s,1 H),6.76(s,1 H),4.31-4.46(m,1 H),4.27(dd,J=11.2,6.8Hz,1 H),4.03(dd,J=12.4,2.4Hz,2 H),3.86(d,J=10.4Hz,1 H),3.64-3.82(m,5 H),3.03-3.26(m,3 H),2.95-3.03(m,5 H),2.58-2.70(m,2 H).

[0288] Example 106 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro(1,2,3,6-tetrahydropyridin-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 104, by using Intermediate I instead of Intermediate G. Example 106 (11.8 mg) was obtained as a white solid. MS found: 567.1 (MH + ). 1 H NMR (400MHz, DMSO-d6): δ ppm 9.53(br s,2 H),8.66(s,3 H),7.91(d,J=8.8Hz,2 H),7.79(d,J=8.8Hz,2 H),6.80(s,1 H),6.72(s,1 H),6.17(s,1 H),4.27(dd,J=11.2,6.8Hz,1 H),4.06(s,1 H),3.92(d,J=9.6Hz,1 H),3.68(br s,6 H),3.16(br s,2 H),2.97(br s,4 H),2.67(d,J=18.0Hz,1 H),2.26(br s,2 H).

[0289] Example 107 and Example 108 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro-[(3R)-3-piperidyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro-[(3S)-3-piperidyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure:

[0290] Step 1: tert-Butyl 3-[2-chloro-6-[4-[4-[(4R)-4-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]pyridine-4-carbonyl]piperidine-1-carboxylate (compound 107a) [ka] To a solution of benzyl N-[(3R)-5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate (280 mg, 557 μmol) and intermediate J (200 mg, 557 μmol) in DMSO (10 mL) was added DIPEA (216 mg, 292 μL, 1.67 mmol). The reaction was stirred at 100 °C for 2 days. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash column (EA in PE = 70-90%) to give intermediate 107a (320 mg, 69.6% yield) as a yellow oil. MS found: 725.2 (MH + ).

[0291] Step 2: tert-Butyl (3R)-3-[[2-[4-[4-[(4R)-4-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]piperidine-1-carboxylate and tert-butyl (3S)-3-[2-[4-[4-[(4R)-4-(benzyloxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]piperidine-1-carboxylate (compounds 107b and 108b)

[0292] [ka] Compound 107a (280 mg, 358 μmol) was dissolved in DAST (10 mL) and the mixture was stirred at room temperature for 2 days. The reaction was quenched by dropwise addition of water in an ice / water bath and then extracted three times with DCM (50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (70-100% EA in PE) and then chiral separation by SFC afforded compound 107b (60 mg, 74.7 μmol, 20.8% yield, faster elution) and compound 108b (56 mg, 69.7 μmol, 19.5% yield, slower elution) as white solids. MS found: 803.0 (MH + ).SFC conditions: Column: AD, i.d. 250×30 mm, 5 μm; Mobile phase: A for CO2, B for ethanol (0.1% NH3H2O); Gradient: B 50%; Flow rate: 50 mL / min; Back pressure: 100 bar; Column temperature: 35 °C.

[0293] Step 3: (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(3R)-3-piperidyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one and (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(3S)-3-piperidyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 107 and Example 108)

[0294] A solution of compound 107b (50 mg, 62.2 μmol) and TFA was stirred at 65° C. for 2 h. The mixture was concentrated and the crude product was purified by preparative HPLC to give Example 107 (20.8 mg, 36.4 μmol, 58.6% yield) as a white solid. MS found: 569.2 (MH + ). 1H NMR(400MHz,DMSO-d6):δ ppm 8.29(br s,2 H),7.92(m,J=8.8Hz,2 H),7.80(m,J=8.8Hz,2 H),6.81(s,1 H),6.72(s,1 H),4.26(dd,J=11.2,6.8Hz,1 H),4.08(br s,1 H),3.74-3.92(m,1 H),3.62-3.72(m,4 H),3.18-3.29(m,2 H),3.08(dd,J=18.0,8.0Hz,2 H),2.96-3.02(m,4 H),2.77(br d,J=12.0Hz,2H),1.90-2.12(m,1 H),1.69-1.87(m,2 H),1.57(q,J=13.2Hz,1 H),1.28-1.47(m,2 H),1.24(br s,1 H).

[0295] Example 108 (23.7 mg) was prepared in a similar manner to the preparation of Example 107, by using compound 108b instead of compound 107b. MS found: 569.2 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.92(m,J=8.98Hz,2 H),7.80(m,J=8.8Hz,2 H),6.80(s,1 H),6.73(s,1 H),4.26(dd,J=11.2,6.98Hz,1 H),4.08(br s,1 H),3.81(m,1 H),3.62-3.72(m,4 H),3.15-3.28(m,2 H),3.08(dd,J=18.0,8.4Hz,2 H),2.98(m,4 H),2.77(m,2 H),1.90-2.12(m,1 H),1.69-1.87(m,2 H),1.57(q,J=13.2Hz,1 H),1.28-1.47(m,2 H)1.24(br s,1 H).

[0296] Example 109 (4R)-4-Amino-1-[4-[4-[4-[azetidin-3-yl(difluoro)methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 104, by using Intermediate I instead of Intermediate K. Example 109 (30 mg) was obtained as a white solid. MS found: 540.9 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.92(d,J=9.2Hz,2H),7.77(d,J=9.2Hz,2H),6.83(s,1H),6.78(s,1H),4.08(dd,J=6.4,9.6Hz,1H),3.80( t,J=9.2Hz,5H),3.55-3.72(m,6H),2.96(t,J=4.8Hz,4H),2.87(dd,J=7.2,16.8Hz,1H),2.30-2.40(m,1H).

[0297] Example 110 3-[4-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(hydroxymethyl)oxazolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0298] Step 1: tert-Butyl 4-[4-[5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl]phenyl]sulfonyl piperazine-1-carboxylate (compound 110a) [ka] A mixture of tert-butyl 4-((4-iodophenyl)sulfonyl)piperazine-1-carboxylate (0.430 g, 951 μmol), 5-(hydroxymethyl)oxazolidin-2-one (111 mg, 951 μmol), DMEDA (29.3 mg, 333 μmol), CuI (63.4 mg, 333 μmol) and K3PO4 (404 mg, 1.9 mmol) in DMF (4 mL) was heated at 75° C. for 1 h in a microwave. The mixture was poured into ice water, extracted with DCM, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel to give compound 110a (310 mg, 702 μmol, 73.9% yield) as a white solid. MS found: 442 (MH + ).

[0299] Step 2: 5-(hydroxymethyl)-3-(4-piperazin-1-ylsulfonylphenyl)oxazolidin-2-one (compound 110b) [ka] A mixture of compound 110a (0.060 g, 136 μmol) and TFA (877 mg) in CH2Cl2 (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated and used directly in the next step. MS found: 342 (MH + ). Step 3: tert-Butyl (2S)-2-[[2-chloro-6-[4-[4-[5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]morpholine-4-carboxylate (compound 110c) [ka] A mixture of compound 110b (0.045 g, 132 μmol), intermediate H (50.5 mg, 132 μmol) and DIPEA (85.1 mg, 115 μl, 659 μmol) in NMP (1.5 mL) was stirred at 100° C. overnight. The mixture was diluted with EA (10 mL) and washed twice with water (10 mL). The organic layer was dried, concentrated and used directly in the next step. MS found: 688 (MH + ). Step 4: 3-[4-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(hydroxymethyl)oxazolidin-2-one (Example 110) A mixture of compound 110c (0.090 g, 131 μmol,) and TFA (844 mg) in CH2Cl2 (1.5 mL) was stirred at room temperature for 1 h. The mixture was concentrated and isolated by preparative HPLC to give Example 110 (24 mg, 29.6% yield) as a white solid. MS found: 588 (MH + ). 1 H NMR(400MHz,DMSO-d6):δ ppm 7.73-7.78(m,2H),7.69-7.71(d,J=8.4Hz,2H),6.75(s,1H),6.67(s,1H),5.16(br s,1H),4.61-4.73(m,1H),3.94-4.16(m,2H),3.81(br dd,J=6.0,9.2Hz,2H),3.55-3.59(m,4H),3.41-3.53(m,2H),2.99(br d,J=12.4Hz,1H),2.90-2.91(m,4H),2.79-2.84(m,1H),2.62-2.77(m,2H).

[0300] Example 111 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro-(5-methylpyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 89, by using 2-bromo-5-methyl-pyrazine instead of 2-bromopyridine. Example 111 (89 mg) was obtained as a white solid. MS found: 578.0 (MH + ). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.87-9.07(m,1 H),8.50-8.68(m,1 H),7.66-8.06(m,3 H),6.64-7.01(m,2 H),3.92-4.15(m,2 H),3.51-3.79(m,7 H),2.89-3.08(m,4 H),2.71-2.91(m,1 H),2.51(br s,3 H),2.21-2.39(m,1 H). 19 F NMR(376MHz,DMSO-d6)δ ppm-97.90--96.24(m,2 F).

[0301] Example 112 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro-(6-methylpyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared similarly to the preparation of Example 89, by using 2-bromo-6-methyl-pyrazine instead of 2-bromopyridine. Example 112 (59 mg) was obtained as a white solid. MS found: 578.2 (MH + ). 1H NMR(400MHz,DMSO-d6)δ ppm 8.82-8.94(m,1 H),8.73(s,1 H),7.91(d,J=9.05Hz,2 H),7.74(d,J=9.05Hz,2 H),6.93(s,1 H),6.81(s,1 H),4.00(dd,J=10.03,6.11Hz,1 H),3.60-3.71(m,5 H),3.49(br dd,J=9.66,3.30Hz,1 H),3.33-3.34(m,3 H),2.89-3.01(m,4 H),2.78(dd,J=16.87,7.09Hz,1 H),2.26(dd,J=16.63,3.91Hz,1 H). 19 F NMR(376MHz,DMSO-d6)δ ppm-97.18(s,2 F).

[0302] Example 113 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[(5-chloro-6-methyl-pyrazin-2-yl)-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a similar manner to the preparation of Example 94, by using methyl 5-chloro-6-methylpyrazine-2-carboxylate instead of methylpyrimidine-2-carboxylate. Example 113 (20 mg) was obtained as a white solid. MS found: 612.3 (MH + ). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.79(s,1 H),7.91(d,J=8.9Hz,2 H),7.74(d,J=8.9Hz,2 H),6.92(s,1 H),6.82(s,1 H),4.0-4.0(m,1 H),3.6-3.7(m,5 H),3.50(br dd,J=3.1,9.8Hz,1 H),2.95(t,J=4.7Hz,4 H),2.7-2.8(m,1 H),2.56(s,3 H),2.26(dd,J=3.8,16.9Hz,1 H). 19F NMR(376MHz,DMSO-d6)δ ppm-96.54(s,2 F).

[0303] Example 114 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[difluoro-[cis-6-methylmorpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0304] Step 1: tert-Butyl cis-2-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]-6-methyl-morpholine-4-carboxylate (compound 114a) [ka] Compound 114a was prepared in a similar manner to the preparation of intermediate G, by using (cis-6-methylmorpholin-2-yl)methanol instead of (R)-N-Boc-2-hydroxymethylmorpholine. Compound 114a (1.2 g) was obtained as a white solid. MS found: 341.0 (MH + -56).

[0305] Step 2: (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[cis-6-methylmorpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 114) The title compound was prepared in a manner similar to the preparation of Example 104, by using compound 114a instead of intermediate G. Example 114 (23.6 mg) was obtained as a white solid. MS found: 585.4 (MH + ). 1H NMR(400MHz,DMSO-d6)δ ppm 8.59(br d,J=2.57Hz,3 H),7.90(d,J=8.93Hz,2 H),7.79(d,J=8.93Hz,2 H),6.85(s,1 H),6.74(s,1 H),4.49(q,J=10.43Hz,1 H),4.26(dd,J=11.07,6.91Hz,1 H),3.84-4.12(m,3 H),3.67(br s,4 H),3.17-3.28(m,2 H),3.06(dd,J=17.85,8.19Hz,1 H),2.97(br d,J=4.16Hz,4 H),2.72-2.85(m,1 H),2.65(br dd,J=17.79,2.75Hz,2H),1.09(d,J=6.24Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ ppm-109.50--105.5(m,2 F).

[0306] Example 115 ((4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-(5-methylmorpholin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0307] Step 1: tert-Butyl 2-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]-5-methyl-morpholine-4-carboxylate (compound 115a) [ka] Compound 115a was prepared in a similar manner to the preparation of intermediate G, by using (5-methylmorpholin-2-yl)methanol instead of (R)-N-Boc-2-hydroxymethylmorpholine. Compound 115a (580 mg) was obtained as a white solid. MS found: 341.2 (MH + -56). Step 2: ((4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-(5-methylmorpholin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one (Example 115) [ka] The title compound was prepared in a manner similar to the preparation of Example 104, by using compound 115a instead of intermediate G. Example 115 (25.4 mg) was obtained as a white solid. MS found: 585.2 (MH + ). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.66(s,3 H),7.91(d,J=8.93Hz,2 H),7.79(d,J=8.93Hz,2 H),6.89(s,1 H),6.77(s,1 H),4.37-4.54(m,1 H),4.27(dd,J=11.07,6.91Hz,1 H),4.06(s,1 H),3.92(d,J=11.25Hz,2 H),3.76(d,J=12.10Hz,1 H),3.68(s,4 H),3.52(d,J=7.09Hz,1 H),3.02-3.15(m,3 H),2.97(s,4 H),2.67(dd,J=17.85,2.81Hz,1 H), 1.29 (d, J = 6.85 Hz, 3 H).

[0308] Example 116 (4R)-4-Amino-1-[4-[4-[4-[[cis-3-azabicyclo[3.1.0]hexan-1-yl]difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0309] Step 1: tert-Butyl cis-1-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (compound 116a) [ka] Compound 116a was prepared similarly to the preparation of intermediate G by using tert-butyl cis-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate instead of (R)-N-Boc-2-hydroxymethylmorpholine. Compound 116a (2.6 g) was obtained as a white solid. MS found: 323.1 (MH + -56). Step 2: (4R)-4-amino-1-[4-[4-[4-[[cis-3-azabicyclo[3.1.0]hexan-1-yl]difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared in a manner similar to the preparation of Example 104, by using compound 116a instead of intermediate G. Example 115 (80.2 mg) was obtained as a white solid. MS found: 567.2 (MH + ). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.55-8.35(m,3 H),7.95-7.88(m,2 H),7.82-7.74(m,2 H),6.84-6.80(m,1 H),6.80-6.77(m,1 H),4.30-4.22(m,1 H),4.11-4.02(m,1 H),3.91-3.84(m,1 H),3.71-3.62(m,4 H),3.28-3.21(m,2 H),3.12-3.01(m,1 H),3.01-2.93(m,4 H),2.66-2.58(m,1 H),2.24-2.16(m,1 H),1.27-1.15(m,2 H). 19 F NMR(376MHz,DMSO-d6)δ-97.642(s,2 F).

[0310] Example 117 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[trans-difluoro-[2-(hydroxymethyl)cyclopropyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0311] Step 1: 2-(2,6-dichloro-4-pyridyl)-2,2-difluoro-acetaldehyde (117a) [ka] To a solution of 2-(2,6-dichloro-4-pyridyl)-2,2-difluoro-ethanol (2.5 g, 10.96 mmol) in DCM (20 mL) was added Dess-Martin periodinane (5.12 g, 12.06 mmol) under N2 at 0 °C. The mixture was stirred at 25 °C for 2 h. After the starting material was consumed, the mixture was poured into water (100 mL) at 0 °C and extracted with EA (150 mL x 3). The organic layer was washed with aqueous NH4Cl (100 mL x 3) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the crude product. The residue was purified by column chromatography on silica gel (EA in PE = 1:100 to 2:1) to give compound 117a (1.8 g, 72.64% yield) as a colorless oil. MS found: 243.7 (MH+18 + ).

[0312] Step 2: Ethyl (E)-4-(2,6-dichloro-4-pyridyl)-4,4-difluoro-but-2-enoate (117b) [ka] To a solution of compound 117a (1.8 g, 7.96 mmol) in THF (15 mL) was added (carbethoxymethylene)triphenylphosphorane (5.55 g, 15.93 mmol) under N2, and the reaction mixture was stirred at 70 °C for 5 h. After the starting material was consumed, the mixture was poured into water (100 mL). Then, it was extracted with EA (150 mL x 3 times). The combined organic layer was washed with aqueous NH4Cl (100 mL x 3) and brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product. The crude product was purified by column chromatography on silica gel (EA in PE = 1:100 to 1:5) to give compound 117b (1.5 g, 60.34% yield) as a colorless oil. MS found: 295.8 (MH + ).

[0313] Step 3: trans-Ethyl 2-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclopropanecarboxylate (Compound 117c) [ka] To a solution of sodium hydride (303.95 mg, 7.6 mmol) in THF (15 mL) and DMSO (15 mL) was added trimethylsulfoxonium iodide (2.23 g, 10.13 mmol) under N2 at 0 °C and compound 117b (1.5 g, 5.07 mmol). The reaction was stirred at 15 °C for 1 h. After the starting material was consumed, the mixture was poured into water (100 mL) at 0 °C. The resulting mixture was extracted with EA (150 mL × 3). The combined organic layers were washed with aqueous NH4Cl (100 mL × 3) and brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product. The crude product was purified by column chromatography on silica gel (EA:PE = 1:10 to 1:1) to give 117c (900 mg, 57.29% yield) as a colorless oil. MS measured value: 310.2 (MH + ).

[0314] Step 4: [trans-2-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclopropyl]methanol (117d) [ka] To a solution of compound 117d (600.0 mg, 1.93 mmol) in ethanol (4 mL) was added sodium borohydride (146.39 mg, 3.87 mmol) slowly at 0° C. The mixture was stirred at 45° C. for 2 h. After the starting material was consumed, the mixture was poured into water (100 mL) at 0° C. and extracted with EA (100 mL×3 times). The combined organic layers were washed with aqueous NH4Cl (100 mL×3) and brine (100 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product, which was purified by preparative HPLC to give 117d (400 mg, 77.12% yield) as a colorless oil. MS found: 267.8 (MH + ).

[0315] Step 4: tert-Butyl N-[(3R)-1-[4-[4-[6-chloro-4-[trans-difluoro-[2-(hydroxymethyl)cyclopropyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (117e) [ka] To a solution of compound 117d (100.0 mg, 0.370 mmol) in DMSO (0.5 mL) was added intermediate D (158.35 mg, 0.370 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.750 mmol) in one portion. The reaction was stirred at 100° C. for 16 h. After completion, the mixture was diluted with water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give 117e (205 mg, 83.76% yield) as a yellow oil. MS found: 656.14 (MH+ ).

[0316] Step 5: (4R)-4-amino-1-[4-[4-[6-chloro-4-[trans-difluoro-[2-(hydroxymethyl)cyclopropyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] To a solution of 117e (190.0 mg, 0.290 mmol) in DCM (2 mL) was added hydrochloric acid in methanol (3.62 mL, 14.48 mmol) in one portion. The reaction was stirred at 25° C. for 1 h. Upon completion, the mixture was concentrated in vacuo to give a crude residue which was purified by preparative HPLC to give Example 117 (98 mg, 59.67% yield) as a white solid. MS found: 556.1 (MH + ). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.56-8.46(m,3 H),7.94-7.89(m,2 H),7.80(s,2 H),6.98-6.94(m,1 H),6.80(s,1 H),4.78-4.68(m,1 H),4.29-4.21(m,1 H),4.09-4.02(m,1 H),3.92-3.86(m,1 H),3.71-3.62(m,4 H),3.47-3.40(m,1 H),3.24-3.17(m,1 H),3.10-3.01(m,1 H),3.00-2.91(m,4 H),2.67-2.60(m,1 H),1.63-1.49(m,1 H),1.36-1.26(m,1 H),0.86-0.78(m,1 H). 19 F NMR(376MHz,DMSO-d6)δ-103.881(s,2 F).

[0317] Example 118 (4R)-4-Amino-1-[4-[4-[4-[[trans-4-(aminomethyl)cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0318] Step 1: trans-Methyl 4-(hydroxymethyl)cyclohexanecarboxylate (118a) [ka] To a solution of trans-4-methoxycarbonylcyclohexanecarboxylic acid (50.0 g, 268.51 mmol) in THF (150 mL) was added BH3·Me2S (53.7 mL, 537.03 mmol) dropwise at 0-10 °C for 1 h. The mixture was stirred at 25 °C for 12 h. After completion, the reaction was quenched by adding methanol (100 mL) dropwise at 0 °C. The mixture was concentrated in vacuo at 40 °C to give a crude residue, which was purified by silica gel chromatography (EA:PE=0-50%) to give compound 118a (28 g, 60.55% yield) as a colorless oil.

[0319] Step 2: trans-Methyl 4-formylcyclohexanecarboxylate (118b) [ka] To a solution of oxalyl chloride (30.95 g, 243.87 mmol) in DCM (100 mL) was added dimethylsulfoxide (25.4 g, 325.17 mmol) at -60 °C and stirred under N2 at -60 °C for 0.5 h. A solution of compound 118b (28.0 g, 162.58 mmol) in DCM (100 mL) was added to the reaction at -60 °C and stirring was continued for another 1 h. Then DIPEA (84.05 g, 650.33 mmol) was added at -60 °C. The reaction was warmed to 0 °C and stirring was continued for 2 h. After completion, the reaction mixture was diluted with EA (600 mL) and washed with aqueous CaCl2 (100 mL x 3) and brine (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude residue, which was purified by flash chromatography on silica gel (EA:PE=3-50%) to give compound 118b (24 g, 86.73% yield) as a pale yellow oil.

[0320] Step 3: trans-Methyl 4-[(2,6-dichloro-4-pyridyl)-hydroxymethyl]cyclohexanecarboxylate (118c) [ka] To a solution of 2,6-dichloro-4-iodo-pyridine (42.48 g, 155 mmol) in THF (50 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex in THF (130.16 mL, 169.2 mmol) under N2 at -40°C. The mixture was stirred at 25°C for 1 h. Then the reaction mixture was added dropwise to a solution of compound 118b (24.0 g, 141 mmol) in THF (100 mL) at -40°C. Once added, the mixture was stirred at 25°C for 3 h. After completion, the reaction mixture was poured into aq. NH4Cl (200 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue, which was purified by flash chromatography on silica gel (EA:PE = 0-30%) to give compound 118c (33 g, 73.55% yield) as a white solid. MS Found (ESI + ) [(M+Cl) + ]:317.8.

[0321] Step 4: trans-Methyl 4-(2,6-dichloropyridine-4-carbonyl)cyclohexanecarboxylate (118d) [ka] To a solution of compound 118c (33.0 g, 103.71 mmol) in THF (150 mL) was added Dess-Martin periodinane (48.39 g, 114 mmol) slowly at 0° C. under N2. The reaction was stirred at 25° C. for 3 h. After completion, the mixture was diluted with EA (500 mL) and poured into aqueous K2CO3 (200 mL). The mixture was kept stirring at room temperature for 0.5 h. The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude compound 118d (30 g, 91.5% yield) as a white solid, which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:315.8.

[0322] Step 5: trans-Methyl 4-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclohexanecarboxylate (118e) [ka] To a solution of compound 118d (29.5 g, 93.3 mmol) in DCM (20 mL) was added DAST (135.35 g, 839.71 mmol) and the reaction was stirred at 45° C. for 12 h. After completion, the reaction mixture was poured into ice water and extracted with EA (200 mL×3). The combined organic layers were washed with aqueous K2CO3 solution (100 mL×2) and brine (100 mL×2) dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude residue. The residue was recrystallized with methanol (150 mL) to give compound 118e (25.6 g, 81.13% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:337.8.

[0323] Step 6: trans-[4-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclohexyl]methanol (118f) [ka] To a solution of 118e (250.0 mg, 0.740 mmol) in THF (5 mL) was added LiAlH4 (42.14 mg, 1.11 mmol) at -10 °C and the reaction was stirred at -10 °C for 2 h. Upon completion, the mixture was warmed to 0 °C and quenched by adding 0.1 mL of H2O followed by 0.15 mL of 15% aqueous solution. After stirring for 0.5 h, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC to give 118f (210 mg, 91.59% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:310.1.

[0324] Step 7: tert-Butyl N-[(3R)-1-[4-[4-[4-[[[trans-4-(aminomethyl)cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxopyrrolidin-3-yl]carbamate (compound 118g) [ka] To a solution of compound 118f (380.0 mg, 0.540 mmol) in DCM (5 mL) was added trifluoromethanesulfonic anhydride (0.18 mL, 1.09 mmol) at -20°C and the reaction was stirred at -20°C for 0.5 h. To the mixture was added ammonia gas in THF (92.68 mg, 5.44 mmol) and stirred at 45°C for 1 h. After completion, the mixture was quenched by slowly adding saturated aqueous ammonium chloride solution (20 mL). The resulting mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 118g (120 mg, 0.170 mmol, 31.62% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:697.2.

[0325] Step 8: (4R)-4-amino-1-[4-[4-[4-[[trans-4-(aminomethyl)cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] To a solution of compound 118 (40.0 mg, 0.060 mmol) in DCM (1 mL) was added TFA (65.4 mg, 0.570 mmol) at 25° C. The reaction was stirred at 25° C. for 15 min. After completion, the mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give Example 118 (24.7 mg, 59.1% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:597.2. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.74-8.26(m,3 H),7.95-7.91(m,2 H),7.85-7.75(m,2 H),6.86-6.76(m,1 H),6.76-6.68(m,1 H),4.35-4.21(m,1 H),4.13-4.00(m,1 H),3.97-3.82(m,1 H),3.75-3.60(m,4 H),3.15-2.88(m,5 H),2.71-2.60(m,3 H),2.22-2.04(m,1 H),1.90-1.74(m,2 H),1.73-1.61(m,2 H),1.56-1.42(m,1 H),1.18-1.01(m,2 H),0.99-0.83(m,2 H). 19 F NMR(376MHz,DMSO-d6)δ-103.881(s,2 F).

[0326] Example 119 (4R)-4-Amino-1-[4-[4-[6-chloro-4-[trans-difluoro-(3-hydroxycyclobutyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] The title compound was prepared according to the following procedure.

[0327] Step 1: trans-(3-benzyloxycyclobutyl)methanol (compound 119a) [ka] To a solution of 3-benzyloxycyclobutanecarboxylic acid (1.2 g, 5.82 mmol) in THF (5 mL) was added borane-methylsulfide complex (1.16 mL, 11.64 mmol) slowly. The reaction was stirred at 20° C. for 2 h. After completion, the reaction was quenched with methanol (5 mL) and diluted with aqueous NH4Cl (20 mL). The aqueous phase was extracted with EA (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give compound 119a (1.05 g, 93.87% yield) as a colorless oil.

[0328] Step 2: trans-3-benzyloxycyclobutanecarbaldehyde (compound 119b) [ka] To a solution of DMSO (0.85 mL, 11.96 mmol) in DCM (20 mL) was added 119a (1000 mg, 5.2 mmol) dropwise at -78 °C. After stirring for 10 min, oxalyl chloride (1056 mg, 8.32 mmol) in DCM (1 mL) was added and the reaction was stirred at -78 °C for 0.5 h. Triethylamine (2.9 mL, 20.81 mmol) was then added and the mixture was stirred at -78 °C for 3 h. After completion, the reaction was diluted with water (30 mL) and then extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude residue, which was purified by column chromatography on silica gel (EA:PE=1:100 to 1:10) to give 119b (980 mg, 99.04% yield) as a pale yellow oil.

[0329] Step 3: trans-(3-benzyloxycyclobutyl)-(2,6-dichloro-4-pyridyl)methanol (compound 119c) [ka] To a solution of 2,6-dichloro-4-iodopyridine (1.55 g, 5.67 mmol) in THF (10 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex in THF (4.76 mL, 6.18 mmol) dropwise at -78 °C. After the addition, the reaction was warmed to 25 °C and stirred for 1 h. Then, compound 119b (980.0 mg, 5.15 mmol) in THF (5 mL) was added at 0 °C. The reaction was stirred at 25 °C for 1 h. The reaction was quenched with aqueous NH4Cl (50 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 119c (760 mg, 43.62% yield) as a yellow oil. MS measured value: 338.1 (MH + ).

[0330] Step 4: trans-(3-benzyloxycyclobutyl)-(2,6-dichloro-4-pyridyl)methanone (compound 119d) [ka] To a solution of compound 119c (660 mg, 1.95 mmol) in DCM (5 mL) was added Dess-Martin periodinane (993 mg, 2.34 mmol) in one portion and the reaction was stirred at 25° C. for 2 h. After completion, the reaction was poured into aqueous K2CO3 solution (100 mL) and stirred for 30 min. The aqueous phase was extracted with EA (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 119d (650 mg, 99.08% yield) as a colorless oil. MS found: 336.1 (MH + ).

[0331] Step 5: trans-4-[(3-benzyloxycyclobutyl)-difluoro-methyl]-2,6-dichloro-pyridine (compound 119e) [ka] To a solution of 119d (600 mg, 1.78 mmol) in DCM (5 mL), DAST (2.88 g, 17.85 mmol) was added in one portion and the reaction was stirred at 25 °C for 16 h. After completion, the reaction mixture was poured into ice water and the pH was adjusted to 7-8 with aqueous NaHCO3. The aqueous phase was extracted with EA (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by flash column on silica gel (EA:PE=1:100-1:10) to give 119e (590 mg, 92.29% yield) as a yellow solid. MS found: 358.1 (MH + ).

[0332] Step 6: trans-3-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclobutanol (compound 119f) [ka] To a solution of compound 119e (550 mg, 1.54 mmol) in DCM (5 mL) was added boron trichloride (4.61 mL, 4.61 mmol) and the reaction was stirred at -78 °C for 1 h. After completion, the mixture was quenched with water (20 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (EA:PE = 1:100-1:10) to give 119 f (340 mg, 82.6% yield) as a yellow oil. MS found: 267.9 (MH + ).

[0333] Step 7: tert-Butyl N-[(3R)-1-[4-[4-[6-chloro-4-[trans-difluoro-(3-hydroxycyclobutyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 119g) [ka] To a solution of compound 119f (40 mg, 0.150 mmol) in DMSO (1 mL) was added intermediate D (63.34 mg, 0.150 mmol), N,N-diisopropylethylamine (0.05 mL, 0.300 mmol) in one portion. The reaction was stirred at 100° C. for 16 h. Upon completion, the reaction was poured into water (10 mL) and the aqueous phase was extracted with EA (10 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 119g (60 mg, 61.29% yield) as a white solid. MS found: 656.1 (MH + ).

[0334] Step 7: (4R)-4-amino-1-[4-[4-[6-chloro-4-[trans-difluoro-(3-hydroxycyclobutyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] To a solution of compound 119g (60 mg, 0.090 mmol) in DCM (0.5 mL) was added TFA (0.5 mL, 6.49 mmol) in one portion. The reaction was stirred at 25° C. for 1 h. Upon completion, the reaction was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give Example 119 (32 mg, 57.63% yield) as a white solid. MS found: 556.1 (MH + ). 1H NMR(400MHz,DMSO-d6)δ ppm 8.48-8.33(m,3 H),7.91(br d,J=8.8Hz,2 H),7.79(br d,J=8.6Hz,2 H),6.84-6.78(m,1 H),6.76-6.68(m,1 H),5.25-5.15(m,1 H),4.32-4.21(m,1 H),4.19-4.10(m,1 H),4.09-4.00(m,1 H),3.88(br s,1 H),3.65(br s,4 H),3.11-3.03(m,1 H),2.96(br s,4 H),2.64(br s,1 H),2.23(br d,J=4.9Hz,2 H),2.02-1.88(m,2 H),1.32-1.14(m,1 H). 19 F NMR(376MHz,DMSO-d6)δ-103.606(s,2 F).

[0335] Example 120 trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka] The title compound was prepared according to the following procedure.

[0336] Step 1: trans-Methyl 4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylate (compound 120a) [ka] To a solution of compound intermediate D (50 mg, 0.118 mmol) and compound 118d (60 mg, 0.177 mmol) in DMSO (1 mL) was added K2CO3 (48 mg, 0.353 mmol). The mixture was stirred at 90 °C for 12 h. After completion, the mixture was diluted with EA (50 mL) and water (30 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give crude compound 120a (60 mg, 70.73% yield) as a yellow solid, which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:726.4.

[0337] Step 2: trans-4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylic acid (compound 120b) [ka] To a solution of compound 120a (2.4 g, 3.3 mmol) in MeCN (30 mL) and water (10 mL) was added LiBr (2.87 g, 33.06 mmol) and TEA (2.3 mL, 16.52 mmol). The mixture was stirred at 50 °C for 5 h. After completion, the mixture was diluted with EA (200 ml) and adjusted to pH = 5 with 1 M HCl solution. The organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel flash column (EA:PE = 1:5 to 3:1) to give compound 120b (640 mg, 27.19% yield) as a yellow solid. MS observed (ESI + )[(M+H) + ]:712.2.

[0338] Step 3: trans-tert-butyl N-[(3R)-1-[4-[4-[4-[(4-carbamoylcyclohexyl)-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate (compound 120c) [ka] A mixture of ammonium chloride (20 mg, 0.374 mmol), compound 120b (100 mg, 0.140 mmol), HATU (106.71 mg, 0.281 mmol) and DIPEA (54.38 mg, 73.49 μL, 0.421 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. After completion, the mixture was diluted with EA and washed with water (100 mL) and brine (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give crude product 120c (50 mg, 50.07%) as a white solid, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:710.9.

[0339] Step 4: trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka] Compound 120c (90 mg, 0.127 mmol) and TFA (1 mL) were dissolved in DCM (5 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the reaction was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give Example 120 (50.8 mg, 62.41% yield) as a white solid. MS found: 611.1 (MH + ). 1H NMR(400MHz,METHANOL-d6)δ ppm 7.88-7.98(m,2 H),7.70-7.79(m,2 H),6.75-6.80(m,1 H),6.69-6.72(m,1 H),3.90-4.07(m,1 H),3.59-3.78(m,5 H),3.46-3.59(m,1 H),2.88-3.03(m,4 H),2.74-2.89(m,1 H),2.26-2.40(m,1 H),2.10-2.25(m,1 H),1.92-2.07(m,2 H),1.70-1.81(m,2 H),1.58-1.70(m,2 H),1.18-1.37(m,4 H), 0.96-1.18(m,3 H). 19 F NMR(376MHz,METHANOL-d4)δ ppm-107.25(br d,J=14.99Hz,2 F).

[0340] Biological Examples Example 121: Median inhibitory concentration (IC) for UDP-2,3-diacylglucosamine hydrolase (LpxH) 50 ) The inhibitory potency of molecules against UDP-2,3-diacylglucosamine hydrolase (LpxH) was determined using the UMP / CMP-Glo™ glycosyltransferase assay kit. LpxH hydrolyzes the pyrophosphate bond of UDP-2,3-diacylglucosamine (UDP-DAG) to generate 2,3-diacylglucosamine 1-phosphate (Lipid X) and UMP. The assay kit could quantitate UMP production by converting UMP to ATP and generating light in a luciferase reaction. The effect of compounds on LpxH activity is detected by measuring light using a luminometer (Envision).

[0341] [Table 1]

[0342] Example 122: Minimum inhibitory concentration protocol (MIC) assay: The in vitro potency of compounds to inhibit the growth of E. coli (ATCC 25922) and K. pneumoniae (ATCC 43816) was evaluated by MIC (minimum inhibitory concentration) assay. Samples were prepared from 10 mM DMSO stock solutions. After serial 2-fold dilutions with DMSO on a master plate (Greiner, Cat. No.: 651201), 180 μL of sterile distilled water was added to each 20 μL aliquot of sample. 10 μL of diluted compound was then transferred to a new assay plate (Costar, 3599).

[0343] Growth medium Cation-Adjusted Mueller Hinton Broth (CAMHB) was prepared by adding 20 mg / L CaCl2 and 20 mg / L MgCl2 to MHB medium (Jianglai Company, sterilized).

[0344] Vials of each test organism were kept frozen in the vapor phase of a liquid nitrogen freezer. The bacteria E. coli ATCC 25922 (KWIKSTIK, 0335K) and K. pneumoniae ATCC 43816 were removed from the liquid nitrogen freezer, then thawed at room temperature and diluted with CAMHB medium to achieve a final inoculum of 5 x 105 CFU / mL. 90 μL of CAMHB containing the bacteria was dispensed into the assay plate and pipetted five times.

[0345] The assay plates were then incubated for 20 hours in ambient air at 35° C. After incubation, the MIC (μg / mL), the lowest concentration of drug that inhibited visible growth of the microorganism, was read and recorded microscopically.

[0346] [Table 2-1] [Table 2-2]

Claims

1. A compound of formula (I), 【Chemistry 1】 (In the formula, R １ is unsubstituted or amino C １－６ 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl substituted by alkyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, Amino C １－６ Alkyl or C １－６ Alkylamino C １－６ 2-oxo-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepinyl substituted by alkyl, Hydroxy and Hydroxy C １－６ 2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl substituted twice with substituents independently selected from alkyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, Hydroxy and Hydroxy C １－６ 2-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d]oxazolyl substituted three times by substituents independently selected from alkyl; 3-oxo-2,6,9-triazaspiro[4.5]decanyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 3-oxo-2,8-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl, oxoazetidinyl substituted by amino, ((Amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, (C １－６ alkyl) ２ Amino C １－６ Alkyl, (dihydroxypyrrolidinyl)C １－６ Alkyl, (pyrrolidinylamino)C １－６ Alkyl, 2,6-diazaspiro[3.3]heptanyl C １－６ Alkyl, dihydroxy (C １－６ Alkoxy)tetrahydrofuranyl, aminoazetidinyl C １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkyl, C １－６ Alkylamino C １－６ Alkyl, C １－６ Alkylcarbonylamino C １－６ Alkyl, hydroxy C １－６ Alkyl and piperazinyl C １－６ oxooxazolidinyl substituted once or twice with substituents independently selected from alkyl, or (((C １－６ alkyl) ２ Amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, ((amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, ((amino C ３－７ Cycloalkyl)azetidinyl)C １－６ Alkyl, ((C １－６ Alkylamino)azetidinyl)C １－６ Alkyl, (aminoazetidinyl)C １－６ Alkyl, (amino C １－６ alkyl)azetidinyl, (azetidinyl C １－６ alkylamino)C １－６ Alkyl, (C １－６ alkylpiperazinyl)C １－６ Alkyl, (hydroxy C １－６ alkyl)piperazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, amino(hydroxy)piperidinyl, amino, amino(hydroxy)pyrrolidinyl, aminoazetidinyl, amino C １－６ Alkyl, (amino C １－６ alkyl)amino, aminopyrrolidinyl, azetidinylamino, C １－６ Alkyl, C １－６ Alkylamino, dihydroxypyrrolidinyl, (hydroxy C １－６ Alkyl)amino, piperazinyl, piperazinyl C １－６ oxopyrrolidinyl substituted once, twice or three times with substituents independently selected from alkyl, piperidinylamino and pyrrolidinylamino; R ２ is H or cyano, R ３ is benzyl, C ３－７ cycloalkylsulfonyl, Cyano C ３－７ cycloalkyl, Phenoxy, Phenyl C ３－７ cycloalkyl, tetrahydropyranylsulfonyl, or Halogen, (amino C １－６ alkyl) C ３ -7 cycloalkyl, (hydroxy C １－６ alkyl) C ３－７ Cycloalkyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dioxanyl, 3,6-dihydro-2H-pyranyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 8-oxabicyclo[3.2.1]octanyl, azetidinyl, C １－６ Alkylhalopyrazinyl, C １－６ Alkylmorpholinyl, C １－６ Alkylpyrazinyl, carbamoyl C ３－７ Cycloalkyl, hydroxy C ３－７ C substituted twice or three times with substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, and pyridinyl; １－６ is alkyl, R ４ is a halogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Alkoxy or C ２－６ is alkynyl, Q １ is N or CR ａ and R ａ is H or a halogen, Q ２ is N or CR ｂ and R ｂ is H or a halogen, Q ３ is N or CH, Q ４ is N or CH, Q ５ is N or CH, Y is O or NH. or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia), 【Chemistry 2】 (In the formula, R １ is unsubstituted or amino C １－６ 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl substituted by alkyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, Amino C １－６ Alkyl or C １－６ Alkylamino C １－６ 2-oxo-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepinyl substituted by alkyl, Hydroxy and Hydroxy C １－６ 2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl substituted twice with substituents independently selected from alkyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, Hydroxy and Hydroxy C １－６ 2-oxo-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d]oxazolyl substituted three times by substituents independently selected from alkyl; 3-oxo-2,6,9-triazaspiro[4.5]decanyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 3-oxo-2,8-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, 7-oxo-2,6-diazaspiro[3.4]octanyl, oxoazetidinyl substituted by amino, ((Amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, (C １－６ alkyl) ２ Amino C １－６ Alkyl, (dihydroxypyrrolidinyl)C １－６ Alkyl, (pyrrolidinylamino)C １－６ Alkyl, 2,6-diazaspiro[3.3]heptanyl C １－６ Alkyl, dihydroxy (C １－６ Alkoxy)tetrahydrofuranyl, aminoazetidinyl C １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkyl, C １－６ Alkylamino C １－６ Alkyl, C １－６ Alkylcarbonylamino C １－６ Alkyl, hydroxy C １－６ Alkyl and piperazinyl C １－６ oxooxazolidinyl substituted once or twice with substituents independently selected from alkyl, or (((C １－６ alkyl) ２ Amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, ((amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, ((amino C ３－７ Cycloalkyl)azetidinyl)C １－６ Alkyl, ((C １－６ Alkylamino)azetidinyl)C １－６ Alkyl, (aminoazetidinyl)C １－６ Alkyl, (amino C １－６ alkyl)azetidinyl, (azetidinyl C １－６ alkylamino)C １－６ Alkyl, (C １－６ alkylpiperazinyl)C １－６ Alkyl, (hydroxy C １－６ alkyl)piperazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,6-diazaspiro[3.3]heptanyl, amino, amino(hydroxy)piperidinyl, amino(hydroxy)pyrrolidinyl, aminoazetidinyl, amino C １－６ Alkyl, (amino C １－６ alkyl)amino, aminopyrrolidinyl, azetidinylamino, C １－６ Alkyl, C １－６ Alkylamino, dihydroxypyrrolidinyl, (hydroxy C １－６ Alkyl)amino, piperazinyl, piperazinyl C １－６ oxopyrrolidinyl substituted once, twice or three times with substituents independently selected from alkyl, piperidinylamino and pyrrolidinylamino; R ２ is H or cyano, R ３ is benzyl, C ３－７ cycloalkylsulfonyl, Cyano C ３－７ cycloalkyl, Phenoxy, Phenyl C ３－７ cycloalkyl, tetrahydropyranylsulfonyl, or Halogen, (amino C １－６ alkyl) C ３ -7 cycloalkyl, (hydroxy C １－６ alkyl) C ３－７ Cycloalkyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dioxanyl, 3,6-dihydro-2H-pyranyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 8-oxabicyclo[3.2.1]octanyl, azetidinyl, C １－６ Alkylhalopyrazinyl, C １－６ Alkylmorpholinyl, C １－６ Alkylpyrazinyl, carbamoyl C ３－７ Cycloalkyl, hydroxy C ３－７ C substituted twice or three times with substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, and pyridinyl; １－６ is alkyl, R ４ is a halogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Alkoxy or C ２－６ is alkynyl, Q １ is N or CR ａ and R ａ is H or a halogen, Q ２ is CR ｂ and R ｂ is H or a halogen, Q ３ is N, Q ４ is N or CH, Q ５ is N or CH, Y is O. or a pharmaceutically acceptable salt thereof.

3. R １ 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, Hydroxy and Hydroxy C １－６ 2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl substituted twice with substituents independently selected from alkyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, ((Amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, (C １－６ alkyl) ２ Amino C １－６ Alkyl, dihydroxy (C １－６ Alkoxy)tetrahydrofuranyl, amino C １－６ Alkyl, C １－６ Alkyl, C １－６ Alkylamino C １－６ Alkyl, hydroxy C １－６ Alkyl and piperazinyl C １－６ oxooxazolidinyl substituted once or twice with substituents independently selected from alkyl, or ((Amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, ((amino C ３－７ Cycloalkyl)azetidinyl)C １－６ Alkyl, (aminoazetidinyl)C １－６ Alkyl, (C １－６ alkylpiperazinyl)C １－６ Alkyl, (hydroxy C １－６ (alkyl)piperazinyl, amino, amino(hydroxy)piperidinyl, amino(hydroxy)pyrrolidinyl, amino C １－６ Alkyl, aminopyrrolidinyl, C １－６ Alkylamino, dihydroxypyrrolidinyl, (hydroxy C １－６ Alkyl)amino, piperazinyl, piperazinyl C １－６ oxopyrrolidinyl substituted by substituents selected from alkyl and piperidinylamino; 3. The compound of claim 1 or 2.

4. R １ 2-oxo-1-oxa-3,8-diazaspiro[4.5]decanyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridinyl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridinyl, 2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazolyl substituted twice with substituents independently selected from hydroxy and hydroxymethyl; 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazolyl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepinyl, 3-oxo-2,6-diazaspiro[4.5]decanyl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrolyl, 6-oxo-5-oxa-2,7-diazaspiro[3.4]octanyl, oxooxazolidinyl substituted once or twice by substituents independently selected from (3-(aminomethyl)azetidin-1-yl)methyl, (dimethylamino)methyl, 3,4-dihydroxy-5-methoxy-tetrahydrofuran-2-yl, aminomethyl, aminomethyl, hydroxymethyl, methyl, (methylamino)methyl and piperazin-1-ylmethyl, or 4. The compound of claim 3, which is an oxopyrrolidinyl substituted by a substituent selected from (3-(1-aminocyclopropyl)azetidin-1-yl)methyl, (3-(aminomethyl)azetidin-1-yl)methyl, (3-aminoazetidin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl, 3-(hydroxymethyl)piperazin-1-yl, 3,4-dihydroxypyrrolidin-1-yl, 3-amino-4-hydroxypiperidin-1-yl, 3-amino-4-hydroxypyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 4-piperidinylamino, amino, aminomethyl, (hydroxyethyl)amino, methylamino, piperazin-1-yl, and piperazin-1-ylmethyl.

5. R １ 2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-3-yl, 2-oxo-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridin-1-yl, 2-oxo-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-3-yl, 2-oxo-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepine- 3-yl, 3-oxo-2,6-diazaspiro[4.5]decan-2-yl, 4-((3-(1-aminocyclopropyl)azetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-((3-aminoazetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-((4-methylpiperazin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-(2-hydroxyethylamino)-2-oxo-pyrrolidin-1-yl, 4-(3-(aminomethyl)azetidin-1-yl )methyl)-2-oxo-pyrrolidin-1-yl, 4-(3-(hydroxymethyl)piperazin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3,4-dihydroxypyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino-4-hydroxypiperidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino-4-hydroxy-pyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino-4-hydroxy-pyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-aminopyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl 4-(4-piperidinylamino)-2-oxo-pyrrolidin-1-yl, 4-(methylamino)-2-oxo-pyrrolidin-1-yl, 4-(piperazin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(piperazin-1-ylmethyl)-2-oxo-pyrrolidin-1-yl, 4-amino-2-oxo-pyrrolidin-1-yl, 4-aminomethyl-2-oxo-oxazolidin-3-yl, 4-aminomethyl-2-oxo-pyrrolidin-1-yl, 4-methyl-2-oxo-5-(3,4-dihydroxy-5-methoxy-tetrahydrofuran-2-yl)oxazolidin-3-yl, 5-((3-(aminomethyl)azetidin-1-yl)methyl)-2-oxo-oxazolidin-3-yl, 5-((dimethylamino)methyl)-2-oxo-oxazolidin-3-yl, 5-(2-aminoethyl)-2-oxo-oxazolidin-3-yl, 5-(methylaminomethyl)-2-oxo-oxazolidin-3-yl, 5-(piperazin-1-ylmethyl)-2-oxo-oxazolidin 5. The compound according to claim 4, which is 5-aminomethyl-2-oxo-oxazolidin-3-yl, 5-hydroxymethyl-2-oxo-oxazolidin-3-yl, 5-oxo-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-4-yl, 6-hydroxy-5-hydroxymethyl-2-oxo-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazol-3-yl, or 6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-7-yl.

6. R １ However, ((Amino C １－６ Alkyl)azetidinyl)C １－６ Alkyl, ((amino C ３－７ Cycloalkyl)azetidinyl)C １－６ Alkyl, (aminoazetidinyl)C １－６ Alkyl, (C １－６ alkylpiperazinyl)C １－６ Alkyl, (hydroxy C １－６ (alkyl)piperazinyl, amino, amino(hydroxy)piperidinyl, amino(hydroxy)pyrrolidinyl, amino C １－６ Alkyl, aminopyrrolidinyl, C １－６ Alkylamino, dihydroxypyrrolidinyl, (hydroxy C １－６ Alkyl)amino, piperazinyl, piperazinyl C １－６ 4. The compound of claim 3, which is an oxopyrrolidinyl substituted with a substituent selected from alkyl and piperidinylamino.

7. R １ 4-((3-(1-aminocyclopropyl)azetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-((3-aminoazetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-((4-methylpiperazin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-(2-hydroxyethylamino)-2-oxo-pyrrolidin-1-yl, 4-(3-(aminomethyl)azetidin-1-yl)methyl)-2-oxo-pyrrolidin-1-yl, 4-(3-(hydroxymethyl)piperazin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3,4-dihydroxypyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino 10. The compound of claim 6, wherein the compound is 4-(3-amino-4-hydroxy-pyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-amino-4-hydroxy-pyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(3-aminopyrrolidin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(4-piperidinylamino)-2-oxo-pyrrolidin-1-yl, 4-(methylamino)-2-oxo-pyrrolidin-1-yl, 4-(piperazin-1-yl)-2-oxo-pyrrolidin-1-yl, 4-(piperazin-1-ylmethyl)-2-oxo-pyrrolidin-1-yl, 4-amino-2-oxo-pyrrolidin-1-yl, or 4-aminomethyl-2-oxo-pyrrolidin-1-yl.

8. R ３ Benzyl, phenyl C ３－７ cycloalkyl, or halogen, (hydroxy C １－６ alkyl) C ３ -7 cycloalkyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dioxanyl, 3,6-dihydro-2H-pyranyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 8-oxabicyclo[3.2.1]octanyl, C １－６ Alkylhalopyrazinyl, C １－６ Alkylpyrazinyl, carbamoyl C ３－７ Cycloalkyl, hydroxy C ３－７ C substituted three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, pyrazinyl, pyridinyl, tetrahydropyranyl, and phenyl; １－６ 3. The compound of claim 1 or 2, wherein the compound is alkyl.

9. R ３ However, halogen, (hydroxy C １－６ alkyl) C ３－７ Cycloalkyl, 1,4-dioxanyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, C １－６ Alkylhalopyrazinyl, C １－６ Alkylpyrazinyl, hydroxy C ３－７ C substituted three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, phenyl, pyridinyl, and tetrahydropyranyl １－６ The compound of claim 8, wherein the compound is alkyl.

10. R ３ is difluoro(1,4-dioxan-2-yl)methyl, difluoro(2-(hydroxymethyl)cyclopropyl)methyl, difluoro(2-pyridinyl)methyl, difluoro(3-hydroxycyclobutyl)methyl, difluoro(3-oxabicyclo[3.1.0]hexan-6-yl)methyl, difluoro(5-chloro-6-methyl-pyrazin-2-yl)methyl, difluoro(6-methylpyrazin-2-yl)methyl, difluoro(morpholin-2-yl)methyl, difluoro(oxetan-3-yl)methyl, difluoro(phenyl)methyl, difluoro(tetrahydropyran-4-yl)methyl or difluoro[3-azabicyclo[3.1.0]hexan-1-yl]methyl.

11. R ２ 3. The compound of claim 1 or 2, wherein is H.

12. R ４ is halogen or C １－６ 3. The compound of claim 1 or 2, wherein the compound is alkyl.

13. R ４ The compound of claim 12, wherein is chloro or methyl.

14. Q １ is CR ａ and R ａ 3. The compound of claim 1 or 2, wherein is H or a halogen.

15. Q １ is CR ａ and R ａ 15. The compound of claim 14, wherein is H or fluoro.

16. Q ２ 3. The compound of claim 1 or 2, wherein is CH.

17. R １ but amino or amino C １－６ oxopyrrolidinyl substituted by alkyl; R ２ is H, R ３ However, halogen, (hydroxy C １－６ alkyl) C ３－７ Cycloalkyl, 1,4-dioxanyl, 3-azabicyclo[3.1.0]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, C １－６ Alkylhalopyrazinyl, C １－６ Alkylpyrazinyl, hydroxy C ３－７ C substituted three times by substituents independently selected from cycloalkyl, morpholinyl, oxetanyl, phenyl, pyridinyl, and tetrahydropyranyl １－６ is alkyl, R ４ is halogen or C １－６ is alkyl, Q １ But, CR ａ and R ａ is H or a halogen; Q ２ is CH, Q ３ is N, Q ４ is N or CH; Q ５ is N or CH; Y is O; A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

18. R １ is oxopyrrolidinyl substituted by amino or aminomethyl, R ２ is H, R ３ is difluoro(1,4-dioxan-2-yl)methyl, difluoro(2-(hydroxymethyl)cyclopropyl)methyl, difluoro(2-pyridinyl)methyl, difluoro(3-hydroxycyclobutyl)methyl, difluoro(3-oxabicyclo[3.1.0]hexan-6-yl)methyl, difluoro(5-chloro-6-methyl-pyrazin-2-yl)methyl, difluoro(6-methylpyrazin-2-yl)methyl, difluoro(morpholin-2-yl)methyl, difluoro(oxetan-3-yl)methyl, difluoro(phenyl)methyl, difluoro(tetrahydropyran-4-yl)methyl or difluoro[3-azabicyclo[3.1.0]hexan-1-yl]methyl, R ４ is chloro or methyl, Q １ But, CR ａ and R ａ is H or fluoro; Q ２ is CH, Q ３ is N, Q ４ is N or CH; Q ５ is N or CH; Y is O; 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof.

19. A compound selected from: 4-amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-(aminomethyl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-phenyl]pyrrolidin-2-one; 5-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; N-[[3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide; 4-amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3,3-dimethyl-pyrrolidin-2-one; 4-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; (3S)-3-amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]azetidin-2-one; 3-amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 5-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; 2-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6-diazaspiro[4.5]decan-3-one; 2-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,8-diazaspiro[4.5]decan-3-one; 6-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6-diazaspiro[3.4]octan-7-one; 7-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxa-2,7-diazaspiro[3.4]octan-6-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; (3aR,6aS)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-one; (3aR,7aS)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one; (3aR,7aS)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridin-2-one; (3aS,7aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one; (3aS,8aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4,5,6,7,8,8a-hexahydro-3aH-oxazolo[4,5-c]azepin-2-one; 4-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-5-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-6-hydroxy-5-(hydroxymethyl)-3a,5,6,6a-tetrahydrofuro[2,3-d]oxazol-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(3S,4R,5R)-3,4-dihydroxy-5[-methoxy-tetrahydrofuran-2-yl]-4-methyl-oxazolidin-2-one; (3aS,5S,6S,7S,7aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5,7-dihydroxy-6-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[2,3-d]oxazol-2-one; 8-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; (3aS,8aR)-5-(2-aminoethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepin-2-one; (3aS,8aR)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[2-(methylamino)ethyl]-3a,4,6,7,8,8a-hexahydrooxazolo[4,5-c]azepin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(methylaminomethyl)oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(dimethylamino)methyl]oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(piperazin-1-ylmethyl)oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[[cis-3,4-dihydroxypyrrolidin-1-yl]methyl]oxazolidin-2-one; 5-[(3-aminoazetidin-1-yl)methyl]-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(2,6-diazaspiro[3.3]heptan-2-ylmethyl)oxazolidin-2-one; 5-[[3-(aminomethyl)azetidin-1-yl]methyl]-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; 3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-[(pyrrolidin-3-ylamino)methyl]oxazolidin-2-one; 4-[[3-(aminomethyl)azetidin-1-yl]methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(4-methylpiperazin-1-yl)methyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-[(dimethylamino)methyl]azetidin-1-yl]methyl]pyrrolidin-2-one; 4-[(azetidin-3-ylmethylamino)methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-[[3-(1-aminocyclopropyl)azetidin-1-yl]methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-[(3-aminoazetidin-1-yl)methyl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(piperazin-1-ylmethyl)pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-(dimethylamino)azetidin-1-yl]methyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[3-(methylamino)azetidin-1-yl]methyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(methylamino)pyrrolidin-2-one; 4-(2-aminoethylamino)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(2-hydroxyethylamino)pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-piperazin-1-yl-pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3S,4R)-3,4-dihydroxypyrrolidin-1-yl]pyrrolidin-2-one; 4-[3-(aminomethyl)azetidin-1-yl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-(3-aminopyrrolidin-1-yl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-(3-aminoazetidin-1-yl)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3S)-3-(hydroxymethyl)piperazin-1-yl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(3R)-3-(hydroxymethyl)piperazin-1-yl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]]heptan-2-yl]pyrrolidin-2-one; 4-[(3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl]-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-((3R,4R)-3-amino-4-hydroxypiperidin-1-yl)-1-(4-((4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)pyrrolidin-2-one; 4-(azetidin-3-ylamino)-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(pyrrolidin-3-ylamino)pyrrolidin-2-one; 1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-(4-piperidylamino)pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-methyl-pyrrolidin-2-one; 4-amino-1-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]pyrrolidin-2-one; 5-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-fluoro-phenyl]oxazolidin-2-one; 5-(aminomethyl)-3-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-fluorophenyl]oxazolidin-2-one; 4-amino-1-[4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[4-(trideuteriomethyl)-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonyl-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine-2-carbonitrile; 4-amino-1-[4-[4-[6-chloro-4-(difluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-(6-chloro-4-cyclopropylsulfonyl-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-(6-chloro-4-tetrahydropyran-4-ylsulfonyl-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 1-[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]cyclopropanecarbonitrile; 4-amino-1-[4-[4-(6-chloro-4-phenoxy-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-(4-benzyl-6-chloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-(1-phenylcyclopropyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[4-[difluoro(phenyl)methyl]-6-methyl-pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[2-chloro-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[4-chloro-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[2-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[4-cyclopropyl-6-[difluoro(phenyl)methyl]pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-methoxy-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[4-[difluoro(phenyl)methyl]-6-methoxy-pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-methyl-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-[difluoro(phenyl)methyl]-2-vinyl-pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 2-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2,6,9-triazaspiro[4.5]decan-3-one; 5-(aminomethyl)-1-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (3aR,7aS)-3-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-one; 5-(aminomethyl)-3-[4-[4-[6-chloro-4-[difluoro(phenyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]oxazolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(2-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(3-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(4-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(pyrimidin-5-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(pyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(pyrimidin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydropyran-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydrofuran-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(oxetan-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[3,6-dihydro-2H-pyran-4-yl(difluoro)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(tetrahydropyran-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 4-amino-1-[4-[4-[6-chloro-4-[difluoro(8-oxabicyclo[3.2.1]octan-3-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro(3-oxabicyclo[3.1.0]hexan-6-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[[(2S)-1,4-dioxan-2-yl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[[(2R)-1,4-dioxan-2-yl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(2R)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro(1,2,3,6-tetrahydropyridin-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(3R)-3-piperidyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[(3S)-3-piperidyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[4-[azetidin-3-yl(difluoro)methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; 3-[4-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-(hydroxymethyl)oxazolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-(5-methylpyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-(6-methylpyrazin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[(5-chloro-6-methyl-pyrazin-2-yl)-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[cis-6-methylmorpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; ((4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-(5-methylmorpholin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[4-[[cis-3-azabicyclo[3.1.0]hexan-1-yl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[trans-difluoro-[2-(hydroxymethyl)cyclopropyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[4-[[trans-4-(aminomethyl)cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; (4R)-4-amino-1-[4-[4-[6-chloro-4-[trans-difluoro-(3-hydroxycyclobutyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; and trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; or a pharmaceutically acceptable salt thereof.

20. 10. A process for the preparation of a compound according to claim 1 or 2, comprising the steps of: a) reacting a compound of formula (VII) with a compound of formula (VII) in the presence of a catalyst and a base 【Transformation 3】 and lactam or carbamate, R １ Coupling reaction with H Including, In step a), the catalyst is CuI and the base is Cs ２ CO ３ and R １ , R ２ , R ３ , R ４ , Y, Q １ , Q ２ , Q ３ , Q ４ and Q ５ is defined as in claim 1 or 2.

21. 3. A compound or a pharmaceutically acceptable salt according to claim 1 or 2 for use as a therapeutically active substance.

22. A pharmaceutical composition comprising a compound according to claim 1 or 2 and a therapeutically inert carrier.

23. 10. Use of a compound according to claim 1 or 2 for the inhibition of LpxH.

24. 3. Use of a compound according to claim 1 or 2 for the treatment or prevention of a bacterial infection, in particular for the treatment or prevention of a bacterial infection wherein the bacteria is a gram-negative bacteria.

25. 10. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of a bacterial infection, in particular for the treatment or prevention of a bacterial infection wherein said bacteria is a gram-negative bacteria.

26. 26. Use of a compound according to claim 24 or 25, wherein the gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

27. 27. The use of a compound according to claim 26, wherein the Gram-negative bacterium is Enterobacteriaceae, and the Enterobacteriaceae is Klebsiella pneumoniae or Escherichia coli.

28. 3. A compound or a pharmaceutically acceptable salt according to claim 1 or 2 for the treatment or prevention of a bacterial infection, in particular for the treatment or prevention of a bacterial infection wherein the bacteria is a gram-negative bacteria.

29. 29. The compound of claim 28, wherein the Gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Pylori, Acinetobacter baumannii, and Pseudomonas aeruginosa.

30. 30. The compound of claim 29, wherein the Gram-negative bacterium is Enterobacteriaceae, and the Enterobacteriaceae is Klebsiella pneumoniae or Escherichia coli.

31. 21. A compound or a pharmaceutically acceptable salt of claim 1 or 2 when prepared according to the method of claim 20.

32. A method for the treatment or prevention of bacterial infections, particularly bacterial infections wherein the bacteria is a gram-negative bacterium, the method comprising administering a therapeutically effective amount of a compound according to claim 1 or 2.

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