Novel compounds for the treatment of bacterial infections

Abstract

The invention relates to a compound of formula (I) wherein R1-R6, and A1-A7 are as defined in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P39698

[0003] Novel compounds for the treatment of bacterial infections

[0004] The present invention relates to organic compounds useful for the treatment and / or prevention of bacterial infections in a mammal. Specifically these molecules can inhibit the LPS synthesis pathway, in particular to inhibit LpxH, and are useful for treating bacterial infections.

[0005] The invention relates in particular to a compound of formula (I) wherein

[0006] A1is -N- or -CH-;

[0007] A2is -N- or -CH-;

[0008] A3is -N- or -CH-;

[0009] A4is -N- or -CH-;

[0010] A5is -N- or -CR7-;

[0011] A6is -N- or -CR8-;

[0012] A7is -N- or -CR9-;

[0013] Ri is alkyl;

[0014] R2 is alkyl;

[0015] R3 is hydrogen, heterocycloalkyl or aminoalkyl;

[0016] R4 is hydrogen or halogen; Re is hydrogen or halogen; and

[0017] Rs, R7, Rs and R9 are all independently selected from hydrogen, halogen, hydroxyalkoxy, hydroxyl, haloalkoxy, alkoxycarbonyl, alkoxy and nitro; or a pharmaceutically acceptable salt thereof.

[0018] The intensive use of antibiotics has exerted a selective evolutionary pressure on microorganisms to produce genetically based resistance mechanisms. Modern medicine and socioeconomic behaviour exacerbate the problem of resistance development by creating slow growth situations for pathogenic microbes, e.g. in artificial joints, and by supporting long-term host reservoirs, e.g. in immune-compromised patients. In hospital settings, an increasing number of strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., Enterobacteriaceae such as Klebsiella pneumonia, Acinetobacter baumannii and Pseudomonas aeruginosa, major sources of infections, are becoming multi-drug resistant and therefore difficult to treat. This is particularly the case for Gram-negative organisms where the situation is getting worrisome since no novel agents with a differentiated mechanism of action have been approved for decades. Therefore, there is an important medical need for new antibacterial compounds addressing Gram-negative resistant bacteria, in particular third generation cephalosporins- and carbapenem-resistant Enterobacteriaceae and multi-drug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. One way to tackle the problem of cross-resistance to established classes of antibiotics is to inhibit an essential protein or function not targeted by current antibiotics.

[0019] Gram-negative bacteria are unique in that their outer membrane contains Lipopolysaccharide (LPS), which is crucial for maintaining membrane integrity, and is 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 bacteria. Lipid A is synthesized on the cytoplasmic surface of the bacterial inner membrane via a pathway that consists of nine different enzymes. These enzymes are highly conserved in most Gram-negative bacteria. LpxH, a calcineurin-like phosphatase (CLP), catalyzes the hydrolysis of LTDP-2,3-diacyl-glucosamine (UDP-DAGn) to yield Lipid X and UMP. LpxH has no mammalian homologue, making it a good target for the development of novel antibiotics targeting Gram-negative bacteria. The term "alkyl", alone or in combination, denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms, in particular of 1 to 7 carbon atoms, more particular of 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, or tert-butyl. Methyl, ethyl and propyl are particular examples of “alkyl”.

[0020] The term "heterocycloalkyl", alone or in combination, denotes a monovalent saturated or partly unsaturated mono-, bi- or tricyclic ring system of 4 to 12 ring atoms, in particular 5 to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having one or two ring atoms in common. “Hetercycloylkyl” may comprise a carbonyl group, wherein the carbon of the carbonyl group is part of the ring system. The ring system can be attached to the remaining compound via an atom selected from C, N, S and O, in particular via a N atom (“N-heterocycloalkyl). Examples of “heterocycloalkyl” include, but are not limited to, morpholino, morpholin-4-yl, pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin-3-yl, piperidinyl, 1 -piperidyl, 4-piperidyl, 2-oxopyrrolidin-l-yl, piperazinyl, piperazin- 1-yl, azetidinyl, azetidin-l-yl, azeti din-3 -yl, azetidin-l-yl or 5- azoniaspiro[2.4]heptane. A particular examples is piperazinyl.

[0021] The term “alkoxy” or “alkyloxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy. Particular examples of “alkoxy” are methoxy, ethoxy and n-propoxy.

[0022] The term “oxy”, alone or in combination, signifies the -O- group.

[0023] The terms “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to four halogens, i.e. one, two, three or four halogens.

[0024] The term “haloalkoxy”, alone or in combination, denotes an alkoxy group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. A particular “haloalkoxy” is difluoromethoxy. The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group.

[0025] The term “aminoalkyl”, alone or in combination, signifies an amino group linked to an alkyl group, wherein the alkyl group is further linked to the compound as indicated. The term “diaminoalkyl” denotes two amino groups linked to an alkyl group, wherein the alkyl group is further linked to the compound as indicated. A particular “aminoalkyl” is aminomethyl.

[0026] The term “alkoxycarbonyl”, alone or in combination, is an alkoxy group linked to a -C(O)- group, wherein the carbonyl group is further linked to the compound as indicated. A particular “alkoxycarbonyl” is methoxy carbonyl.

[0027] The term “nitro” signifies a -NO2 group.

[0028] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, 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, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes 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, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. The term “pharmaceutically acceptable salts” includes but is not limited to the salts that have been exemplified herein. The term “pharmaceutically acceptable salts” includes those salts wherein the counter-ion has been exchanged by an otherwise suitable counter-ion, in particular by a suitable anion.

[0029] The term “compound(s) of this invention” and “compound(s) of the present invention” refers to compounds of formula (I) and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

[0030] Tautomeric forms, i.e. structural isomers which interconvert with the compound of formula (I), in particular in solution, may in some instances exist and are to be understood as being included in the invention.

[0031] If one of the starting materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyl oxy (Cbz) and p- methoxybenzyloxycarbonyl (Moz).

[0032] The compound of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0033] The term “asymmetric carbon atom” means a carbon atom with four different substituents.

[0034] According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration. Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates, wherever applicable, of the compound of formula (I).

[0035] If desired, racemic mixtures of the compound of the invention may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

[0036] In the embodiments, where an optically pure enantiomer is provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer of the compound. A chirally pure or chirally enriched compound may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

[0037] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Particular examples of such isotopes are2H,3H,13C,14C and18F. For example the structures wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by a13C- or14C- enriched carbon are within the scope of this invention.

[0038] The invention thus relates to the following numbered aspects:

[0039] 1. A compound of formula (I)

[0040] wherein

[0041] A1is -N- or -CH-;

[0042] A2is -N- or -CH-;

[0043] A3is -N- or -CH-;

[0044] A4is -N- or -CH-;

[0045] A5is -N- or -CR7-;

[0046] A6is -N- or -CR8-;

[0047] A7is -N- or -CR9-;

[0048] Ri is alkyl;

[0049] R2 is alkyl;

[0050] R3 is hydrogen, heterocycloalkyl or aminoalkyl;

[0051] R4 is hydrogen or halogen;

[0052] Re is hydrogen or halogen; and

[0053] Rs, R7, R8and R9 are all independently selected from hydrogen, halogen, hydroxyalkoxy, hydroxyl, haloalkoxy, alkoxycarbonyl, alkoxy and nitro; or a pharmaceutically acceptable salt thereof. A compound according to aspect 1, wherein A3and A4are both -CH-. A compound according to aspect 1 or 2, wherein Ri and R2 are both methyl. A compound according to any one of aspects 1 to 3, wherein R3 is hydrogen, piperazinyl or aminomethyl. A compound according to any one of aspects 1 to 4, wherein R4 and Re are both independently selected from hydrogen or fluoro. A compound according to any one of aspects 1 to 5, R4 and Re are both hydrogen. A compound according to any one of aspects 1 to 6, wherein R5, R7, Rs and R9 are all independently selected from hydrogen, chloro, fluoro, hydroxypropoxy, hydroxyethoxy, hydroxy, difluoromethoxy, methoxycarbonyl, methoxy and nitro; A compound according to any one of aspects 1 to 7, wherein R5, R7, Rs and R9 are all independently selected from hydrogen, chloro, fluoro, hydroxypropoxy, hydroxyethoxy, hydroxy, difluoromethoxy, methoxycarbonyl, methoxy and nitro, provided that at least two of R5, R7, R8and R9are hydrogen. A compound selected from

[0054] N-[4-[(4-cyclopentylidene-l-piperidyl)sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide;

[0055] 2-[methyl(methylsulfonyl)amino]-N-[5-[[4-[(2-nitrophenyl)methylene]-l- piperidyl]sulfonyl]-2-pyridyl]-5-piperazin-l-yl-pyridine-3-carboxamide;

[0056] N-(5-((4-((2-chloro-5-fluoropyridin-3-yl)methylene)piperidin-l-yl)sulfonyl)pyridin-2-yl)-

[0057] 3-(N-methylmethylsulfonamido)-6-(piperazin-l-yl)pyridazine-4-carboxamide;

[0058] N-[5-[[4-[(5-fluoro-2-methoxy-3-pyridyl)methylene]-l-piperidyl]sulfonyl]-2-pyridyl]-3- [methyl(methylsulfonyl)amino]-6-piperazin-l-yl-pyridazine-4-carboxamide;

[0059] 2-(N-methylmethylsulfonamido)-N-(6-((4-(2-nitrobenzylidene)piperidin-l- yl)sulfonyl)pyridazin-3-yl)-5-(piperazin-l-yl)nicotinamide;

[0060] N-[4-[4-[Fluoro-(2-nitrophenyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0061] N-[4-[[4-[(5-chloro-3-pyridyl)methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide;

[0062] N-[4-[4-[(4-chloro-2-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide; N-[4-[4-(5-fluoro-2-nitro benzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0063] N-[4-[4-[(6-chloropyrazin-2-yl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0064] N-[4-[4-[(2-chloro-5-fluoro-3-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0065] N-[4-[4-[(5-fluoro-2-methoxy-3-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0066] N-[4-[4-[(5-chloro-2-fluoro-3-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0067] 5-(aminomethyl)-2-[methyl(methylsulfonyl)amino]-N-[4-[[4-[(3-nitrophenyl)methylene]-l- piperidyl]sulfonyl]phenyl]benzamide;

[0068] N-[4-[4-[(3-chloro-2-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0069] N-[4-[4-[(5-fluoro-3-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0070] N-[4-[4-[(3-fluoro-2-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0071] N-[4-[4-(4-fluorobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0072] N-[4-[4-(2-bromobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0073] 2-[mesyl(methyl)amino]-N-[4-[4-(2-nitrobenzylidene)piperidino]sulfonylphenyl]-5- piperazino-benzamide; N-[4-[4-(3-fluorobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0074] N-[4-[4-(2-fluorobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;

[0075] N-[4-[[4-[[2-(3-hydroxypropoxy)phenyl]methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide;

[0076] N-[4-[[4-[(2-hydroxyphenyl)methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide;

[0077] 2-[[l-[4-[[2-[mesyl(methyl)amino]benzoyl]amino]phenyl]sulfonyl-4- piperidylidene]methyl]benzoic acid methyl ester;

[0078] N-[4-[[4-[[5-chloro-2-(2-hydroxyethoxy)phenyl]methylene]-l-piperidyl]sulfonyl]phenyl]- 2-[methyl(methylsulfonyl)amino]benzamide;

[0079] 2-[methyl(methylsulfonyl)amino]-N-[4-[[4-[(2-nitrophenyl)methylene]-l- piperidyl]sulfonyl]phenyl]benzamide;

[0080] N-[4-[[4-[[2-(difluoromethoxy)phenyl]methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide; and

[0081] N-[4-[(4-benzylidene-l-piperidyl)sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide; or a pharmaceutically acceptable salt thereof. A compound according to any one of aspects 1 to 9 for use as therapeutically active substance. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 9 and a therapeutically inert carrier. 12. The use of a compound according to any one of aspects 1 to 9 for the treatment or prophylaxis of bacterial infection, in particular wherein the bacteria is gram -negative bacteria.

[0082] 13. The use of a compound according to any one of aspects 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of bacterial infection, in particular wherein the bacteria is gram-negative bacteria.

[0083] 14. A compound according to any one of aspects 1 to 9 for use in the treatment or prophylaxis of bacterial infection, in particular wherein the bacteria is gram -negative bacteria.

[0084] 15. A method for the treatment or prophylaxis of bacterial infection, particularly an infection of a gram-negative bacteria, which method comprises administering an effective amount of a compound as defined in any one of aspects 1 to 9.

[0085] 16. The use, method or compound for use according to any one of aspects 12 to 15, wherein the gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

[0086] 17. The use, method or compound for use according to aspect 16 wherein the gram-negative bacteria is Enterobacteriaceae , wherein Enter obacteriaceae is Klebsiella pneumoniae or Escherichia coli.

[0087] One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (la) wherein

[0088] A1is -N- or -CH-; A2is -N- or -CH-;

[0089] A3is -N- or -CH-;

[0090] A4is -N- or -CH-;

[0091] A5is -N- or -CR7-;

[0092] A6is -N- or -CR8-;

[0093] A7is -N- or -CR9-;

[0094] Rs is hydrogen, heterocycloalkyl or aminoalkyl;

[0095] R4 is hydrogen or halogen; and

[0096] Rs, R7, Rs and R9 are all independently selected from hydrogen, halogen, hydroxyalkoxy, hydroxyl, haloalkoxy, alkoxycarbonyl, alkoxy and nitro; or a pharmaceutically acceptable salt thereof.

[0097] One embodiment of the invention relates to a compound according to the invention, wherein the compound is a compound of formula (II) wherein

[0098] A1is -N- or -CH-;

[0099] A2is -N- or -CH-;

[0100] A3is -N- or -CH-;

[0101] A4is -N- or -CH-;

[0102] Ri is alkyl;

[0103] R2 is alkyl;

[0104] R3 is hydrogen, heterocycloalkyl or aminoalkyl; and n is n, 1 or 2, in particular 1; or a pharmaceutically acceptable salt thereof. One embodiment of the invention relates to a compound according to the invention, wherein the compound is or a pharmaceutically acceptable salt thereof.

[0105] One embodiment of the invention relates to a compound according to the invention, wherein the compound is or a pharmaceutically acceptable salt thereof.

[0106] One embodiment of the invention relates to a compound according to the invention, wherein the compound is

[0107] or a pharmaceutically acceptable salt thereof.

[0108] One embodiment of the invention relates to a compound according to the invention, wherein the compound is or a pharmaceutically acceptable salt thereof.

[0109] One embodiment of the invention relates to a compound according to the invention, wherein the compound is or a pharmaceutically acceptable salt thereof. The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R1 to R6, Al to A7, and X are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in the art.

[0110] Scheme 1

[0111] Wherein PG is a protecting group, such as tert-butoxycarbonyl or benzyloxycarbonyl, X is Halogen. Compound of formula (IV) could be obtained from a palladium catalyzed cross coupling reaction between compound of formula (II) and aryl halides (III). Alternatively, compound of formula (IV) could be obtained by HWE-Reaction of (VI) with phosphonates (VII) or by Suzuki- Miyaura coupling of compound of formula (VII) with compounds (IX). Compound of formula (VIII) could be obtained according to literature in a Boron-Wittig reaction of (VI). (S. Han, Y. Lee, Y. Jung, S. H. Cho, Angew. Chem. Int. Ed. 2022, 61, e202210532; Angew. Chem. 2022, 134, e202210532) Deprotection of compound of formula (IV) with a suitable acid such as HC1 resulting in compound (V).

[0112] Scheme 2

[0113] Compound of formula (XI) could be obtained by a substitution reaction from compound of formula (X). Reduction of Nitrile-group in compound of formula (XI) to amine (XII) can be performed by using Raney Nickel in the presence of Hydrogen. Compound of formula (XIII) could be obtained by protection of the amine (XII). Hydrolysis of the ester (XIII) to the acid (XIV) can be performed using a base such as Lithium hydroxide.

[0114] Scheme 3

[0115] Compound of formula (XVI) could be obtained by a substitution reaction from compound of formula (XV) using a base such as CS2CO3. Compound of formula (XVII) could be obtained by Buchwald-Hartwig amination of compound (XVI) with a corresponding amine. Hydrolysis of the ester (XVII) to the acid (XVIII) can be performed using a base such as triethylamine and lithium salts such as LiBr.

[0116] Scheme 4

[0117] XIX XX XXI

[0118] Compound of formula (XX) could be obtained by treating compound of formula (XIX) with Alkyl sulfonic anhydride in presence of a base such as NaH. Hydrolysis of the ester (XX) to the acid (XXI) can be performed using a base such as sodium hydroxide.

[0119] Scheme 5

[0120] XXII XXIII XXIV XXV

[0121] Compound of formula (XXIII) could be obtained by a substitution reaction from compound of formula (XXII) using a base such as CS2CO3. N-Alkylation of compound (XXIII) with a corresponding amine in precense of a Base such as DIEA results in compound of formula (XXIV). Hydrolysis of the nitrile (XXIV) to the acid (XXV) can be performed using a base such as NaOH.

[0122] Scheme 7

[0123] XXVI XXVII XXVIII

[0124] Compound of formula (XXVII) could be obtained by reduction of Nitro-group in compound of formula (XXVI) using tetrahydroxydiboron in presence of 2-pyridin-2-yl-pyridine. Sulfonyl chlorides of formula (XXVIII) could be obtained by oxidation of compounds of formula (XXVII) using l,3-dichloro-5,5-dimethylhydantoin.

[0125] Scheme 8

[0126] XL I

[0127] Compound of formula (XXXIX) could be obtained by Amide coupling using common coupling reagents such as TCFH or Ghosez’s reagent. Sulfonyl chlorides of formula (XL) could be obtained by oxidation of compounds of formula (XXXIX) using l,3-dichloro-5,5- dimethylhydantoin. Coupling of compounds of formula (XL) with amine of formula (V) in presence of a Base results in compounds of formula (XLII). Coupling of compounds of formula (XL) with amine of formula (V) in presence of a Base such as N,N-diisopropylethylamine results in compounds of formula (XLI). Compound of formula (XLII) could be obtained Suzuki -Miy aura coupling of compound of formula (XLI) with compounds (III) and deprotection of PG such as tert-butoxycarbonyl or benzyloxycarbonyl.

[0128] Scheme 9 Compound of formula (XLIII) could be obtained by coupling amine (V) with sulfonyl chloride (XXVIII) in presence of a base such as N,N-diisopropylethylamine. Compound of formula (XLII) could be obtained by Amide coupling using common coupling reagents such as TCFH or Ghosez’s reagent and deprotection of PG such as tert-butoxycarbonyl or benzyloxy carbonyl.

[0129] The invention thus also relates to a process for the preparation of a compound according to the invention according to the procedures described above.

[0130] Pharmaceutical Compositions

[0131] Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the invention to prepare such composition and medicament. In one example, the compound of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0132] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0133] The compounds of the 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 if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0134] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0135] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., 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 formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0136] Abbreviations

[0137] ACN: acetonitrile; BHi^ feS: borane dimethyl sulfide complex; Boc: tert-butoxycarbonyl; CaCh: calcium chloride; Cbz: carbobenzoxyl; DCE: 1,2-di chloroethane; DCM: dichloromethane ; DIEA: N,N-Diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; EA: ethyl acetate; ESI: electrospray ionization; EtOAc: ethyl acetate; FA: formic acid; H2O: water; HC1: hydrochloric acid; HPLC: high-performance liquid chromatography; K2CO3: potassium carbonate; MS: mass spectrometry; MTBE: Methyl tertbutyl ether; NaHCCL: sodium bicarbonate; ISfeSCU: sodium sulfate; N2: nitrogen; NaH: sodium hydrogen; NMP: N-methyl-2-pyrrolidinone; NMR: nuclear magnetic resonance; PE: petrol ether; R / : retention factor; THF: tetrahydrofuran; Teoc: 2-(trimethylsilyl)ethoxycarbonyl; TEA: tri ethylamine; TFA: trifluoroacetic acid; TLC: thin layer chromatography.

[0138] PREPARATIVE EXAMPLES

[0139] The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. The following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention:

[0140] Int-1: 4-[[2-[methyl(methylsulfonyl)amino]benzoyl]amino]benzenesulfonyl chloride

[0141] Int-1

[0142] Step 1: l-benzylsulfanyl-4-nitro-benzene

[0143] Int-la

[0144] To a solution of 4 -nitrothiophenol (10.0 g, 64.5 mmol, 1.0 eq) and bromomethylbenzene (11.0 g, 64.5 mmol, 1.0 eq) in DMF (100 mL) was added K2CO3 (19.6 g, 141.8 mmol, 2.2 eq). The mixture was stirred at 50 °C for 12 hours. After cooling to room temperature, the mixture was added EtOAc (200 mL) and water (100 mL). The mixture was separated and the organic phase was washed with sat. brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give Int-la (13.5 g, 55.0 mmol, 85.4% yield) as a yellow solid. The crude product was used in next step directly without purification. MS obsd. (ESI+) ([M+H]+): 246.1. Step 2: 4-benzylsulfanylaniline

[0145] Int-lb

[0146] To a solution of Int-la (10.0 g, 40.8 mmol, 1.0 eq) in DMF (40 mL) was added tetrahydroxydiboron (14.5 g, 163.1 mmol, 4.0 eq) and 2-pyridin-2-yl-pyridine (635.9 mg, 4.08 mmol, 0.1 eq). After stirring at 25 °C for 2 hours, the reaction was poured into water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with sat. brine (100 mL x 3), dried over anhydrous ISfeSCU, filtered and concentrated in vacuo to give Int-lb (8.0 g, 37.2 mmol, 91.1% yield) as yellow oil. The crude product was used in next step directly without purification. MS obsd. (ESI+) ([M+H]+): 216.1.

[0147] Step 3: methyl 2-[methyl(methylsulfonyl)amino]benzoate

[0148] Int-lc

[0149] To a solution of methyl 2-(methylamino)benzoate ( 85-91-6) (24.0 g, 145.3 mmol, 1.0 eq) in THF (100 mL) was added methanesulfonic anhydride (37.9 g, 217.9 mmol, 1.5 eq) and NaH (8.7 g, 217.9 mmol, 1.5 eq). The mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, the mixture was added aq. HC1 (50 mL, 1 N), extracted with EtOAc (150 mL x 3). The organic phase was washed with brine (100 mL x 3), dried over Na2SO4, concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 220 g, PEZEtOAc = 100 / 1 to 2 / 1; TLC: PE / EtOAc = 3 / 1, Rf= 0.6) to give Int-lc (26.0 g, 106.9 mmol, 73.6% yield) as a yellow solid. MS obsd. (ESI+) ([M+H]+): 244.1.

[0150] Step 4: 2-[methyl(methylsulfonyl)amino]benzoic acid

[0151] Int-ld

[0152] To a solution of Int-lc (27.0 g, 110.9 mmol, 1.0 eq) in ethanol (200 mL) and water (50 mL) was added sodium hydroxide (22.2 g, 554.9 mmol, 5.0 eq). After stirring at 25 °C for 4 hours, the mixture was adjusted to pH = 5 with aq. HC1 (1 N) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (150 mL x 3), dried over MgSO4, filtered and concentrated under reduced pressure to give Int-ld (22.0 g, 95.9 mmol, 86.5% yield) as a white solid. The crude product was used in next step directly without purification. MS obsd. (ESI+) ([M+H]+): 230.1.

[0153] Step 5: N-(4-benzylsulfanylphenyl)-2-[methyl(methylsulfonyl)amino]benzamide

[0154] Int-le

[0155] To a solution of Int-ld (3.0 g, 13.1 mmol, 1.0 eq), Int-lb (4.2 g, 19.6 mmol, 1.5 eq) in ACN (30 mL) was added NMI (9.7 g, 117.8 mmol, 9.0 eq) and N-(chloro(dimethylamino)methylene)-N- methylmethanaminium hexafluorophosphate(V) (11.0 g, 39.3 mmol, 3.0 eq). The mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (150 mL) and washed with water (50 mL) and sat. aq. NaCl (50 mL x 3). The organic phase was dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (silica gel, 120 g, PE / EtOAc = 100 / 1 to 3 / 1; TLC: PEZEtOAc = 1 / 1, Rf = 0.5) to give Int-le (5.0 g, 11.7 mmol, 80.6% yield) as a white solid. MS obsd. (ESI+) ([M+H]+): 427.1.

[0156] Step 6: 4-[[2-[methyl(methylsulfonyl)amino]benzoyl]amino]benzenesulfonyl chloride

[0157] Int-1

[0158] To a solution of Int-le (5.5 g, 12.9 mmol, 1.0 eq), acetic acid (10 mL) and water (10 mL) in ACN (100 mL) was added l,3-dichloro-5,5-dimethylhydantoin (7.6 g, 38.7 mmol, 3.0 eq) under 0 °C. After stirred at 25 °C for 1 hr, the reaction was diluted with EtOAc (400 mL), and washed with water (50 mL x 3) and sat. aq. NaCl. (50 mL x 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with MTBE (50 mL) to give Int-1 (1.8 g, 4.5 mmol, 45.3% yield) as a pink solid. MS obsd. (ESI+) ([{35C1}M+H]+): 403.1.

[0159] Int-2 : 5- [ [4- [(2-nitrophenyl)methylene] - 1-piperidyl] sulfonyl] pyridin-2-amine

[0160] Int-2

[0161] Step 1: 5-benzylsulfanyl-2-nitro-pyridine

[0162] Int-2a

[0163] To a solution of 5-fluoro-2-nitropyridine (25.0 g, 175.9 mmol, 1.0 eq) and potassium carbonate (24.3 g, 175.9 mmol, 1.0 eq) in DMF (100 mL) was added benzyl mercaptan (26.2 g, 211.3 mmol, 1.2 eq) under N2. The reaction was stirred at 70 °C for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc (500 ml) and washed with water (100 ml x 3). The organic phase was washed with brine (100 ml x 3), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 2: 1) to give Int-2a (30.0 g, 121.8 mmol, 69.2% yield) as a white solid. MS obsd. (ESI+) ([M+H]+): 247.1.

[0164] Step 2: 5-benzylsulfanylpyridin-2-amine

[0165] Int-2b

[0166] To a solution of lnt-2a (5.0 g, 20.3 mmol, 1.0 eq) and 4,4-dipyridyl (0.3 g, 2.03 mmol, 0.1 eq) in DMF (40 mL) was added tetrahydroxy diboron (7.3 g, 81.2 mmol, 4.0 eq) slowly. After stirred at 25 °C for 1 hr, the mixture was diluted with EtOAc (300 ml) and washed with water (50 ml x 3). The organic layer was washed with brine (50 ml x 3), dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (330 g silica gel, 30% EtOAc / petroleum ether) to give Int-2b (4.0 g, 18.5 mmol, 91.09% yield) as a yellow solid. MS obsd. (ESI+) ([M+H]+): 217.2.

[0167] Step 3: 6-aminopyridine-3-sulfonyl chloride

[0168] Int-2c

[0169] To a solution of 5-benzylsulfanylpyridin-2-amine (2.0 g, 9.3 mmol, 1.0 eq), acetic acid (4 mL) and water (2 mL) in DCM (20 mL) was added l,3-dichloro-5,5-dimethylhydantoin (4.0 g, 20.3 mmol, 2.5 eq). After stirred at 25 °C for 1 hr, the resulting precipitate formed. The precipitate was collected by filtration and dried with evaporation under reduced pressure to give crude Int-2c (1.4 g, 7.3 mmol, 78.6% yield) as a yellow solid. MS obsd. (ESI+) ([{35C1}M+H]+): 193.0.

[0170] Step 4: tert-butyl 4-[(2-nitrophenyl)methylene]piperidine-l-carboxylatee

[0171] Int-2d

[0172] To a solution of tert-butyl 4-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]piperidine- 1-carboxylate (4.5 g, 13.9 mmol, 1.0 eq) in 1,4-dioxane (50 mL) and water (10 mL) was added 1- iodo-2-nitrobenzene (3.8 g, 15.3 mmol, 1.1 eq) and cyclopenta-2,4-dien-l-yl(diphenyl)phosphane; dichloropalladium; iron (2+) (1.02 g, 1.4 mmol, 0.1 eq), potassium phosphate (8.9 g, 41.8 mmol, 3.0 eq) under N2. The reaction was stirring at 80 °C for 2 hours under N2 atmosphere. After cooling to room temperature, the reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column (silica gel, 120 g; PE / EtOAc = 100 / 1 to 3 / 1; TLC: PE / EtOAc = 5 / 1, Rf= 0.5) to give Int-2d (3.6 g, 11.3 mmol, 81.2% yield) as yellow oil. MS obsd. (ESI+) ([M-C4H8+H]+): 263.1.

[0173] Step 5: 4-[(2-nitrophenyl)methylene]piperidine

[0174] Int-2e

[0175] To a solution of Int-2d (3.6 g, 11.3 mmol, 1.0 eq) in DCM (5 mL) was added trifluoroacetic acid (3.9 g, 33.9 mmol, 3.0 eq). After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure to give Int-2e (1.9 g, 8.7 mmol, 76.9% yield) as yellow oil. The crude product was used in next step directly without purification. MS obsd. (ESI+) ([M+H]+): 219.2.

[0176] Step 6: 5-[[4-[(2-nitrophenyl)methylene ]-l -piperidyl sulfonyl ]pyridin-2 -amine

[0177] Int-2

[0178] To a solution of Int-2e (500.0 mg, 1.5 mmol, 1.0 eq) in DCM (5 mL) was added Int-2c (347.8 mg, 1.8 mmol, 1.2 eq) and N,N-diisopropylethylamine (0.8 mL, 4.5 mmol, 3.0 eq). After stirring at 25 °C for 2 hours, the reaction was quenched with water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (30 mL x 3), dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: C18 spherical 20 ~ 35 pm, 80 g, mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 0% - 100%, 15 min) and then lyophilized to give Int-2 (430.0 mg, 1.2 mmol, 76.3% yield) as a white solid. MS obsd. (ESI+) ([M+H]+): 375.1.

[0179] Int-3: 5-((4-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene)piperidin-l- yl)sulfonyl)pyridin-2-amine

[0180] Step 1 : 4-( ( 4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)methylene)piperidine

[0181] Int-3a

[0182] Tert-butyl 4-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]piperidine-l-carboxylate

[0183] (3.0 g, 9.3 mmol, 1.0 eq) was added into HCl / dioxane (20.0 mL, 4 M). After stirring at 25 °C for 2 1 hours, the mixture was concentrated under reduced pressure to give crude Int-3 (2.2 g, 9.9 mmol) as pale yellow oil. The crude product was used in next step directly without purification. MS obsd. (ESI+) ([M+H]+): 224.0.

[0184] Step 2: 5-((4-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene)piperidin-l- yl)sulfonyl)pyridin-2-amine

[0185] To a solution of Int-3a (4.6 g, 20.6 mmol, 1.0 eq) and Int-2c (4.8 g, 24.7 mmol, 1.2 eq) in DCM (50 mL) was added DIEA (1.0 mL, 164.1 mmol, 7.9 eq). After stirring at 25 °C for 2 hours, the mixture was poured into water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (silica gel, 120 g, PEZEtOAc = 10 / 1 to 1 / 3; TLC: PE / EtOAc = 1 / 1, Rf= 0.4) to give Int-3 (4.5 g, 11.9 mmol, 57.6% yield) as a white solid. MS obsd. (ESI+) ([M+H]+): 380.2.

[0186] Int-4: 6-((4-(2-nitrobenzylidene)piperidin-l-yl)sulfonyl)pyridazin-3-amine

[0187] Int-4

[0188] Step 1: 6-(benzylthio)pyridazin-3-amine Int-4a

[0189] To the solution of 3-amino-6-chloropyridazine (50.0 g, 385.9 mmol, 1.0 eq) and CS2CO3 (188.2 g, 578.9 mmol, 1.5 eq) in DMF (200 mL) was added benzyl mercaptan (45.5 g, 366.7 mmol, 1 eq). The reaction was stirred at 70 °C for 16 hours under N2. After cooling to room temperature, the mixture was poured into water (300 mL) and extracted with EtOAc (300 mL x 3). The organic phase was washed with brine (200 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (SiCL, 500 g, PE / EtOAc = 10 / 1 to 1 / 3; TLC: PE / EtOAc = 1 / 1, Rf = 0.4) to give Int-4a (60.0 g, 276.1 mmol, 71.5% yield) as a white solid. MS obsd. (ESI+) ([M+H]+): 218.2.

[0190] Step 2: 6-aminopyridazine-3-sulfonyl chloride

[0191] Int-4b

[0192] To a solution of Int-4a (30.0 g, 138.1 mmol, 1.0 eq) in DCM (200 mL), acetic acid (40 mL), water (20 mL) was added 1,3 -di chi oro-5, 5-dimethylimidazolidine-2, 4-dione (48.9 g, 248.5 mmol, 1.8 eq), After stirring at 0 °C for 2 hours, the mixture was diluted with MTBE (200 mL) and the resulting precipitate was collected by filtration and dried under reduced pressure to give Int-4b (25.0 g, 129.1 mmol, 93.5% yield) as a brown solid. MS obsd. (ESI+) ([{35C1}M+H]+): 194.0.

[0193] Step 3: 6-((4-(2-nitrobenzylidene)piperidin-l-yl)sulfonyl)pyridazin-3-amine

[0194] Int-4

[0195] To a solution of Int-4b (1.5 g, 6.9 mmol, 1.0 eq) and Int-2e (1.3 g, 6.9 mmol, 1.0 eq) in THF (10 mL) and water (1.0 mL) was added NaEtCCL (2.9 g, 34.4 mmol, 5.0 eq). After stirring at 25 °C for 4 hours, the solution was poured into water (50 mL) and extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine (30 mL x 3), dried over ISfeSCU, filtered and concentrated under reduced pressure to give Int-4 (1.2 g, 3.2 mmol, 46.5% yield) a yellow solid. MS obsd. (ESI+) ([M+H]+): 376.1.

[0196] Int-5: 6-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-(N- methylmethylsulfonamido)pyridazine-4-carboxylic acid

[0197] Int-5

[0198] Step 1: N-(6-chloro-4-cyanopyridazin-3-yl)-N-methylmethanesulfonamide

[0199] Int-5a

[0200] To a solution of N-methyl methanesulfonamide (3.8 g, 34.5 mmol, 1.2 eq) and 3,6- dichloropyridazine-4-carbonitrile (CAS: 35857-93-3) (5.0 g, 28.7 mmol, 1.0 eq) in DMF (50 mL) was added Cs2CO3 (11.2 g, 34.5 mmol, 1.2 eq). After stirring at 0 °C for 3 hours, the mixture was diluted with EtOAc (500 mL) and filtered. The filtrate was washed with water (100 mL) aq. CaCL (100 mL x 3) and brine (100 mL x 3) successively. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (silica gel, 220 g, PE / EtOAc = 10 / 1 to 1 / 3; TLC: PEZEtOAc = 2 / 1, Rf = 0.4) to give Int-5a (2.4 g, 9.7 mmol, 33.9% yield) as a brown solid. MS obsd. (ESI+) ([{35C1}M+H]+): 247.0. Step 2: tert-butyl 4-(5-cyano-6-(N-methylmethylsulfonamido)pyridazin-3-yl)piperazine-l- carboxylate

[0201] „ / Boc

[0202] Int-5b

[0203] To the solution of Int-5a (2.4 g, 9.7 mmol, 1.0 eq) in NMP (10 mL) was added DIEA (4.8 mL, 29.2 mmol, 3.0 eq) and 1-BOC-piperazine (2.2 g, 11.7 mmol, 1.2 eq). The mixture was stirred at 110 °C for 1 hour. After cooling to room temperature, the solution was poured into water (50 mL) and extracted with EtOAc (70 mL><3), the combined organic layers were washed with brine (50 mL><3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (silica gel, 80 g, PEZEtOAc = 10 / 1 to 1 / 3; TLC: PEZEtOAc = 2 / 1, Rf = 0.3) to give Int-5b (3.4 g, 8.6 mmol, 88.1% yield) as a yellow solid. MS obsd. (ESI+) ([M- C4H8+H]+): 341.1.

[0204] Step 3: 6-(4-(tert-butoxycarbonyl)piperazin-l-yl)-3-(N-methylmethylsulfonamido)pyridazine-4- carboxylic acid

[0205] Int-5

[0206] To the solution of Int-5b (3.4 g, 8.6 mmol, 1.0 eq) in Ethanol (30 mL) and water (15 mL) was added NaOH (3.4 g, 86 mmol, 10 eq) and the mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and adjusted to pH = 4 with 1 N aq. HC1. Then the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude Int-5 (3.5 g, 8.4 mmol, 98.2% yield) as a yellow solid. The crude product was used in next step directly without purification. MS obsd. (ESI+) ([M-C4Hs+H]+): 416.2.

[0207] Int-6: 5-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-(N-methylmethylsulfonamido)nicotinic acid

[0208] Cbz

[0209] Int-6

[0210] Step 1: methyl 5-bromo-2-(N-methylmethylsulfonamido)nicotinate

[0211] Int-6a

[0212] To a solution of methyl 5 -bromo-2-fluoro-pyridine-3 -carboxylate (78686-79-0) (5.0 g, 21.4 mmol, 1.0 eq) and N-methyl methanesulfonamide (2.8 g, 25.6 mmol, 1.2 eq) in DMF (20 mL) was added CS2CO3 (3.2 g, 23.5 mmol, 1.1 eq). The mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, concentrated under reduced pressure. The residue was purified by silica gel column (PE: EA = 1 : 1) to give Int-6a (3.1 g, 9.6 mmol, 43.1% yield) as a yellow solid. MS obsd. (ESI+) ([{79Br}M+H]+): 322.9. Step 2: benzyl 4-(5-(methoxycarbonyl)-6-(N-methylmethylsulfonamido)pyridin-3-yl)piperazine-l- carboxylate

[0213] Int-6b

[0214] To the solution of 1-CBZ-piperazine (1.6 g, 7.4 mmol, 1.2 eq) and Int-6a (2.0 g, 6.2 mmol, 1.0 eq) in 1,4-Dioxane (10 mL) was added DavePhos (590.5 mg, 0.8 mmol, 0.1 eq), Pd2(dba)s (355.9 mg, 0.6 mmol, 0.1 eq) and K3PO4 (3.94 g, 18.6 mmol, 3.0 eq), the mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the solution was poured into water (50 mL), and the mixture was extracted with EtOAc (50 mL><3), the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was further purified by silica gel column (PE: EA=1 : 3) to give Int-6b (900.0 mg, 2.0 mmol, 26.1% yield) as a yellow solid. MS obsd. (ESI+) ([M+H]+): 463.1.

[0215] Step 3: 5-( 4-( ^benzyloxy)carbonyl)piperazin-l-yl)-2-(N-methylmethylsulfonamido)nicotinic acid

[0216] Cbz

[0217] Int-6

[0218] To a solution of Int-6b (900.0 mg, 2.0 mmol, 1.0 eq),N,N-diethylethanamine (984.5 mg, 9.7 mmol, 5.0 eq) in ACN (10 mL) and water (2 mL) was added lithium bromide (506.9 mg, 5.8 mmol, 3.0 eq), the mixture was stirred at 50 °C for 4 hours. After cooling to room temperature, the reaction was poured into water (50 mL) and adjusted to pH = 5 with 1 N aq. HC1. Then the mixture was extracted with EtOAc (100 mL x 3). And the combined organic layers were washed with brine (50 mL x 3), dried over ISfeSCL, filtered and concentrated under reduced pressure to give Int-6 (700.0 mg, 1.6 mmol, 80.2% yield) as a black solid. MS obsd. (ESI+) ([M+H]+): 449.1.

[0219] Example 1: 7V-[4-[(4-cyclopentylidene-l-piperidyl)sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide

[0220] Step 1: 5-bromopentyl(triphenyl)phosphonium bromide la

[0221] To a solution of triphenylphosphine (1.1 g, 4.4 mmol, 1.0 eq) in toluene (10 mL) was added 1,5- dibromopentane (1.0 g, 4.4 mmol, 1.0 eq). The mixture was stirred at 90 °C for 6 hours. After cooling to room temperature, the reaction mixture was concentrated to afford the crude la (1.2 g, 2.4 mmol, 56.1% yield) as a white solid. The crude product was used in next step directly without purification. MS obsd. (ESI+) ([M+H]+): 413.0.

[0222] Step 2: benzyl 4-cyclopentylidenepiperidine-l -carboxylate Cbz lb To a solution of la (600.0 mg, 1.2 mmol, 1.0 eq) in THF (6 mL) was added potassium; 2- methylpropan-2-olate (2.9 mL, 2.9 mmol, 2.4 eq). After stirring at 25 °C for 1 hr, the N- benzyloxycarbonyl-4-piperidone (0.2 mL, 1.2 mmol, 1.0 eq) was added into the reaction and the mixture was stirred at 25 °C for 6 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: C18 spherical 20 - 35 pm, 80 g, mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 0% - 100%, 15 min) to give lb (30.0 mg, 0.1 mmol, 8.6% yield) as a yellow oil. MS obsd. (ESI+) ([M+H]+): 286.2.

[0223] Step 3: 4-cyclopentylidenepiperidine (CAS: 1517546-66-5)

[0224] 1c

[0225] To a solution of lb (10.0 mg, 0.04 mmol, 1.0 eq) in DCM (1 mL) was added triethylamine (0.01 mL, 0.1 mmol, 3.0 eq), triethylsilane (8.2 mg, 0.07 mmol, 2.0 eq) and dichloropalladium (3.1 mg, 0.02 mmol, 0.5 eq). After stirring at 20 °C for 1 hour, the mixture was used directly in next step without work-up. Compound 1c (25 mg, crude) in DCM (1 mL) was obtained. MS obsd. (ESI+) ([M+H]+): 152.4.

[0226] Step 4: N-[ 4-[ ( 4-cyclopentylidene-l -piperidyl ) sulfonyl Jphenyl ]-2-

[0227] [methyl(methylsulfonyl)amino]benzamide (Example 1)

[0228] To a solution of 1c (23.4 mg, 0.2 mmol, 2.0 eq) in DCM (1 mL) was added N,N- diisopropylethylamine (9 mg, 0.07 mmol, 1.0 eq) and Int-1 (30.0 mg, 0.07 mmol, 1.0 eq). After stirring at 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Cl 8 spherical 20 - 35 pm, 20 g, mobile phase: [A: water (0.1% FA) - B: ACN]; B%: 0% - 100%, 15 min) and lyophilized. Example 1 (1.41 mg, 0.01 mmol, 3.4% yield) was obtained as a white solid. MS obsd. (ESI+) ([M+H]+): 518.3.

[0229] Example 2: 2-[methyl(methylsulfonyl)amino]-A-[5-[[4-[(2-nitrophenyl)methylene]-l- piperidyl]sulfonyl]-2-pyridyl]-5-piperazin-l-yl-pyridine-3-carboxamide

[0230] Step 1: benzyl 4-[6-[methyl(methylsulfonyl)amino]-5-[[5-[[4-[(2-nitrophenyl)methylene]-l- piperidyl sulfonyl ]-2-pyridyl carbamoyl ]-3-pyridyl piperazine- 1 -carboxylate

[0231] 2a

[0232] To a solution of Int-6 (100.0 mg, 0.2 mmol, 1.0 eq) in DCE (1 mL) was added Ghosez’s reagent (59.3 mg, 0.5 mmol, 2.0 eq) under N2 and it was stirred at 25 °C for 0.5 hour. Then mixture was added Int-2 (83.5 mg, 0.2 mmol, 1.0 eq) and pyridine (0.05 mL, 0.7 mmol, 3.0 eq) under N2. The reaction was continuing to be stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated in vacuo and the residue was directly purified by prep-HPLC (column: C18 spherical 20 ~ 35 pm, 20 g, mobile phase: [A: water (0.1% FA) - B: ACN]; B%: 0% - 100%, 15 min) to give 2a (20.0 mg, 0.02 mmol, 11.1% yield) as a white solid. MS obsd. (ESI+) ([M+H]+): 805.4.

[0233] Step 2: 2-[methyl(methylsulfonyl)amino]-N-[5-[[4-[(2-nitrophenyl)methylene]-l- piperidyl] sulfonyl] -2-pyridyl]-5-piperazin-l-yl-pyridine-3-carboxamide; formic acid (Ex.2)

[0234] The solution of 2a (10.0 mg, 0.01 mmol, 1.0 eq) in trifluoroacetic acid (1.0 mL) was stirring at 50 °C for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Cl 8 spherical 20 - 35 pm, 20 g, mobile phase: [A: water (0.1% FA) - B: ACN]; B%: 0% - 100%, 20 min) and lyophilized. Example 2 (6.6 mg, 0.01 mmol, 78.3% yield) was obtained as a white solid. MS obsd. (ESI+) ([M+H]+): 671.2.

[0235] Example 3: V-(5-((4-((2-chloro-5-fluoropyridin-3-yl)methylene)piperidin-l- yl)sulfonyl)pyridin-2-yl)-3-(N-methylmethylsulfonamido)-6-(piperazin-l-yl)pyridazine-4- carboxamide Step 1: tert-butyl 4-(6-(N-methylmethylsulfonamido)-5-((5-((4-((4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)methylene)piperidin-l-yl)sulfonyl)pyridin-2-yl)carbamoyl)pyridazin-3- yl)piperazine-l -carboxylate

[0236] 3a

[0237] To a solution of Int-5 (2.02 g, 5.3 mmol, 0.9 eq) in DCE (20 mL) was added Ghosez’s reagent (1.7 g, 12.5 mmol, 2.0 eq). After stirring at 25 °C for 0.5 hr under N2, the solution of Int-3 (2.6 g, 6.3 mmol, 1.0 eq) in pyridine (20 mL) was added into the reaction and the mixture was continuing to be stirred at 60 °C for 0.5 hour. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL><3). The combined organic layers were washed with brine (30 mL x 3), dried over ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (silica gel, 80 g, 40% to 50% EtOAc in PE, TLC: Petroleum ether / EA = 1 : 3, Rf = 0.6) to give 3a (3.0 g, 3.9 mmol, 61.7% yield) as a yellow solid. MS obsd. (ESI+) ([M+H]+): 777.3

[0238] Step 2: tert-butyl 4-(5-((5-((4-((2-chloro-5-fluoropyridin-3-yl)methylene)piperidin-l- yl)sulfonyl)pyridin-2-yl)carbamoyl)-6-(N-methylmethylsulfonamido)pyridazin-3-yl)piperazine-l- carboxylate

[0239]

[0240] A mixture of 3a (100.0 mg, 0.1 mmol, 1.0 eq), Pd(dppf)C12 (9.4 mg, 0.01 mmol, 0.1 eq), 3-bromo- 2-chloro-5-fluoro-pyridine (54.2 mg, 0.3 mmol, 2.0 eq) and K3PO4 (81.9 mg, 0.4 mmol, 3.0 eq) in 1,4-di oxane (2 mL) and water (0.4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 2 hours under N2. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether / EA=5 / l to 1 : 1) to afford 3b (100.0 mg, 0.1 mmol, 99.5% yield). MS obsd. (ESI+) ([{35C1}M+H]+): 780.2

[0241] Step 3: N-(5-((4-( (2-chloro-5-fluoropyridin-3-yl)methylene)piperidin-l-yl)sulfonyl)pyridin-2-yl)- 3-(N-methylmethylsulfonamido)-6-(piperazin-l-yl)pyridazine-4-carboxamide (Ex.3)

[0242] To a solution of 3b (100.0 mg, 0.1 mmol, 1.0 eq) in DCM (2 mL) was added TFA (1.0 mL). After stirring at 20 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Cl 8 spherical 20 - 35 pm, 80 g, mobile phase: [A: water (0.1% FA) - B: ACN]; B%: 0% - 100%, 20 min) to afford Example 3 (53.8 mg, 0.08 mmol, 61.1% yield) as a white solid. MS obsd. (ESI+) ([{35C1}M+H]+): 680.1 Example 4: Az-[5-[[4-[(5-fluoro-2-methoxy-3-pyridyl)methylene]-l-piperidyl]sulfonyl]-2- pyridyl]-3-[methyl(methylsulfonyl)amino]-6-piperazin-l-yl-pyridazine-4-carboxamide

[0243] Example 4 was prepared in analogy to the preparation of Example 3 by using 3-bromo-5-fluoro- 2-methoxypyridine instead of 3-bromo-2-chloro-5-fluoro-pyridine in step 2. Example 4 (61.1 mg, 0.09 mmol, 66.1% yield) as a white solid was obtained. MS obsd. (ESI+) ([M+H]+): 676.2.

[0244] Example 5: 2-(7V-methylmethylsulfonamido)-7V-(6-((4-(2-nitrobenzylidene)piperidin-l- yl)sulfonyl)pyridazin-3-yl)-5-(piperazin-l-yl)nicotinamide

[0245] Example 5 was prepared in analogy to the preparation of Example 2 by using Int-4 instead of Int- 2 in step 1. Example 5 (20.9 mg, 0.03 mmol, 62.5% yield) as a white solid was obtained. MS obsd. (ESI+) ([M+H]+): 672.2.

[0246] Example 6: Az-[4-[4-[Fluoro-(2-nitrophenyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide

[0247] Step 1 : 4-[Fluoro-( 4, 4, 5, 5 -tetr ame thy l-l , 3, 2-dioxaborolan-2-y I) methylene ]piperidine-l- carboxylic acid tert-butyl ester

[0248] Int-6a

[0249] (S. Han, Y. Lee, Y. Jung, S. H. Cho, Angew. Chem. Int. Ed. 2022, 61, e202210532; Angew.

[0250] Chem. 2022, 134, e202210532.)

[0251] LiTMP (255 mg, 1.73 mmol, 1.5 eq) was added to a dried round-bottomed flask, was sealed with a rubber septum and removed from the glove-box. THF, extra dry (2.2 mL) was added and the mixture was stirred at -78 °C for 15 min. A solution of 2-[fluoro-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)methyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (660 mg, 2.31 mmol, 2.0 eq) in THF, extra dry (3.75 mL), was added dropwise for 15 min, and the solution was stirred at -78 °C for additional 10 min. To this mixture, a solution of l-Boc-4-piperidone (230 mg, 1.15 mmol, 1.0 eq) in THF, extra dry (2.2 mL) was added dropwise at -78 °C for 10 min, and stirred at -78 °C for an additional 4 hours. The reaction mixture was filtered through celite, washed with diethyl ether (50 mL). The solvent concentrated in vacuo and the residue was purified by column chromatography on silica gel (heptane / EA, 0-50 %). (TLC was stained with KMnO4.) The corresponding product fractions were combined and evaporated in vacuo to give Int-6a (185 mg, 45 %) as a white powder. GC / MS: 341.2 (EI+). 1H NMR (600 MHz, CHLOROFORM-d) 5 ppm 3.34-3.51 (m, 4 H), 2.50 (td, J=5.8, 1.7 Hz, 2 H), 2.41 (br s, 2 H), 1.47 (s, 9 H), 1.30 (s, 12 H), 19F NMR (565 MHz, CHLOROFORM-d) 5 = -125.38- -143.78 (m, IF), 11B NMR (128 MHz, CHLOROFORM-d, 25 °C): 5 = 29.1 ppm

[0252] Step 2: 4-[fluoro-(2-nitrophenyl)methylene]piperidine hydrogen chloride

[0253] Int-6b l-Bromo-2-nitro-benzene (14.2 mg, 70.3 umol, 1.2 eq) and Int-6a (20 mg, 58.6 umol, 1.0 eq) were added to dry 1,4-dioxane (1 mL) and potassium carbonate (32.4 mg, 234 umol, 4.0eq) in water (1 mL). Tetrakis(triphenylphosphine)palladium(0) (3.4 mg, 2.93 umol, 0.05 eq) was added and the reaction was stirred at 90 °C overnight. The mixture was quenched with aq. Na2CO3 sat. (10 ml) and extracted with EA (2 x 10 ml). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. 4 M HC1 in dioxane (275uL, 1.1 mmol, 15.000 eq) and DCM (2.5 mL) was added and the reaction mixture was stirred for 6 hr at RT. Concetrated The crude was purified by prep HPLC to give Int-6b (21 mg, 78 %) as a yellow waxy solid and was used without further purification in the next step. MS obsd. (ESI+) ([M+H]+): 237.1 [M+H]+.

[0254] Step 3: N- 4-[ 4-[Fluoro-(2-nitrophenyl)methylene ]piperidino ] sulfonylphenyl ]-2- [mesyl(methyl)amino Jbenzamide

[0255] Example 6 was prepared in analogy to the preparation of Example 1 by using Int-6b instead of 4- cyclopentylidenepiperidine in step 3 to give Example 6 (10.7 mg, 39.08%) as white lyoph powder. MS obsd. (ESI+) ([M+H]+): 603.2

[0256] Example 7: N-[4-[[4-[(5-chloro-3-pyridyl)methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide

[0257] Step 1: 2-[Mesyl(methyl)amino ]-N-[ 4-[ 4- [(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)methylene ]piperidino ] sulfonylphenyl (benzamide

[0258] Int-7

[0259] Int-1 (380 mg, 943 umol, 1.0 eq) was dissolved in DCM (10 mL). Int-3a (337 mg, 1.04 mmol, 1.1 eq) and trimethylamine (334 mg, 460 uL, 3.3 mmol, 3.5 eq) were added and the mixture was stirred at 20 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (silica gel, 40 g, 10% to 100% EtOAc in Heptane), to give Example 7 (470 mg, 70 %) as a white powder. MS obsd. (ESI+) ([M+H]+): 590.3.

[0260] Step 2: N-[ 4-[[4-[ (5-chloro-3-pyridyl)methylene ]-l-piperidyl ] sulfonyl (phenyl (-2- [methyl(methylsulfonyl)amino]benzamide (Example 7)

[0261] 2-bromo-6-chloro-pyrazine Int-7a (5.3 mg 0.03 mmol, 1.1 eq.) was added to potassium carbonate (16.6 mg, 120 pmol, 4.0 eq) dissolved in water (1 mL). Int-7 (17.7 mg, 0.030 mmol, 1.0 eq) was dissolved in 1,4-dioxane (1 mL) and added to the suspension. Tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 3 pmol, 0.1 eq) was added and the reaction was placed on a shaker at 90 °C for 4 hours. The completed reactions were allowed to cool down to RT. Isolute® Si-TMT (0.5 eq.) was added and the suspension was placed on a shaker for 30 min at RT. The reactions were then filtered, concentrated, dissolved in DSMO (750 uL) and purified by prep- HPLC to give Example 7. Appearance not characterized (5.4 mg, 38 %) MS obsd. (ESI+) ([M+H]+): 575.1

[0262] The following Examples 8 to 13, 16, and 17 were prepared in analogy to the procedure described for the preparation of Example 7, using Int-7 in Step 2, and replacing the aryl halide Int-7a in Step 2, by the indicated Aryl halide with Int-8 to 13, Int-16, and Int-17 in Table 1.

[0263] Table 1: Compound synthesis and characterization

[0264] Example 14: 5-(aminomethyl)-2-[methyl(methylsulfonyl)amino]-7V- [4-[[4-[(3- nitrophenyl)methylene]-l-piperidyl]sulfonyl]phenyl]benzamide

[0265]

[0266] Step 1: methyl 5-(aminomethyl)-2-[methyl(methylsulfonyl)amino]benzoate

[0267] Int-14a

[0268] To a solution of N-methyl methanesulfonamide (16.8 g, 153.5 mmol, 1.1 eq) and methyl 5-cyano- 2-fluorobenzoate (CAS: 337362-21-7) (25.0 g, 139.6 mmol, 1.0 eq) in DMSO (150.0 mL) was added cesium carbonate (68.2 g, 209.3 mmol, 1.5 eq) at 25 °C and the mixture was stirred at 60 °C for 1 h. After cooled to room temperature, the mixture was diluted with EA (500 mL) and filtered. The filtrate was washed with water (100 mL x 2), and brine (100 mL x 2). The organic layer was dried by anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column (silica gel: 330 g, PE: EA = 2: 1 ~ 1 : 3) to give methyl 5-cyano-2- [methyl(methylsulfonyl)amino]benzoate (Int-14a) (18.0 g, 67.1 mmol, 48.1% yield) as yellow solid. MS obsd. (ESI+) [(M+H)+]: 269.0.

[0269] Step 2: methyl 5-(aminomethyl)-2-[methyl(methylsulfonyl)amino]benzoate Int-14b

[0270] To a slution of methyl 5-cyano-2-[methyl(methylsulfonyl)amino]benzoate (10.5 g, 39.14 mmol, 1.0 eq) in Ethanol (200 mL) was added Raney Ni (1.68 g, 19.57 mmol, 0.5 eq) under H2. The mixture was purged with H2 for several times and then stirred at 60 °C for 16 hours. The mixture was filtered, and removed the solvent to give methyl 5-(aminomethyl)-2- [methyl(methylsulfonyl)amino]benzoate (9.8 g, 35.99 mmol, 91.95% yield) as a light yellow solid. MS obsd. (ESI+) [(M+H)+]: 528.1[2M+1]+

[0271] Step 3: methyl 5-[(tert-butoxycarbonylamino)methyl]-2-[methyl(methylsulfonyl)amino]benzoate

[0272] Int-14c

[0273] To a solution of di -t-butyl di carb onate (11.46 g, 52.51 mmol, 1.3 eq) and methyl 5-(aminomethyl)- 2-[methyl(methylsulfonyl)amino]benzoate (11.0 g, 40.39 mmol, 1.0 eq) in DCM (100 mL) was stirred at 25 °C for 2 hours. The mixture was poured into water (100 mL), and the mixture was extracted with EA (100 mL *2), and the combined organic layer was washed with brine, dried over Na2SO4, filtered and removed the solvent to give a crude. The crude was purified by column (silica gel: 220 g, PE:EA=1 :2) to give methyl 5-[(tert-butoxycarbonylamino)methyl]-2- [methyl(methylsulfonyl)amino]benzoate (12 g, 32.22 mmol, 71.79% yield) as a white solid. MS obsd. (ESI+) ([M+Na]+) 395.1

[0274] Step 4: 5-[(tert-butoxycarbonylamino)methyl]-2-[methyl(methylsulfonyl)amino]benzoic acid

[0275]

[0276] Int-14d

[0277] To a solution of methyl 5-[(tert-butoxycarbonylamino)methyl]-2- [methyl(methylsulfonyl)amino]benzoate (12000.0 mg, 32.22 mmol, 1.0 eq) in Ethanol (60 mL) and water (10 mL) was added sodium hydroxide (6443.52 mg, 161.1 mmol, 5.0 eq) in one portion. The reaction was stirred at 25 °C for 2 hours. The reaction was added HC1 (aq.) and then extracted with EtOAc (100 mL*2). The organics were then separated and dried (MgSCh) before concentration to dryness to afford 5-[(tert-butoxycarbonylamino)methyl]-2- [methyl(methylsulfonyl)amino]benzoic acid (11.0 g, 30.69 mmol, 95.25% yield) as white solid. MS obsd. (ESI+) ([M+Na]+) 381.1

[0278] Step 5: tert-butyl N-[[3-[(4-benzylsulfanylphenyl)carbamoyl]-4- [methyl(methylsulfonyl)amino]phenyl]methyl] carbamate

[0279] Int-14e

[0280] To a solution of 1 -methylimidazole (7.56 mL, 94.86 mmol, 4.0 eq), 5-[(tert- butoxycarbonylamino)methyl]-2-[methyl(methylsulfonyl)amino]benzoic acid (8.5 g mg, 23.72 mmol, 1.0 eq), Int-lb (6.64 g, 30.83 mmol, 1.3 eq) in ACN (80 mL) was added N‘,N‘- Tetramethylchloroformamidinium-hexafluorophosphate (13.31 g, 47.43 mmol, 2.0 eq) in one portion under N2. The reaction was stirred at 60 °C for 1 hour. The reaction was added water (100 mL) and EtOAc (100 mL). The organic layer was separated and then washed with brine (100 mL), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated in vacuo to afford a residue, which was purified by silica gel column (SiO2, Petrol / EtOAc=50 / l to 1 / 3) to afford Int- 14e tert-butyl-N-[[3-[(4-benzylsulfanylphenyl)carbamoyl]-4-

[0281] [methyl(methylsulfonyl)amino]phenyl]methyl]carbamate (13 g, 23.39 mmol, 98.64% yield) as a yellow solid. MS obsd. (ESI+) ([M +H]+): 556.3

[0282] Step 6: tert-butyl N-[[3-[(4-chlorosulfonylphenyl)carbamoyl]-4- [methyl(methylsulfonyl)amino]phenyl]methyl] carbamate

[0283] Int-14f

[0284] To a solution of Int-14e (13 g, 23.4 mmol, 1.0 eq) in Acetic acid (8 mL) and ACN (80 mL) and water (8 mL) was added l,3-dichloro-5,5-dimethylhydantoin (11.52 g, 58.48 mmol, 2.5 eq) in one portion under N2. The reaction was stirred at 20 °C for 1 hour. The reaction was added water (50 mL), extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated in vacuo to afford a residue, which was purified by silica gel column (Petrol ether / EtOAC=50 / l to 1 / 3) to give tert-butyl N-[[3-[(4-chlorosulfonylphenyl)carbamoyl]-4-

[0285] [methyl(methylsulfonyl)amino]phenyl]methyl]carbamate Int-14f (4.2g , 7.89 mmol, 29.7 % yield) as a white solid. MS obsd. (ESI+) ([M-tBu+H]+): 476.0 Example 18: V-[4-[4-(4-fluorobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide

[0286] Step 1 : 4-[ ( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)methylene ]piperidin-l-ium chloride

[0287] •HCI

[0288] Int-18a

[0289] 4-[(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)methylene]piperidine-l-carboxylic acid tert-butyl ester (500 mg, 1.55 mmol, 1.0 eq) was dissolved in DCM (1 mL). 4 M HC1 (4.64 g, 3.87 mL, 15.47 mmol, 10 eq) was added and the mixture was stirred at 23 °C for 18 hours. The mixture was evaporated to dryness to afford Int-18a as a light yellow solid (465 mg, 99.59 % yield). MS obsd. (ESI pos) ([M+H]+): 224.2.

[0290] Step 2: 2-[mesyl(methyl)amino ]-N-[ 4-[ 4-[ ( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)methylene ]piperidino ] sulfonylphenyl benzamide In a vial Int-1 (650 mg, 1.37 mmol, 1.0 eq) was dissolved in DCM (1.96 mL). Int-18a(455.34 mg, 1.51 mmol, 1.1 eq) and TEA (416.32 mg, 573.44 uL, 4.11 mmol, 3.0 eq) were added and the mixture was stirred at 23 °C for 3 hours. The mixture was evaporated to dryness and purified via flash chromatography (Silica Gel 24g, 0-100%B, Heptane / EtOAc, 20min) to afford Int-18b (1004.6 mg, 99.41% yield) as a light red waxy solid. MS obsd. (ESI pos) ([M+H]+): 590.4.

[0291] Step 3: N- 4-[ 4-(4-jluorobenzylidene)piperidino ] sulfonylphenyl ]-2- [mesyl(methyl)amino Jbenzamide

[0292] In a vial, Int-18b (25.67 mg, 34.83 umol, 1.00 eq) was dissolved in 1,4-dioxane (513.4 uL). 1- fluoro-4-iodo-benzene (8.51 mg, 38.32 umol, 1.1 eq), tetrakis(triphenylphosphine)palladium (805.07 ug, 696.69 nmol, 0.02 eq) and potassium carbonate (19.26 mg, 139.34 umol, 4.0 eq) were added followed by water (513.4 uL). The mixture was stirred at 100 °C for 4 hours. The mixture was evaporated to dryness and purified via prepHPLC to afford Example 18 (12.7 mg, 65.38% yield) as white solid. MS obsd. (ESI neg) ([M-H]'): 557.2.

[0293] Example 19: 7V-[4-[4-(2-bromobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide

[0294] Example 19 was synthesized in analogy to Example 18 to afford Example 19 (69.2 mg, 37.15% yield) as a white crystalline. MS obsd. (ESI neg) ([M-H]'): 616.1. Example 20: 2-[mesyl(methyl)amino]-7V-[4-[4-(2- nitrobenzylidene)piperidino]sulfonylphenyl]-5-piperazino-benzamide

[0295] Int-20: benzyl 4-(3-((4-(chlorosulfonyl)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-l-carboxylate

[0296] Int-20

[0297] Step 1: l-benzylsulfanyl-4-nitro-benzene (Int-20a)

[0298] Int-20a To a solution of 4 -nitrothiophenol (10.0 g, 64.5 mmol) and bromomethylbenzene (11.0 g, 64.5 mmol) in DMF (100 mL) was added K2CO3 (19.6 g, 141.8 mmol) at 25 °C and the mixture was stirred at 50 °C for 12 hours. After cooling down to room temperature, the mixture was poured into water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude lb (13.5 g, 55.0 mmol, 85.4% yield) as a yellow solid. The crude product was used directly in next step without purification. MS obsd. (ESI+) ([M+H]+): 246.1.

[0299] Step 2: 4-benzylsulfanylaniline (Int-20b)

[0300] Int-20b

[0301] To a solution of lb (10.0 g, 40.8 mmol) in DMF (100 mL) was added 2-pyridin-2-ylpyridine (636.0 mg, 4.1 mmol) and hypoboric acid (14.5 g, 163.1 mmol) slowly at 25 °C. After addition, the mixture was stirred at 25 °C for 1 h. Then the mixture was poured into water (100 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over ISfeSCU, filtered and concentrated under reduced pressure to give crude 1c (8.0 g, 37.2 mmol, 91.1% yield) as yellow oil. The crude product was used directly in next step without purification. MS obsd. (ESI+) ([M+H]+): 216.1.

[0302] Step 3: methyl 5-bromo-2-(methylsulfonamido)benzoate (Int-20c)

[0303] Int-20c To a solution of methyl 2-amino-5-bromo-benzoate (10.0 g, 43.5 mmol) in THF (150 mL) was added pyridine (30.9 g, 391.2 mmol) and methyl sulfonyl methanesulfonate (22.7 g, 130.4 mmol) at 25 °C and the mixture was stirred at 50 °C for 16 hours. After cooled to room temperature, the mixture was diluted with EtOAc (300 mL). The organic phase was washed with water (100 mL x 3) and brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, concentrated in vacuum to give crude le (15.0 g, 48.7 mmol, 95.2% yield) as a brown solid, which was used directly in next step without purification. MS obsd. (ESI+) ([{81Br}M+H]+): 309.8.

[0304] Step 4: methyl 5-bromo-2-(N-methylmethylsulfonamido)benzoate (In-20d)

[0305] Int-20d

[0306] To a solution of le (15.0 g, 48.7 mmol) in DMF (150 mL) was added K2CO3 (20.2 g, 146.0 mmol) and iodomethane (17.3 g, 121.7 mmol). The mixture was stirred at 50 °C for 4 hours. After cooling to room temperature, the mixture was poured into a mixture of EtOAc (500 mL) and water (300 mL). The organic phase was washed with brine (100 mL x 3), dried over ISfeSCU, concentrated under reduced pressure to give crude If (15.0 g, 46.6 mmol, 81.3% yield) as a brown solid, which was used directly in next step without purification. MS obsd. (ESI+) ([{79Br}M+Na]+): 343.9.

[0307] Step 5: benzyl 4-[3-methoxycarbonyl-4-[methyl(methylsulfonyl)amino]phenyl]piperazine-l- carboxylate (Int-20e)

[0308]

[0309] Int-20e

[0310] To a solution of If (5.0 g, 15.5 mmol), 1-CBZ-piperazine (4102.2 mg, 18.6 mmol), CS2CO3 (15169.9 mg, 46.6 mmol), (5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane (1.8 g, 3.1 mmol) and palladium acetate (696.9 mg, 3.1 mmol) in toluene (150 mL) under N2 and the mixture was stirred at 100 °C for 16 hours under N2. After cooled to room temperature, the mixture was diluted with EtOAc (300 mL) and filtered. The filtrate was washed with water (100 mL), brine (100 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (PEZEA = 1 / 0 to 1 / 1; TLC: PEZEA = 3 / 1, Rf = 0.6) to give 1g (4.2 g, 9.1 mmol, 58.6% yield) as a brown solid. MS obsd. (ESI+) ([M+H]+): 462.2.

[0311] Step 6: 5-(4-benzyloxycarbonylpiperazin-l-yl)-2-[methyl(methylsulfonyl)amino]benzoic acid (Int-20J)

[0312] Int-20f

[0313] To a solution of 1g (3.8 g, 8.2 mmol) in Ethanol (150 mL) and water (30 mL) was added NaOH (1.7 g, 41.2 mmol) at 0°C. The mixture was stirred at 50 °C for 1 h. After cooling to room temperature, the mixture was adjusted pH to 5 with 1 M HC1 and extracted with EtOAc (100 mL x 3). The combined organic layers wer washed with brine (100 mL x 3), dried over Na2SO4, concentrated under reduced pressure to give crude Ih (3.7 g, 8.3 mmol, 84.4% yield) as a yellow solid. The crude product was used directly in next step without purification. MS obsd. (ESI+) ([M+H]+): 448.2.

[0314] Step 7: benzyl 4-(3-((4-(benzylthio)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-l-carboxylate (Int-20g)

[0315] Int-20g

[0316] To a solution of Ih (3.4 g, 7.6 mmol), 1c (3.3 g, 15.2 mmol) and 1 -methylimidazole (3.6 mL, 45.6 mmol) in ACN (60 mL) was added N-(chloro(dimethylamino)methylene)-N- methylmethanaminium hexafluorophosphate(V) (6.4 g, 22.8 mmol) at 0 °C. After stirred at 25 °C for 4 hours, the mixture was poured into water (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over ISfeSCL, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (PEZEA = 1 / 0 to 1 / 1; TLC: PEZEA = 5 / 1, Rf = 0.5) to give li (4.0 g, 6.2 mmol, 81.7% yield) a white solid. MS obsd. (ESI+) ([M+H]+): 645.4.

[0317] Step 8: benzyl 4-(3-((4-(chlorosulfonyl)phenyl)carbamoyl)-4-(N- methylmethylsulfonamido)phenyl)piperazine-l-carboxylate (Int-20)

[0318]

[0319] To a solution of li (2.0 g, 3.1 mmol) in THF (10 mL), acetic acid (10 mL) and water (3 mL) was added sulfuryl chloride (1.3 mL, 15.5 mmol) at 0 °C. After stirred at 25 °C for 2 hours, the mixture was poured into ice-water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over ISfeSCL, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (PEZEA = 1 / 0 to 1 / 1; TLC: PEZEA = 5 / 1, Rf = 0.3). Int-20 (999.0 mg, 1.6 mmol, 50.5% yield) was obtained as a white solid. MS obsd. (ESI+) [({35C1}M+H)+]: 621.2.

[0320] Step 9: l-(diethoxyphosphorylmethyl)-2-nitro-benzene

[0321] Int-20h

[0322] In a vial l-(bromomethyl)-2-nitro-benzene (1.5 g, 6.94 mmol, 1.0 eq) was dissolved in toluene (8.56 mL). Triethyl phosphite (17.31 g, 18.12 mL, 104.15 mmol, 15.0 eq) was added and the mixture was refluxed for 17 hours. The crude mixture was evaporated to dryness and purified via flash chromatography (Silica Gel 40g, 0-100 %B, HeptaneZEA, 23 min) to afford Int-20a (1.89g, 99.63 % yield) as a light yellow oil. MS obsd. (ESI pos) ([M+H]+): 274.1.

[0323] Step 10: 4-(2-nitrobenzylidene)piperidine-l-carboxylic acid tert-butyl ester

[0324] Int-20i

[0325] In a flask Int-20a (1.89 g, 4.15 mmol, 1.0 eq) and l-Boc-4-piperidone (992.38 mg, 4.98 mmol, 1.200 eq) were dissolved in THF (14.46 mL). NaH (332.04 mg, 8.3 mmol, 2.0 eq) was added and the mixture was stirred at 22 °C for 10 min. The crude mixture was evaporated to dryness and purified via flash chromatography (Silica Gel 40g, 0-100 %B, HeptaneZEA, 20min) to afford Int- 20b (1.59 g, 99.87 % yield) as a light yellow oil. MS obsd. (ESI pos) ([M+H-BOC] ): 219.1.

[0326] Step 11: 4-(2-nitrobenzylidene)piperidin-l-ium .1:1 chloride

[0327] •HCI

[0328] Int-20b was dissolved in DCM (35 mL) and treated with an excess of HCI in Dioxane (4.53 g, 3.48 mL, 124.35 mmol, 30.0 eq). The solution was stirred at 22 °C for 22 hours and evaporated to afford Int-20c (1.19 g, 95.8% yield) as a white crystalline solid. MS obsd. (ESI pos) ([M+H]+): 220.1.

[0329] Step 12: 2-[mesyl(methyl)amino ]-N-[ 4-[ 4-(2-nitrobenzylidene)piperidino ] sulfonylphenyl ]-5- piperazino-benzamide (Example 20) Int-20 (25.28 mg, 38.91 umol, 1.000 eq) was dissolved in DCM (1 mL). Int-20j (12.83 mg, 42.8 umol, 1.1 eq) and triethylamine (11.81 mg, 15.54 uL, 116.73 umol, 3.0 eq) were added and the mixture was stirred at 23°C for 4 hours. LC / MS showed reaction complete. TFA (221.83 mg, 149.88 uL, 1.95 mmol, 50.0 eq) was added and the mixture was stirred at 100 °C for overnight. The mixture was evaporated to dryness. The crude was purified via prep. HPLC. The corresponding fractions were combined and evaporated to give Example 202-[mesyl(methyl)amino]-N-[4-[4-(2- nitrobenzylidene)piperidino]sulfonylphenyl]-5-piperazino-benzamide (5.5 mg, 19.02%) as light brown solid. MS obsd. (ESI neg) ([M-H]-): 667.3.

[0330] Example 22: V-[4-[4-(2-fluorobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide

[0331] Step 1: 4-[(E)-(tosylhydrazono)methyl]piperidine-l-carboxylic acid tert-butyl ester lnt-22a p-toluenesulfonhydrazide (192.11 mg, 1.03 mmol, 1.1 eq) was dissolved in toluene (1 mL). 4- formylpiperidine-1 -carboxylic acid tert-butyl ester (200 mg, 937.78 umol, 1.0 eq) was added and the mixture was stirred at 22 °C for 1 hour. The crude material was evaporated to dryness and purified via prep-HPLC (column: XXX, mobile phase: [A: water (0.05% FA) - B: [ACN], B%: 20% -95%, 6 min) to afford Int-22.a (325.4 mg, 77.3 % yield) as a white solid. MS obsd. (ESI neg) ([M-H]-): 380.29.

[0332] Step 2: 4-(2-jluorobenzylidene)piperidine lnt-22.b

[0333] In an inert vial Int-22a was dissolved in 1,4-Dioxane. l-bromo-2-fluorobenzene (21.45 mg, 13.32 uL, 122.55 umol, l.leq ), Pd2(dba)3 (5.1 mg, 5.57 umol, 0.050 eq), x-phos (5.31 mg, 11.14 umol, 0.1 eq) and 1 M lithium tert-butoxide in hexanes (245.09 uL, 245.09 umol, 2.2 eq) were added, the mixture was degassed with Ar and placed on a shaker at 90 °C for 2 hours. Another l-bromo-2- fluorobenzene (21.45 mg, 13.32 uL, 122.55 umol, 1.1 eq), Pd2(dba)3 (5.1 mg, 5.57 umol, 0.05 eq) and x-phos (5.31 mg, 11.14 umol, 0.1 eq) were added and the mixture was placed on a shaker at 100 °C for 17 hours. The crude material was evaporated to dryness, dissolved in DCM (1 mL) and treated with an excess of 4 M HC1 in dioxane (501.32 mg, 417.77 uL, 1.67 mmol, 15.0 eq). The mixture was stirred at 22 °C for 3 hours. The crude material was evaporated to dryness and purified via prep-HPLC to afford Int-22.2 (8.55 mg, 34.91% yield) as a light yellow solid. MS obsd. (ESI pos) ([M+H]+): 192.2.

[0334] Step 3: N-[ 4-[ 4-(2-fluorobenzylidene)piperidino ] sulfonylphenyl -2- [mesyl(methyl)amino Jbenzamide

[0335] To a solution of Int-1 (18.91 mg, 45.06 umol, 1.158 eq) in DCM (1.5 mL) was added Int-22.b (8.55 mg, 0.039 mmol, 1.0 eq) and TEA (11.81 mg, 16.29 uL, 116.69 umol, 3.0 eq ). The mixture was stirred at 22 °C for 4 hours and then at 40 °C for 2 hours and then at 70 °C for 10 hours. The crude mixture was purified via prep-HPLC and evaporated to afford Example 22 (2.4 mg, xx mmol, 10.62 % yield) as a light yellow solid. MS obsd. (ESI+) ([M+H]+): 558.4.

[0336] Example 23: A [4-[[4-[[2-(3-hydroxypropoxy)phenyl]methylene]-l- piperidyl]sulfonyl]phenyl]-2-[methyl(methylsulfonyl)amino]benzamide

[0337] To 3-bromopropoxy-tert-butyl-dimethyl-silane (5.32 mg, 0.021 mmol, 1.5 eq) was added a solution of Example 24 (11.44 mg, 0.014 mmol, 1 eq) dissolved in N,N-dimethylformamide (1 mL), followed by the addition of K2CO3 (9.67 mg, 70 umol, 5.0 eq) . The mixture was stirred at 90 °C overnight. The K2CO3 was filtered off and the filtrate was treated with an excess of 4 M HC1 in dioxane (0.5 mL). The crude mixture was purified by preparative HPLC to afford the title compound (4.3 mg, 42.04%). MS obsd. (ESI+) ([M+H]+): 614.3.

[0338] Example 24: A [4-[[4-[(2-hydroxyphenyl)methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide

[0339] Int-18b (637 mg, 864.42 umol, 1.000 eq) was dissolved in a mix of degassed solvents 1,4-dioxane (10 mL) and water (2 mL). (2-bromophenoxy)-tert-butyl-dimethyl-silane (310.4 mg, 1.08 mmol, 1.250 eq), tetrakis(triphenylphosphine)palladium (19.98 mg, 17.29 umol, 0.020 eq) and potassium carbonate (477.87 mg, 3.46 mmol, 4.000 eq) were added. The mixture was stirred at 100 °C for 2 hours. The mixture was diluted with water and the product extracted twice with AcOEt (50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting TBDMS protected intermediate was dissolved in DCM (10 mL) and treated with an excess of 4 M HC1 in dioxane (6.81 g, 6.48 mL, 25.93 mmol, 30.000 eq) at RT for 2 hours. The mixture was adsorbed on Isolute and purified over flash chromatography (EtOAc in Heptane gradient) to yield Example 24 as light yellow solid (230.6 mg, 32.65%). MS obsd. (ESI+) ([M+H]+): 556.2.

[0340] Example 25: 2-[[l-[4-[[2-[mesyl(methyl)amino]benzoyl]amino]phenyl]sulfonyl-4- piperidylidene] methyl] benzoic acid methyl ester

[0341] Step 1: 4-(2-carbomethoxybenzylidene)piperidine-l -carboxylic acid tert-butyl ester

[0342] 4-[(E)-(tosylhydrazono)methyl]piperidine-l-carboxylic acid tert-butyl ester Int-22a (204 mg, 454.53 umol, 1.0 eq) was dissolved in 1,4-dioxane, extra dry (10 mL). Methyl 2-bromobenzoate (122.18 mg, 79.86 uL, 568.17 umol, 1.25 eq), Pd2(dba)3 (20.81 mg, 22.73 umol, 0.05 eq) and x- phos (21.67 mg, 45.45 umol, 0.1 eq) and 1 M lithium tert-butoxide IM in hexanes (999.97 uL, 999.97 umol, 2.2 eq) were added, the mixture was degassed with Ar and the mixture was placed on a shaker at 100 °C for 19 hours. LC / MS showed reaction complete. The reaction mixture was evaporated to dryness. The mixture was dissolved in EtOAc (30 mL). Water (30 mL) was added and the mixture was extracted. The aqueous layer was extracted again with 30mL EtOAc. The organic layers were combined, dried with sodium sulphate and evaporated on Isolute. The mixture was purified via flash chromatography (24g Silica Gel, HP / EtOAc 0-50%B, 15 min). The corresponding fractions were combined and evaporated to give 4-(2- carbomethoxybenzylidene)piperidine-l -carboxylic acid tert-butyl ester Int-25a (169.6 mg, 81.06%) as yellow oil. MS obsd. (ESI+) ([M+H-Buten]+): 232.2.

[0343] Step 2: 2-(piperidin-l-ium-4-ylidenemethyl)benzoic acid methyl ester chloride

[0344] Int-25b

[0345] 4-(2-carbomethoxybenzylidene)piperidine-l -carboxylic acid tert-butyl ester Int-25a (169.6 mg, 0.368 mmol, 1.0 eq) was dissolved in DCM (3 mL). 4 M HCI in Dioxane (1.66 g, 1.38 mL, 5.53 mmol, 15.0 eq) was added and the mixture was stirred at 22 °C for 12 hours. LC / MS showed reaction complete. The compound 2-(piperidin-l-ium-4-ylidenemethyl)benzoic acid methyl ester chloride was obtained as a light yellow solid and was used without further purification. MS obsd. (ESI+) ([M+H]+): 233.1.

[0346] Step 3: 2-[[l-[4-[[2-[mesyl( methyl)amino ] benzoyl amino ] phenyl ]sulfonyl-4- piperidylidene]methyl]benzoic acid methyl ester

[0347] Example 25 was prepared in analogy to the preparation of Example 1 by using Int-25b instead of 4-cyclopentylidenepiperidine in step 3 to give Example 25 (170 mg, 95.49%) as white solid. MS obsd. (ESI+) ([M+H]+): 598.4 Example 26: A [4-[[4-[[5-chloro-2-(2-hydroxyethoxy)phenyl]methylene]-l- piperidyl]sulfonyl]phenyl]-2-[methyl(methylsulfonyl)amino]benzamide

[0348] Example 26 was prepared in analogy to the preparation of Example 23 to give Example 26 (12.9 mg, 50.9%). MS obsd. (ESI+) ([M+H]+): 634.4

[0349] Example 27: 2-[methyl(methylsulfonyl)amino]-A [4-[[4-[(2-nitrophenyl)methylene]-l- piperidyl]sulfonyl]phenyl]benzamide

[0350] Example 27 was prepared in analogy to the preparation of Example 1 by using Int-20j instead of 4-cyclopentylidenepiperidine in step 3 to give Example 27 (12.4 mg, 55.8 %). MS obsd. (ESI+) ([M+H]+): 585.3

[0351] Example 28: Az-[4-[[4-[[2-(difluoromethoxy)phenyl]methylene]-l- piperidyl]sulfonyl]phenyl]-2-[methyl(methylsulfonyl)amino]benzamide

[0352] Example 28 was prepared in analogy to the preparation of Example 1 by using 4-[[2- (difluoromethoxy)phenyl]methylene]piperidine (CAS: 2353117-98-1) instead of 4- cyclopentylidenepiperidine in step 3 to give Example 28 (14.2 mg, 61.7 %). MS obsd. (ESI+) ([M+H]+): 606.3.

[0353] Example 29: 7V-[4-[(4-benzylidene-l-piperidyl)sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide

[0354] Example 29 was prepared in analogy to the preparation of Example 1 by using

[0355] 4-benzalpiperidine (CAS: 164650-58-2) instead of 4-cyclopentylidenepiperidine in step 3 to give

[0356] Example 29 (19 mg, 62.5 %). MS obsd. (ESI+) ([M+H]+): 540.2

[0357] Biological Example - Minimal Inhibitory Concentration Protocol (MIC) Assay:

[0358] The antibacterial activity of the compounds of the present invention was evaluated against the commonly used quality control strain Escherichia coli ATCC 25922, which was originally derived from human clinical samples and is available from ATCC (American Type Culture Collection). The in vitro potency of compounds to inhibit Escherichia coli (ATCC 25922) growth was assessed by the MIC (Minimal Inhibitory Concentration) broth dilution method. Specifically compound dilutions were prepared from 10 mM DMSO stock solutions as follows: i) serial 2-fold dilution in 20 pL DMSO were prepared in a master plate (Greiner, Cat No: 651201), ii) 180 pL sterile distilled water was added to each aliquot and iii) 10 pL diluted compounds were transferred into a new assay plate (Costar, 3599).

[0359] Vials of each test microorganisms were maintained frozen in the vapor phase of a liquid nitrogen freezer. Single-use frozen vials of the strain Escherichia coli ATCC 25922 (KWIKSTIK, 0335K) with predetermined CFU / mL, were taken out from the freezer, thawed at room temperature, and diluted in Cation-Adjusted Mueller Hinton Broth (CAMHB) to achieve a final inoculum of 5 x io5CFU / mL. 90 pL bacteria containing broth was dispensed to the assay plate containing the pre-dispensed compound dilutions and mixed by pipetting 5 times.

[0360] Then the assay plates were incubated for 20 hours at 35 °C in ambient air. Following incubation, the MIC (pg / mL), the lowest concentration of drug that inhibits visible growth of the microorganism was read with the help of a magnification mirror and recorded.

[0361] Table 2: MIC values of the compounds of this invention against E. coli

[0362]

[0363] Example A Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0364] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat. Example B

[0365] Capsules containing the following ingredients can be manufactured in a conventional manner:

[0366] The components are sieved and mixed and filled into capsules of size 2.

[0367] Example C

[0368] Injection solutions can have the following composition:

[0369] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims

Claims1. A compound of formula (I)whereinA1is -N- or -CH-;A2is -N- or -CH-;A3is -N- or -CH-;A4is -N- or -CH-;A5is -N- or -CR7-;A6is -N- or -CR8-;A7is -N- or -CR9-;Ri is alkyl;R2 is alkyl;R3 is hydrogen, heterocycloalkyl or aminoalkyl;R4 is hydrogen or halogen;Re is hydrogen or halogen; andRs, R7, Rs and R9 are all independently selected from hydrogen, halogen, hydroxyalkoxy, hydroxyl, haloalkoxy, alkoxycarbonyl, alkoxy and nitro; or a pharmaceutically acceptable salt thereof.

2. A compound according to aspect 1, wherein A3and A4are both -CH-.

3. A compound according to aspect 1 or 2, wherein Ri and R2 are both methyl.

4. A compound according to any one of aspects 1 to 3, wherein R3 is hydrogen, piperazinyl or aminomethyl.

5. A compound according to any one of aspects 1 to 4, wherein R4 and Re are both independently selected from hydrogen or fluoro.

6. A compound according to any one of aspects 1 to 5, R4 and Re are both hydrogen.

7. A compound according to any one of aspects 1 to 6, wherein R5, R7, Rs and R9 are all independently selected from hydrogen, chloro, fluoro, hydroxypropoxy, hydroxyethoxy, hydroxy, difluoromethoxy, methoxycarbonyl, methoxy and nitro;8. A compound according to any one of aspects 1 to 7, wherein R5, R7, Rs and R9 are all independently selected from hydrogen, chloro, fluoro, hydroxypropoxy, hydroxyethoxy, hydroxy, difluoromethoxy, methoxycarbonyl, methoxy and nitro, provided that at least two of R5, R7, R8and R9are hydrogen.

9. A compound selected fromN-[4-[(4-cyclopentylidene-l-piperidyl)sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide;2-[methyl(methylsulfonyl)amino]-N-[5-[[4-[(2-nitrophenyl)methylene]-l- piperidyl]sulfonyl]-2-pyridyl]-5-piperazin-l-yl-pyridine-3-carboxamide;N-(5-((4-((2-chloro-5-fluoropyridin-3-yl)methylene)piperidin-l-yl)sulfonyl)pyridin-2-yl)-3-(N-methylmethylsulfonamido)-6-(piperazin-l-yl)pyridazine-4-carboxamide;N-[5-[[4-[(5-fluoro-2-methoxy-3-pyridyl)methylene]-l-piperidyl]sulfonyl]-2-pyridyl]-3- [methyl(methylsulfonyl)amino]-6-piperazin-l-yl-pyridazine-4-carboxamide;2-(N-methylmethylsulfonamido)-N-(6-((4-(2-nitrobenzylidene)piperidin-l- yl)sulfonyl)pyridazin-3-yl)-5-(piperazin-l-yl)nicotinamide;N-[4-[4-[Fluoro-(2-nitrophenyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[[4-[(5-chloro-3-pyridyl)methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide;N-[4-[4-[(4-chloro-2-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-(5-fluoro-2-nitro benzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-[(6-chloropyrazin-2-yl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-[(2-chloro-5-fluoro-3-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-[(5-fluoro-2-methoxy-3-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-[(5-chloro-2-fluoro-3-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;5-(aminomethyl)-2-[methyl(methylsulfonyl)amino]-N-[4-[[4-[(3-nitrophenyl)methylene]-l- piperidyl]sulfonyl]phenyl]benzamide;N-[4-[4-[(3-chloro-2-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-[(5-fluoro-3-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-[(3-fluoro-2-pyridyl)methylene]piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-(4-fluorobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-(2-bromobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;2-[mesyl(methyl)amino]-N-[4-[4-(2-nitrobenzylidene)piperidino]sulfonylphenyl]-5- piperazino-benzamide;N-[4-[4-(3-fluorobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[4-(2-fluorobenzylidene)piperidino]sulfonylphenyl]-2- [mesyl(methyl)amino]benzamide;N-[4-[[4-[[2-(3-hydroxypropoxy)phenyl]methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide;N-[4-[[4-[(2-hydroxyphenyl)methylene]-l-piperidyl]sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide;2-[[l-[4-[[2-[mesyl(methyl)amino]benzoyl]amino]phenyl]sulfonyl-4- piperidylidene]methyl]benzoic acid methyl ester;N-[4-[[4-[[5-chloro-2-(2-hydroxyethoxy)phenyl]methylene]-l-piperidyl]sulfonyl]phenyl]- 2-[methyl(methylsulfonyl)amino]benzamide;2-[methyl(methylsulfonyl)amino]-N-[4-[[4-[(2-nitrophenyl)methylene]-l- piperidyl]sulfonyl]phenyl]benzamide;N-[4-[[4-[[2-(difluoromethoxy)phenyl]methylene]-l-piperidyl]sulfonyl]phenyl]-2-[methyl(methylsulfonyl)amino]benzamide; andN-[4-[(4-benzylidene-l-piperidyl)sulfonyl]phenyl]-2- [methyl(methylsulfonyl)amino]benzamide; or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of aspects 1 to 9 for use as therapeutically active substance.

11. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 9 and a therapeutically inert carrier.

12. The use of a compound according to any one of aspects 1 to 9 for the treatment or prophylaxis of bacterial infection, in particular wherein the bacteria is gram -negative bacteria.

13. The use of a compound according to any one of aspects 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of bacterial infection, in particular wherein the bacteria is gram-negative bacteria.

14. A compound according to any one of aspects 1 to 9 for use in the treatment or prophylaxis of bacterial infection, in particular wherein the bacteria is gram -negative bacteria.

15. A method for the treatment or prophylaxis of bacterial infection, particularly an infection of a gram-negative bacteria, which method comprises administering an effective amount of a compound as defined in any one of aspects 1 to 9.

16. The use, method or compound for use according to any one of aspects 12 to 15, wherein the gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

17. The use, method or compound for use according to aspect 16 wherein the gram-negative bacteria is Enterobacteriaceae, wherein Enterobacteriaceae is Klebsiella pneumoniae or Escherichia coli.

18. The invention as hereinbefore described.

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