Sulfonylpiperazinyl compounds for the treatment of bacterial infections - Patents.com

Abstract

The present invention relates to a compound represented by formula (I) TIFF2024538778000228.tif34110 (in the formula, R 1 ~R 3 , A, Q 1 , Q 2 , W and X are as described herein) and pharma- ceutically acceptable salts thereof, as well as compositions comprising and methods of using said compounds.

Description

[Technical field]

[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 treating bacterial infections. [Background technology]

[0002] The extensive use of antibiotics has exerted selective evolutionary pressure on microorganisms, giving rise to gene-based resistance mechanisms. Modern medical and socio-economic behaviors exacerbate the problem of resistance development, for example by creating slow growth conditions for pathogenic microorganisms in artificial joints, and by supporting long-term host carriage, for example in immunocompromised patients. In the hospital environment, an increasing number of strains of Enterobacteriaceae, such as Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., Klebsiella pneumonia, Acinetobacter baumannii and Pseudomonas aeruginosa, are the main source of infections, have become multidrug resistant and therefore difficult to treat. This is especially true for Gram-negative organisms, where the situation is becoming troubling as no new 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 survival (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 an excellent target for the development of novel antibiotics targeting Gram-negative bacteria. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Ann.Rev.Biochem 76:295-329,2007 Summary of the Invention

[0005] The present invention relates to novel compounds of formula (I) [ka] (In the formula, R 1 Amino, hydroxy C 1~6 Alkyl, C 1~6 Alkylamino, Amino C 1~6 alkylamino or piperazinyl; R 2 is halogen or C 1~6 is alkyl; R 3 is -YC(O)-R 4 and; Y is C3~10 cycloalkyl, phenyl, pyrazinyl or pyridinyl; R 4 Amino Acid C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((amino C 1~6 Alkyl)pyrrolidiniumyl)C 1~6 Alkylamino, ((amino C 1~6 Alkylcarbonyl)amino)C 1~6 Alkylamino, ((C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((C 1~6 Alkyl)3ammonio)C 1~6 Alkylamino, (amino C 1~6 Alkoxy)C 1~6 Alkylamino, (amino C 1~6 Alkyl(C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (C 1~6 Alkyl(amino C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, ((amino C 1~6 Alkylcarbonyl)amino)C 3~10 Cycloalkylamino, ((amino C 1~6 Alkyl)2pyrrolidinyl)C 3~10 Cycloalkylamino, (amino C 1~6 Alkyl)2amino, (amino C 1~6 Alkyl)azetidinyl, (amino C 1~6 Alkyl)C 3~10 Cycloalkylamino, (amino C 1~6 Alkyl)piperazinyl, (amino C 1~6 Alkylamino)C 1~6 Alkylamino, (amino C 1~6 Alkylcarbonyl)aminocarbamoyl, (aminopyrrolidinyl)C 3~10 Cycloalkylamino, (azetidinyl C 1~6 Alkylamino)C 1~6 Alkylamino, (C 1~6 Alkylamino)C 1~6 Alkylamino, (C 1~6Alkylpyrrolidiniumyl)C 1~6 Alkylamino, (diaminopiperidinyl)C 1~6 Alkylamino, (diaminopiperidinyl)C 3~10 Cycloalkylamino, (piperidinylcarbonylamino)carbamoyl, 3-azabicyclo[3.1.0]hexanylamino, amino, amino(C 1~6 Alkoxy)C 1~6 Alkylamino, Amino(C 1~6 Alkyl)piperidinyl, (amino C 1~6 Alkyl)2pyrrolidinyl, amino(hydroxy)C 1~6 Alkylamino, Amino C 1~6 Alkylamino, Amino C 3~10 Cycloalkylamino, aminocarbonyl C 1~6 Alkylamino, aminopyrrolidinylamino, amino(C 1~6 Alkyl)pyrrolidinylamino, azetidinyl C 1~6 Alkylamino, C 1~6 Alkoxy, C 1~6 Alkyl(amino C 1~6 Alkyl)amino, C 1~6 Alkylpyrrolidinylamino, C 1~6 Alkyl(amino C 1~6 Alkyl)piperaziniumyl, C 1~6 Alkyl-2,6-diazaspiro[3.3]heptanyl, C 1~6 Alkylamino, Diamino C 1~6 Alkylamino, diaminopiperidinyl, hydroxy C 1~6 Alkylamino, hydroxypyrrolidinylamino, morpholinyl C 1~6 Alkylamino or pyrrolidinyl C 1~6 is alkylamino; X is CH or O; A is CH or N; Q 1 is CH or N; Q 2 is CH or N; W is for Halo C 1~6 (It is alkyl) or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] 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 The "alkyl" groups are methyl, ethyl and propyl.

[0007] "C 1~6 The term "alkoxy" refers to 1~6 It represents alkyl-O-.

[0008] The term "amino", alone or in combination, means a primary amino group, a secondary amino group, or a tertiary amino group.

[0009] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.

[0010] "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 Represents an alkyl group. HaloC 1~6 Examples of alkyl include mono-, di- or trifluoromethyl, mono-, di- or trifluoroethyl, or mono-, di- or trifluoropropyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, trifluoroethyl, fluoromethyl, difluoromethyl, difluoroethyl or trifluoromethyl.

[0011] "C 3~10The term "cycloalkyl" refers to a saturated carbocyclic monocyclic, bicyclic or tricyclic ring containing 3 to 10 carbon atoms, particularly 3 to 8 carbon atoms. 3~10 Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, norbornanyl, adamantanyl, and the like. 3~10 "Cycloalkyl" groups are bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, cyclohexanyl, cyclopentanyl and norbornanyl.

[0012] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0013] 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, as well as organic acids selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxy, 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, maloneic 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.

[0014] The term "pharmaceutically acceptable base addition salt" refers to pharmaceutically acceptable salts formed with organic or inorganic bases. 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 the 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.

[0015] The term "pharmacologically active metabolite" refers to a pharmacologically active product produced through metabolism in the body of a specified 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 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.

[0016] 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, alleviates 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 will vary depending on the compound, the condition 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.

[0017] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with a pharmaceutically acceptable excipient to be administered to a mammal, such as a human in need thereof.

[0018] Inhibitors of UDP-2,3-diacylglucosamine hydrolase (LpxH) The present invention relates to a compound of formula (I) [ka] (In the formula, R 1 Amino, hydroxy C 1~6 Alkyl, C 1~6 Alkylamino, Amino C 1~6 alkylamino or piperazinyl; R 2 is halogen or C 1~6 is alkyl; R 3 is -YC(O)-R 4 and; Y is C 3~10 cycloalkyl, phenyl, pyrazinyl or pyridinyl; R 4 Amino C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((amino C 1~6 Alkyl)pyrrolidiniumyl)C 1~6Alkylamino, ((amino C 1~6 Alkylcarbonyl)amino)C 1~6 Alkylamino, ((C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((C 1~6 Alkyl)3ammonio)C 1~6 Alkylamino, (amino C 1~6 Alkoxy)C 1~6 Alkylamino, (amino C 1~6 Alkyl(C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (C 1~6 Alkyl(amino C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, ((amino C 1~6 Alkylcarbonyl)amino)C 3~10 Cycloalkylamino, ((amino C 1~6 Alkyl)2pyrrolidinyl)C 3~10 Cycloalkylamino, (amino C 1~6 Alkyl)2amino, (amino C 1~6 Alkyl)azetidinyl, (amino C 1~6 Alkyl)C 3~10 Cycloalkylamino, (amino C 1~6 Alkyl)piperazinyl, (amino C 1~6 Alkylamino)C 1~6 Alkylamino, (amino C 1~6 Alkylcarbonyl)aminocarbamoyl, (aminopyrrolidinyl)C 3~10 Cycloalkylamino, (azetidinyl C 1~6 Alkylamino)C 1~6 Alkylamino, (C 1~6 Alkylamino)C 1~6 Alkylamino, (C 1~6 Alkylpyrrolidiniumyl)C 1~6 Alkylamino, (diaminopiperidinyl)C 1~6 Alkylamino, (diaminopiperidinyl)C 3~10 Cycloalkylamino, (piperidinylcarbonylamino)carbamoyl, 3-azabicyclo[3.1.0]hexanylamino, amino, amino(C1~6 Alkoxy)C 1~6 Alkylamino, Amino(C 1~6 Alkyl)piperidinyl, (amino C 1~6 Alkyl)2pyrrolidinyl, amino(hydroxy)C 1~6 Alkylamino, Amino C 1~6 Alkylamino, Amino C 3~10 Cycloalkylamino, aminocarbonyl C 1~6 Alkylamino, aminopyrrolidinylamino, amino(C 1~6 Alkyl)pyrrolidinylamino, azetidinyl C 1~6 Alkylamino, C 1~6 Alkoxy, C 1~6 Alkyl(amino C 1~6 Alkyl)amino, C 1~6 Alkylpyrrolidinylamino, C 1~6 Alkyl(amino C 1~6 Alkyl)piperaziniumyl, C 1~6 Alkyl-2,6-diazaspiro[3.3]heptanyl, C 1~6 Alkylamino, Diamino C 1~6 Alkylamino, diaminopiperidinyl, hydroxy C 1~6 Alkylamino, hydroxypyrrolidinylamino, morpholinyl C 1~6 Alkylamino or pyrrolidinyl C 1~6 is alkylamino; X is CH or O; A is CH or N; Q 1 is CH or N; Q 2 is CH or N; W is for Halo C 1~6 is alkyl; or a pharma- ceutically acceptable salt thereof.

[0019] The present invention relates to a compound of formula (I) [ka] (In the formula, R 1Amino, hydroxy C 1~6 Alkyl, Amino C 1~6 alkylamino or piperazinyl; R 2 is halogen or C 1~6 is alkyl; R 3 is -YC(O)-R 4 and; Y is C 3~10 cycloalkyl, phenyl, pyrazinyl or pyridinyl; R 4 Amino Acid C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((amino C 1~6 Alkyl)pyrrolidiniumyl)C 1~6 Alkylamino, ((amino C 1~6 Alkylcarbonyl)amino)C 1~6 Alkylamino, ((C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((C 1~6 Alkyl)3ammonio)C 1~6 Alkylamino, (amino C 1~6 Alkoxy)C 1~6 Alkylamino, (amino C 1~6 Alkyl(C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (amino C 1~6 Alkyl)2amino, (amino C 1~6 Alkyl)azetidinyl, (amino C 1~6 Alkyl)C 3~10 Cycloalkylamino, (amino C 1~6 Alkyl)piperazinyl, (amino C 1~6 Alkylamino)C 1~6 Alkylamino, (amino C 1~6 Alkylcarbonyl)aminocarbamoyl, (azetidinyl C 1~6 Alkylamino)C 1~6 Alkylamino, (C 1~6 Alkylamino)C 1~6 Alkylamino, (C 1~6 Alkylpyrrolidiniumyl)C1~6 Alkylamino, (diaminopiperidinyl)C 1~6 Alkylamino, (piperidinylcarbonylamino)carbamoyl, 3-azabicyclo[3.1.0]hexanylamino, amino, amino(C 1~6 Alkoxy)C 1~6 Alkylamino, Amino(C 1~6 Alkyl) piperidinyl, amino(hydroxy)C 1~6 Alkylamino, Amino C 1~6 Alkylamino, Amino C 3~10 Cycloalkylamino, aminocarbonyl C 1~6 Alkylamino, aminopyrrolidinylamino, azetidinyl C 1~6 Alkylamino, C 1~6 Alkoxy, C 1~6 Alkyl(amino C 1~6 Alkyl)amino, C 1~6 Alkyl(amino C 1~6 Alkyl)piperaziniumyl, C 1~6 Alkyl-2,6-diazaspiro[3.3]heptanyl, C 1~6 Alkylamino, Diamino C 1~6 Alkylamino, diaminopiperidinyl, hydroxy C 1~6 Alkylamino, hydroxypyrrolidinylamino, morpholinyl C 1~6 Alkylamino or pyrrolidinyl C 1~6 is alkylamino; X is CH or O; A is CH or N; Q 1 is CH or N; Q 2 is CH or N; W is for Halo C 1~6 is alkyl; or a pharma- ceutically acceptable salt thereof.

[0020] A further aspect of the present invention is (ii') R 1 Amino or hydroxy C 1~6 or a pharma- ceutically acceptable salt thereof.

[0021] A further aspect of the present invention is (ii) R 1 Amino, C 1~6 Alkylamino or hydroxy C 1~6 or a pharma- ceutically acceptable salt thereof.

[0022] A further aspect of the present invention is (iii') R 1 is amino or hydroxymethyl, or a pharma- ceutically acceptable salt thereof.

[0023] A further aspect of the present invention is (iii) R 1 is amino, methylamino or hydroxymethyl; or a pharma- ceutically acceptable salt thereof.

[0024] A further aspect of the present invention is (iv) R 2 is halogen; or a pharma- ceutically acceptable salt thereof.

[0025] A further aspect of the present invention is (v) R 2 is chloro.

[0026] A further aspect of the present invention is (vi) R 3 But -YC(O)-R 4 and Y is C 3~10 The compound of formula (I) as defined in any one of (i) to (v) or a pharma- ceutically acceptable salt thereof, wherein R is cycloalkyl, phenyl or pyrazinyl.

[0027] A further aspect of the present invention is (vii') R 3 But -YC(O)-R 4and Y is bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, cyclohexanyl, phenyl or pyrazinyl, or a pharma- ceutically acceptable salt thereof.

[0028] A further aspect of the present invention is (vii) R 3 But -YC(O)-R 4 and Y is bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, cyclohexanyl, norbornanyl, phenyl or pyrazinyl, or a pharma- ceutically acceptable salt thereof.

[0029] A further aspect of the present invention is (viii') R 3 But -YC(O)-R 4 and R 4 However, ((Amino C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((amino C 1~6 Alkyl)pyrrolidiniumyl)C 1~6 Alkylamino, (amino C 1~6 Alkyl(C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (amino C 1~6 Alkyl)2amino, (diaminopiperidinyl)C 1~6 Alkylamino, Amino, Amino(hydroxy)C 1~6 Alkylamino or Amino C 1~6 The compound of formula (I) according to any one of (i) to (vii), or a pharma- ceutically acceptable salt thereof, is alkylamino.

[0030] A further aspect of the present invention is (viii) R 3 But -YC(O)-R 4 ;R 4 However, amino (C 1~6 alkyl)pyrrolidinylamino, ((amino C 1~6 Alkyl)2Amino)C 1~6Alkylamino, ((amino C 1~6 Alkyl)2pyrrolidinyl)C 3~10 Cycloalkylamino, ((amino C 1~6 Alkyl)pyrrolidiniumyl)C 1~6 Alkylamino, (amino C 1~6 Alkyl(C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (amino C 1~6 Alkyl)2amino, (amino C 1~6 Alkyl)2pyrrolidinyl, (amino C 1~6 Alkyl)C 3~10 Cycloalkylamino, (C 1~6 Alkyl(amino C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (aminopyrrolidinyl)C 3~10 Cycloalkylamino, (C 1~6 Alkyl(amino C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (diaminopiperidinyl)C 1~6 Alkylamino, (diaminopiperidinyl)C 3~10 Cycloalkylamino, amino, amino(hydroxy)C 1~6 Alkylamino, Amino C 1~6 Alkylamino, Amino C 3~10 Cycloalkylamino, C 1~6 Alkylpyrrolidinylamino, diamino C 1~6 The compound of formula (I) as defined in any one of (i) to (vii) or a pharma- ceutically acceptable salt thereof, wherein the compound is alkylamino or diaminopiperidinyl.

[0031] A further aspect of the present invention is (ix') R 4is ((2-aminoethyl)2amino)propylamino, ((2-aminoethyl)pyrrolidin-1-ium-1-yl)ethylamino, (2-aminoethyl(dimethyl)ammonio)ethylamino, (3-aminopropyl)2amino, (3,5-diamino-1-piperidinyl)propylamino, amino, 3-amino-2-hydroxy-propylamino, 3-aminopropylamino, 3-aminopropylamino or 2-aminoethylamino, or a pharma- ceutically acceptable salt thereof.

[0032] A further aspect of the present invention is (ix) R 4 However, ((2-aminoethyl)2-amino)propylamino, ((2-aminoethyl)pyrrolidin-1-ium-1-yl)ethylamino, (2-aminoethyl(dimethyl)ammonio)ethylamino, (2-aminoethyl)2-amino, (3,5-diamino-1-piperidinyl)propylamino, (3-aminocyclopentyl)amino, (3-aminopropyl)2-amino, (4-methylpyrrolidin-3-yl)amino, [3-(3,5-diamino-1-piperidinyl)cyclopentyl]amino, [3-[3,4-bis(aminomethyl)pyrrolidin-1-yl]cyclopentyl]amino, [3-[3-aminopyrrolidin-1-yl]cyclopentyl]amino, 1-(aminomethyl)cyclo propylamino, 2-(2-aminoethylamino)ethylamino, 2,3-diaminopropylamino, 2-aminoethylamino, 3,4-bis(aminomethyl)pyrrolidin-1-yl, 3,5-diaminopiperidinyl, 3-[3-aminopropyl(dimethyl)ammonio]propylamino, 3-[bis(2-aminoethyl)-methyl-ammonio]propylamino, 3-amino-2-hydroxy-propylamino, 3-aminopropylamino, 3-hydroxypropylamino, 4-amino-2-methyl-pyrrolidin-1-yl, amino or aminopropylamino, or a pharma- ceutically acceptable salt thereof.

[0033] A further aspect of the present invention is a compound of formula (I) as defined in any one of (i) to (ix) or a pharma- ceutically acceptable salt thereof, wherein (x) A is CH.

[0034] A further aspect of the present invention is (xi) Q 1 is N; or a pharma- ceutically acceptable salt thereof.

[0035] A further aspect of the present invention is (xii) Q 2 is CH; or a pharma- ceutically acceptable salt thereof.

[0036] A further aspect of the present invention is a compound of formula (I) as defined in any one of (i) to (xii) or a pharma- ceutically acceptable salt thereof, wherein (xiii) W is CF2.

[0037] A further aspect of the present invention is (xiv') R 1 but amino or hydroxy C 1~6 is alkyl; R 2 is a halogen; R 3 But -YC(O)-R 4 and; Y is C 3~10 cycloalkyl, phenyl or pyrazinyl; R 4 However, ((Amino C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((amino C 1~6 Alkyl)pyrrolidiniumyl)C 1~6 Alkylamino, (amino C 1~6 Alkyl(C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (amino C 1~6 Alkyl)2amino, (diaminopiperidinyl)C 1~6 Alkylamino, Amino, Amino(hydroxy)C 1~6Alkylamino or Amino C 1~6 is alkylamino; X is CH2 or O; A is CH; Q 1 is N; Q 2 is CH; W is Haro C 1~6 is alkyl; The compound of formula (I) is represented by any one of (i) to (xiii) or a pharma- ceutically acceptable salt thereof.

[0038] A further aspect of the present invention is a compound comprising: R 1 but amino or hydroxy C 1~6 is alkyl; R 2 is a halogen; R 3 But -YC(O)-R 4 and; Y is C 3~10 cycloalkyl, phenyl or pyrazinyl; R 4 However, amino (C 1~6 alkyl)pyrrolidinylamino, ((amino C 1~6 Alkyl)2Amino)C 1~6 Alkylamino, ((amino C 1~6 Alkyl)2pyrrolidinyl)C 3~10 Cycloalkylamino, ((amino C 1~6 Alkyl)pyrrolidiniumyl)C 1~6 Alkylamino, (amino C 1~6 Alkyl(C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (amino C 1~6 Alkyl)2amino, (amino C 1~6 Alkyl)2pyrrolidinyl, (amino C 1~6 Alkyl)C 3~10 Cycloalkylamino, (C 1~6 Alkyl(amino C 1~6 Alkyl)2ammonio)C 1~6Alkylamino, (aminopyrrolidinyl)C 3~10 Cycloalkylamino, (C 1~6 Alkyl(amino C 1~6 Alkyl)2ammonio)C 1~6 Alkylamino, (diaminopiperidinyl)C 1~6 Alkylamino, (diaminopiperidinyl)C 3~10 Cycloalkylamino, amino, amino(hydroxy)C 1~6 Alkylamino, Amino C 1~6 Alkylamino, Amino C 3~10 Cycloalkylamino, C 1~6 Alkylpyrrolidinylamino, diamino C 1~6 alkylamino or diaminopiperidinyl; X is CH2 or O; A is CH; Q 1 is N; Q 2 is CH; W is Haro C 1~6 is alkyl; The compound of formula (I) is represented by any one of (i) to (xiii) or a pharma- ceutically acceptable salt thereof.

[0039] A further aspect of the present invention is (xv') R 1 is amino or hydroxymethyl; R 2 is chloro; R 3 But -YC(O)-R 4 and; Y is bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, cyclohexanyl, phenyl or pyrazinyl; R 4is ((2-aminoethyl)2amino)propylamino, ((2-aminoethyl)pyrrolidin-1-ium-1-yl)ethylamino, (2-aminoethyl(dimethyl)ammonio)ethylamino, (3-aminopropyl)2amino, (3,5-diamino-1-piperidinyl)propylamino, amino, 3-amino-2-hydroxy-propylamino, 3-aminopropylamino, 3-aminopropylamino or 2-aminoethylamino; X is CH2 or O; A is CH; Q 1 is N; Q 2 is CH; W is CF2; The compound of formula (I) is represented by any one of (i) to (xiv) or a pharma- ceutically acceptable salt thereof.

[0040] A further aspect of the present invention is a compound comprising: R 1 is amino or hydroxymethyl; R 2 is chloro; R 3 But -YC(O)-R 4 and; Y is bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, cyclohexanyl, phenyl or pyrazinyl; R 4However, ((2-aminoethyl)2-amino)propylamino, ((2-aminoethyl)pyrrolidin-1-ium-1-yl)ethylamino, (2-aminoethyl(dimethyl)ammonio)ethylamino, (2-aminoethyl)2-amino, (3,5-diamino-1-piperidinyl)propylamino, (3-aminocyclopentyl)amino, (3-aminopropyl)2-amino, (4-methylpyrrolidin-3-yl)amino, [3-(3,5-diamino-1-piperidinyl)cyclopentyl]amino, [3-[3,4-bis(aminomethyl)pyrrolidin-1-yl]cyclopentyl]amino, [3-[3-aminopyrrolidin-1-yl] cyclopentyl]amino, 1-(aminomethyl)cyclopropylamino, 2-(2-aminoethylamino)ethylamino, 2,3-diaminopropylamino, 2-aminoethylamino, 3,4-bis(aminomethyl)pyrrolidin-1-yl, 3,5-diaminopiperidinyl, 3-[3-aminopropyl(dimethyl)ammonio]propylamino, 3-[bis(2-aminoethyl)-methyl-ammonio]propylamino, 3-amino-2-hydroxy-propylamino, 3-aminopropylamino, 3-hydroxypropylamino, 4-amino-2-methyl-pyrrolidin-1-yl, amino or aminopropylamino; X is CH2 or O; A is CH; Q 1 is N; Q 2 is CH; W is CF2; The compound of formula (I) is represented by any one of (i) to (xiv) or a pharma- ceutically acceptable salt thereof.

[0041] Another aspect of the present invention is a compound of formula (I) selected from: trans-Methyl 4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylate; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(azetidin-3-ylmethyl)cyclohexanecarboxamide; trans-4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-hydroxypropyl)cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-(4-amino-4-methyl-piperidine-1-carbonyl)cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-(4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[4-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)cyclohexyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(4-hydroxypyrrolidin-3-yl)cyclohexanecarboxamide; trans-N-(3-aminocyclobutyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(2-amino-1-methyl-ethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(2-pyrrolidin-1-ylethyl)cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[cis-4-aminopyrrolidin-3-yl]cyclohexanecarboxamide; trans-N-[1-(aminomethyl)cyclopropyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-[4-(2-aminoethyl)piperazine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; 4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-hydroxypropyl)benzamide; 4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-aminopropyl)benzamide; N-(2-aminoethyl)-4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]benzamide; N-(3-amino-2-hydroxy-propyl)-4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]benzamide; N-(3-amino-2-hydroxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]benzamide; 4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(dimethylamino)propyl]benzamide; N-(3-aminopropyl)-5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxamide; N-(3-amino-2-hydroxy-propyl)-5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxamide; 5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(dimethylamino)propyl]pyrazine-2-carboxamide; N-(2-aminoethyl)-5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxamide; 5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(2-morpholinoethyl)pyrazine-2-carboxamide; N-(3-aminopropyl)-6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyridine-3-carboxamide; 6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(dimethylamino)propyl]pyridine-3-carboxamide; N-[2-(2-aminoethylamino)ethyl]-6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyridine-3-carboxamide; 5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(methylamino)propyl]pyridine-2-carboxamide; trans-N-(2-aminoethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-methyl-cyclohexanecarboxamide; cis-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; cis-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(3-hydroxypropyl)cyclohexanecarboxamide; N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[2.2.2]octane-1-carboxamide; N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]norbornane-1-carboxamide; N-(3-aminopropyl)-3-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclopentanecarboxamide; trans-N-(3-amino-2-hydroxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; 3-[[4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]benzoyl]amino]propyl-trimethyl-ammonium; 4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(1-methylpyrrolidin-1-ium-1-yl)propyl]benzamide; 5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(2-hydroxyethylamino)propyl]pyridine-2-carboxamide; N-(3-aminopropyl)-3-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[1.1.1]pentane-1-carboxamide; trans-N-(2-aminoethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-[2-(2-aminoethoxy)ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N,N-bis(2-aminoethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N,N-bis(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; N,N-Bis(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[2.2.2]octane-1-carboxamide; N,N-bis(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]norbornane-1-carboxamide; trans-N-[3-[bis(2-aminoethyl)amino]propyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[6-chloro-4-[[4-cis-(3,5-diaminopiperidine-1-carbonyl)cyclohexyl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-[cis-3,5-diamino-1-piperidyl]propyl]cyclohexanecarboxamide; trans-N'-(2-aminoacetyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbohydrazide; trans-N'-[4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]piperidine-4-carbohydrazide; trans-N-(2-amino-3-hydroxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; (2R,5S)-5-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-aminopropyl)bicyclo[2.2.2]octane-2-carboxamide; trans-N-(3-aminopropyl)-4-[difluoro-[6-methyl-2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]pyrimidin-4-yl]methyl]cyclohexanecarboxamide; N-(3-aminopropyl)-6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[3.1.0]hexane-3-carboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-[3-(aminomethyl)azetidine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(5S)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(5R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-(2-oxo-4-piperazin-1-yl-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[[6-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]-3-pyridyl]sulfonyl]piperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonyl-1-piperidyl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; cis-N-(2-amino-2-oxo-ethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; (4R)-4-amino-1-[4-[4-[4-[[4-[(2S,4S)-4-amino-2-methyl-pyrrolidine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-bis(2-aminoethyl)-[3-[[4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl]-methyl-ammonium; trans-N-[(1R,3S)-3-aminocyclopentyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-[cis-3,4-bis(aminomethyl)pyrrolidine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(3R,4S)-4-methylpyrrolidin-3-yl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-(methylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-[4-(2-aminoethyl)-4-methyl-piperazin-4-ium-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-N-[2-(2-aminoethylamino)ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-2-aminoethyl-[2-[[4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]ethyl]-dimethyl-ammonium; trans-N-[2-[1-(2-aminoethyl)pyrrolidin-1-ium-1-yl]ethyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-[2-[(2-aminoacetyl)amino]ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-amino-2-methoxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(2,3-diaminopropyl)cyclohexanecarboxamide; 4-[[2-[4-[4-[4-(3-aminopropylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-methyl-benzamide; trans-N-[(1R,3S)-3-[(2-aminoacetyl)amino]cyclopentyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(1S,3R)-3-[cis-3,4-bis(aminomethyl)pyrrolidin-1-yl]cyclopentyl]cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[(1S)-3-[cis-3,5-diamino-1-piperidyl]cyclopentyl]cyclohexanecarboxamide; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(1S,3R)-3-[(3R)-3-aminopyrrolidin-1-yl]cyclopentyl]cyclohexanecarboxamide; and trans-3-[[4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl-(3-aminopropyl)-dimethyl-ammonium; or a pharma- ceutically acceptable salt thereof.

[0042] A further aspect of the present invention is (xviii) a compound of formula (I) as defined in any one of (i) to (xvi) or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance.

[0043] A further aspect of the present invention is a pharmaceutical composition comprising a compound according to any one of (xix)(i) to (xvi) and a therapeutically inert carrier.

[0044] A further aspect of the present invention is (xx) the use of a compound according to any one of (i) to (xvi) for the inhibition of LpxH.

[0045] A further aspect of the invention is (xxi) the use of a compound according to any one of (i) to (xvi) for the treatment or prevention of a bacterial infection, particularly a bacterial infection wherein the bacteria is a gram-negative bacteria.

[0046] A further aspect of the present invention is (xxii) the use of a compound according to any one of (i) to (xvi) for the preparation of a medicament for the treatment or prevention of a bacterial infection, in particular a bacterial infection wherein the bacteria is a gram-negative bacteria.

[0047] A further aspect of the present invention is the use of a compound according to (xxi) or (xxii), wherein the gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylori, Acinetobacter baumannii and Pseudomonas aeruginosa.

[0048] A further aspect of the present invention is the use of the compound according to (xxiii), wherein (xxiv) the gram-negative bacterium is Enterobacteriaceae, and the Enterobacteriaceae is Klebsiella pneumoniae or Escherichia coli.

[0049] A further embodiment of the present invention is (xxv) a compound according to any one of (i) to (xvi) for the treatment or prevention of a bacterial infection, particularly a bacterial infection wherein the bacteria is a gram-negative bacteria.

[0050] A further embodiment of the present invention is the compound according to (xxvi), wherein the gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylori, Acinetobacter baumannii and Pseudomonas aeruginosa.

[0051] A further embodiment of the present invention is the compound according to (xxvi), wherein the gram-negative bacterium is Enterobacteriaceae, and the Enterobacteriaceae is Klebsiella pneumoniae or Escherichia coli.

[0052] A further aspect of the present invention is (xxviii) a method for the treatment or prevention of a bacterial infection, particularly a bacterial infection wherein the bacteria is a gram-negative bacteria, comprising administering a therapeutically effective amount of a compound according to any one of (i) to (xvi).

[0053] 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 galenic dosage forms by mixing at ambient temperature, at an appropriate pH, and with 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 depends primarily on the particular application and the concentration of the compound, but is preferably 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 can be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0054] The composition is formulated, dosed, and administered in a manner consistent with medical standards. Factors to be considered in this regard include the specific disease to be treated, the specific mammal to be treated, the clinical condition of the individual patient / animal, the cause of the disorder, the site of delivery 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 inhibition of lipid A biosynthesis by targeting the LpxH enzyme. For example, such an amount may be below the amount that is toxic to normal cells or to the mammal as a whole.

[0055] In one example, the pharma- ceutical effective amount of the compound of the invention administered parenterally per dose ranges from about 0.1 to 1000 mg / kg of patient body weight, or alternatively from 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 the compound of the invention.

[0056] 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, if desired for localized treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

[0057] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers and additional active agents.

[0058] Typical preparation is prepared by mixing the compound of the present invention with 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 product (i.e., a medicament).

[0059] 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 an isotonicity agent, for example, a salt such as sodium chloride, if desired. The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0060] Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or excipient.

[0061] Another embodiment includes pharmaceutical compositions comprising a compound of formula (I) for use in the treatment and / or prevention of a bacterial infection.

[0062] The following example compositions A and B illustrate typical compositions of the present invention, but serve merely as representative thereof.

[0063] Composition A The compounds of the present 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

[0064] Composition B The compounds of the present invention can be used as an active ingredient in a manner known per se to produce capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0065] Indications and methods of treatment The compounds of the present invention are inhibitors of the LpxH enzyme, a key enzyme in the LPS synthesis pathway that is essential in most Gram-negative bacteria. Thus, the compounds of the invention are capable of inhibiting bacterial growth in susceptible organisms and are effective in preventing the proliferation of Gram-negative bacteria such as third generation cephalosporin and carbapenem resistant Enterobacteriaceae (e.g. Klebsiella pneumoniae, Escherichia coli) and multi-drug resistant Pseudomonas aeruginosa and Acinetobacter baumannii or Acinetobacter spp. such as Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylori, Bacteroides spp. such as Bacteroides fragilis, fragilis, Bacteroides thetaiotaomicron, Bacteroides distasonis, Campylobacter jejuni, Campylobacter fetus or Campylobacter coli, Francisella tularensis and Providencia spp., such as Providencia stuartii, Providencia rettgeri or Providencia alcalifaciens and Pseudomonas spp.), preferably gram-negative bacterial infections (all claimed), such as hospital-acquired pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, eye infections, intraperitoneal infections, pulmonary infections and diabetic foot infections, as well as for cleaning purposes, such as for removing pathogenic microorganisms and bacteria from surgical instruments, catheters and artificial implants, or for rendering a room or area sterile.

[0066] The products of the present invention can be administered, for example, parenterally, for example by injection, or orally, perorally, 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 desired, with conventional pharmaceutical auxiliaries. It is believed 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 optional ingredients, any of a variety of auxiliaries 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 listed herein are given as examples only, and the present invention is not limited to their use. Other such auxiliary agents 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 (depending on the nature of the active substance; however, in the case of soft gelatin capsules, no carrier is required) for example, vegetable oils, waxes, fats and semi-solid and liquid polyols. Suitable carrier materials for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid 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.

[0067] synthesis The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds and their starting materials are provided in the following schemes and the examples that follow. All substituents, particularly R 1 ~R 4 , Y, A, Q 1 , Q 2 , W and X are defined as follows, unless otherwise indicated: Further, unless otherwise indicated, all reactions, reaction conditions, abbreviations and symbols have the meanings known to those of skill in the art. [ka] In the formula, Q 1 is N;B 1 is a halogen;PG 1 and P.G. 2 are independently protecting groups such as tert-butoxycarbonyl and benzyloxycarbonyl groups.

[0068] Compounds of formula (VI) can be obtained from a sulfonation reaction between halogenated phenylsulfonyl chlorides (IV) and compounds of formula (V). Compounds of formula (VIII) can be obtained by coupling reaction of compounds of formula (VI) with cyclic amides such as lactams or carbamates (VII) using a catalyst such as CuI in the presence of a base such as Cs2CO3. Compounds of formula (IX) can be obtained by deprotecting compounds of formula (VIII) with a suitable acid such as trifluoroacetic acid or a reducing agent such as palladium on carbon in the presence of H2. [ka] In the formula, Q 1 is CH.

[0069] Alternatively, the compound of formula (IX) may also be prepared by the process shown in Scheme 2. The reaction of the compound of formula (XXIII) with the compound of formula (XXII) in the presence of a suitable Mitsunobu reagent, such as N,N,N,N-tetramethylazodicarboxamide and tributylphosphine, gives the compound of formula (XXIV). The compound of formula (XXV) may be obtained from the oxidation of the compound of formula (XXIV) using a suitable oxidation reagent, such as m-CPBA. The coupling reaction of the compound of formula (XXV) with a cyclic amide, such as a lactam, or a carbamate (VII), using a catalyst, such as CuI, in the presence of a base, such as Cs2CO3, gives the sulfoxide (XXVI). The oxidation of the sulfoxide (XXVI) with a suitable oxidation reagent, such as m-CPBA, gives the compound of formula (XXVII). The compound of formula (IX) may be obtained by deprotecting the compound of formula (VIII) with a suitable acid, such as trifluoroacetic acid, or with a reducing reagent, such as palladium on carbon, in the presence of H2. [ka] In the formula, B 3 is a halogen; B 2 is halogen or methylsulfonyl; R 5 is an aldehyde, acyl chloride or ester; R 6 is C 1~6 It is an alkyl.

[0070] Magnesium-halogen exchange of compound of formula (X) with a suitable Grignard reagent such as isopropylmagnesium chloride-lithium chloride complex, followed by addition of compound of formula (XI) gives compound of formula (XII). Compound of formula (XIII) can be obtained from oxidation of compound of formula (XII) in the presence of a suitable oxidizing agent such as Dess-Martin reagent. Fluorination of compound of formula (XIII) in the presence of a suitable reagent such as DAST gives compound of formula (XIV). [ka] In the ceremony, P.G. 2is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl; R 4 ' is R 4 or R 4 -PG 3 and P.G. 3 is a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl.

[0071] Nucleophilic substitution between a compound of formula (IX) and a compound of formula (XIV) gives the ester (XV). Hydrolysis of the ester (XV) under suitable basic conditions such as LiOH or suitable acid conditions such as HCl gives the acid (XVI). Coupling of the acid (XVI) with an amine or alcohol of a compound of formula (XVII) using a suitable reagent such as HATU gives the compound of formula (XVIII). The final compound of formula (XIX) can be obtained from deprotection of the compound of formula (XVIII) using a suitable acid such as trifluoroacetic acid or a reducing reagent such as palladium on carbon in the presence of H2. [ka]

[0072] Alternatively, the compound of formula (XIX) can be prepared according to scheme 5. Hydrolysis of the compound of formula (XIV) under suitable basic conditions such as LiOH or acid conditions such as HCl gives the compound of formula (XX). Coupling of the compound of formula (XX) with the amine or alcohol of the compound of formula (XVII) using a suitable reagent such as HATU gives the compound of formula (XXI). Nucleophilic displacement of the compound of formula (XXI) with the compound of formula (IX) in the presence of a suitable base such as K2CO3 gives the compound of formula (XVIII). The final compound of formula (XIX) can be obtained from deprotection of the compound of formula (XVIII) using a suitable acid such as trifluoroacetic acid or a reducing reagent such as palladium on carbon in the presence of H2. [ka] In the ceremony, P.G. 4and P.G. 5 is a protecting group such as tert-butoxycarbonyl and benzyloxycarbonyl; L 1 is C 1~6 Alkyl or C 3~10 Cycloalkyl; R 7 is C 1~6 Alkyl, Amino C 1~6 Alkyl or Amino C 3~10 Cycloalkyl; R 7’ is R 7 -PG 5 It is.

[0073] The compound of formula (XVI) can be reacted with the compound of formula (XXVIII-1) using a suitable coupling reagent such as HATU to give the compound of formula (XXIX). Oxidation of the alcohol of the compound of formula (XXIX) with a suitable oxidizing agent such as Dess-Martin reagent gives the compound of formula (XXX). The compound of formula (XXXIII) can be obtained from reductive amination of the compound of formula (XXX) with the compound of formula (XXVIII-3) in the presence of a suitable reducing reagent such as sodium triacetoxyborohydride.

[0074] Compounds of formula (XXXIII) can also be achieved from the alternative route in scheme 6. Compounds of formula (XXXI) can be prepared from coupling of compounds of formula (XVI) with amine (XXVIII-2) using a suitable coupling reagent such as HATU. Deprotection of compounds of formula (XXXI) in the presence of a suitable acid such as trifluoroacetic acid gives compounds of formula (XXXII). Compounds of formula (XXXIII) can be obtained from displacement of compounds of formula (XXXII) with compounds of formula (XXVIII-4) under basic conditions such as DIPEA or through displacement reaction with coupling reagents such as HATU.

[0075] Final compounds of formula (XXXIV) may be obtained from deprotection of compounds of formula (XXXIII) using a suitable acid such as trifluoroacetic acid, or a reducing reagent such as palladium on carbon in the presence of H2. Alternative final compounds of formula (XXXV) may be obtained from methylation of compounds of formula (XXXIII) using a suitable reagent such as MeI, followed by deprotection with a suitable acid such as trifluoroacetic acid, or a reducing reagent such as palladium on carbon in the presence of H2. [ka] In the formula, L 1 is C 1~6 Alkyl or C 3~10 Cycloalkyl; R 7 is C 1~6 Alkyl, Amino C 1~6 Alkyl or Amino C 3~10 Cycloalkyl; R 7’ is R 7 -PG 5 It is.

[0076] Compounds of formula (XXXVI) can be obtained by coupling of compounds of formula (XVI) with compounds of formula (XXVIII-5) using a suitable coupling reagent such as HATU. Substitution of compounds of formula (XXXVI) with compounds of formula (XXVIII-4) in the presence of a suitable base such as DIPEA gives compounds of formula (XXXVII). Final compounds of formula (XXXVIII) can be obtained by deprotection of compounds of formula (XXXVII) with a suitable acid such as trifluoroacetic acid or a reducing agent such as palladium on carbon in the presence of H2.

[0077] The compounds of the invention may be obtained as mixtures of diastereomers or enantiomers, which mixtures of diastereomers or enantiomers may be separated by methods well known in the art, for example (chiral) HPLC or SFC.

[0078] The present invention also relates to a method for producing a method for manufacturing a semiconductor device comprising the steps of: a) Compounds of formula (XVIII) using a suitable acid such as trifluoroacetic acid or a reducing agent such as palladium on carbon in the presence of H [ka] via deprotection of the compound of formula (XIX) [ka] Formation of; b) Compounds of formula (XXXIII) using a suitable reagent such as MeI [ka] followed by deprotection with a suitable acid such as trifluoroacetic acid or a reducing agent such as palladium on carbon in the presence of H to give a compound of formula (XXXV) [ka] Formation of c) Compounds of formula (XXXIII) using a suitable acid such as trifluoroacetic acid or a reducing agent such as palladium on carbon in the presence of H [ka] via deprotection of the compound of formula (XXXIV) [ka] Formation of; d) Compounds of formula (XXXVII) using a suitable acid such as trifluoroacetic acid or a reducing agent such as palladium on carbon in the presence of H [ka] via deprotection of the compound of formula (XXXVIII) [ka] Formation of; Including, In the formula, R 4 ' is R4 or R 4 -PG 3 And;L 1 is C 1~6 Alkyl or C 3~10 Cycloalkyl; R 7 is C 1~6 Alkyl, Amino C 1~6 Alkyl or Amino C 3~10 Cycloalkyl; R 7’ is R 7 -PG 5 PG 2 , P.G. 3 and P.G. 5 are independently a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl; It also relates to processes for the preparation of compounds of formula (I).

[0079] The compounds of formula (I) when prepared by the above process are also a subject of the present invention. EXAMPLES

[0080] The present invention will be more fully understood by reference to the following examples, which should not be construed as limiting the scope of the invention.

[0081] Abbreviation The present invention will be more fully understood by reference to the following examples, which should not be construed as limiting the scope of the invention.

[0082] The abbreviations used herein are as follows: MeCN: Acetonitrile aq.Aqueous solution DAST: Diethylaminosulfur trifluoride DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DMAP: 4-dimethylaminopyridine DMEDA: 1,2-Dimethylethylenediamine DMP: Dess-Martin periodinane FA: Formic acid I C 50 : The molar concentration of an inhibitor that produces 50% of the maximum response possible for that inhibitor. FBS: Fetal bovine serum HPLC: High Performance Liquid Chromatography MS(ESI): Mass spectrometry (electrospray ionization) Ms: methylsulfonyl MTBE: Methyl tert-butyl ether obsd.:Actual measurement PE: Petroleum ether DCM: dichloromethane TFA: Trifluoroacetic acid DIPEA: N,N-diisopropylethylamine TEA: Triethylamine HATU: 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate δ: chemical shift SFC: Supercritical Fluid Chromatography TLC: Thin Layer Chromatography

[0083] 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. Silica gel brand and pore size: 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.

[0084] 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, detectors: Micromass ZQ and UV2487, 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: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0085] 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 systems: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure 100 bar, UV detection at 254 or 220 nm.

[0086] LC / MS spectra of the compounds were obtained using 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 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 HO, B: 0.01875% TFA in acetonitrile, Basic condition I: A: 0.1% NH3·H2O in H2O, B: acetonitrile; Basic conditions II: A: 0.025% NH3·H2O in H2O, B: acetonitrile; Neutral conditions: A: H2O, B: Acetonitrile Mass Spectra (MS): Generally, only ions representing parent masses are reported, and unless otherwise stated, the mass ions quoted are the positive mass ions (M−H) + It is.

[0087] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0088] 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 suppliers without further purification unless otherwise noted.

[0089] Preparation Examples 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.

[0090] Intermediate 1: tert-Butyl N-[5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)-pyrrolidin-3-yl]carbamate [ka]

[0091] Step 1: Benzyl 4-(4-iodophenyl)sulfonylpiperazine-1-carboxylate [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 room temperature for 2 h. The mixture was concentrated in vacuo to give a residue, which was triturated in PE and washed with water to give the desired compound intermediate 1a (18.0 g, 37.0 mmol, 95.2% yield) as a white solid. MS observed (ESI + )[(M+H) + ]:487.0. 1 H NMR(400MHz, CDCl3)δ ppm 7.94(br d,J=8.8Hz,2H),7.89(m,2H),7.43(m,1H),7.32-7.33(m,4H),5.01(s,2H),3.12-3.14(m,8H).

[0092] Step 2: Benzyl 4-((4-(4-((tert-butoxycarbonyl)amino)-2-oxopyrrolidin-1-yl)phenyl)sulfonyl)piperazine-1-carboxylate [ka] To a mixture of compound intermediate 1a (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) and N1,N2-dimethylcyclohexane-1,2-diamine (5.26 g, 37.0 mmol). The mixture was stirred at 90° C. under nitrogen for 2 h. The mixture was diluted with EtOAc (200 mL) and then filtered through a fritted glass funnel. The filtrate was diluted with NH 3· The mixture was washed with HO (2 wt%, 200 mL), aqueous CaCl (150 mL, 2N) and brine (150 mL x 2). The filtrate was collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by preparative HPLC to give the desired compound intermediate 1b (13.5 g, 24.2 mmol, 65.3% yield) as a grey solid. MS Found (ESI + )[(M+H) + ]:559.3.

[0093] Step 3: tert-Butyl N-[5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate [ka] To a solution of compound intermediate 1b (500 mg, 0.90 mmol) in methanol (10 mL) was added Pd / C (10 wt%, 100.0 mg). The mixture was stirred at room temperature under H2 (15 psi) for 2 h. The mixture was diluted with MeOH (100 mL), filtered through a pad of Celite, and concentrated in vacuo to give the desired compound intermediate 1 (300 mg, 0.710 mmol, 78.96% yield) as a grey solid. MS Found (ESI + )[(M+H) + ]:425.3.

[0094] Intermediate 2: tert-Butyl N-[(3R)-5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate [ka] The title compound was prepared similarly to the preparation of compound intermediate 1 by using tert-butyl N-[(3R)-5-oxopyrrolidin-3-yl]carbamate instead of tert-butyl N-(5-oxopyrrolidin-3-yl)carbamate. Compound intermediate 2 was obtained as a white solid. MS observed (ESI + )[(M+H) + ]:425.2.

[0095] Intermediates 3A and 3B: (5S)-5-(hydroxymethyl)-3-(4-piperazin-1-ylsulfonylphenyl)oxazolidin-2-one and (5R)-5-(hydroxymethyl)-3-(4-piperazin-1-ylsulfonylphenyl)oxazolidin-2-one [ka]

[0096] Step 1: tert-Butyl 4-(4-iodophenyl)sulfonylpiperazine-1-carboxylate [ka] To a solution of 4-iodobenzenesulfonyl chloride (1.0 g, 3.31 mmol) and tert-butyl piperazine-1-carboxylate (739 mg, 3.97 mmol) in DCM (100 mL) was added TEA (668 mg, 6.61 mmol) dropwise at room temperature. The mixture was washed with aqueous NaHCO3 (100 mL), extracted with DCM (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give compound intermediate 3a (1.5 g, 3.32 mmol, 100% yield), which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:452.98.

[0097] Step 2: tert-Butyl 4-[4-[(5S)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl]phenyl]sulfonyl piperazine-1-carboxylate (Intermediate 5bA) and tert-Butyl 4-[4-[(5R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl]phenyl]sulfonyl piperazine-1-carboxylate (Intermediate 5bB) [ka] A degassed mixture of compound intermediate 3a (0.430 g, 951 μmol), 5-(hydroxymethyl)oxazolidin-2-one (111 mg, 951 μmol), N,N'-dimethylethane-1,2-diamine (29.3 mg, 333 μmol), CuI (63.4 mg, 333 μmol) and K3PO4 (404 mg, 1.9 mmol) in DMF (4 ml) was heated in a microwave reactor at 75 °C for 1 h. After completion, the mixture was poured into ice water, extracted with DCM (25 mL x 3), dried over anhydrous sodium sulfate and concentrated in vacuum to give the crude product, which was purified by silica gel chromatography (eluent of EtOAc:PE = 0-80%) to give an enantiomeric mixture of intermediate 3bA and intermediate 3bB (310 mg, 702 μmol, 73.9% yield). MS measured value (ESI + )[(M+H) + ]: 442.1. The resulting solid was then separated by SFC to give the two enantiomers intermediate 3bA (fast eluted) and intermediate 3bB (slow eluted). SFC conditions: Column: IA (250 mm x 30 mm, 5 um); 0.1% NH3H2OEtOH; Start B 50%, End B 50%; Flow rate (ml / min): 50.

[0098] Step 3: (5S)-5-(hydroxymethyl)-3-(4-piperazin-1-ylsulfonylphenyl)oxazolidin-2-one (Intermediate 3A) and (5R)-5-(hydroxymethyl)-3-(4-piperazin-1-ylsulfonylphenyl)oxazolidin-2-one (Intermediate 3B) [ka] Compound intermediate 3bA (60 mg, 0.136 mmol) and TFA (0.5 mL, 6.49 mmol) were mixed in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h. After completion, the residue was concentrated in vacuo to give crude compound intermediate 3A (45 mg, 97%) as a pale yellow oil. MS observed (ESI + )[(M+H) + ]:342.1. Intermediate 3B was prepared similarly to the procedure described for the preparation of intermediate 3A by using intermediate 3bB instead of intermediate 3bA as the starting material. MS (ESI + )[(M+H) + ]:342.1.

[0099] Intermediate 4: tert-Butyl 4-[5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]piperazine-1-carboxylate [ka]

[0100] Step 1: Benzyl 4-[4-(4-hydroxy-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazine-1-carboxylate [ka] To a solution of compound intermediate 3a (5.5 g, 11.31 mmol), 4-hydroxypyrrolidin-2-one (2.29 g, 22.62 mmol) and potassium carbonate (4.69 g, 33.93 mmol) in NMP (25 mL) was added copper iodide (1.51 g, 7.92 mmol) and trans-N,N-dimethylcyclohexane (1.13 g, 7.92 mmol) under nitrogen. The mixture was stirred at 90 °C. After 2 h, the mixture was diluted with EtOAc (600 mL) and filtered. The filtrate was washed with 2% NH3·H2O aqueous solution (100 mL × 2), CaCl2 aqueous solution (100 mL × 3) and brine (100 mL × 2). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was triturated in PE (100 mL) to give compound intermediate 4a (4.5 g, 9.81 mmol, 86.78% yield) as a brown solid. MS observed (ESI + )[(M+H) + ]:459.9.

[0101] Step 2: Benzyl 4-[4-(5-oxo-2H-pyrrol-1-yl)phenyl]sulfonylpiperazine-1-carboxylate [ka] To a solution of compound intermediate 4a (4.5 g, 9.79 mmol) and DIPEA (5.05 g, 39.17 mmol) in DCM (80 mL) was added methanesulfonyl chloride (1.58 mL, 20.35 mmol) slowly at 0° C. The mixture was then stirred at room temperature for 3 h. After completion, the reaction mixture was poured into water (100 mL) at 0° C. and stirred at room temperature for 30 min. The solution was then extracted with DCM (200 mL×3) and washed with aqueous NaOH (0.5 N, 100 mL×3) and brine (100 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was triturated in PE / MTBE (100 mL, v / v=1:1) to give compound intermediate 4b (3.5 g, 7.95 mmol, 81.13% yield) as a grey solid. MS measured value (ESI + )[(M+H) +]:441.9.

[0102] Step 3: tert-Butyl 4-[1-[4-(4-benzyloxycarbonylpiperazin-1-yl)sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]piperazine-1-carboxylate [ka] To a solution of compound intermediate 4b (2.0 g, 4.53 mmol) in NMP (0.5 mL) was added 1-BOC-piperazine (10.0 g, 53.69 mmol). The mixture was stirred at 90 °C for 2 h. After completion, the mixture was diluted with water (100 mL), extracted with EtOAc (100 mL x 2), and washed with brine (100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluent of EtOAc:PE = 0-100%) to give compound intermediate 4c (1.6 g, 2.55 mmol, 56.26% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:628.3.

[0103] Step 4: tert-Butyl 4-[5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]piperazine-1-carboxylate [ka] To a solution of compound intermediate 4c (1.5 g, 2.39 mmol) in THF (4 mL) was added Pd / C (800 mg, 2.39 mmol). The mixture was stirred under H2 (15 psi) at 25°C for 2 h. Upon completion, the mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give compound intermediate 4 (550 mg, 1.11 mmol, 38.18% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:494.3.

[0104] Intermediate 5: trans-4-[[2-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylic acid [ka]

[0105] Step 1: trans-Methyl 4-(hydroxymethyl)cyclohexanecarboxylate [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 under nitrogen 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 (eluent of EtOAc:PE=0-50%) to give compound intermediate 5a (28 g, 162.58 mmol, 60.55% yield) as a colorless oil.

[0106] Step 2: trans-Methyl 4-formylcyclohexanecarboxylate [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 nitrogen at -60 °C for 0.5 h. Then a solution of compound intermediate 5a (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 EtOAc (600 mL) and washed with aqueous CaCl2 (100 mL x 3) and brine (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluent: EtOAc:PE=3-50%) to give compound intermediate 5b (24 g, 141 mmol, 86.73% yield) as a pale yellow oil.

[0107] Step 3: trans-Methyl 4-[(2,6-dichloro-4-pyridyl)-hydroxy-methyl]cyclohexanecarboxylate [ka] To a solution of 2,6-dichloro-4-iodo-pyridine (42.48 g, 155.1 mmol) in THF (50.0 mL) was added isopropylmagnesium chloride·lithium chloride complex in THF (130.16 mL, 169.2 mmol) under nitrogen 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 intermediate 5b (24.0 g, 141 mmol) in THF (100 mL) at −40° C. The mixture was stirred at 25° C. for 3 h. After completion, the reaction mixture was poured into saturated aqueous NH4Cl solution (200 mL) and extracted with EtOAc (300 mL×3). The organic layer was washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluent of EtOAc:PE = 0-30%) to give compound intermediate 5c (33 g, 103.71 mmol, 73.55% yield) as a white solid. MS observed (ESI + ) [(M+Cl) + ]:317.8.

[0108] Step 4: trans-Methyl 4-(2,6-dichloropyridine-4-carbonyl)cyclohexanecarboxylate [ka] To a solution of compound intermediate 5c (33.0 g, 103.71 mmol) in THF (150 mL) was added DMP (48.39 g, 114.08 mmol) slowly at 0° C. under nitrogen. The reaction was stirred at 25° C. for 3 h. After completion, the mixture was diluted with EtOAc (500 mL) and then poured into aqueous K2CO3 (200 mL) and kept stirring at room temperature for 0.5 h. The organic layer was separated, washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude compound intermediate 5d (30 g, 94.88 mmol, 91.49% yield) as a white solid, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:315.8.

[0109] Step 5: trans-Methyl 4-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclohexanecarboxylate [ka] To a solution of compound intermediate 5d (29.5 g, 93.3 mmol) in DCM (20 mL) was added DAST (135.35 g, 839.71 mmol) and stirred at 45° C. for 12 h. After completion, the reaction mixture was poured into ice water and extracted with EtOAc (200 mL×3). The combined organic layers were washed with aqueous KCO (100 mL×2) and brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. The residue was recrystallized with MeOH (150 mL) to give compound intermediate 5e (25.6 g, 75.7 mmol, 81.13% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:337.8.

[0110] Step 6: trans-Methyl 4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylate [ka] To a solution of compound intermediate 5e (3.58 g, 10.6 mmol) and compound intermediate 2 (4.5 g, 10.6 mmol) in DMSO (10 mL) was added DIPEA (5.55 mL, 31.8 mmol). The mixture was stirred at 115° C. for 18 h. Upon completion, the reaction mixture was concentrated in vacuo and purified by preparative HPLC to give compound intermediate 5f (7 g, 9.64 mmol, 90.93% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:670.1.

[0111] Step 7: trans-4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylic acid [ka] To a solution of compound intermediate 5e (7.0 g, 9.64 mmol) in MeCN (100 mL) and water (10 mL) was added TEA (13.43 mL, 96.39 mmol), lithium bromide (16.74 g, 192.78 mmol) in one portion. The reaction was stirred at 40° C. for 12 hours. Upon completion, the reaction was diluted with 2-methyltetrahydrofuran (500 mL) and adjusted to pH 5 with 2N aqueous HCl. The resulting organic layer was washed with 0.2N aqueous HCl (100.0 mL×2) and brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was recrystallized with MeCN (100 mL) to give compound intermediate 5 (6.7 g, 9.41 mmol, 97.6% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:712.1.

[0112] Intermediate 6: trans-4-[[2-chloro-6-[4-[4-(4-methyl-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylic acid [ka] Compound intermediate 6 was prepared similarly to the procedure described for the preparation of compound intermediate 5 by using compound intermediate 2 instead of compound intermediate 1 as the coupling reagent in step 6. MS observed (ESI + )[(M+H) + ]:656.1.

[0113] Intermediate 7: cis-4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylic acid [ka] Compound intermediate 7 was prepared similarly to the procedure described for the preparation of compound intermediate 5 by using cis-4-methoxycarbonylcyclohexanecarboxylic acid instead of trans-4-methoxycarbonylcyclohexanecarboxylic acid in step 1. MS observed (ESI + )[(M+H) + ]:712.2.

[0114] Intermediate 8: 3-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclopentanecarboxylic acid [ka] The title compound was prepared in a similar manner to the preparation of compound intermediate 5, by using 3-methoxycarbonylcyclopentanecarboxylic acid instead of trans-4-methoxycarbonylcyclohexanecarboxylic acid in step 1. Compound intermediate 8 (20.0 mg) was obtained as a pale yellow oil. MS Found (ESI + ) [(M+Cl) + ]:698.1.

[0115] Intermediate 9: 4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]norbornane-1-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 5 by using 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid instead of trans-4-methoxycarbonylcyclohexanecarboxylic acid in step 1. Compound intermediate 9 (150.0 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:724.4.

[0116] Intermediate 10: 4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[2.2.2]octane-1-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 5 by using 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid instead of trans-4-methoxycarbonylcyclohexanecarboxylic acid in step 1. Compound intermediate 10 (250.0 mg) was obtained as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:738.4.

[0117] Intermediate 11: 3-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[1.1.1]pentane-1-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 5 by using 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of trans-4-methoxycarbonylcyclohexanecarboxylic acid in step 1. Compound intermediate 11 (150.0 mg) was obtained as a pale yellow oil. MS Found (ESI + )[(M+H) + ]:696.0.

[0118] Intermediate 12: 4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]benzoic acid [ka]

[0119] Step 1: Methyl 4-[(2,6-dichloro-4-pyridyl)-hydroxy-methyl]benzoate [ka] To a mixture of 2,6-dichloro-4-iodo-pyridine (36.71 g, 134.02 mmol) in THF (180 mL) was added isopropylmagnesium chloride·lithium chloride complex solution (1.3 M in THF, 121.83 mL) at −40° C. under nitrogen. The mixture was stirred at 25° C. for 2 h. Then, to the mixture was added methyl 4-formylbenzoate (20 g, 121.83 mmol) in THF (200 mL) at −40° C. The mixture was stirred at 25° C. for 2 h. After completion, the mixture was added to saturated aqueous NH4Cl solution (1 L) in ice-water bath and extracted with EtOAc (500 mL×2). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound intermediate 12a (30 g, 96.11 mmol, 78.88% yield) as a yellow solid. MS observed (ESI + )[(M+H) + ]:312.1.

[0120] Step 2: Methyl 4-(2,6-dichloropyridine-4-carbonyl)benzoate [ka] To a solution of compound intermediate 12a (25 g, 80.09 mmol) in THF (250 mL) was added DMP (37.37 g, 88.10 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. After completion, the reaction mixture was filtered and the filtrate was diluted with water (200 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was suspended in PE (50 mL) and the resulting precipitate was collected by filtration. Compound intermediate 12b (20.3 g, 65.46 mmol, 81.73% yield) was obtained as a white solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.21 (d, J = 8.44 Hz, 2H), 7.86 (d, J = 8.44 Hz, 2H), 7.54 (s, 2H), 3.99 (s, 3H).

[0121] Step 3: Methyl 4-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]benzoate [ka] To a mixture of compound intermediate 12b (20.3 g, 65.46 mmol) in DCM (150 mL), DAST (84.41 g, 523.65 mmol) was added and stirred at 40 °C for 12 h. After completion, the mixture was added to aqueous NaHCO3 (500 mL) in an ice-water bath and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (EtOAc:PE = 2-5%) to give compound intermediate 12c (20.2 g, 60.82 mmol, 92.92% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:332.0.

[0122] Step 4: Methyl 4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]benzoate [ka] To a solution of compound intermediate 2 (100.0 mg, 0.240 mmol) and compound intermediate 12c (78.24 mg, 0.240 mmol) in DMSO (1 mL) was added DIPEA (0.2 mL, 0.710 mmol). The mixture was stirred at 110° C. for 12 h. After completion, the mixture was diluted with EtOAc (50 mL) and water (30 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude residue compound intermediate 12d (120 mg, 0.170 mmol, 70.73% yield) as a yellow solid, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:720.3.

[0123] Step 5: 4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]benzoic acid [ka] To a solution of compound intermediate 12d (116.74 mg, 0.160 mmol) in MeCN (5 mL) and water (1 mL) was added LiBr (69.71 mg, 0.810 mmol) and TEA (100.5 mg, 0.810 mmol). The mixture was stirred at 60° C. for 12 h. After completion, the mixture was diluted with EtOAc (50 mL) and water (30 mL). The organic phase was washed with aqueous HCl (1M, 50 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the residue compound intermediate 12 (105 mg, 0.150 mmol, 91.73% yield) as a yellow solid, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:706.4.

[0124] Intermediate 13: 4-[[2-[4-[4-[4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]benzoic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 12 by using compound intermediate 1 instead of compound intermediate 2 in step 4. Compound intermediate 13 (280.0 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:706.0.

[0125] Intermediate 14: 5-[[2-chloro-6-[4-[4-[(4R)-4-methyl-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyridine-2-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 12 by using methyl 5-formylpyridine-2-carboxylate instead of methyl 4-formylbenzoate in step 1. Compound intermediate 14 (105 mg, 0.150 mmol, 91.73% yield) was obtained as a yellow solid. MS (ESI + )[(M+H) + ]:707.4.

[0126] Intermediate 15: 6-[[2-chloro-6-[4-[4-[(4R)-4-methyl-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyridine-3-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 12 by using methyl 6-formylpyridine-3-carboxylate instead of methyl 4-formylbenzoate in step 1. Compound intermediate 15 (886 mg, 1.25 mmol, 80% yield) was obtained as a yellow solid. MS (ESI + )[(M+H) + ]:707.4.

[0127] Intermediate 16: 5-[[2-chloro-6-[4-[4-[(4R)-4-methyl-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxylic acid [ka]

[0128] Step 1: Pyrazine-2,5-dicarbonyl chloride [ka] To a solution of pyrazine-2,5-dicarboxylic acid (25.0 g, 148.71 mmol) in thionyl chloride (106.15 g, 892.27 mmol) was added DMF (0.5 mL, 148.71 mmol). The reaction was stirred at 60° C. for 3 hours. Upon completion, the mixture was concentrated in vacuo to give crude compound intermediate 16a (27.8 g, 135.61 mmol, 91.19% yield) as a brown solid, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]: 197.2 (quenched with MeOH).

[0129] Step 2: Dimethylpyrazine-2,5-dicarboxylate [ka] To a solution of methanol (100 mL, 2469 mmol) and TEA (53.03 mL, 380.49 mmol) in THF (100 mL) was added compound intermediate 16a (26.0 g, 126.83 mmol) in THF (150 mL) dropwise at 0° C. The reaction was then stirred at 20° C. for 3 h. After completion, the mixture was diluted with EtOAc (600 mL) and water (50 mL). The organic layer was washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was recrystallized with MTBE (200 mL) to give compound intermediate 16b (23.5 g, 119.8 mmol, 94.46% yield) as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:197.2([M+H] + ).

[0130] Step 3: Methyl 5-(2,6-dichloropyridine-4-carbonyl)pyrazine-2-carboxylate [ka] To a solution of 2,6-dichloro-4-iodopyridine (20.0 g, 73.02 mmol) in THF (60 mL) was added isopropylmagnesium chloride·lithium chloride complex (59 mL, 76.67 mmol) under nitrogen. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was then added dropwise to a solution of compound intermediate 16b (23.5 g, 119.8 mmol) in THF (360 mL) at 70 °C for 1 h. After addition, the reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluent: EtOAc:PE = 5-50%) to give compound intermediate 16c (10.8 g, 34.6 mmol, 47.39% yield) as a pale yellow solid. MS observed (ESI + )[(M+H) + ]:312.1.

[0131] Step 4: Methyl 5-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]pyrazine-2-carboxylate [ka] To a solution of compound intermediate 16c (10.8 g, 34.6 mmol) in DCM (40 mL) was added DAST (55.78 g, 346.03 mmol) in one portion. The reaction was stirred at 50 °C for 32 h. Upon completion, the reaction was poured into ice water and then the pH was adjusted to 7-8 with saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent of EtOAc:PE = 5-25%) to give intermediate 16d (10.2 g, 30.53 mmol, 86.46% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:334.1. 1H NMR (400MHz, DMSO-d6) δ ppm:9.38-9.43(m,1H),,9.30-9.35(m,1H),7.95-8.01(m,2H),3.98-4.02(m,3H).

[0132] Step 5: Methyl 5-[[2-chloro-6-[4-[4-[(4R)-4-methyl-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxylate [ka] A mixture of compound intermediate 2 (639 mg, 1.51 mmol), compound intermediate 16d (504 mg, 1.51 mmol), and DIPEA (584 mg, 4.52 mmol) in DMSO (3 mL) was stirred at 120 °C for 12 h. After completion, the mixture was poured into water and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent of EtOAc:PE = 10-25%) to give compound intermediate 16e (762 mg, 70% yield) as a white solid. MS observed (ESI + )[(M+H) + ]:722.2.

[0133] Step 6: 5-[[2-chloro-6-[4-[4-[(4R)-4-methyl-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxylic acid [ka] A mixture of compound intermediate 16e (150 mg, 208 μmol), lithium hydroxide hydrate (85.2 mg, 2.08 mmol) in MeOH (3 mL) and water (0.5 mL) was heated at 60° C. for 1 h. After removal of the solvent, the resulting residue was treated with 5N aqueous HCl to adjust pH=5. The mixture was extracted with EtOAc (100 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give compound intermediate 16 (132.4 mg, 0.187 mmol, 90% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:708.2.

[0134] Intermediate 17: tert-Butyl N-[1-(3-aminopropyl)-5-(tert-butoxycarbonylamino)-3-piperidyl]carbamate [ka]

[0135] Step 1: tert-Butyl N-[5-(tert-butoxycarbonylamino)-3-pyridyl]carbamate [ka] To a solution of pyridine-3,5-diamine (200 mg, 1.74 mmol) in 1,4-dioxane (10 mL) was added Boc2O (1.9 g, 8.71 mmol) and DMAP (638.10 mg, 5.22 mmol) at 25° C. The mixture was stirred at 110° C. for 12 h. After completion, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL×3). The organic layer was washed with brine (50 ml×2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. To the obtained residue was added MeOH (20 mL) and K2CO3, and the mixture was stirred at 25° C. for 1 h. The mixture was then filtered and concentrated in vacuo to give the crude compound, which was purified by silica gel chromatography (eluent: EtOAc:PE=0.5-50%) to give compound intermediate 17a (500 mg, yield: 92.8%) as a yellow solid. MS observed (ESI+ )[(M+H) + ]:309.9.

[0136] Step 2: tert-Butyl N-[5-(tert-butoxycarbonylamino)-3-piperidyl]carbamate [ka] To a solution of compound intermediate 17a (6.2 g, 20.04 mmol) in THF (1 mL) and acetic acid (4.0 mL, 0.320 mmol) was added PtO2 (100.0 mg, 0.320 mmol). The mixture was stirred under H2 at 60 °C for 12 h. The mixture was then filtered through a Celite pad, and the filtrate was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give compound intermediate 17b (1.6 g, 5.07 mmol, 25.31% yield). MS observed (ESI + )[(M+H) + ]:316.2.

[0137] Step 3: tert-Butyl N-[1-[3-(benzyloxycarbonylamino)propyl]-5-(tert-butoxycarbonylamino)-3-piperidyl]carbamate [ka] A solution of benzyl N-(3-oxopropyl)carbamate (105 mg, 0.510 mmol) and compound intermediate 17b (160.0 mg, 0.510 mmol) in methanol (3 mL) was stirred for 1 h. Sodium cyanoborohydride (95.63 mg, 1.52 mmol) was then added and the reaction was stirred at 20° C. for 2 h. Upon completion, the reaction was added with aqueous LiOH (1 M, 20 mL) and diluted with EtOAc (20 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound intermediate 17c (77 mg, 0.150 mmol, 29.96% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:507.4.

[0138] Step 4: tert-Butyl N-[1-(3-aminopropyl)-5-(tert-butoxycarbonylamino)-3-piperidyl]carbamate [ka] To a solution of compound intermediate 17c (67.0 mg, 0.130 mmol) in methanol (1 mL) was added Pd / C (280.36 mg, 2.64 mmol) and formic acid (3043.35 mg, 66.12 mmol) in one portion. The reaction was stirred at 25° C. for 1 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was resuspended in saturated aqueous Na2CO3 (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound intermediate 17 (49 mg, 0.130 mmol, 99.47% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:373.3.

[0139] Intermediate 18: tert-Butyl N-[2-[3-aminopropyl-[2-(tert-butoxycarbonyl-amino)ethyl]amino]ethyl]carbamate [ka]

[0140] Step 1: tert-Butyl N-[2-[3-(benzyloxycarbonylamino)propyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl]carbamate [ka] To a solution of tert-butyl N-[2-[2-(tert-butoxycarbonylamino)ethylamino]ethyl]carbamate (500.0 mg, 1.65 mmol) in THF (5 mL) and MeOH (5 mL) was added benzyl N-(3-oxopropyl)carbamate (512.27 mg, 2.47 mmol) and NaBH3CN (1035.6 mg, 16.48 mmol). After stirring at 45°C for 3 h, the reaction was concentrated in vacuo. The resulting residue was dissolved in EtOAc (20 ml) and washed with water (30 mL) and brine (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude compound, which was purified by preparative HPLC to give compound intermediate 18a (350 mg, 0.710 mmol, 42.94% yield) as a colorless oil. MS Found (ESI + )[(M+H) + ]:495.0.

[0141] Step 2: tert-Butyl N-[2-[3-aminopropyl-[2-(tert-butoxycarbonylamino)ethyl]amino]ethyl]carbamate [ka] To a solution of compound intermediate 18a (350 mg, 0.710 mmol) in MeOH (2 mL) was added Pd / C (1000 mg, 0.710 mmol) under nitrogen, then degassed with H2 (1.0 L x 3) and stirred at 20 °C for 2 h. After completion, the reaction mixture was filtered through a Celite pad. The filtrate was then washed with MeOH (20 mL) and concentrated in vacuo to give compound intermediate 18 (200 mg, 0.550 mmol, 78.4% yield) as a colorless oil. MS observed (ESI + )[(M+H) + ]:361.1.

[0142] Intermediate 19: tert-Butyl 6-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]bicyclo[3.1.0]-hexane-3-carboxylate [ka]

[0143] Step 1: tert-Butyl 6-formylbicyclo[3.1.0]hexane-3-carboxylate [ka] To a solution of tert-butyl 6-(hydroxymethyl)bicyclo[3.1.0]hexane-3-carboxylate (4.5 g, 21.2 mmol) and TEMPO (0.33 g, 2.12 mmol) in EtOAc (23.55 mL) under nitrogen at 0° C. was added trichloroisocyanuric acid (4.93 g, 21.2 mmol). 。 The mixture was stirred at 0° C. for 2 h. After completion, the mixture was diluted with water (300 mL), extracted with EtOAc (500 mL×2), washed with aqueous HCl (1N, 100 mL), aqueous K2CO3 (300 ml) and brine (200 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound intermediate 19a (3.1 g, 14.74 mmol, 69.55% yield) as a yellow oil.

[0144] Step 2: tert-Butyl 6-[(2,6-dichloro-4-pyridyl)-hydroxy-methyl]bicyclo[3.1.0]-hexane-3-carboxylate [ka] To a solution of 2,6-dichloro-4-iodopyridine (4.84 g, 17.69 mmol) in THF (10 mL) was added isopropylmagnesium chloride·lithium chloride complex solution (1.3 M in THF, 17.01 mL, 22.11 mmol) at -40 °C. The mixture was stirred at 25 °C for 1 h. Then, compound intermediate 19a (3.1 g, 14.74 mmol) in THF (10 mL) was added to the reaction at -40 °C and the mixture was stirred at 25 °C for 1 h. After completion, the mixture was quenched with saturated aqueous NH4Cl solution (300 mL), extracted with EtOAc (500 mL x 2) and washed with brine (300 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give the crude residue, which was purified by silica gel column (eluent of EtOAc:PE=0-100%). Compound intermediate 19b (4.3 g, 12 mmol, 81.41% yield) was obtained as a yellow oil. MS (ESI + )[(M+H) + ]:358.1.

[0145] Step 3: tert-Butyl 6-(2,6-dichloropyridine-4-carbonyl)bicyclo[3.1.0]hexane-3-carboxylate [ka] To a solution of DMP (5.82 g, 13.73 mmol) in THF (30 mL) was added compound intermediate 19b (4.1 g, 11.44 mmol). The reaction mixture was stirred at 25° C. for 1 h. After completion, the mixture was diluted with EtOAc (300 mL) and adjusted to pH=9 with aqueous K2CO3. The resulting mixture was then filtered through a fritted glass funnel. The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give compound intermediate 19c (3.9 g, 10.95 mmol, 95.66% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:356.1.

[0146] Step 4: tert-Butyl 6-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]bicyclo[3.1.0]-hexane-3-carboxylate [ka] To a solution of compound intermediate 19c (3.8 g, 10.67 mmol) in DCM (5 mL), DAST (30 mL, 10.67 mmol) was added and the mixture was stirred at 50 °C for 60 h. After completion, the mixture was quenched with ice water and adjusted to pH = 9 with 1M NaHCO3 aqueous solution. The mixture was extracted with EtOAc (500 mL x 2) and washed with brine (500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue, which was purified by silica gel column (eluent of EtOAc:PE = 0-10%) and preparative HPLC to give compound intermediate 19 (200 mg, 0.260 mmol, 2.48% yield). MS observed (ESI + )[(M+H) + ]:378.3.

[0147] Intermediate 20: tert-Butyl N-[(3R)-5-oxo-1-(5-piperazin-1-ylsulfonyl-2-pyridyl)pyrrolidin-3-yl]carbamate [ka]

[0148] Step 1: 6-Bromopyridine-3-sulfonyl chloride [ka] To a solution of 6-bromopyridin-3-amine (5.0 g, 28.9 mmol) in HCl (85 mL, 1020 mmol) was slowly added NaNO2 (1.79 g, 26.01 mmol) in water (25 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. To a stirred solution of CuCl2 (1976.76 mg, 11.56 mmol) in acetic acid (50 mL) was bubbled with SO2 at 0 °C for 0.5 h. The diazotized reaction mixture prepared above was then added. The resulting mixture was slowly warmed to room temperature and stirred for 30 min. After completion, EtOAc (200 mL) and water (200 mL) were added to the mixture. The organic phase was washed with aqueous Na2CO3, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound intermediate 20a (5 g, 23.58 mmol, 81.59% yield) as a yellow oil, which was used directly in the next step.

[0149] Step 2: Benzyl 4-[(6-chloro-3-pyridyl)sulfonyl]piperazine-1-carboxylate [ka] To a solution of compound intermediate 20a (4.13 g, 19.49 mmol) in DCM (1 mL) was added DIPEA (12.1 g, 97.47 mmol) and 1-Cbz-piperazine (4.29 g, 19.49 mmol). The mixture was stirred at 25° C. for 30 min. The mixture was then concentrated in vacuo to give a crude residue, which was triturated in MeOH to give compound intermediate 20b (4.5 g, 11.37 mmol, 52.43% yield) as a white solid. MS observed (ESI + )[(M+H)] + :395.8.

[0150] Step 3: Benzyl 4-[(6-iodo-3-pyridyl)sulfonyl]piperazine-1-carboxylate [ka] To a solution of compound intermediate 20c (4.0 g, 10.1 mmol) in acetone (100 mL) was added NaI (4.5 g, 30.31 mmol) and TFA (2.0 mL, 10.1 mmol). The mixture was stirred at 25° C. for 12 h. Upon completion, the mixture was concentrated in vacuo to give a crude residue which was triturated in MeOH to give compound intermediate 20c (2.5 g, 5.13 mmol, 50.77% yield) as a white solid. MS Found (ESI + )[(M+H)] + :487.7.

[0151] Step 4: Benzyl 4-[[6-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]-3-pyridyl]sulfonyl]piperazine-1-carboxylate [ka] To a solution of tert-butyl N-[(3R)-5-oxopyrrolidin-3-yl]carbamate (123.27 mg, 0.620 mmol) and compound intermediate 20c (200.0 mg, 0.410 mmol) in DMF (1 mL) was added CuI (62.38 mg, 0.330 mmol), K2CO3 (169.91 mg, 1.23 mmol) and DMEDA (28.89 mg, 0.330 mmol). The mixture was stirred at 70 °C under nitrogen for 2 h. After completion, the mixture was added with EtOAc (50 mL) and filtered. To the organic phase was added NH3·H2O (5%, 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by preparative HPLC to give compound intermediate 20d (160 mg, 0.290 mmol, 69.66% yield) as a white solid. MS Found (ESI+) [(M+H)] + :560.0.

[0152] Step 5: tert-Butyl N-[(3R)-5-oxo-1-(5-piperazin-1-ylsulfonyl-2-pyridyl)pyrrolidin-3-yl]carbamate [ka] To a solution of compound intermediate 20d (160.0 mg, 0.290 mmol) in methanol (20 mL) was added Pd / C (80.0 mg, 0.060 mmol). The mixture was stirred under H2 (15 psi) at 25°C for 2 h. After completion, the mixture was filtered through Celite. The filtrate was concentrated in vacuo to give crude compound intermediate 20 (100 mg, 0.240 mmol, 82.2% yield) as a white solid, which was used directly in the next step. MS Found (ESI+) [(M+H)] + :426.2.

[0153] Intermediate 21: tert-butyl N-[(3R)-5-oxo-1-[4-(4-piperidylsulfonyl)phenyl]pyrrolidin-3-yl]carbamate [ka]

[0154] Step 1: Benzyl 4-(4-iodophenyl)sulfanylpiperidine-1-carboxylate [ka] To a solution of 4-bromobenzenethiol (5.0 g, 26.45 mmol), benzyl 4-hydroxypiperidine-1-carboxylate (4.4 mL, 29.09 mmol) and tributylphosphine (8.03 g, 39.67 mmol) in THF (150 mL) was added N,N,N,N-tetramethylazodicarboxamide (6.83 g, 39.67 mmol) at 0° C. The mixture was stirred at 45° C. for 2 h. After completion, the reaction mixture was diluted with water (400 mL), extracted with EtOAc (400 mL×2) and washed with brine (500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel column (eluent of EtOAc:PE=0-10%) to give compound intermediate 21a (7.5 g, 18.46 mmol, 69.79% yield) as a colorless oil. MS Found (ESI+) [(M+H)] + :407.2.

[0155] Step 2: Benzyl 4-(4-iodophenyl)sulfinylpiperidine-1-carboxylate [ka] To a solution of compound intermediate 21a (7.3 g, 17.97 mmol) in THF (100 mL) was added m-CPBA (4.38 g, 21.56 mmol). The reaction was stirred at 25° C. for 2 h. Upon completion, the reaction mixture was quenched with saturated aqueous Na2SO3 and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column to give compound intermediate 21b (5.7 g, 13.5 mmol, 75.12% yield) as a white solid. MS Found (ESI+) [(M+H)] + :424.1.

[0156] Step 3: Benzyl 4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfinylpiperidine-1-carboxylate [ka] To a solution of compound intermediate 21c (237.04 mg, 1.18 mmol) in DMF (5 mL) was added tert-butyl N-[(3R)-5-oxopyrrolidin-3-yl]carbamate (355.57 mg, 1.78 mmol), CuI (157.74 mg, 0.830 mmol), DMEDA (72.93 mg, 0.830 mmol) and K2CO3 (490.13 mg, 3.55 mmol) at 30° C. The reaction mixture was stirred at 90° C. under nitrogen for 2 h. After completion, the reaction mixture was filtered and the filtrate was dissolved in EtOAc (200 mL). The organic layer was washed with brine (50 mL×3) and concentrated in vacuo to give a crude residue. The residue was purified by preparative HPLC to give compound intermediate 21c (450 mg, 0.830 mmol, 70.17% yield) as a colorless oil. MS Found (ESI+) [(M+H)] + :542.2.

[0157] Step 4: Benzyl 4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperidine-1-carboxylate [ka] To a solution of compound intermediate 21c (220.0 mg, 0.410 mmol) in THF (5 mL) was added m-CPBA (164.92 mg, 0.810 mmol) at 30° C. The reaction mixture was stirred at 30° C. for 2 h. After completion, the reaction mixture was quenched with saturated aqueous Na2SO3 (20 mL) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give compound intermediate 21d (180 mg, 0.320 mmol, 79.47% yield) as a white solid. MS observed (ESI+) [(M+H)] + :558.3.

[0158] Step 5: tert-Butyl N-[(3R)-5-oxo-1-[4-(4-piperidylsulfonyl)phenyl]pyrrolidin-3-yl]carbamate [ka] To a solution of compound intermediate 21d (180.0 mg, 0.320 mmol) in methanol (5 mL) was added formic acid (5 mL) and Pd / C (100 mg) under nitrogen at 30° C. After stirring at 30° C. for 16 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a crude residue, which was purified by preparative HPLC to give compound intermediate 21 (100 mg, 0.240 mmol, 73.15% yield) as a white solid. MS observed (ESI+) [(M+H)] + :424.2.

[0159] Intermediate 22: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate [ka]

[0160] Step 1: Benzyl 4-[4-[4-(3-hydroxypropylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazine-1-carboxylate [ka] To a solution of compound intermediate 4b (5.0 g, 11.33 mmol) in NMP (50 mL) was added 3-amino-1-propanol (5.2 mL, 67.95 mmol). The mixture was stirred at 90° C. for 2 h. After completion, the mixture was diluted with water (150 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude residue compound intermediate 22a, which was used in the next step without further purification. MS observed (ESI +)[(M+H) + ]:517.2.

[0161] Step 2: Benzyl 4-[4-[4-[tert-butoxycarbonyl(3-hydroxypropyl)amino]-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazine-1-carboxylate [ka] To a solution of compound intermediate 22a (5.2 g, 10.07 mmol) in DCM (50 mL), DIPEA (7.01 mL, 40.26 mmol) and di-t-butyl dicarbonate (4.63 mL, 20.13 mmol) were added in an ice-water bath, and the reaction was then stirred at 25° C. for 2 h. After completion, the mixture was concentrated in vacuo and purified by silica gel chromatography (eluent of MeOH:DCM=0%-10%) to give compound intermediate 22b (5.8 g, 9.4 mmol, 93.43% yield) as a pale yellow solid. MS observed (ESI + )[(M+H) + ]:617.3.

[0162] Step 3: Benzyl 4-[4-[4-[3-bromopropyl(tert-butoxycarbonyl)amino]-2-oxo-pyrrolidin-1-yl]phenyl]sulfonyl piperazine-1-carboxylate [ka] To a solution of compound intermediate 22b (5.8 g, 9.4 mmol) in DCM (60 mL) was added carbon tetrabromide (6.24 g, 18.81 mmol) under nitrogen at 0° C. 、 Then triphenylphosphine (6.17 g, 23.51 mmol, 2.5 equiv) was added into the solution. The mixture was stirred at 0° C. for 2 h. After completion, the mixture was washed with brine (60 mL×3). The organic layer was concentrated in vacuo to give the crude, which was purified by reverse phase chromatography to give compound intermediate 22c (5.4 g, 7.95 mmol, 84.49% yield) as a pale yellow solid. MS Found (ESI + )[(M+H)+ ]:679.2.

[0163] Step 4: Benzyl 4-[4-[4-[3-aminopropyl(tert-butoxycarbonyl)amino]-2-oxo-pyrrolidin-1-yl]phenyl]sulfonyl piperazine-1-carboxylate [ka] To a solution of compound intermediate 22c (5.0 g, 7.36 mmol) in ethanol (50 mL) was added ammonium hydroxide (10.0 mL, 30%). The mixture was stirred at 50° C. for 4 hours. Upon completion, the mixture was concentrated in vacuo to give compound intermediate 22d (3.2 g, 5.2 mmol, 64.99% yield) as a yellow solid. MS observed (ESI + )[(M+H) + ]:616.3.

[0164] Step 5: Benzyl 4-[4-[4-[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)-propyl]amino]-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazine-1-carboxylate [ka] To a solution of compound intermediate 22d (2.0 g, 3.25 mmol) in DCM (20 mL) was added DIPEA (1.7 mL, 9.74 mmol) and di-t-butyl dicarbonate (1.49 mL, 6.5 mmol) in an ice-water bath, and the reaction was then stirred at 25° C. for 2 h. After completion, the mixture was concentrated in vacuo and purified by silica gel chromatography (eluent of MeOH:DCM=0%-10%) to give compound intermediate 22e (2.1 g, 2.93 mmol, 90.31% yield) as a white solid. MS observed (ESI + )[(M+Na) + ]:738.3.

[0165] Step 6: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate [ka] To a solution of compound intermediate 22e (1.0 g, 1.4 mmol) in THF (30 mL) was added Pd / C (100 mg). The mixture was stirred under H2 at 50 °C for 16 h. After completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column (eluent of MeOH:DCM = 0% to 10%) to give compound intermediate 22 (620 mg, 1.07 mmol, 72.48% yield) as a white solid. MS observed (ESI + )[(M+H) + ]:582.3. 1 H NMR(400MHz,DMSO)δ 7.99(d,J=8.7Hz,2H),7.71(d,J=8.8Hz,2H),6.81(s,1H),4.36(s,1H),4.14(t,J=9.2Hz,1H),3.84(dd,J=9.6,5.3 Hz,1H), 3.23(d,J=5.7Hz,2H),2.93-2.88(m,2H),2.76-2.72(m,10H),1.65-1.54(m,2H),1.36(d,J=11.1Hz,18H).

[0166] Intermediate 23: trans-4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]sulfanyl]cyclohexanecarboxylic acid [ka]

[0167] Step 1: 4-Benzylsulfanyl-2,6-dichloro-pyridine [ka] To a solution of benzyl mercaptan (4.58 g, 36.86 mmol), 4-bromo-2,6-dichloro-pyridine (8.2 g, 36.14 mmol) in DMF (50 mL) was added TEA (15.11 mL, 108.42 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.32 g, 1.45 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.09 g, 3.61 mmol) in one portion under nitrogen. 。 The reaction was stirred at 80° C. for 2 h. After completion, the reaction was diluted with water (100 ml) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with saturated aqueous CaCl2 (200 mL×3) and brine (200 mL×3). The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluent of EtOAc:PE=0-100%) to give compound intermediate 23a (8.8 g, 32.57 mmol, 90.12% yield) as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:269.8.

[0168] Step 2: 2,6-Dichloropyridine-4-thiol [ka] To a solution of compound intermediate 23a (4.0 g, 14.8 mmol) in DCM (50 mL) was added aluminum trichloride (9.87 g, 74.02 mmol). The reaction was stirred at 25° C. for 2 h. After completion, the reaction mixture was poured into water (300 mL) in an ice-water bath and extracted with EtOAc (300 mL×3). The combined organic layer was washed with brine (200 mL×2) and dried over anhydrous sodium sulfate. 、 Filtration and concentration in vacuo gave the crude product, which was purified by preparative HPLC to give compound intermediate 23b (1.5 g, 8.33 mmol, 56.27% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:180.4.

[0169] Step 3: trans-Methyl 4-[(2,6-dichloro-4-pyridyl)sulfanyl]cyclohexanecarboxylate [ka] To a solution of compound intermediate 23c (500.0 mg, 2.78 mmol), triphenylphosphine (3637.68 mg, 13.88 mmol) and methyl 4-hydroxycyclohexanecarboxylate (900.0 mg, 5.69 mmol) in THF (5 mL) was added diisopropyl azodicarboxylate (1683.61 mg, 8.33 mmol) dropwise at 0° C. The mixture was stirred at 70° C. for 16 h. After completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue, which was analyzed by preparative TLC (PE:EA=5:1, R f =0.35) and purified by preparative HPLC. Compound intermediate 23c (260 mg, 0.810 mmol, 29.33% yield) was obtained as a colorless oil. MS Found (ESI + )[(M+H) + ]:320.2.

[0170] Step 4: trans-4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]sulfanyl]cyclohexanecarboxylic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 5 by substituting compound intermediate 23c for intermediate 5e in step 6. Compound intermediate 23 (470 mg) was obtained as a pale yellow solid. MS (ESI + )[(M+H) + ]:694.2.

[0171] Intermediate 24: trans-4-[difluoro-[6-methyl-2-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]pyrimidin-4-yl]methyl]cyclohexanecarboxylic acid [ka]

[0172] Step 1: Chlorolithium; Chloro-(2,2,6,6-tetramethyl-1-piperidyl)magnesium [ka] To a solution of isopropylmagnesium chloride·lithium chloride complex solution (1.3 M in THF, 50.0 mL, 65 mmol) was added 2,2,6,6-tetramethylpiperidine (12.07 mL, 71.5 mmol) dropwise at -40 °C. The reaction was stirred at 25 °C under nitrogen for 1 day. Compound intermediate 24a (60 g, 247.52 mmol, 86.55% yield) in THF (60.0 mL) was obtained and used directly in the next step.

[0173] Step 2: trans-Methyl 4-[(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-hydroxy-methyl]cyclohexanecarboxylate [ka] To a solution of 4-chloro-2-methylsulfanyl-pyrimidine (3.0 g, 18.68 mmol) in THF (8 mL) was added compound intermediate 24a (18.68 mL, 20.55 mmol) at -40°C. The mixture was stirred at 0°C for 40 min and then added to a solution of trans-methyl 4-formylcyclohexanecarboxylate (3.5 g, 20.55 mmol) in THF (12 mL) at -40°C. The reaction mixture was stirred at 25°C for 1 h. After the starting material was consumed, the mixture was poured into water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (eluent: EtOAc:PE = 0-100%) to give compound intermediate 24b (1.8 g, 5.44 mmol, 29.13% yield) as a pale yellow oil. MS Found (ESI + )[(M+H) + ]:331.3.

[0174] Step 3: trans-Methyl 4-(6-chloro-2-methylsulfanyl-pyrimidine-4-carbonyl)cyclohexanecarboxylate [ka] To a solution of compound intermediate 24b (1.7 g, 5.14 mmol) in THF (10 mL) was added DMP (2.62 g, 6.17 mmol) at 0 °C, and the mixture was stirred at 25 °C for 2 h. After completion, the mixture was quenched with ice water and adjusted to pH = 9 with aqueous NaHCO3. The mixture was extracted with EtOAc (100 mL x 2) and washed with brine (100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel column (eluent of EtOAc:PE = 0-50%) to give compound intermediate 24c (1.6 g, 4.87 mmol, 94.7% yield) as a yellow solid. MS observed (ESI + )[(M+H) + ]:329.3.

[0175] Step 4: trans-Methyl 4-[(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-difluoro-methyl]cyclohexanecarboxylate [ka] To a solution of compound intermediate 24c (1.6 g, 4.87 mmol) in THF (10 mL) was added DAST (10.0 mL, 4.87 mmol). The mixture was stirred at 25 °C for 2 h. After completion, the mixture was quenched with ice water and adjusted to pH = 9 with aqueous NaHCO3. 、 Extraction with EtOAc (200 mL x 2) was performed. The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel column (eluent of EtOAc:PE=0-20%) to give compound intermediate 24d (1.5 g, 4.28 mmol, 87.87% yield) as a yellow solid. MS observed (ESI + )[(M+H) + ]:351.3.

[0176] Step 5: trans-Methyl 4-[difluoro-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)methyl]cyclohexanecarboxylate [ka] To a solution of compound intermediate 24d (900.0 mg, 2.57 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (201.85 mg, 0.260 mmol) and potassium phosphate (1.6 g, 7.7 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was added trimethylboroxine (9.66 mL, 30.79 mmol). The mixture was stirred at 80° C. under nitrogen for 12 hours. After completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by silica gel column (eluent: EtOAc:PE=10-30%) to give compound intermediate 24e (420 mg, 1.27 mmol, 34.69% yield) as a yellow oil. MS observed (ESI + )[(M+H) + ]:331.3.

[0177] Step 6: trans-Methyl 4-[difluoro-(6-methyl-2-methylsulfonyl-pyrimidin-4-yl)methyl]cyclohexanecarboxylate [ka] To a solution of compound intermediate 24e (400.0 mg, 0.850 mmol) in THF (5 mL), m-CPBA (516.18 mg, 2.54 mmol) was added and the mixture was stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched by saturated aqueous Na2SO3 and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was purified by silica gel column (eluent of EtOAc:PE = 5-50%) to give compound intermediate 24f (355 mg, 0.980 mmol, 87.85% yield) as a yellow oil. MS observed (ESI + )[(M+H) +]:363.2.

[0178] Step 7: trans-4-[difluoro-[6-methyl-2-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]pyrimidin-4-yl]methyl]cyclohexanecarboxylic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 5, by substituting compound intermediate 24f for compound intermediate 5e in step 6. Compound intermediate 24 (260 mg) was obtained as a pale yellow solid. MS (ESI + )[(M+H) + ]:693.4.

[0179] Intermediate 25: tert-Butyl N-methyl-N-[(3R)-5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate [ka]

[0180] Step 1: Benzyl 4-[4-[(4(R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazine-1-carboxylate [ka] To a solution of intermediate 1a (412 mg, 2.06 mmol) in DMF (10 mL) was added benzyl 4-(4-iodophenyl)sulfonylpiperazine-1-carboxylate (1 g, 2.06 mmol), K2CO3, (853 mg, 6.17 mmol), CuI (195.81 mg, 1.03 mmol) and DMEDA (72.42 mg, 0.820 mmol). The suspension was stirred under N2 at 80 °C for 2 h. Upon completion, the reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by trituration in EtOAc (20 mL), filtered, and the filtrate was concentrated to give intermediate 25a (660 mg, 1.18 mmol, 57.45% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:559.1.

[0181] Step 2: Benzyl 4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazine-1-carboxylate [ka] A mixture of intermediate 25a (660.0 mg, 1.18 mmol) and TFA (6.0 mL) in DCM (6 mL) was stirred at room temperature for 2 h. After the starting material was consumed, the mixture was concentrated in vacuo to give intermediate 25b (660 mg, 1.15 mmol, 97.57% yield) as a pale yellow gum. MS observed (ESI + )[(M+H) + ]:459.2.

[0182] Step 3: Benzyl 4-[4-[(4R)-4-[(3,4-dimethoxyphenyl)methyl-methyl-amino]-2-oxo-pyrrolidin-1-yl]phenyl]sulfonyl piperazine-1-carboxylate [ka] To a solution of intermediate 25b (660.0 mg, 1.44 mmol) in THF (1 mL) was added Ti(i-PrO)4 (4.1 g, 14.39 mmol) and 2,4-dimethoxybenzaldehyde (239.18 mg, 1.44 mmol) at 15° C. and then warmed to 25° C. The mixture was stirred at 25° C. for 2 h. The mixture was cooled to 15° C. and then methanol (1 mL) and NaBH3CN (452.25 mg, 7.2 mmol) were added. After stirring at 25° C. for 12 h, paraformaldehyde (705.9 mg, 7.2 mmol, 5 equiv.) was added and the reaction was continued to stir at 25° C. for another 12 h. After completion, the mixture was diluted with DCM (50 mL) and water (50 mL). The aqueous phase was extracted with DCM (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc:PE = 0-50%) to give intermediate 25c (210 mg, 0.340 mmol, 23.43% yield) as a white solid. MS observed (ESI + )[(M+H) + ]:623.3.

[0183] Step 4: tert-Butyl N-methyl-N-[(3R)-5-oxo-1-(4-piperazin-1-ylsulfonylphenyl)pyrrolidin-3-yl]carbamate [ka] To a solution of intermediate 25c (100.0 mg, 0.160 mmol) in a mixture of THF (0.1 mL) and IPA (1 mL) was added Pd / C (10.0 mg, 5%, wet) in one portion under N2. The mixture was degassed under vacuum and purged with H2 three times. The reaction mixture was stirred under a H2 balloon at 40 °C for 12 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give intermediate 25 (75 mg, 0.150 mmol, 95.59% yield) as a white solid. MS observed (ESI + )[(M+H) + ]:489.3.

[0184] Intermediate 26: 5-[[2-chloro-6-[4-[4-[(4R)-4-methyl-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[2.2.2]octane-2-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound intermediate 5 by using 5-methoxycarbonylbicyclo[2.2.2]octane-2-carboxylic acid instead of trans-4-methoxycarbonylcyclohexanecarboxylic acid in step 1. Compound intermediate 26 (450 mg) was obtained as a grey solid. MS Found (ESI + )[(M+H) + ]:738.3.

[0185] Example 001: trans-Methyl 4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylate [ka]

[0186] Step 1: trans-Methyl 4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylate [ka] Compound intermediate 5e (250 mg, 344 μmol) was dissolved in DCM (10 mL) and then TFA (265 μL, 3.44 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction mixture was then concentrated in vacuo and purified by preparative HPLC to give product Example 001 (35 mg, 0.056 mmol, 15.4% yield) as a white solid. MS observed (ESI + )[(M+H)]+ :626.2.

[0187] Example 001: 1 H NMR(400MHz,DMSO-d6)δ ppm 7.91(m,J=8.93Hz,2H),7.75(m,J=8.93Hz,2H),6.76(s,1H),6.69(s,1H),4 .00(dd,J=9.90,6.11Hz,1H),3.60-3.70(m,6H),3.45-3.54(m,1H),3.32(br s,3H),2.96(br t,J=4.65Hz,4H),2.78(dd,J=16.87,6.97Hz,1H),2.52-2.53(m,1H),2.11-2.38(m,3H),1.91(br d,J=10.64Hz,2H),1.66(br d,J=10.64Hz,2H),1.11-1.35(m,4H). 19 F NMR (376MHz, DMSO-d6) δ ppm-103.88 (br d, J=14.98Hz, 1F).

[0188] Example 002: trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(azetidin-3-ylmethyl)cyclohexanecarboxamide [ka]

[0189] Step 1: trans-4-[[2-chloro-6-[4-[4-[(4R)-4-methyl-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(cyclobutylmethyl)cyclohexanecarboxamide [ka] A mixture of azetidin-3-ylmethanamine (24.52 mg, 0.132 mmol), compound intermediate 5 (75 mg, 0.105 mmol), HATU (57 mg, 0.15 mmol) and DIPEA (55.12 μL, 0.316 mmol) in DCM (15 mL) was stirred at room temperature overnight. After completion, the reaction mixture was diluted with EtOAc (50 mL×3) and washed with brine (50 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude compound 002a (80 mg, 86.28% yield) as a pale yellow solid, which was used directly in the next step. MS Found (ESI + )[(M+H)] + :880.5.

[0190] Step 2: trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(azetidin-3-ylmethyl)cyclohexanecarboxamide [ka] Compound 002a (80 mg, 91 μmol) was dissolved in DCM (5 mL) followed by the addition of TFA (265 μL, 3.44 mmol). The reaction was stirred at room temperature for 1 h and went to completion. The reaction was then concentrated in vacuo and purified by preparative HPLC to give the product Example 002 (19 mg, 30.7% yield) as a white solid. MS Found (ESI + )[(M+H)] + :680.2.

[0191] Example 002: 1H NMR(400MHz, methanol-d4)δ ppm 7.95(m,J=8.93Hz,2H),7.86(m,J=8.93Hz,2H),6.67(d,J=9.41Hz,2H),5.27-5.46 (m,1H),4.95-5.16(m,2H),4.42(dd,J=11.43,7.03Hz,1H),4.14-4.27(m,1H),4.0 2-4.11(m,2H),3.84-4.00(m,3H),3.64-3.77(m,4H),3.36-3.44(m,2H),3.21(dd, J=18.16,8.25Hz,1H),3.03-3.13(m,5H),2.71(dd,J=18.03,3.00Hz,1H),2.50(br s,1H),2.00-2.07(m,2H),1.57(br d,J=5.75Hz,6H),1.33(br d,J=18.10Hz,1H). 19 F NMR (376 MHz, methanol-d4) δ ppm-111.94--101.94 (m, 1F).

[0192] The following Examples 003-052 were prepared similarly to the procedure described for the preparation of Example 002, substituting compound intermediate 5 for "linker" in step 1, substituting azetidin-3-ylmethanamine for "tail" in step 1, and with the reagents shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

[0193] Example 055: N-(3-aminopropyl)-6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[3.1.0]hexane-3-carboxamide [ka]

[0194] Step 1: 6-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]bicyclo[3.1.0]hexane-3-carboxylic acid [ka] To a solution of compound intermediate 19 (200.0 mg, 0.530 mmol) in DCM (2 mL), TFA (2.0 mL, 25.96 mmol) was added and the mixture was stirred at 25° C. for 2 h. After completion, the mixture was concentrated in vacuo to give a crude residue, which was purified by preparative HPLC. Compound 055a (120 mg, 0.370 mmol, 70.45% yield) was obtained as a yellow oil. MS Found (ESI+) [(M+H) + ]:322.2.

[0195] Step 2: tert-Butyl N-[3-[[6-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]bicyclo[3.1.0]hexane-3-carbonyl]amino]propyl]carbamate [ka] To a solution of compound 055a (120.0 mg, 0.370 mmol), N-Boc-1,3-diaminopropane (194.72 mg, 1.12 mmol) and DIPEA (0.19 mL, 1.12 mmol) in DMF (0.5 mL) was added HATU (212.47 mg, 0.560 mmol). The mixture was stirred at 25° C. for 2 h. After completion, the mixture was diluted with water (100 mL), extracted with EtOAc (100 mL×2) and washed with brine (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue, which was purified by preparative HPLC to give compound 055b (120 mg, 0.250 mmol, 67.34% yield) as a yellow solid. MS Found (ESI+) [(M+H) + ]:421.9.

[0196] Step 3: tert-Butyl N-[3-[[6-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[3.1.0]hexane-3-carbonyl]amino]propyl]carbamate [ka] To a solution of compound 055b (120 mg, 0.250 mmol) and compound intermediate 5 (117.14 mg, 0.280 mmol) in DMSO (2 mL) was added DIPEA (1.0 mL, 5.74 mmol). The mixture was stirred at 100° C. for 12 h. After completion, the mixture was diluted with water (100 mL), extracted with EtOAc (100 mL×2), and washed with brine (100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue, which was purified by preparative TLC (developing solvent of EtOAc:PE=33%) and preparative HPLC. Compound 054c (40 mg, 0.050 mmol, 18.4% yield) was obtained as a yellow solid. MS Found (ESI+) [(M+H) + ]:866.3.

[0197] Step 4: N-(3-aminopropyl)-6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[3.1.0]hexane-3-carboxamide [ka] To a solution of compound 055c (40.0 mg, 0.050 mmol) in DCM (2 mL) was added TFA (2.0 mL, 25.96 mmol). The mixture was stirred at 25° C. for 1 h. After completion, the mixture was concentrated in vacuo to give a crude residue, which was purified by preparative HPLC to give Example 055 (10.6 mg, 0.020 mmol, 29.24% yield) as a white solid. MS Found (ESI+) [(M+H) + ]:666.5.

[0198] Example 055: 1H NMR(400MHz,DMSO-d6)δ ppm 8.61(br s,3H),8.02-8.27(m,1H),7.94-8.02(m,3H),7.91(d,J=8.93Hz,2H),7.76-7.81(m,2H),6.65-6.88(m,2H),4.26(br dd,J=11.07,6.91Hz,1H),4.05(br s,1H),3.90(br d,J=11.00Hz,1H),3.66(br s,4H),3.01-3.16(m,3H),2.96(br s,4H),2.58-2.79(m,3H),1.94-2.39(m,2H),1.28-2.45(m,3H). 19 F NMR (376MHz, DMSO-d6) δ ppm-96.02 (br s, 2F).

[0199] Example 056: trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka]

[0200] Step 1: trans-4-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclohexanecarboxylic acid [ka] To a solution of compound intermediate 5e (2.0 g, 5.91 mmol) and lithium bromide (5.1 g, 60 mmol) in MeCN (10 mL) and water (3 mL) was added TEA (3.0 mL, 21.52 mmol). The mixture was stirred at 50° C. for 12 h. After completion, the mixture was adjusted to pH=5 with 1M HCl solution, extracted with EtOAc (300 mL×2) and washed with brine (300 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 056a (1.8 g, 5.55 mmol, 93.9% yield) as a white solid. MS Found (ESI+) [(M+H) + ]:323.8.

[0201] Step 2: trans-N-butyl-4-[(2,6-dichloro-4-pyridyl)-difluoro-methyl]cyclohexanecarboxamide [ka] To a solution of compound 056a (150 mg, 463 μmol), HATU (264 mg, 694 μmol) and DIPEA (242 μL, 1.39 mmol) in DMF (5 mL) was added tert-butyl N-(3-aminopropyl)carbamate (96.8 mg, 555 μmol). The mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was diluted with EtOAc (10 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (eluent of EtOAc:PE=0-40%) to give compound 056b (180 mg, 375 μmol, 81% yield) as a yellow oil. MS observed (ESI+) [(M+H) + ]:480.6.

[0202] Step 3: trans-tert-butyl N-[3-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl]carbamate [ka] A solution of compound intermediate 5 (100 mg, 236 μmol), compound 056b (147 mg, 306 μmol) and DIPEA (152 mg, 1.18 mmol) in DMSO (2 mL) was stirred at 100° C. overnight. After completion, the mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired product compound 056c (205 mg, 236 μmol, 100% yield) as a yellow oil, which was used directly in the next step. MS Found (ESI+) [(M+H) + ]:868.8.

[0203] Step 4: trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka] A solution of compound 056c (205 mg, 236 μmol) and TFA (364 μL, 4.72 mmol) was stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the desired product, Example 056 (89 mg, 124 μmol, 52.5% yield) as a yellow solid. MS Found (ESI + )[(M+H)] + :668.2.

[0204] Example 056: 1H NMR (400MHz, methanol-d4)ppm δ 7.84(br d,J=8.8Hz,2H),7.72(d,J=8.7Hz,2H),6.58(s,1H),6.55(s,1H),4.32(br dd,J=11.2,6.9Hz,1H),4.12(br s,1H),3.98-3.84(m,1H),3.59(br s,4H),3.19-2.98(m,4H),2.96(br s,4H),2.91-2.78(m,2H),2.64(dd,J=18.1,2.8Hz,1H),2.10-1.89(m,3H),1.82-1.65(m,7H),1.41-1.26(m,2H),1.24-1.04(m,3H). 19 F NMR (376 MHz, methanol-d4) δ ppm -106.88 (s, 1F), -106.92 (s, 1F).

[0205] The following Examples 057-062 were prepared similarly to the procedure described for the preparation of Example 056, substituting compound intermediate 5 for "linker" in step 3, substituting tert-butyl N-(3-aminopropyl)carbamate for "tail" in step 2, and with the reagents shown in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0206] Example 071: trans-(4R)-4-amino-1-[4-[4-[4-[[4-[4-(2-aminoethyl)-4-methyl-piperazin-4-ium-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka]

[0207] Step 1: trans-tert-butyl N-[(3R)-1-[4-[4-[4-[[4-[4-[2-(tert-butoxycarbonylamino)ethyl]piperazine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate [ka] A mixture of N-(2-piperazinoethyl)carbamic acid tert-butyl ester (72.45 mg, 0.316 mmol), compound intermediate 5 (150 mg, 0.211 mmol), HATU (160.07 mg, 0.421 mmol) and DIPEA (110.23 μL, 0.632 mmol) in DCM (15 mL) was stirred at room temperature for 2 h. After completion, the mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude compound 071a (190 mg, 97.68%) as a pale yellow viscous oil. MS Found (ESI+) [(M+H) + ]:923.6.

[0208] Step 2: trans-tert-butyl N-[2-[4-[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]-1-methyl-piperazin-1-ium-1-yl]ethyl]carbamate [ka] Compound 071a (100 mg, 0.108 mmol) and DIPEA (28.37 μL, 0.162 mmol) were dissolved in DCM (5.15 mL). Iodomethane (6.77 μL, 0.108 mmol) was added to the stirred solution. The reaction was stirred at room temperature overnight. The reaction was then concentrated in vacuo to give the desired product Compound 071b (90 mg, 96 μmol, 88.56% yield) as a pale yellow oil, which was used directly in the next step. MS Found (ESI+) [(M+H) + ]:939.7.

[0209] Step 3: trans-(4R)-4-amino-1-[4-[4-[4-[[4-[4-(2-aminoethyl)-4-methyl-piperazin-4-ium-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one [ka] Compound 071b (90 mg, 0.096 mmol) and TFA (0.5 mL, 6.5 mmol) were mixed in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h to reach completion. After completion, the residue was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the desired product Example 071 (35 mg, 46.96%) as a white solid. MS Found (ESI+) [(M+H) + ]:737.4.

[0210] Example 071: 1H NMR(400MHz, methanol-d4)δ ppm 8.43(br s,1H),7.92(m,J=9.05Hz,2H),7.82(m,J=9.05Hz,2H),6.67(d,J=7.34Hz,2H), 4.91-4.95(m,1H),4.34(dd,J=11.13,6.85Hz,1H),3.94-4.17(m,3H),3.89(br dd,J=11.07,2.63Hz,2H),3.79(br d,J=15.16Hz,1H),3.65-3.73(m,4H),3.41-3.62(m,6H),3.22-3.29(m,5H),3.01-3.16(m,5H),2.57-2.69(m,2H),1.99-2.15(m,1H),1.81(br t,J=11.62Hz,4H),1.45(dt,J=6.69,1.60Hz,2H),1.25-1.39(m,2H). 19 F NMR (376 MHz, methanol-d4) δ ppm -106.86 (s, 1F), -106.89 (s, 1F).

[0211] Example 072: trans-N-[2-(2-aminoethylamino)ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka]

[0212] Step 1: trans-tert-butyl N-[(3R)-1-[4-[4-[6-chloro-4-[difluoro-[4-(2-hydroxyethylcarbamoyl)cyclohexyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate [ka] To a solution of compound intermediate 5 (300.0 mg, 0.420 mmol) in DMF (3 mL) was added HATU (208.21 mg, 0.550 mmol), DIPEA (0.22 mL, 1.26 mmol), 2-hydroxyethylamine (0.03 mL, 0.460 mmol) in one portion under nitrogen. The reaction was stirred at 25° C. for 16 h. Upon completion, the reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give a crude residue, which was purified by preparative HPLC to give compound 072a (220 mg, 0.290 mmol, 69.15% yield) as a white solid. MS Found (ESI + )[(M+H)] + :755.6.

[0213] Step 2: trans-tert-butyl N-[(3R)-1-[4-[4-[6-chloro-4-[difluoro-[4-(2-oxoethylcarbamoyl)cyclohexyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate [ka] To a solution of compound 072a (180.0 mg, 0.240 mmol) in DCM (3 mL) was added DMP (111.19 mg, 0.260 mmol) in one portion under nitrogen. The reaction was stirred at 25° C. for 1 h. Upon completion, the reaction was quenched with saturated aqueous Na2CO3 (100 mL) and extracted with EtOAc (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give compound 072b (150 mg, 0.200 mmol, 83.56% yield) as a yellow solid, which was used directly for the next step. MS Found (ESI + )[(M+H)] + :755.6.

[0214] Step 3: trans-tert-butyl N-[2-[2-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]ethylamino]ethyl]carbamate [ka] A solution of compound 072b (130.0 mg, 0.170 mmol), N-Boc-ethylenediamine (55.3 mg, 0.350 mmol) in methanol (1 mL) was stirred at 25° C. for 1 h. Sodium cyanoborohydride (54.23 mg, 0.860 mmol) was then added and the reaction was stirred at 25° C. for an additional 1 h. Upon completion, the reaction was diluted with water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC to give compound 072c (85 mg, 0.090 mmol, 54.88% yield) as a colorless oil. MS Found (ESI + )[(M+H)] + :897.0.

[0215] Step 4: trans-N-[2-(2-aminoethylamino)ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka] To a solution of compound 072c (35.0 mg, 0.040 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.5 mmol) in one portion. The reaction was stirred at 25° C. for 1 h. Upon completion, the reaction was concentrated in vacuo to give a residue which was purified by preparative HPLC to give Example 072 (20 mg, 0.029 mmol, 71% yield) as a white solid. MS Found (ESI+ )[(M+H)] + :697.0.

[0216] Example 072: 1 H NMR(400MHz,DMSO-d6)δ ppm 8.34-8.26(m,3H),8.21-8.12(m,3H),8.10-8.03(m,1H),7.94-7.90(m,2H),7.82-7.78(m,2H),6.81-6.77(m,1H),6.73-6.69(m,1H),4.2 8-4.22(m,1H),4.10-4.04(m,1H),3.87-3.82(m,1H),3.68-3.63(m,4H),3.21-3.14(m,4H),3.14-3.05(m,2H),3.05-3.00(m,2H),2.97(br d,J=2.8Hz,4H),2.61(br s,1H),2.21-1.98(m,2H),1.87-1.78(m,2H),1.70-1.63(m,2H),1.39-1.25(m,2H),1.19-1.08(m,2H). 19 F NMR (376MHz, DMSO-d6) δ ppm-104.086 (br s, 2F).

[0217] Example 073: trans-2-aminoethyl-[2-[[4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]ethyl]-dimethyl-ammonium [ka]

[0218] Step 1: trans-2-(tert-butoxycarbonylamino)ethyl-[2-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]ethyl]-dimethyl-ammonium [ka] To a solution of compound 072c (35.0 mg, 0.040 mmol) in DCM (1 mL) was added sodium bicarbonate (32.76 mg, 0.390 mmol) and methyl trifluoromethane-sulfonate (19.2 mg, 0.120 mmol) in one portion. The reaction was stirred at 25 °C for 1 h. Upon completion, the reaction was filtered and NH3·H2O was added to the filtrate. The reaction was concentrated in vacuo to give compound 073a (28 mg, 0.030 mmol, 77.49% yield) as a white solid. MS Found (ESI + )[(M+H)] + :925.4.

[0219] Step 2: trans-2-aminoethyl-[2-[[4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]ethyl]-dimethyl-ammonium [ka] To a solution of compound 073a (41.0 mg, 0.040 mmol) in DCM (1 mL) was added TFA (0.17 mL, 2.21 mmol) in one portion. The reaction was stirred at 25° C. for 1 h. Upon completion, the reaction was concentrated in vacuo to give a residue which was purified by preparative HPLC to give Example 073 (20 mg, 0.030 mmol, 58.33% yield) as a white solid. MS Found (ESI + )[(M+H)] + :725.1.

[0220] Example 073: 1H NMR(400MHz,DMSO-d6)δ ppm 8.52-8.41(m,5H),8.33-8.24(m,1H),7.96-7.88(m,2H),7.79(d,J=9.0Hz,2H),6.78(s,1H),6.71(s,1H) ,4.31-4.22(m,1H),4.11-4.02(m,1H),3.90-3.85(m,1H),3.69-3.57(m,6H),3.48-3.41(m,2H),3.38(br s,2H),3.15(s,6H),3.10-3.04(m,1H),2.97(br s,4H),2.66-2.59(m,1H),2.24-2.05(m,2H),1.82-1.73(m,2H),1.67(br d,J=10.1Hz,2H),1.39-1.26(m,2H),1.14(br s,2H). 19 F NMR (376 MHz, DMSO-d6) δ ppm-104.004 (br s, 2F).

[0221] Example 074: trans-N-[2-[1-(2-aminoethyl)pyrrolidin-1-ium-1-yl]ethyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka]

[0222] Step 1: trans-tert-butyl N-[(3R)-1-[4-[4-[6-chloro-4-[difluoro-[4-(2-pyrrolidin-1-ylethylcarbamoyl)cyclohexyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate [ka] A mixture of 2-pyrrolidinoethylamine (24.05 mg, 0.211 mmol), compound intermediate 5 (100 mg, 0.140 mmol), HATU (106.71 mg, 0.281 mmol) and DIPEA (73.49 μL, 0.421 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. After completion, the mixture was diluted with EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude product 074a (100 mg, 88.1% yield) as a yellow viscous oil. MS Found (ESI+) [(M+H) + ]:808.7.

[0223] Step 2: trans-tert-butyl N-[2-[1-[2-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]ethyl]pyrrolidin-1-ium-1-yl]ethyl]carbamate [ka] Compound 074a (100 mg, 0.124 mmol) and N-(2-bromoethyl)carbamic acid tert-butyl ester (138.61 mg, 0.619 mmol) were dissolved in anhydrous MeCN (8 mL). Into the stirred solution, DIPEA (64.81 μL, 0.371 mmol) and 0.1 mg DMAP were added. The reaction mixture was stirred at 90° C. overnight. LCMS showed that half of the starting material was converted. The reaction was then cooled to room temperature and concentrated in vacuo to give crude compound 074b (57 mg, 49%) as a yellow oil, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:951.5.

[0224] Step 3: trans-N-[2-[1-(2-aminoethyl)pyrrolidin-1-ium-1-yl]ethyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka] Compound 074b (100 mg, 0.105 mmol) and TFA (1 mL, 13 mmol) were dissolved in DCM (10 mL). The reaction was stirred at room temperature for 2 h. Upon completion, the reaction was concentrated in vacuo and purified by preparative HPLC to give the desired product, Example 074 (18.1 mg, 20.63%) as a white solid. MS Found (ESI + )[(M+H) + ]:751.8.

[0225] Example 074: 1 H NMR(400MHz, methanol-d4)δ ppm 7.83(m,J=8.93Hz,2H),7.73(m,J=8.93Hz,2H),6.57(d,J=7.70Hz,2H),4.30(dd,J=11.43,7.03Hz,1H),4.06-4 .13(m,1H),3.86(dd,J=11.43,2.51Hz,1H),3.37-3.64(m,14H),3.29-3.35(m,2H),3.05-3.17(m,1H),2.98(br t,J=4.89Hz,4H),2.60(dd,J=18.10,3.06Hz,1H),1.89-2.17(m,7H),1.78(br d,J=11.13Hz,2H),1.70(br d,J=11.00Hz,2H),1.09-1.37(m,8H). 19 F NMR (376 MHz, methanol-d4) δ ppm -106.97 (s, 1F), -107.01 (s, 1F).

[0226] Example 075: trans-N-[2-[(2-aminoacetyl)amino]ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka]

[0227] Step 1: trans-tert-butyl N-[(3R)-1-[4-[4-[4-[[4-(2-aminoethylcarbamoyl)cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate [ka] To a solution of compound intermediate 5 (100.0 mg, 0.140 mmol) in DMF, DIPEA (52.23 mg, 0.420 mmol) and HATU (80.09 mg, 0.210 mmol) were added. The mixture was stirred at 25° C. for 1 h. Ethylenediamine (337 mg, 5.6 mmol) in DMF (3 mL) was then added to the mixture. After stirring at 25° C. for 1 h, the mixture was diluted with EtOAc (50 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound 075a (100 mg, 0.130 mmol, 94.42% yield) as a white solid. The residue was used directly in the next step. MS Found (ESI + )[(M+H) + ]:754.3.

[0228] Step 2: trans-tert-butyl N-[2-[2-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]ethylamino]-2-oxo-ethyl]carbamate [ka] To a solution of compound 075a (100.0 mg, 0.130 mmol) and BOC-glycine (23.22 mg, 0.130 mmol) in DMF (1 mL) was added DIPEA (49.32 mg, 0.400 mmol) and HATU (46.79 mg, 0.200 mmol). After stirring at 25° C. for 1 h, the mixture was diluted with EtOAc (50 mL) and water (30 mL). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a crude residue, which was purified by preparative TLC (PE:EA=1:1) to give compound 075b (95 mg, 0.100 mmol, 78.62% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:911.5.

[0229] Step 3: trans-N-[2-[(2-aminoacetyl)amino]ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka] To a solution of compound 075b (90.0 mg, 0.100 mmol) in DCM (5 mL) was added TFA (56.28 mg, 0.490 mmol). The mixture was stirred at 25° C. for 2 h. After completion, the mixture was concentrated in vacuo to give a crude residue, which was purified by preparative HPLC to give Example 075 (22.7 mg, 0.030 mmol, 30.8% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:711.2.

[0230] Example 075: 1 H NMR(400MHz,DMSO-d6)δ ppm 8.50(d,J=12.47Hz,4H),8.11(s,3H),7.91(d,J=8.93Hz,3H),7.80(d,J=8.93Hz,2H ),6.78(s,1H),6.71(s,1H),4.21-4.32(m,1H),4.07(s,1H),3.89(d,J=9.29Hz,1H) ,3.66(s,5H),2.91-3.31(m,8H),2.64(dd,J=17.91,2.75Hz,1H),2.17(t,J=11.98H z,1H),1.97-2.08(m,1H),1.59-1.83(m,4H),1.22-1.39(m,2H),1.02-1.19(m,2H). 19 F NMR(376MHz,DMSO-d6)δ ppm-105.48--102.95(m,2F).

[0231] Example 076: trans-N-(3-amino-2-methoxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka]

[0232] Step 1: trans-tert-butyl N-[3-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]-2-hydroxy-propyl]carbamate [ka] To a solution of compound intermediate 5 (250.0 mg, 0.350 mmol) in DMF (4 mL), tert-butyl N-(3-amino-2-hydroxy-propyl)carbamate (133.56 mg, 0.700 mmol), HATU (200.21 mg, 0.530 mmol) and DIPEA (136.1 mg, 1.05 mmol) were added. The reaction mixture was stirred at 20° C. for 1 h. After completion, the reaction mixture was diluted with EtOAc (200 mL) and the organic layer was washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue, which was purified by reverse phase column to give compound 076a (260 mg, 0.290 mmol, 83.75% yield) as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:886.5.

[0233] Step 2: trans-tert-butyl N-[3-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]-2-methoxy-propyl]carbamate [ka] To a solution of compound 076a (150.0 mg, 0.170 mmol) in MeCN (2 mL) was added Ag2O (589.52 mg, 2.54 mmol) and MeI (240.73 mg, 1.7 mmol) at 20° C. The reaction was stirred at 20° C. for 16 h. The reaction mixture was then concentrated in vacuo and purified by preparative TLC (PE:EA=1:3) to give compound 076b (40 mg, 0.040 mmol, 26.25% yield) as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:900.2.

[0234] Step 3: trans-N-(3-amino-2-methoxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide [ka] To a solution of compound 076 (60.0 mg, 0.070 mmol) in DCM (2 mL) was added TFA (761.44 mg, 6.68 mmol) at 30° C. The reaction mixture was stirred at 30° C. for 1 h. After completion, the reaction mixture was concentrated in vacuo to give a crude residue, which was purified by preparative HPLC to give Example 076 (23.9 mg, 0.030 mmol, 49.77% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:700.2.

[0235] Example 076: 1H NMR (400MHz, heavy water) δ ppm 7.69(br d,J=8.6Hz,2H),7.56(br d,J=8.6Hz,2H),6.56(s,2H),4.39-4.11(m,2H),4.10-3.95(m,1H),3.57(br s,1H),3.47(br s,4H),3.35(s,3H),3.29(br d,J=4.2Hz,2H),3.22-3.01(m,2H),2.88-2.68(m,6H),2.07-1.74(m,2H),1.69-1.41(m,4H),1.19-0.86(m,4H). 19 F NMR (400MHz, heavy water) δ ppm: -105.02 (br s, 2F).

[0236] Example 077: trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(2,3-diaminopropyl)cyclohexanecarboxamide [ka]

[0237] Step 1: trans-tert-butyl N-[3-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]-2-oxo-propyl]carbamate [ka] To a solution of compound 076a (100.0 mg, 0.110 mmol) in THF (2 mL) was added DMP (143.87 mg, 0.340 mmol) at 20° C. The reaction was stirred at 20° C. for 2 h. After completion, the reaction mixture was purified by preparative TLC (PE:EtOAc=1:3) to give 077a (50 mg, 0.060 mmol, 50.11% yield) as a white solid. MS Found (ESI +)[(M+H) + ]:882.4.

[0238] Step 2: trans-tert-butyl N-[(3R)-1-[4-[4-[6-chloro-4-[difluoro-[4-[[(2E)-3-(tert-butoxycarbonylamino)-2-hydroxyimino-propyl]carbamoyl]cyclohexyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate [ka] To a solution of compound 077a (120.0 mg, 0.140 mmol) in ethanol (2 mL) was added hydroxylamine hydrochloride (18.9 mg, 0.270 mmol) at 30° C. The reaction was stirred at 30° C. for 2 h. Upon completion, the mixture was diluted with EtOAc (200 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give compound 077b (122 mg, 0.140 mmol, 99.97% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:897.0.

[0239] Step 3: trans-tert-butyl N-[2-amino-3-[[4-[[2-chloro-6-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl]carbamate [ka] To a solution of compound 077b (120.0 mg, 0.130 mmol) in ethanol (10 mL) was added Pt / C (500.0 mg, 7.69 mmol) at 30° C. The reaction was stirred under H2 at 30° C. for 24 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a crude residue, which was purified by preparative TLC to give compound 077c (30 mg, 0.030 mmol, 25.4% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:883.0.

[0240] 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]-N-(2,3-diaminopropyl)cyclohexanecarboxamide [ka] To a solution of compound 077c (30.0 mg, 0.030 mmol) in DCM (1 mL) was added TFA (1.0 mL, 12.98 mmol) in one portion. After the addition, the mixture was stirred at 25° C. for 30 min. After completion, the reaction was concentrated in vacuo and then purified by preparative HPLC to give Example 077 (10.0 mg, 0.010 mmol, 37.67% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:683.2.

[0241] Example 077: 1H NMR(400MHz,DMSO-d6)δ ppm 8.45-8.03(m,7H),7.95-7.85(d,2H),7.80-7.60(d,2H),6.78(s,1H),6.71(s,1H),4.30-4.20(m,2H),3.80-3.73(m,1H),3.70-3.62(m,4) H),3.20-2.95(m,9H),2.65-2.52(m,2H),2.25-2.05(m,2H),1.90-1.75(m,2H),1.74-1.60(m,2H),1.40-1.26(m,2H),1.35-1.08(m,2H). 19 F NMR (376MHz, DMSO-d6) δ ppm-104.025 (br s, 2F).

[0242] Example 078: 4-[[2-[4-[4-[4-(3-aminopropylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-methyl-benzamide [ka]

[0243] Step 1: 4-[[2-[4-[4-[4-[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]benzoic acid [ka] Compound 078a was prepared similarly to the preparation of compound intermediate 12, by using compound intermediate 22 instead of compound intermediate 2 in step 4. Compound intermediate 078a (235.3 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:863.3.

[0244] Step 2: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[1-[4-[4-[6-chloro-4-[difluoro-[4-(methylcarbamoyl)phenyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate [ka] A mixture of compound 078a (61 mg, 70.8 μmol), methanamine hydrochloride (14.2 mg, 212 μmol), HATU (40.4 mg, 106 μmol) and TEA (21.5 mg, 212 μmol) in DCM (3 mL) was stirred at room temperature for 12 h. After completion, the residue was washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product compound 078b (50 mg, 0.571 mmol, 80% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:876.3.

[0245] Step 4: 4-[[2-[4-[4-[4-(3-aminopropylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-methyl-benzamide [ka] A mixture of compound 078b (34.5 mg, 39.4 μmol) and TFA (89.8 mg, 787 μmol) in DCM (3 mL) was stirred at room temperature for 1 h. After completion, the reaction mixture was concentrated in vacuo to give a crude residue, which was purified by preparative HPLC to give Example 078 (6.8 mg, 0.01 mmol, 11% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:676.1.

[0246] Example 078: 1H NMR (400MHz, methanol-d4) δ ppm 1.64-1.85(m,2H),2.54-2.60(m,1H),2.67(br d,J=1.83Hz,1H),2.72-2.89(m,7H),2.96(m,4H),3.67(m,4H),4.09(m,1H),6.79(s,1H),6.96(s ,1H),7.68(d,J=8.44Hz,2H),7.77(d,J=8.93Hz,2H),7.91(t,J=8.50Hz,4H),8.53-8.58(m,1H). 19 F NMR(376MHz,DMSO-d6)δ ppm-92.70(s,2F).

[0247] Example 079: trans-N-[(1R,3S)-3-[(2-aminoacetyl)amino]cyclopentyl]-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 similarly to the preparation of Example 075 by using (1S,3R)-cyclopentane-1,3-diamine instead of ethylenediamine in step 1. Example 079 (24 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:751.4. 1H NMR(500MHz,DMSO-d6)δ ppm 8.35-8.45(m,1H),8.16-8.28(m,2H),7.87-8.00(m,2H),7.73-7.85(m,2H),6.77-6.86(m,1H), 6.61-6.76(m,1H),4.20-4.33(m,1H),4.05-4.15(m,1H),3.87-4.05(m,3H),3.74-3.87(m,2H), 3.60-3.74(m,5H),3.02-3.16(m,2H),2.92-3.02(m,4H),2.13-2.27(m,2H),1.93-2.03(m,1H), 1.78-1.93(m,3H),1.59-1.78(m,5H),1.40-1.59(m,3H),1.17-1.40(m,4H),0.94-1.17(m,3H). 19 F NMR (471MHz, DMSO-d6) δ ppm-104.30 (br s, 1F).

[0248] Example 080: trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(1S,3R)-3-[cis-3,4-bis(aminomethyl)pyrrolidin-1-yl]cyclopentyl]cyclohexanecarboxamide [ka]

[0249] Step 1: Benzyl N-[(1S)-3-oxocyclopentyl]carbamate [ka] To a solution of oxalyl chloride (0.81 g, 6.38 mmol) in DCM (10 mL) was added a solution of DMSO (0.73 g, 9.35 mmol) in DCM (10 mL) under N2 at -78 °C. The reaction was stirred at -78 °C for 1 h, then a solution of benzyl N-[(1S)-3-hydroxycyclopentyl]-carbamate (1.0 g, 4.25 mmol) in DCM (10 mL) was added. After stirring at -78 °C for 1 h, DIEA (1.72 g, 17 mmol) was added at -78 °C, then the reaction was warmed to 20 °C. After the starting material was consumed, the reaction mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by silica gel column (eluted with EtOAc:PE=30%) to give 080a (820 mg, 3.52 mmol, 82.71% yield) as a white solid. MS observed (ESI + )[(M+H) + ]:234.0.

[0250] Step 2: tert-Butyl N-[[cis-1-[(1R,3S)-3-(benzyloxycarbonylamino)cyclopentyl]-4-[(tert-butoxycarbonylamino)methyl]pyrrolidin-3-yl]methyl]carbamate [ka] To a solution of 080a (30.0 mg, 0.130 mmol) and tert-butyl N-[[cis-4-[(tert-butoxycarbonylamino)methyl]pyrrolidin-3-yl]methyl]carbamate (42.37 mg, 0.130 mmol) in 1,2-dichloroethane (0.5 mL) was added AcOH (46.3 mg, 0.770 mmol) and sodium triacetoxyborohydride (41 mg, 0.2 mmol). The mixture was stirred at 25° C. for 4 h. After completion, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude residue which was purified by preparative HPLC followed by preparative TLC to give 080ba (80 mg, 0.150 mmol, 7.11% yield) as a white solid and 080bb (100 mg, 0.180 mmol, 9% yield). 080ba: MS observed (ESI + )[(M+H) + ]:547.4. The cis and trans configurations were determined by 2D NMR. Step 3: tert-Butyl N-[[cis-1-[(1R,3S)-3-aminocyclopentyl]-4-[(tert-butoxycarbonylamino)methyl]pyrrolidin-3-yl]methyl]carbamate [ka] To a solution of Pd / C (110.0 mg) powder in a mixture of THF (1 mL) and IPA (1 mL) was added 080ba (100.0 mg, 0.180 mmol). The mixture was stirred at 45 °C under H2 atmosphere for 3 h. After the starting material was consumed, the mixture was filtered through celite and concentrated in vacuo to give 080c (100.0 mg, 0.180 mmol) as a white solid. MS observed (ESI + )[(M+H) + ]:412.4.

[0251] Step 4: tert-Butyl N-[(3R)-1-[4-[4-[[4-[[(1S,3R)-3-[cis-3,4-bis[(tert-butoxycarbonylamino)methyl]pyrrolidin-1-yl]cyclopentyl]carbamoyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-5-oxo-pyrrolidin-3-yl]carbamate [ka] To a solution of intermediate 5 (120 mg, 0.170 mmol) in DMF (1 mL) was added HATU (96.04 mg, 0.250 mmol) and DIEA (108.68 mg, 0.840 mmol). The reaction mixture was stirred at 25 °C for 15 min. Then 080c (70 mg, 0.170 mmol) was added and the mixture was stirred at 25 °C for 2 h. After the starting material was consumed, the reaction mixture was quenched by adding water (100 mL) and diluted with EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC and preparative TLC to give 080d (40 mg, 0.040 mmol, 21.5% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:1106.6.

[0252] Step 5: trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(1S,3R)-3-[cis-3,4-bis(aminomethyl)pyrrolidin-1-yl]cyclopentyl]cyclohexanecarboxamide [ka] To a solution of 080d (40.0 mg, 0.040 mmol) in DCM (1 mL) was added TFA (1 mL) in one portion. The mixture was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give Example 080 (25.5 mg, 0.030 mmol, 83.37% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:806.3.

[0253] Example 080: 1 H NMR(400MHz,DMSO-d6)δ ppm 8.30-8.49(m,3H),8.04-8.27(m,6H),7.92(d,J=9.01Hz,2H),7.79(d,J=8.88Hz,2H),6.78(s,1H),6.71(s,1H),4.26(dd,J= 11.26,7.00Hz,1H),3.98-4.10(m,2H),3.82-3.89(m,1H),3.57-3.76(m,7H),3.02-3.16(m,5H),2.90-3.01(m,6H),2.63(br s,2H),2.12-2.30(m,2H),2.00-2.09(m,1H),1.89-1.98(m,2H),1.69- 1.86(m,4H),1.55-1.69(m,4H),1.27-1.40(m,2H),1.01-1.18(m,2H). 19 F NMR(376MHz,DMSO-d6)δ ppm-105.40--102.96(m,2F).

[0254] Example 081: trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[(1S)-3-[cis-3,5-diamino-1-piperidyl]cyclopentyl]cyclohexanecarboxamide [ka] The title compound was prepared similarly to the preparation of Example 080 by using tert-butyl N-[cis-5-(tert-butoxycarbonylamino)-3-piperidyl]carbamate instead of tert-butyl N-[[cis-4-[(tert-butoxycarbonylamino)methyl]pyrrolidin-3-yl]methyl]carbamate in step 4. Example 081 (50 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:792.5.

[0255] Example 081: 1 H NMR(400MHz,DMSO-d6)δ ppm 7.84-7.92(m,2H),7.75-7.83(m,2H),6.70(br d,J=18.51Hz,2H),4.23-4.34(m,1H),4.05(br s,1H),3.82(br d,J=10.63Hz,1H),3.50-3.70(m,9H),3.08(br dd,J=18.07,8.32Hz,1H),2.94(br s,4H),2.75-2.84(m,2H),2.61(br d,J=2.13Hz,1H),2.30-2.47(m,2H),1.96-2.14(m,4H),1.52-1.92(m,9H),1.29(br d,J=11.38Hz,2H),1.10(br d,J=12.76Hz,2H). 19 F NMR(376MHz,DMSO-d6)δ ppm-106.09--102.01(m,2F).

[0256] Example 082: trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(1S,3R)-3-[(3R)-3-aminopyrrolidin-1-yl]cyclopentyl]cyclohexanecarboxamide [ka] The title compound was prepared similarly to the preparation of Example 080 by using tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate instead of tert-butyl N-[[cis-4-[(tert-butoxycarbonylamino)methyl]pyrrolidin-3-yl]methyl]carbamate in step 4. Example 082 (60 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:763.3.

[0257] Example 082: 1 H NMR(400MHz,DMSO-d6)δ ppm 7.94(d,J=9.2Hz,2H),7.83(d,J=8.8Hz,2H),6.67(s,1H),4.65(s,1H),4.38-4.43(m,1H),4.15-4. 20(m,2H),4.07-4.11(m,1H),3.91-3.98(m,2H),3.76-3.81(m,1H),3.69-3.71(m,4H),3.57-3.63( m,1H),3.17-3.23(m,2H),3.07(t,J=4.8Hz,2H),2.71(dd,J=3.2Hz,J=18.0Hz,2H),2.51-2.58(m,1 H),2.14-2.25(m,3H),1.95-2.10(m,3H),1.76-1.86(m,6H),1.42-1.45(m,2H),1.21-1.28(m,2H). 19 F NMR(376MHz,DMSO-d6)δ ppm-104.55--102.79(m,2F).

[0258] Example 084: trans-3-[[4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl-(3-aminopropyl)-dimethyl-ammonium [ka]

[0259] Step 1: trans-tert-butyl N-[3-[3-[[4-[[2-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl-methyl-amino]propyl]carbamate [ka] To a mixture of intermediate 5 (110.0 mg, 0.150 mmol) and N,N-diisopropylethylamine (70.0 mg, 0.540 mmol) in anhydrous DMF (4 mL) was added HATU (75.0 mg, 0.2 mmol) in one portion. The reaction mixture was stirred at 20° C. for 1 h. Then, N′-(3-aminopropyl)-N′-methylpropane-1,3-diamine (60.0 mg, 0.410 mmol) was added into the reaction mixture and stirred for 11 h. After the starting material was consumed, the reaction mixture was filtered and purified by preparative HPLC. The resulting residue was then dissolved in DCM (3 mL) and Boc2O (100 mg) was added into the solution. The reaction was stirred at 25° C. for 12 h. After completion, the mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 084a (101 mg, 0.110 mmol, 79.14% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:938.3.

[0260] Step 2: trans-3-[[4-[[2-[4-[4-[(4R)-4-(tert-butoxycarbonylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl-[3-(tert-butoxycarbonylamino)propyl]-dimethyl-ammonium [ka] To a solution of 084a (60.0 mg, 0.060 mmol) in DMSO (1 mL) was added sodium bicarbonate (160.9 mg, 1.90 mmol) and iodomethane (0.3 mL, 0.12 mmol). The mixture was stirred at 40° C. for 12 h. After completion, the reaction mixture was purified by preparative HPLC to give 084b (50 mg, 0.050 mmol, 82.02% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:953.1.

[0261] Step 3: trans-3-[[4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl-(3-aminopropyl)-dimethyl-ammonium [ka] To a solution of 084b (30.0 mg, 0.030 mmol) in DCM (0.5 mL) was added TFA (0.5 mL, 0.040 mmol). The mixture was stirred at 20° C. for 2 h. The reaction mixture was then filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC to give Example 084 (10.2 mg, 0.010 mmol, 41.89% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:753.4.

[0262] Example 084: 1H NMR(400MHz, methanol-d4)δ ppm 7.94(br d,J=8.56Hz,2H),7.82(br d,J=8.44Hz,2H),6.66-6.70(m,1H),6.65(s,1H),4.42(br d,J=4.16Hz,1H),4.22(br s,1H),4.00(br d,J=10.51Hz,1H),3.69(br s,4H),3.48(br dd,J=2.63,1.41Hz,2H),3.35-3.43(m,2H),3.24-3.29(m,2H),3.21(br d,J=10.03Hz,1H),3.14(s,6H),3.06(br s,6H),2.74(dd,J=18.03,2.26Hz,1H),2.18(br s,3H),1.96-2.11(m,3H),1.88(br d,J=10.15Hz,2H),1.78(br d,J=11.74Hz,2H),1.43(br d,J=12.10Hz,2H),1.24(br d,J=11.74Hz,2H). 19 F NMR (376 MHz, methanol-d4) δ ppm-107.09--106.74 (m, 2F).

[0263] The compound JH-LPH-33, which has been disclosed in the literature (Bioorganic Chemistry (2020), 102, 104055) and has been reported to have LPS synthesis pathway inhibitory activity and to exhibit antibiotic activity against efflux-deficient Escherichia coli strains, was selected as a reference compound in the present invention. [ka]

[0264] Biological Examples Example 085: Median inhibitory concentration (IC) of Escherichia coli UDP-2,3-diacylglucosamine hydrolase (LpxH) 50 ) The inhibitory potency of compounds on Escherichia coli UDP-2,3-diacylglucosamine hydrolase (LpxH) was determined in an enzyme assay. UDP-2,3-diacylglucosamine (UDP-DAG) was purified from Caulobacter crescentus LpxI D225A mutant protein containing tightly bound UDP-DAG molecules. The enzyme was diluted using assay buffer containing 50 mM NaCl, 20 mM Tris-HCl pH 7.5, 2.5 mM MnCl2, 0.01% Triton X-100, 1 mg / mL BSA to a final concentration of 2 nM. Compounds were diluted by Agilent liquid handler Bravo, with serial dilution doses of compounds ranging from 100 μM to 1.7 nM. The mixture of enzyme and compound was then incubated at room temperature for 10 min. The enzyme assay was started by adding UDP-DAG (FAC is 5 μM) and incubated at room temperature for 20 min. The plate was then heated to 95°C for 15 min on a water batch to stop the reaction. Hydrolysis of UDP-DAG by LpxH yielded 2,3-diacylglucosamine 1-phosphate (Lipid X) and UMP, which was converted to ATP and quantified by luciferase reaction using Promega's UMP / CMP-Glo™ Glycosyltransferase Assay kit. The inhibitory effect of compounds on LpxH is determined by measuring the change in light using a luminometer (Envision). [Table 3]

[0265] Example 086: Minimum inhibitory concentration protocol (MIC) assay: Antibacterial activity of the molecules was evaluated against the commonly used quality control strains Escherichia coli BW 25113, Escherichia coli ATCC 25922 and the rifampin-resistant mutant strain Klebsiella pneumonia ATCC 43816. Escherichia coli BW 25113 was obtained from the Coli Genetic Stock Center (CGSC) (strain 7636). Both Escherichia coli ATCC 25922 and Klebsiella pneumonia ATCC 43816 were originally derived from human clinical samples and are available from the American Type Culture Collection (ATCC). The in vitro potency of compounds to inhibit the growth of Escherichia coli (BW 25113, ATCC 25922) and Klebsiella pneumonia (ATCC 43816) was assessed by the MIC (minimum inhibitory concentration) broth dilution method. Specifically, compound dilutions were prepared from a 10 mM DMSO stock solution as follows: i) serial 2-fold dilutions in 20 μL DMSO were prepared in a master plate (Greiner, Cat. No.: 651201), ii) 180 μL of sterile distilled water was added to each aliquot, and iii) 10 μL of diluted compound was transferred to a new assay plate (Costar, 3599).

[0266] Vials of each test organism were kept frozen in the vapor phase of a liquid nitrogen freezer. Disposable cryovials of three strains, Escherichia coli BW 25113, Escherichia coli ATCC 25922 (KWIKSTIK, 0335K), and Klebsiella pneumonia ATCC 43816, with the indicated CFU / mL were removed from the freezer, thawed at room temperature, and diluted in cation-adjusted Mueller-Hinton broth (CAMHB) to 5 × 10 5A final inoculum of CFU / mL was achieved. 90 μL of broth containing bacteria was dispensed into the assay plates containing pre-aliquoted compound dilutions and mixed 5 times by pipetting.

[0267] The assay plates were then incubated for 20 hours at 35° C. in ambient air. After incubation, the MIC (μg / mL), the lowest concentration of drug that inhibited visible growth of the microorganism, was read and recorded with the help of a magnifying glass. [Table 4-1] [Table 4-2]

[0268] Example 087: Human Microsome Stability Assay A human microsomal stability assay is used for preliminary assessment of the metabolic stability of test compounds in human liver microsomes. Human liver microsomes (Cat. NO.: 452117, Corning, USA) were pre-incubated with test compounds for 10 min at 37°C in 100 mM potassium phosphate buffer, pH 7.4. The reaction was started by adding NADPH regenerating system. The final incubation mixture contained 1 μM test compound, 0.5 mg / mL liver microsomal protein, 1 mM MgCl2, 1 mM NADP, 1 unit / mL isocitrate dehydrogenase and 6 mM isocitrate in 100 mM potassium phosphate buffer, pH 7.4. After 0, 3, 6, 9, 15 and 30 min incubation time at 37°C, the reaction was terminated by adding 300 μL cold acetonitrile (containing internal standard) to 100 μL incubation mixture. After precipitation and centrifugation, the amount of compound remaining in the sample was determined by LC-MS / MS. Controls without NADPH regeneration at 0 and 30 minutes were also prepared and analyzed. Compounds of the present invention showed good human liver microsomal stability as measured in the assay described above. The results are shown in Table 5 below. (Human microsomal clearance: <7 mL / min / kg: low; 7-16.2 mL / min / kg: medium; >16.2 mL / min / kg: high) [Table 5]

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, R １ is amino, hydroxy C １～６ Alkyl, C １～６ Alkylamino, Amino C １～６ alkylamino or piperazinyl; R ２ is halogen or C １～６ is alkyl; R ３ is -Y-C(O)-R ４ and Y is C ３～１０ cycloalkyl, phenyl, pyrazinyl or pyridinyl; R ４ Amino C １～６ Alkyl) ２ Amino) C １～６ Alkylamino, ((amino C １～６ Alkyl)pyrrolidiniumyl)C １～６ Alkylamino, ((amino C １～６ Alkylcarbonyl)amino)C １～６ Alkylamino, ((C １～６ Alkyl) ２ Amino) C １～６ Alkylamino, ((C １～６ Alkyl) ３ Ammonio) C １～６ Alkylamino, (amino C １～６ Alkoxy)C １～６ Alkylamino, (amino C １～６ Alkyl (C １～６ Alkyl) ２ Ammonio) C １～６ Alkylamino, (C １～６ Alkyl (amino C １～６ Alkyl) ２ Ammonio) C １～６ Alkylamino, ((amino C １～６ Alkylcarbonyl)amino)C ３～１０ Cycloalkylamino, ((amino C １～６ Alkyl) ２ Pyrrolidinyl) C ３～１０ Cycloalkylamino, (amino C １～６ Alkyl) ２ Amino, (Amino C １～６ alkyl)azetidinyl, (amino C １～６ Alkyl)C ３～１０ Cycloalkylamino, (amino C １～６ alkyl)piperazinyl, (amino C １～６ Alkylamino)C １～６ Alkylamino, (amino C １～６ alkylcarbonyl)aminocarbamoyl, (aminopyrrolidinyl)C ３～１０ Cycloalkylamino, (azetidinyl C １～６ Alkylamino)C １～６ Alkylamino, (C １～６ Alkylamino)C １～６ Alkylamino, (C １～６ Alkylpyrrolidiniumyl)C １～６ Alkylamino, (diaminopiperidinyl)C １～６ Alkylamino, (diaminopiperidinyl)C ３～１０ Cycloalkylamino, (piperidinylcarbonylamino)carbamoyl, 3-azabicyclo[3.1.0]hexanylamino, amino, amino(C １～６ Alkoxy)C １～６ Alkylamino, amino (C １～６ alkyl) piperidinyl, (amino C １～６ Alkyl) ２ Pyrrolidinyl, amino(hydroxy)C １～６ Alkylamino, Amino C １～６ Alkylamino, Amino C ３～１０ Cycloalkylamino, aminocarbonyl C １～６ Alkylamino, aminopyrrolidinylamino, amino(C １～６ Alkyl)pyrrolidinylamino, azetidinyl C １～６ Alkylamino, C １～６ Alkoxy, C １～６ Alkyl (amino C １～６ Alkyl)amino, C １～６ Alkylpyrrolidinylamino, C １～６ Alkyl (amino C １～６ Alkyl)piperaziniumyl, C １～６ Alkyl-2,6-diazaspiro[3.3]heptanyl, C １～６ Alkylamino, Diamino C １～６ Alkylamino, diaminopiperidinyl, hydroxy C １～６ Alkylamino, hydroxypyrrolidinylamino, morpholinyl C １～６ Alkylamino or pyrrolidinyl C １～６ alkylamino; X is CH ２ or O; A is CH or N; Q １ is CH or N; Q ２ is CH or N; W is for Halo C １～６ is alkyl) or a pharma- ceutically acceptable salt thereof.

2. R １ But Amino, C １～６ Alkylamino or hydroxy C １～６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is 0 or 1;

3. R １ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein: is amino, methylamino or hydroxymethyl.

4. R ２ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

5. R ２ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is chloro.

6. R ３ is -Y-C(O)-R ４ and Y is C ３～１０ 6. The compound according to any one of claims 1 to 5, which is cycloalkyl, phenyl or pyrazinyl, or a pharma- ceutically acceptable salt thereof.

7. R ３ is -Y-C(O)-R ４ and Y is bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, cyclohexanyl, norbornanyl, phenyl or pyrazinyl, or a pharma- ceutically acceptable salt thereof.

8. R ３ is -Y-C(O)-R ４ and R ４ But amino (C １～６ alkyl)pyrrolidinylamino, ((amino C １～６ Alkyl) ２ Amino) C １～６ Alkylamino, ((amino C １～６ Alkyl) ２ Pyrrolidinyl) C ３～１０ Cycloalkylamino, ((amino C １～６ Alkyl)pyrrolidiniumyl)C １～６ Alkylamino, (amino C １～６ Alkyl (C １～６ Alkyl) ２ Ammonio) C １～６ Alkylamino, (amino C １～６ Alkyl) ２ Amino, (Amino C １～６ Alkyl) ２ Pyrrolidinyl, (amino C １～６ Alkyl)C ３～１０ Cycloalkylamino, (C １～６ Alkyl (amino C １～６ Alkyl) ２ Ammonio) C １～６ Alkylamino, (aminopyrrolidinyl)C ３～１０ Cycloalkylamino, (C １～６ Alkyl (amino C １～６ Alkyl) ２ Ammonio) C １～６ Alkylamino, (diaminopiperidinyl)C １～６ Alkylamino, (diaminopiperidinyl)C ３～１０ Cycloalkylamino, amino, amino(hydroxy)C １～６ Alkylamino, Amino C １～６ Alkylamino, Amino C ３～１０ Cycloalkylamino, C １～６ Alkylpyrrolidinylamino, diamino C １～６ 8. The compound of any one of claims 1 to 7, which is alkylamino or diaminopiperidinyl, or a pharma- ceutically acceptable salt thereof.

9. R ３ is -Y-C(O)-R ４ and R ４ ((2-aminoethyl) ２ (2-aminoethyl)pyrrolidin-1-ium-1-yl)ethylamino, (2-aminoethyl(dimethyl)ammonio)ethylamino, (2-aminoethyl) ２ Amino, (3,5-diamino-1-piperidinyl)propylamino, (3-aminocyclopentyl)amino, (3-aminopropyl) ２ Amino, (4-methylpyrrolidin-3-yl)amino, [3-(3,5-diamino-1-piperidinyl)cyclopentyl]amino, [3-[3,4-bis(aminomethyl)pyrrolidin-1-yl]cyclopentyl]amino, [3-[3-aminopyrrolidin-1-yl]cyclopentyl]amino, 1-(aminomethyl)cyclopropylamino, 2-(2-aminoethylamino)ethylamino, 2,3-diaminopropylamino, 2-aminoethylamino, 3,4-bis(aminomethyl)pyrrolidin 9. The compound of any one of claims 1 to 8, which is lysin-1-yl, 3,5-diaminopiperidinyl, 3-[3-aminopropyl(dimethyl)ammonio]propylamino, 3-[bis(2-aminoethyl)-methyl-ammonio]propylamino, 3-amino-2-hydroxy-propylamino, 3-aminopropylamino, 3-hydroxypropylamino, 4-amino-2-methyl-pyrrolidin-1-yl, amino or aminopropylamino, or a pharma- ceutically acceptable salt thereof.

10. 10. The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein A is CH.

11. Q １ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein:

12. Q ２ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is CH.

13. W is CF ２ 13. The compound according to any one of claims 1 to 12, wherein:

14. R １ is amino or hydroxy C １～６ is alkyl; R ２ is a halogen; R ３ is -Y-C(O)-R ４ and Y is C ３～１０ cycloalkyl, phenyl or pyrazinyl; R ４ But amino (C １～６ alkyl)pyrrolidinylamino, ((amino C １～６ Alkyl) ２ Amino) C １～６ Alkylamino, ((amino C １～６ Alkyl) ２ Pyrrolidinyl) C ３～１０ Cycloalkylamino, ((amino C １～６ Alkyl)pyrrolidiniumyl)C １～６ Alkylamino, (amino C １～６ Alkyl (C １～６ Alkyl) ２ Ammonio) C １～６ Alkylamino, (amino C １～６ Alkyl) ２ Amino, (Amino C １～６ Alkyl) ２ Pyrrolidinyl, (amino C １～６ Alkyl)C ３～１０ Cycloalkylamino, (C １～６ Alkyl (amino C １～６ Alkyl) ２ Ammonio) C １～６ Alkylamino, (aminopyrrolidinyl)C ３～１０ Cycloalkylamino, (C １～６ Alkyl (amino C １～６ Alkyl) ２ Ammonio) C １～６ Alkylamino, (diaminopiperidinyl)C １～６ Alkylamino, (diaminopiperidinyl)C ３～１０ Cycloalkylamino, amino, amino(hydroxy)C １～６ Alkylamino, Amino C １～６ Alkylamino, Amino C ３～１０ Cycloalkylamino, C １～６ Alkylpyrrolidinylamino, diamino C １～６ alkylamino or diaminopiperidinyl; X is CH ２ or O; A is CH; Q １ is N; Q ２ is CH; W is Halo C １～６ 14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

15. R １ is amino or hydroxymethyl; R ２ is chloro; R ３ is -Y-C(O)-R ４ and Y is bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, cyclohexanyl, phenyl or pyrazinyl; R ４ ((2-aminoethyl) ２ (2-aminoethyl)pyrrolidin-1-ium-1-yl)ethylamino, (2-aminoethyl(dimethyl)ammonio)ethylamino, (2-aminoethyl) ２ Amino, (3,5-diamino-1-piperidinyl)propylamino, (3-aminocyclopentyl)amino, (3-aminopropyl) ２ amino, (4-methylpyrrolidin-3-yl)amino, [3-(3,5-diamino-1-piperidinyl)cyclopentyl]amino, [3-[3,4-bis(aminomethyl)pyrrolidin-1-yl]cyclopentyl]amino, [3-[3-aminopyrrolidin-1-yl]cyclopentyl]amino, 1-(aminomethyl)cyclopropylamino, 2-(2-aminoethylamino)ethylamino, 2,3-diaminopropylamino, 2-aminoethylamino, 3,4-bis(aminomethyl)pyrrolidin-1-yl, 3,5-diaminopiperidinyl, 3-[3-aminopropyl(dimethyl)ammonio]propylamino, 3-[bis(2-aminoethyl)-methyl-ammonio]propylamino, 3-amino-2-hydroxy-propylamino, 3-aminopropylamino, 3-hydroxypropylamino, 4-amino-2-methyl-pyrrolidin-1-yl, amino or aminopropylamino; X is CH ２ or O; A is CH; Q １ is N; Q ２ is CH; W is CF ２ 15. The compound according to any one of claims 1 to 14, wherein:

16. trans-methyl 4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxylate; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(azetidin-3-ylmethyl)cyclohexanecarboxamide; trans-4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-hydroxypropyl)cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-(4-amino-4-methyl-piperidine-1-carbonyl)cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-(4R)-4-amino-1-[4-[4-[6-chloro-4-[difluoro-[4-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)cyclohexyl]methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(4-hydroxypyrrolidin-3-yl)cyclohexanecarboxamide; trans-N-(3-aminocyclobutyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(2-amino-1-methyl-ethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(2-pyrrolidin-1-ylethyl)cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[cis-4-aminopyrrolidin-3-yl]cyclohexanecarboxamide; trans-N-[1-(aminomethyl)cyclopropyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-[4-(2-aminoethyl)piperazine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; 4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-hydroxypropyl)benzamide; 4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-aminopropyl)benzamide; N-(2-aminoethyl)-4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]benzamide; N-(3-amino-2-hydroxy-propyl)-4-[[2-[4-[4-(4-amino-2-oxo-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]benzamide; N-(3-amino-2-hydroxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]benzamide; 4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(dimethylamino)propyl]benzamide; N-(3-aminopropyl)-5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxamide; N-(3-amino-2-hydroxy-propyl)-5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxamide; 5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(dimethylamino)propyl]pyrazine-2-carboxamide; N-(2-aminoethyl)-5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyrazine-2-carboxamide; 5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(2-morpholinoethyl)pyrazine-2-carboxamide; N-(3-aminopropyl)-6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyridine-3-carboxamide; 6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(dimethylamino)propyl]pyridine-3-carboxamide; N-[2-(2-aminoethylamino)ethyl]-6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]pyridine-3-carboxamide; 5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(methylamino)propyl]pyridine-2-carboxamide; trans-N-(2-aminoethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-methyl-cyclohexanecarboxamide; cis-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; cis-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(3-hydroxypropyl)cyclohexanecarboxamide; N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[2.2.2]octane-1-carboxamide; N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]norbornane-1-carboxamide; N-(3-aminopropyl)-3-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclopentanecarboxamide; trans-N-(3-amino-2-hydroxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; 3-[[4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]benzoyl]amino]propyl-trimethyl-ammonium; 4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(1-methylpyrrolidin-1-ium-1-yl)propyl]benzamide; 5-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-(2-hydroxyethylamino)propyl]pyridine-2-carboxamide; N-(3-aminopropyl)-3-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[1.1.1]pentane-1-carboxamide; trans-N-(2-aminoethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-[2-(2-aminoethoxy)ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N,N-bis(2-aminoethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N,N-bis(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; N,N-bis(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[2.2.2]octane-1-carboxamide; N,N-bis(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]norbornane-1-carboxamide; trans-N-[3-[bis(2-aminoethyl)amino]propyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[6-chloro-4-[[4-cis-(3,5-diaminopiperidine-1-carbonyl)cyclohexyl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[3-[cis-3,5-diamino-1-piperidyl]propyl]cyclohexanecarboxamide; trans-N'-(2-aminoacetyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbohydrazide; trans-N'-[4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]piperidine-4-carbohydrazide; trans-N-(2-amino-3-hydroxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; (2R,5S)-5-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-aminopropyl)bicyclo[2.2.2]octane-2-carboxamide; trans-N-(3-aminopropyl)-4-[difluoro-[6-methyl-2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]pyrimidin-4-yl]methyl]cyclohexanecarboxamide; N-(3-aminopropyl)-6-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]bicyclo[3.1.0]hexane-3-carboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-[3-(aminomethyl)azetidine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(5S)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(5R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-(2-oxo-4-piperazin-1-yl-pyrrolidin-1-yl)phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[[6-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]-3-pyridyl]sulfonyl]piperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonyl-1-piperidyl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; cis-N-(2-amino-2-oxo-ethyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; (4R)-4-amino-1-[4-[4-[4-[[4-[(2S,4S)-4-amino-2-methyl-pyrrolidine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-bis(2-aminoethyl)-[3-[[4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl]-methyl-ammonium; trans-N-[(1R,3S)-3-aminocyclopentyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-[cis-3,4-bis(aminomethyl)pyrrolidine-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(3R,4S)-4-methylpyrrolidin-3-yl]cyclohexanecarboxamide; trans-N-(3-aminopropyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-(methylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-(4R)-4-amino-1-[4-[4-[4-[[4-[4-(2-aminoethyl)-4-methyl-piperazin-4-ium-1-carbonyl]cyclohexyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyrrolidin-2-one; trans-N-[2-(2-aminoethylamino)ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-2-aminoethyl-[2-[[4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]ethyl]-dimethyl-ammonium; trans-N-[2-[1-(2-aminoethyl)pyrrolidin-1-ium-1-yl]ethyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-[2-[(2-aminoacetyl)amino]ethyl]-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-N-(3-amino-2-methoxy-propyl)-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-(2,3-diaminopropyl)cyclohexanecarboxamide; 4-[[2-[4-[4-[4-(3-aminopropylamino)-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-methyl-benzamide; trans-N-[(1R,3S)-3-[(2-aminoacetyl)amino]cyclopentyl]-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarboxamide; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(1S,3R)-3-[cis-3,4-bis(aminomethyl)pyrrolidin-1-yl]cyclopentyl]cyclohexanecarboxamide; trans-4-[[2-chloro-6-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-4-pyridyl]-difluoro-methyl]-N-[(1S)-3-[cis-3,5-diamino-1-piperidyl]cyclopentyl]cyclohexanecarboxamide; trans-4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[(1S,3R)-3-[(3R)-3-aminopyrrolidin-1-yl]cyclopentyl]cyclohexanecarboxamide; and trans-3-[[4-[[2-[4-[4-[(4R)-4-amino-2-oxo-pyrrolidin-1-yl]phenyl]sulfonylpiperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexanecarbonyl]amino]propyl-(3-aminopropyl)-dimethyl-ammonium; or a pharma- ceutically acceptable salt thereof.

17. The following steps: a) an acid, the acid being trifluoroacetic acid, or a reducing reagent, the reducing reagent being H ２ Compound of formula (XVIII) using a reducing agent which is palladium on carbon in the presence of 【Chemistry 2】 via deprotection of the compound of formula (XIX) 【Chemistry 3】 Formation of; b) Compound of formula (XXXIII) using a suitable reagent, said reagent being MeI 【Chemistry 4】 followed by methylation of the compound with an acid, said acid being trifluoroacetic acid, or a reducing agent, said reducing agent being H ２ via deprotection with a reducing agent which is palladium on carbon in the presence of 【Chemistry 5】 Formation of c) an acid, the acid being trifluoroacetic acid, or a reducing agent, the reducing agent being H ２ Compound of formula (XXXIII) using a reducing agent which is palladium on carbon in the presence of 【Chemistry 6】 via deprotection of the compound of formula (XXXIV) 【Chemistry 7】 Formation of; d) an acid, the acid being trifluoroacetic acid, or a reducing agent, the reducing agent being H ２ Compound of formula (XXXVII) using a reducing agent which is palladium on carbon in the presence of 【Chemistry 8】 via deprotection of the compound of formula (XXXVIII) 【Chemistry 9】 Formation of; Including any of the following: In the formula, R ４ ' is R ４ Or R ４ -PG ３ and L １ is C １～６ Alkyl or C ３～１０ is cycloalkyl; R ７ is C １～６ Alkyl, Amino C １～６ Alkyl or Amino C ３～１０ is cycloalkyl; R ７’ is R ７ -PG ５ and ２ , P.G. ３ and P.G. ５ is independently selected from tert-butoxycarbonyl or benzyloxycarbonyl; R １ , R ２ , Y, A, Q １ , Q ２ and X is as defined in any one of claims 1 to 15. A process for the preparation of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt according to any one of claims 1 to 16 for use as a therapeutically active substance.

19. A pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt according to any one of claims 1 to 16 and a therapeutically inert carrier.

20. A pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt according to any one of claims 1 to 16 for the inhibition of LpxH.

21. 17. Use of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a bacterial infection, in particular a bacterial infection, wherein said bacterium is a Gram-negative bacterium.

22. 22. The use according to claim 21, wherein the gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylori, Acinetobacter baumannii and Pseudomonas aeruginosa.

23. 23. The use according to claim 22, wherein the Gram-negative bacterium is Enterobacteriaceae, the Enterobacteriaceae being Klebsiella pneumoniae or Escherichia coli.

24. 17. A pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt according to any one of claims 1 to 16 for the treatment or prevention of a bacterial infection, in particular a bacterial infection wherein the bacterium is a Gram-negative bacterium.

25. 25. The pharmaceutical composition of claim 24, wherein the gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylori, Acinetobacter baumannii, and Pseudomonas aeruginosa.

26. 26. The pharmaceutical composition of claim 25, wherein the Gram-negative bacterium is Enterobacteriaceae, and the Enterobacteriaceae is Klebsiella pneumoniae or Escherichia coli.

27. A method for the treatment or prevention of a bacterial infection, in particular a bacterial infection wherein said bacteria is a Gram-negative bacteria, comprising administering to a non-human subject a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof.

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