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

Abstract

The present invention relates to a compound represented by formula (I) TIFF2025507783000282.tif2567(in the formula, R 1 ~R 8 , Y, A, Q, X and M are as described herein) and their pharma- ceutically acceptable salts, compositions comprising said compounds 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 can inhibit the LPS synthesis pathway, in particular inhibit LpxH, and are useful in the treatment of bacterial infections. [Background technology]

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

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

[0004] The present invention relates to a compound represented by formula (I) [ka] (C in the formula R 1 is COR 9 and; R 9 is ((hydroxy C 1-6 Alkyl)amino)C 1-6 Alkyl, 1-oxa-2,9-diazaspiro[4.5]dec-2-enyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, C 1-6 alkyl-substituted 4,6-dihydropyrrolo[3,4-c]pyrazolyl; 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, Amino or Amino C 1-6 alkylamino-substituted indanyl; Isoindolinyl, Piperazinyl C 1-6 Alkyl, pyrazolo[1,5-a]pyrimidinyl, Amino C 1-6 Alkyl, Azetidinyl, C 1-6 pyrazolyl substituted once or twice with substituents independently selected from alkyl and carboxy; (Amino C 1-6 Alkylamino)C 1-6 alkyl-substituted pyridinyl, or ((amino(carboxy)C 1-6 Alkyl)amino)C 1-6 Alkyl, ((amino C 1-6 Alkyl)-3-azabicyclo[3.1.0]hexanyl)C 1-6 Alkyl, ((amino C 1-6 Alkyl)pyrrolidinyl)C 1-6 Alkyl, ((amino C 3-7 Cycloalkyl)C 1-6 Alkylamino)C 1-6 Alkyl, ((amino C3-7 cycloalkyl)pyrrolidinyl)C 1-6 Alkyl, ((oxooxazolidinyl)C 1-6 Alkylamino)C 1-6 Alkyl, ((oxopyrrolidinyl)C 1-6 Alkylamino)C 1-6 Alkyl, ((piperidinyl)C 1-6 Alkylamino)C 1-6 Alkyl, (3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrolyl)C 1-6 Alkyl, (3,6-diazabicyclo[3.1.1]heptanyl)C 1-6 Alkyl, (amino-2-azaspiro[3.3]heptanyl)C 1-6 Alkyl, (amino-5-azaspiro[2.4]heptanyl)C 1-6 Alkyl, (amino C 1-6 Alkyl)piperazinyl, (amino C 1-6 Alkyl)pyrrolidinyl, (amino C 1-6 Alkylamino)C 1-6 Alkyl, (aminopyrrolidinyl)C 1-6 Alkyl, (C 1-6 Alkyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl)C1-6 Alkyl, (Diamino C 1-6 Alkylcarbonyl)amino, (morpholinyl C 1-6 Alkylamino)C 1-6 Alkyl, (Piperazinyl C 1-6 Alkylamino)C 1-6 Alkyl, (piperidinyl C 1-6 Alkylamino)C 1-6 Alkyl, [((C 1-6 Alkyl)2 Aminocarbonyl C 1-6 Alkyl)amino]C 1-6 Alkyl, [((hydroxy C 1-6 Alkyl)2Amino)C 1-6 Alkylamino]C 1-6 Alkyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, amino C 1-6 Alkoxy, Amino C 1-6 Alkyl, aminopyrrolidinyl, azetidinyl C 1-6 Alkoxy, Azetidinyl C 1-6 Alkylamino, C 1-6 Alkylcarbonyloxy, C 1-6 phenyl substituted once or twice with substituents independently selected from alkoxy, carboxy, hydroxy, and piperazinyl; R 2 is H; R 3 is H, hydroxy or C 1-6 is alkoxy; or R 2 and R 3 together with the atom to which they are attached to form pyrrolidinyl; R 4 is H, hydroxy or C 1-6 is alkoxy; R 5 is H or C 1-6 is alkyl; R 6 is H or C 1-6 is alkyl; or R 5 and R 6together with the atoms to which they are attached, C 3-7 Forming a cycloalkyl; R 7 is halogen, cyano, haloC 1-6 Alkyl or C 1-6 is an alkoxycarbonyl; R 8 is H, halogen, cyano, amino, C 3-7 Cycloalkoxy, C 1-6 Alkyl, C 1-6 Alkoxy or haloC 1-6 is alkyl; Y is CH or N; A is O, N(CN) or N(C 1-6 alkyl); Q is CH or N; X is CH or N; M is N or CR 10 ;R 10 H, halogen, C 1-6 Alkyl or C 3-7 is cycloalkyl; However, Q, X and M are not simultaneously N. or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0006] "C 1-6 The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a bi-branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. 1-6Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0007] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.

[0008] "Haro C 1-6 The term "alkyl" refers to 1-6 At least one of the hydrogen atoms of the alkyl group is replaced by the same or different halogen atom, in particular a fluoro atom. 1-6 Indicates an alkyl group. HaloC 1-6 Examples of alkyl include monofluoromethyl, difluoromethyl, or trifluoromethyl, monofluoroethyl, difluoroethyl, or trifluoroethyl, or monofluoropropyl, difluoropropyl, or trifluoropropyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, trifluoroethyl, fluoromethyl, difluoromethyl, difluoroethyl, or trifluoromethyl.

[0009] "C 3-7 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical containing 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl.

[0010] "C 3-7 The term "cycloalkoxy" refers to 3-7 Cycloalkyl-O- is represented.

[0011] "COR 9 The term " [ka] Shows.

[0012] The term "oxo" refers to a divalent oxygen atom, ═O.

[0013] The term "phenylene" refers to a divalent phenyl group.

[0014] The term "pyrazolylene" refers to a divalent pyrazolyl group.

[0015] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0016] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from the aliphatic, alicyclic, aromatic, aryl-containing aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0017] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, piperidine, N-ethylpiperidine, and polyamine resins.

[0018] The term "pharmacologically active metabolite" refers to a pharmacologically active product produced through metabolism in the body of a particular compound or its salt. After entering the body, most drugs become substrates for chemical reactions that can change their physical properties and biological effects. These metabolic transformations usually affect the polarity of the compounds of the present invention and change the way the drug is distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect.

[0019] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. The therapeutically effective amount may vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0020] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharma- ceutically acceptable excipients, for administration to a mammal, e.g., a human in need thereof.

[0021] Inhibitors of UDP-2,3-diacylglucosamine hydrolase (LpxH) The present invention relates to a compound represented by the formula (I): [ka] (In the formula, R 1 is COR 9 and; R 9 is ((hydroxy C 1-6 Alkyl)amino)C 1-6 Alkyl, 1-oxa-2,9-diazaspiro[4.5]dec-2-enyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, C 1-6 alkyl-substituted 4,6-dihydropyrrolo[3,4-c]pyrazolyl; 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, Amino or Amino C 1-6 alkylamino-substituted indanyl; Isoindolinyl, Piperazinyl C1-6 Alkyl, pyrazolo[1,5-a]pyrimidinyl, Amino C 1-6 Alkyl, Azetidinyl, C 1-6 pyrazolyl substituted once or twice with substituents independently selected from alkyl and carboxy; (Amino C 1-6 Alkylamino)C 1-6 alkyl-substituted pyridinyl, or ((amino(carboxy)C 1-6 Alkyl)amino)C 1-6 Alkyl, ((amino C 1-6 Alkyl)-3-azabicyclo[3.1.0]hexanyl)C 1-6 Alkyl, ((amino C 1-6 Alkyl)pyrrolidinyl)C 1-6 Alkyl, ((amino C 3-7 Cycloalkyl)C 1-6 Alkylamino)C 1-6 Alkyl, ((amino C3-7 cycloalkyl)pyrrolidinyl)C 1-6 Alkyl, ((oxooxazolidinyl)C 1-6 Alkylamino)C 1-6 Alkyl, ((oxopyrrolidinyl)C 1-6 Alkylamino)C 1-6 Alkyl, ((piperidinyl)C 1-6 Alkylamino)C 1-6 Alkyl, (3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrolyl)C 1-6 Alkyl, (3,6-diazabicyclo[3.1.1]heptanyl)C 1-6 Alkyl, (amino-2-azaspiro[3.3]heptanyl)C 1-6 Alkyl, (amino-5-azaspiro[2.4]heptanyl)C 1-6 Alkyl, (amino C 1-6 Alkyl)piperazinyl, (amino C 1-6 Alkyl)pyrrolidinyl, (amino C 1-6 Alkylamino)C 1-6 Alkyl, (aminopyrrolidinyl)C 1-6 Alkyl, (C1-6 Alkyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl)C 1-6 Alkyl, (Diamino C 1-6 Alkylcarbonyl)amino, (morpholinyl C 1-6 Alkylamino)C 1-6 Alkyl, (Piperazinyl C 1-6 Alkylamino)C 1-6 Alkyl, (piperidinyl C 1-6 Alkylamino)C 1-6 Alkyl, [((C 1-6 Alkyl)2 Aminocarbonyl C 1-6 Alkyl)amino]C 1-6 Alkyl, [((hydroxy C 1-6 Alkyl)2Amino)C 1-6 Alkylamino]C 1-6 Alkyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, amino C 1-6 Alkoxy, Amino C 1-6 Alkyl, aminopyrrolidinyl, azetidinyl C 1-6 Alkoxy, Azetidinyl C 1-6 Alkylamino, C 1-6 Alkylcarbonyloxy, C 1-6 phenyl substituted once or twice with substituents independently selected from alkoxy, carboxy, hydroxy, and piperazinyl; R 2 is H; R 3 is H, hydroxy or C 1-6 is alkoxy; or R 2 and R 3 together with the atom to which they are attached to form pyrrolidinyl; R 4 is H, hydroxy or C 1-6 is alkoxy; R 5 is H or C 1-6 is alkyl; R 6 is H or C 1-6is alkyl; or R 5 and R 6 together with the atoms to which they are attached, C 3-7 Forming a cycloalkyl; R 7 is halogen, cyano, haloC 1-6 Alkyl or C 1-6 is an alkoxycarbonyl; R 8 is H, halogen, cyano, amino, C 3-7 Cycloalkoxy, C 1-6 Alkyl, C 1-6 Alkoxy or haloC 1-6 is alkyl; Y is CH or N; A is O, N(CN) or N(C 1-6 alkyl); Q is CH or N; X is CH or N; M is N or CR 10 ;R 10 H, halogen, C 1-6 Alkyl or C 3-7 is cycloalkyl; However, Q, X and M are not simultaneously N. or a pharma- ceutically acceptable salt thereof.

[0022] A further embodiment of the invention is (ii) a compound of formula (I), wherein R 1 COR 9 and; R 9 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, Amino or Amino C 1-6 alkylamino-substituted indanyl; Isoindolinyl, pyrazolo[1,5-a]pyrimidinyl, (Amino C 1-6 Alkylamino)C 1-6 alkyl-substituted pyridinyl, or ((Amino C 1-6 Alkyl)-3-azabicyclo[3.1.0]hexanyl)C 1-6 Alkyl, (amino C 1-6 Alkyl)pyrrolidinyl, (amino C 1-6 Alkylamino)C 1-6 Alkyl, Amino C 1-6 Alkoxy, Amino C 1-6 Alkyl, aminopyrrolidinyl, azetidinyl C 1-6 The compound is phenyl substituted once or twice with substituents independently selected from alkoxy, carboxy and piperazinyl.

[0023] A further embodiment of the present invention is a compound comprising: 1 COR 9 ;R 9 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, aminoindanyl, (3-aminopropylamino)indanyl, isoindolinyl, pyrazolo[1,5-a]pyrimidinyl, ((3-aminopropylamino)methyl)pyridinyl, ((3-aminopropylamino)methyl)phenyl, ((3-aminopropylamino)ethyl)phenyl, carboxyphenyl, (aminoethoxy)phenyl, (azetidin-3-ylmethoxy)phenyl, (aminopyrrolidine or a pharma- ceutically acceptable salt thereof. In another aspect, the compound of formula (I) according to (i) or (ii) is (1-(3-aminopropyl)pyrrolidin-2-yl)phenyl, (1-(3-aminopropyl)pyrrolidin-3-yl)phenyl, (1-(3-aminopropyl)pyrrolidin-3-yl)phenyl or [[1-(aminomethyl)-3-azabicyclo[3.1.0]hex-3-yl)methyl]phenyl.

[0024] Further embodiments of the present invention include (iv) R 2 is H;R 3 is H; or R 2 and R 3or a pharma- ceutically acceptable salt thereof, wherein:

[0025] A further embodiment of the present invention is a compound comprising: 4 is H;R 5 is H;R 6 is H.

[0026] A further embodiment of the present invention is a compound comprising: 7 is halogen or haloC 1-6ア or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group; and R is an alkyl group.

[0027] A further embodiment of the present invention is a compound comprising: 7 is bromo, trifluoromethyl or difluoroethyl, or a pharma- ceutically acceptable salt thereof.

[0028] Further embodiments of the present invention include (viii) R 8 But halogen or C 1-6 or a pharma- ceutically acceptable salt thereof.

[0029] Further embodiments of the present invention include (ix) R 8 is chloro or methyl, or a pharma- ceutically acceptable salt thereof.

[0030] A further embodiment 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) Y is CH.

[0031] A further embodiment of the present invention is a compound of formula (I) as defined in any one of (i) to (x) or a pharma- ceutically acceptable salt thereof, wherein (xi) A is O.

[0032] A further embodiment of the present invention is a compound of formula (I) as defined in any one of (i) to (xi) or a pharma- ceutically acceptable salt thereof, wherein (xii) X is N.

[0033] A further embodiment 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) M is CH.

[0034] A further embodiment of the present invention is a compound comprising: R 1 COR 9 and; R 9 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, Amino or Amino C 1-6 alkylamino-substituted indanyl; Isoindolinyl, pyrazolo[1,5-a]pyrimidinyl, (Amino C 1-6 Alkylamino)C 1-6 alkyl-substituted pyridinyl, or ((Amino C 1-6 Alkyl)-3-azabicyclo[3.1.0]hexanyl)C 1-6 Alkyl, (amino C 1-6 Alkyl)pyrrolidinyl, (amino C 1-6 Alkylamino)C 1-6 Alkyl, Amino C 1-6 Alkoxy, Amino C 1-6 Alkyl, aminopyrrolidinyl, azetidinyl C 1-6 phenyl substituted once or twice with substituents independently selected from alkoxy, carboxy and piperazinyl; R 2 is H; R 3 is H; or R 2 and R 3 together with the atom to which they are attached to form pyrrolidinyl; R 4 is H; R 5 is H; R 6 is H; R 7 But halogen or haloC 1-6 is alkyl; R 8 But halogen or C 1-6 is alkyl; Y is CH; A is O; Q is CH or N; X is N; M is CH; A compound of formula (I) or a pharma- ceutically acceptable salt thereof:

[0035] A further embodiment of the present invention is a compound comprising: R 1 COR 9 ;R 9 is 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, aminoindanyl, (3-aminopropylamino)indanyl, isoindolinyl, pyrazolo[1,5-a]pyrimidinyl, ((3-aminopropylamino)methyl)pyridinyl, ((3-aminopropylamino)methyl)phenyl, ((3-aminopropylamino)ethyl)phenyl, carboxyphenyl, (aminoethoxy)phenyl, (azetidin-3-ylmethoxy)phenyl, (aminopyrrolidin-1-yl)phenyl, (aminoethyl)phenyl, (piperazin-1-yl)phenyl, (3-aminopropoxy)2phenyl, (1-(3-aminopropyl)pyrrolidin-2-yl)phenyl, (1-(3-aminopropyl)pyrrolidin-3-yl)phenyl or [[1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl]phenyl; R 2 is H; R 3is H; or R 2 and R 3 together with the atom to which they are attached to form pyrrolidinyl; R 4 is H; R 5 is H; R 6 is H; R 7 is bromo, trifluoromethyl or difluoroethyl; R 8 is chloro or methyl; Y is CH; A is O; Q is CH or N; X is N; M is CH; A compound of formula (I) or a pharma- ceutically acceptable salt thereof:

[0036] Another embodiment of the present invention is: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[5-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[3-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[2-chloro-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[2-amino-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-(4-bromo-6-chloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[5-cyclopropyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-ethoxy-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-ethyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[5-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-(4,5-dichloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[4-cyano-6-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[6-cyano-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[6-chloro-4-(1,1-difluoroethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; Methyl 2-[4-[4-[[3-[(3-aminopropylamino)methyl]benzoyl]amino]phenyl]sulfonylpiperazin-1-yl]-6-chloro-pyridine-4-carboxylate; 3-[(3-aminopropylamino)methyl]-N-[4-[4-(6-chloro-4-cyano-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl-piperazin-1-yl]sulfonylphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-methyl-piperazin-1-yl]sulfonylphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[[5-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2,5-diazabicyclo[4.2.0]octan-2-yl]sulfonyl]phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[2-(3-aminopropylamino)ethyl]-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-cyano-sulfonimidoyl]phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-methyl-sulfonimidoyl]phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-methoxy-phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-hydroxy-phenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-methoxyphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-hydroxy-phenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide; [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-pyrazolo[1,5-a]pyrimidin-3-yl-methanone; 4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]-2-methyl-pyrazole-3-carboxylic acid; [1-(azetidin-3-yl)pyrazol-4-yl]-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]methanone; [1-(3-aminopropyl)pyrazol-4-yl]-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]methanone; [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methanone; [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-(1-oxa-2,9-diazaspiro[4.5]dec-2-en-3-yl)methanone; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-piperazin-1-yl-acetamide; 1-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-2-(2-hydroxyethylamino)ethanone; 2-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]benzoic acid; [2-acetoxy-4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]phenyl]acetate; N-[4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide; N-[4-[4-[6-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]isoindoline-5-carboxamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide; 3-(2-aminoethoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-(Azetidin-3-ylmethylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-(azetidin-3-ylmethoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(3R)-3-aminopyrrolidin-1-yl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[3,6-diazabicyclo[3.2.0]heptan-3-yl]benzamide; 3-(2-aminoethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-piperazin-1-yl-benzamide; 2-Amino-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indan-5-carboxamide; 5-(aminomethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-hydroxy-benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(2,4-diaminobutanoylamino)benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-2-carboxamide; 6-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-2-carboxamide; 5-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-3-carboxamide; 2-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indan-5-carboxamide; 3-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indan-5-carboxamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-5-[(5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl)methyl]benzamide; 1-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indan-5-carboxamide; 3,4-Bis(3-aminopropoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[1-(3-aminopropyl)pyrrolidin-2-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[1-(3-aminopropyl)pyrrolidin-3-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[4-(3-aminopropyl)piperazin-1-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopyrrolidin-1-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(7-amino-2-azaspiro[3.3]heptan-2-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl)ethyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[(2S)-2-(2-aminoethyl)pyrrolidin-1-yl]methyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(3-morpholinopropylamino)ethyl]benzamide; 4-[2-(2-amino-5-azaspiro[2.4]heptan-5-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)ethyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(4-piperidylmethylamino)methyl]benzamide; 3-[[(3-aminocyclobutyl)methylamino]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(3-piperazin-1-ylpropylamino)methyl]benzamide; 3-[[3-(1-aminocyclopropyl)pyrrolidin-1-yl]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[[3-[bis(2-hydroxyethyl)amino]propylamino]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-5-[[3-(4-piperidyl)propylamino]methyl]benzamide; 3-[[1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; (2R)-2-amino-4-[[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methylamino]butanoic acid; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[(2-oxooxazolidin-4-yl)methylamino]methyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[(5-oxopyrrolidin-3-yl)methylamino]methyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[[3-(dimethylamino)-3-oxo-propyl]amino]methyl]benzamide; 5-(3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrol-1-ylmethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-benzamide; and 2-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; or a pharma- ceutically acceptable salt thereof.

[0037] A further embodiment of the invention is (xviii) a compound or a pharma- ceutically acceptable salt according to any one of (i) to (xvi) for use as a therapeutically active substance.

[0038] A further embodiment of the invention is (xix) a pharmaceutical composition comprising a compound according to any one of claims (i) to (xvi) and a therapeutically inert carrier.

[0039] A further embodiment of the invention is (xx) the use of a compound according to any one of (i) to (xvi) for the inhibition of LpxH.

[0040] A further aspect of the present 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.

[0041] 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.

[0042] 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 pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

[0043] A further aspect of the present invention is the use of the compound according to (xxiii), wherein the gram-negative bacterium is Enterobacteriaceae, and the Enterobacteriaceae is Klebsiella pneumoniae or Escherichia coli.

[0044] A further embodiment of the invention is (xxv) a compound or a pharma- ceutically acceptable salt according to any one of (i) to (xvi) for use in the treatment or prophylaxis of a bacterial infection, particularly a bacterial infection wherein the bacteria is a gram-negative bacteria.

[0045] 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 pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

[0046] 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.

[0047] A further embodiment of the invention is a compound or a pharma- ceutically acceptable salt according to any one of (i) to (xvi) when prepared according to the process of (xxviii)(xvii).

[0048] A further embodiment of the invention is (xxix) a method for treating or preventing a bacterial infection, in particular a bacterial infection wherein the bacteria is a gram-negative bacteria, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound defined in any one of (i) to (xvi).

[0049] Pharmaceutical Compositions and Administration Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and therapeutically inert carriers, diluents or excipients, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, the compounds of formula (I) can be formulated into galenical dosage forms by mixing at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably 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.

[0050] The composition is formulated, dosed, and administered in a manner consistent with good medical practice.Factors to be considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the delivery site of the drug, the method of administration, the administration schedule, and other factors known to medical practitioners.The "effective amount" of the compound to be administered is governed by such considerations and is the minimum amount required to reduce bacterial load or improve host survival through the inhibition of lipid A biosynthesis by targeting LpxH enzyme.For example, such amount may be below the amount that is toxic to normal cells, or to the mammal as a whole.

[0051] In one example, a pharma- ceutical effective amount of a compound of the invention administered parenterally per dose will range from about 0.1 to 1000 mg / kg of patient body weight, or alternatively about 1 to 100 mg / kg of patient body weight per day, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 5 to about 5000 mg of a compound of the invention.

[0052] 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, epidural and intranasal, and, where desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0053] The compounds of the present invention may be administered in any convenient dosage form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceuticals, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0054] 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, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a drug product).

[0055] 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 tablets using conventional equipment. An example of an aerosol formulation can be prepared by dissolving, for example, 5-1000 mg of the compound of the present invention in a suitable buffer solution, for example, phosphate buffer, and adding, if desired, an isotonicity agent, for example, a salt such as sodium chloride. The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0056] Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharma- ceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or excipient.

[0057] Another embodiment includes pharmaceutical compositions comprising a compound of formula (I) for use in the treatment and / or prevention of a bacterial infection.

[0058] The following Compositions A and B illustrate typical compositions of the present invention and serve merely as representative thereof.

[0059] Composition A The compounds of the present invention can be used in a manner known per se to produce tablets of the following composition as active ingredient: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0060] Composition B The compounds of the present invention can be used as an active ingredient in a manner known per se to produce capsules having the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0061] Indications and Treatment Methods The compounds of the invention are inhibitors of the LpxH enzyme, a key enzyme in the LPS synthesis pathway, which is essential in most Gram-negative bacteria. Thus, the compounds of the invention can prevent bacterial growth in susceptible organisms and can be used to treat bacterial infections, 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 Gram-negative bacteria such as third generation cephalosporin-resistant and carbapenem-resistant Klebsiella pneumoniae (e.g., Klebsiella pneumoniae, Escherichia coli) and multi-resistant Pseudomonas aeruginosa and Acinetobacter baumannii or Acinetobacter spp., e.g., Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Bacteroides spp., e.g., Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides distasonis, Campylobacter jejuni, Campylobacter fetus or Campylobacter coli, Francisella tularensis and Providencia spp., e.g. Providencia stuartii, Providencia rettgeri or Providencia alcalifaciens and Pseudomonas spp.; as well as for cleaning purposes, e.g. to remove pathogenic microorganisms and bacteria from surgical instruments, catheters and artificial implants or to render a room or area sterile.

[0062] The products of the present invention can be administered, for example, parenterally, for example by injection, or orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, for example in the form of suppositories. Pharmaceutical compositions containing these compounds can be prepared using conventional procedures well known to those skilled in the art, for example by combining the ingredients into a dosage form together with suitable non-toxic inert therapeutically compatible solid or liquid carrier materials, and, if necessary, with conventional pharmaceutical adjuvants. It is considered that the compounds will ultimately be embodied into a composition of suitable oral, parenteral or topical dosage form. The compositions of the present invention can contain, as an optional ingredient, any of a variety of adjuvants that are commonly used in the manufacture of pharmaceutical preparations. Thus, for example, when formulating the compositions of the present invention into the desired oral dosage form, optional ingredients may be used, such as fillers, for example, co-precipitated aluminum hydroxide-calcium carbonate, dicalcium phosphate or lactose; disintegrants, such as corn starch; and lubricants, such as talc, calcium stearate, etc. However, it should be fully understood that any component specified herein is given as an example only, and the present invention is not limited to its use. Other such adjuvants known in the art can be used in carrying out the present invention. Suitable as such carrier materials are inorganic carrier materials as well as organic carrier materials. Thus, for tablets, coated tablets, dragees and hard gelatin capsules, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substance. However, for soft gelatin capsules, no carrier is required). Suitable carrier materials for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.As pharmaceutical adjuvants, conventional preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for changing osmotic pressure, buffers, coating agents and antioxidants may be considered.

[0063] synthesis The compounds of the present invention may be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are illustrated in the following schemes and examples. All substituents, particularly R 1 , R 2 , R 3 , R 4 , Y, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is defined above. Further, unless otherwise specified, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to one of ordinary skill in the art of organic chemistry.

[0064] A general synthetic route for preparing compounds of formula (I) is given below. Scheme 1: [ka] In the formula, B 1 and B. 2 is a halogen; PG 1 is a protecting group such as a tert-butoxycarbonyl or benzyloxycarbonyl group; PG 2 is a protecting group such as an acetyl group.

[0065] Nucleophilic substitution reaction between compounds of formula (II) and formula (III) gives compounds of formula (IV), which are deprotected with a suitable acid such as TFA or a reducing agent such as palladium on carbon under H2 to give compounds of formula (VI). Alternatively, compounds of formula (VI) could be obtained directly using a nucleophilic substitution reaction between compounds of formula (II) and compounds of formula (V) in the presence of a suitable base such as TEA. Compounds of formula (VIII) could be obtained from a sulfonation reaction between halogenated phenylsulfonyl chlorides (VII) and compounds of formula (VI). Formation of compound (IX) can be achieved by treating compounds of formula (VIII) with a suitable acid such as HCl or a base such as K2CO3.

[0066] Scheme 2: [ka] In the ceremony, P.G. 2 is a protecting group such as an acetyl group.

[0067] Alternatively, the compound of formula (VIII) may be prepared as shown in Scheme 2. The compound of formula (XI) may be obtained by a coupling reaction between the compound of formula (VI) and the compound of formula (X) in the presence of a catalyst such as CuO. The compound of formula (XI) may be oxidized to give the compound of formula (VIII) in the presence of a suitable oxidant reagent such as PIDA.

[0068] Scheme 3: [ka] In the formula, R a is halogen or OH; R b is C, such as methyl or ethyl. 1-6 is alkyl, R 11 is pyrazolylene, phenylene or amino C 1-6 Alkylamino C 1-6 It is alkylene.

[0069] The compound of formula (Ia) may be prepared by a coupling reaction between a compound of formula (IX) and a compound of formula (XII) in the presence of a condensing reagent such as TCFH, or an acylation reaction in the presence of a base such as TEA.

[0070] The compound of formula (Ib) may be prepared by starting from a coupling reaction or acylation reaction between the compound of formula (IX) and the compound of formula (XIII) to obtain the compound of formula (XIV). Hydrolysis of the compound of formula (XIV) in the presence of a suitable base such as LiOH gives the compound of formula (Ib).

[0071] Scheme 4: [ka] The compound of formula (XV) can be obtained by a nucleophilic substitution reaction between the compound of formula (III) and the compound of formula (VII) in the presence of a suitable base such as DIPEA or TEA. Deprotection of the compound of formula (XV) in the presence of a suitable acid such as HCl or a base such as K2CO3 gives the compound of formula (XVI). The compound of formula (XVII) can be obtained by an acylation reaction between the compound of formula (XVI) and the compound of formula (XII) in the presence of a suitable base such as TEA. In some cases, the compound of formula (XVII) can be obtained by the acylation reaction between the compound of formula (XVI) and the compound of formula (XII) in the presence of a suitable base such as TEA. 1 Deprotection of the compound of formula (XVII) using a suitable acid such as TFA or a reducing agent such as palladium on carbon under H2 atmosphere gives the compound of formula (XVIII). Nucleophilic substitution between the compound of formula (II) and the compound of formula (XVIII) in the presence of a suitable base such as Cs2CO3 gives the compound of formula (Ia). In some cases, the compound of formula (Ia) can be further deprotected to give PG. 1 needs to be removed.

[0072] The compounds of the invention may be obtained as mixtures of diastereomers or enantiomers which may be separated by methods well known in the art, for example (chiral) HPLC or SFC.

[0073] The present invention also relates to a process for the preparation of a compound of formula (I) comprising any of the following steps: a) A compound of formula (IX) [ka] and a compound of formula (XII) [ka] via a coupling reaction or an acylation reaction between [ka] forming a b) A compound of formula (XIV) [ka] via hydrolysis of the compound of formula (Ib) [ka] forming a c) A compound of formula (XVIII) [ka] and a compound of formula (II) [ka] via nucleophilic substitution between [ka] forming a (In the formula, B 1 is a halogen; PG 1 is a protecting group such as a tert-butoxycarbonyl or benzyloxycarbonyl group; PG 2 is a protecting group such as an acetyl group; R a is halogen or OH; R b is C, such as methyl or ethyl. 1-6 is alkyl, R11 is pyrazolylene, phenylene or amino C 1-6 Alkylamino C 1-6 It is alkylene.

[0074] Compounds of formula (I) when prepared by the above process are also an object of the present invention. EXAMPLES

[0075] Working Example The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0076] Abbreviation The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0077] The abbreviations used herein are as follows: aq.Aqueous solution DAST: Diethylaminosulfur trifluoride DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMEDA: 1,2-Dimethylethylenediamine DMP: Dess-Martin periodinane FA: Formic acid FBS: Fetal bovine serum HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate I C 50 : The molar concentration of an inhibitor that produces 50% of the maximum response possible for that inhibitor. HPLC: High-performance liquid chromatography MS(ESI): Mass spectrometry (electrospray ionization) MeCN: Acetonitrile MsCl: methylsulfonyl chloride MTBE: Methyl tert-butyl ether obsd:actual value PE: Petroleum ether PIDA: Phenyl iodine(III) diacetate TCFH: Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TFA: Trifluoroacetic acid TEA: Triethylamine δ: chemical shift SFC: Supercritical Fluid Chromatography TLC: Thin Layer Chromatography

[0078] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 cartridge module, ii) ISCO combi-flash chromatography instrument. Brand and pore size of silica gel: i) KP-SIL 60 Å, particle size: 40-60 μm; ii) CAS registration 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.

[0079] Intermediates and final compounds were analyzed using XBridge (商標) Prep-C18 (5 μm, OBD™ 30 × 100 mm) column, SunFire (商標) Prep-C18 (5 μm, OBD (商標)Purification was by preparative HPLC on reversed-phase columns using a Phenomenex Synergi-C18 (10 μm, 25×150 mm) or Phenomenex Gemini-C18 (10 μm, 25×150 mm) column, a Waters AutoP purification system (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, Solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water), or a 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).

[0080] 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 Thar 80 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, detection UV 254 or 220 nm.

[0081] The LC / MS spectra of the compounds were analyzed by LC / MS (Waters (商標) Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. LC / MS conditions were as follows (run time 3 min or 1.5 min): Acidic conditions I: A: 0.1% TFA in HO; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in HO; B: 0.01875% TFA in acetonitrile; Basic conditions 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.

[0082] Mass spectra (MS): Generally, only ions that represent the parent mass are reported; unless otherwise stated, the mass ions quoted are the positive mass ions (M−H). + It is.

[0083] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0084] Microwave-assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise stated.

[0085] Preparation Example The following examples are intended to illustrate the meaning of the invention but do not in any way represent a limitation within the scope of the meaning of the invention.

[0086] Intermediate 1: 4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylaniline [ka]

[0087] Step 1: 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine [ka] To a solution of piperazine (47.86 g, 555.58 mmol) in 1,4-dioxane (150 mL) was added 2,6-dichloro-4-(trifluoromethyl)pyridine (15.0 g, 69.45 mmol) slowly. The mixture was stirred at 60 °C for 1 h. After completion, the mixture was diluted with water (300 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (300 mL x 4), dried over anhydrous Na2SO4 and concentrated to give compound Int-1a (18 g, 67.76 mmol, 97.6% yield) as a white solid. MS found: 265.8 (MH+).

[0088] Step 2: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]acetamide [ka] To a solution of compound Int-1a (500.0 mg, 1.88 mmol) and DIPEA (0.81 mL, 4.63 mmol) in DCM (15 mL) was added 4-acetamidobenzenesulfonyl chloride (468.0 mg, 2.0 mmol) at 0° C. The mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. After completion, the mixture was poured into water (20 mL) and extracted with DCM (20 mL×3). The combined organic layer was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give compound Int-1b (800 mg, 92% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:463.2.

[0089] Step 2: 4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylaniline [ka] To a solution of compound Int-1a (970.0 mg, 2.1 mmol) in THF (10 mL) was added hydrochloric acid (12 M, 5 mL) at room temperature. The mixture was heated at 40° C. for 1 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was diluted with saturated NaHCO3 (aq, 30 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound Int-1 (830 mg, 94.11% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:421.2.

[0090] Intermediate 2: 4-(chloromethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] To a solution of compound Int-1 (820.0 mg, 1.95 mmol) and TEA (0.81 mL, 5.85 mmol) in DCM (20 mL), 4-(chloromethyl)benzoyl chloride (736.68 mg, 3.9 mmol) was added at room temperature and stirred for 1 h. After completion, the mixture was quenched with water (30 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (TFA as additive) to give compound Int-2 (600 mg, 1.05 mmol, 53.7% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:573.2.

[0091] Intermediate 3: 3-(chloromethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] To a solution of compound Int-1 (2.0 g, 4.75 mmol) and TEA (1.6 mL, 11.7 mmol) in DCM (40 mL), 3-(chloromethyl)benzoyl chloride (1.08 g, 5.7 mmol) was added at room temperature and the reaction mixture was stirred for 1 h. After completion, the mixture was quenched with water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give Int-3 (2.0 g, 3.49 mmol, 73.4% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:573.2.

[0092] Intermediate 4: 5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline [ka]

[0093] Step 1: 1-Indolin-1-ylethanone [ka] A solution of indoline (6.5 g, 54.5 mmol) in acetic anhydride (20 mL) was heated at 80° C. for 2 h. The reaction mixture was then concentrated to give crude Int-4a (8.9 g, 54.6 mmol, 100% yield) as a yellow gum, which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:162.1.

[0094] Step 2: 1-acetylindoline-5-sulfonyl chloride [ka] A solution of compound Int-4a (8.2 g, 50.9 mmol) in sulfuric acid (237 g, 2.03 mol) was stirred at room temperature for 2 h. The mixture was then poured onto ice and extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give crude compound Int-4b (3.0 g, 22.7% yield), which was used directly in the next step.

[0095] Step 3: 1-[6-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]ethanone [ka] To a solution of compound Int-1a (1.8 g, 6.78 mmol) and TEA (1.8 g, 17.3 mmol) in DCM (100 mL) was added compound Int-4b (1.5 g, 5.8 mmol) in portions at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was then quenched with water (50 mL) and extracted with DCM (100 mL×3). The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give compound Int-4c (2.5 g, 75.3%) as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:489.3.

[0096] Step 4: 6-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline [ka] To a solution of compound Int-4c (2.0 g, 4.09 mmol) in THF (20 mL) was added hydrochloric acid (12 M, 5 mL) at room temperature. The mixture was heated at 70° C. for 1 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was diluted with saturated NaHCO3 (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound Int-4 (1.0 g, 54.7% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:447.2.

[0097] Intermediate 5: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[[4-[(4-piperazin-1-ylsulfonylphenyl)carbamoyl]phenyl]methyl]carbamate [ka] Step 1: Benzyl 4-(4-acetamidophenyl)sulfonylpiperazine-1-carboxylate [ka] To a solution of benzylpiperazine-1-carboxylate (5 g, 22.7 mmol) and 4-acetamidobenzenesulfonyl chloride (5.3 g, 22.7 mmol) in DCM (100 mL) was added TEA (6.88 g, 68.1 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was then quenched with aqueous NaHCO3 (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were concentrated under reduced pressure to give the crude product, which was rinsed with hexane to give the desired product Int-5a (9.2 g, 97.1% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:418.2.

[0098] Step 2: Benzyl 4-(4-aminophenyl)sulfonylpiperazine-1-carboxylate [ka] To a mixture of Int-5a (9.2 g, 22 mmol) in MeOH (100 mL) was added AcCl (8 mL, 22 mmol) dropwise at room temperature. ℃ The mixture was heated at RT for 4 h. The reaction mixture was then concentrated to give crude compound Int-5b (8.0 g, 96.7% yield) as a white solid. MS (ESI + )[(M+H) + ]:376.2.

[0099] Step 3: Benzyl 4-[4-[[4-(chloromethyl)benzoyl]amino]phenyl]sulfonyl piperazine-1-carboxylate [ka] To a solution of compound Int-5b (2.0 g, 5.32 mmol) and TEA (1.6 mL, 11.7 mmol) in DCM (40 mL), 4-(chloromethyl)benzoyl chloride (1.08 g, 5.7 mmol) was added at room temperature and stirred for 1 h. After completion, the mixture was quenched with water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give compound Int-5c (2.0 g, 73.4% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:528.2.

[0100] Step 4: Benzyl 4-[4-[[4-[[3-(tert-butoxycarbonylamino)propylamino]methyl]benzoyl]amino]phenyl]sulfonyl piperazine-1-carboxylate [ka] A mixture of compound Int-5c (2.0 g, 3.78 mmol), DIPEA (2.7 mL, 15.3 mmol) and tert-butyl N-(3-aminopropyl)carbamate (1.2 mL, 5.6 mmol) in THF (100 mL) was stirred at 70° C. for 16 h. After completion, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (TFA as additive) to give compound Int-5d (1.5 g, 59.5% yield). MS observed (ESI + )[(M+H) + ]:666.3.

[0101] Step 5: Benzyl 4-[4-[[4-[[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]methyl]benzoyl]amino]phenyl]sulfonyl piperazine-1-carboxylate [ka] To a mixture of compound Int-5d (1.5 g, 2.25 mmol) and DIPEA (1.0 mL, 5.7 mmol) in DCM (40 mL), Boc anhydride (1.0 g, 4.58 mmol) was added portionwise at room temperature and stirred at room temperature for 1 h. After completion, the mixture was quenched with saturated aqueous NaHCO3 (40 mL) and extracted with DCM (40 mL x 3). The combined organic layer was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with MeOH:DCM = 10%) to give compound Int-5e (1.6 g, 2.08 mmol, 92.8% yield). MS observed (ESI + )[(M+H) + ]:766.3.

[0102] Step 7: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[[4-[(4-piperazin-1-ylsulfonylphenyl)carbamoyl]phenyl]methyl]carbamate [ka] A mixture of compound Int-5e (1.6 g, 2.08 mmol) and Pd / C (200 mg, 10% Pd on carbon) was stirred at room temperature for 8 h under a H2 balloon. Upon completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to give crude Int-5 (1.2 g, 91.3%), which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:632.3.

[0103] Intermediate 6: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[[3-[(4-piperazin-1-ylsulfonylphenyl)carbamoyl]phenyl]methyl]carbamate [ka] The title compound was prepared similarly to the preparation of compound Int-5 by replacing 4-(chloromethyl)benzoyl chloride with 3-(chloromethyl)benzoyl chloride in step 3. Compound Int-6 (1.0 g) was obtained. MS Found (ESI + )[(M+H) + ]:623.3.

[0104] Intermediate 7: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[2-[4-[(4-piperazin-1-ylsulfonylphenyl)carbamoyl]phenyl]ethyl]carbamate [ka] The title compound was prepared similarly to the preparation of compound Int-5 by replacing 4-(chloromethyl)benzoyl chloride with 4-(2-bromoethyl)benzoyl chloride in step 3. Compound Int-7 (1.1 g) was obtained. MS Found (ESI + )[(M+H) + ]:646.3.

[0105] Intermediate 8: 2,6-Dichloro-4-(1,1-difluoroethyl)pyridine [ka] 1-(2,6-Dichloro-4-pyridyl)ethanone (300.0 mg, 1.58 mmol, 1 equiv) was dissolved in DAST (2.0 mL) and the reaction was stirred at room temperature for 6 h. After completion, the mixture was poured into ice water (40 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (TFA buffer) to give compound Int-8 (167 mg, 44.90% yield). MS Found (ESI + )[(M+H) + ]:212.1.

[0106] Intermediate 9: 3-[[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]methyl]benzoic acid [ka]

[0107] Step 1: Methyl 3-[[3-(tert-butoxycarbonylamino)propylamino]methyl]benzoate [ka] A mixture of methyl 3-(bromomethyl)benzoate (2.0 g, 8.73 mmol), tert-butyl N-(3-aminopropyl)carbamate (2.28 g, 13.1 mmol), K2CO3 (12.1 g, 8.73 mmol,) and KI (0.05 mL, 0.870 mmol) in MeCN (20 mL) was heated to 60 °C for 1 h. After completion, the mixture was concentrated under reduced pressure to give the crude product, which was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound Int-9a (2.8 g, 49.74% yield) as a colorless oil, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:323.1.

[0108] Step 2: Methyl 3-[[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]methyl]benzoate [ka] To a solution of methyl Int-9a (2.8 g, 8.68 mmol) in THF (10 mL) and water (10 mL), Na2CO3 (1.84 g, 17.37 mmol) and BOC anhydride (1.90 g, 8.68 mmol) were added. The reaction mixture was stirred at 20 °C for 1 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound Int-9b (3.5 g, 47.69% yield) as a colorless oil, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:423.2.

[0109] Step 3: 3-[[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]methyl]benzoic acid [ka] To a solution of Int-9b (3.5 g, 8.28 mmol) in EtOH (20 mL) and water (10 mL), NaOH (1.66 g, 41.42 mmol) was added in one portion. The reaction mixture was stirred at 20 °C for 2 h. After completion, the mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with water (20 mL) and then the pH was adjusted to 5-6 with HCl (aqueous solution 2 mol / L). The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (TFA as additive) to give compound Int-9 (1.4 g, 41.37% yield) as a colorless oil. MS Found (ESI + )[(M+H) + ]:409.2.

[0110] Intermediate 10: 3-[2-[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]ethyl]benzoic acid [ka] The title compound was prepared similarly to the preparation of compound Int-9 by replacing methyl 3-(bromomethyl)benzoate with methyl 3-(2-bromoethyl)benzoate in step 1. Compound Int-10 (1.2 g) was obtained. MS Found (ESI + )[(M+H) + ]:423.1.

[0111] Intermediate 11: N-(4-methylsulfinamoylphenyl)acetamide [ka]

[0112] Step 1: 4-Acetamidobenzenesulfinic acid [ka] To a solution of sodium sulfite (12.84 g, 101.85 mmol) and NaHCO3 (10.27 g, 122.22 mmol) in water (55 mL) was added N-acetylsulfanilyl chloride (11.9 g, 50.93 mmol) slowly at 70 °C. After addition, the mixture was stirred at 70 °C for 2 h. After completion, the mixture was diluted with water (100 mL) and acidified with 60% H2SO4 (50 mL) at 0 °C, and the resulting precipitate was collected by filtration. The filter cake was washed with 20% aqueous H2SO4 (100 mL) and dried under reduced pressure to give compound Int-11a (8 g, 78.85% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:200.0.

[0113] Step 2: 4-Acetamidobenzenesulfinyl chloride [ka] To a solution of compound Int-11a (7.0 g, 35.14 mmol) in DCM (30 mL) and THF (30 mL) was added SOCl2 (16.72 g, 140.54 mmol) in one portion. The mixture was stirred at 15 °C for 4 h. The mixture was concentrated under reduced pressure to give crude compound Int-11b (7 g, 91.53% yield) as a yellow solid, which was used directly in the next step.

[0114] Step 3: N-(4-methylsulfinamoylphenyl)acetamide [ka] To a solution of monomethylamine (27.56 mL, 55.13 mmol) in THF (20 mL) was added 4-acetamidobenzenesulfinyl chloride (1.5 g, 6.89 mmol) in DCM (5.0 mL) dropwise. The mixture was stirred at 15° C. for 1 h. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound Int-11 (1.2 g, 82.04% yield) as a yellow solid, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:212.8.

[0115] Intermediates 12A and 12B: 2-Methyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (Int-12A) and 1-Methyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (Int-12B) [ka]

[0116] Step 1: tert-Butyl 2-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate (Int-11Aa) and tert-Butyl 1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate (Int-11Ba) [ka] To a solution of tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate (600 mg, 2.87 mmol) in DMF (30 mL) was added NaH (229.4 mg, 5.74 mmol) at 0.05°C. ℃ The resulting suspension mixture was stirred at room temperature for 15 minutes. Iodomethane (1221 mg, 8.6 mmol) was then added to the mixture, and the mixture was stirred for 25 minutes. ℃ The mixture was stirred at rt for 4 h. Upon completion, the reaction was quenched with ice water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=50%) to give a mixture of Int-12Aa and 12Ba (400 mg, 37.48% yield) as a brown oil. MS observed (ESI + )[(M+H) + ]:224.1.

[0117] Step 2: 2-Methyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (Int-12A) and 1-Methyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (Int-12B) [ka] A mixture of compounds Int-12Aa and 12Ba (400 mg, 1.792 mmol) in DCM (10 mL) and TFA (2 mL) was stirred at room temperature for 4 h. After completion, the mixture was concentrated under reduced pressure to give the TFA salts of Int-12A and 12B (200 mg, 56.48% yield) as brown oils. MS observed (ESI + )[(M+H) + ]:124.1.

[0118] Intermediate 13: 4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylaniline [ka] The title compound was prepared similarly to the preparation of compound Int-1 by replacing 2,6-dichloro-4-(trifluoromethyl)pyridine with 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine in step 1. Compound Int-13 (1.2 g) was obtained. MS Found (ESI + )[(M+H) + ]:402.1.

[0119] Intermediate 14: 2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid [ka]

[0120] Step 1: 2-tert-butyl 5-(2,4,6 trichlorophenyl)isoindoline-2,5-dicarboxylate [ka] To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (238.0 mg, 0.800 mmol) in toluene (4 mL), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (92.37 mg, 0.160 mmol), palladium(II) acetate (17.92 mg, 0.080 mmol), TEA (0.22 mL, 1.6 mmol, 2 eq.) and (2,4,6-trichlorophenyl)formate (215.95 mg, 0.960 mmol) were added in sequence. The reaction mixture was heated at 90° C. under N2 for 15 h. After completion, the reaction mixture was concentrated to give a residue, which was purified by preparative HPLC (FA as additive) to give compound Int-14a (260 mg, 73.58% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:442.0.

[0121] Step 2: 2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid [ka] A solution of compound Int-14a (240.0 mg, 0.540 mmol) and NaOH (216.84 mg, 5.42 mmol) in THF (1.02 mL) and water (0.102 mL) was stirred at 20° C. for 2 h. After completion, the mixture was acidified to pH=6 with 1N HCl. The solution was extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give compound Int-14 (130 mg, 91.08% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:264.0.

[0122] Intermediate 15: 3-[2-(tert-butoxycarbonylamino)ethyl]benzoic acid [ka] The title compound was prepared similarly to the preparation of compound Int-14 by replacing tert-butyl 5-bromoisoindoline-2-carboxylate with tert-butyl N-[2-(3-bromophenyl)ethyl]carbamate in step 1. Compound Int-15 (1.3 g) was obtained. MS Found (ESI + )[(M+H) + ]:266.0.

[0123] Intermediate 16: 2-(tert-butoxycarbonylamino)indan-5-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound Int-14 by replacing tert-butyl 5-bromoisoindoline-2-carboxylate with tert-butyl N-(5-bromoindan-2-yl)carbamate in step 1. Compound Int-16 (1.1 g) was obtained. MS Found (ESI + )[(M+H) + ]:278.1.

[0124] Intermediate 17: 6-[[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]methyl]pyridine-2-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound Int-9 by replacing methyl 3-(bromomethyl)benzoate with methyl 6-(bromomethyl)pyridine-2-carboxylate in step 1. Compound Int-17 (1.0 g) was obtained. MS Found (ESI + )[(M+H) + ]:410.2

[0125] Intermediate 18: 2-[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]indan-5-carboxylic acid [ka]

[0126] Step 1: tert-Butyl N-[3-[(5-bromoindan-2-yl)amino]propyl]carbamate [ka] A mixture of 5-bromoindan-2-one (600.0 mg, 2.84 mmol), tert-butyl N-(3-aminopropyl)carbamate (0.99 g, 5.69 mmol) and anhydrous Na2SO4 (400 mg, 2.84 mmol) in MeOH (5 mL) and THF (5 mL) was stirred at 25 °C for 3 h. Then sodium cyanoborohydride (893.21 mg, 14.21 mmol) was added to the mixture and stirred at 25 °C for another 12 h. After completion, the mixture was poured into ice water (100 mL) and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude compound Int-18a (800 mg, 76.2% yield) as a pale yellow oil, which was used directly in the next step. MS Observed Value (ESI+) [(M+H)+ ]:369.1.

[0127] Step 2: tert-Butyl N-(5-bromoindan-2-yl)-N-[3-(tert-butoxycarbonylamino)propyl]carbamate [ka] To a solution of compound Int-18a (800.0 mg, 2.17 mmol) and Boc anhydride (0.57 g, 2.6 mmol) in THF (20 mL) was added TEA (0.3 mL, 2.17 mmol) dropwise. The mixture was stirred at 15° C. for 12 h. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give compound Int-18b (900 mg, 88.51% yield) as a yellow oil. MS Found (ESI+) [(M+H) + ]:469.3.

[0128] Step 3: (2,4,6-trichlorophenyl) 2-[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]indan-5-carboxylate [ka] The title compound was prepared similarly to the preparation of compound Int-14a by substituting compound 18b for tert-butyl 5-bromoisoindoline-2-carboxylate in step 1. Compound Int-18c (800 mg) was obtained as a yellow solid. MS Found (ESI + )[(M+H) + ]:613.0.

[0129] Step 4: 2-[tert-butoxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]indan-5-carboxylic acid [ka] The title compound was prepared similarly to the preparation of compound Int-14 by replacing compound Int-14a with compound Int-18c in step 2. Compound Int-18 (300 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:435.2.

[0130] Intermediate 19: 3-[1-[3-(tert-butoxycarbonylamino)propyl]pyrrolidin-2-yl]benzoic acid [ka]

[0131] Step 1: tert-Butyl N-[3-[2-(3-bromophenyl)pyrrolidin-1-yl]propyl]carbamate [ka] A mixture of 2-(3-bromophenyl)pyrrolidine (2.0 g, 8.85 mmol), K2CO3 (2.44 g, 17.69 mmol), KI (0.23 mL, 4.42 mmol) and tert-butyl N-(3-chloropropyl)carbamate (2.56 g, 13.27 mmol) in MeCN (10 mL) was stirred at 65 °C for 2 h. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (FA as additive) to give compound Int-18a (2.5 g, 73.73% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:383.2.

[0132] Step 2: Methyl 3-[1-[3-(tert-butoxycarbonylamino)propyl]pyrrolidin-2-yl]benzoate [ka] A mixture of Int-19a (1000.0 mg, 2.61 mmol), TEA (0.65 mL, 4.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (114.53 mg, 0.160 mmol) was purged with carbon dioxide and heated at 80° C. under CO atmosphere for 16 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluted with EtOAc:PE=10%) to give compound int-19b (500 mg, 1.38 mmol) as a yellow oil. MS Found (ESI + )[(M+H) + ]:363.3.

[0133] Step 3: 3-[1-[3-(tert-butoxycarbonylamino)propyl]pyrrolidin-2-yl]benzoic acid [ka] A mixture of compound Int-19b (400.0 mg, 1.1 mmol) and LiOH (264.31 mg, 11.04 mmol) in THF (9.35 mL) and water (9.35 mL) was stirred at 60 °C for 2 h. After completion, the mixture was acidified to PH = 5-6 using 1N HCl solution. The mixture was extracted with EA:MeOH = 10:1 (100 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was further purified by silica gel chromatography (MeOH:DCM = 20%) to give compound Int-19 (100 mg, 26.01% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:349.1.

[0134] Intermediate 20: 3-[1-[3-(tert-butoxycarbonylamino)propyl]pyrrolidin-3-yl]benzoic acid [ka] The title compound was prepared similarly to the preparation of compound Int-19 by replacing 2-(3-bromophenyl)pyrrolidine with 3-(3-bromophenyl)pyrrolidine in step 1. Compound Int-20 (300 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:349.1.

[0135] Example 001: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0136] Step 1: tert-Butyl N-[3-[[4-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methylamino]propyl]carbamate [ka] To a solution of compound Int-2 (60.0 mg, 0.100 mmol) in MeCN (10 mL), tert-butyl N-(3-aminopropyl)carbamate (36.46 mg, 0.210 mmol), K2CO3 (28.92 mg, 0.210 mmol) and KI (8.3 mg, 0.050 mmol) were added in one portion. The mixture was heated at 60° C. for 2 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was diluted with water (20 mL). The aqueous layer was extracted with DCM (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1) to give compound 001a (55 mg, 73.91% yield) as a yellow solid. MS Found (ESI + )[(M+H)] + :711.3.

[0137] Step 2: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] To a solution of compound 001a (55.0 mg, 0.080 mmol) in DCM (1 mL) was added TFA (0.6 mL, 7.73 mmol) in one portion. The mixture was stirred at 25° C. for 1 h. After completion, the mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl as additive) to give Example 001 (25 mg, 48.07% yield) as a white solid. MS Found (ESI + )[(M+H)] + :611.3. Example 001: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.78(s,1H),9.68-9.53(m,2H),8.15-8.01(m,7H),7.80-7.73(m,4H),7.13-7.06(m,1H),6.96(s, 1H),4.26-4.18(m,2H),3.76-3.68(m,4H),3.06-2.95(m,6H),2.94-2.85(m,2H),2.08-1.99(m,2H).

[0138] Example 002: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing the compound 2,6-dichloro-4-(trifluoromethyl)pyridine with 2-chloro-4-(trifluoromethyl)pyridine in step 1 of the preparation of Int-1. Example 002 (100 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:577.2. Example 002:1 H NMR(400 MHz,DMSO-d6)δ ppm 10.71(s,1H),8.30(d,J=4.9 Hz,1H),8.08(d,J=8.3 Hz,2H),7.94(d,J=7.3 Hz,2H),7.75(d,J=8.3 Hz,2H),7.52(d,J=7.1 Hz,2H),7.09(s,1H),6.89(d,J=5.0 Hz,1H),3.82(s,2H),3.71(s,4H),2.97(s,4H),2.86(s,2H),2.62(s,2H),1.74(s,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.57(s,3F).

[0139] Example 003: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[5-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0140] Step 1: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[[4-[[4-[4-[5-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methyl]carbamate [ka] A mixture of 2,5-dichloro-4-(trifluoromethyl)pyridine (38.83 mg, 0.180 mmol), compound Int-5 (80.0 mg, 0.180 mmol) and Cs2CO3 (mg, 0.180 mmol) in NMP (5 mL) was heated at 100° C. for 1 h. After completion, the mixture was poured into 50 mL of water and extracted with EtOAc (25 mL×2). The combined organic layers were washed with brine (25 mL×2), dried over Na2SO4 and concentrated to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=30%) to give the desired product Compound 003a (65 mg, 40.11% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:811.2.

[0141] Step 2: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[5-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A solution of compound 003a (55.0 mg, 0.070 mmol) in TFA / dioxane (4 M, 5 mL) was stirred at room temperature for 4 hours. After completion, the solvent was removed under reduced pressure to give the crude product, which was purified by preparative HPLC (TFA as additive) to give Example 003 (35 mg, 78.2% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:611.2. Example 003: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.70(s,1H),8.31(s,1H),8.08(d,J=8.8 Hz,2H),7.94(d,J=8.1 Hz,2H),7.75(d,J=8.8 Hz,2H),7.51(d,J=8.0 Hz,2H),7.18(s,1H),3.80(s,2H),3.71(s,4H),2.98(s,4H),2.85(t,J=6.9 Hz,2H),2.60(t,J=6.3 Hz,2H),1.65-1.79(m,2H). 19F NMR(376 MHz,DMSO-d6)δ ppm-63.43(s,3F).

[0142] Example 004: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[3-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0143] Step 1: tert-Butyl 4-[3-chloro-5-(trifluoromethyl)phenyl]piperazine-1-carboxylate [ka] A mixture of 1-chloro-3-iodo-5-(trifluoromethyl)benzene (2.0 g, 6.53 mmol), tert-butyl piperazine-1-carboxylate (1.82 g, 9.79 mmol), copper(I) iodide (1.24 g, 6.53 mmol), K2CO3 (1.8 g, 13.1 mmol), proline (225 mg, 1.96 mmol) in DMF (30 mL) was stirred in a microwave reactor at 130 °C for 3 h. After completion, the mixture was diluted with EtOAc (150 mL) and washed with water (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE = 20%) to give compound 004a (1.0 g, 42.0% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:365.1.

[0144] Step 2: 1-[3-chloro-5-(trifluoromethyl)phenyl]piperazine [ka] A mixture of compound 004a (800 mg, 2.19 mmol) and TFA (2.5 g, 21.9 mmol) in DCM (15 mL) was stirred at room temperature for 2 h. The reaction mixture was then concentrated to give crude compound 004b (580 mg, 100% yield) as a yellow gum, which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:265.1.

[0145] Step 3: N-[4-[4-[3-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylphenyl]acetamide [ka] A mixture of compound 004b (580 mg, 2.18 mmol), 4-acetamidobenzenesulfonyl chloride (510 mg, 2.18 mmol) and DIPEA (500 mg, 3.87 mmol) in DCM (20 mL) was stirred at room temperature for 1 h. The mixture was then washed with saturated aqueous NaHCO3 (20 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatography (eluted with EtOAc:PE = 15%) to give compound 004c (1.0 g, 42.0% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:462.1.

[0146] Step 4: 4-[4-[3-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylaniline [ka] A mixture of compound 004c (400 mg, 866 μmol), aqueous HCl (1 mL, 866 μmol) in MeOH (3 mL) was heated in a microwave reactor at 100° C. for 10 min. After removal of the solvent, the residue was dissolved in DCM (20 mL) and washed with saturated NaHCO3 solution (20 mL×2) and brine (20 mL×2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude compound 004d (363.6 mg, 100%) as a white solid, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:419.9.

[0147] Step 5: 4-(chloromethyl)-N-[4-[4-[3-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A mixture of compound 004d (190 mg, 453 μmol), 4-(chloromethyl)benzoyl chloride (128 mg, 679 μmol) and pyridine (107 mg, 1.36 mmol) in DCM (3 mL) was stirred at room temperature for 4 h. After completion, the reaction mixture was concentrated to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give compound 004e (36.1 mg, 30.0% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:572.1.

[0148] Step 6: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[3-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A mixture of compound 004d (80 mg, 140 μmol), propane-1,3-diamine (51.8 mg, 699 μmol) in DMF (5 mL) was stirred at 100° C. for 3 h. After completion, the reaction mixture was concentrated and the residue was purified by preparative HPLC (TFA as additive) to give Example 004 (29.1 mg, 32.94%). MS Found (ESI + )[(M+H) + ]:610.3. Example 004: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.35(s,1H),8.08(d,2H,J=8.8 Hz),7.93(d,2H,J=8.3 Hz),7.77(d,2H,J=8.9 Hz),7.49(d,2H,J=8.2 Hz),7.23(s,1H),7.15(s,1H),7.11(s,1H),3.76(s,2H),3.3-3.4(m,4H),3.0-3.0(m,4H),2.8-2.9(m,2H),2.56(s,2H),1.6-1.7(m,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-61.38(s,3F).

[0149] Example 005: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[2-chloro-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] By replacing the compound 2,5-dichloro-4-(trifluoromethyl)pyridine with the compound 2,4-dichloro-6-(trifluoromethyl)pyrimidine in step 1 and carrying out the reaction at room temperature The title compound was prepared similarly to the preparation of Example 003. Example 005 (32 mg) was obtained as a white solid. MS (ESI + )[(M+H) + ]:612.1. Example 005: 1H NMR(400 MHz,DMSO-d6)δ ppm 10.70(s,1H),8.67(s,1H),8.07(d,J=8.1 Hz,2H),7.94(s,2H),7.74(d,J=8.2 Hz,2H),7.51(s,2H),3.88(s,4H),3.80(s,2H),2.99(s,4H),2.86(s,2H),2.57(d,J=20.2 Hz,2H),1.73(s,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-69.48(s,3F).

[0150] Example 006: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[2-amino-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound 2,5-dichloro-4-(trifluoromethyl)pyridine with compound 2-chloro-6-(trifluoromethyl)pyrimidin-4-amine in step 1 and heating the reaction at 160° C. for 1 hour in a microwave reactor. Example 006 (10 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:593.2. Example 006: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.70(s,1H),8.09(d,J=8.8 Hz,2H),7.96(d,J=8.0 Hz,2H),7.73(d,J=8.8 Hz,2H),7.54(d,J=8.0 Hz,2H),7.12(s,2H),6.10(s,1H),3.84(s,2H),3.78(s,4H),2.80-2.97(m,6H),2.65(s,2H),1.77(s,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.43(s,3F).

[0151] Example 007: 4-[(3-aminopropylamino)methyl]-N-[4-[4-(4-bromo-6-chloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound 2,5-dichloro-4-(trifluoromethyl)pyridine with 4-bromo-2,6-dichloro-pyridine in step 1. Example 007 (8 mg) was obtained as an off-white solid. MS Found (ESI + )[(M+H) + ]:621.1. Example 007: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.65(s,1H),8.07(d,J=8.8 Hz,2H),7.93(d,J=8.0 Hz,2H),7.75(d,J=8.8 Hz,2H),7.50(d,J=7.9 Hz,2H),7.04(s,1H),6.93(s,1H),3.77(s,2H),3.63(s,4H),2.96(d,J=4.3 Hz,4H),2.85(s,2H),2.56(d,J=6.3 Hz,2H),1.70(s,2H).

[0152] Example 008: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[5-cyclopropyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0153] Step 1: tert-Butyl N-[[4-[[4-[4-[5-bromo-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methyl]-N-[3-(tert-butoxycarbonylamino)propyl]carbamate [ka] Compound 008a was prepared similarly to the preparation of compound 003a, by replacing 2,5-dichloro-4-(trifluoromethyl)pyridine with 5-bromo-2-chloro-4-(trifluoromethyl)pyridine in step 1. Compound 008a (48 mg) was obtained. MS observed (ESI + )[(M+H) + ]:855.1.

[0154] Step 2: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[[4-[[4-[4-[5-cyclopropyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methyl]carbamate [ka] A mixture of Pd(OAc)2 (4.72 mg, 0.020 mmol), compound 008a (72.0 mg, 0.080 mmol), potassium cyclopropyltrifluoroborate (3.11 mg, 0.020 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.86 mg) in toluene (8.17 mL) and water (0.817 mL) was bubbled with N2 and stirred at 90 °C for 12 h. Upon completion, the reaction was filtered through a Buchner funnel and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (FA as additive) to give compound 008b (32 mg, 41.9% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:817.1.

[0155] Step 3: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[5-cyclopropyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] Compound 008b (30.0 mg, 0.040 mmol) in 4MTFA / dioxane (5 mL) was stirred at room temperature for 4 hours. After completion, the solvent was removed under reduced pressure to give the crude product, which was purified by preparative HPLC to give Example 008 (8 mg, 23.53% yield). MS observed (ESI + )[(M+H) + ]:617.1. Example 008: 1 H NMR(400 MHz,DMSO-d6)δ 10.69(s,1H),8.39(s,2H),8.07(d,J=8.5 Hz,2H),8.01(s,1H),7.93(d,J=7.5 Hz,2H),7.75(d,J=8.5 Hz,2H),7.50(d,J=7.4 Hz,2H),7.01(s,1H),3.78(s,2H),3.71(s,1H),3.64(s,4H),2.97(s,4H),2.85(s,2H),2.58(s,2H),1.85(s,1H),1.71(s,2H),0.87(d,J=7.6 Hz,2H),0.69(d,J=4.7 Hz,2H). 19 F NMR(376 MHz,DMSO-d6)δ-61.59(s,3F).

[0156] Example 009: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0157] Step 1: 2,6-Dibromo-4-(trifluoromethyl)pyridine [ka] To a flask charged with 2,6-dichloro-4-(trifluoromethyl)pyridine (2.65 mL, 18.1 mmol), HBr in AcOH (30 mL, 166 mmol) was added. The reaction was heated at 85° C. and stirred overnight. After completion, the reaction was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude compound 009a (4.31 g, 78% yield) as a yellow oil, which was used directly in the next step.

[0158] Step 2: 2-Bromo-6-(cyclopropoxy)-4-(trifluoromethyl)pyridine [ka] Compound 009a (0.4 g, 1.31 mmol) was dissolved in THF (5 mL) followed by the addition of cyclopropanol (100 mg, 1.72 mmol) followed by NaH (78.7 mg, 1.97 mmol) in a sealed tube. The reaction was heated at 90° C. and continued to stir at the same temperature overnight. After completion, the reaction was cooled to room temperature and quenched by adding water (50 mL). The resulting residue was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give compound 009b (366 mg, 100% yield) as a yellow oil. MS Found (ESI+) [(M+H) + ]:282.0.

[0159] Step 3: tert-Butyl 4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazine-1-carboxylate [ka] Compound 009b (800 mg, 2.84 mmol), tert-butyl piperazine-1-carboxylate (1.06 g, 5.67 mmol) and K2CO3 (1.18 g, 8.51 mmol) were dissolved in DMSO (20 mL). The reaction was heated at 100 °C and stirred overnight. After the starting material was consumed, the reaction was cooled to room temperature and quenched by adding water (50 mL). The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give compound 009c (1.0 g, 91% yield) as a yellow oil. MS Found (ESI+) [(M+H) + ]:388.4.

[0160] Step 4: 1-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazine [ka] Compound 009c (1.0 g, 2.58 mmol) was dissolved in DCM (2.5 mL) followed by the addition of TFA (2.5 mL, 1.86 mmol). The reaction was stirred at room temperature and was complete after 1 h. The reaction mixture was then concentrated under reduced pressure and the residue formed was azeotroped twice with toluene to give compound 009d (0.6 g, 80% yield) as a yellow solid. MS Found (ESI+) [(M+H) + ]:288.4.

[0161] Step 5: N-[4-[4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]acetamide [ka] A mixture of compound 009d (74 mg, 258 μmol), pyridine (249 μL, 3.09 mmol) and 4-acetamidobenzenesulfonyl chloride (300 mg, 1.28 mmol) in DCM (12.5 mL) was stirred at 0° C. for 30 min and then warmed to room temperature. Upon completion, the reaction was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude compound 009e (100 mg, 80.6% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:485.2.

[0162] Step 5: 4-[4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylaniline [ka] Compound 009e (100 mg, 206 μmol) was dissolved in MeOH (5 mL). To the stirred solution was added HCl (2 mL, 8 mmol) dropwise. The mixture was then heated at 70° C. and kept stirring overnight. After completion, the reaction was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound 009f (90 mg, 98.6% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:443.2.

[0163] Step 6: 4-(chloromethyl)-N-[4-[4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] Compound 009f (100 mg, 226 μmol), 4-(chloromethyl)benzoyl chloride (128 mg, 678 μmol) and TEA (94.5 μL, 678 μmol) were stirred at room temperature overnight. After completion, the mixture was quenched with water (50 mL) and diluted with DCM (30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=25%) to give compound 009g (120 mg, 89.2% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:595.0.

[0164] Step 7: tert-Butyl N-[3-[[4-[[4-[4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methylamino]propyl]carbamate [ka] Compound 009g (0.1 g, 168 μmol) and tert-butyl (3-aminopropyl)carbamate (58.6 mg, 336 μmol) were dissolved in MeCN (1.68 mL) followed by the addition of potassium carbonate (69.7 mg, 504 μmol). ℃ The mixture was stirred at rt for 3 h. After completion, the reaction was cooled to room temperature and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound 009h (105 mg, 85.7% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:733.3.

[0165] Step 8: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] Compound 009h (0.2 g, 273 μmol) was dissolved in DCM (10 mL), followed by the addition of TFA (2.5 mL, 1.86 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (TFA as additive) to give Example 009 (20 mg, 7.3% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:633.1. Example 009: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.91-9.08(m,1 H),8.00-8.15(m,3 H),7.73-7.79(m,3 H),7.56-7.69(m,2 H),6.54-6.71(m,1 H),6.22-6.37(m,1 H),4.04-4.32(m,3 H),3.60-3.83(m,4 H),2.92-3.07(m,6 H),2.75-2.92(m,2 H),2.02-2.15(m,1 H),1.80-2.00(m,2 H),0.70-0.82(m,2 H),0.55-0.70(m,2 H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.48(m,3F).

[0166] Example 010: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-ethoxy-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 009 by using ethanol instead of cyclopropanol in step 2. Example 010 (15 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:621.1. Example 010: 1H NMR(400 MHz,DMSO-d6)δ ppm 7.98-8.17(m,3 H),7.73-7.87(m,4 H),7.59-7.70(m,2 H),6.48-6.61(m,1 H),6.17-6.31(m,1 H),4.15-4.36(m,4 H),3.62-3.76(m,4 H),2.93-3.09(m,6 H),2.79-2.93(m,2 H),1.78-1.98(m,2 H),1.18-1.34(m,3 H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.55(m,3F).

[0167] Example 011: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-ethyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0168] Step 1: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[[4-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methyl]carbamate [ka] The title compound was prepared similarly to step 1 of the preparation of compound 003a by replacing compound 2,5-dichloro-4-(trifluoromethyl)pyridine with compound 2,6-dichloro-4-(trifluoromethyl)pyridine. Compound 011a (1.0 g) was obtained. MS Found (ESI + )[(M+H) + ]:811.3.

[0169] Step 2: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[[4-[[4-[4-[6-ethyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methyl]carbamate [ka] Compound 011a (40.0 mg, 0.050 mmol) and bis(tri-tert-butylphosphine)palladium(0) (50.0 mg) were dissolved in DCM (5 mL). Al(Et)3 (11.26 mg, 0.10 mmol) was then added and the reaction was stirred at room temperature for 12 h. The solid was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=40%) to give compound 011b (35 mg, 79.38% yield). MS observed (ESI + )[(M+H) + ]:805.3.

[0170] Step 3: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-ethyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound 003a with compound 011b in step 2. Example 011 (14 mg) was obtained. MS observed (ESI + )[(M+H) + ]:605.2. Example 011: 1H NMR(400 MHz,DMSO-d6)δ ppm 10.68(s,1H),8.08(d,J=8.4 Hz,2H),7.94(d,J=7.2 Hz,2H),7.75(d,J=8.4 Hz,2H),7.50(d,J=6.3 Hz,2H),6.88(s,1H),6.77(s,1H),3.81(d,J=17.2 Hz,2H),3.70(s,4H),2.98(s,4H),2.85(s,2H),2.70-2.54(m,4H),1.72(s,2H),1.17(t,J=7.5 Hz,3H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.43(s,3F).

[0171] Example 012: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing 2,5-dichloro-4-(trifluoromethyl)pyridine with 2-chloro-4-(trifluoromethyl)pyrimidine in step 1. Example 012 (14 mg) was obtained. MS Found (ESI + )[(M+H) + ]:578.3. Example 012: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.70(s,1H),8.67(d,J=4.6 Hz,1H),8.07(d,J=8.1 Hz,2H),7.94(s,2H),7.74(d,J=8.2 Hz,2H),7.51(s,2H),7.04(d,J=4.7 Hz,1H),3.88(s,4H),3.80(s,2H),2.99(s,4H),2.86(s,2H),2.57(d,J=20.2 Hz,2H),1.73(s,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-69.48(s,3F).

[0172] Example 013: 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[5-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0173] Step 1: tert-Butyl N-[2-[4-[[4-[4-[5-bromo-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]ethyl]-N-[3-(tert-butoxycarbonylamino)propyl]carbamate [ka] The title compound was prepared similarly to the preparation of compound 003a by replacing 2,5-dichloro-4-(trifluoromethyl)pyridine with 5-bromo-2-chloro-4-(trifluoromethyl)pyridine in step 1 and compound Int-5 with compound Int-7. Compound 013a (31 mg) was obtained. MS Found (ESI + )[(M+H) + ]:869.3.

[0174] Step 2: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[2-[4-[[4-[4-[5-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]ethyl]carbamate [ka] A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52.16 mg, 0.070 mmol), compound 013a (31.0 mg, 0.040 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.1 mmol) in 1,4-dioxane (2.31 mL) was bubbled with N2 and then heated at 110 °C in a microwave reactor for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE = 50%) to give compound 013b (21 mg, 65.88% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:805.1.

[0175] Step 3: 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[5-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound 003a with compound 013b in step 2. Example 013 (6 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:605.3. Example 013: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.71(s,1H),8.14(s,1H),8.07(d,J=8.5 Hz,2H),7.90(d,J=7.5 Hz,2H),7.74(d,J=8.4 Hz,2H),7.39(d,J=7.4 Hz,2H),7.02(s,1H),3.64(s,4H),2.97(s,4H),2.82(s,6H),2.67(s,2H),2.22(s,3H),1.68(s,2H). 19F NMR(376 MHz,DMSO-d6)δ ppm-62.89(s,3F).

[0176] Example 014: 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-(4,5-dichloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound 2,5-dichloro-4-(trifluoromethyl)pyridine with 2,4,5-trichloropyridine and compound Int-5 with compound Int-7 in step 1. Example 014 (31 mg) was obtained. MS Found (ESI + )[(M+H) + ]:591.2. Example 014: 1 H NMR(400 MHz,CD3OD)δ ppm 8.04(s,1H),7.92(d,J=8.2 Hz,2H),7.85(d,J=7.6 Hz,2H),7.71(d,J=8.1 Hz,2H),7.36(d,J=7.7 Hz,2H),6.97(s,1H),3.23(d,J=4.0 Hz,4H),3.10(d,J=15.0 Hz,6H),2.98(s,6H),1.93(s,2H).

[0177] Example 015: 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[4-cyano-6-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound 2,5-dichloro-4-(trifluoromethyl)pyridine with 2-chloro-6-(trifluoromethyl)pyridine-4-carbonitrile and compound Int-5 with compound Int-7 in step 1. Example 015 (10 mg) was obtained as a white solid. MS Found (ESI+ )[(M+H) + ]:616.3. Example 015: 1 H NMR(400 M Hz,DMSO-d6)δ ppm 10.68(s,1H),8.06(d,J=8.7 Hz,2H),7.90(d,J=8.0 Hz,2H),7.75(d,J=8.7 Hz,2H),7.67(s,1H),7.44(s,1H),7.39(d,J=7.9 Hz,2H),3.76(s,5H),3.00(s,4H),2.81(s,6H),2.66(s,2H),1.67(s,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-67.72(s,3F).

[0178] Example 016: 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[6-cyano-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound 2,5-dichloro-4-(trifluoromethyl)pyridine with 6-chloro-4-(trifluoromethyl)pyridine-2-carbonitrile and compound Int-5 with compound Int-7 in step 1. Example 016 (10 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:616.2. Example 016: 1 H NMR(400 MHz,DMSO-d6)δ ppm10.68(s,1H),8.36(s,2H),8.04(d,J=8.7 Hz,2H),7.87(d,J=7.9 Hz,2H),7.72(d,J=8.7 Hz,2H),7.56(s,1H),7.45(s,1H),7.37(d,J=7.8 Hz,2H),3.74(s,4H),2.97(s,4H),2.79(s,6H),2.64(s,2H),1.65(s,2H). 19F NMR(376 MHz,DMSO-d6)δ ppm-63.71(s,3F).

[0179] Example 017: 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[6-chloro-4-(1,1-difluoroethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound 2, 5-dichloro-4-(trifluoromethyl)pyridine with compound Int-8 and compound Int-5 with compound Int-7 in step 1. Example 015 (8 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:621.1. Example 017: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.70(s,1H),8.37(s,2H),8.08(d,J=8.6 Hz,2H),7.91(d,J=7.6 Hz,2H),7.75(d,J=8.6 Hz,2H),7.39(d,J=7.6 Hz,2H),6.87(s,1H),6.79(s,1H),3.67(s,4H),2.98(s,4H),2.83(s,6H),2.69(s,2H),1.91(t,J=19.2 Hz,3H),1.70(s,2H). 19 F NMR(376 MHz,DMSO)δ ppm-87.87(s,2F).

[0180] Example 018: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing 2,5-dichloro-4-(trifluoromethyl)pyridine with 2-chloro-6-methyl-4-(trifluoromethyl)pyridine in step 1 and compound Int-5 with compound Int-6. Example 018 (8 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:591.1. Example 018: 1 H NMR(CD3OD,400 MHz)δ ppm 7.99(s,1H),7.9-8.0(m,3H),7.7-7.7(m,2H),7.6-7.7(m,1H),7.5-7.6(m,1H),6.67(s,1H),6.62(s,1 H),4.2-4.3(m,2H),3.6-3.6(m,4H),3.1-3.1(m,2H),2.9-3.0(m,6H),2.3-2.3(s,3H),2.0-2.1(m,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-66.52(s,3F).

[0181] Example 019: Methyl 2-[4-[4-[[3-[(3-aminopropylamino)methyl]benzoyl]amino]phenyl]sulfonylpiperazin-1-yl]-6-chloro-pyridine-4-carboxylate [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing 2,5-dichloro-4-(trifluoromethyl)pyridine with methyl 2,6-dichloropyridine-4-carboxylate in step 1 and replacing compound Int-5 with compound Int-6. Example 019 (12 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:601.1. Example 019: 1H NMR(CD3OD,400 MHz)δ ppm 7.98(s,1H),7.9-8.0(m,3H),7.7-7.7(m,2H),7.62(d,1H,J=7.6 Hz),7.5-7.6(m,1H),7.09(d,1H,J=0.7 Hz),6.96(d,1H,J=0.7 Hz),4.19(s,2H),3.79(s,3H),3.6-3.6(m,4H),2.9-3.1(m,8H),1.98(quin,2H,J=7.7 Hz).

[0182] Example 020: 3-[(3-aminopropylamino)methyl]-N-[4-[4-(6-chloro-4-cyano-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing 2,5-dichloro-4-(trifluoromethyl)pyridine with 2,6-dichloropyridine-4-carbonitrile and compound Int-5 with compound Int-6 in step 1. Example 020 (15 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:568.2. Example 020: 1 H NMR(CD3OD,400 MHz)δ ppm 8.0(s,1H),7.91(d,3H,J=8.8 Hz),7.70(d,2H,J=8.8 Hz),7.6-7.7(m,1H),7.5-7.6(m,1H),6.94(s,1H),6.77(s,1H),4.23(s, 2H),3.6-3.7(m,4H),3.1-3.1(m,2H),2.9-3.0(m,6H),2.01(t,2H,J=7.7 Hz).

[0183] Example 021: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl-piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0184] Step 1: tert-Butyl 4-(4-acetamidophenyl)sulfonyl-3-methyl-piperazine-1-carboxylate [ka] To a solution of 4-N-BOC-2-methylpiperazine (857.11 mg, 4.28 mmol), TEA (1.19 mL, 8.56 mmol) in DCM (10 mL) was added N-acetylsulfanyl chloride (1.0 g, 4.28 mmol) in one portion and the reaction was carried out at 25° C. for 1 h. After completion, the mixture was diluted with DCM (20 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 021a (1.5 g, 88.18% yield) as a yellow solid, which was used directly in the next step. MS Found (ESI + )[(M+Na) + ]:420.3.

[0185] Step 2: N-[4-(2-methylpiperazin-1-yl)sulfonylphenyl]acetamide [ka] A mixture of compound 021a (1.5 g, 3.77 mmol) in DCM (15 mL) and TFA (14.54 mL, 188.68 mmol) was stirred at 20° C. for 1 h. After completion, the mixture was concentrated under reduced pressure to give compound 021b (1.5 g, 96.62% yield) as a yellow oil, which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:297.9.

[0186] Step 3: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl-piperazin-1-yl]sulfonylphenyl]acetamide [ka] A mixture of compound 021b (1.5 g, 3.65 mmol), DIPEA (1.27 mL, 7.29 mmol), 2,6-dichloro-4-(trifluoromethyl)pyridine (787.52 mg, 3.65 mmol) in DMSO (20 mL) was heated at 90° C. for 24 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (TFA as additive) to give compound 021c (400 mg, 23% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:477.1.

[0187] Step 4: 4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl-piperazin-1-yl]sulfonylaniline [ka] Compound 021d was prepared similarly to the preparation of compound 004d by replacing compound 004c with compound 021c. Compound 021d (180 mg) was obtained as a white solid. MS (ESI + )[(M+Na) + ]:435.2.

[0188] Step 5: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl-piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methyl]carbamate [ka] To a solution of compound Int-9 (100.0 mg, 0.240 mmol) in MeCN (2 mL), 3-methylpyridine (45.6 mg, 0.490 mmol), methanesulfonyl chloride (0.03 mL, 0.370 mmol) were added in one portion and the mixture was stirred at room temperature for 1 h. Compound 021d (117.1 mg, 0.270 mmol) was then added to the mixture and the reaction was stirred at room temperature for 2 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (TFA as additive) to give compound 021e (78 mg, 37.96% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:825.3.

[0189] Step 6: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl-piperazin-1-yl]sulfonylphenyl]benzamide [ka] A mixture of compound 021e (78.0 mg, 0.090 mmol) in DCM (1 mL) and TFA (0.36 mL) was stirred at 20° C. for 1 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 as additive) to give Example 021 (28 mg, 47.03% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:625.5. Example 021: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.10-7.97(m,2H),7.93-7.88(m,1H),7.86-7.76(m,3H),7.63-7.54(m,1H),7.51-7.44(m,1H),7.03(s,1H),6.92(s,1H),4.17-4.0 7(m,2H),4.06-3.98(m,1H),3.77(s,2H),3.71-3.63(m,1H),3.20-3.13(m,2H),3.03-2.92(m,2H),1.57-1.45(m,2H),1.02(d,3H).

[0190] Example 022: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-methyl-piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 021 by substituting 4-N-BOC-2-methylpiperazine for 4-N-BOC-3-methylpiperazine in step 1. Example 022 (18 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:625.1. Example 022: 1 H NMR(400MHz,DMSO-d6)δ ppm 8.12-8.04(m,2H),7.95-7.89(m,1H),7.86-7.79(m,1H),7.77-7.71(m,2H),7.60 -7.52(m,1H),7.52-7.43(m,1H),7.04(s,1H),7.00-6.94(m,1H),4.74-4.63(m,1 H),4.28-4.16(m,1H),3.76(s,2H),3.72-3.66(m,1H),3.54-3.47(m,2H),3.27-3 .16(m,2H),2.91-2.72(m,2H),2.46-2.29(m,2H),1.70-1.50(m,2H),1.19(d,3H).

[0191] Example 023: 3-[(3-aminopropylamino)methyl]-N-[4-[[5-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2,5-diazabicyclo[4.2.0]octan-2-yl]sulfonyl]phenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 021 by substituting tert-butyl 2,5-diazabicyclo[4.2.0]octane-2-carboxylate for 4-N-BOC-2-methylpiperazine in step 1. Example 023 (10 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:637.2. Example 023: 1 H NMR(400MHz,DMSO-d6)δ 11.01-10.70(m,1H),9.75-9.44(m,2H),8.33-8.26(m,1H),8.20-8.08(m,5H),8.05-7 .96(m,1H),7.86-7.75(m,3H),7.65-7.54(m,1H),7.07-6.98(m,1H),6.85-6.73(m,1H) ,4.52-4.40(m,1H),4.32-4.18(m,2H),4.10-3.98(m,1H),3.85-3.73(m,1H),3.65-3. 51(m,2H),3.10-2.99(m,2H),2.98-2.87(m,3H),2.22-2.10(m,2H),2.07-1.92(m,4H).

[0192] Example 024: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 003 by replacing compound Int-5 with compound Int-6 in step 1. Example 024 (10 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:611.1. Example 024: 1H NMR(CD3OD,400 MHz)δ ppm 8.01(s,1H),7.96(d,3H,J=8.7 Hz),7.8-7.8(m,2H),7.65(d,1H,J=7.8 Hz),7.5-7.6(m,1H),6.83(s,1H),6.70(s,1H),4.41(d,2H,J=13.7 Hz),4.24(s,2H),3.1-3.1(m,2H),2.9-3.0(m,2H),2.8-2.9(m,2H),1.9-2.1(m,4H),1.57(dq,2H,J=4.3,12.5 Hz).

[0193] Example 025: 3-[2-(3-aminopropylamino)ethyl]-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-cyano-sulfonimidoyl]phenyl]benzamide [ka]

[0194] Step 1: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfanylphenyl]acetamide [ka] A mixture of 4-acetamidothiophenol (2.64 g, 15.81 mmol), compound Int-1a (3.5 g, 13.17 mmol), 1,10-phenanthroline (474.84 mg, 2.63 mmol) and copper oxide (210.8 mg, 2.63 mmol) in DMSO (25 mL) was stirred at 60 °C under oxygen (1.5 L, 0.750 mmol) (15 Psi, one balloon) for 24 h. After completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with EtOAc:PE = 20%) to give compound 025a (3 g, 52.85% yield) as a yellow solid. MS Found (ESI +)[(M+H) + ]:430.9.

[0195] Step 2: N-[4-[[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonimidoyl]phenyl]acetamide [ka] To a solution of compound 025a (800.0 mg, 1.86 mmol) and ammonia in THF (2.79 mL, 2.79 mmol) in methanol (15 mL) was added PIDA (1.79 g, 5.57 mmol) in portions at room temperature. The reaction mixture was stirred at 15° C. for 12 h. After completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=10%) to give compound 025b (600 mg, 69.96% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:461.9.

[0196] Step 3: N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-cyano-sulfonimidoyl]phenyl]acetamide [ka] To a solution of compound 025b (550.0 mg, 1.19 mmol) in MeCN (20 mL) was added 2,2'-azobis(2-methylpropionitrile) (293.3 mg, 1.79 mmol), potassium carbonate (329.14 mg, 2.38 mmol) and copper iodide (45.36 mg, 0.240 mmol). The reaction mixture was stirred at 75°C under oxygen (1.5 L, 1.19 mmol, 1 equiv) (1 balloon pressure) for 12 h. Upon completion, the mixture was diluted with EA (200 mL) and filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography (15% EA in PE) to give compound 025c (300 mg, 50.32% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:487.0.

[0197] Step 4: [(4-aminophenyl)-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-oxo-λ^{6}-sulfanylidene]cyanamide [ka] To a solution of compound 025c (120.0 mg, 0.250 mmol) in isopropyl alcohol (4 mL) was added concentrated hydrochloric acid (1.0 mL, 12 mmol) in one portion. The mixture was stirred at 25° C. for 12 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue which was purified by preparative TLC (eluted with EtOAc:PE=50%) to give compound 025d (70 mg, 63.85% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:444.9.

[0198] Step 5: tert-Butyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[2-[3-[[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-cyano-sulfonimidoyl]phenyl]carbamoyl]phenyl]ethyl]carbamate [ka] To a solution of compound Int-9 (79.78 mg, 0.190 mmol) and 3-methylpyridine (43.96 mg, 0.470 mmol, 3 equiv.) in MeCN (1.5 mL), MsCl (0.02 mL, 0.240 mmol) was added and the mixture was stirred at 15° C. for 3 h. Compound 025c (70.0 mg, 0.160 mmol) was then added to the mixture and the mixture was stirred at 30° C. for 12 h. After completion, the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (FA as additive) to give compound 025d (80 mg, 59.86% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:849.3.

[0199] Step 6: 3-[2-(3-aminopropylamino)ethyl]-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-cyano-sulfonimidoyl]phenyl]benzamide [ka] A mixture of compound 025d (70.0 mg, 0.080 mmol) in DCM (2 mL) and TFA (0.3 mL, 0.080 mmol) was stirred at 15° C. for 2 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (TFA as additive) to give Example 025 (20.5 mg, 29.92% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:649.3. Example 025: 1H NMR(400 MHz,DMSO-d6)δ ppm 8.33-8.43(m,1 H),8.15-8.24(m,2 H),7.97-8.07(m,2 H),7.83-7.91(m,2 H),7.49-7.58(m,2 H),7.15-7.18(m,1 H),7.01-7.06(m,1 H),3.80-3.84(m,4 H),3.23-3.32(m,4 H),2.86-2.95(m,6 H),2.73-2.81(m,2 H),1.70-1.81(m,2 H).

[0200] Example 026: 3-[(3-aminopropylamino)methyl]-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-methyl-sulfonimidoyl]phenyl]benzamide [ka]

[0201] Step 1: N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-methyl-sulfonimidoyl]phenyl]acetamide [ka] To a solution of compound Int-1a (1.0 g, 3.77 mmol) in THF (40 mL) was added NCS (1.11 g, 8.29 mmol) in one portion. The mixture was stirred at 45° C. for 1 h. Then, triethylamine (1.58 mL, 11.31 mmol) and compound Int-11 (800.0 mg, 3.77 mmol) were added successively to the reaction mixture and stirred at 45° C. for 3 h. After completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (20% EA in PE) to give compound 026a (800 mg, 40.79% yield) as a white solid. MS Found (ESI + )[(M+H)+ ]:476.0.

[0202] Step 2: 4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-methyl-sulfonimidoyl]aniline [ka] A mixture of compound 026a (700.0 mg, 1.47 mmol) and concentrated hydrochloric acid (4.0 mL, 48 mmol) in THF (15 mL) was stirred at 50 °C for 2 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH3·H2O as additive) to give compound 026b (500 mg, 77.1% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:433.9.

[0203] Step 3: 3-(chloromethyl)-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-methyl-sulfonimidoyl]phenyl]benzamide [ka] To a mixture of compound 026b (150.0 mg, 0.350 mmol) and 3-(chloromethyl)benzoyl chloride (78.43 mg, 0.410 mmol) in DCM (4 mL) was added TEA (0.14 mL, 1.04 mmol) dropwise. The mixture was stirred at 20° C. for 2 h. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA as additive) to give compound 026c (150 mg, 73.25% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:586.3.

[0204] Step 4: 3-[2-(3-aminopropylamino)ethyl]-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-cyano-sulfonimidoyl]phenyl]benzamide [ka] A mixture of compound 026c (100.0 mg, 0.170 mmol), 1,3-diaminopropane (101.11 mg, 1.36 mmol), K2CO3 (70.7 mg, 0.510 mmol) and KI (0.01 mL, 0.170 mmol) was stirred at 60° C. for 1 hour. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) to give Example 026 (68.4 mg, 64.19% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:624.3. Example 026: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.95-11.12(m,1 H),9.63-9.87(m,2 H),8.31-8.40(m,1 H),8.15-8.27(m,4 H),7.98-8.08(m,1 H),7.87-7.94(m,2 H),7.76-7.87(m,1 H),7.54-7.64(m,1 H),7.07-7.19(m,1 H),6.92-7.01(m,1 H),4.15-4.30(m,2 H),3.65-3.83(m,4 H),2.99-3.20(m,6 H),2.88-2.98(m,2 H),2.74-2.84(m,3 H), 1.98-2.16(m,2 H).

[0205] Example 027: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-methoxyphenyl]benzamide [ka]

[0206] Step 1: 1-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-4-(2-methoxy-4-nitro-phenyl)sulfonyl-piperazine [ka] The title compound was prepared similarly to the preparation of compound Int-1b by replacing 4-acetamidobenzenesulfonyl chloride with 2-methoxy-4-nitrobenzenesulfonyl chloride. Compound 027a (400 mg) was obtained as a pale yellow solid. MS (ESI + )[(M+H) + ]:483.0.

[0207] Step 2: 4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-methoxyaniline [ka] A mixture of compound 027a (400.0 mg, 0.830 mmol) and Fe (465.84 mg, 8.32 mmol) in methanol (15 mL) and NH4Cl (sat. 3 mL) was heated at 65°C for 1 h. After completion, the mixture was filtered and the filtrate was poured into water (25 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4 and concentrated under reduced pressure to give crude compound 027b (320 mg, 81.91% yield), which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:451.1.

[0208] Step 3: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-methoxy-phenyl]-4-formyl-benzamide [ka] To a mixture of 4-formylbenzoic acid (49.95 mg, 0.330 mmol) in DCM (12.86 mL) was added oxalyl chloride (42.23 mg, 0.330 mmol, 1 eq) and 1 drop of DMF. The resulting mixture was stirred at room temperature. After completion, the solvent was removed under reduced pressure to give a residue, which was added to a mixture of compound 027b (150.0 mg, 0.330 mmol) and TEA (0.2 mL), DMAP (25 mg) in DCM (12.86 mL). The mixture was stirred at room temperature for 1 h. After completion, the solvent was removed under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=50%) to give the desired product compound 027c (180 mg, 33.81% yield) as a colorless oil. MS Found (ESI + )[(M+H) + ]:583.0.

[0209] Step 4: tert-Butyl N-[3-[[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-methoxy-phenyl]carbamoyl]phenyl]methylamino]propyl]carbamate [ka] A mixture of N-BOC-1,3-diaminopropane (89.66 mg, 0.510 mmol), compound 027c (150.0 mg, 0.260 mmol) and Ti(OEt)4 (58.69 mg, 0.260 mmol) in THF (15 mL) was stirred at 25° C. for 2 h. Then sodium cyanoborohydride (32.34 mg, 0.510 mmol, 2 eq.) was added to the mixture and the resulting mixture was stirred at room temperature for another 1 h. After completion, brine (20 mL) was added to the mixture. The mixture was extracted with EtOAc (25 mL×2), washed with brine (25 mL), dried over Na2SO4, and purified by silica gel chromatography (eluted with EtOAc:PE=50%) to give the desired product, compound 027d (40 mg, 19.3% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:741.2.

[0210] Step 4: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-methoxy-phenyl]benzamide [ka] A mixture of compound 027d (60.0 mg, 0.080 mmol) in HCl-dioxane (5 mL, 4 M) was stirred at 25° C. for 1 h. After completion, the solvent was removed under reduced pressure to give a residue, which was purified by preparative HPLC (ACN / water=35-45%) to give the desired product Example 027 (TFA as additive) as a white solid. MS Found (ESI + )[(M+H) + ]:641.2. Example 027: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.68(s,1H),8.23(s,1H),7.99(s,1H),7.85(d,J=7.8 Hz,1H),7.80(d,J=1.6 Hz,1H),7.70(d,J=8.7 Hz,1H),7.54-7.64(m,2H),7.48(t,J=7.7 Hz,1H),7.07(s,1H),6.96(s,1H),3.85(s,3H),3.81(s,2H),3.66-3.62(m,4H),3.11-3.18(m,4H),2.84(t,J=7.3 Hz,2H),2.62(t,J=6.7 Hz,2H),1.74(dd,J=14.0,6.9 Hz,2H). 19 F NMR(376 MHz,CDCl3)δ ppm-58.72(s,3F).

[0211] Example 028: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-hydroxy-phenyl]benzamide [ka] To a mixture of Example 027 (40.0 mg, 0.060 mmol) in DCM (10 mL) was added BBr3 (156.31 mg, 0.620 mmol) dropwise. The mixture was stirred at room temperature for 2 h. After completion, the mixture was poured into 20 mL of ice water and extracted with DCM (10 mL x 2). The combined organic layer was washed with aqueous NaHCO3 (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (TFA as additive) to give Example 028 (2.6 mg, 6.03% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:627.2. Example 028: 1 H NMR(400 MHz,CD3OD)δ ppm 8.06(s,1H),8.00(d,J=7.4 Hz,1H),7.58-7.77(m,4H),7.24(d,J=8.4 Hz,1H),6.93(s,1H),6.83(s,1H),4.32(s,2H),3.71(s,4H),3.26-3.29(m,4H),3.19(s,2H),3.05(s,2H),2.10(s,2H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.50(s,3F).

[0212] Example 029: 4-[(3-aminopropylamino)methyl]-N-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]benzamide [ka]

[0213] Step 1: 1-[(6-bromo-3-pyridyl)sulfonyl]-4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazine [ka] The title compound was prepared similarly to the preparation of compound Int-1b by replacing 4-acetamidobenzenesulfonyl chloride with bromo-pyridine-3-sulfonyl chloride. Compound 029a (350 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:484.9.

[0214] Step 2: N-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]-1,1-diphenyl-methanimine [ka] A mixture of compound 029a (350.0 mg, 0.720 mmol), benzenemethanimine (200 mg, 1.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (65.99 mg, 0.070 mmol), (R)-BINAP (44.87 mg, 0.070 mmol) and Cs2CO3 (352.18 mg, 1.08 mmol) in 1,4-dioxane (15 mL) was heated at 90 °C under N2 for 16 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give the desired product compound 029b (300 mg, 39.07% yield) as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:586.1.

[0215] Step 3: 5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylpyridin-2-amine [ka] To a mixture of compound 029b (200.0 mg, 0.340 mmol) in THF (10 mL) was added hydrochloric acid (0.5 mL, 6 mmol). The mixture was stirred at 25° C. for 1 h. After completion, the solvent was removed under reduced pressure and purified by silica gel chromatography (eluted with EtOAc:PE=70%) to give the desired product compound 029c (120 mg, 80.02% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:422.1.

[0216] Step 4: 4-(chloromethyl)-N-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]benzamide [ka] Compound 029d was prepared similarly to the preparation of compound Int-2 by replacing compound Int-1 with compound 029c. Compound 029d (17 mg) was obtained as a white solid. MS (ESI + )[(M+H) + ]:574.0.

[0217] Step 5: tert-Butyl N-[3-[[4-[[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]carbamoyl]phenyl]methylamino]propyl]carbamate [ka] Compound 029e was prepared similarly to the preparation of compound 001a by replacing compound Int-2 with compound 029d in step 1. Compound 029e (40 mg) was obtained as a colorless oil. MS (ESI + )[(M+H) + ]:712.1.

[0218] Step 6: 4-[(3-aminopropylamino)methyl]-N-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing compound 001a with compound 029e in step 2. Example 029 (4 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:612.2. Example 029: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.71(d,J=2.3 Hz,1H),8.44(d,J=8.9 Hz,1H),8.35(s,2H),8.21(dd,J=8.9,2.3 Hz,1H),7.99(d,J=8.0 Hz,2H),7.47(d,J=8.0 Hz,2H),7.10(s,1H),6.97(s,1H),3.76(s,6H),3.07(s,4H),2.84(s,2H),2.56(d,J=6.2 Hz,2H),1.69(s,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.45(s,3F).

[0219] Example 030: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-methoxy-phenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 027 by substituting 3-methoxy-4-nitrobenzenesulfonyl chloride for 2-methoxy-4-nitrobenzenesulfonyl chloride in step 1. Example 030 (4 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:641.2. Example 030: 1 H NMR(400 MHz,DMSO-d6)δ ppm 9.61(s,1H),8.23(d,J=8.4 Hz,1H),7.92(s,1H),7.82(d,J=7.6 Hz,1H),7.58(d,J=7.1 Hz,1H),7.49(t,J=7.4 Hz,1H),7.41(dd,J=8.4,1.6 Hz,1H),7.32(d,J=1.5 Hz,1H),7.10(s,1H),6.97(s,1H),3.97(s,3H),3.75(d,J=19.4 Hz,6H),3.05(s,4H),2.84(s,2H),2.60(s,2H),1.71(s,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.46(s,3F).

[0220] Example 031: 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-hydroxy-phenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 028 by substituting Example 030 for Example 027. Example 031 (6 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:627.2. Example 031: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.27(d,J=8.4 Hz,1H),7.95(s,1H),7.81(d,J=7.4 Hz,1H),7.56(d,J=7.4 Hz,1H),7.49(t,J=7.6 Hz,1H),7.16(s,1H),7.07(s,1H),6.98(d,J=8.7 Hz,2H),3.80(s,2H),3.66(s,4H),2.87(dd,J=19.4,12.4 Hz,6H),2.61(t,J=6.3 Hz,2H),1.65-1.81(m,2H). 19F NMR(376 MHz,DMSO-d6)δ ppm-63.50(s,3F).

[0221] Examples 032 and 033: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide (Example 032) and N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide (Example 033) [ka] To a mixture solution of compound Int-1 (130 mg, 0.309 mmol) in DCM (5 mL), DIEA (0.204 mL, 1.24 mmol), triphosgene (45.83 mg, 0.154 mmol) were added and stirred at 0° C. for 15 min. Then, a mixture of compounds Int-12A and 12B (80.6 mg, 0.340 mmol) was added to the mixture and stirred at 0° C. for another 2 h. After completion, the mixture was quenched with water (20 mL) and extracted with DCM (10 mL×2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 as additive) to give 110 mg of the mixture of desired products. Further SFC purification afforded pure Example 032 (19.2 mg, 10.73% yield) as a white solid and Example 033 (19.2 mg, 10.73% yield) as a white solid. Example 032: 1 H NMR(400 MHz, CDCl3)δ ppm 7.55-7.61(m,4H),6.70(s,1H),6.59(s,1H),6.53(s,1H),4.59(s,2H),4.52(s,2H),3.78(s,3H),3.65(s,4H),3.01(s,4H). 19 F NMR (376 MHz, CDCl3) - 65.03. MS observed value (ESI + )[(M+H) +]:570.1. Example 033: 1 H NMR(400 MHz,CDCl3)δ ppm 7.64-7.69(m,4H),7.18(s,1H),6.77(s,1H),6.60(s,1H),4.62(d,J=6.9 Hz,4H),3.93(s,3H),3.72(s,4H),3.09(s,4H). 19 F NMR (376 MHz, CDCl3) - 65.03. MS observed value (ESI + )[(M+H) + ]:570.1.

[0222] Example 034: [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-pyrazolo[1,5-a]pyrimidin-3-yl-methanone [ka] To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (84.44 mg, 0.520 mmol) in DCM (6 mL) was added oxalyl chloride (0.3 mL) and the reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was redissolved in 4 mL of DCM. The above solution was added dropwise to a solution of compound Int-4 (50.0 mg, 0.110 mmol) and DIPEA (129 mg, 1.0 mmol) in DCM (4 mL). The reaction was stirred at room temperature for 4 h. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography (eluted with EtOAc:PE=50%) to give Example 034 (9 mg, 13.54% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:592.1. Example 034: 1H NMR(400 MHz,DMSO-d6)δ ppm 9.28(dd,J=7.0,1.7 Hz,1H),8.70-8.77(m,1H),8.60(d,J=4.5 Hz,1H),8.15(d,J=7.8 Hz,1H),7.63(s,1H),7.48(dd,J=39.6,7.9 Hz,1H),7.23-7.29(m,1H),7.10(s,1H),6.97(s,1H),4.37(dd,J=10.3,6.5 Hz,2H),3.73(s,4H),3.21(t,J=7.0 Hz,2H),2.99(s,4H). 19 F NMR(376 MHz,DMSO-d6):δ ppm-63.46(s,3F).

[0223] Example 035: 4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]-2-methyl-pyrazole-3-carboxylic acid [ka]

[0224] Step 1: Ethyl 4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]-2-methyl-pyrazole-3-carboxylate [ka] Compound 035a was prepared similarly to the preparation of Example 034 by replacing pyrazolo[1,5-a]pyrimidine-3-carboxylic acid with 5-ethoxycarbonyl-1-methyl-pyrazole-4-carboxylic acid. Compound 035a (50 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:627.2.

[0225] Step 2: 4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]-2-methyl-pyrazole-3-carboxylic acid [ka] A solution of ethyl compound 035a (20 mg, 0.032 mmol) and LiOH (2.93 mg, 0.128 mmol) in THF / MeOH / water (4 / 4 / 1 mL). The resulting mixture was stirred at room temperature for 16 hours. To the mixture was added 0.1 mL of 2M aqueous HCl. The resulting mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give Example 035 (3.5 mg, 18.21% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:599.1. Example 035: 1 H NMR(400 MHz,CD3OD)δ ppm 8.41(d,J=8.4 Hz,1H),7.83(s,1H),7.75-7.65(m,2H),6.93(s,1H),6.83(s,1H),4.04(s,2H),3.86(s,3H),3.74(dd,J=12.5,7.6 Hz,4H),3.24(t,J=7.7 Hz,2H),3.07(dd,J=16.9,12.0 Hz,4H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.46(s,3F).

[0226] Example 036: [1-(azetidin-3-yl)pyrazol-4-yl]-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]methanone [ka]

[0227] Step 1: Methyl 1-(1-tert-butoxycarbonylazetidin-3-yl)pyrazole-4-carboxylate [ka] To a solution of methyl 1H-pyrazole-4-carboxylate (63 mg, 0.500 mmol) in MeCN (10 mL) was added Cs2CO3 (325.56 mg, 0.999 mmol) and tert-butyl 3-bromoazetidine-1-carboxylate (129.75 mg, 0.999 mmol). The resulting suspension mixture was stirred for 90 ℃ The mixture was stirred at rt for 16 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=50%) to give the desired crude compound 036a (50 mg, 71.32% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:281.0.

[0228] Step 2: 1-(1-tert-butoxycarbonylazetidin-3-yl)pyrazole-4-carboxylic acid [ka] A solution of compound 036a (50 mg, 0.178 mmol) and LiOH (8.18 mg, 0.355 mmol) in THF / MeOH / water (5 / 5 / 0.5 mL) was stirred at room temperature for 16 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=50%) to give the desired crude compound 036b (30 mg, 63.05% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:267.1.

[0229] Step 3: tert-Butyl 3-[4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]pyrazol-1-yl]azetidine-1-carboxylate [ka] To a solution of compound 036b (30 mg, 0.112 mmol) in MeCN (45 mL) was added 1-methylimidazole (27.61 mg, 0.337 mmol), TCFH (62.86 mg, 0.224 mmol). The resulting mixture was stirred at room temperature for 15 minutes. Then, a solution of compound Int-4 was added to the mixture, and the mixture was stirred for 25 minutes. ℃ The mixture was stirred at rt for 16 h. After completion, the reaction was quenched with 10 mL of water and extracted with DCM (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (EtOAc:PE = 50%) to give compound 036c (30 mg, 19.2% yield) as a colorless oil. MS Found (ESI + )[(M+H) + ]:696.1.

[0230] Step 4: [1-(azetidin-3-yl)pyrazol-4-yl]-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]methanone [ka] To a solution of compound 036 (30 mg, 0.034 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at 25° C. for 3 h. The mixture was then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give Example 036 (5 mg, 11.08% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:596.1.

[0231] Example 036: 1H NMR(400 MHz,CD3OD)δ ppm 8.28(d,J=7.2 Hz,2H),8.14(s,1H),7.60(dd,J=40.0,31.3 Hz,2H),6.91(s,1H),6.82(s,1H),5.54-5.42(m,1H),4.52(d,J=6.8 Hz,4H),4.43(t,J=8.4 Hz,2H),3.77-3.68(m,4H),3.34(d,J=8.4 Hz,2H),3.12-3.02(m,4H). 19 F NMR(376 MHz,CD3OD)δ ppm-63.46(s,3F). Example 037: [1-(3-aminopropyl)pyrazol-4-yl]-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]methanone [ka] The title compound was prepared similarly to the preparation of Example 036 by replacing tert-butyl 3-bromoazetidine-1-carboxylate with tert-butyl N-(3-aminopropyl)carbamate in step 1. Compound 037a (50 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:597.2. Example 037: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.44(d,J=22.7 Hz,2H),8.26(d,J=8.5 Hz,1H),7.97(s,1H),7.60(d,J=11.2 Hz,1H),7.46(dd,J=40.1,7.7 Hz,1H),7.09(s,1H),6.96(s,1H),4.40(s,2H),4.26(s,2H),3.72(s,4H),3.28(d,J=6.2 Hz,2H),2.97(s,4H),2.67(s,2H),2.03(s,2H). 19 F NMR(376 MHz,DMSO)δ ppm-63.47(s,3F).

[0232] Example 038: [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methanone [ka]

[0233] Step 1: tert-Butyl 3-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate [ka] The title compound was prepared similarly to the preparation of Example 034 by substituting 5-tert-butoxycarbonyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3-carboxylic acid for pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. Compound 038a (95 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:696.2.

[0234] Step 2: [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methanone [ka] Compound 038a (95.0 mg, 0.140 mmol) in 2M HCl / EA (10 mL) was stirred at room temperature for 4 hours. After completion, the solvent was removed under reduced pressure to give the crude product, which was purified by preparative HPLC (TFA as additive) to give Example 038 (40 mg, 46.11% yield). MS observed (ESI + )[(M+H) + ]:596.2. Example 038: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.20(d,J=8.5 Hz,1H),7.94(s,1H),7.63-7.54(m,2H),7.09(s,1H),6.97(s,1H),4.40(t,J=8.4 Hz,2H),4.09(d,J=11.5 Hz,2H),4.02(s,2H),3.72(s,4H),3.24(t,J=8.3 Hz,2H),3.12(s,2H),2.97(d,J=4.2 Hz,4H). 19 F NMR(376 MHz,DMSO)δ ppm-63.47(s,3F).

[0235] Example 039: [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-(1-oxa-2,9-diazaspiro[4.5]dec-2-en-3-yl)methanone [ka]

[0236] Step 1: tert-Butyl 3-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]-1-oxa-2,9-diazaspiro[4.5]dec-2-ene-9-carboxylate [ka] To a solution of 7-(tert-butoxycarbonyl)-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-3-carboxylic acid (35 mg, 123 μmol) in MeCN (2.5 mL) was added 1-methylimidazole (30.3 mg, 369 μmol) and HATU (69.1 mg, 246 μmol). The resulting mixture was stirred at room temperature for 15 minutes. Then, a solution of compound Int-4 (59 mg, 132 μmol) in MeCN was added. The mixture was stirred for 25 minutes. ℃The mixture was stirred at rt for 5 h. After completion, the reaction was quenched with water (10 mL). The reaction mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 039a (80 mg, 91% yield) as a yellow oil. MS Found (ESI + )[(M+Na) + ]:735.60.

[0237] Step 2: [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-(1-oxa-2,9-diazaspiro[4.5]dec-2-en-3-yl)methanone [ka] Compound 039a (70 mg, 98.2 μmol) was dissolved in DCM (7.5 mL) followed by the addition of TFA (2 mL, 98.2 μmol). The reaction was stirred at room temperature and allowed to go to completion for 2 hours. Upon completion, the reaction was concentrated under reduced pressure to give the crude product which was purified by preparative HPLC to give Example 039 (34.87 mg, 46.4% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:613.3. Example 039: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.8-9.1(m,1H),8.6-8.8(m,1H),8.24(br d,1H,J=7.6 Hz),7.5-7.8(m,2H),7.09(s,1H),6.98(s,1H),4.42(s,2H),3.7-3.8(m,4H),3.1-3.3(m,6H),2.9-3.0(m,5H),1.7-2.1(m,4H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.46(m,3F).

[0238] Example 040: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-piperazin-1-yl-acetamide [ka] Step 1: 2-Chloro-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]acetamide [ka] Compound Int-1 (100 mg, 238 μmol), chloroacetyl chloride (67.1 mg, 594 μmol) and DIPEA (468 mg, 3.62 mmol) were stirred at room temperature for 4 h. After completion, the reaction mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product 040a (118 mg, 100% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:496.8.

[0239] Step 2: tert-Butyl 4-[2-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylanilino]-2-oxoethyl]piperazine-1-carboxylate [ka] Compound 040b (60 mg, 121 μmol) and tert-butyl piperazine-1-carboxylate (44.9 mg, 241 μmol) were dissolved in DCM (10 mL) followed by the addition of DIPEA (46.8 mg, 63.2 μL, 362 μmol). The reaction was stirred at room temperature for 1 h. Upon completion, the reaction mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product 040b (75 mg, 96.1% yield) as a yellow oil. MS Found (ESI+ )[(M+H) + ]:647.8.

[0240] Step 3: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-piperazin-1-yl-acetamide [ka] Compound 040b (70 mg, 108 μmol) in DCM (5 mL) and TFA (2 mL, 108 μmol) was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (TFA as additive) to give Example 040 (29 mg, 38.5% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:547.5. Example 040: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.4-8.7(m,2H),7.82(d,2H,J=8.7 Hz),7.66(d,2H,J=8.8 Hz),7.01(s,1H),6.8-6.9(m,1H),3.64(br d,4H,J=4.6 Hz),3.10(s,6H),2.89(d,4H,J=4.4 Hz),2.7-2.8(m,4H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.46(m,3F).

[0241] Example 041: 1-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-2-(2-hydroxyethylamino)ethanone [ka] The title compound was prepared similarly to the preparation of Compound 040 by replacing Compound Int-1 with Compound Int-4 in step 1 and replacing tert-butyl piperazine-1-carboxylate with 2-aminoethanol in step 2. Example 041 (20 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:548.5. Example 041: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.8-9.1(m,2H),8.21(d,1H,J=8.3 Hz),7.5-7.8(m,2H),7.09(s,1H),6.9-7.0(m,1H),4.0-4.3(m,4H),3.72(br s,6H),3.08(s,2H),2.97(s,4H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.45(m,3F).

[0242] Example 042: 2-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]benzoic acid [ka] The title compound was prepared similarly to the preparation of Example 035 by replacing 5-ethoxycarbonyl-1-methyl-pyrazole-4-carboxylic acid with 2-methoxycarbonylbenzoic acid in step 1. Example 042 (15.1 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:595.2. Example 042: 1 H NMR(400MHz,DMSO-d6)δ ppm 8.30(br d,J=8.4 Hz,1H),8.08-7.93(m,1H),7.79-7.55(m,4H),7.53-7.43(m,1H),7.09(s,1H),6.97(s,1H),3.76-3.63(m,6H),3.14(br s,1H),3.06-2.82(m,5H).

[0243] Example 043: [2-Acetoxy-4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]phenyl]acetate [ka] The title compound was prepared similarly to the preparation of compound 039a by replacing (tert-butoxycarbonyl)-1-oxa-2,7-diazaspiro[4.5]dec-2-ene-3-carboxylic acid with 7-3,4-diacetoxybenzoic acid. Example 043 (9 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:667.6. Example 043: 1 H NMR(400 MHz,DMSO-d6)δ ppm 7.5-7.8(m,4H),7.42(s,1H),7.10(s,1H),6.97(s,1H),5.75(s,1H),3.9-4.2(m,2H),3.6-3.8(m,4H),3.1-3.3(m,2H),2.97(br t,4H,J=4.8 Hz),2.30(d,6H,J=8.8 Hz). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.46(m,3F).

[0244] Example 044: N-[4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide [ka]

[0245] Step 1: tert-Butyl 3-[[4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]carbamoyl]-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate [ka] To a solution of 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid (80.0 mg, 0.300 mmol) in ACN (1 mL) was added 3-methylpyridine (56.38 mg, 0.610 mmol), methanesulfonyl chloride (0.04 mL, 0.450 mmol, 1.5 equiv) in one portion. The reaction was heated at 50° C. for 1 h, and then compound Int-13 (133.66 mg, 0.330 mmol) was added to the mixture. The reaction was stirred at 50° C. for an additional 3 h. Upon completion, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (TFA as additive) to give Example 044a (85 mg, 43.36% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:648.2.

[0246] Step 2: N-[4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide hydrochloride [ka] A mixture of compound 044a (85.0 mg, 0.130 mmol) in DCM (1.0 mL) and TFA (0.5 mL) was diluted with 25 ℃ The mixture was stirred at rt for 1 h. Upon completion, the reaction solution was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) to give Example 044 (74 mg, 95.99% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:548.2. Example 044: 1H NMR(400 MHz,DMSO-d6)δ ppm 11.03-10.97(m,1H),10.30-10.09(m,2H),9.11-9.05(m,1H),8.41-8.32(m,1H),8.11-8.01(m,2H),7.79-7.71 (m,2H),6.96(s,1H),4.68-4.62(m,2H),4.59-4.53(m,2H),3.90-3.79(m,4H),3.03-2.92(m,4H),2.37(s,3H).

[0247] Example 045: N-[4-[4-[6-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide [ka]

[0248] Step 1: tert-Butyl 3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate [ka] Compound 045a was prepared similarly to the preparation of compound 044a by replacing compound Int-13 with compound Int-1. Compound 045a (34 mg) was obtained as a white solid. MS (ESI + )[(M+H) + ]:667.2.

[0249] Step 2: N-[4-[4-[6-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide [ka] A mixture of trimethylboroxine (33.95 mg, 0.270 mmol), compound 045b (150.0 mg, 0.220 mmol), K3PO4 (67.9 mg, 0.320 mmol) and chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (15.03 mg, 0.020 mmol) in THF (8 mL) and water (0.800 mL) was stirred under Ar at 70 °C for 3 h. After completion, the mixture was poured into water (100 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (FA as additive) to give compound 045b (105 mg, 85.44% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:647.2.

[0250] Step 3: N-[4-[4-[6-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide [ka] A solution of compound 045b (100.0 mg, 0.150 mmol) in DCM (2 mL) and TFA (1.0 mL) was stirred at 25° C. for 1 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) to give Example 045 (48.3 mg, 53.55% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:547.3. Example 045: 1H NMR(400 MHz,DMSO-d6)δ ppm 11.09-11.24(m,1 H),10.38-10.62(m,2 H),9.06-9.14(m,1 H),8.36-8.42(m,1 H),8.04-8.16(m,2 H),7.67-7.86(m,2 H),6.90-6.98(m,1 H),6.76-6.85(m,1 H),4.57(br t,J=5.50 Hz,4 H),3.68-3.79(m,4 H),2.90-3.04(m,4 H),2.35-2.43(m,3 H).

[0251] Example 046: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]isoindoline-5-carboxamide [ka] The title compound was prepared similarly to the preparation of Example 044 by replacing 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid with compound Int-14 and compound Int-13 with compound Int-1 in step 1. Example 045 (22.85 mg) was obtained. MS Found (ESI + )[(M+H) + ]:566.1. Example 046: 1 H NMR(400MHz,DMSO-d6)δ ppm 10.87-10.64(m,1H),10.11-9.70(m,2H),8.12-8.03(m,2H),8.01-7.93(m,2H),7.82-7.68(m,2H) ,7.61-7.52(m,1H),7.13-7.02(m,1H),6.95(s,1H),4.75-4.42(m,4H),3.78-3.64(m,4H),2.98(br t,J=4.6 Hz,4H).

[0252] Example 047: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide [ka] Step 1: 3-Bromo-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A mixture of compound Int-1 (0.5 g, 1.19 mmol), 3-bromobenzoyl chloride (0.3 g, 1.36 mmol) and TEA (331 μL, 2.38 mmol) in DCM (12 mL) was stirred at room temperature overnight. After completion, the mixture was quenched with water (20 mL) and diluted with DCM (30 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude compound 047a (700 mg, 95.7% yield) as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:604.8.

[0253] Step 2: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] A mixture of compound 047a (1.0 g, 1.66 mmol), bis(pinacolato)diboron (463 mg, 1.82 mmol) and potassium acetate (406 mg, 4.14 mmol) in 1,4-dioxane (5 mL) was degassed for 5 min and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (67.6 mg, 82.8 μmol) was added. The reaction mixture was stirred at 90° C. for 2 h in a sealed tube. After completion, the reaction was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=30%) to give compound 047b (0.6 g, 55.4% yield) as an orange oil. MS Found (ESI+) [(M+H) + ]:651.3.

[0254] Step 3: [3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]boronic acid [ka] Compound 047b (0.5 g, 768 μmol) was dissolved in 1,4-dioxane (10 mL) followed by the addition of 6N HCl (2 mL, 12 mmol). The reaction was heated at 90° C. for 4 h. Upon completion, the reaction was concentrated under reduced pressure to give crude 047c (0.4 g, 91.6%) as a brown oil which was used directly in the next step.

[0255] Step 4: tert-Butyl 5-[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [ka] A mixture of compound 047c (130 mg, 229 μmol), tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (45.3 mg, 229 μmol), copper(I) chloride (22.6 mg, 229 μmol), TEA (100 μL, 686 μmol) and molecular sieves 4 Å (0.2 g, 229 μmol) in MeCN (5 mL) was stirred in air for 12 h. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a crude green residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=40%) to give compound 047d (90 mg, 54.6% yield) as a yellow oil. MS Found (ESI+) [(M+H) + ]:721.2.

[0256] Step 5: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide [ka] Compound 047d (100 mg, 139 μmol) was dissolved in DCM (5 mL) followed by the addition of TFA (2 mL, 139 μmol). The reaction was stirred at room temperature for 1 h. Upon completion, the reaction was concentrated under reduced pressure and purified by preparative HPLC (TFA as additive) to give Example 047 (1.5 mg, 1.4% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:621.2. Example 047: 1H NMR(400 MHz,CD3OD)δ ppm 8.00(d,2H,J=8.8 Hz),7.82(d,2H,J=8.8 Hz),7.3-7.5(m,2H),7.23(s,1H),6.95(s,2H),6.85(s,1H),4.78(s,1H),4.53(s,1H),3.82(dd,1H,J=2.4,10.6 Hz),3.7-3.8(m,4H),3.41(br s,3H),3.1-3.2(m,5H),2.35(br d,1H,J=11.4 Hz),2.0-2.2(m,1H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.49(m,3F).

[0257] Example 048: 3-(2-aminoethoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0258] Step 1: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-methoxy-benzamide [ka] To a solution of compound Int-1 (800.0 mg, 1.9 mmol, 1 equiv.) in DCM (8 mL), TEA (0.79 mL, 5.7 mmol, 3 equiv.) and 3-methoxybenzoyl chloride (0.53 mL, 3.8 mmol, 2 equiv.) were added in sequence. ℃ The mixture was stirred at rt for 1 h. After completion, the mixture was diluted with DCM (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (TFA as additive) to give compound 048a (1000 mg, 94.79% yield) as a red solid. MS Found (ESI+) [(M+H) + ]:555.2.

[0259] Step 2: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-hydroxy-benzamide [ka] A solution of compound 048a (980.0 mg, 1.77 mmol, 1 equiv.), BBr3 (0.01 mL, 2.65 mmol) in DCM (20 mL) was ℃ The mixture was stirred at rt for 2 h. After completion, the mixture was quenched with MeOH (10 mL) and water (20 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give compound 048b (810 mg, 84.8% yield) as a red solid. MS Found (ESI + )[(M+H) + ]:563.2.

[0260] Step 3: tert-Butyl N-[2-[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenoxy]ethyl]carbamate [ka] A mixture of compound 048b (150.0 mg, 0.280 mmol), tert-butyl N-(2-bromoethyl)carbamate (124.28 mg, 0.550 mmol) and K2CO3 (114.97 mg, 0.830 mmol) in DMF (1.25 mL) was diluted with 100 mL of DMF for 90 min. ℃ The mixture was stirred at rt for 2 h. After completion, the mixture was diluted with water (20 mL) and then extracted with EtOAc (20 mL×3). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (TFA as additive) to give compound 048c (110 mg, 57.98% yield) as a white solid. MS Found (ESI+) [(M+H)+ ]:684.2.

[0261] Step 4: 3-(2-aminoethoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A mixture of compound 048c (110.0 mg, 0.160 mmol) in DCM (1 mL) and TFA (0.5 mL) was diluted with 20 ℃ The mixture was stirred at rt for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl as additive) to give Example 048 (45 mg, 45.1% yield) as a white solid. MS Found (ESI+) [(M+H) + ]:584.1. Example 048: 1 H NMR(400 MHz,DMSO-d6)δ ppm:10.73(s,1H),8.21-8.13(m,3H),8.11-8.05(m,2H),7.78-7.73(m,2H),7.64-7.60(m,1H),7.57-7.54(m,1H),7.52-7.46(m,1) H),7.26-7.21(m,1H),7.09(s,1H),6.99-6.94(m,1H),4.31-4.24(m,2H),3.75-3.66(m,4H),3.27-3.21(m,2H),3.02-2.94(m,4H).

[0262] Example 049: 3-(azetidin-3-ylmethylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; [ka] The title compound was prepared similarly to the preparation of Example 047 by substituting tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate with tert-butyl 3-(aminomethyl)azetidine-1-carboxylate in step 4. Example 049 (1 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:609.4. Example 049: 1 H NMR(400 MHz,CD3OD)δ ppm 7.8-7.9(m,2H),7.69(d,2H,J=8.8 Hz),7.3-7.5(m,1H),7.0-7.2(m,3H),6.7-6.9(m,3H),5.25(br,2H,J=4.6 Hz),4.06(dd,1H,J=9.4,10.7 Hz),3.82(dd,1H,J=7.2,10.9 Hz),3.6-3.7(m,4H),3.34(d,2H,J=6.8 Hz),2.9-3.1(m,4H),2.10(t,2H,J=7.5 Hz). 19 F NMR(376 MHz,CD3OD)δ ppm-66.48(m,3F).

[0263] Example 050: 3-(azetidin-3-ylmethoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 048 by substituting tert-butyl N-(2-bromoethyl)carbamate with tert-butyl 3-(bromomethyl)azetidine-1-carboxylate in step 3. Example 050 (56 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:610.4. Example 050: 1H NMR(400 MHz,DMSO-d6)δ ppm 10.74-10.69(m,1H),9.12-8.98(m,2H),8.08(d,J=8.9 Hz,2H),7.78-7.73(m,2H),7.62-7.55(m,2H),7.52-7.46(m,1H),7.26-7.22(m,1H),7.10-7.07(m,1H),6.98-6.9 5(m,1H),4.27-4.22(m,2H),4.13-4.04(m,2H),3.90-3.81(m,2H),3.75-3.66(m,4H),3.26-3.15(m,1H),2.98(br t,J=4.6 Hz,4H).

[0264] Example 051: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(3R)-3-aminopyrrolidin-1-yl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 052 by replacing tert-butyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate with tert-butyl (R)-pyrrolidin-3-ylcarbamate hydrochloride in step 2. Example 051 (18 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:609.9. Example 051: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.56(s,1H),8.0-8.2(m,5H),7.75(d,2H,J=8.8 Hz),7.3-7.4(m,1H),7.28(s,1H),7.0-7.2(m,2H),6.97(s,1H),6.82(dd,1H,J=1.9,8.1 Hz),3.99(br s,1H),3.7-3.8(m,4H),3.5-3.6(m,3H),3.0-3.1(m,4H),2.3-2.4(m,1H),2.0-2.2(m,1H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-63.46(m,3F).

[0265] Example 052: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(3,6-diazabicyclo[3.2.0]heptan-3-yl)benzamide [ka]

[0266] Step 1: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-iodo-benzamide [ka] Compound Int-1 (0.15 g, 356 μmol), 3-iodobenzoyl chloride (190 mg, 713 μmol) and TEA (100 μL, 713 μmol) were stirred at room temperature overnight. After completion, the mixture was quenched with water (10 mL) and diluted with DCM (30 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=20%) to give compound 052a (180 mg, 77.6% yield) as a yellow oil. MS Found (ESI + )[(M+H) + ]:651.2.

[0267] Step 2: tert-Butyl-3-[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate [ka] A mixture of Cs2CO3 (150 mg, 461 μmol), chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (15.4 mg, 23 μmol), tert-butyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (45.7 mg, 230 μmol), N-(4-((4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)-3-iodobenzamide (75 mg, 115 μmol) in degassed 1,4-dioxane (2.5 mL) was heated for 75 min in a microwave reactor. ℃ After completion, the mixture was poured into ice water (20 mL), extracted with DCM (10 mL×3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=40%) to give compound 052b (50 mg, 60.2% yield) as a yellow oil. MS observed (ESI + )[(M+H) + ]:721.2.

[0268] Step 3: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(3,6-diazabicyclo[3.2.0]heptan-3-yl)benzamide [ka] Compound 052b (50 mg, 69.3 μmol) was dissolved in DCM (5 mL) followed by the addition of TFA (2 mL, 69.3 μmol). The reaction was stirred at room temperature and was complete after 1 h. Upon completion, the reaction was concentrated under reduced pressure and purified by preparative HPLC (TFA as additive) to give Example 052 (2.7 mg, 5.2% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:621.2. Example 052: 1H NMR(400 MHz,DMSO-d6)δ ppm 8.01(d,2H,J=8.9 Hz),7.82(d,2H,J=8.9 Hz),7.46(d,3H,J=5.0 Hz),7.1-7.3(m,1H),6.95(s,1H),6.85(s,1H),4.60(s,3H),4.19(d,1H,J=12.6 Hz),3.98(d,1H,J=10.6 Hz),3.7-3.8(m,4H),3.5-3.6(m,2H),3.1-3.2(m,4H),3.0-3.1(m,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-66.49(m,3F).

[0269] Example 053: 3-(2-aminoethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 044 by replacing 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid with compound Int-15 and compound Int-13 with compound Int-1 in step 1. Example 053 (93.9 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:568.3. Example 053: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.51-10.84(m,1 H),8.03-8.11(m,2 H),7.72-7.83(m,4 H),7.41-7.47(m,2 H),7.07-7.12(m,1 H),6.94-6.99(m,1 H),3.65-3.80(m,4 H),2.99(br t,J=4.77 Hz,4 H),2.70-2.87(m,4 H).

[0270] Example 054: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-piperazin-1-yl-benzamide [ka] The title compound was prepared similarly to the preparation of Example 044 by replacing 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid with 3-(4-tert-butoxycarbonylpiperazin-1-yl)benzoic acid and compound Int-13 with compound Int-1 in step 1. Example 054 (100.2 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:609.3. Example 054: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.46-10.70(m,1 H),7.98-8.14(m,2 H),7.69-7.84(m,2 H),7.29-7.51(m,3 H),7.08-7.20(m,2 H),6.94-7.01(m,1 H),3.64-3.83(m,4 H),3.08-3.16(m,4 H),2.98(br t,J=4.63 Hz,4 H),2.86(br d,J=4.50 Hz,4 H).

[0271] Example 055: 2-Amino-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indan-5-carboxamide [ka] The title compound was prepared similarly to the preparation of Example 044 by replacing 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid with compound Int-16 and compound Int-13 with compound Int-1 in step 1. Example 055 (49.6 mg) was obtained as a white solid. MS Found (ESI + )[(M+H)+ ]:580.3. Example 055: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.47-10.64(m,1 H),8.04-8.14(m,2 H),7.70-7.87(m,4 H),7.30-7.40(m,1 H),7.08-7.15(m,1 H),6.93-6.99(m,1 H),3.65-3.83(m,5 H),3.09-3.15(m,2 H),2.99(br d,J=4.16 Hz,4 H),2.60-2.70(m,2 H).

[0272] Example 056: 5-(aminomethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-hydroxy-benzamide [ka]

[0273] Step 1: N-(4-((4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)-5-(chloromethyl)-2-methoxybenzamide [ka] To a solution of 5-(chloromethyl)-2-methoxy-benzoic acid (100.0 mg, 0.500 mmol) in DCM (1 mL) was added SOCl2 (92.84 mg, 1 mmol) dropwise. The mixture was stirred at 20° C. for 30 min. The reaction mixture was then concentrated and the residue was redissolved in dry DCM (5 mL). Compound Int-1 (0.21 g, 0.500 mmol) and TEA (0.10 g, 1.0 mmol) were then added to the above solution. The mixture was stirred at 20° C. for 3 h. After completion, the reaction mixture was concentrated under reduced pressure to give compound 056a (280 mg, 93.09% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:603.2.

[0274] Step 2: 5-(aminomethyl)-N-(4-((4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)-2-methoxybenzamide [ka] To a solution of compound 056a (200.0 mg, 0.330 mmol) in MeCN (5 mL) was added NH3·H2O (1.0 mL, 0.430 mmol) in one portion. The mixture was stirred in a sealed tube at 50 °C for 4 h. After completion, the solution was poured into water (15 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude compound 056b (185 mg, 95.58% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:584.1.

[0275] Step 3: 5-(aminomethyl)-N-(4-((4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)sulfonyl)phenyl)-2-hydroxybenzamide [ka] To a mixture of compound 056b (100.0 mg, 0.170 mmol, 1 equiv) in DCM (5 mL) was added AlCl3 (112.92 mg, 0.860 mmol) and the mixture was stirred at 20° C. for 15 h. After completion, the solvent was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (HCl as additive) to give Example 056 (6.1 mg, 6.13% yield) as a blue solid. MS Found (ESI + )[(M+H) + ]:570.0. Example 056: 1H NMR(400MHz,DMSO-d6)δ ppm11.65-11.45(m,1H),10.77(s,1H),8.34-8.17(m,3H),8.07-7.98(m,3H),7.80-7.70(m,2H),7.56- 7.48(m,1H),7.11-7.04(m,2H),6.96(s,1H),4.07-3.94(m,2H),3.76-3.66(m,4H),3.06-2.94(m,4H).

[0276] Example 057: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(2,4-diaminobutanoylamino)benzamide [ka]

[0277] Step 1: tert-Butyl N-[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]carbamate [ka] A mixture of 3-(tert-butoxycarbonylamino)benzoic acid (563.75 mg, 2.38 mmol) and SOCl2 (2.83 g, 23.76 mmol) in dry DCM (10.0 mL) and THF (10.0 mL) was stirred at 25° C. for 6 h. The mixture was then concentrated under reduced pressure to give a residue, which was redissolved in dry DCM (10.0 mL) and added to a mixture of compound Int-1 (500.0 mg, 1.19 mmol) and TEA (0.5 mL, 3.56 mmol) in DCM (10 mL). The mixture was stirred at 15° C. for 2 h. After completion, the mixture was diluted with EtOAc (200 mL) and washed with brine (50 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (FA as additive) to give compound 057a (620 mg, 81.53% yield) as a pale yellow solid. MS observed (ESI + )[(M+H)+ ]:640.1.

[0278] Step 2: 3-amino-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A mixture of compound 057a (620.0 mg, 0.970 mmol), hydrochloric acid in dioxane (20.0 mL, 80 mmol) was stirred at 25° C. for 2 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was redissolved in EtOAc (300 mL) and basified to pH 8.0 with aqueous K2CO3. The organic layer was washed with brine (50 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 057b (500 mg, 95.6% yield) as a pale yellow solid. MS Found (ESI) + )[(M+H) + ]:540.1.

[0279] Step 3: tert-Butyl N-[3-(tert-butoxycarbonylamino)-4-[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]anilino]-4-oxo-butyl]carbamate [ka] To a solution of 2,4-bis(tert-butoxycarbonylamino)butanoic acid (176.89 mg, 0.560 mmol) and 3-methylpyridine (137.98 mg, 1.48 mmol) in MeCN (3.03 mL) was added MsCl (0.05 mL, 0.590 mmol) and stirred at 15° C. for 4 h. Compound 057b (200.0 mg, 0.370 mmol) was then added to the above mixture, which was stirred at 50° C. for 2 h. After completion, the mixture was concentrated under reduced pressure to give crude compound 057c (200 mg, 64.26% yield) as a yellow oil, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:840.3.

[0280] Step 4: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(2,4-diaminobutanoylamino)benzamide [ka] A mixture of compound 057c (200.0 mg, 0.240 mmol) in HCl in dioxane (5.0 mL, 20 mmol) was stirred at 25° C. for 2 hours. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 as additive) to give Example 057 (32.8 mg, 21.27% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:640.2. Example 057: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.27-10.96(m,1 H),8.17-8.30(m,1 H),8.04-8.11(m,2 H),7.90-7.96(m,1 H),7.73-7.81(m,2 H),7.60-7.69(m,1 H),7.44-7.53(m,1 H),7.07-7.11(m,1 H),6.94-6.99(m,1 H),3.70-3.80(m,4 H),3.29-3.44(m,5 H),2.99(br t,J=4.52 Hz,4 H).

[0281] Example 058: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-2-carboxamide; [ka] Step 1: 4-(Chloromethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-2-carboxamide [ka] Compound 058a was prepared similarly to the preparation of compound 057a by replacing 3-(tert-butoxycarbonylamino)benzoic acid with 4-(chloromethyl)pyridine-2-carboxylic acid. Compound 058a (200 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:574.2.

[0282] Step 2: tert-Butyl N-[3-[[2-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]-4-pyridyl]methylamino]propyl]carbamate [ka] A mixture of compound 058a (200.0 mg, 0.350 mmol), K2CO3 (144.37 mg, 1.04 mmol), KI (0.01 mL, 0.170 mmol) and tert-butyl N-(3-aminopropyl)carbamate (121.34 mg, 0.700 mmol) in MeCN (5 mL) was stirred at 70 °C for 2 h. After completion, the mixture was concentrated in vacuo to give crude compound 058b (200 mg, 80.65% yield) as a yellow oil, which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:712.2.

[0283] Step 3: 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-2-carboxamide [ka] A mixture of compound 058b (200.0 mg, 0.280 mmol) in DCM (4 mL) and TFA (3.2 g, 28.08 mmol) was stirred at 25° C. for 1 h. After completion, the mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (NH4HCO3 as additive) to give Example 058 (97.5 mg, 56.3% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:612.3. Example 058: 1 H NMR(400 MHz,DMSO-d6)δ ppm 11.25-10.84(m,1H),8.66(d,J=4.9 Hz,1H),8.30-8.08(m,3H),7.76(d,J=8.8 Hz,2H),7.64(br d,J=4.6 Hz,1H),7.08(s,1H),6.95(s,1H),4.61-3.83(s,2H),3.75-3.65(m,4H),3 .07-2.95(m,4H),2.95-2.85(m,2H),2.58-2.51(m,2H),1.69-1.40(m,2H).

[0284] Example 059: 6-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-2-carboxamide [ka] The title compound was prepared similarly to the preparation of Example 044 by replacing 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid with compound Int-17 and compound Int-13 with compound Int-1 in step 1. Example 059 (51.3 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:612.3. Example 059: 1H NMR(400 MHz,DMSO-d6)δ ppm 8.20(d,J=7.9 Hz,2H),8.02(d,J=4.8 Hz,2H),7.79(d,J=8.9 Hz,2H),7.69(t,J=4.5 Hz,1H),7.09(s,1H),6.97(s,1H),3.92(s,2H),3.80-3.69(m,5H),3.01(t,J=4.8 Hz,5H),2.62-2.57(m,2H),1.55(t,J=6.8 Hz,2H).

[0285] Example 060: 5-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-3-carboxamide; [ka] The title compound was prepared similarly to the preparation of Example 058 by substituting 5-(bromomethyl)pyridine-3-carboxylic acid for 4-(chloromethyl)pyridine-2-carboxylic acid in step 1. Example 060 (38 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:612.0. Example 060: 1 H NMR(400 MHz,DMSO-d6)δ ppm:8.95(s,1H),8.75-8.64(m,1H),8.31-8.17(m,1H),8.10-8.03(m,2H),7.80-7. 74(m,2H),7.09(s,1H),6.98-6.91(m,1H),3.77(s,2H),3.74-3.68(m,4H),2.99(br s,4H),2.66-2.52(m,4H),1.51(s,2H).

[0286] Example 061: 2-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indane-5-carboxamide; [ka] The title compound was prepared similarly to the preparation of Example 044 by replacing 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid with compound Int-18 and compound Int-13 with compound Int-1 in step 1. Example 061 (87.9 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:637.2. Example 061: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.66-10.82(m,1 H),9.71-9.97(m,2 H),8.07-8.37(m,5 H),7.82-7.96(m,2 H),7.70-7.78(m,2 H),7.40-7.51(m,1 H),7.05-7.15(m,1 H),6.87-7.00(m,1 H),3.98-4.15(m,1 H),3.63-3.79(m,4 H),3.22-3.37(m,4 H),3.08-3.18(m,2 H),2.91-3.02(m,6 H),2.00-2.10(m,2 H).

[0287] Example 062: 3-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indane-5-carboxamide; [ka]

[0288] Step 1: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-oxo-indan-5-carboxamide [ka] To a mixture of 3-oxoindane-5-carboxylic acid (200.0 mg, 1.14 mmol), compound Int-1 (477.77 mg, 1.14 mmol) and 3-methylpyridine (0.43 mL, 4.54 mmol) in MeCN (5 mL) was added MsCl (520.18 mg, 4.54 mmol) dropwise at room temperature. The mixture was heated to 45° C. and stirred for 2 h. After completion, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (FA as additive) to give compound 062a (180 mg, 27.38% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:579.2.

[0289] Step 2: tert-Butyl N-[3-[[6-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]indan-1-yl]amino]propyl]carbamate [ka] A mixture of compound 062a (100.0 mg, 0.170 mmol), tert-butyl N-(3-aminopropyl)carbamate (60.19 mg, 0.350 mmol) and titanium(IV) isopropoxide (98.18 mg, 0.350 mmol) in toluene (10 mL) was stirred at 50° C. for 15 hours. The mixture was then concentrated under reduced pressure to give a residue. Sodium cyanoborohydride (43.41 mg, 0.690 mmol) in MeOH was added to the above residue and the mixture was stirred at 50° C. for 4 hours. After completion, the mixture was concentrated under reduced pressure to give crude compound 062b (100 mg, 78.54% yield) as a yellow oil, which was used directly in the next step. MS Found (ESI + )[(M+H) + ]:737.4.

[0290] Step 3: 3-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indan-5-carboxamide [ka] A mixture of compound 062b (100.0 mg, 0.140 mmol) in DCM (5 mL) and TFA (10.0 mL) was stirred at 25° C. for 2 h. The solvent was evaporated and the residue was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (HCl as additive) to give Example 062 (1.9 mg, 2.16% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:637.3. Example 062: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.85(s,1H),9.66-9.23(m,2H),8.37(s,1H),8.20-8.05(m,4H),8.00(dd,J=1.2,7.9 Hz,3H),7.76(d,J=8.8 Hz,2H),7.09(s,1H),6.97(s,1H),4.80(br d,J=1.8 Hz,1H),3.82-3.65(m,4H),3.31-3.23(m,2H),3.23-3.09(m,2H),3.04-2.89(m,7H),2.47-2.42(m,1H),2.13-1.96(m,2H).

[0291] Example 063: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-5-[(5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl)methyl]benzamide [ka] Step 1: 5-(chloromethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-benzamide [ka] A mixture of 5-(chloromethyl)-2-methoxybenzoyl chloride (687 mg, 3.14 mmol), compound Int-1 (0.660 g, 1.57 mmol) and TEA (794 mg, 7.84 mmol) in DCM (10 mL) was stirred at room temperature for 16 h. After completion, the mixture was quenched with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude compound 063a (946 mg, 100%), which was used directly in the next step. MS Found (ESI + )[(M+H)] + :603.1

[0292] Step 2: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-5-[(5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl)methyl]benzamide [ka] A mixture of compound 063a (0.060 g, 99.4 μmol), DIPEA (38.6 mg, 298 μmol) and 5-methyloctahydropyrrolo[3,4-b]pyrrole (25.1 mg, 199 μmol) in DMF (10 mL) was stirred at 80° C. overnight. After completion, the mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (TFA as additive) to give the product (1 mg, 1.41%) as a white solid. MS Found (ESI + )[(M+H)] + :693.1 Example 063: 1H NMR(400 MHz,DMSO-d6)δ ppm 10.53(s,1H),8.00-7.96(m,2H),7.76-7.71(m,2H),7.60(br s,1H),7.48(br d,J=7.7 Hz,1H),7.14(d,J=8.7 Hz,1H),7.09(s,1H),6.97(s,1H),3.93-3.90(m,1H),3.88-3.86(m,3H),3.80-3.75(m,1H),3.73-3.70(m,4H),3.43-3.37 (m,3H),3.00-2.95(m,6H),2.80-2.72(m,4H),2.64-2.58(m,1H),2.20-2.09(m,1H),2.06-1.96(m,1H),1.56-1.46(m,1H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.55(s,3F).

[0293] Example 064: 1-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indane-5-carboxamide; [ka] The title compound was prepared similarly to the preparation of Example 062 by substituting 1-oxoindan-5-carboxylic acid for 3-oxoindan-5-carboxylic acid in step 1. Example 064 (87.9 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:637.3. Example 064: 1H NMR(400 MHz,DMSO-d6)δ ppm 10.79(s,1H),10.03-9.45(m,2H),8.15(br d,J=8.9 Hz,4H),8.04-7.92(m,3H),7.80(d,J=8.8 Hz,2H),7.12(s,1H),6.97(s,1H),5.92-5.67(m,1H),4.87(br s,1H),3.86-3.73(m,4H),3.70-3.60(m,2H),3.12(br s,2H),3.07-2.93(m,7H),2.18-2.06(m,1H),1.86-1.73(m,2H).

[0294] Example 065: 3,4-Bis(3-aminopropoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0295] Step 1: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3,4-dimethoxy-benzamide [ka] SOCl2 (4.0 mL, 0.750 mmol, 1 equiv) was added to a solution of 3,4-dimethoxybenzoic acid (274.44 mg, 1.51 mmol) in toluene (4 mL) at room temperature. It was then heated to 100 °C for 3 h. The reaction mixture was then concentrated and the residue was redissolved in 4 mL of DCM, which was added dropwise to a mixture of compound Int-1 (317 mg, 0.8 mmol) and DIPEA (0.3 mL) in DCM (10 mL) at room temperature. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (eluted with EtOAc:PE=50%) to give compound 065a (387 mg, 83.43% yield). MS observed (ESI + )[(M+H) + ]:585.1.

[0296] Step 2: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3,4-dihydroxy-benzamide [ka] To a solution of compound 065b (187.0 mg, 0.320 mmol) in DCM (4 mL) was added BBr3 (240.24 mg, 0.960 mmol) dropwise at 25° C. The resulting mixture was stirred at room temperature for 2 h. After completion, MeOH (5 mL) was added to quench the reaction. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (TFA as additive) to give compound 065b (96 mg, 48.53% yield) as a pale yellow solid. MS Found (ESI + )[(M+H) + ]:557.1.

[0297] Step 3: tert-Butyl N-[3-[2-[3-(tert-butoxycarbonylamino)propoxy]-4-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenoxy]propyl]carbamate [ka] A mixture of compound 065b (56.0 mg, 0.100 mmol), K2CO3 (20.0 mg) and tert-butyl N-(3-iodopropyl)carbamate (0.08 mL, 0.150 mmol) in DMF (1.4 mL) was stirred at 25 °C for 16 h. The mixture was then poured into water (5 mL) and extracted with EtOAc (8 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (TFA as additive) to give compound 065c (45 mg, 46.23% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:871.3.

[0298] Step 4: 3,4-bis(3-aminopropoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] Compound 065c (45.0 mg, 0.050 mmol) was dissolved in 4M TFA / dioxane (4 mL) and the mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (TFA as additive) to give Example 065 (23 mg, 65.69% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:671.3. Example 065: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.67(s,1H),8.08(d,J=8.6 Hz,2H),7.74(d,J=8.6 Hz,2H),7.70-7.59(m,2H),7.16-7.05(m,2H),6.97(s,1H),4.16(s,4H),3.72(s,4H),2.99(s,8H),2.04(s,4H). 19 F NMR(376 MHz,DMSO)δ ppm-63.46(s,3F).

[0299] Example 066: 3-[1-(3-aminopropyl)pyrrolidin-2-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 044 by replacing 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid with compound Int-19 and compound Int-13 with compound Int-1 in step 1. Example 066 (22.85 mg) was obtained. MS Found (ESI + )[(M+H) + ]:651.2. Example 066: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.06(d,J=8.8 Hz,2H),7.88(s,1H),7.84(br d,J=7.8 Hz,1H),7.76(d,J=8.8 Hz,2H),7.61-7.55(m,1H),7.53-7.46(m,1H),7.09(s,1H),6.97(s,1H),3.78-3.69(m,4H),3.00(br t,J=4.5 Hz,4H),2.60-2.55(m,2H),2.47-2.41(m,2H),2.25-2.06(m,4H),1.95-1.72(m,2H),1.67-1.47(m,3H).

[0300] Example 067: 3-[1-(3-aminopropyl)pyrrolidin-3-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 044 by replacing 6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylic acid with compound Int-20 and compound Int-13 with compound Int-1 in step 1. Example 067 (22.85 mg) was obtained. MS Found (ESI + )[(M+H) + ]:651.2. Example 067: 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.06(d,J=8.9 Hz,2H),7.86-7.79(m,1H),7.77(s,3H),7.59-7.52(m,1H),7.49-7.42(m,1H),7.13-7.05(m,1H),6.99-6.93(m,1H),3.72(br s,4H),3.02-2.96(m,4H),2.92-2.86(m,1H),2.75-2.60(m,4H),2.32-2.23(m,1H),1.87-1.72(m,1H),1.68-1.50(m,2H).

[0301] Example 068: 3-[4-(3-aminopropyl)piperazin-1-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka]

[0302] Step 1: tert-Butyl 4-[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]piperazine-1-carboxylate [ka] A mixture of 3-(4-tert-butoxycarbonylpiperazin-1-yl)benzoic acid (300.0 mg, 0.980 mmol), 3-methylpyridine (182.39 mg, 1.96 mmol) and MsCl (0.11 mL, 1.47 mmol) in MeCN (5 mL) was stirred at 25° C. for 1 h. Compound Int-1 (412.1 mg, 0.980 mmol) was then added to the mixture, which was stirred at room temperature for another 2 h. After completion, the mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (TFA as additive) to give compound 068a (210 mg, 30.24% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:709.2.

[0303] Step 2: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-piperazin-1-yl-benzamide [ka] A mixture of compound 068a (210.0 mg, 0.300 mmol) in DCM (1 mL) and TFA (1.14 mL) was stirred at 25° C. for 1 h. After completion, the mixture was concentrated under reduced pressure to give compound 068b (180 mg, 99.8% yield) as a yellow oil, which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:609.1.

[0304] Step 3: tert-Butyl N-[3-[4-[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]piperazin-1-yl]propyl]carbamate [ka] A mixture of compound 068b (190.0 mg, 0.310 mmol), KI (0.0 mL, 0.030 mmol), DIPEA (0.11 mL, 0.620 mmol) and tert-butyl N-(3-chloropropyl)carbamate (90.62 mg, 0.470 mmol) in DMF (10 mL) was stirred at 80° C. for 16 h. After completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (DCM / MeOH=10 / 1) to give compound 068c (120 mg, 50.2% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:766.2.

[0305] Step 4: 3-[4-(3-aminopropyl)piperazin-1-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A mixture of compound 068c (120.0 mg, 0.160 mmol) in DCM (1 mL) and TFA (0.6 mL) was stirred at room temperature for 1 h. After completion, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (NH4HCO3 as additive) to give Example 068 (65 mg, 62.01% yield) as a yellow solid. MS Found (ESI + )[(M+H) + ]:666.0. Example 067: 1 H NMR(400 MHz,DMSO-d6)δ ppm:8.07-8.01(m,2H),7.75(s,2H),7.43-7.39(m,1H),7.39-7.30(m,2H),7.19-7.14(m,1H),7.10-7.06(m ,1H),6.96(s,1H),3.74-3.67(m,4H),3.23-3.18(m,4H),2.97(s,4H),2.37-2.32(m,2H),1.60-1.50(m,2H).

[0306] Example 069: 4-[2-(3-aminopyrrolidin-1-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] Step 1: 4-(2-chloroethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] To a mixture of compound Int-1 (1.26 g, 2.99 mmol) and TEA (1.51 g, 2.09 mL) in DCM (20 mL) was added a solution of 4-(2-chloroethyl)benzoyl chloride (1.03 g, 5.09 mmol) in DCM (3 mL) dropwise at 0° C. The mixture was slowly warmed to room temperature and stirred for 40 min. After completion, the mixture was quenched with water (30 mL) and extracted with DCM (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=10%) to give compound 069a (0.850 g, 48%). MS Found (ESI + )[(M+H)] + :587.1

[0307] Step 2: tert-Butyl N-[1-[2-[4-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]ethyl]pyrrolidin-3-yl]carbamate [ka] A mixture of tert-butyl pyrrolidin-3-ylcarbamate (66.6 mg, 357 μmol), compound 069a (0.070 g, 119 μmol) and K2CO3 (49.4 mg, 357 μmol) in DMF (10 mL) was stirred at 80° C. for 2 h. After completion, the mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). The organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude compound 069b (87.9 mg, 100%), which was used directly in the next step. MS Found (ESI + )[(M+H)] + :736.9.

[0308] Step 3: 4-[2-(3-aminopyrrolidin-1-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A mixture of compound 069b (0.0879 g, 119 μmol) in TFA (1 mL) was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (TFA as additive) to give Example 069 (8 mg, 10.5%) as a white solid. MS Found (ESI + )[(M+H)] + :637.2 Example 069: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.59(s,1H),8.08-8.03(m,2H),7.92-7.87(m,2H),7.78-7.72(m,2H),7.44-7.39(m,2H),7.09(s,1 H),6.96(s,1H),3.75-3.69(m,4H),3.67-3.60(m,1H),3.01-2.95(m,4H),2.86-2.81(m,2H),2.78(br dd,J=3.0,8.6 Hz,1H),2.72-2.67(m,3H),2.61-2.58(m,1H),2.48-2.41(m,1H),2.20-2.04(m,1H),1.65(br d,J=4.2 Hz,1H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.53(s,3F).

[0309] Example 070: 4-[2-(7-amino-2-azaspiro[3.3]heptan-2-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 069 by replacing tert-butyl pyrrolidin-3-ylcarbamate with tert-butyl (2-azaspiro[3.3]heptan-5-yl)carbamate in step 2. Example 070 (3 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:663.1. Example 070:1 H NMR(400 MHz,DMSO-d6)δ ppm 10.62(s,1H),8.07(s,1H),8.05(s,1H),8.00-7.95(m,J=8.1 Hz,2H),7.76(d,J=8.9 Hz,2H),7.48-7.40(m,2H),7.09(s,1H),6.97(s,1H),4.14-3.92(m,4H),3. 75-3.70(m,4H),3.45(m,3H),3.01-2.96(m,4H),2.94-2.86(m,2H),2.22(br d,J=7.6 Hz,1H),2.16-2.01(m,2H),1.90(br d,J=6.6 Hz,1H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.44(s,3F).

[0310] Example 071: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl)ethyl]benzamide [ka] The title compound was prepared similarly to the preparation of compound 069b by replacing tert-butyl pyrrolidin-3-ylcarbamate with 5-methyloctahydropyrrolo[3,4-b]pyrrole in step 2. Example 071 (4 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:676.8. Example 071: 1H NMR(400 MHz,DMSO-d6)δ ppm 10.59(s,1H),8.09-8.04(m,J=8.9 Hz,2H),7.94-7.88(m,J=8.2 Hz,2H),7.77-7.73(m,J=8.9 Hz,2H),7.46-7.39(m,J=8.3 Hz,2H),7.09(s,1H),6.96(s,1H),3.75-3.69(m,4H),3.24-3.17(m,2H),3.14- 3.04(m,2H),3.01-2.97(m,4H),2.93-2.80(m,5H),2.70-2.63(m,2H),2.52(br s,3H),2.44-2.33(m,1H),2.02(br s,1H),1.56(br t,J=11.3 Hz,1H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.55(s,2F)

[0311] Example 072: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[(2S)-2-(2-aminoethyl)pyrrolidin-1-yl]methyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing the compound tert-butyl N-(3-aminopropyl)carbamate with tert-butyl N-[2-[(2R)-pyrrolidin-2-yl]ethyl]carbamate in step 1. Example 072 (31 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:651.1. Example 072: 1H NMR(400 MHz,DMSO-d6)δ ppm 8.09-8.01(m,2H),7.95-7.88(m,2H),7.77-7.70(m,2H),7.50-7.42(m,2H),7.11-7.05(m,1H),6.95(s,1H),4.08-4.02(m,1H) ),3.75-3.70(m,4H),3.26-3.21(m,1H),3.03-2.95(m,4H),2.82-2.68(m,4H),2.11-2.00(m,1H),1.95-1.75(m,2H),1.61(br s,2H),1.52-1.39(m,2H).

[0312] Example 073: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(3-morpholinopropylamino)ethyl]benzamide [ka] The title compound was prepared similarly to the preparation of compound 069b by replacing tert-butyl pyrrolidin-3-ylcarbamate with 3-morpholinopropan-1-amine in step 2. Example 073 (10 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:695.2. Example 073: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.62(s,1H),8.10-8.03(m,J=8.9 Hz,2H),7.97(d,J=8.3 Hz,2H),7.79-7.73(m,J=8.9 Hz,2H),7.48-7.40(m,2H),7.11-7.07(m,1H),6.97(s,1H),4.00(br s,2H),3.82-3.61(m,8H),3.24(br s,4H),3.07-2.95(m,10H),2.00(br s,2H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.35(s,3F).

[0313] Example 074: 4-[2-(2-amino-5-azaspiro[2.4]heptan-5-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 069 by replacing tert-butyl pyrrolidin-3-ylcarbamate with tert-butyl (5-azaspiro[2.4]heptan-1-yl)carbamate hydrochloride in step 2. Example 074 (5.5 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:663.1. Example 074: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.62(s,1H),8.09-8.04(m,J=8.8 Hz,2H),8.00-7.95(m,2H),7.78-7.74(m,J=8.8 Hz,2H),7.49-7.43(m,2H),7.09(s,1H),6.97(s,1H),3.74-3.69(m,4H),3.47-3.43(m,2H),3.25-3.15(m,2H),3.13-3.03(m,2H),2.99 (br t,J=4.6 Hz,4H),2.88-2.68(m,2H),2.59-2.52(m,1H),2.03(br s,2H),1.26-1.13(m,1H),1.11-0.97(m,1H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.42(s,3F).

[0314] Example 075: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)ethyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 069 by substituting tert-butyl pyrrolidin-3-ylcarbamate with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate in step 2. Example 075 (3 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:649.1. Example 075: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.62(s,1H),8.09-8.04(m,J=8.8 Hz,2H),7.99-7.94(m,J=8.2 Hz,2H),7.78-7.74(m,J=8.8 Hz,2H),7.50-7.44(m,J=8.3 Hz,2H),7.11-7.08(m,1H),6.98-6.96(m,1H),3.74-3.70(m,4H),3.50-3.38(m,8H),3.01-2.97(m,4H),2.60-2.52(m,4H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.31(s,3F).

[0315] Example 076: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(4-piperidylmethylamino)methyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing compound tert-butyl N-(3-aminopropyl)carbamate with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate in step 1 and replacing Int-2 with Int-3. Example 076 (10 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:651.1. Example 076: 1H NMR(CD3OD,400 MHz)δ ppm 8.01(s,1H),7.9-8.0(m,3H),7.7-7.7(m,2H),7.65(d,1H,J=7.8 Hz),7.5-7.6(m,1H),6.82(s,1H),6.73(s,1H),4.24(s,2H),3.6-3.7(m,4H),3.34(br d,2H,J=13.0 Hz),2.9-3.0(m,8H),1.9-2.1(m,3H),1.3-1.5(m,2H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.48(s,3F).

[0316] Example 077: 3-[[(3-aminocyclobutyl)methylamino]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing compound tert-butyl N-(3-aminopropyl)carbamate with tert-butyl N-[(3-aminocyclobutyl)methyl]carbamate in step 1 and replacing Int-2 with Int-3. Example 077 (10 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:637.1. Example 077: 1 H NMR(CD3OD,400 MHz)δ ppm 8.0-8.0(m,1H),7.8-8.0(m,3H),7.7-7.8(m,2H),7.6-7.7(m,1H),7.5-7.6(m,1H),6.82 (s,1H),6.73(s,1H),4.1-4.3(m,2H),3.6-3.8(m,5H),3.1-3.2(m,1H),3.09(d,1H,J=6.8 Hz),3.0-3.0(m,4H),2.4-2.6(m,2H),2.2-2.4(m,2H),1.8-2.0(m,1H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.48(s,3F).

[0317] Example 078: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(3-piperazin-1-ylpropylamino)methyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing compound tert-butyl N-(3-aminopropyl)carbamate with tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate in step 1 and replacing Int-2 with Int-3. Example 078 (12 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:680.2. Example 078: 1 H NMR(CD3OD,400 MHz)δ 8.0-8.0(m,1H),7.9-8.0(m,3H),7.7-7.7(m,2H),7.6-7.7(m,1H),7.5-7.6(m,1H),6.83(s,1H),6. 73(s,1H),4.23(s,2H),3.6-3.7(m,4H),3.1-3.2(m,4H),3.1-3.1(m,2H),3.0-3.0(m,4H),2.62(br s,4H),2.49(t,2H,J=6.6 Hz),1.8-1.9(m,2H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.49(s,3F).

[0318] Example 079: 3-[[3-(1-aminocyclopropyl)pyrrolidin-1-yl]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing tert-butyl N-(3-aminopropyl)carbamate with tert-butyl N-(1-pyrrolidin-3-ylcyclopropyl)carbamate in step 1 and replacing compound Int-2 with compound Int-3. Example 079 (46 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:663.1. Example 079: 1 H NMR(CD3OD,400 MHz)δ ppm 8.02(s,1H),7.9-8.0(m,3H),7.6-7.8(m,3H),7.5-7.6(m,1H),6.82(s,1H),6.73(s,1H),4.4-4.5(m,2H),3 .6-3.7(m,4H),3.5-3.6(m,1H),3.3-3.5(m,2H),3.0-3.0(m,4H),2.9-3.1(m,1H),2.7-2.9(m,1H),2.17(br dd,1H,J=5.1,11.7 Hz),1.6-1.8(m,1H),0.89(s,4H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.47(s,3F).

[0319] Example 080: 3-[[3-[bis(2-hydroxyethyl)amino]propylamino]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the process for preparing compound 001a by substituting 2-[3-aminopropyl(2-hydroxyethyl)amino]ethanol for compound tert-butyl N-(3-aminopropyl)carbamate and Int-3 for Int-2. Example 080 (18 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:699.1. Example 080: 1H NMR(CD3OD,400 MHz)δ ppm 8.0-8.0(m,1H),7.9-8.0(m,3H),7.7-7.7(m,2H),7.6-7.7(m,1H),7.5-7.6(m,1H),6.83(s,1H),6.73(s,1H),4.2 3(s,2H),3.6-3.7(m,4H),3.1-3.2(m,4H),3.1-3.1(m,2H),3.0-3.0(m,4H),2.64-2.60(m,4H),2.49(t,2H,J=6.6 Hz),1.8-1.9(m,2H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.49(s,3F).

[0320] Example 081: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-5-[[3-(4-piperidyl)propylamino]methyl]benzamide [ka]

[0321] Step 1: tert-Butyl 4-[3-[[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]-4-methoxy-phenyl]methylamino]propyl]piperidine-1-carboxylate [ka] A mixture of compound 056a (60 mg, 99.4 μmol), DIPEA (38.6 mg, 298 μmol) and tert-butyl 4-(3-aminopropyl)piperidine-1-carboxylate (48.2 mg, 199 μmol) in THF (5 mL) was stirred at 80° C. overnight. The mixture was diluted with EtOAc (20 mL) and washed with water (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude compound 081a (80 mg, 100%), which was used directly in the next step. MS observed (ESI + )[(M+H)] +:809.0

[0322] Step 2: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-5-[[3-(4-piperidyl)propylamino]methyl]benzamide [ka] A mixture of compound 081a (80 mg, 98.8 μmol) in TFA (1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by HPLC (TFA as additive) to give Example 081 (3 mg, 4%) as a white solid. MS Found (ESI + )[(M+H)] + :709.1. Example 081: 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.57-10.53(m,1H),8.73-8.69(m,1H),8.01-7.95(m,2H),7.78-7.74(m,4H),7.11-7.07(m,1H),6.99-6.96(m,1H),4.17-4.14(m,1H) ,3.92-3.91(m,3H),3.73-3.71(m,4H),3.00-2.99(m,4H),2.89-2.86(m,4H),1.79-1.76(m,2H),1.62-1.56(m,5H),1.27-1.23(m,5H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.46(s,3F).

[0323] Example 082: 3-[[1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing compound tert-butyl N-(3-aminopropyl)carbamate with tert-butyl N-(3-azabicyclo[3.1.0]hexan-1-ylmethyl)carbamate in step 1 and compound Int-2 with compound Int-3. Example 082 (26.1 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:649.2. Example 082: 1 H NMR(CD3OD,400 MHz)δ 8.0-8.0(m,1H),7.96(d,1H,J=7.8 Hz),7.9-7.9(m,2H),7.7-7.7(m,2H),7.64(d,1H,J=7.9 Hz),7.5-7.6(m,1H),6.82(s,1H),6.73(s,1H),4.3-4.5(m,2H),3.6-3.7(m,4H),3.4-3.6(m,4H),3.32(d,1H,J=13.8 Hz),2.9-3.1(m,5H),1.89(br s,1H),0.9-1.3(m,2H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.48(s,3F).

[0324] Example 083: (2R)-2-amino-4-[[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methylamino]butanoic acid; [ka] The title compound was prepared similarly to the preparation of Example 001 by replacing compound tert-butyl N-(3-aminopropyl)carbamate with (2R)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid and compound Int-2 with compound Int-3 in step 1. Example 084 (2 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:655.1. Example 083: 1H NMR(CD3OD,400 MHz)δ ppm 8.11(t,1H,J=1.5 Hz),8.0-8.1(m,3H),7.8-7.9(m,2H),7.7-7.8(m,1H),7.6-7.7(m,1H),6.94(s,1H),6.85(s,1H),4.36(s,2H),4.09(dd,1H,J=5.2,8.4 Hz),3.7-3.8(m,4H),3.3-3.5(m,2H),3.1-3.2(m,4H),2.2-2.5(m,2H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.49(s,3F).

[0325] Example 084: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[(2-oxooxazolidin-4-yl)methylamino]methyl]benzamide [ka] The title compound was prepared similarly to the preparation of Compound 001a by replacing tert-butyl N-(3-aminopropyl)carbamate with 4-(aminomethyl)oxazolidin-2-one in step 1 and replacing Compound Int-2 with Compound Int-3. Example 084 (20 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:653.1. Example 084: 1 H NMR(CD3OD,400 MHz)δ ppm 7.8-8.0(m,2H),7.7-7.8(m,2H),7.7-7.7(m,2H),7.3-7.5(m,2H),6.83(s,1H),6.7 3(s,1H),4.3-4.4(m,2H),3.6-3.7(m,5H),3.3-3.4(m,3H),3.10(dd,1H,J=5.7,9.1 Hz),3.0-3.0(m,4H). 19 F NMR(376 MHz,CD3OD)δ ppm-66.49(s,3F).

[0326] Example 085: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[(5-oxopyrrolidin-3-yl)methylamino]methyl]benzamide [ka] The title compound was prepared similarly to the preparation of Compound 001a by replacing Compound tert-butyl N-(3-aminopropyl)carbamate with 4-(aminomethyl)pyrrolidin-2-one and Compound Int-2 with Compound Int-3 in step 1. Example 085 (32 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:651.2. Example 085: 1 H NMR(CD3OD,400 MHz)δ ppm 8.01(s,1H),7.9-8.0(m,1H),7.9-7.9(m,2H),7.7-7.8(m,2H),7.65(d,1H,J=7.8 Hz),7.5-7.6(m,1H),6.83(s,1H),6.73(s,1H),4.24(s,2H),3.6-3.7(m,4H),3.50(dd,1H,J=7.9,10.1 Hz),3.15(dd,2H,J=3.6,7.3 Hz),3.08(dd,1H,J=6.6,10.1 Hz),3.0-3.0(m,4H),2.79(quind,1H,J=7.7,15.3 Hz),2.44(dd,1H,J=8.8,16.9 Hz),2.12(dd,1H,J=7.7,16.9 Hz). 19 F NMR(376 MHz,CD3OD)δ ppm-66.49(s,3F).

[0327] Example 086: N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[[3-(dimethylamino)-3-oxo-propyl]amino]methyl]benzamide [ka] The title compound was prepared similarly to the preparation of compound 001a by substituting compound tert-butyl N-(3-aminopropyl)carbamate with 3-amino-N,N-dimethylpropanamide and compound Int-2 with compound Int-3. Example 086 (32 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:653.1. Example 086: 1 H NMR(CD3OD,400 MHz)δ ppm 8.00(s,1H),7.9-8.0(m,3H),7.71(d,2H,J=8.8 Hz),7.65(d,1H,J=7.8 Hz),7.5-7.6(m,1H),6.82(s,1H),6.73(s,1H),4.26(s,2H),3.6-3.7(m,4H), 3.0-3.0(m,4H),2.94(s,3H),2.86(s,3H),2.8-2.8(m,2H),2.73(t,2H,J=6.2 Hz). 19 F NMR(376 MHz,CD3OD)δ ppm-66.48(s,3F). Example 087: 5-(3,3a,4,5,6,6a-Hexahydro-2H-pyrrolo[3,4-b]pyrrol-1-ylmethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-benzamide [ka] The title compound was prepared similarly to the preparation of Example 081 by replacing tert-butyl 4-(3-aminopropyl)piperidine-1-carboxylate with tert-butyl 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[2,3-c]pyrrole-5-carboxylate in step 1. Example 087 (20 mg) was obtained as a white solid. MS Found (ESI + )[(M+H) + ]:679.0. Example 087: 1H NMR(400 MHz,DMSO-d6)δ ppm 10.46(s,1H),7.91(d,J=8.7 Hz,2H),7.66(d,J=8.9 Hz,2H),7.49(d,J=2.1 Hz,1H),7.38(dd,J=2.2,8.4 Hz,1H),7.06(d,J=8.6 Hz,1H),7.02(s,1H),6.90(s,1H),3.83-3.76(m,4H),3.68-3.61(m,4H),3.38-3.36(m,2H),3.13-3.02 (m,3H),2.93-2.89(m,4H),2.79-2.63(m,3H),2.12-1.99(m,1H),1.96-1.85(m,1H),1.43-1.32(m,1H). 19 F NMR(376 MHz,DMSO-d6)δ ppm-68.53(s,3F).

[0328] Example 088: 2-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] Step 1: 2-(chloromethyl)-N-[2-(chloromethyl)benzoyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] To a mixture of compound Int-1 (400 mg, 950 μmol) and TEA (288 mg, 2.85 mmol) in DCM (5 mL), 2-(chloromethyl)benzoyl chloride (216 mg, 1.14 mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2 h. After completion, the mixture was quenched with saturated aqueous NaHCO3 (40 mL) and extracted with DCM (30 mL x 3). The combined organic layer was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluted with EtOAc:PE=10%) to give compound 088a (200 mg, 29% yield) as a white solid. MS Found (ESI + )[(M+H) + ]:725.2.

[0329] Step 2: tert-Butyl N-[3-[[2-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methylamino]propyl]carbamate [ka] A mixture of compound 089a (120 mg, 165 μmol), tert-butyl (3-aminopropyl)carbamate (43.2 mg, 248 μmol) and DIEA (64 mg, 496 μmol) in THF (5 mL) was heated at 70° C. for 10 h. After completion, the mixture was diluted with DCM (20 mL) and washed with aqueous NaHCO3 (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude compound 088b (118 mg, 100% yield), which was used directly in the next step. MS observed (ESI + )[(M+H) + ]:711.2.

[0330] Step 3: 2-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide [ka] A crude solution of compound 088 (70 mg, 98.4 μmol) in TFA (10 mL) was stirred at room temperature for 2 h. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (TFA as additive) to give example 088 (10 mg, 15.8% yield). MS observed (ESI + )[(M+H) + ]:611.1. Example 088: 1 H NMR(CD3OD,400 MHz)δ ppm 7.9-7.9(m,2H),7.8-7.9(m,1H),7.7-7.7(m,2H),7.5-7.6(m,3H),6.83(s,1H),6.74(s, 1H),4.20(s,2H),3.6-3.7(m,4H),3.1-3.2(m,2H),2.9-3.0(m,6H),2.05(quin,2H,J=7.7 Hz). 19 F NMR(376 MHz,CD3OD)δ ppm-66.48(s,3F).

[0331] Compound F-1, which has been disclosed in the literature (Bioorganic Chemistry (102), 2020, 104055) and has been reported to have LPS synthesis pathway inhibitory activity and exhibit antibiotic activity against efflux-deficient Escherichia coli strains, was selected as a reference compound in the present invention. [ka]

[0332] Biological Examples Example 089: Minimum Inhibitory Concentration Protocol (MIC) Assay: The antibacterial activity of the compounds of the present invention was evaluated against the commonly used quality control strain Escherichia coli ATCC 25922 and rifampin-resistant mutant strain Klebsiella pneumonia ATCC 43816. Both were originally derived from human clinical samples and are available from ATCC (American Type Culture Collection). The in vitro potency of the compounds to inhibit the growth of E. coli (ATCC 25922) and Klebsiella pneumoniae (ATCC 43816) was evaluated by MIC (minimum inhibitory concentration) broth dilution method. Specifically, compound dilutions were prepared from 10 mM DMSO stock solutions as follows: i) serial 2-fold dilutions in 20 μL DMSO were prepared in a master plate (Greiner, Cat#: 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).

[0333] Vials of each test organism were kept frozen in the vapor phase of a liquid nitrogen freezer. Single-use frozen vials of two strains, E. coli ATCC 25922 (KWIKSTIK, 0335K) and K. pneumoniae ATCC 43816, with the desired CFU / mL were removed from the freezer, thawed at room temperature, and diluted in cation-adjusted Mueller-Hinton broth (CAMHB) to 5 × 10 5 A final inoculum of 100 CFU / mL was achieved. 90 μL of broth containing bacteria was dispensed into the assay plate containing pre-aliquoted compound dilutions and mixed 5 times by pipetting.

[0334] 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 with the aid of a magnifying glass and recorded.

[0335] [Table 1]

[0336] Example 090: 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 2 below. (Human microsomal clearance: <7 mL / min / kg (low); 7-16.2 mL / min / kg (medium); >16.2 mL / min / kg (high)

[0337] [Table 2]

Claims

1. Formula (I), 【Chemistry 1】 (In the formula, R １ is COR ９ and R ９ is ((hydroxy C １－６ Alkyl)amino)C １－６ Alkyl, 1-oxa-2,9-diazaspiro[4.5]dec-2-enyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, C １－６ alkyl-substituted 4,6-dihydropyrrolo[3,4-c]pyrazolyl; 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, Amino or Amino C １－６ alkylamino substituted indanyl; Isoindolinyl, Piperazinyl C １－６ Alkyl, pyrazolo[1,5-a]pyrimidinyl, Amino C １－６ Alkyl, Azetidinyl, C １－６ pyrazolyl substituted once or twice with substituents independently selected from alkyl and carboxy; (Amino C １－６ Alkylamino)C １－６ alkyl-substituted pyridinyl, or ((amino(carboxy)C １－６ Alkyl)amino)C １－６ Alkyl, ((amino C １－６ alkyl)-3-azabicyclo[3.1.0]hexanyl)C １－６ Alkyl, ((amino C １－６ Alkyl)pyrrolidinyl)C １－６ Alkyl, ((amino C ３－７ Cycloalkyl)C １－６ Alkylamino)C １－６ Alkyl, ((amino C3-7 cycloalkyl)pyrrolidinyl)C １－６ Alkyl, ((oxooxazolidinyl)C １－６ Alkylamino)C １－６ Alkyl, ((oxopyrrolidinyl)C １－６ Alkylamino)C １－６ Alkyl, ((piperidinyl)C １－６ Alkylamino)C １－６ Alkyl, (3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrolyl)C １－６ Alkyl, (3,6-diazabicyclo[3.1.1]heptanyl)C １－６ Alkyl, (amino-2-azaspiro[3.3]heptanyl)C １－６ Alkyl, (amino-5-azaspiro[2.4]heptanyl)C １－６ Alkyl, (amino C １－６ alkyl)piperazinyl, (amino C １－６ alkyl)pyrrolidinyl, (amino C １－６ Alkylamino)C １－６ Alkyl, (aminopyrrolidinyl)C １－６ Alkyl, (C １－６ Alkyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrolyl)C １－６ Alkyl, (diamino C １－６ Alkylcarbonyl)amino, (morpholinyl C １－６ Alkylamino)C １－６ Alkyl, (piperazinyl C １－６ Alkylamino)C １－６ Alkyl, (piperidinyl C １－６ Alkylamino)C １－６ Alkyl, [((C １－６ Alkyl) ２ Aminocarbonyl C １－６ alkyl)amino]C １－６ Alkyl, [((hydroxy C １－６ Alkyl) ２ Amino) C １－６ Alkylamino]C １－６ Alkyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, amino C １－６ Alkoxy, Amino C １－６ Alkyl, aminopyrrolidinyl, azetidinyl C １－６ Alkoxy, Azetidinyl C １－６ Alkylamino, C １－６ Alkylcarbonyloxy, C １－６ phenyl substituted once or twice with substituents independently selected from alkoxy, carboxy, hydroxy and piperazinyl; R ２ is H; R ３ is H, hydroxy or C １－６ is alkoxy; or R ２ and R ３ together with the atom to which they are attached form pyrrolidinyl; R ４ is H, hydroxy or C １－６ is alkoxy; R ５ is H or C １－６ is alkyl; R ６ is H or C １－６ is alkyl; or R ５ and R ６ together with the atoms to which they are attached, C ３－７ Forming a cycloalkyl; R ７ is halogen, cyano, haloC １－６ Alkyl or C １－６ alkoxycarbonyl; R ８ is H, halogen, cyano, amino, C ３－７ Cycloalkoxy, C １－６ Alkyl, C １－６ Alkoxy or haloC １－６ is alkyl; Y is CH or N; A is O, N(CN) or N(C １－６ alkyl); Q is CH or N; X is CH or N; M is N or CR １０ and R １０ is H, halogen, C １－６ Alkyl or C ３－７ is cycloalkyl; However, Q, X and M are not simultaneously N. or a pharma- ceutically acceptable salt thereof.

2. R １ COR ９ and R ９ is 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, Amino or Amino C １－６ alkylamino substituted indanyl; Isoindolinyl, pyrazolo[1,5-a]pyrimidinyl, (Amino C １－６ Alkylamino)C １－６ alkyl-substituted pyridinyl, or ((Amino C １－６ alkyl)-3-azabicyclo[3.1.0]hexanyl)C １－６ Alkyl, (amino C １－６ alkyl)pyrrolidinyl, (amino C １－６ Alkylamino)C １－６ Alkyl, Amino C １－６ Alkoxy, Amino C １－６ Alkyl, aminopyrrolidinyl, azetidinyl C １－６ 2. The compound of claim 1 which is phenyl substituted once or twice with substituents independently selected from alkoxy, carboxy and piperazinyl.

3. R １ COR ９ and R ９ but 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, aminoindanyl, (3-aminopropylamino)indanyl, isoindolinyl, pyrazolo[1,5-a]pyrimidinyl, ((3-aminopropylamino)methyl)pyridinyl, ((3-aminopropylamino)methyl)phenyl, ((3-aminopropylamino)ethyl)phenyl, carboxyphenyl, (aminoethoxy)phenyl, (azetidin-3-ylmethoxy)phenyl, (aminopyrrolidin-1-yl)phenyl, (aminoethyl)phenyl, (piperazin-1-yl)phenyl, (3-aminopropoxy) ２ 3. The compound according to claim 1 or 2, which is phenyl, (1-(3-aminopropyl)pyrrolidin-2-yl)phenyl, (1-(3-aminopropyl)pyrrolidin-3-yl)phenyl or [[1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl]phenyl.

4. R ２ is H; R ３ is H; or R ２ and R ３ A compound according to any one of claims 1 to 3, wherein together with the atom to which they are attached form pyrrolidinyl.

5. R ４ is H; R ５ is H; R ６ The compound according to any one of claims 1 to 4, wherein is H.

6. R ７ is halogen or haloC １－６ The compound according to any one of claims 1 to 5, which is alkyl.

7. R ７ The compound according to any one of claims 1 to 6, wherein is bromo, trifluoromethyl or difluoroethyl.

8. R ８ is halogen or C １－６ The compound according to any one of claims 1 to 7, which is alkyl.

9. R ８ The compound according to any one of claims 1 to 8, wherein is chloro or methyl.

10. The compound according to any one of claims 1 to 9, wherein Y is CH.

11. The compound according to any one of claims 1 to 10, wherein A is O.

12. The compound according to any one of claims 1 to 11, wherein X is N.

13. The compound according to any one of claims 1 to 12, wherein M is CH.

14. R １ COR ９ and R ９ is 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, Amino or Amino C １－６ alkylamino substituted indanyl; Isoindolinyl, pyrazolo[1,5-a]pyrimidinyl, (Amino C １－６ Alkylamino)C １－６ alkyl-substituted pyridinyl, or ((Amino C １－６ alkyl)-3-azabicyclo[3.1.0]hexanyl)C １－６ Alkyl, (amino C １－６ alkyl)pyrrolidinyl, (amino C １－６ Alkylamino)C １－６ Alkyl, Amino C １－６ Alkoxy, Amino C １－６ Alkyl, aminopyrrolidinyl, azetidinyl C １－６ phenyl substituted once or twice with substituents independently selected from alkoxy, carboxy and piperazinyl; R ２ is H; R ３ is H; or R ２ and R ３ together with the atom to which they are attached form pyrrolidinyl; R ４ is H; R ５ is H; R ６ is H; R ７ is halogen or haloC １－６ is alkyl; R ８ is halogen or C １－６ is alkyl; Y is CH; A is O; Q is CH or N; X is N; M is CH; 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

15. R １ COR ９ and R ９ but 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, aminoindanyl, (3-aminopropylamino)indanyl, isoindolinyl, pyrazolo[1,5-a]pyrimidinyl, ((3-aminopropylamino)methyl)pyridinyl, ((3-aminopropylamino)methyl)phenyl, ((3-aminopropylamino)ethyl)phenyl, carboxyphenyl, (aminoethoxy)phenyl, (azetidin-3-ylmethoxy)phenyl, (aminopyrrolidin-1-yl)phenyl, (aminoethyl)phenyl, (piperazin-1-yl)phenyl, (3-aminopropoxy) ２ phenyl, (1-(3-aminopropyl)pyrrolidin-2-yl)phenyl, (1-(3-aminopropyl)pyrrolidin-3-yl)phenyl or [[1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl]phenyl; R ２ is H; R ３ is H; or R ２ and R ３ together with the atom to which they are attached form pyrrolidinyl; R ４ is H; R ５ is H; R ６ is H; R ７ is bromo, trifluoromethyl or difluoroethyl; R ８ is chloro or methyl; Y is CH; A is O; Q is CH or N; X is N; M is CH; 15. The compound of claim 14 or a pharma- ceutically acceptable salt thereof.

16. 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[5-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[3-chloro-5-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[2-chloro-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[2-amino-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-(4-bromo-6-chloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[5-cyclopropyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-(cyclopropoxy)-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-ethoxy-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-ethyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[5-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-(4,5-dichloro-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[4-cyano-6-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[6-cyano-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopropylamino)ethyl]-N-[4-[4-[6-chloro-4-(1,1-difluoroethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; Methyl 2-[4-[4-[[3-[(3-aminopropylamino)methyl]benzoyl]amino]phenyl]sulfonylpiperazin-1-yl]-6-chloro-pyridine-4-carboxylate; 3-[(3-aminopropylamino)methyl]-N-[4-[4-(6-chloro-4-cyano-2-pyridyl)piperazin-1-yl]sulfonylphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2-methyl-piperazin-1-yl]sulfonylphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-3-methyl-piperazin-1-yl]sulfonylphenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[[5-[6-chloro-4-(trifluoromethyl)-2-pyridyl]-2,5-diazabicyclo[4.2.0]octan-2-yl]sulfonyl]phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[2-(3-aminopropylamino)ethyl]-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-cyano-sulfonimidoyl]phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[S-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]-N-methyl-sulfonimidoyl]phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-methoxy-phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3-hydroxy-phenyl]benzamide; 4-[(3-aminopropylamino)methyl]-N-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-pyridyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-methoxy-phenyl]benzamide; 3-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2-hydroxy-phenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide; [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-pyrazolo[1,5-a]pyrimidin-3-yl-methanone; 4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]-2-methyl-pyrazole-3-carboxylic acid; [1-(azetidin-3-yl)pyrazol-4-yl]-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]methanone; [1-(3-aminopropyl)pyrazol-4-yl]-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]methanone; [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methanone; [5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-(1-oxa-2,9-diazaspiro[4.5]dec-2-en-3-yl)methanone; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-piperazin-1-yl-acetamide; 1-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindolin-1-yl]-2-(2-hydroxyethylamino)ethanone; 2-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]benzoic acid; [2-acetoxy-4-[5-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylindoline-1-carbonyl]phenyl]acetate; N-[4-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide; N-[4-[4-[6-methyl-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]isoindoline-5-carboxamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide; 3-(2-aminoethoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-(azetidin-3-ylmethylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-(azetidin-3-ylmethoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(3R)-3-aminopyrrolidin-1-yl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[3,6-diazabicyclo[3.2.0]heptan-3-yl]benzamide; 3-(2-aminoethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-piperazin-1-yl-benzamide; 2-amino-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indane-5-carboxamide; 5-(aminomethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-hydroxy-benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-(2,4-diaminobutanoylamino)benzamide; 4-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-2-carboxamide; 6-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-2-carboxamide; 5-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]pyridine-3-carboxamide; 2-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indane-5-carboxamide; 3-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indane-5-carboxamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-5-[(5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl)methyl]benzamide; 1-(3-aminopropylamino)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]indane-5-carboxamide; 3,4-bis(3-aminopropoxy)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[1-(3-aminopropyl)pyrrolidin-2-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[1-(3-aminopropyl)pyrrolidin-3-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[4-(3-aminopropyl)piperazin-1-yl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(3-aminopyrrolidin-1-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 4-[2-(7-amino-2-azaspiro[3.3]heptan-2-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl)ethyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[[(2S)-2-(2-aminoethyl)pyrrolidin-1-yl]methyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(3-morpholinopropylamino)ethyl]benzamide; 4-[2-(2-amino-5-azaspiro[2.4]heptan-5-yl)ethyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-4-[2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)ethyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(4-piperidylmethylamino)methyl]benzamide; 3-[[(3-aminocyclobutyl)methylamino]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[(3-piperazin-1-ylpropylamino)methyl]benzamide; 3-[[3-(1-aminocyclopropyl)pyrrolidin-1-yl]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; 3-[[3-[bis(2-hydroxyethyl)amino]propylamino]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-5-[[3-(4-piperidyl)propylamino]methyl]benzamide; 3-[[1-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl]methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; (2R)-2-amino-4-[[3-[[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]carbamoyl]phenyl]methylamino]butanoic acid; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[(2-oxooxazolidin-4-yl)methylamino]methyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[(5-oxopyrrolidin-3-yl)methylamino]methyl]benzamide; N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-3-[[[3-(dimethylamino)-3-oxo-propyl]amino]methyl]benzamide; 5-(3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,4-b]pyrrol-1-ylmethyl)-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]-2-methoxy-benzamide; and 2-[(3-aminopropylamino)methyl]-N-[4-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonylphenyl]benzamide; or a pharma- ceutically acceptable salt thereof.

17. A process for preparing a compound according to any one of claims 1 to 16, comprising the steps of: a) a compound of formula (IX) 【Chemistry 2】 and a compound of formula (XII) 【Chemistry 3】 via a coupling reaction or an acylation reaction between 【Chemistry 4】 forming b) Formula (XIV), 【Chemistry 5】 via hydrolysis of a compound of formula (Ib) 【Chemistry 6】 forming c) A compound of formula (XVIII) 【Chemistry 7】 and a compound of formula (II) 【Chemistry 8】 via nucleophilic substitution between 【Chemistry 9】 forming Including any of the following: In step a), the coupling reaction is carried out in the presence of a condensation reagent, said condensation reagent being TCFH; said acylation reaction is carried out in the presence of a base, said base being TEA; In step b), the hydrolysis reaction is carried out in the presence of a base, the base being LiOH; In step c), the nucleophilic substitution reaction is carried out in the presence of a base, and the base is Cs ２ CO ３ and In the formula, B １ is a halogen; １ is a protecting group such as a tert-butoxycarbonyl or benzyloxycarbonyl group; PG ２ is a protecting group such as an acetyl group; R ａ is halogen or OH; R ｂ is C such as methyl or ethyl １－６ alkyl; R １１ is pyrazolylene, phenylene or amino C １－６ Alkylamino C １－６ alkylene; R ２ ~R ９ , Y, A, Q, X and M are defined as in any one of claims 1 to 15.

18. 17. 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 according to any one of claims 1 to 16 and a therapeutically inert carrier.

20. Use of a compound according to any one of claims 1 to 16 for the inhibition of LpxH.

21. Use of a compound according to any one of claims 1 to 16 for the treatment or prevention of a bacterial infection, in particular a bacterial infection, wherein said bacteria is a Gram-negative bacteria.

22. Use of a compound according to any one of claims 1 to 16 for the preparation of a medicament for the treatment or prevention of a bacterial infection, in particular a bacterial infection, wherein said bacteria is a Gram-negative bacteria.

23. 23. Use of a compound according to claim 21 or 22, wherein the gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

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

25. 17. A compound or a pharma- ceutically acceptable salt according to any one of claims 1 to 16 for use in the treatment or prophylaxis of a bacterial infection, particularly a bacterial infection wherein the bacterium is a Gram-negative bacterium.

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

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

28. 18. A compound or a pharma- ceutically acceptable salt according to any one of claims 1 to 16 when prepared according to the process of claim 17.

29. A method for treating or preventing a bacterial infection, in particular a bacterial infection wherein said bacteria is a gram-negative bacteria, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound according to any one of claims 1 to 16.

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