WO2009086835A1 - Novel cyanoguanidines - Google Patents

Novel cyanoguanidines Download PDF

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Publication number
WO2009086835A1
WO2009086835A1 PCT/DK2009/000006 DK2009000006W WO2009086835A1 WO 2009086835 A1 WO2009086835 A1 WO 2009086835A1 DK 2009000006 W DK2009000006 W DK 2009000006W WO 2009086835 A1 WO2009086835 A1 WO 2009086835A1
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compound
optionally substituted
nmr
general procedure
starting materials
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PCT/DK2009/000006
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French (fr)
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Fredrik Björkling
Mette Knak Christensen
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Topotarget A/S
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • This invention relates to cyanoguanidine compounds which are useful for the inhibiting of the enzyme nicotinamide phosphoribosyltransferase (NAMPRT), and to medical use of such cyanoguanidine compounds.
  • NAMPRT nicotinamide phosphoribosyltransferase
  • NAMPRT nicotinamide phosphoribosyltransferase
  • Tumor cells have elevated expression of NAMPRT and a high rate of NAD turnover due to high ADP-ribosylation activity required for DNA repair, genome stability, and telomere maintenance making them more susceptible to NAMPRT inhibition than normal cells. This also provides a rationale for the use of compounds of this invention in combination with DNA damaging agents for future clinical trials.
  • NAMPRT is involved in the biosynthesis of nicotinamide adenine dinucleotide (NAD) and NAD(P).
  • NAD can be synthesized in mammalian cells by three different pathways starting either from tryptophan via quinolinic acid, from nicotinic acid (niacin) or from nicotinamide (niacinamide).
  • niacin mononucletide niacin mononucletide
  • Nicotinic acid niacin
  • PRPP niacin mononucleotide
  • dNAM niacin mononucleotide
  • Nicotinamide (niacinamide) reacts with PRPP to give niacinamide mononucleotide (NAM) using the enzyme nicotinamide phosphoribosyltransferase (NAMPRT) O which is also widely distributed in various tissues.
  • NAM niacinamide mononucleotide
  • NAMPRT nicotinamide phosphoribosyltransferase
  • Niacin mononucleotide and niacinamide mononucleotide react with ATP to form niacin adenine dinucleotide (dNAD) and niacinamide adenine dinucleotide (NAD) respectively. Both reactions, although they take place on different pathways, are catalysed by the same enzyme, NAD pyrophosphorylase O.
  • NAD niacin adenine dinucleotide
  • NAD niacinamide adeinine dinucleotide
  • NAD NAD synthetase
  • NAD is the immediate precursor of niacinamide adenine dinucleotide phosphate (NAD(P))
  • NAD kinase For details see, e.g., Cory J. G. Purine and pyrimidine nucleotide metabolism In: Textbook of Biochemistry and Clinical Correlations 3 rd edition ed. Devlin, T, Wiley, Brisbane 1992, pp 529-574.
  • Normal cells can typically utilize both precursors niacin and niacinamide for NAD(P) synthesis, and in many cases additionally tryptophan or its metabolites. Accordingly, murine glial cells use niacin, niacinamide and quinolinic acid (Grant et al. (1998) J. Neurochem. 70: 1759-1763). Human lymphocytes use niacin and niacinamide (Carson et al (1987) J. Immunol. 138: 1904-1907; Berger et al (1982) Exp. Cell Res. 137; 79-88).
  • Rat liver cells use niacin, niacinamide and tryptophan (Yamada et al (1983) Int. J. Vit. Nutr. Res. 53: 184-1291; Shin et al (1995) Int. J. Vit. Nutr. Res. 65: 143-146; Dietrich (1971) Methods Enzymol. 18B; 144-149).
  • Human erythrocytes use niacin and niacinamide (Rocchigiani et al (1991) Purine and pyrimidine metabolism in man VII Part B ed. Harkness et al Plenum Press New York pp337-3490).
  • NAD(P) is involved in a variety of biochemical reactions which are vital to the cell and have therefore been thoroughly investigated.
  • the role of NAD(P) in the development and growth of tumours has also been studied. It has been found that many tumour cells utilize niacinamide for cellular NAD(P) synthesis. Niacin and tryptophan which constitute alternative precursors in many normal cell types cannot be utilized in tumour cells, or at least not to an extent sufficient for cell survival. Selective inhibition of an enzyme which is only on the niacinamide pathway (such as NAMPRT) would constitute a method for the selection of tumour specific drugs. This has been exemplified by the NAMPRT inhibitor APO866. (see Hasmann and Schemainda, Cancer Res 63(21) :7463-7442.)
  • Huang et al (WO 00/61559) describe the following compound as a potential antitumor agent.
  • Huang et al (WO 2000/061559) describe the following compound as a potential antitumor agent.
  • novel compounds of the invention are acting on the enzyme nicotinamide phosphoribosyltransferase (NAMPRT), and that the down-stream inhibition of NF-kB is the result of the lowering of cellular concentrations of nicotinamide adenine dinucleotide (NAD).
  • NAMPRT nicotinamide phosphoribosyltransferase
  • the present invention provides compounds of the general formula (I) according to claim 1, and the utilization of these compounds in medicine, cf. claims 16, 17, 19 and 20.
  • the compounds of the invention are - contrary to many of the known related cyanoguanidines - fairly soluble in water and physiological fluids, for what reason the formulation of the compound for medical uses is believed to be less challenging.
  • Figure 1 illustrates the pathway of NAD biosynthesis (from Biedermann E. et al, WO 00/50399).
  • the present invention La relates to particular cyanoguanidine compounds which are useful for the inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPRT).
  • NAMPRT nicotinamide phosphoribosyltransferase
  • the present invention relates to compounds of the formula (I)
  • n is an integer of 0-12, wherein the sum m+n is 1-20;
  • R 1 is selected from optionally substituted heteroaryl
  • R 2 is selected from hydrogen, optionally substituted optionally substituted C3-i2-cycloalkyl, -[CH 2 CH 2 0]i-io-(optionally substituted Ci -6 -alkyl), optionally substituted Ci- 12 -alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; and R 3 is selected from optionally substituted Ci- 12 -alkyl, optionally substituted C 3- i 2 -cycloalkyl, -
  • each of R 4 and R 4* independently is independently selected from hydrogen, optionally substituted Ci-i 2 -alkyl and optionally substituted Ci_i 2 -alkenyl;
  • Ci-i 2 -alkyl and “Ci- 6 -alkyl” are intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 12 carbon atoms and 1 to 6 carbon atoms, respectively, such as methyl, ethyl, propyl, /so-propyl, cyclopropyl, butyl, /so-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl.
  • C 3- i 2 -cycloall ⁇ yl is encompassed by the term “Ci-i 2 -alkyl”, it refers specifically to the mono- and bicyclic counterparts, including alkyl groups having exo-cyclic atoms, e.g. cyclohexyl-methyl.
  • C 2 -i2-alkenyl and “C 2-6 -alkenyl” are intended to cover linear, cyclic or branched hydrocarbon groups having 2 to 12 carbon atoms and 2 to 6 carbon atoms, respectively, and comprising (at least) one unsaturated bond.
  • alkenyl groups are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl.
  • Preferred examples of alkenyl are vinyl, allyl, butenyl, especially allyl.
  • C 3- i 2 -cycloalkenyl is encompassed by the term “C 2 -i 2 -alkenyl”, it refers specifically to the mono- and bicyclic counterparts, including alkenyl groups having exo-cyclic atoms, e.g. cyclohexenyl-methyl and cyclohexyl-allyl.
  • alkoxy alkenyl
  • cycloalkenyl cycloalkenyl
  • the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-6-alkoxy (i.e.
  • Ci-6-alkyl-oxy C 2 - 6 -alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci -6 -alkoxycarbonyl, Cnralkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, aryloxycarbonyl, arylcarbonyloxy, arylaminocarbonyl, arylcarbonylamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, heteroarylaminocarbonyl, heteroarylcarbonylcarbonyloxy, heteroarylaminocarbonyl, heteroarylcarbonylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heterocyclyloxycarbonyl,
  • the substituents are selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-6- alkoxy (i.e. Ci- 6 -alkyl-oxy), C 2- 6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci -6 -alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, amino, mono- and di(Ci -6 - alkyl)amino; carbamoyl, mono- and di(Ci -6 -alkyl)aminocarbonyl, amino-Ci -6 -alkyl- aminocarbonyl, mono- and dKCi- ⁇ -alkyOamino
  • substituents are selected from hydroxy, Ci- 6 -alkoxy, amino, mono- and di(Ci- 6 -alkyl)amino, carboxy, d- 6 -alkylcarbonylamino, Ci -6 -alkylamino- carbonyl, or halogen.
  • halogen includes fluoro, chloro, bromo, and iodo.
  • aryl is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferred example.
  • heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furanyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl.
  • heteroaryl groups are benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl in particular benzimidazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, furyl, thienyl, quinolyl, tetrazolyl, and isoquinolyl.
  • heterocyclyl groups examples include imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothioph
  • the most interesting examples are tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane, oxazepane, thiazolane, thiazinane, and thiazepane, in particular tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane, oxazinane (morpholine), and thiazinane.
  • N-containing heterocyclic or heteroaromatic ring are intended to encompass those mentioned under “heterocyclyl” and “heteroaryl”, respectively, which include one or more heteroatoms, at least one of which begin a nitrogen atom. Examples hereof are piperazine, isoxazole, isoxazolidine, and morpholine, etc.
  • N,O-containing heterocyclic or heteroaromatic ring are intended to encompass those mentioned under “heterocyclyl” and “heteroaryl”, respectively, which include two or more heteroatoms, two of which being neighbouring nitrogen and oxygen atoms. Examples hereof are isoxazole, isoxazolidine, morpholine, etc.
  • the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-5 times, in particular 1-3 times, with group(s) selected from hydroxy (which when present in an enol system may be represented in the tautomeric keto form), Ci-e-alkyl, Ci- ⁇ -alkoxy, C 2 -6-alkenyloxy, oxo (which may be represented in the tautomeric enol form), oxide (only relevant as the N-oxide), carboxy, Ci-6-alkoxycarbonyl, Ci- 6 -alkylcarbonyl, formyl, aryl, aryloxy, arylamino, aryloxycarbony
  • the substituents are selected from hydroxy, Ci- 6 -alkyl, Ci -6 -alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, C 1-6 - alkylcarbonyl, formyl, amino, mono- and di(Ci- 6 -alkyl)amino; carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci- 6 -alkyl-aminocarbonyl, Ci -6 -alkylcarbonylami- no, guanidino, carbamido, Ci -6 -alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci- 6 -alkyl-suphonyl, Ci -6 -alkyl-sulphinyl, Ci -6 - alkylsulphonyloxy,
  • the substituents are selected from Ci -6 -alkyl, Ci -6 -alkoxy, amino, mono- and di(Ci- 6 -alkyl)amino, sulphanyl, carboxy or halogen, where any alkyl, alkoxy and the like, representing substituents may be substituted with hydroxy, Ci- 6 -alkoxy, C 2 - 6 -alkenyloxy, amino, mono- and di(Ci -6 -alkyl)amino, carboxy, Ci- 6 -alkylcarbonylamino, halogen, Ci -6 - alkylthio, Ci -6 -alkyl-sulphonyl-amino, or guanidino.
  • Groups including C 3- i 2 -cycloalkyl, C 3- i 2 -cycloalkenyl and/or aryl as at least a part of the substituent are said to include "a carbocyclic ring”.
  • Groups including heterocyclyl or heteroaryl as at least a part of the substituent are said to include "a heterocyclic ring” and "a heteroaromatic ring", respectively.
  • salts is intended to include acid addition salts and basic salts.
  • acid addition salts are pharmaceutically acceptable salts formed with non-toxic acids.
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
  • Examples of basic salts are salts where the (remaining) counter ion is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions C + N(R) 3 R 1 , where R and R 1 independently designates optionally substituted Ci -6 -alkyl, optionally substituted C 2 -6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl).
  • Pharmaceutically acceptable salts are, e.g., those described in Remington's Pharmaceutical Sciences, 17. Ed. Alfonso R.
  • an acid addition salt or a basic salt thereof used herein is intended to comprise such salts.
  • the compounds as well as any intermediates or starting materials may also be present in hydrate form.
  • prodrug used herein is intended to mean a compound which - upon exposure to physiological conditions - will liberate a derivative said compound which then will be able to exhibit the desired biological action.
  • Typical examples are labile esters ⁇ i.e. a latent hydroxyl group or a latent acid group).
  • the compounds may be present as racemic mixtures or the individual stereoisomers such as enantiomers or diastereomers.
  • the present invention encompasses each and every of such possible stereoisomers ⁇ e.g. enantiomers and diastereomers) as well as racemates and mixtures enriched with respect to one of the possible stereoisomers.
  • B is selected from -O- and -NR 6 -, in particular B is - O-.
  • B is a single bond.
  • this substituents is preferably optionally substituted pyridinyl, in particular optionally substituted pyridin-4-yl.
  • the length of the spacer element is defined by m and n.
  • m is an integer of 0-10 and n is an integer of 0-10, wherein the sum m+n is 1-12; in particular m is an integer of 1-8 and n is an integer of 0-3, wherein the sum m+n is 3-8.
  • m is an integer of 2-8 and n is 0.
  • R 2 and R 3 includes a carbocyclic ring, heterocyclic ring or a heteroaromatic ring, or R 2 and R 3 together with the intervening atoms form an optionally substituted N-containing heterocyclic or heteroaromatic ring.
  • R 2 and R 3 together with the intervening atoms form an optionally substituted N,O-containing heterocyclic or heteroaromatic ring.
  • R 4 is preferably selected from hydrogen, Ci -6 -alkyl and optionally substituted benzyl and R 4* is hydrogen.
  • B is -O-
  • n is 0;
  • R 2 is selected from hydrogen, optionally substituted C 3 -i 2 -cycloalkyl, -[CH 2 CH 2 0]i-io- (optionally substituted Ci -6 -alkyl), -(CH 2 )o- 2 -(optionally substituted aryl),
  • R 3 is selected from optionally substituted C 3 -i 2 -cycloalkyl, -[CHaCHaOji-io-Coptionally substituted Ci- 6 -alkyl), optionally substituted Ci-i 2 -alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;
  • R 4 is selected from hydrogen, optionally substituted C 3 -i 2 -cycloalkyl, -(CH 2 )o- 2 -(optionally substituted aryl), -(CH 2 )o- 2 -(optionally substituted heteroaryl) and -(CH 2 )o- 2 -(optionally substituted heterocyclyl); and
  • R 4* is hydrogen
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods outline below, together with methods known in the art of organic synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • novel compounds of formula (I) may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected.
  • synthetic methods described below it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be compatible with the reagents and reactions proposed. Not all molecules of formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used.
  • Compounds of general formula (I), which are hydroxamic acid esters (Ia) can be prepared from dimethyl /V-cyanodithio-iminocarbonate and an amine to yield intermediates of general formula (II), followed by reaction with amino acids of general formula (III).
  • the resulting acid (IV) can subsequently be coupled with a hydroxylamine (V) using a peptide coupling reagent, e.g. EDC or HATU.
  • Diphenyl cyanocarbonimidate may be employed instead of ⁇ /-cyanodithio-iminocarbonate.
  • Hydroxylamines (V) are either commercially available or can be prepared from N- hydroxyphtalimide (or alternatively tert-butylhydroxycarbamate) by alkylation with a halogenide and a base (e.g. DBU) or a Mitsunobu reaction with an alcohol (using e.g. DEAD), followed by deprotection with hydrazine or methylhydrazine, resulting in hydroxylamine (Va).
  • the resulting hydroxylamine (Va) may be submitted to reductive amination with an aldehyde or ketone followed by reduction with e.g. sodium cyanoborohydride as described in the literature ⁇ e.g. B.J. Mavunkel et a ⁇ . ⁇ Eur.J.Med.Chem. (1994) 29, 659-666; T. Ishikawa eta/.: J.Antibiotics (2000), 53 (10), 1071-1085; J.Ishwara Bhat et al. : J.Chem.Soc, Perkin Trans. 2 (2000),1435- 1446).
  • an aldehyde or ketone followed by reduction with e.g. sodium cyanoborohydride as described in the literature ⁇ e.g. B.J. Mavunkel et a ⁇ . ⁇ Eur.J.Med.Chem. (1994) 29, 659-666; T. Ishikawa eta/.: J.Antibiotics
  • alkylation of the hydroxylamine (Va) can be achieved by a Mitsunobu reaction or alkylation after protection with e.g. 2- nitrophenylsulfonylchloride and subsequent removal of the protecting group (using e.g. thiophenol and cesium carbonate).
  • Compounds of general formula (I), which are ⁇ /-alkyl- or /V-arylhydrazides, N,N ' - dialkyl- or /V / ⁇ / ' -diarylhydrazides (Ib) can be prepared from acids general formula (IV)) by coupling with hydrazines of general formula (VI)) using a peptide coupling reagent, e.g. EDC or HATU.
  • a peptide coupling reagent e.g. EDC or HATU.
  • Hydrazines are either commercially available or can - in the case where R 2 is H - be prepared from hydrazine hydrate by alkylation in the presence of a base according to literature procedures (e.g. D.J. Drain et a : J.Med.Chem. (1963) 6 63- 9; G. B. Marini-Bettolo et al. : Rend.Ist.Super.Sanita (1960) 23 1110-27). N,N '-
  • Disubstituted hydrazines can be obtained from monosubstituted hydrazines (V ⁇ a)by reaction with an aldehyde or ketone followed by redcuction with e.g. hydrogen, LiAIH 4 , or borane according to literature procedures (e.g. H.Dorn etal. : Zeitschrift f ⁇ r Chemie (1972) 12(4) 129-30; R.L.
  • Compounds of general formula (I), which are hydroxamic acid esters, ⁇ /-alkyl- or N- arylhydrazides, /V,/V '-dialkyl- or /V ⁇ /V '-diarylhydrazides containing a substituent ⁇ to the carbonyl group (Ic) can be prepared from amino acids of general formula (Ilia) or their enantiomers (obtained, as described in the literature e.g K. S. Orwig et al.: Tet.Lett (2005) 46 7007-7009) by coupling to compounds of general formula (II) and subsequent coupling to hydroxylamines (V) or hydrazines (VI) as described above.
  • Compounds (I) of the present invention which are /V-alkoxy- or /V- aryloxythioamides, or thiohydrazides (Id) can be prepared from the corresponding carbonyl compounds (Ia) or (Ib) by treatment with Lawesson reagent according to literature procedures (e.g. Thomsen et al.: Org. Synth. (1984) 62, 158, R.A. Cherkasov et al.: TeL (1985) 41, 2567; M. P. Cava, MJ. Levinson Tet. (1985) 41, 5061).
  • Lawesson reagent e.g. Thomsen et al.: Org. Synth. (1984) 62, 158, R.A. Cherkasov et al.: TeL (1985) 41, 2567; M. P. Cava, MJ. Levinson Tet. (1985) 41, 5061).
  • carboxylic acids of general formula (IV) can be converted into an activated species of general formula (VII) according to literature procedures (M. A: Shalaby et al.: J.Org.Chem. (1996) 61 9045-48) and subsequently allowed to react with hydroxylamines (V) or hydrazines (VI) as depicted below.
  • Compounds (I) of the present invention which are /V-alkoxy-P- alkylphosphonamidates or ⁇ /-aryloxy-P-alkylphosphonamidates, P- alkylphosphonamidates or P-alkylphosphonohydrazidates (Ig) can be obtained by reaction of the phtalimido protected phosphonochloridates (XI) (prepared as described in the literature, e.g. S.Gobecet a/.; Tet.Lett. (2002) 43 167-170; U.Urleb et al.: Lett.
  • XI phtalimido protected phosphonochloridates
  • Compounds (I) of the present invention which are /V-a!koxy-P-alkylphosphinic amides or ⁇ /-aryloxy-P-alkylphosphinic amides, P-alkylphosphinic amides or P- akylphosphinic hydrazides (Ih) can be obtained by reaction of the phtalimido protected alkylphosphinic chlorides (XIV) ⁇ e.g. S. Gobec et al.: Lett. In Peptide Science (1998) 5 109-114) with hydroxylamines, amines or hydrazines, respectively, in the presence of a base followed by deprotection with hydrazine hydrate. The resulting amine (XVI) is subsequently allowed to react with compounds of general formula (II) to obtain compounds of formula (Ih).
  • Other protecting groups than phtalimido may be employed.
  • the protecting group Pg e.g phthalimido, BOC or other
  • Pg e.g phthalimido, BOC or other
  • XXI methyl ⁇ / '-cyano- ⁇ /- heteroarylcarbamimidothioates
  • the compounds of the invention is believed to be particularly useful for down- regulating NAD via inhibition of NAMPRT, and such compounds are therefore particularly useful for treating diseases in which activation of NF- ⁇ B is implicated.
  • diseases including inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and CPOD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, C
  • the present invention provides a compound of the formula (I) for use as a medicament; more particular for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT), especially for the treatment of the above- mentioned diseases and conditions.
  • NAMPRT nicotinamide phosphoribosyltransferase
  • the invention also provides a method of inhibiting the enzymatic activity of nicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said method comprising the step of administering to said mammal a pharmaceutically relevant amount of a compound of the general formula (I).
  • NAMPRT nicotinamide phosphoribosyltransferase
  • the invention provides a method of treating a disease or condition (in particular the diseases and condtions mentioned above) caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said method comprising the step of administering to said mammal a pharmaceutically relevant amount of a compound of the general formula (I).
  • a disease or condition in particular the diseases and condtions mentioned above
  • NAMPRT nicotinamide phosphoribosyltransferase
  • the compound may be administered in combination with a DNA damaging agent.
  • the compounds of the general formula (I) are suitably formulated in a pharmaceutical composition so as to suit the desirable route of administration.
  • the administration route of the compounds may be any suitable route which leads to a concentration in the blood or tissue corresponding to a therapeutic effective concentration.
  • the following administration routes may be applicable although the invention is not limited thereto: the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route and the ocular route.
  • the administration route is dependent on the particular compound in question; particularly the choice of administration route depends on the physico-chemical properties of the compound together with the age and weight of the patient and on the particular disease or condition and the severity of the same.
  • the compounds may be contained in any appropriate amount in a pharmaceutical composition, and are generally contained in an amount of about 1-95%, e.g. 1- 10%, by weight of the total weight of the composition.
  • the composition may be presented in a dosage form which is suitable for the oral, parenteral, rectal, cutaneous, nasal, vaginal and/or ocular administration route.
  • the composition may be in form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols and in other suitable form.
  • compositions may be formulated according to conventional pharmaceutical practice, see, e.g., "Remington's Pharmaceutical Sciences” and
  • the compounds defined herein are formulated with (at least) a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers or excipients are those known by the person skilled in the art. Formation of suitable salts of the compounds of the Formula (I) will also be evident in view of the before-mentioned.
  • the present invention provides in a further aspect a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the general Formula (I) in combination with a pharmaceutically acceptable carrier.
  • compositions according to the present invention may be formulated to release the active compound substantially immediately upon administration or at any substantially predetermined time or time period after administration.
  • the latter type of compositions is generally known as controlled release formulations.
  • controlled release formulation embraces i) formulations which create a substantially constant concentration of the drug within the body over an extended period of time, ii) formulations which after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time, iii) formulations which sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance (saw-tooth kinetic pattern), iv) formulations which attempt to localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ, v) formulations which attempt to target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type.
  • Controlled release formulations may also be denoted “sustained release”, “prolonged release”, “programmed release”, “time release”, “rate-controlled” and/or “targeted release” formulations.
  • Controlled release pharmaceutical compositions may be presented in any suitable dosage forms, especially in dosage forms intended for oral, parenteral, cutaneous nasal, rectal, vaginal and/or ocular administration.
  • suitable dosage forms especially in dosage forms intended for oral, parenteral, cutaneous nasal, rectal, vaginal and/or ocular administration.
  • Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, liposomes, delivery devices such as those intended for oral, parenteral, cutaneous, nasal, vaginal or ocular use.
  • Capsules, tablets and pills etc. may contain for example the following compounds: microcrystalline cellulose, gum or gelatin as binders; starch or lactose as excipients; stearates as lubricants; various sweetening or flavouring agents.
  • the dosage unit may contain a liquid carrier like fatty oils.
  • coatings of sugar or enteric agents may be part of the dosage unit.
  • the pharmaceutical compositions may also be emulsions of the compound(s) and a lipid forming a micellular emulsion.
  • the pharmaceutical composition may include a sterile diluent, buffers, regulators of tonicity and antibacterials.
  • the active compound may be prepared with carriers that protect against degradation or immediate elimination from the body, including implants or microcapsules with controlled release properties.
  • the preferred carriers are physiological saline or phosphate buffered saline.
  • the pharmaceutical composition is in unit dosage form.
  • each unit dosage form typically comprises 0.1-500 mg, such as 0.1- 200 mg, e.g. 0.1-100 mg, of the compound.
  • the compound are preferably administered in an amount of about 0.1-250 mg per kg body weight per day, such as about 0.5-100 mg per kg body weight per day.
  • the dosage is normally 0.5 mg to 1 g per dose administered 1-4 times daily for 1 week to 12 months depending on the disease to be treated.
  • the dosage for oral administration of the composition in order to prevent diseases or conditions is normally 1 mg to 100 mg per kg body weight per day.
  • the dosage may be administered once or twice daily for a period starting 1 week before the exposure to the disease until 4 weeks after the exposure.
  • compositions adapted for rectal use for preventing diseases a somewhat higher amount of the compound is usually preferred, i.e. from approximately 1 mg to 100 mg per kg body weight per day.
  • a dose of about 0.1 mg to about 100 mg per kg body weight per day is convenient.
  • a dose of about 0.1 mg to about 20 mg per kg body weight per day administered for 1 day to 3 months is convenient.
  • a dose of about 0.1 mg to about 50 mg per kg body weight per day is usually preferable.
  • a solution in an aqueous medium of 0.5-2% or more of the active ingredients may be employed.
  • a dose of about 1 mg to about 5 g administered 1-10 times daily for 1 week to 12 months is usually preferable.
  • MS was performed using a Micromass LCT with an AP-ESI-probe or LC-MS using a Bruker Esquire 3000+ ESI Iontrap with an Agilent 1200 HPLC-system.
  • HPLC purifications were performed using an X-Bridge Prep C18 OBD 19x150 mm column, using a gradients of Buffer A (0.1% TFA in H 2 O) and Buffer B (0.1% TFA in acetonitrile).
  • the organic solvents used were anhydrous.
  • Oxime as prepared above was then dissolved in methanol, sodium cyanoborohydride (6 eq.) and a crystal of methyl orange were added followed by dropwise addition of 3 M methanolic HCI (35 eq.) and stirred overnight, concentrated, taken up in a few mL of water and the pH was adjusted to ca. 10 using 32% aqueous NaOH, transferred to a separatory funnel and extracted with EtOAc (2x), dried over Mg 2 SO 4 , filtered and concentrated.
  • Phtalimidoalkanesulfonylchlorides (prepared as described in the literature, e.g. GJ. Atwell et aL: J.Med.Chem. (1977) 20(9) 1128-134; J. Humljan et al.i: Tet.Letters, 46 4069-4072) was added in small portions to a solution of hydroxylamines (V) (1.02 eq.), amine or hydrazine (VI) and triethyamine or N- methylmorpholine (1.1 eq., or 2.2 eq. if the hydroxylamine, amine or hydrazine is a salt) in DCM at -20 0 C with stirring. The mixture was gradually allowed to reach rt, stirred overnight, concentrated, purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc) to yield intermediates of general formula (IX).
  • the oxalic acid salt of compound of general formula (I) may be obtained by dissolving compound of general formula (I) (1 eq.) in MeCN and adding a solution of oxalic acid (2 eq.) in MeCN. The precipitate was filtered and dried to give the oxalic acid salt of urea of general formula (I).
  • Preoa ration 23 O-cvclohexyl- ⁇ /-phenethylhvdroxylamine (compound 231.
  • Preparation 28 O-cvclohexyl- ⁇ /-(naphtalen-l-ylmetv ⁇ hvdroxylamine (compound 281.
  • Preparation 106 6-amino- ⁇ /-ethyl- ⁇ H3-morpholinopropy0hexane-l-sulfonamide (compound 106 1 ).
  • Preparation 110 6-amino- ⁇ /-cvcloheptyl- ⁇ /-(3-morpholinopropy ⁇ hexane-l- sulfonamide (compound 110).
  • Preparation 120 6-amino- ⁇ /-cvclohexyl- ⁇ /-f2-morpholinoethv0hexane-l- sulfonamide (compound 1120 ⁇ .
  • Phtalic anhydride (4.44 g, 30 mmol) and 6-aminohexanol (3.62 g, 30.9 mmol) were heated with stirring at 140 0 C for 5 h, cooled to rt, transferred to a separatory funnel with EtOAc, washed with NaHCO 3 (sat.), H 2 O, 10% citric acid, brine, dried (MgSO 4 ) and concentrated to yield 2-(6-hydroxyhexyl)isoindoline-l,3-dione.
  • Preparation 130 5-amino- ⁇ /-cvclopentyl-/V-f3-morpholinopropyQpentane-l- sulfonamide (compound 130 " ).
  • Preparation 138 4-amino- ⁇ /-cyclopentyl- ⁇ /-(3-morpholinopropyl)butane-l- sulfonamide (compound 138 ⁇ .
  • Preparation 140 6-amino-/V-f4-chlorophenvO- ⁇ /-methylhexane-l-sulfonamide (compound 140).
  • Example 3 ⁇ /-(2-(4-Chlorophenoxy ' )ethoxy)-6-f2-cvano-3-(pyridin-4- vO ⁇ uanidinoihexanamide (compound 10031.
  • Example 4 ⁇ /-(4-ChlorobenzyloxyV6-(2-cvano-3-(pyridin-4- v ⁇ quanidino " )hexanamide (compound 10041 L General procedure 4. Starting materials: compound 2 and O-(4- chlorophenoxy)methyl)hydroxylamine.
  • Example 7 ⁇ /-(4-Chlorobenzyloxy " )-5-f2-cvano-3-(pyridin-4- v ⁇ uanidinoloentanamide ( compound 1007I.
  • Example 8 /V-(4-Chlorobenzyloxy)-8-(2-cvano-3-(pyridin-4- vQquanidinoioctanamide (compound 10081.
  • Example 9 7-(2-Cvano-3-(pyridin-4-yl)quanidino> ⁇ /-(2-(2-(2- methoXyethoXViethoXVtethoXViheptanamide (compound 1009).
  • Example 12 5-f2-Cvano-3-fpyridin-4-y ⁇ uanidino ' )- ⁇ /-rtetrahvdro-2AV-pyran-2- yloxylpentanamide fcompound 10121.
  • Example 13 5-r2-Cvano-3-rpyridin-4-v ⁇ uanidino ' )- ⁇ /-r2-f2-f2- methoxyethoxy ' jethoxy ⁇ ethoxylpentanamide fcompound 10131.
  • Example 14 8-(2-Cvano-3-fpyridin-4-yl)quanidinoy/ ⁇ Htetrahvdro-2rt-pyran-2- yloxyioctanamide fcompound 1014 " ).
  • Example 15 8-f2-Cvano-3-(pyridin-4-yn ⁇ uanidinoV ⁇ /-f2-( r 2-f2- methoxyethoxyiethoxyiethoxyioctanamide (compound 1015).
  • Example 17 / ⁇ H2-(4-chlorophenoxy ' )ethoxy>5-f2-cyano-3-fpyridin-4- vOquanidino " )pentanamide fcompound 10171.
  • Example 20 ⁇ /-(2-(4-Chlorophenoxy)ethoxy ' )-8-(2-cvano-3-(pyridin-4- v ⁇ uanidinoioctanamide (com pound 1020 " ).
  • Example 21 7-(2-Cvano-3-(pyridin-4-vD ⁇ uanidino ' )- ⁇ /-(pyridin-4- ylmethoxyiheptanamide (compound 10211.
  • Example 22 7-(2-Cvano-3-(pyridin-4-v ⁇ quanidinoV ⁇ /-(pyridin-3- ylmethoxyiheptanamide (compound 10221.
  • Example 23 7-(2-Cvano-3-(pyridin-4-v0 ⁇ uanidino ' )- ⁇ /-(2- morpholinoethoxyiheptanamide (compound 10231.
  • Example 25 5-r2-Cvano-3-fpyridin-4-v ⁇ uanidinoV ⁇ /-fpyridin-3- ylmethoxyipentanamide (compound 10251.
  • Example 27 8-(2-Cvano-3-(pyridin-4-v0quanidinoV ⁇ /-(pyridin-4- ylmethoxyioctanamide (compound 10271.
  • Example 28 8-(2-Cvano-3-(pyridin-4-yl ' )quanidino ' )- ⁇ /-(2- morpholinoethoxy)octanamide (compound 10281.
  • Example 29 6-(2-Cvano-3-(pyridin-4-vnquanidinoV/V-(pyridin-4- ylmethoxyihexanamide ( " compound 1029).
  • Example 30 7-(2-Cvano-3-(pyridin-4-v0quanidino)-/V-(ftetrahvdrofuran-2- v ⁇ methoxy " )heptanamide (compound 1030).
  • Example 32 8-(2-Cvano-3-(pyridin-4-v ⁇ quanidinoV/V-fftetrahvdrofuran-2- v ⁇ methoxy ' ⁇ octanamide (compound 1032 " ).
  • Example 34 6-f2-Cvano-3-(pyridin-4-v0 ⁇ uanidino " )- ⁇ H2- morpholinoethoxvihexanamide (compound 10341.
  • Example 35 7-f2-Cyano-3-(pyridin-4-y0quanidino1- ⁇ /-ftetrahydro-2AY-pyran-4- yloxyiheptanamide (compound 10351.
  • Example 36 7-f2-Cyano-3-fpyridin-4-v ⁇ uanidinoV ⁇ /-( ' cvclohexyloxy1heptanannide (compound 10361.
  • Example 37 8-(2-Cvano-3-(Pyridin-4-vn ⁇ uanidino')-/V-(cvclohexyloxy ' )octanamide (compound 10371.
  • Example 38 8-(2-Cvano-3-fpyridin-4-v ⁇ uanidino)-/V-0:etrahydrofuran-3- yloxyloctanamide (compound 10381.
  • Example 39 7-(2-Cvano-3-(pyridin-4-vnquanidinoV ⁇ /-(tetrahvdrofuran-3- yloxylheptanamide (compound 1039T.
  • Example 40 8-f2-Cvano-3-fpyridin-4-y0quanidino ' )- ⁇ /-(tetrahydro-2H-pyran-4- yloxyioctanamide ( " compound 104O-).
  • Example 41 7-( 3-f 2-chloropyridin-4-v ⁇ -2-cyano ⁇ uanidino1- ⁇ /-f tetra hydro- 2/f- pyran-2-yloxy ' )heptanamide (compound 1041 " ).
  • Example 42 7-f2-Cyano-3-fpyridin-4-y ⁇ quanidinoV ⁇ /-methoxyheptanamide ( " compound 10421.
  • Example 44 7-f2-Cvano-3-(pyridin-4-v0quanidinoV ⁇ Hcycloheptyloxy ' )heptanamide (compound 10441.
  • Example 46 7-(2-Cyano-3-(pyridin-4-vQquanidino1-/V- (cvclohexylmethoxyiheptanamide (compound 10461.
  • Example 47 7-(2-Cyano-3-(pyrdin-4-yl1quanidino1- ⁇ /-(cvclopentyloxy1heptanamide (compound 10471.
  • Example 48 7-(2-Cvano-3-(pyridin-4-v ⁇ uanidino ' )- ⁇ /-methoxy- ⁇ /- methylheptanamide (compound 1048 " ).
  • Example 50 /V-Benzyl-7-(2-cvano-3-(pyridin-4-v0 ⁇ uanidino)- ⁇ /- (cvclohexyloxyiheptanamide (compound 1050).
  • Example 51 7-(2-Cyano-3-( pyridin-4-v ⁇ uanidino>/V-( ' cyclohexyloxy ' )-/V- methylheptanamide (compound 1051).
  • Example 52 ⁇ /-Benzyl-6-f2-cvano-3-fpyridin-4-v ⁇ uanidino)hexane-2-sulfonamide (compound 10521.
  • Example 54 6-(2-Cyano-3-(pyridin-4-ynquanidino')-/V-cvclohexylhexane-l- sulfonamide (compound 1054 " ).
  • Example 56 ⁇ /-rBenzyloxy ' )-6-(2-cyano-3-rpyridin-4-y ⁇ uanidino ' )hexane-l- sulfonamide (compound 10561.
  • Example 57 6-f2-Cvano-3-fpyridin-4-yl1 ⁇ uanidino1- ⁇ /-(tetrahydro-2/-y-pyran-2- yloxyihexane-1-sulfonamide (compound 10571.
  • Example 58 6-f2-Cvano-3-fpyridin-4-yl)quanidino ' )-/ ⁇ /-(cvcloheptyloxy " )hexane-l- sulfonamide (compound 10581.
  • Example 60 6-(2-Cvano-3-fpyridin-4-v ⁇ quanidinoV/V-f2-cvclohexylethoxy1hexane- 1-sulfonamide (compound 10601.
  • Example 61 6-(2-Cvano-3-(pyridin-4-v0quanidinoV ⁇ /-(cvclopentyloxy ' )hexane-l- sulfonamide (compound 10611.
  • Example 63 6-(2-Cvano-3-(pyridin-4-vQquanidino ' )- ⁇ H2- morpholinoethoxy)hexane-l-sulfonamide (compound 1063 7 ).
  • Example 64 6-f2-Cvano-3-(pyridin-4-yQquanidino)- ⁇ /-methoxy- ⁇ /-methylhexane-l- sulfonamide (compound 1064).
  • Example 65 (RV7-(2-Cvano-3-( r pyridin-4-v ⁇ uanidino ' )- ⁇ /-fcvclohexyloxy ' )-2- methylheptanamide (compound 1065 " ).
  • Example 70 fS)-7-(2-Cvano-3-f pyridin-4-yl)quanidinoV ⁇ /-f cvclohexyloxy ' )-2- methylheptanamide (compound 1070).
  • Example 72 7-f2-Cvano-3-fpyridin-4-y0quanidino ' )- ⁇ /-(cvclohexyloxy ' )- ⁇ H2-(2-(2- methoxyethoxy ' tethoxy ' ⁇ etrivOheptanamide (compound 10721.
  • Example 73 ⁇ /-Benzyl-7-(2-cvano-3-(pyridin-4-v0quanidino)- ⁇ /-(2- morpholinoethoxy ⁇ heptanamide (compound 1073 " ).
  • Example 74 7-(2-Cvano-3-(pyridin-4-yl)quanidino ' )- ⁇ /-(cvclohexyloxy ' )- ⁇ /-(3,3- dimethylbutvOheptanamide (compound 1074).
  • Example 75 7-(2-Cvano-3-(Dyridin-4-v0quanidino')-/V-(cyclohexyloxyV ⁇ /-(3- hvdroxvpropvltheptanamide (compound 1075).
  • Example 76 7-f2-Cvano-3-(pyridin-4-v0 ⁇ uanidino> ⁇ /-(cvclohexyloxy)- ⁇ Hpyridin-3- ylmethvOheptanamide fcompound 1076 " ).
  • Example 77 7-f2-Cvano-3-(pyridin-4-vDquanidino)-/ ⁇ HcvclohexyloxyV/V- isopropylheptanamide fcompound 10771.
  • Example 78 7-(2-Cvano-3-(pyridin-4-vQquanidino ' )- ⁇ /-(cvclohexyloxyV/ ⁇ /-(2- hvdroxyethv ⁇ heptanamide (compound 1078).
  • Example 79 7-(2-Cvano-3-(pyridin-4-vQquanidino ' )- ⁇ /-(cyclohexyloxyV ⁇ /-(3- phenylpropy ⁇ heptanamide (compound 1079 " ).
  • Example 80 7-(2-Cvano-3-(pyridin-4-v ⁇ quanidinoV ⁇ /-(cvclohexyloxy)-/V- phenvlethvlheptanamide (compound 1080).
  • Example 81 /V-Butyl-7-f2-cvano-3-fpyridin-4-yQquanidino ' )-/ ⁇ /- fcvclohexyloxy ' lheptanamide (compound 1081).
  • Example 82 7-f2-Cvano-3-fpyridin-4-v0 ⁇ uanidino)- ⁇ /-(cvclohexyloxy ' )- ⁇ /- (naphtalen-2-ylmethyl)heptanamide (compound 1082 " ).
  • Example 83 7-f 2-Cyano-3-(pyridin-4-yl1quanidino1- ⁇ /-( cvclohexyloxy1-/V- ethvlheptanamide (compound 10831.
  • Example 84 7-(2-Cvano-3-(pyridin-4-yl1quanidino1-/V-(cvclohexyloxy1-/V-(pyridin-2- ylmethv ⁇ heptanamide (compound 10841.
  • Example 85 7-(2-Cvano-3-(pyridin-4-yl1 ⁇ uanidino1-/V-cyclohexyl- ⁇ /-(2- morpholinoethoxviheptanamide (compound 10851.
  • Example 86 ⁇ /-Benzyl-6-( " 2-cvano-3-(pyridin-4-v ⁇ quanidinoV ⁇ /-f2- morpholinoethoxy ' lhexane-l-sulfonamide (compound 1086 " ).
  • Example 87 7-f2-Cvano-3-(pyridin-4-yl)quanidino ' )- ⁇ /-(cvclohexyloxy ' )- ⁇ /-f2- morpholinoethv ⁇ heptanamide (compound 10871.
  • Example 88 7-f2-Cvano-3-(pyridin-4-v0quanidinoV ⁇ /-( r cvclohexyloxyV ⁇ /- fnaphtalen-l-ylmethvDheptanamide (compound 1088 " ).
  • Example 91 7-( 2-Cyano-3-( pyridin ⁇ -vOguanidinoV/V-f cvclohexyloxy " )-/V- octylheptanamide (compound 1091).
  • Example 92 ⁇ /-(3-aminopropy ⁇ -7-(2-cvano-3-(pyridin-4-v ⁇ uanidinoV ⁇ /- (cvclohexyloxylheptanamide (compound 1092).
  • Example 93 /V-f 3-Acetamidopropyn-7-f 2-cvano-3-f pyridin ⁇ -yliquanidinoV/V- (cvclohexyloxyiheptanamide (compound 1093 " ).
  • Example 95 2-Cvano-l-(6-(morpholinosulfonv ⁇ hexy0-3-(pyridin-4-v0quanidine (compound 1095).
  • Example 98 7-(2-cvano-3-fpyridin-4-v0 ⁇ uanidino ' )- ⁇ /-(cyclohexyloxy1- ⁇ 2-f2-(2- hvdroxyethoxyiethoxyiethvOheptanamide (compound 10981.
  • Example 100 7-(2-Cvano-3-(pyridin-4-v0quanidino ' )-/V-(2-morpholinoethoxy ' )-/V- (tetrahvdro-2/-/-Pyran-4-v ⁇ heptanamide (compound 11001.
  • Example 101 6-(2-Cyano-3-f pyridin-4-v0 ⁇ uanidino)- ⁇ /-(2-morpholinoethv0r ⁇ exane- 1-sulfonamide (compound 1101 " ).
  • Example 102 6-r2-Cvano-3-fpyridin-4-v ⁇ uanidino ' )-/V-cvcloheptylhexane-l- sulfonamide ( " compound 11021.
  • Example 103 6-r2-Cvano-3-fpyridin-4-v ⁇ quanidino ' )- ⁇ /-f3- morpholinopropyOhexane-1-sulfonamide ( " compound 11031.
  • Example 104 ⁇ /-f2-f2-f2-Aminoethoxy')ethoxy)ethv ⁇ -7-f2-cvano-3-fPyridin-4- vQquanidino ' )-/ ⁇ Hcvclohexyloxy)heptanamide (compound 1104).
  • Example 105 /V-f2-(2-f2-acetamidoethoxy ' )ethoxy')ethy0-7-( ' 2-cvano-3-fpyridin-4- yl ' )quanidino'>-/V-fcvclohexyloxy)heptanamide fcompound HOST.
  • Example 106 6-f2-Cvano-3-fpyridin-4-y ⁇ quanidinoV ⁇ /-f2-cvclohexylethy ⁇ hexane- 1-sulfonamide (compound 1106).
  • Example 107 6-(2-Cvano-3-rpyridin-4-v ⁇ uanidino " )- ⁇ /-f2-cvclohexylethoxy')- ⁇ /-f2- (2-(2-methoxyethoxy')ethoxy ' )ethv0hexane-l-sulfonamide (compound 1107).
  • Example 108 6-(3-(2-chloropyridin-4-y0-2-cyanoquanidinoV ⁇ /-(2- cvclohexylmethoxy)-hexane-l-sulfonamide (compound 11081.
  • Example 110 6-r2-cvano-3-rpyridin-4-v ⁇ uanidino ' )- ⁇ /-f2-cvclohexylethoxy ' )- ⁇ /-f2- morpholinoethv ⁇ hexane-1-sulfonamide (compound lllO ' ).
  • Example 111 7-f2-cvano-3-(2,6-dichloropyridin-4-v ⁇ uanidinoV ⁇ /-cyclohexyl-/ ⁇ /-f2- morpholinoethoxyiheptanamide fcompound 1111).
  • Example 112 ⁇ /-benzyl-6-f2-cvano-3-fpyridin-4-v ⁇ quanidino ' )- ⁇ /-(2- cvclohexylethoxy ⁇ hexane-l-sulfonamide (compound 1112 ⁇ .
  • Example 113 6-r2-cyano-3-fpyridin-4-v ⁇ quanidino ' )- ⁇ /-( ' 2-cvclohexylethoxy ' )- ⁇ /- methylhexane-1-sulfonamide (compound 1113).
  • Example 114 6-(2-cyano-3-f2.6-dichloropyridin-4-v0quanidinoV/V-f2- cyclohexylmethoxyihexane-l-sulfonamide (compound 1114).
  • Example 115 6-( " 2-cvano-3-fpyridin-4-v ⁇ uanidinoV ⁇ /-rcvclohexylmethoxy)- ⁇ /-f2- f2-(2-methoxyethoxy ' )ethoxy)ethv0hexane-l-sulfonamide (compound Ills ' ).
  • Example 116 ⁇ /-benzyl-8-(2-cvano-3-(pyridin-4-y ⁇ quanidinoV ⁇ /-(2- morpholinoethoxyVoctanamide (compound 1116 ⁇ .
  • Example 117 ⁇ /-benzyl-6-f2-cyano-3-fpyridin-4-vnquanidino)- ⁇ /-f2- morpholinoethoxy)-hexanamide fcompound 11171.
  • Example 118 6-(2-cvano-3-(pyridin-4-y0quanidinoV ⁇ /-cvcloheptyl- ⁇ /-methylhexan- 1-sulfonamide fcompound Ills ' ).
  • Example 119 6-f2-cvano-3-(pyridin-4-v0quanidinoV ⁇ /-f3-morpholinopropy0- ⁇ /- fpyridin-3-ylmethyl)hexan-l-sulfonamide fcompound 11191.
  • Example 120 6-f2-cvano-3-fpyridin-4-v0quanidinoV ⁇ /-f2-morpholinoethy0-/V-f3- morpholinopropy ⁇ hexan-1-sulfonamide fcompound 11201.
  • Example 121 6-f 2-cvano-3-fpyridin-4-v ⁇ uanidino)- ⁇ K cvclohexylmethoxyV/V-f 2- morpholinoethv ⁇ hexan-1-sulfonamide fcompound 11211.
  • Example 122 7-(2-cyano-3-(pyridin-3-vnquanidino " )- ⁇ /-cvclohexyl- ⁇ /-(2- morpholinoethoxy ' ⁇ heptanamide (compound 11221.
  • Example 123 6-r2-cvano-3-rpyridin-3-v ⁇ uanidinoV ⁇ /-fcyclohexylmethoxy ' )hexane- 1-sulfonamide (compound 1123 " ).
  • Example 124 6-f2-cvano-3-(pyridin-4-v0 ⁇ uanidino ' )-/V-cvcloheptyl-/V-f2- morpholinoethv ⁇ hexane-1-sulfonamide (compound 1124 " ).
  • Example 125 6-f2-cvano-3-(pyridin-4-y ⁇ quanidinoV ⁇ /-methyl- ⁇ H2- morpholinoethoxy) hexane-1-sulfonamide fcompound 1125).
  • Example 127 l-(6-(azapan-l-ylsulfonv ⁇ hexy ⁇ -2-cvano-3-(pyridin-4-yl)quanidine (compound 1127 ⁇ .
  • Example 128 6-(2-cvano-3-(pyridin-4-y ⁇ quanidino ' )- ⁇ /-(2-morpholinoethoxyV ⁇ /- (pyridin-3-ylmethv ⁇ hexane-l-sulfonamide (compound 1128 " ).
  • Example 130 7-f2-cyano-3-(2-fluoropyridin-4-y ⁇ quanidinoV ⁇ /-cyclohexyl-/V-(2- morpholinethoxy)heptanamide (compound 11301.
  • Example 131 6-(2-cvano-3-(pyridin-4-yl1quanidino1-/V-(2-morpholinoethoxy1-/V-f2- morpholinethvDhexan-1-sulfonamide ( " compound 11311.
  • Example 132 2-cvano-l-fpyridin-4-vO-3-f6-pyrrolidine-l- ylsulfonvOhexynquanidine (compound 1132 ⁇ .
  • Example 133 2-cyano-l-f6-morpholinosulfonv0hexy0-3-fpyridin-3-v0 ⁇ uanidine (compound 1133 ⁇ .
  • Example 135 6-(2-cyano-3-pyridin-4-v ⁇ quanidino ' )-/ ⁇ /-fcyclohexylmethoxyV ⁇ /-(2- fluoroethyl)hexane-l-sulfonamide (compound 1135).
  • Example 136 6-r2-cvano-3-pyridin-3-v ⁇ quanidino)- ⁇ /-(cvclohexylmethoxyV ⁇ /-C2- f2-(2-methoxvethoxv ' )ethoxv)ethvDhexane-l-sulfonamide f compound 11361.
  • Example 137 6-f2-cvano-3-f2-fluoropyridin-4-yliQuanidino)-/V- (cvdohexylmethoxyV/V-f2-f2-methoxyethoxy)ethoxy)ethv0hexane-l- sulfonamide (compound 1137).
  • Example 138 2-cyano-l-(6-f4-methylpiperazin-l-ylsulfony0hexy0-3-fpyridin-4- vDguanidine (compound 1138).
  • Example 139 4-f2-cvano-3-(6-(N- cvclohexylmethoxy ⁇ sulfamov ⁇ hexyO ⁇ uanidinoipyridin-l-oxide (compound 1139 " ).
  • Example 140 7-f2-cvano-3-fpyridin-4-v ⁇ uanidino " )- ⁇ /-isopropyl- ⁇ /-(tetrahvdro-2H- Pyran-4-yloxyiheptanamide (compound 1140).

Abstract

This application discloses novel cyanoguanidines of the formula (I) wherein A is selected from -C(=O)-, -S(=O)2-, -C(=S)-, and -P(=O)(R5)-, wherein R5 is selected from C1-6-alkyl, C1-6-alkoxy, and hydroxy; B is selected from a single bond, -O-, -NR6- and -C(=O)-NR6-, wherein R6 is selected from hydrogen, optionally substituted C1-12-alkyl, optionally substituted C1-12-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; and m is an integer of 0-12 and n is an integer of 0-12, wherein the sum m+n is 1-20; and R1 is selected from optionally substituted heteroaryl; and pharmaceutically acceptable salts thereof, and prodrugs thereof. The compounds are usefuld for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT).

Description

NOVEL CYANOGUANIDINES
FIELD OF THE INVENTION
This invention relates to cyanoguanidine compounds which are useful for the inhibiting of the enzyme nicotinamide phosphoribosyltransferase (NAMPRT), and to medical use of such cyanoguanidine compounds.
BACKGROUND OF THE INVENTION
Inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPRT) results in the inhibition of NF-kB, the inhibition of NF-kB being a result of the lowering of cellular concentrations of nicotinamide adenine dinucleotide (NAD) (Beauparlant et al (2007) AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2007 Oct 22-26 Abstract nr A82; and Roulson et al (2007) AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2007 Oct 22-26 Abstract nr A81). Tumor cells have elevated expression of NAMPRT and a high rate of NAD turnover due to high ADP-ribosylation activity required for DNA repair, genome stability, and telomere maintenance making them more susceptible to NAMPRT inhibition than normal cells. This also provides a rationale for the use of compounds of this invention in combination with DNA damaging agents for future clinical trials.
The pathways of NAD biosynthesis are shown in Figure 1.
NAMPRT is involved in the biosynthesis of nicotinamide adenine dinucleotide (NAD) and NAD(P). NAD can be synthesized in mammalian cells by three different pathways starting either from tryptophan via quinolinic acid, from nicotinic acid (niacin) or from nicotinamide (niacinamide).
Quinolinic acid reacts with phosphoribosyl pyrophosphate to form niacin mononucletide (dNAM) using the enzyme quinolinic acid phosphoribosyltransferase © which is found in liver kidney and brain. Nicotinic acid (niacin) reacts with PRPP to form niacin mononucleotide (dNAM), using the enzyme niacin phosphoribosyltransferase © which is widely distributed in various tissues.
Nicotinamide (niacinamide) reacts with PRPP to give niacinamide mononucleotide (NAM) using the enzyme nicotinamide phosphoribosyltransferase (NAMPRT) O which is also widely distributed in various tissues.
The subsequent addition of adenosine monophosphate to the mononucleotides results in the formation of the corresponding dinucleotides: Niacin mononucleotide and niacinamide mononucleotide react with ATP to form niacin adenine dinucleotide (dNAD) and niacinamide adenine dinucleotide (NAD) respectively. Both reactions, although they take place on different pathways, are catalysed by the same enzyme, NAD pyrophosphorylase O.
A further amidation step is required to convert niacin adenine dinucleotide (dNAD) to niacinamide adeinine dinucleotide (NAD) The enzyme which catalyses this reaction is NAD synthetase Θ. NAD is the immediate precursor of niacinamide adenine dinucleotide phosphate (NAD(P)) The reaction is catalysed by NAD kinase. For details see, e.g., Cory J. G. Purine and pyrimidine nucleotide metabolism In: Textbook of Biochemistry and Clinical Correlations 3rd edition ed. Devlin, T, Wiley, Brisbane 1992, pp 529-574.
Normal cells can typically utilize both precursors niacin and niacinamide for NAD(P) synthesis, and in many cases additionally tryptophan or its metabolites. Accordingly, murine glial cells use niacin, niacinamide and quinolinic acid (Grant et al. (1998) J. Neurochem. 70: 1759-1763). Human lymphocytes use niacin and niacinamide (Carson et al (1987) J. Immunol. 138: 1904-1907; Berger et al (1982) Exp. Cell Res. 137; 79-88). Rat liver cells use niacin, niacinamide and tryptophan (Yamada et al (1983) Int. J. Vit. Nutr. Res. 53: 184-1291; Shin et al (1995) Int. J. Vit. Nutr. Res. 65: 143-146; Dietrich (1971) Methods Enzymol. 18B; 144-149). Human erythrocytes use niacin and niacinamide (Rocchigiani et al (1991) Purine and pyrimidine metabolism in man VII Part B ed. Harkness et al Plenum Press New York pp337-3490). Leukocytes of guinea pigs use niacin (Flechner et al (1970), Life Science 9: 153-162). NAD(P) is involved in a variety of biochemical reactions which are vital to the cell and have therefore been thoroughly investigated. The role of NAD(P) in the development and growth of tumours has also been studied. It has been found that many tumour cells utilize niacinamide for cellular NAD(P) synthesis. Niacin and tryptophan which constitute alternative precursors in many normal cell types cannot be utilized in tumour cells, or at least not to an extent sufficient for cell survival. Selective inhibition of an enzyme which is only on the niacinamide pathway (such as NAMPRT) would constitute a method for the selection of tumour specific drugs. This has been exemplified by the NAMPRT inhibitor APO866. (see Hasmann and Schemainda, Cancer Res 63(21) :7463-7442.)
Huang et al (WO 00/61559) describe the following compound as a potential antitumor agent.
Figure imgf000005_0001
Huang et al (WO 2000/061559) describe the following compound as a potential antitumor agent.
Figure imgf000005_0002
Schou et al (WO 98/54144) describe the following compounds as cell proliferation inhibitors.
Figure imgf000006_0001
Figure imgf000007_0001
Schou et al (WO 98/54141) describe the following compounds as cell proliferation inhibitors.
Figure imgf000007_0002
BRIEF DESCRIPTION OF THE INVENTION
It is believed that the novel compounds of the invention are acting on the enzyme nicotinamide phosphoribosyltransferase (NAMPRT), and that the down-stream inhibition of NF-kB is the result of the lowering of cellular concentrations of nicotinamide adenine dinucleotide (NAD).
Hence, the present invention provides compounds of the general formula (I) according to claim 1, and the utilization of these compounds in medicine, cf. claims 16, 17, 19 and 20.
The compounds of the invention are - contrary to many of the known related cyanoguanidines - fairly soluble in water and physiological fluids, for what reason the formulation of the compound for medical uses is believed to be less challenging.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the pathway of NAD biosynthesis (from Biedermann E. et al, WO 00/50399).
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the invention
The present invention La. relates to particular cyanoguanidine compounds which are useful for the inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPRT).
The present invention relates to compounds of the formula (I)
Figure imgf000009_0001
(I)
wherein
A is selected from -C(=O)-, -S(=O)2-, -C(=S)-, and -P(=O)(R5)-, wherein R5 is selected from Ci-6-alkyl, Ci-6-alkoxy, and hydroxy;
B is selected from a single bond, -O-, -NR6- and -C(=O)-NR6-, wherein R6 is selected from hydrogen, optionally substituted Ci-12-alkyl, optionally substituted Ci- 12-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;
m is an integer of 0-12 and n is an integer of 0-12, wherein the sum m+n is 1-20;
R1 is selected from optionally substituted heteroaryl;
R2 is selected from hydrogen, optionally substituted
Figure imgf000009_0002
optionally substituted C3-i2-cycloalkyl, -[CH2CH20]i-io-(optionally substituted Ci-6-alkyl), optionally substituted Ci-12-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; and R3 is selected from optionally substituted Ci-12-alkyl, optionally substituted C3-i2-cycloalkyl, -
[CH2CH2θ]i-io-(optionally substituted d-6-alkyl), optionally substituted Ci-i2-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or R2 and R3 together with the intervening atoms (i.e. -N-B-) form an optionally substituted N-containing heterocyclic or heteroaromatic ring;
each of R4 and R4* independently is independently selected from hydrogen, optionally substituted Ci-i2-alkyl and optionally substituted Ci_i2-alkenyl;
and pharmaceutically acceptable salts thereof, and prodrugs thereof; with the proviso that when B is a single bond, then A is selected from -S(=O)2-, - C(=S)-, and -P(=O)(R5)-.
Definitions
In the present context, the terms "Ci-i2-alkyl" and "Ci-6-alkyl" are intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 12 carbon atoms and 1 to 6 carbon atoms, respectively, such as methyl, ethyl, propyl, /so-propyl, cyclopropyl, butyl, /so-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl.
Although the term "C3-i2-cycloall<yl" is encompassed by the term "Ci-i2-alkyl", it refers specifically to the mono- and bicyclic counterparts, including alkyl groups having exo-cyclic atoms, e.g. cyclohexyl-methyl.
Similarly, the terms "C2-i2-alkenyl" and "C2-6-alkenyl" are intended to cover linear, cyclic or branched hydrocarbon groups having 2 to 12 carbon atoms and 2 to 6 carbon atoms, respectively, and comprising (at least) one unsaturated bond. Examples of alkenyl groups are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl. Preferred examples of alkenyl are vinyl, allyl, butenyl, especially allyl.
Although the term "C3-i2-cycloalkenyl" is encompassed by the term "C2-i2-alkenyl", it refers specifically to the mono- and bicyclic counterparts, including alkenyl groups having exo-cyclic atoms, e.g. cyclohexenyl-methyl and cyclohexyl-allyl.
In the present context, i.e. in connection with the terms "alkyl", "cycloalkyl",
"alkoxy", "alkenyl", "cycloalkenyl" and the like, the term "optionally substituted" is intended to mean that the group in question may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-6-alkoxy (i.e. Ci-6-alkyl-oxy), C2-6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci-6-alkoxycarbonyl, Cnralkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, aryloxycarbonyl, arylcarbonyloxy, arylaminocarbonyl, arylcarbonylamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, heteroarylaminocarbonyl, heteroarylcarbonylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclylaminocarbonyl, heterocyclylcarbonylamino, amino, mono- and di(Ci-6-alkyl)amino, -N(Ci-4-alkyl)3 +, carbamoyl, mono- and diCCi-β-alkyOaminocarbonyl, Ci-6-alkylcarbonylamino, cyano, guanidino, carbamido, Ci-6-alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci-6- alkanoyloxy, Ci-6-alkyl-sulphonyl, Ci-6-alkyl-sulphinyl, Ci-6-alkylsulphonyloxy, nitro, Ci-6-alkylthio, and halogen, where any aryl, heteroaryl and heterocyclyl may be substituted as specifically described below for aryl, heteroaryl and heterocyclyl, and any alkyl, alkoxy, and the like, representing substituents may be substituted with hydroxy, Ci-6-alkoxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-6-alkyl- carbonylamino, Ci-6-alkylaminocarbonyl, or halogen(s).
Typically, the substituents are selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-6- alkoxy (i.e. Ci-6-alkyl-oxy), C2-6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci-6-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, amino, mono- and di(Ci-6- alkyl)amino; carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl- aminocarbonyl, mono- and dKCi-β-alkyOamino-Ci-e-alkyl-aminocarbonyl, Ci-6-alkyl- carbonylamino, guanidino, carbamido, Ci-6-alkyl-sulphonyl-amino, Ci-6-alkyl- sulphonyl, Ci-6-alkyl-sulphinyl, Ci-6-alkylthio, halogen, where any aryl, heteroaryl and heterocyclyl may be substituted as specifically described below for aryl, heteroaryl and heterocyclyl.
In some embodiments, substituents are selected from hydroxy, Ci-6-alkoxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, d-6-alkylcarbonylamino, Ci-6-alkylamino- carbonyl, or halogen.
The term "halogen" includes fluoro, chloro, bromo, and iodo.
In the present context, the term "aryl" is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferred example.
The term "heteroaryl" is intended to mean a fully or partially aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen (=N- or -NH-), sulphur, and/or oxygen atoms. Examples of such heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furanyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl. Particularly interesting heteroaryl groups are benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl in particular benzimidazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, furyl, thienyl, quinolyl, tetrazolyl, and isoquinolyl.
The term "heterocyclyl" is intended to mean a non-aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen (=N- or -NH-), sulphur, and/or oxygen atoms. Examples of such heterocyclyl groups (named according to the rings) are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, tetrahydrothiopyrane, thiepane, dithiane, dithiepane, dioxane, dioxepane, oxathiane, oxathiepane. The most interesting examples are tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane, oxazepane, thiazolane, thiazinane, and thiazepane, in particular tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane, oxazinane (morpholine), and thiazinane. The term "N-containing heterocyclic or heteroaromatic ring" are intended to encompass those mentioned under "heterocyclyl" and "heteroaryl", respectively, which include one or more heteroatoms, at least one of which begin a nitrogen atom. Examples hereof are piperazine, isoxazole, isoxazolidine, and morpholine, etc.
The term "N,O-containing heterocyclic or heteroaromatic ring" are intended to encompass those mentioned under "heterocyclyl" and "heteroaryl", respectively, which include two or more heteroatoms, two of which being neighbouring nitrogen and oxygen atoms. Examples hereof are isoxazole, isoxazolidine, morpholine, etc.
In the present context, i.e. in connection with the terms "aryl", "heteroaryl", "heterocyclyl", "N,O-containing heterocyclic or heteroaromatic ring" and the like (e.g. "aryloxy", "heterarylcarbonyl", etc.), the term "optionally substituted" is intended to mean that the group in question may be substituted one or several times, preferably 1-5 times, in particular 1-3 times, with group(s) selected from hydroxy (which when present in an enol system may be represented in the tautomeric keto form), Ci-e-alkyl, Ci-β-alkoxy, C2-6-alkenyloxy, oxo (which may be represented in the tautomeric enol form), oxide (only relevant as the N-oxide), carboxy, Ci-6-alkoxycarbonyl, Ci-6-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl, heteroarylamino, amino, mono- and di(Ci-6-alkyl)amino; carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6- alkyl-aminocarbonyl, mono- and di(Ci-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6- alkylcarbonylamino, cyano, guanidino, carbamido, Ci-β-alkanoyloxy, C1-6-alkyl- sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci-6-alkyl- suphonyl, Ci-6-alkyl-sulphinyl, Ci-6-alkylsulphonyloxy, nitro, sulphanyl, amino, amino-sulfonyl, mono- and di(C1-6-alkyl)amino-sulfonyl, dihalogen-Ci-4-alkyl, trihalogen-Ci_4-alkyl, halogen, where aryl and heteroaryl representing substituents may be substituted 1-3 times with Ci-4-alkyl, Ci-4-alkoxy, nitro, cyano, amino or halogen, and any alkyl, alkoxy, and the like, representing substituents may be substituted with hydroxy, Ci-6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(d-6- alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, halogen, Ci-5-alkylthio, Ci-6-alkyl- sulphonyl-amino, or guanidino.
Typically, the substituents are selected from hydroxy, Ci-6-alkyl, Ci-6-alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, C1-6- alkylcarbonyl, formyl, amino, mono- and di(Ci-6-alkyl)amino; carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbonylami- no, guanidino, carbamido, Ci-6-alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci-6-alkyl-suphonyl, Ci-6-alkyl-sulphinyl, Ci-6- alkylsulphonyloxy, sulphanyl, amino, amino-sulfonyl, mono- and di(Ci-6-alkyl)amino- sulfonyl or halogen, where any alkyl, alkoxy and the like, representing substituents may be substituted with hydroxy, Ci-6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-6-alkylcarbonylamino, halogen, Ci-6-alkylthio, Ci-6- alkyl-sulphonyl-amino, or guanidino. In some embodiments, the substituents are selected from Ci-6-alkyl, Ci-6-alkoxy, amino, mono- and di(Ci-6-alkyl)amino, sulphanyl, carboxy or halogen, where any alkyl, alkoxy and the like, representing substituents may be substituted with hydroxy, Ci-6-alkoxy, C2-6-alkenyloxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-6-alkylcarbonylamino, halogen, Ci-6- alkylthio, Ci-6-alkyl-sulphonyl-amino, or guanidino.
Groups (e.g. R2 and R3) including C3-i2-cycloalkyl, C3-i2-cycloalkenyl and/or aryl as at least a part of the substituent are said to include "a carbocyclic ring".
Groups (e.g. R2 and R3) including heterocyclyl or heteroaryl as at least a part of the substituent are said to include "a heterocyclic ring" and "a heteroaromatic ring", respectively.
The term "pharmaceutically acceptable salts" is intended to include acid addition salts and basic salts. Illustrative examples of acid addition salts are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. Examples of basic salts are salts where the (remaining) counter ion is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions C+N(R)3R1, where R and R1 independently designates optionally substituted Ci-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl). Pharmaceutically acceptable salts are, e.g., those described in Remington's Pharmaceutical Sciences, 17. Ed. Alfonso R. Gennaro (Ed.), Mack Publishing Company, Easton, PA, U.S.A., 1985 and more recent editions and in Encyclopedia of Pharmaceutical Technology. Thus, the term "an acid addition salt or a basic salt thereof" used herein is intended to comprise such salts. Furthermore, the compounds as well as any intermediates or starting materials may also be present in hydrate form.
The term "prodrug" used herein is intended to mean a compound which - upon exposure to physiological conditions - will liberate a derivative said compound which then will be able to exhibit the desired biological action. Typical examples are labile esters {i.e. a latent hydroxyl group or a latent acid group).
Moreover, it should be understood that the compounds may be present as racemic mixtures or the individual stereoisomers such as enantiomers or diastereomers. The present invention encompasses each and every of such possible stereoisomers {e.g. enantiomers and diastereomers) as well as racemates and mixtures enriched with respect to one of the possible stereoisomers.
Embodiments
In one important embodiment, B is selected from -O- and -NR6-, in particular B is - O-. Within one important variant of this embodiment, A is-S(=O)2- and B is -O-. Within another important variant of this embodiment, A is-C(=O)- and B is -O-.
In another embodiment, B is a single bond. Within one important variant of this embodiment, A is -S(=O)2-.
In a further embodiment, B is -C(=O)-NR6-.
With respect to R1, this substituents is preferably optionally substituted pyridinyl, in particular optionally substituted pyridin-4-yl. The length of the spacer element is defined by m and n. Preferably, m is an integer of 0-10 and n is an integer of 0-10, wherein the sum m+n is 1-12; in particular m is an integer of 1-8 and n is an integer of 0-3, wherein the sum m+n is 3-8. In a currently most preferred variant, m is an integer of 2-8 and n is 0.
It appears that - besides A and B - R2 and R3 (and in part also R4 and R4*) play an important role for the efficacy of the compounds of the invention. Hence, in one particularly interesting embodiment, at least one of R2 and R3 includes a carbocyclic ring, heterocyclic ring or a heteroaromatic ring, or R2 and R3 together with the intervening atoms form an optionally substituted N-containing heterocyclic or heteroaromatic ring.
In one variant hereof, R2 and R3 together with the intervening atoms form an optionally substituted N,O-containing heterocyclic or heteroaromatic ring.
Moreover, R4 is preferably selected from hydrogen, Ci-6-alkyl and optionally substituted benzyl and R4* is hydrogen.
In one currently particularly relevant embodiment,
A is selected from -C(=O)- and -S(=O)2-;
B is -O-;
m is an integer of 2-8 and n is 0;
R2 is selected from hydrogen, optionally substituted C3-i2-cycloalkyl, -[CH2CH20]i-io- (optionally substituted Ci-6-alkyl), -(CH2)o-2-(optionally substituted aryl),
-(CH2)o-2-(optionally substituted heteroaryl) and -(CH2)o-2-(optionally substituted heterocyclyl);
R3 is selected from optionally substituted C3-i2-cycloalkyl, -[CHaCHaOji-io-Coptionally substituted Ci-6-alkyl), optionally substituted Ci-i2-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; R4 is selected from hydrogen, optionally substituted C3-i2-cycloalkyl, -(CH2)o-2-(optionally substituted aryl), -(CH2)o-2-(optionally substituted heteroaryl) and -(CH2)o-2-(optionally substituted heterocyclyl); and
R4* is hydrogen;
with the proviso that at least one of R2 and R4 is not hydrogen.
This being said, currently most interesting compounds are those selected from compounds 1001-1183 described in the following:
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Preparation of the compounds of Formula (I)
The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods outline below, together with methods known in the art of organic synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
The novel compounds of formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be compatible with the reagents and reactions proposed. Not all molecules of formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used.
Compounds of general formula (I), which are hydroxamic acid esters (Ia) can be prepared from dimethyl /V-cyanodithio-iminocarbonate and an amine to yield intermediates of general formula (II), followed by reaction with amino acids of general formula (III). The resulting acid (IV) can subsequently be coupled with a hydroxylamine (V) using a peptide coupling reagent, e.g. EDC or HATU. Diphenyl cyanocarbonimidate may be employed instead of Λ/-cyanodithio-iminocarbonate.
Figure imgf000041_0001
(V) - a)
Hydroxylamines (V) are either commercially available or can be prepared from N- hydroxyphtalimide (or alternatively tert-butylhydroxycarbamate) by alkylation with a halogenide and a base (e.g. DBU) or a Mitsunobu reaction with an alcohol (using e.g. DEAD), followed by deprotection with hydrazine or methylhydrazine, resulting in hydroxylamine (Va).
When R2 is not hydrogen, the resulting hydroxylamine (Va) may be submitted to reductive amination with an aldehyde or ketone followed by reduction with e.g. sodium cyanoborohydride as described in the literature {e.g. B.J. Mavunkel et a\.\ Eur.J.Med.Chem. (1994) 29, 659-666; T. Ishikawa eta/.: J.Antibiotics (2000), 53 (10), 1071-1085; J.Ishwara Bhat et al. : J.Chem.Soc, Perkin Trans. 2 (2000),1435- 1446). Alternatively, alkylation of the hydroxylamine (Va) can be achieved by a Mitsunobu reaction or alkylation after protection with e.g. 2- nitrophenylsulfonylchloride and subsequent removal of the protecting group (using e.g. thiophenol and cesium carbonate).
Figure imgf000041_0002
Figure imgf000042_0001
Compounds of general formula (I), which are Λ/-alkyl- or /V-arylhydrazides, N,N '- dialkyl- or /V/Λ/ '-diarylhydrazides (Ib) can be prepared from acids general formula (IV)) by coupling with hydrazines of general formula (VI)) using a peptide coupling reagent, e.g. EDC or HATU.
Figure imgf000042_0002
(IV) (Vl) (Ib)
Hydrazines (VI) are either commercially available or can - in the case where R2 is H - be prepared from hydrazine hydrate by alkylation in the presence of a base according to literature procedures (e.g. D.J. Drain et a : J.Med.Chem. (1963) 6 63- 9; G. B. Marini-Bettolo et al. : Rend.Ist.Super.Sanita (1960) 23 1110-27). N,N '-
Disubstituted hydrazines can be obtained from monosubstituted hydrazines (VΙa)by reaction with an aldehyde or ketone followed by redcuction with e.g. hydrogen, LiAIH4, or borane according to literature procedures (e.g. H.Dorn etal. : Zeitschrift fϋr Chemie (1972) 12(4) 129-30; R.L. Hinman: JACS (1957) 79 414-417; J.A.Blair: JCS (Section) C: Organic (1970) (12) 1714-17) or alternatively by Boc-protection of hydrazine hydrate, alkylation with an alkylhalogenide in the presence of sodium hydride, followed by a second alkylation with another alkylhalogenide in the presence of sodium hydride and finally removal of the Boc-protecting groups (L.Ling et ai..-Bioorg. Med. Chem. Lett. (2001) (11) 2715-2717).
Base N 1 R2 N Reduction D2 H
N2H4H2O + R3-X 1 H2N-1V + FTV ^N'^R3 "≠W
R H
(Via) (Vl)
N2H4-H2O !U^° BooNHNHBoc N_£L?2-χ BocNR2NHBoc "^J?* BOCNR2NHR=BOC -IE- RV%3
H ^1) Compounds of general formula (I), which are hydroxamic acid esters, Λ/-alkyl- or N- arylhydrazides, /V,/V '-dialkyl- or /V^/V '-diarylhydrazides containing a substituent α to the carbonyl group (Ic) can be prepared from amino acids of general formula (Ilia) or their enantiomers (obtained, as described in the literature e.g K. S. Orwig et al.: Tet.Lett (2005) 46 7007-7009) by coupling to compounds of general formula (II) and subsequent coupling to hydroxylamines (V) or hydrazines (VI) as described above.
Figure imgf000043_0001
Figure imgf000043_0002
N (but not alkyl) (|c)
Compounds (I) of the present invention which are /V-alkoxy- or /V- aryloxythioamides, or thiohydrazides (Id) can be prepared from the corresponding carbonyl compounds (Ia) or (Ib) by treatment with Lawesson reagent according to literature procedures (e.g. Thomsen et al.: Org. Synth. (1984) 62, 158, R.A. Cherkasov et al.: TeL (1985) 41, 2567; M. P. Cava, MJ. Levinson Tet. (1985) 41, 5061).
Ii r i R4* I Lawesson reagent N , , R4* *?
B = O, N (not alkyl) (Ia) or (Ib) (Id)
Alternatively, carboxylic acids of general formula (IV) can be converted into an activated species of general formula (VII) according to literature procedures (M. A: Shalaby et al.: J.Org.Chem. (1996) 61 9045-48) and subsequently allowed to react with hydroxylamines (V) or hydrazines (VI) as depicted below.
■
Figure imgf000043_0003
Compounds (I) according to the present invention which are Λ/-alkoxy or Λ/-aryloxy sulfonamides, sulfonamides or sulfonylhydrazides (If) can be obtained by reaction of phtalimidoalkanesulfonylchlorides (VIII)) (prepared as described in the literature, e.g. G.J. Atwell et al. : J.Med.Chem. (1977) 20(9) 1128-134; J. Humljan et al.i: Tet.Letters, 46 4069-4072) with hydroxylamines, amines or hydrazines, respectively, in the presence of a base (e.g. triethyamine or Λ/-methylmorpholine) followed by deprotection with hydrazine hydrate. The resulting amine (X) is subsequently allowed to react with compounds of general formula (II) to obtain compounds (If). Other protecting groups than phtalimido may be used.
Figure imgf000044_0001
(X) (H) (If)
Alternatively, intermediates of general formula (IXa) (R2=H) may be alkylated by an alkyl halogenide or by a Mitsunobu reaction followed by deprotection as described above.
Figure imgf000044_0002
Compounds (I) of the present invention which are /V-alkoxy-P- alkylphosphonamidates or Λ/-aryloxy-P-alkylphosphonamidates, P- alkylphosphonamidates or P-alkylphosphonohydrazidates (Ig) can be obtained by reaction of the phtalimido protected phosphonochloridates (XI) (prepared as described in the literature, e.g. S.Gobecet a/.; Tet.Lett. (2002) 43 167-170; U.Urleb et al.: Lett. In Peptide Science (1995) 2 193-197) with hydroxylamines, amines or hydrazines, respectively, in the presence of a base followed by deprotection with hydrazine hydrate. The resulting amine (XIII) is subsequently allowed to react with compounds of general formula (II) to obtain compounds (Ig). Other protecting groups than phtalimido may be used.
Figure imgf000045_0001
Compounds (I) of the present invention which are /V-a!koxy-P-alkylphosphinic amides or Λ/-aryloxy-P-alkylphosphinic amides, P-alkylphosphinic amides or P- akylphosphinic hydrazides (Ih) can be obtained by reaction of the phtalimido protected alkylphosphinic chlorides (XIV) {e.g. S. Gobec et al.: Lett. In Peptide Science (1998) 5 109-114) with hydroxylamines, amines or hydrazines, respectively, in the presence of a base followed by deprotection with hydrazine hydrate. The resulting amine (XVI) is subsequently allowed to react with compounds of general formula (II) to obtain compounds of formula (Ih). Other protecting groups than phtalimido may be employed.
Figure imgf000045_0002
(XVI) (H) (ig)
Compounds (I) of the present invention which are sulfonylureas (Ii) can be prepared from known literature procedures (e.g. B. Hδkfelt et al. :J.Med.&Pharm. Chem. (1962) 5 231-9; R.Tull et al. JCS Section C:0rganic (1967) (8) 701-2;B. Loev: J.Med.Chem. (1963) 6(5) 506-8; D.R.Cassady et al. : J.Org.Chem. (1958) 23 923-6; D. Freitag: Tetrahedron (2005) 61 5615-21; Y. Kanbe et.al.: Bioorg. Med. Chem. Lett. (2006) 16 4090-94; I. Ubarretxena-Belandia et.al.: Eur.J.Biochem. (1999) 260 794-800; B.D.Roth et al.: Bioorg. Med. Chem. Lett. (1995) 5(20) 2367-70 ), for instance by reaction of suitably protected aminoalkanesulfonylchlorides (XVII) with an ammonia equivalent or amine, followed by reaction with an alkyl chloroformate in the presence of a base to yield carbamates of general formula (XIX), which are subsequently allowed to react with amines R2R3NH2 to yield sulfonylureas of general formula (XX). Alternatively, sulfonamides of general formula (XVIII) can react directly with isocyanates to yield protected sulfonylureas (XX).
Figure imgf000046_0001
R2 R2
P9~N π*Λ R4 f O'^2 +R3NCO — p^ M# R4tl O'V O^3 (XV"1) (χχ)
The protecting group Pg (e.g phthalimido, BOC or other) can subsequently be removed and the resulting amines (XXI) allowed to react with methyl Λ/ '-cyano-Λ/- heteroarylcarbamimidothioates (II) to yield sulfonylureas of general formula (Ii):
Figure imgf000046_0002
(XX) (XXI) (H) (Ii)
Compounds (I) of the present invention can also be prepared by reaction of methyl /V'-cyano-Λ/-heteroarylcarbamimidothioates (II) with amines of general formula (XXII):
Figure imgf000046_0003
(II) (XXII) (I) Compounds (I) of the present invention can also be prepared by reaction of isothiocyanates of general formula (XXIII) (which are either commercially available or prepared by literature procedures, e.g. by reaction of the corresponding amine and di(2-pyridyl)thionocarbonate: S. Kim, K.Y. Yi:7et Lett. (1985) 26, 1661) and an amine of general formula (XXII); the resulting thiourea (XXIII) can subsequently be converted into the corresponding cyanoguanidine as described in the literature (e.g. S. K. Hamilton et al.: Org.Lett. (2005) 7 (12)2429-2431; Bioorg.Med.Chem.Lett. (1997) (24) 3095-3100; J. K. Lynch et al.:Synth.Comm. (2005) 35(1) 1-7) e.g. by reaction with cyanamide, dicyclohexylcarbodiimide and triethylamine, by reaction with EDC, cyanamide, 2,6-lutidine and titanium isopropoxide or by methylation and subsequent reaction with sodium hydrogencyanamide.
S 4. R2 EDC, H2NCN, 2,6-lut[dιne,
R1
Figure imgf000047_0002
H H R4 m or H2NCN, DCCl, NEt3
Figure imgf000047_0001
(XXIII) (XXII) (XXIV) (I) NCN
Figure imgf000047_0003
(XXV)
Medical uses
The compounds of the invention is believed to be particularly useful for down- regulating NAD via inhibition of NAMPRT, and such compounds are therefore particularly useful for treating diseases in which activation of NF-κB is implicated. Such methods are useful in the treatment of a variety of diseases including inflammatory and tissue repair disorders; particularly rheumatoid arthritis, inflammatory bowel disease, asthma and CPOD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukaemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telengiectasia.
Hence, the present invention provides a compound of the formula (I) for use as a medicament; more particular for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT), especially for the treatment of the above- mentioned diseases and conditions.
Moreover, the invention also provides a method of inhibiting the enzymatic activity of nicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said method comprising the step of administering to said mammal a pharmaceutically relevant amount of a compound of the general formula (I).
Further, the invention provides a method of treating a disease or condition (in particular the diseases and condtions mentioned above) caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said method comprising the step of administering to said mammal a pharmaceutically relevant amount of a compound of the general formula (I).
In such methods, the compound may be administered in combination with a DNA damaging agent.
Formulation of pharmaceutical compositions
The compounds of the general formula (I) are suitably formulated in a pharmaceutical composition so as to suit the desirable route of administration.
The administration route of the compounds may be any suitable route which leads to a concentration in the blood or tissue corresponding to a therapeutic effective concentration. Thus, e.g., the following administration routes may be applicable although the invention is not limited thereto: the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route and the ocular route. It should be clear to a person skilled in the art that the administration route is dependent on the particular compound in question; particularly the choice of administration route depends on the physico-chemical properties of the compound together with the age and weight of the patient and on the particular disease or condition and the severity of the same.
The compounds may be contained in any appropriate amount in a pharmaceutical composition, and are generally contained in an amount of about 1-95%, e.g. 1- 10%, by weight of the total weight of the composition. The composition may be presented in a dosage form which is suitable for the oral, parenteral, rectal, cutaneous, nasal, vaginal and/or ocular administration route. Thus, the composition may be in form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols and in other suitable form.
The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice, see, e.g., "Remington's Pharmaceutical Sciences" and
"Encyclopedia of Pharmaceutical Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988. Typically, the compounds defined herein are formulated with (at least) a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers or excipients are those known by the person skilled in the art. Formation of suitable salts of the compounds of the Formula (I) will also be evident in view of the before-mentioned.
Thus, the present invention provides in a further aspect a pharmaceutical composition comprising a compound of the general Formula (I) in combination with a pharmaceutically acceptable carrier.
Pharmaceutical compositions according to the present invention may be formulated to release the active compound substantially immediately upon administration or at any substantially predetermined time or time period after administration. The latter type of compositions is generally known as controlled release formulations.
In the present context, the term "controlled release formulation" embraces i) formulations which create a substantially constant concentration of the drug within the body over an extended period of time, ii) formulations which after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time, iii) formulations which sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance (saw-tooth kinetic pattern), iv) formulations which attempt to localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ, v) formulations which attempt to target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type.
Controlled release formulations may also be denoted "sustained release", "prolonged release", "programmed release", "time release", "rate-controlled" and/or "targeted release" formulations.
Controlled release pharmaceutical compositions may be presented in any suitable dosage forms, especially in dosage forms intended for oral, parenteral, cutaneous nasal, rectal, vaginal and/or ocular administration. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, liposomes, delivery devices such as those intended for oral, parenteral, cutaneous, nasal, vaginal or ocular use.
Preparation of solid dosage forms for oral use, controlled release oral dosage forms, fluid liquid compositions, parenteral compositions, controlled release parenteral compositions, rectal compositions, nasal compositions, percutaneous and topical compositions, controlled release percutaneous and topical compositions, and compositions for administration to the eye will be well-known to those skilled in the art of pharmaceutical formulation. Specific formulations can be found in "Remington's Pharmaceutical Sciences".
Capsules, tablets and pills etc. may contain for example the following compounds: microcrystalline cellulose, gum or gelatin as binders; starch or lactose as excipients; stearates as lubricants; various sweetening or flavouring agents. For capsules the dosage unit may contain a liquid carrier like fatty oils. Likewise coatings of sugar or enteric agents may be part of the dosage unit. The pharmaceutical compositions may also be emulsions of the compound(s) and a lipid forming a micellular emulsion.
For parenteral, subcutaneous, intradermal or topical administration the pharmaceutical composition may include a sterile diluent, buffers, regulators of tonicity and antibacterials. The active compound may be prepared with carriers that protect against degradation or immediate elimination from the body, including implants or microcapsules with controlled release properties. For intravenous administration the preferred carriers are physiological saline or phosphate buffered saline.
Dosages
In one embodiment, the pharmaceutical composition is in unit dosage form. In such embodiments, each unit dosage form typically comprises 0.1-500 mg, such as 0.1- 200 mg, e.g. 0.1-100 mg, of the compound.
More generally, the compound are preferably administered in an amount of about 0.1-250 mg per kg body weight per day, such as about 0.5-100 mg per kg body weight per day.
For compositions adapted for oral administration for systemic use, the dosage is normally 0.5 mg to 1 g per dose administered 1-4 times daily for 1 week to 12 months depending on the disease to be treated.
The dosage for oral administration of the composition in order to prevent diseases or conditions is normally 1 mg to 100 mg per kg body weight per day. The dosage may be administered once or twice daily for a period starting 1 week before the exposure to the disease until 4 weeks after the exposure.
For compositions adapted for rectal use for preventing diseases, a somewhat higher amount of the compound is usually preferred, i.e. from approximately 1 mg to 100 mg per kg body weight per day. For parenteral administration, a dose of about 0.1 mg to about 100 mg per kg body weight per day is convenient. For intravenous administration, a dose of about 0.1 mg to about 20 mg per kg body weight per day administered for 1 day to 3 months is convenient. For intraarticular administration, a dose of about 0.1 mg to about 50 mg per kg body weight per day is usually preferable. For parenteral administration in general, a solution in an aqueous medium of 0.5-2% or more of the active ingredients may be employed.
For topical administration on the skin, a dose of about 1 mg to about 5 g administered 1-10 times daily for 1 week to 12 months is usually preferable.
EXPERIMENTALS
General Procedures, Preparations and Examples
For nuclear magnetic resonance 1H NMR spectra (300 MHz) and 13C NMR (75.6) chemical shift values (δ) (in ppm) are quoted, unless otherwise specified, for deuteriochloroform solutions relative to tetramethylsilane (δ= 0.0) or chloroform (δ = 7.25) or deuteriochloroform (δ = 76.81 for 13C NMR) standards. The value of a multiplet, either defined (dublet (d), triplet (t), double dublet (dd), double triplet (dt), quartet (q)) or not (m) at the approximate mid point is given unless a range is quoted, (bs) indicates a broad singlet.
MS was performed using a Micromass LCT with an AP-ESI-probe or LC-MS using a Bruker Esquire 3000+ ESI Iontrap with an Agilent 1200 HPLC-system.
HPLC purifications were performed using an X-Bridge Prep C18 OBD 19x150 mm column, using a gradients of Buffer A (0.1% TFA in H2O) and Buffer B (0.1% TFA in acetonitrile).
The organic solvents used were anhydrous.
S-Methyl Λ/-cyano-Λ/ '-4-pyridylisothiourea was prepared as described in Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100. (S)-7-Amino-2-benzylheptanoic acid was prepares, e.g., as described in K.S. Orwig et al.: Tet.Lett. (2005) 46 7007-7009.
The following abbreviations have been used throughout:
DCM dichloromethane DEAD diethyl azodiarboxylate
DMF Λ/,Λ/-dinnthylformamide
DMAP N,N dimethylaminopryridine
EDC /V-CdimethylaminopropyO-N '-ethylcarbodiimide hydrochloride
EtOAc ethyl acetate HATU O-(7-Azabenzotriazol-l-yl)-Λ/,Λ/,Λ/1,Λ/'-tetramethyluronium hexafluorophosphate
HOBt 1-hydroxybenzotriazole
MS mass spectroscopy
NMM Λ/-methylmorpholine NMR nuclear magnetic resonance rt room temperature
TBAF /V-tetrabutylammonium fluoride
THF tetrahydrofurane
TLC thin layer chromatography
General Procedure 1: Reaction of amines with dimethyl N-cvanocarbonimidodithioate to form intermediates of general formula fill.
The amine and dimethyl /V-cyanodithio-iminocarbonate (1.16 eq.) were dissolved in DMF and cooled on an icebath. Sodium hydride (1.19 eq.) was added in small portions with stirring. Stirred at O0C for 5 h, then at rt overnight.
Ether: petroleum ether (5: 1) were added. After decanting of the supernatant phase the oily residue was stirred twice with ether: petroleum ether (5:1). After decantings, the resulting semi-solid was treated with ice-water and filtered. The stirred ice-cooled filtrate was treated with glacial acetic acid, and the precipitate was collected by filtration and washed with water and small portions of ether. Alternatively, DMF was evaporated under reduced pressure and the residue purified by chromatography (chloroform: methanol: NH3 (25% aq.) 90: 10:1 or 80:20: 1, or 1- 5% methanol in DCM) to afford compounds of general formula (II).
General Procedure 2: Reaction of amines with dimethyl N-cvanocarbonimidodithioate to form intermediates of general I formula CID.
The amine and dimethyl /V-cyanodithio-iminocarbonate (1.03 eq.) were dissolved in ethanol and refluxed until no more amine remained (typically 4-8 hours). Cooled on an icebath and the resulting precipitate was collected by filtration and washed with ethanol. Alternatively ethanol was evaporated under reduced pressure and the residue purified by chromatography (chloroform: methanol: NH3 (25% aq.) 90: 10:1 or 80:20: 1, 1-5% methanol in DCM, or mixtures of petroleum ether and EtOAc) to afford compounds of general formula (II).
General Procedure 3: Preparation of acids of general formula fIVI.
Compounds of general formula (II) were dissolved in pyridine, amino acid of general formula (III) (1.1 eq.), triethylamine (1 eq.) and DMAP (catalytic amount) were added and the mixture heated with stirring at 7O 0C overnight or until consumption of starting material (II). The warm solution was filtered, the filtrate concentrated twice with toluene, methanol was added and the resulting precipitate was collected by filtration and washed with methanol. Alternatively the residue purified by chromatography (chloroform: methanol: NH3 (25% aq.) 80:20:1) to afford acids of general formula (IV).
General Procedure 4: Coupling of acids of general formula (IV) with hvdroxylamines (V) or hydrazines fVII using EDC to yield compounds of general formula (P.
Acid of general formula (IV), hydroxylamine of general formula (V) (1.1 eq.) or hydrazine of general formula (VI) (1.1 eq.), HOBt (1.2 eq.), NMM (1.1 eq or 2.2 eq. if the hydroxylamine or hydrazine is a salt) were dissolved in DMF, and EDC (1.3 eq.) was added and the mixture stirred overnight, concentrated and the residue purified by chromatography (chloroform:methanol:NH3 (25% aq.) 98:2:02 or 95:5:0.5) to afford compounds of general formula (Ia) or (Ib). General Procedure 5: Coupling of acids of general formula flV) with hvdroxylamines CV) or hydrazines TVI) using HATU to yield compounds of general formula (ϊ).
Acid of general formula (IV), hydroxylamine of general formula (V) (1 eq.) or hydrazine of general formula (VI) (1 eq.), and NMM (1.1 eq. or 2.2 eq. if the hydroxylamine or hydrazine is a salt) were dissolved in DMF, HATU (1.25 eq.) was added and the mixture stirred overnight, concentrated and the residue purified by chromatography (chloroform: methanol: NH3 (25% aq.) 98:2:02 or 95:5:0.5) to afford compounds of general formula (I).
General Procedure 6: Preparation of hvdroxylamines of general formula (V) by reductive amination.
Using aldehydes: Hydroxylamines of formula (Va) and an aldehyde (1 eq.) were dissolved in 1,2-dichloroethane and stirred at rt overnight, concentrated and used as the crude oxime or purified by chromatography ((1% methanol in DCM or mixtures of petroleum ether and EtOAc).
Using ketones: Hydroxylamines of formula (Va) and a ketone (1 eq.) were dissolved in ethanol, concentrated H2SO4 (catalytic amount) was added and the mixture heated to 750C with stirring overnight. The mixture was concentrated, transferred to a separatory funnel with 5% Na2CO3 and extracted with EtOAc (2x), dried over Mg2SO4, filtered and concentrated to yield the oxime.
Oxime as prepared above was then dissolved in methanol, sodium cyanoborohydride (6 eq.) and a crystal of methyl orange were added followed by dropwise addition of 3 M methanolic HCI (35 eq.) and stirred overnight, concentrated, taken up in a few mL of water and the pH was adjusted to ca. 10 using 32% aqueous NaOH, transferred to a separatory funnel and extracted with EtOAc (2x), dried over Mg2SO4, filtered and concentrated.
The residue was purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc) to afford hydroxylamines of general formula (V). General Procedure 7: Preparation of hvdroxylamines of general formula (V) by a Mitsunobu reaction or alkylation after protection with 2-nitrophenylsulfonylchloride and subsequent removal of the protecting group.
Hydroxylamine (Va) and 2-nitrophenylsulfonylchloride (1.1 eq) were taken up in DCM, cooled on icebath and triethylamine (1.2 eq. or 2.2 eq. if the hydroxylamine is a salt) was added with stirring. The mixture was gradually allowed to react rt and stirred overnight, transferred to a separatory funnel with 5% K2C03 and extracted with DCM (2x), dried over Mg2SO4, filtered and concentrated. Used as the crude N- alkoxysulfonamide or purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc).
Alkylation: Λ/-alkoxysulfonamide as prepared above was dissolved in DMF, alkylhalogenide (1.06 eq.), NaI (catalytic amount) and Cs2CO3 (1.12 eq.) were added and the mixture stirred at rt until consumption of the sulfonamide. The reaction mixture was transferred to a separatory funnel with water and extracted with EtOAc (2x), dried over Mg2SO4, filtered and concentrated. Used as the crude product or purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc).
Mitsunobu: Λ/-alkoxysulfonamide as prepared above, the alcohol (1.05 eq.) and triphenphosphine (1.7 eq.) were dissolved in THF and DEAD (2.7 eq.) was added with stirring. Stirred at rt overnight, concentrated and purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc) to yield N- alkylated Λ/-alkoxysulfonamide
Deprotection: Λ/-alkylated Λ/-alkoxysulfonamide as prepared by either alkylation or Mitsunobu was dissolved in acetonitrile, thiophenol (1.2 eq.) and Cs2CO3 (1.6 eq.) were added and the mixture stirred at rt until consumption of the starting material. The reaction mixture was transferred to a separatory funnel with water and extracted with DCM (2x), dried over Mg2SO4, filtered and concentrated. Purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc) to yield hydroxylamines of general formula (V). General Procedure 8: Preparation of amines of general formula (X) by reaction of phtalimidoalkanesulfonylchlorides (VlIl) with hvdroxylamines (V) or amines or hydrazines (VII and subsequent deprotection.
Phtalimidoalkanesulfonylchlorides (VIII) (prepared as described in the literature, e.g. GJ. Atwell et aL: J.Med.Chem. (1977) 20(9) 1128-134; J. Humljan et al.i: Tet.Letters, 46 4069-4072) was added in small portions to a solution of hydroxylamines (V) (1.02 eq.), amine or hydrazine (VI) and triethyamine or N- methylmorpholine (1.1 eq., or 2.2 eq. if the hydroxylamine, amine or hydrazine is a salt) in DCM at -200C with stirring. The mixture was gradually allowed to reach rt, stirred overnight, concentrated, purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc) to yield intermediates of general formula (IX).
Deprotection: intermediate of general formula (IX) was dissolved in ethanol, hydrazine hydrate (2.9 eq.) was added and the mixture heated in a microwave oven at 12O0C until consumption of the starting material (typically 10-30 min). The mixture was filtered, filtercake washed with ethanol, the filtrate was concentrated and purifed by chromatography (chloroform: methanol: NH3 (25% aq.) 98:2:02 or 90: 10:1) to afford amines of general formula (X).
General Procedure 9: Preparation of amines of general formula (XI by a Mitsunobu reaction or alkylation of intermediate (IXa) and subsequent removal of the protecting group.
Mitsunobu: intermediate of general formula (IXa) (prepared as described in general procedure 8), the alcohol (1.05 eq.) and triphenphosphine (1.7 eq.) were dissolved in THF, and DEAD (2.7 eq.) was added with stirring. Stirred at rt overnight, concentrated and purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc).
Alkylation: intermediate of general formula (IXa) (prepared as described in general procedure 8) was dissolved in DMF, alkylhalogenide (1.06 eq.), NaI (catalytic amount) and Cs2CO3 (1.12 eq.) were added and the mixture stirred at rt until consumption starting matarial. The reaction mixture was transferred to a separatory funnel with water and extracted with EtOAc (2x), dried over Mg2SO4, filtered and concentrated. Used as the crude Λ/-alkoxysulfonamide (IX) or purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc).
Deprotection : intermediate of general formula (IX) was dissolved in ethanol, hydrazine hydrate (2.9 eq.) was added and the mixture heated in a microwave oven at 12O0C until consumption of the starting material (typically 10-30 min). The mixture was filtered, filtercake washed with ethanol, the filtrate was concentrated and purifed by chromatography (chloroform: methanol :NH3 (25% aq.) 98:2:02 or 90:10:1) to afford amines of general formula (X).
General Procedure 10: Preparation of compounds of general formula (ϊ) by reaction of intermediates of general formula (TD with amines of general formula (XXIP.
Intermediates of general formula (II) were dissolved in pyridine, amine of general formula (XXII) (1.05eq.), triethylamine (1.1 eq.) and DMAP (catalytic amount) were added and the mixture heated with stirring at 750C overnight or until consumption of starting material (II). The reaction mixture was concentrated twice with toluene, the residue purified by chromatography (chloroform: methanol :NH3 (25% aq.) 98:2:0.2 or 90:10: 1) to afford compounds of general formula (I).
The oxalic acid salt of compound of general formula (I) may be obtained by dissolving compound of general formula (I) (1 eq.) in MeCN and adding a solution of oxalic acid (2 eq.) in MeCN. The precipitate was filtered and dried to give the oxalic acid salt of urea of general formula (I).
Preparation 1: 7-(2-cvano-3-(pyridin-4-v0ouanidino')heptanoic acid (compound 1").
Figure imgf000058_0001
General procedure 3. Starting materials: S-methyl Λ/-cyano-Λ/ '-4-pyridylisothiourea and 7-aminoheptanoic acid. 1H-NMR (DMSO-d6) δ 11.5 (bs, IH), 9.6 (bs, IH), 8.38 (m, 2H), 7.90 (bs, IH), 7.22 (m, 2H), 3.27 (m, 2 H), 2.20 (t, 2H), 1.51 (m, 4H); 1.30 (m, 4H).
Preparation 2: 6-(2-cvano-3-fpyridin-4-v0quanidino')hexanoic (compound 2).
Figure imgf000059_0001
General procedure 3. Starting materials: S-methyl /V-cyano-Λ/'-4-pyridylisothiourea and 6-aminohexanoic acid. 1H-NMR (DMSOd6) δ 12.0 (bs, IH), 9.38 (bs, IH), 8.39 (m, 2H), 7.88 (t, IH), 7.22 (m, 2H), 3.26 (m, 2 H), 2.22 (t, 2H), 1.52 (m, 4H); 1.31 (m, 2H).
Preparation 3: 5-(2-cvano-3-(pyridin-4-vQquanidino')pentanoic (compound 3).
Figure imgf000059_0002
General procedure 3. Starting materials: S-methyl Λ/-cyano-Λ/ '-4-pyridylisothiourea and 5-aminopentanoic acid. 1H-NMR (DMSOd6) δ 12.0 (bs, IH), 9.37 (bs, IH), 8.39 (m, 2H), 7.86 (t, IH), 7.23 (m, 2H), 3.27 (m, 2 H), 2.25 (t, 2H), 1.54 (m, 4H).
Preparation 4: 8-(2-cvano-3-(pyridin-4-vπquanidino')octanoic acid (compound 4).
Figure imgf000059_0003
General procedure 3. Starting materials: S-methyl /V-cyano-Λ/ '-4-pyridylisothiourea and 8-aminooctanoic acid. 1H-NMR (DMSO-d6) δ 11.95 (bs, IH), 9.4 (bs, IH), 8.39 (m, 2H), 7.81 (bs, IH), 7.22 (m, 2H), 3.27 (m, 2 H), 2.20 (t, 2H), 1.51 (m, 4H); 1.29 (m, 6H). Preparation 5: 10-f2-cvano-3-f pyridin-4-vQq uanidino)decanoic acid fcom pound 5).
Figure imgf000060_0001
General procedure 3. Starting materials: S-methyl Λ/-cyano-Λ/ '-4-pyridylisothiourea and 10-aminodecanoic acid. 1H-NMR (DMSO-d6) δ 8.5 (m, 2H), 7.22 (m, 2H), 3.30 (t, 2 H), 2.13 (t, 2H), 1.48 (m, 4H); 1.25 (m, 10H).
Preparation 6: S-Methyl Λ/-cyano-Λ/ '-2-chloropyridin-4-ylisothiourea Nfcompound 6L
Figure imgf000060_0002
General procedure 1. Starting material: 4-amino-2-chloropyridine. 1H-NMR (DMSO- d6) δ 10.4 (bs, IH), 8.36 (d, IH), 7.66 (d, IH), 7.57 (dd, IH), 2.79 (s, 3 H).
Preparation 7: 7-f3-(2-chloropyridin-4-yl>2-cvanoquanidino')heptanoic acid fcompound 7).
Figure imgf000060_0003
General procedure 3. Starting materials: Compound 6 and 7-aminoheptanoic acid. 1H-NMR (DMSO-de) δ 8.16 (m, IH), 7.30 (m, IH), 7.21 (m, IH), 3.31 (t, 2H), 2.22 (t, 2H), 1.50 (m, 4H), 1.29 (m, 4H).
Preparation 8: fS)-Benzyl-7-f2-cvano-3-fpyridine-4-vπquanidine')hePtanoic acid fcompound 8).
Figure imgf000061_0001
General procedure 3. Starting materials: . S-methyl Λ/-cyano-Λ/ '-4-pyridylisothiourea and (S)-7-amino-2-benzylheptanoic acid. 1H-NMR (CD3OD): 8.37 (d, 2H), 7.34 (d, 2H), 7.3-7.1 (m, 5H), 3.37 (m, 2H), 2.94 (dd, IH), 2.69 (dd, IH), 2.57 (m, IH), 1.7-1.25 (m, 8H).
Preparation 9: fR1-Benzyl-7-f2-cvano-3-fpyridine-4-yπαuanidine')heptanoic acid (compound 9).
Figure imgf000061_0002
General procedure 3. Starting materials: S-methyl Λ/-cyano-Λ/ '-4-pyridylisothiourea and (R)-7-amino-2-benzylheptanoic acid. 1H-NMR (CD3OD) : 8.37 (d, 2H), 7.34 (d, 2H), 7.3-7.1 (m, 5H), 3.37 (m, 2H), 2.94 (dd, IH), 2.69 (dd, IH), 2.57 (m, IH), 1.7-1.25 (m, 8H).
Preparation 10: fSV7-f2-cvano-3-fpyridine-4-vπαuanidine1-2-methylheptanoic acid ("compound 10").
Figure imgf000061_0003
General procedure 3. Starting materials: S-methyl Λ/-cyano-Λ/ '-4-pyridylisothiourea and (S)-7-amino-2-methylheptanoic acid. 1H-NMR (CD3OD): 8.30 (d, 2H), 7.28 (d, 2H), 3.34 (t, 2H), 2.30 (m, IH), 1.57 (m, 3H), 1.33 (m, 5H), 1.06 (d, 3H). Preparation 11: fRV7-f2-cvano-3-(pyridine-4-vnauanidiney2-methylheptanoic acid (compound 111.
Figure imgf000062_0001
General procedure 3. Starting materials: S-methyl Λ/-cyano-Λ/ '-4-pyridylisothiourea and (R)-7-amino-2-methylheptanoic acid. MS [M-H]+= 302.2
Preparation 12: /V-Benzyl-O-cvclohexylhvdroxylamine (compound 121.
Figure imgf000062_0002
General procedure 7. Starting materials: O-cyclohexylhydroxylamine and benzyl bromide (alkylation). 1H-NMR (CDCI3): 7.30-7.20 (m, 5H), 5.3 (bs, IH), 3.96 (s, 2H), 3.45 (m, IH), 1.84 (m, 2H), 1.61 (m, 2H), 1.43 (m, IH), 1.25-1.1 (m, 5H).
Preparation 13: Q-Cvclohexyl-Λ/-methylhvdroxylamine (compound 13).
Figure imgf000062_0003
General procedure 7. Starting materials: O-cyclohexylhydroxylamine and methyl iodide (alkylation). 1H-NMR (CDCI3): 5.2 (bs, IH), 3.47 (m, IH), 2.65 (s, 3H), 1.86 (m, 2H), 1.65 (m, 2H), 1.45 (m, IH), 1.25-1.05 (m, 5H).
Preparation 14: 0-Cvclohexyl-/V-(2-(2-(2-methoxyethoxy')ethoxyV ethvπhvdroxylamine (compound 14~).
Figure imgf000062_0004
General procedure 7. Starting materials: O-cyclohexylhydroxylamine and 2-(2-(2- meyhoxyethoxy)ethoxy)ethanol (Mitsunobu). 1H-NMR (CDCI3): 5.2 (bs, IH), 3.7-3.5 (m, 10H), 3.37 (s, 3H), 3.06 (t, 2H), 1.91 (m, 2H), 1.69 (m, 2H), 1.51 (m, IH), 1.35-1.1 (m, 5H).
Preparation 15: S-fcvclohexyloxyaminoipropan-l-ol (compound 15^.
Figure imgf000063_0001
General procedure 7, adding an extra step of removing the triisopropylsilyl protecting group with TBAF (as described in the paper below) prior to removal of the 2-nitrosulfonamide group. Starting materials: O-cyclohexylhydroxylamine and 3- (triisopropylsilyloxy)propan-l-ol (prepared as described for 2-
(triisopropylsilyloxy)ethanol in J.Med. Chem. (2006), 49 (7), 2333-2338 using 1,3- propanediol as starting material) (Mitsunobu). 1H-NMR (CDCI3): 4.0 (bs, 2H), 3.76 (t, 2H), 3.59 (m, IH), 3.11 (t, 2H), 1.93 (m, 2H), 1.72 (m, 2H), 1.54 (m, IH), 1.4- 1.1 (m, 5H).
Preparation 16: O-cvclohexyl-/V-fpyridine-3-ylmethv0hvdroxylamine (compound 16X
Figure imgf000063_0002
General procedure 7. Starting materials: O-cyclohexylhydroxylamine and 3- (chloromethyl)pyridine (alkylation). 1H-NMR (CDCI3): 8.58 (d, IH), 8.51 (m, IH) 7.68 (m, IH), 7.25 (m, IH), 5.5 (bs, IH), 4.02 (s, 2H), 3.44 (m, IH), 1.84 (m, 2H), 1.65 (m, 2H), 1.50 (m, IH), 1.18 (m, 5H).
Preparation 17: 2-(cvclohexyloxyamino') ethanol (compound 17).
Figure imgf000063_0003
General procedure 7, adding an extra step of removing the triisopropylsilyl protecting group with TBAF (as described in the paper below) prior to removal of the 2-nitrosulfonamide group. Starting materials: O-cyclohexylhydroxylamine and 2- (triisopropylsilyloxy)ethanol (J.Med. Chem. (2006), 49 (7), 2333-2338) (Mitsunobu). 1H-NMR (CDCI3): 5.7 (bs, IH), 3.78 (t, 2H), 3.56 (m, IH), 3.08 (t, 2H), 2.5 (bs, IH), 1.96 (m, 2H), 1.72 (m, 2H), 1.56 (m, IH), 1.4-1.1 (m, 5H).
Preparation 18: O-cvclohexyl-Λ/-f2-morpholinoethv0hvdroxylamine (compound 18").
Figure imgf000064_0001
General procedure 7. Starting materials: O-cyclohexylhydroxylamine and 4-(2- chloroethyl)- morpholine hydrochloride (alkylation). 1H-NMR (CDCI3): 5.4 (bs, IH),
3.68 (m, 4H), 3.51 (m, 1H),2.99 (t, 2H), 2.49 (t, 2H), 2.44 (m, 4H), 1.92 (m, 2H),
1.69 (m, 2H), 1.51 (m, IH), 1.35-1.1 (m, 5H).
Preparation 19: 2-f2-(2-fcvclohexyloxyamino')ethoxy')ethoxy')ethanol (compound 19Λ
^y0- N^^O^^O^^OH ^^
General procedure 7, adding an extra step of removing the triisopropylsilyl protecting group with TBAF (as described in the paper below) prior to removal of the 2-nitrosulfonamide group. Starting materials: O-cyclohexylhydroxylamine and 3,3- diisopropyl-2-methyl-4,7,10-trioxa-3-siladodecan-12-ol (prepared as described for 2-(triisopropylsilyloxy)ethanol in J.Med. Chem. (2006), 49 (7), 2333-2338 using triethyleneglycol as starting material) (Mitsunobu). 1H-NMR (CDCI3): 4.2 (bs, 2H),
3.70 (m, 2H), 3.65-3.55 (m, 8H), 3.50 (m, IH), 3.05 (t, 2H), 1.90 (m, 2H), 1.67 (m, 2H), 1.48 (m, IH), 1.35-1.05 (m, 5H).
Preparation 20: O-cvclohexyl-Λ/-f3,3-dimethylbutvnhvdroxylamine (compound 201.
Figure imgf000065_0001
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and 3,3- dimethylbutanal. 1H-NMR (CDCI3): 4.5 (bs, IH), 3.44 (m, IH), 2.85 (m, 2H), 1.90 (m, 2H), 1.64 (m, 2H), 1.49 (m, IH), 1.30 (m, 2H), 1.3-1.05 (m, 5H), 0.84 (s, 9 H).
Preparation 21: /V-Benzyl-O-f2-morpholinoethvnhvdroxylamine (compound 21").
Figure imgf000065_0002
General procedure 6. Starting materials: O-(2-morpholinoethyl)hydroxylamine and benzaldehyde. 1H-NMR (CDCI3): 7.45-7.30 (m, 5H), 5.8 (bs, IH), 4.08 (s, 2H), 3.79 (t, 2H), 3.71 (m, 4H), 2.54 (t, 2H), 2.43 (m, 4H).
Preparation 22: O-cvclohexyl-/V-isopropylvdroxylamine (compound 22).
Figure imgf000065_0003
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and acetone. 1H-NMR (CDCI3): 4.8 (bs, IH), 3.43 (m, IH), 3.06 (m, IH), 1.88 (m, 2H), 1.64 (m, 2H), 1.45 (m, IH), 1.3-1.05 (m, 5H), 0.98 (d, 6 H).
Preoa ration 23: O-cvclohexyl-Λ/-phenethylhvdroxylamine (compound 231.
Figure imgf000065_0004
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and 2- phenylacetaldehyde. 1H-NMR (CDCI3): 7.3-7.05 (m, 5H), 5.2 (bs, IH), 3.48 (m, IH), 3.09 (t, 2H), 2.77 (t, 2H), 1.86 (m, 2H), 1.64 (m, 2H), 1.46 (m, IH), 1.3-1.05 (m, 5H).
Preparation 24: Q-cvclohexyl-Λ/-(3-phenylpropy0hvdroxylamine (compound 24).
Figure imgf000066_0001
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and 3- phenylpropanal. 1H-NMR (CDCI3): 7.35-7.15 (m, 5H), 5.4 (bs, IH), 3.55 (m, IH), 2.96 (t, 2H), 2.70 (t, 2H), 1.97 (m, 2H), 1.87 (m, 2H), 1.73 (m, 2H), 1.55 (m, IH), 1.4-1.15 (m, 5H).
Preparation 25: /V-butyl-O-cvclohexylhvdroxylamine (compound 25).
r H
1^rJ °τ
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and butyraldehyde. 1H-NMR (CDCI3): 5.2 (bs, IH), 3.45 (m, IH), 2.83 (t, 2H), 1.87 (m, 2H), 1.64 (m, 2H), 1.5-1.0 (m, 8H), 0.85 (t, 3 H).
Pre pa ration 26: O-cvclohexyl-/V-ethylhvdroxylamine (compound 26).
Figure imgf000066_0002
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and acetaldehyde. 1H-NMR (CDCI3): 5.3 (bs, IH), 3.54 (m, IH), 2.97 (q, 2H), 1.96 (m, 2H), 1.72 (m, 2H), 1.55 (m, IH), 1.4-1.15 (m, 5H), 1.11 (t, 3 H).
Preparation 27: O-cyclohexyl-Λ/-(naphtalen-2-ylmety0hydroxylamine (compound 2ZL
Figure imgf000067_0001
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and 2- (naphtalen-2-yl)acetaldehyde. 1H-NMR (CDCI3): 7.85 (m, 4H), 7.50 (m, 3H), 5.5 (bs, IH), 4.22 (s, 2H), 3.57 (m, IH), 1.94 (m, 2H), 1.87 (m, 2H), 1.71 (m, 2H), 1.52 (m, IH), 1.4-1.15 (m, 5H).
Preparation 28: O-cvclohexyl-Λ/-(naphtalen-l-ylmetvπhvdroxylamine (compound 281.
Figure imgf000067_0002
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and 2- (naphtalen-l-yl)acetaldehyde. 1H-NMR (CDCI3): 7.9-7.6 (m, 4H), 7.55-7.3 (m, 3H), 5.5 (bs, IH), 4.45 (s, 2H), 3.57 (m, IH), 2.1-0.9 (m, 10H).
Preparation 29: Q-cvclohexyl-Λ/-(pyridyl-2-ylmetv0hvdroxylamine ("compound 29V
Figure imgf000067_0003
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and 2- pyridinecarboxaldehyde. 1H-NMR (CDCI3): 8.57 (m, IH), 7.63 (m, IH), 7.31 (m,
IH), 7.17 (m, IH), 6.1 (bs, IH), 4.15 (s, 2H), 3.57 (m, IH), 1.91 (m, 2H), 1.68 (m, 2H), 1.48 (m, IH), 1.21 (m, 5H).
Preparation 30: Λ/-Cvclohexyl-O-(2-morpholinoethv0hvdroxylamine (compound 30").
Figure imgf000067_0004
General procedure 6. Starting materials: O-(2-morpholinoethyl)hydroxylamine and cyclohexanone. 1H-NMR (CDCI3): 5.3 (bs, IH), 3.83 (t, 2H), 3.74 (m, 4H), 2.86 (m, IH), 2.58(t, 2H), 2.50 (m, 4H), 1.93-1.58 (m, 5H), 1.4-1.0 (m, 5H).
Preparation 31: O-cvclohexyl-Λ/-octylhvdroxylamine (compound 31").
Figure imgf000068_0001
General procedure 6. Starting materials: O-cyclohexylhydroxylamine and octylaldehyde. 1H-NMR (CDCI3): 5.2 (bs, IH), 3.52 (m, IH), 2.91 (t, 2H), 1.96 (m, 2H), 1.8-1.1 (m, 20H), 0.90 (m, 3 H).
Preparation 32: Λ/-(l-methylpiperidin-4-ylVO-(2-morpholinoethvπhvdroxylamine (compound 32").
Figure imgf000068_0002
General procedure 6. Starting materials: 0-(2-morpholinoethyl)hydroxylamine and l-methylpiperidin-4-one. 1H-NMR (CDCI3): 5.5 (bs, IH), 3.83 (t, 2H), 3.73 (m, 4H), 2.95-2.7 (m, 3H), 2.58 (t, 2H), 2.50 (m, 4H), 2.30 (s, 3H), 2.05 (m, 2H), 1.89 (m, 2H), 1.48 (m, 2H).
Preparation 33: 0-(2-morpholinoethvπ-Λ/-(tetrahydro-2AV-pyran-4-vπhydroxylamine (compound 331.
Figure imgf000068_0003
General procedure 6. Starting materials: 0(2-morpholinoethyl)hydroxylamine and tetrahydro-4W-pyran-4-one. 1H-NMR (CDCI3): 5.2 (bs, IH), 4.00 (m, 2H), 3.9-3.65 (m, 6H), 3.43 (m, 2H), 3.12 (m, IH), 2.54 (m, 6H), 1.83 (m, 2H), 1.46 (m, 2H). Preparation 34: 6-Amino-Λ/-(benzyloxy)hexane-l-sulfonamide (compound 34").
Figure imgf000069_0001
General procedure 8. Starting materials: O-benzylhydroxylamine hydrochloride and 6-(l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 7.56-7.48 (m, 2H), 7.41-7.36 (m, 3H), 4.98 (s, 2H), 3.44-3.38 (m, 2H), 3.27-3.22 (m, 2H), 1.90-1.80 (m, 2H), 1.62-1.38 (m, 6H).
Preparation 35: 6-Amino-Λ/-benzylhexane-l-sulfonamide (compound 351.
Figure imgf000069_0002
General procedure 8. Starting materials: benzylamine and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 7.41-7.30 (m, 5H), 4.31 (s, 2H), 2.94-2.89 (m, 2H), 2.67 (t, 2H), 1.81-1.71 (m, 2H), 1.47-1.27 (m, 6H).
Preparation 36: 6-Amino-Λ/-cvclohexylhexane-l-sulfonamide (compound 36V
Figure imgf000069_0003
General procedure 8. Starting materials: cyclohexylamine and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.33-3.23 (m, IH), 3.04-2.99 (m, 2H), 2.71 (t, 2H), 2.02-1.97 (m, 2H), 1.89-1.71 (m, 4H), 1.65- 1.57 (m, IH), 1.50-1.15 (m, HH).
Preparation 37: 6-Amino-Λ/-phenylhexane-l-sulfonamide (compound 371.
Figure imgf000070_0001
General procedure 8. Starting materials: aniline and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 7.30-7.23 (m, 2H), 7.16-7.06 (m, 3H), 3.03-2.98 (m, 2H), 2.59 (t, 2H), 1.80-1.70 (m, 2H), 1.39-1.18 (m, 6H).
Preparation 38: 6-Amino-Λ/-fcvclohexylmethvπhexane-l-sulfOnamide (compound 38L
Figure imgf000070_0002
General procedure 8. Starting materials: cyclohexylmethylamine and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.04-2.99 (m, 2H), 2.71 (t, 2H), 1.88-1.67 (m, 6H), 1.53-0.87 (m, 15H).
Preparation 39:6-Amino-/V-fcvclohexylmethoxy')hexane-l-sulfonamide ("compound 39JL
Figure imgf000070_0003
General procedure 8. Starting materials: O-(cyclohexylmethyl)hydroxylamine and 6- (l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3) : δ 3.83-3.81 (m, 2H), 3.24-3.19 (m, 2H), 1.87-0.89 (m, 21H).
Preparation 40: 6-Amino-Λ/-ftetrahydro-2AV-pyran-2-yloxy")hexane-l-sulfonamide (compund 401.
9
H2N' O H XJ General procedure 8. Starting materials: O-(tetrahydro-2W-pyran-2- yl)hydroxylamine and 6-(l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. Crude product used without identification.
Preparation 41: β-Amino-yv-fcvcloheptyloxyihexane-l-sulfonamide (compound 41Λ
Figure imgf000071_0001
General procedure 8. Starting materials: O-cycloheptylhydroxylamine and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.10-4.01 (m, IH), 3.15-3.10 (m, 2H), 2.63 (t, 2H), 1.99-1.28 (M, 20H).
Preparation 42: 6-Amino-Λ/-(cvclohexylethoxy')hexane-l-sulfonamide (compound 42L
Figure imgf000071_0002
General procedure 8. Starting materials: O-(cyclohexylethyl)hydroxylamine and 6- (l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.00-3.94 (m, 2H), 3.15-3.10 (m, 2H), 2.64 (t, 2H), 1.80-0.79 (m, 21H).
Preparation 43: 6-Amino-Λ/-(cvclopentyloxy')hexane-l-sulfonamide (compound 43V
O H
M N ^S' O
General procedure 8. Starting materials: O-cyclopentylhydroxylamine and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.63-4.58 (m, IH), 3.22-3.17 (m, 2H), 2.72 (t, 2H), 1.94-1.39 (m, 16H).
Preparation 44: 6-Amino-Λ/-(cyclohexyloxy")hexane-l-sulfonamide (compound 441.
Figure imgf000072_0001
General procedure 8. Starting materials: O-cyclohexylhydroxylamine and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.16-3.11 (m, 2H), 2.63 (t, 2H), 1.97-1.17 (m, 19H).
Preparation 45: 6-Amino-Λ/-(2-morpholinoethoxy')hexane-l-sulfonamide (compound 45V
Figure imgf000072_0002
General procedure 8. Starting materials: O-(2-morpholinoethyl)hydroxylamine and 6-(l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.08 (t, 2H), 3.71-3.68 (m, 4H), 3.22-3.17 (m, 2H), 2.69-2.64 (m, 4H), 2.55-2.52 (m, 4H), 1.85-1.75 (m, 2H), 1.57-1.33 (m, 6H).
Preparation 46: 6-Amino-Λ/-methoxy-Λ/-methylhexane-l-sulfonamide (compound 46 V
Figure imgf000072_0003
General procedure 8. Starting materials: N1O -dimethylhydroxylamine hydrochloride and 6-(l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.71 (s, 3H), 3.03-2.97 (m, 2H), 2.95 (s, 3H), 2.64 (t, 2H), 1.89-1.77 (m, 2H), 1.47- 1.27 (m, 6H).
Preparation 47: 6-Amino-Λ/-benzyl-Λ/-(2-morpholinoethoxy)hexane-l-sulfonamide (compound 47V
Figure imgf000073_0001
General procedure 8. Starting materials: compound 21 and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCl3): δ 7.47-7.42 (m, 2H), 7.40-7.33 (m, 3H), 4.37 (s, 2H), 3.82 (t, 2H), 3.62-3.59 (m, 4H), 3.12 (t, 2H), 2.72 (t, 2H), 2.33 (t, 2H), 2.23-2.20 (m, 4H), 2.00-1.90 (m, 2H), 1.55-1.34 (m, 6H).
Preparation 48: 6-Amino-/V-benzyl-Λ/-(cvclohexylmethoxy')hexane-l-sulfonamide (compound 48)
Figure imgf000073_0002
General procedure 9. Starting materials: Λ/-(cyclohexylmethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and bezylbromide. 1H-NMR (CDCI3): δ 7.45-7.34 (m, 5H), 4.34 (s, 2H), 3.47 (d, 2H), 3.08 (t, 2H), 2.77 (t, 2H), 2.00-1.89 (m, 2H), 1.61-1.29 (m, 12H), 1.18-1.04 (m, 3H), 0.81-0.68 (m, 2H).
Preparation 49: 6-Amino-Λ/-cyclohexyl-Λ/-(2-morpholinoethoxy')hexane-l- sulfonamide (compound 491.
Figure imgf000073_0003
General procedure 8. Starting materials: compound 30 and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.19 (m, 2H), 3.72-3.69 (m, 4H), 3.65-3.55 (m, IH), 2.74 (t, 2H), 2.62-2.49 (m, 8H), 1.94-1.05 (m, 18H). Preparation 50: 6-fmorpholinosulfonvπhexan-l-amine (compound 501.
Figure imgf000074_0001
General procedure 8. Starting materials: tetrahydro-l,2-oxazinium hydrochloride(J. Chem.Soc, Pekin Trans 2 (2000), 1435-144) and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.13 (t, 2H), 3.41 (t, 2H), 3.19-3.14 (m, 2H), 2.73 (t, 2H), 1.94-1.83 (m, 4H), 1.76-1.69 (m, 2H), 1.56-1.36 (m, 6H).
Preparation 51: 6-fIsoxazolidin-2-ylsulfonvπhexan-l-amine (compound 51).
Figure imgf000074_0002
General procedure 8. Starting materials: isoxazolidinium chloride {J. Chem.Soc,
Pekin Trans 2 (2000), 1435-144) and 6-(l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.26-4.15 (m, 2H), 3.75-3.64 (m, 2H), 3.36-3.23 (m, 2H), 2.83-2.66 (m, 2H), 2.49-2.32 (m, 2H), 2.02-1.85 (m, 2H), 1.71-1.35 (m, 6H).
Preparation 52: 6-Amino-Λ/-(2-morpholinoethvπhexane-l-sulfonamide (compound 52},.
Figure imgf000074_0003
General procedure 8. Starting material: O-(2-morpholinoethyl)hydroxylamine and 6- (l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCl3): δ 3.73-3.70 (m, 4H), 3.20 (t, 2H), 3.07-3.02 (m, 2H), 2.71 (t, 2H), 2.55 (t, 2H), 2.50-2.46 (m, 4H), 1.89-1.79 (m, 2H), 1.54-1.35 (m, 6H).
Preparation 53: 6-Amino-Λ/-cvcloheptvlhexane-l-sulfonamide (compound 53").
Figure imgf000075_0001
General procedure 8. Starting material: cyclohexylamine and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.03-2.98 (m, 2H), 2.71 (t, 2H), 2.04-1.96 (m, 2H), 1.88-1.78 (m, 2H), 1.69-1.33 (M, 17H).
Preparation 54:6-Amino-ΛH3-morpholinopropy0hexane-l-sulfonamide (compound 54).
Figure imgf000075_0002
General procedure 8. Starting material: 4-(2-aminoethyl)morpholine and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.73 (t, 4H), 3.24 (t, 2H), 3.03-2.97 (m, 2H), 2.73 (t, 2H), 2.56-2.49 (m, 6H), 1.87-1.35 (m, 10H).
Preparation 55: 6-Amino-Λ/-(2-cvclohexylethv0hexane-l-sulfonamide (compound 55),
Figure imgf000075_0003
General procedure 8. Starting material: 2-cyclohexylethanamine and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 7.25 (t, 2H), 7.15-7.10 (m, 2H), 6.83 (t, 2H), 5.99-4.98 (m, 21H).
Preparation 56: 6-Amino-Λ/-(2-cvclohexylethoxyVN-(2-(2-(2- methoxvethoxv^ethoxv'jethvπhexane-l-sulfonamide (compound 56"ϊ
Figure imgf000076_0001
General procedure 9. Starting materials: Λ/-(2-cyclohexylethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and 2-(2-(2- methoxyethoxy)ethoxy)ethanol. 1H-NMR (CDCI3): δ 3.99 (t, 2H), 3.65 (t, 2H), 3.59 (m, 6H), 3.48 (m, 2H), 3.36 (m, 2H), 3.32 (s, 3H), 3.20 (bs, 2H), 3.00 (t, 2H), 2.69 (t, 2H), 1.82 (m, 2H), 1.7-1.1 (m, 17H), 0.82 (m, 2H).
Preparation 57: tert-butyl 7-(cvclohexyl(2-morpholinoethoxy)amino')-7- oxoheptylcarbamate (compound 571.
Figure imgf000076_0002
Compound 18 (1.16 g, 5.07 mmol), 7-(tert-butoxycarbonylamino)heptanoic acid
(1.22 g, 4.98 mmol), HATU (2.28 g, 6.01 mmol) and NMM (675 μl, 6.14 mmol) were dissolved in DMF under nitrogen and stirred at it overnight. The reaction mixture was concentrated and purified by chromatography (2% MeoH in DCM) to yield compound 57. MS [MH-H]+= 456.4.
Preparation 58: 7-amino-/V-cvclohexyl-Λ/-(2-morpholinoethoxy')heptanarnide (compound 58").
Figure imgf000077_0001
Compound 57 (2.27 g, 4.98 mmol) was dissolved in 3N HCI in MeOH and stirred at rt for 3h, concentrated and purified chromatography (chloroform: methanol :NH3 (25% aq.) 90: 10:1) to yield compound 58. MS [M+H]+= 356.3.
Preparation 59: 6-Amino-Λ/-(2-cyclohexylethoxy')-Λ/-(2-morpholinoethv0hexane-l- sulfonamide (compound 59")
Figure imgf000077_0002
General procedure 9. Starting materials: Λ/-(2-cyclohexylethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and 4-(2-chloroethyl)-morpholine hydrochloride. 1H-NMR (CDCI3): δ 4.09 (t, 2H), 3.71 (m, 4H), 3.68 (t, 2H), 3.08 (t, 2H), 2.78 (bs (2H), 2.76 (t, 2H), 2.66 (t, 2H), 2.51 (m, 4H), 1.91 (m, 2H), 1.8-1.1 (m, 17H), 0.93 (m, 2H).
Preparation 60: Methyl Λr-cvano-Λ/-f2,6-dichloropyridin-4-y0carbarnimidothioate (compound 60).
Figure imgf000077_0003
General procedure 1. Starting material: 4-amino-2,6-dichloropyridine. 1H-NMR (DMSO-de) δ 10.54 (bs, IH), 7.71 (s, 2H), 2.80 (s, 3 H). Preparation 61: 6-Amino-Λ/-benzyl-ΛH2-cvclohexylethoxy)hexane-l-sulfonamide (compound 61)
Figure imgf000078_0001
General procedure 9. Starting materials: Λ/-(2-cyclohexylethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and benzylbromide. 1H-NMR (CDCI3): δ 7.5-7.3 (m, 5H), 4.33 (s, 2H), 3.7 (m, 4H), 3.10 (t, 2H), 2.77 (t, 2H), 1.95 (m, 2H), 1.7-1.0 (m, 17H), 0.71 (m, 2H).
Preparation 62: 6-Amino-Λ/-(2-cvclohexylethoxy)-Λ/-methylhexane-l-sulfonamide (compound 62)
Figure imgf000078_0002
General procedure 9. Starting materials: /V-(2-cyclohexylethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and methyliodide. 1H-NMR (CDCI3): δ 4.01 (t, 2H), 3.06 (m, 2H), 3.02 (s, IH), 2.7 (m, 2H), 2.15 (bs, 2H), 1.91 (m, 2H), 1.8-1.1 (m, 17H), 0.93 (m, 2H).
Preparation 63: 6-Amino-Λ/-(cyclohexylmethoxy)-N-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)hexane-l-sulfonamide (compound 63).
Figure imgf000078_0003
General procedure 9. Starting materials: Λ/-(cyclohexylmethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and 2-(2-(2- methoxyethoxy)ethoxy)ethanol. 1H-NMR (CD3OD): δ 3.86 (m, 2H), 3.73 (m, 2H), 3.66 (m, 6H), 3.56 (m, 2H), 3.44 (m, 2H), 3.38 (s, 3H), 3.19 (m, 2H), 2.73 (m, 2H), 1.89 (m, 2H), 1.85-1.15 (m, 15H), 1.05 (m, 2H).
Preparation 64: te/t-butyl 8-fbenzylf2-morpholinoethoxy')amino')-8- oxooctylcarbamate (compound 64).
Figure imgf000079_0001
Compound 21 (303, 1.8 mmol), 8-(£ert-butoxycarbonylamino)octanoic acid (337mg, 1.30 mmol), HOBt (264 mg, 1.72 mmol), NMM (185 μl, 1.68 mmol) and EDC were dissolved in DMF under nitrogen and stirred at rt overnight. The reaction mixture was concentrated and purified by chromatography (1-2% MeoH in DCM) to yield compound 64. 1H-NMR (CDCI3): δ 7.32 (m, 5H), 4.81 (s, 2H), 4.54 (bs, IH), 3.90 (t, 2H), 3.69 (m, 4H), 3.10 (m, 2H), 2.6-2.35 (m, 8H), 1.66 (m, 2H), 1.45 (m, HH), 1.34 (m, 6H).
Preparation 65: 8-amino-Λ/-benzyl-Λ/-(2-morpholinoethoxy')octanamide (compound
Figure imgf000079_0002
Compound 64 (322 mg, 0.67 mmol) was dissolved in HCOOH (4 ml_). After 4h the mixture was concentrated to dryness, extracted with DCM/ 5% Na2CO3. The aqeous phase was extracted once more with DCM. The collected organic phases were dried over Mg2SO4, filtered and concentrated to yield compound 65. 1H-NMR (CDCI3): δ 7.32 (m, 5H), 4.81 (s, 2H), 4.8 (bs, 2H), 3.87 (t, 2H), 3.67 (m, 4H), 2.89 (m, 2H), 2.50 (m, 4H), 2.40 (m, 4H), 1.63 (m, 4H), 1.3 (m, 6H).
Preparation 66: te/t-butyl 6-(benzyl(2-morpholinoethoxylaminoV6- oxohexylcarbamate (compound 66).
Figure imgf000080_0001
Same procedure as described in preparation 64, using compound 21 and 6-(tert- butoxycarbonylamino)hexanoic acid. 1H-NMR (CDCI3): δ 7.33 (m, 5H), 4.82 (s, 2H), 4.56 (bs, IH), 3.8 (t, 2H), 3.69 (m, 4H), 3.13 (m, 2H), 2.53 (m, 4H), 2.41 (m, 4H), 1.66 (m, 2H), 1.50 (m, 2H), 1.46 (s, 9H), 1.38 (m, 2H).
Preparation 67: 8-amino-Λ/-benzyl-Λ/-(2-morpholinoethoxy')octanamide (compound 6ZL
Figure imgf000080_0002
Same procedure as described in preparation 65, using compound 66. MS [M+H]+= 350.3.
Preparation 68: 6-Amino-Λ/-cvcloheptyl-Λ/-methylhexane-l-sulfonamide (compound 681
Figure imgf000080_0003
General procedure 9. Starting materials: /V-cycloheptyl-6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonamide and methyliodide. 1H-NMR (CDCI3): δ 3.32 (m, IH), 2.91 (m, 2H), 2.79 (s, 3H), 2.73 (t, 2H), 2.2 (bs, 2H), 1.9-1.2 (m, 21H).
Preparation 69: 6-Amino-Λ/-("3-morpholinopropyπ-Λ/-fpyridin-3-vπhexane-l- sulfonamide (compound 691
Figure imgf000081_0001
General procedure 9. Starting materials: 6-(l,3-dioxoisoindolin-2-yl)-/V-(3- morpholinopropyl)hexane-l-sulfonamide and 3-(chloromethyl)pyridine hydrochloride. 1H-NMR (CDCI3): δ 8.56 (m, 2H), 7.80 (m IH), 7.32 (m, IH), 4.41 (s, 2H), 3.64 (m, 4H), 3.23 (m, 2H), 2.96 (m, 2H), 2.69 (m, 2H), 2.29 (m, 4H), 2.23 (m, 2H), 2.0-1.25 (m, 10H).
Preparation 70: 6-Amino-ΛH2-morpholinoethyπ-Λ/-f3-morpholinopropyQhexane-l- sulfonamide fcompound 70)
Figure imgf000081_0002
General procedure 9. Starting materials: 6-(l,3-dioxoisoindolin-2-yl)-Λ/-(3- morpholinopropyl)hexane-l-sulfonamide and 4-(2-chloroethyl)morpholine hydrochloride. 1H-NMR (CDCI3): δ 3.69 (m, 8H), 3.34 (m, 2H), 3.26 (m, 2H), 3.05 (m, 2H), 2.69 (m, 2H), 2.6-2.3 (m, 12H), 1.8 (m, 6H), 1.40 (m, 6H).
Preparation 71: 6-Amino-Λ/-fcvdohexylrnethoxyVΛ/-f2-morpholinoethyl)hexane-l- sulfonamide fcompound 711
Figure imgf000082_0001
General procedure 9. Starting materials: /V-(cyclohexylmethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and 4-(2-chloroethyl)morpholine hydrochloride. 1H-NMR (CDCI3): δ 3.89 (d, 2H), 3.72 (m, 4H), 3.38 (t, 2H), 3.09 (m, 2H), 2.9 (bs, 2H), 2.77 (t, 2H), 2.67 (t, 2H), 2.52 (m, 4H), 1.92 (m, 2H), 1.8-1.0 (m, 15H), 1.00 (m, 2H).
Preparation 72: Methyl /\r-cvano-/V-fpyridine-3-vncarbamimidothioate (compound ZZL
Figure imgf000082_0002
General procedure 1. Starting material: 3-amino-pyridine. 1H-NMR (DMSOd6) δ
10.26 (bs, IH), 8.63 (d, IH), 8.44 (dd, IH), 7.90 (m, IH), 7.46 (m, IH), 2.74 (s, 3 H).
Preparation 73: 6-Amino-Λ/-cvcloheptyl-Λ/-(2-morpholinoethvπhexane-l-sulfonamide (compound 73).
Figure imgf000082_0003
General procedure 9. Starting materials: Λ/-cycloheptyl-6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonamide and 4-(2-chloroethy|)morpholine hydrochloride. 1H-NMR (CD3OD): δ 3.70 (m, 5H), 3.09 (m, 2H), 2.71 (t, 2H), 2.59 (t, 2H), 2.53 (m, 4H), 2.0-1.3 (m, 20H).
Preparation 74: 6-Amino-Λ/-methyl-Λ/-f2-morpholinoethoxy')hexane-l-sulfonamide (compound 74).
Figure imgf000083_0001
General procedure 9. Starting materials: Λ/-(2-morpholinoethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and methyliodide. 1H-NMR (CDCI3): δ 4.14 (t, 2H), 3.73 (m, 4H), 3.11 (m, 2H), 3.08 (s, 3H), 2.98 (bs, 2H), 2.80 (t, 2H), 2.64 (t, 2H), 2.51 (m, 4H), 1.94 (m, 2H), 1.65-1.35 (m, 6H).
Preparation 75: 6-fmorpholinosulfonvπhexane-l-amine (compound 75").
Figure imgf000083_0002
General procedure 8. Starting material: morpholine and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.77 (m, 4H), 3.27 (m, 4H), 2.92 (m, 2H), 2.73 (t, 2H), 1.95 (bs, 2H), 1.85 (m, 2H), 1.55-1.3 (m, 6H).
Preparation 76: 6-fazepan-l-ylsulfonvπhexane-l-amine (compound 76).
Figure imgf000083_0003
General procedure 8. Starting material: azepane and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCl3): δ 3.36 (m, 4H)7 2.95 (m, 2H), 2.75 (t, 2H), 2.53 (bs, 2H), 1.76 (m, 6H), 1.65 (m, 4H), 1.46 (m, 6H).
Preparation 77: 6-Amino-Λ/-f2-morpholinoethoxyVΛ/-(pyridin-3-ylmethvπhexane-l- sulfonamide (compound 771
Figure imgf000084_0001
General procedure 9. Starting materials: Λ/-(2-morpholinoethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and 3-(chloromethyl)pyridine hydrochloride. 1H-NMR (CDCI3): δ 8.60 (d, IH), 8.54 (dd, IH), 7.76 (m, IH), 7.27 (m, IH), 4.33 (s, 2H), 3.75 (t, 2H), 3.56 (m, 4H), 3.3 (bs, 2H), 3.08 (m, 2H), 2.75 (t, 2H), 2.27 (m, 2H), 2.19 (m, 4H), 1.89 (m, 2H), 1.6-1.2 (m, 6H).
Preparation 78: Methyl Λ/'-cvano-Λ/-fpyridine-3-vπcarbamimidothioate f compound zrn.
Figure imgf000084_0002
General procedure 1. Starting material: 2-fluoropyridine-4-amine. 1H-NMR (DMSO- d6) δ 10.54 (bs, IH), 8.21 (d, IH), 7.50 (m, IH), 7.36 (d, IH), 7.46 (m, IH), 2.81 (s, 3 H).
Preparation 79: 6-Amino-/V-(2-morpholinoethoxyVΛ/-(2-morpholinoethv0hexane-l- sulfonamide (compound 79).
Figure imgf000085_0001
General procedure 9. Starting materials: Λ/-(2-morpholinoethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and 4-(2-chloroethyl)morpholine hydrochloride. 1H-NMR (CDCI3): δ 4.14 (t, 2H), 3.64 (m, 4H), 3.32 (t, 2H), 3.05 (m, 2H), 2.80 (t, 2H), 2.62 (t, 2H), 2.53 (t, 2H), 2.43 (m, 4H), 1.84 (m, 2H), 1.59 (bs, IH), 1.5-1.2 (m, 6H).
Preparation 80: 6-fpyrrolidin-l-ylsulfonvπhexane-l-amine (compound 801.
Figure imgf000085_0002
General procedure 8. Starting material: pyrrolidine and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.37 (m, 4H), 2.97 (m, 2H), 2.89 (bs, 2H), 2.79 (t, 2H), 1.95 (m, 4H), 1.84 (m, 2H), 1.6-1.3 (m, 6H).
Preparation 81: 6-fpiperin-l-ylsulfonvnhexane-l-amine fcompound 81).
Figure imgf000085_0003
General procedure 8. Starting material: piperidine and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.24 (m, 4H), 3.07 (bs, 2H), 2.88 (m, 2H), 2.76 (t, 2H), 1.82 (m, 2H), 1.-1.3 (m, 12H).
Preparation 82: 6-amino-/V-fcyclohexylmethoxyVΛ/-f2-fluoroethvπhexane-l- sulfonamide fcompound 82).
Figure imgf000086_0001
General procedure 9. Starting materials: Λ/-(cyclohexylmethoxy)-6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonamide and 2-fluoroethanol and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.64 (dt, 2H), 3.90 (d, 2H), 3.57 (dt, 2H), 3.10 (m, 2H), 2.9 (bs, 2H), 2.78 (t, 2H), 1.92 (m, 2H), 1.8-1.1 (m, 15H), 1.01 (m, 2H).
Preparation 83: tert-butyl 4-f6-l,3-dioxoisoindolin-2-yπhexylsulfonvπpiperazine-l- carboxylate (compound 831.
Figure imgf000086_0002
General procedure 8 - without the deprotection step. Starting material: tert-butyl piperazine-1-carboxylate and 6-(l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (DMSO-de) δ 7.85 (m, 4H), 3.56 (t, 2H), 3.38 (m, 4H), 3.11 (m, 4H), 3.02 (m, 2H), 1.61 (m, 4H), 1.41 (s, 9H), 1.32 (m, 4H).
Preparation 84: 6-(4-methylpiperazin-l-ylsulfonv0hexane-l-amine (compound 84^.
Figure imgf000086_0003
Compound 83 (526 mg, 1.1 mmol) was dissolved in DCM and 3M HCI in MeOH was added with stirring. After 4h the mixture was concentrated to dryness. The resulting hydrochloride (426 mg, 1.02 mmol) was dissolved in DMF (10 ml_), Cs2CO3 ( 729 mg, 2.23 mmol) and methyliodide (75 μl, 2.20 mmol) were added and the reaction mixture stirred overnight, concentrated and purified by chromatography (1% MeOH in DCM) to yield 2-(6-(4-methylpiperazin-l-ylsulfonyl)hexyl)isoindoline-l,3-dione. This compound was subsequently deprotected as described in general procedure 8 to yield compound 84. 1H-NMR (DMSOd6) δ 3.12 (bs, 2H), 3.01 (m, 4H), 2.88 (m, 2H), 2.4 (m, 2H), 2.22 (m, 4H), 2.07 (s, 3H), 1.52 (m, 2H), 1.3-1.1 (m, 6H).
Preparation 85: Λ/-Isopropyl-0-tetrahvdro-2H-pyran-4-vπhvdroxylamine (compound 85).
Figure imgf000087_0001
General procedure 6. Starting materials: acetone and 0-(tetrahydro-2H-pyran-4- yl)hydroxylamine. 1H-NMR (CDDI3): δ 3.92 (m, 2H), 3.77 (m, IH), 3.43 (m, 2H), 3.16 (m, IH), 1.95 (m, 2H), 1.58 (m, 2H), 1.07 (d, 6H).
Preparation 86: 6-Amino-/V-(cvclohexylmethoxy1-/V-f2-hvdroxyethv0hexane-l- sulfonamide fcompound 86").
Figure imgf000087_0002
General procedure 9. Prior to removal of the phtalimido group the silyl protecting group was removed by refluxing the intermediate for 30 minutes in 1% HCI in ethanol. Starting materials: Λ/-(cyclohexylmethoxy)-6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonamide and 2-(te/tbutyldimethylsilyloxy)ethanol. 1H-NMR (CDCI3): δ 3.87 (d, 2H), 3.83 (t, 2H), 3.40 (m, 2H), 3.09 (m, 2H), 2.70 (t, 2H), 2.0-1.1 (m, 20H), 1.00 (m, 2H).
Preparation 87: Λ/-isopropyl-O-f2-morpholinoethv0hvdroxylamine (compound 87).
Figure imgf000087_0003
General procedure 6. Starting materials: O-(2-morpholinoethyl)hydroxylamine and acetone. 1H-NMR (CDCI3): δ 5.10 (bs, IH), 3.82 (t, 2H), 3.72 (m, 4H), 3.16 (m, IH), 2.59 (t, 2H), 2.51 (m, 4H), 1.02 (d, 2H).
Preparation 88: 6-Amino-Λ/-isopropyl-Λ/-(2-morpholinoethoxy')hexane-l-sulfonamide (compound 88).
Figure imgf000088_0001
General procedure 8. Starting materials: compound 87 and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.19 (m, 2H), 3.99 (m, IH), 3.72 (m, 4H), 3.22 (m, 2H), 2.67 (m, 4H), 2.56 (m, 4H), 1.89 (m, 2H), 1.53 (m, 4H), 1.44 (m, 2H), 1.30 (d, 6H).
Preparation 89: 6-Aminohexane-l-sulfonamide (compound 89).
Figure imgf000088_0002
General procedure 8. Starting materials: ammonium hydroxide (25% aq.) and 6- (l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (DMSOd6): δ 4.5 (bs, 2H), 2.94 (m, 2H), 2.60 (t, 2H), 1.67 (m, 2H), 1.5-1.2 (m, 6H).
Preparation 90: 6-(2-cyano-3-(pyridin-4-yQquanidino)hexane-l-sulfonamide (compound 901.
Figure imgf000088_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 89. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.42 (t, 2H), 3.10 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H), 1.50 (m, 4H).
Preparation 91: Λ/-(3-morpholinopropyπcvclohexanamine (compound 91).
Figure imgf000089_0001
3-Morpholinopropylamine (1.46 ml, 10 mmol) and cyclohexanone (1.04 ml, 10 mmol) were dissolved in dichloroethane, sodium triacetoxyborohydride (3,18g, 15 mmol) was added in small portions with stirring, and the mixture was stirred at room temperature overnight. 1 N NaOH was added carefully, and the mixture extracted 3 times with DCM. The collected organic phases were washed with brine, dried (MgSO4) and concentrated to yield compound 91. 1H-NMR (DMSO-d6): δ 3.55 (m, 4H), 2.53 (t, 2H), 2.31 (m, 7H), 1.78 (m, 2H), 1.65 (m, 2H), 1.53 (m, 2H) 1.17 (m, 4H), 0.99 (m, 2H).
Preparation 92: 6-amino-Λ/-cvclohexyl-Λ/-(3-morpholinopropyπhexane-l- sulfonamide (compound 92V
Figure imgf000089_0002
General procedure 8. Starting materials: compound 91 and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 3.71 (m, 4H), 3.52 (m, IH), 3.24 (m, 2H), 3.03 (m, 2H), 2.66 (t, 2H), 2.48 (m, 4H), 2.39 (m, 2H), 1.95-1.3 (m, 19H), 1.18 (m, IH).
Preparation 93: 7-amino-Λ/-cvclohexyl-/V-(2-morpholinoethoxy")heptane-l- sulfonamide (compound 93V
Figure imgf000090_0001
General procedure 8. Starting materials: compound 30 and 7-(l,3-dioxoisoindolin-2- yl)heptane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.13 (m, 2H), 3.70 (m, 4H), 3.59 (m, IH), 3.12 (m, 2H), 2.84 (t, 2H), 2.60 (t, 2H), 2.50 (m, 4H), 2.0-1.2 (m, 18H), 1.12 (m, IH).
Preparation 94: 5-amino-Λ/-cyclohexyl-ΛH2-morpholinoethoxy')pentane-l- sulfonamide (compound 94^.
Figure imgf000090_0002
General procedure 8, Starting materials: compound 30 and 5-(l,3-dioxoisoindolin-2- yl)pentane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.13 (m, 2H), 3.70 (m, 4H), 3.59 (m, IH), 3.15 (m, 2H), 2.95 (t, 2H), 2.60 (t, 2H), 2.51 (m, 4H), 2.0-1.45(m, 13H), 1.30 (m, 2H), 1.12 (m, IH).
Preparation 95: S-amino-ΛHcyclohexylmethoxy'ipentane-l-sulfOnamide (compound 95^.
Figure imgf000090_0003
General procedure 8. Starting material: O-(cyclohexylmethyl)hydroxylamine and 5- (l,3-dioxoisoindolin-2-yl)pentane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 3.82 (d, 2H), 3.36 (t, 2H), 3.21 (m, 2H), 1.95-1.15 (m, 16H), 0.97 (m, IH). Preparation 96: 7-amino-Λ/-(cvclohexylmethoxy)heptane-l-sulfonamide (compound 96k
Figure imgf000091_0001
General procedure 8. Starting materials: CHcyclohexylmethyOhydroxylamine and 7- (l,3-dioxoisoindolin-2-yl)heptane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 8.10 (bs, 2H), 3.80 (d, 2H), 3.30 (t, 2H), 3.20 (m, 2H), 1.9-0.8 (m, 21H).
Preparation 97: 7-(morpholinosulfonvπheptan-l-amine (compound 971.
Figure imgf000091_0002
General procedure 8. Starting materials: tetrahydro-l,2-oxazinium hydrochloride^. Chem.Soc, Pekin Trans 2 (2000), 1435-144) and 7-(l,3- dioxoisoindolin-2-yl)heptane-l-sulfonyl chloride. 1H-NMR (CDCl3): δ 8.27 (bs, 2H), 4.13 (t, 2H), 3.40 (m, 2H), 3.15 (m, 2H), 3.01 (m, 2H), 1.9-0.8 (m, 14H).
Preparation 98: 4-Nitrophenyl cvclohexylcarbamate (compound 98").
Figure imgf000091_0003
Cyclohexylamine (240 μl, 2.1 mmol) and 4-nitrophenyl chloroformate (404 mg, 2.0 mmol) were dissolved in ethyl acetate, and DIEA (410 μl, 2.4 mmol) was added with stirring. After 1 h the reaction mixture was washed with IN HCI, H2O, 5% Na2CO3, H2O (3 times), brine, dried (MgSO4) and concentrated to afford compound 98. 1H- NMR (CDCI3): δ 8.24 (m, 2H), 7.32 (m, 2H), 4.02 (d, IH), 3.57 (m, IH), 2.02 (m, 2H), 1.75 (m, 2H), 1.62 (m, 2H), 1.5-1.1 (m, 4H).
Preparation 99: 4-Nitrophenyl cvcloheptylcarbamate (compound 99).
Figure imgf000092_0001
Cyclohexylamine (268 μl, 2.1 mmol) and 4-nitrophenyl chloroformate (404 mg, 2.0 mmol) were dissolved in ethyl acetate, and DIEA (410 μl, 2.4 mmol) was added with stirring. After 1 h the reaction mixture was washed with IN HCI, H2O, 5% Na2CO3, H2O (3 times), brine, dried (MgSO4) and concentrated to afford compound 99. 1H- NMR (CDCI3): δ 8.24 (m, 2H), 7.31 (m, 2H), 5.08 (d, IH), 3.77 (m, IH), 2.02 (m, 2H), 1.59 (m, 10H).
Preparation 100: /V-isopropyl-3-morpholinopropan-l-amine (compound IQOV
Figure imgf000092_0002
3-Morpholinopropylamine (1.46 ml, 10 mmol) and acetone (0.88 ml, 12 mmol) were dissolved in dichloroethane, sodium triacetoxyborohydride (3,18g, 15 mmol) was added in small portions with stirring, and the mixture was stirred at room temperature overnight. 1 N NaOH was added carefully, and the mixture extracted 3 times with DCM. The collected organic phases were washed with brine, dried (MgSO4) and concentrated to yield compound 100. 1H-NMR (CDCI3): δ 3.70 (m, 4H), 2.84 (m, IH), 2.70 (t, 2H), 2.44 (m, 6H), 1.72 (m, 2H), 1.10 (d, 6H).
Preparation 101: 6-amino-Λ/-isopropyl-Λ/-(3-morpholinopropy0hexane-l- sulfonamide (compound 101).
Figure imgf000092_0003
General procedure 8. Starting materials: compound 100 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.00 (m, IH), 3.72 (m, 4H), 3.22 (m, 2H), 3.04 (m, 2H), 2.66 (t, 2H), 2.49 (m, 4H), 2.40 (t, 2H), 1.83 (m, 4H), 1.49 (m, 6H), 1.27 (d, 6H). Preparation 102: ΛHS-morpholinopropyπcvclopentanamine fcompound 102).
Figure imgf000093_0001
3-Morpholinopropylamine (1.46 ml, 10 mmol) and cyclopentanone (0.90 ml, 10.2 mmol) were dissolved in dichloroethane, sodium triacetoxyborohydride (3,18g, 15 mmol) was added in small portions with stirring, and the mixture was stirred at room temperature overnight. 1 N NaOH was added carefully, and the mixture extracted 3 times with DCM. The collected organic phases were washed with brine, dried (MgSO4) and concentrated to yield compound 102.1H-NMR (CDCI3): δ 3.70 (m, 4H), 3.04 (m, IH), 2.63 (t, 2H), 2.41 (m, 6H), 1.83 (m, 2H), 1.67 (m, 4H), 1.52 (m, 2H), 1.30 (m, 2H).
Preparation 103: 6-amino-Λ/-cvclopentyl-Λ/-(3-rnorpholinopropy0hexane-l- sulfonamide fcompound 103).
Figure imgf000093_0002
General procedure 8. Starting materials: compound 102 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.07 (m, IH), 3.71 (m, 4H), 3.18 (m, 2H), 3.03 (m, 2H), 2.71 (t, 2H), 2.47 (m, 4H), 2.39 (t, 2H), 2.0-1.3 (m, 18H).
Preparation 104: S-fmorpholinosulphonvπpentan-l-amine (compound 104").
Figure imgf000093_0003
General procedure 8. Starting materials: tetrahydro-l,2-oxazinium hydrochloride (J.Chem.Soc, Pekin Trans 2 (2000), 1435-144) and 5-(l,3-dioxoisoindolin-2- yl)pentane-l-sulfonyl chloride. 1H-NMR (CDCI3): δ 4.12 (t, 2H), 3.39 (m, 2H), 3.18 (m, 2H), 3.04 (m, 2H), 2.0-1.4 (m, 10H).
Preparation 105: 6-amino-/V-benzyl-Λ/-(3-morpholinopropyπhexane-l-sulfonamide (compound 1051.
Figure imgf000094_0001
General procedure 9. Starting materials: 6-(l,3-dioxoisoindolin-2-yl)-Λ/-(3- morpholinopropyl)hexane-l-sulfonamide and benzyl bromide. 1H-NMR (CD3OD): δ 7.41 (m, 5H), 4.42 (s, 2H), 3.62 (m, 4H), 3.27 (t, 2H), 3.08 (m, 2H), 2.68 (t, 2H), 2.29 (m, 4H), 2.24 (t, 2H), 1.81 (m, 2H), 1.62 (m, 2H), 1.46 (m, 6H).
Preparation 106: 6-amino-Λ/-ethyl-ΛH3-morpholinopropy0hexane-l-sulfonamide (compound 1061).
Figure imgf000094_0002
General procedure 9. Starting materials: 6-(l,3-dioxoisoindolin-2-yl)-/V-(3- morpholinopropyl)hexane-l-sulfonamide and ethyl iodide. 1H-NMR (CD3OD): δ 3.71 (m, 4H), 3.30 (m, 4H), 3.04 (m, 2H), 2.66 (t, 2H), 2.49 (m, 4H), 2.42 (t, 2H), 1.80 (m, 4H), 1.46 (m, 6H), 1.22 (t, 3H).
Preparation 107: Λ/-Cvclopentyl-O-(2-morpholinoethv0hvdroxylamine (compound 1071).
Figure imgf000094_0003
General procedure 6. Starting materials: O-(2-morpholinoethyl)hydroxylamine and cyclopentanone. 1H-NMR (CD3OD): 3.86 (t, 2H), 3.71 (m, 4H), 3.50 (m, IH), 2.60 (t, 2H), 2.54 (m, 4H), 1.85-1.35 (m, 8H).
Preparation 108: 6-amino-/V-cvclopentyl-/V-(2-morpholinoethoxy)hexane-l- sulfonamide (compound 108).
Figure imgf000095_0001
General procedure 8. Starting materials: compound 107 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.17 (bs, 2H), 4.02 (m, IH), 3.69 (m, 4H), 3.18 (m, 2H), 3.05 (bs, 2H), 2.70 (t, 2H), 2.58 (t, 2H), 2.48 (m, 4H), 2.0-1.2 (m, 16H).
Preparation 109: /V-(3-morpholinopropy0cvcloheptanamine (compound 109).
Figure imgf000095_0002
3-Morpholinopropylamine (1.46 ml, 10 mmol) and cycloheptanone (1.17 ml, 10 mmol) were dissolved in dichloroethane, sodium triacetoxyborohydride (3.25g, 15.3 mmol) was added in small portions with stirring, and the mixture was stirred at room temperature overnight. 1 N NaOH was added carefully, and the mixture extracted 3 times with DCM. The collected organic phases were washed with brine, dried (MgSO4) and concentrated to yield compound 109. 1H-NMR (CDCI3): δ 3.69 (m, 4H), 2.69 (t, 2H), 2.64 (m, IH), 2.42 (m, 4H), 2.40 (t, 2H), 1.83 (m, 2H), 1.75- 1.30 (m, 12H).
Preparation 110: 6-amino-Λ/-cvcloheptyl-Λ/-(3-morpholinopropyπhexane-l- sulfonamide (compound 110).
Figure imgf000096_0001
Genera! procedure 8. Starting materials: compound 109 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 3.71 (m, 5H), 3.23 (m, 2H), 3.01 (m, 2H), 2.68 (t, 2H), 2.47 (m, 4H), 2.38 (t, 2H), 2.0-1.25 (m, 22H).
Preparation 111 : Λ/-Cvcloheptyl-O-f2-morpholinoethv0hvdroxylamine (compound IIP.
Figure imgf000096_0002
General procedure 6. Starting materials: O-(2-morpholinoethyl)hydroxylamine and cycloheptanone. 1H-NMR (CD3OD): 3.84 (t, 2H), 3.71 (m, 4H), 3.02 (m, IH), 2.60 (t, 2H), 2.54 (m, 4H), 1.88 (m, 2H), 1.8-1.25 (m, 10H).
Preparation 112: 6-amino-/V-cvcloheptyl-/V-f2-rnorpholinoethoxy')hexane-l- sulfonamide (compound 112V
Figure imgf000096_0003
General procedure 8. Starting material: compound 111 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.20 (t, 2H), 3.83 (m, IH), 3.72 (m, 4H), 3.21 (m, 2H), 2.71 (t, 2H), 2.66 (t, 2H), 2.56 (m, 4H), 2.1-1.35 (m, 20H).
Preparation 113: /V-Cvclobutyl-O-f2-morpholinoethv0hvdroxylamine (compound im
Figure imgf000097_0001
General procedure 6. Starting materials: O-(2-morpholinoethyl)hydroxylamine and cyclobutanone. 1H-NMR (CD3OD): 3.85 (t, 2H), 3.71 (m, 4H), 3.65 (m, IH), 2.60 (t, 2H), 2.54 (m, 4H), 2.12 (m, 2H), 1.94 (m, 2H), 1.78 (m, 2H).
Preparation 114: 6-amino-Λ/-cyclobutyl-Λ/-(2-morpholinoethoxy')hexane-l- sulfonamide (compound 114).
Figure imgf000097_0002
General procedure 8. Starting material: compound 113 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.22 (m, 3H), 3.72 (m, 4H), 3.08 (t, 2H), 2.68 (m, 4H), 2.57 (m, 4H), 2.41 (m, 2H), 2.15 (m, 2H), 1.86 (m, 2H), 1.76 (m, 2H), 1.51 (m, 4H), 1.42 (m, 2H).
Preparation 115: Λ/-f3-morpholinopropy0cvclobutanamine (compound 115").
Figure imgf000097_0003
3-Morpholinopropylamine (1.46 ml, 10 mmol) and cyclobutanone (0.75 ml, 10 mmol) were dissolved in dichloroethane, sodium triacetoxyborohydride (3.25g, 15.3 mmol) was added in small portions with stirring, and the mixture was stirred at room temperature overnight. 1 N NaOH was added carefully, and the mixture extracted 3 times with DCM. The collected organic phases were washed with brine, dried (MgSO4) and concentrated to yield compound 109. 1H-NMR (CDCI3): δ 3.94 (bs, IH), 3.70 (m, 4H), 3.33 (m, IH), 2.69 (t, 2H), 2.46 (m, 4H), 2.44 (t, 2H), 2.25 (m, 2H), 2.0-1.55 (m, 6H). Preparation 116: 6-amino-Λ/-cvclobutyl-Λ/-(3-morpholinopropy0hexane-l- sulfonamide (compound 1161.
Figure imgf000098_0001
General procedure 8. Starting material: compound 115 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.21 (m, IH), 3.71 (m, 4H), 3.30 (m, 2H), 2.98 (m, 2H), 2.66 (t, 2H), 2.47 (m, 4H), 2.41 (t, 2H), 2.21 (m, 4H), 1.9-1.35 (m, 12H).
Preparation 117: Λ/I-cvclohexyl-Λ/3,Λ/3-dimethylpropane-l,3-diamine (compound 117).
Figure imgf000098_0002
3-(Dimethylamino)-l-propylamine (1.26 ml, 10 mmol) and cyclohexanone (1.04 ml, 10 mmol) were dissolved in dichloroethane, sodium triacetoxyborohydride (3.25g, 15.3 mmol) was added in small portions with stirring, and the mixture was stirred at room temperature overnight. 1 N NaOH was added carefully, and the mixture extracted 3 times with DCM. The collected organic phases were washed with brine, dried (MgSO4) and concentrated to yield compound 117. 1H-NMR (CDCI3): δ 3.01 (bs, IH), 2.72 (t, 2H), 2.46 (m, IH), 2.33 (t, 2H), 2.22 (s, 6H), 1.89 (m, 2H), 1.8- 1.5 (m, 5H), 1.35-1.0 (m, 5H).
Preparation 118: 6-amino-Λ/-cvclohexyl-Λ/-(dimethylamino')propyπhexane-l- sulfonamide (compound Ills').
Figure imgf000098_0003
General procedure 8. Starting material: compound 117 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 3.52 (m, IH), 3.21 (m, 2H), 3.03 (m, 2H), 2.67 (t, 2H), 2.35 (t, 2H), 2.26 (s, 6H), 1.9-1.25 (m, 19H), 1.18 (m, IH).
Preparation 119: Λ/-r2-morphlinoethyl)cvclohexanamine ("compound 119).
Figure imgf000099_0001
4-(2-aminoethyl)-morpholine (1.30 ml, 10 mmol) and cyclohexanone (1.04 ml, 10 mmol) were dissolved in dichloroethane, sodium triacetoxyborohydride (3.25g, 15.3 mmol) was added in small portions with stirring, and the mixture was stirred at room temperature overnight. 1 N NaOH was added carefully, and the mixture extracted 3 times with DCM. The collected organic phases were washed with brine, dried (MgSO4) and concentrated to yield compound 119. 1H-NMR (CD3OD): δ 3.71 (m, 4H), 2.76 (t, 2H), 2.51 (t, 2H), 2.48 (m, 5H), 1.94 (m, 2H), 1.78 (m, 2H), 1.67 (m, IH), 1.4-1.0 (m, 5H).
Preparation 120: 6-amino-Λ/-cvclohexyl-Λ/-f2-morpholinoethv0hexane-l- sulfonamide (compound 1120^.
Figure imgf000099_0002
General procedure 8. Starting materials: compound 119 and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 3.70 (m, 4H), 3.53 (m, IH), 3.35 (m, 2H), 3.12 (m, 2H), 2.68 (t, 2H), 2.55 (m, 6H), 1.83 (m, 6H), 1.75-1.25 (m, HH), 1.18 (m, IH).
Preparation 121: 6-amino-Λ/-fcvclohexylmehyl)-Λ/-f3-morpholinopropyπhexane-l- sulfonamide (compound 121L
Figure imgf000100_0001
General procedure 9. Starting materials: 6-(l,3-dioxoisoindolin-2-yl)-Λ/-(3- morpholinopropyl)hexane-l-sulfonamide and (bromomethyl)cyclohexane. 1H-NMR (CD3OD): δ 3.71 (m, 4H), 3.25 (t, 2H), 3.03 (m, 4H), 2.71 (t, 2H), 2.48 (m, 4H), 2.40 (t, 2H), 1.9-1.1 (m, 19H), 0.95 (m, 2H).
Preparation 122: 2-(6-bromohexy0isoindoline-l,3-dione (compound 122*).
Figure imgf000100_0002
Phtalic anhydride (4.44 g, 30 mmol) and 6-aminohexanol (3.62 g, 30.9 mmol) were heated with stirring at 140 0C for 5 h, cooled to rt, transferred to a separatory funnel with EtOAc, washed with NaHCO3 (sat.), H2O, 10% citric acid, brine, dried (MgSO4) and concentrated to yield 2-(6-hydroxyhexyl)isoindoline-l,3-dione.
2-(6-hydroxyhexyl)isoindoline-l,3-dione (7.14 g, 28.9 mmol) was dissolved in CH3CN, PPh3 (7.57g, 28.9 mol), and CBr4 (9.77 g, 29.5 mmol) were added and the mixture was stirred at rt overnight. The reaction mixture was concentrated and the residue was purified by chromatography (petroleum ether: EtOAc 9:1) to afford compound 122.1H-NMR (CDCI3): δ 7.85 (m, 2H), 7.72 (m, 2H), 3.68 (t, 2H), 3.39 (t, 2H), 1.85 (m, 2H), 1.69 (m, 2H), 1.48 (m, 2H), 1.36 (m, 2H).
Preparation 123: Diethyl 6-(l,3-dioxoisoindolin-2-yl)hexylphosphonate (compound 123^).
Figure imgf000101_0001
Compound 122 (2.33 g, 7.5 mmol) and triethyl phosphite (2.61 ml, 15 mmol) were heated with stirring at 150 0C for 6 h, cooled to rt and purified by chromatography (petroleum ether: EtOAc 2:1) to afford compound 123. 1H-NMR (CDCI3): δ 7.83 (m, 2H), 7.70 (m, 2H), 4.06 (m, 4H), 3.66 (t, 2H), 1.8-1.25 (m, 10H), 1.29 (t, 6H).
Preparation 124: Ethyl P-6-aminohexyl-Λ/-cyclohexylphosphonimidate (compound 124V
Figure imgf000101_0002
Compound 123 (0.41 g, 1.12 mmol) was dissolved in toluene, PCI5 (0.7g, 3.36 mmol) was added and the reaction mixture refluxed overnight, concentrated, redissolved in DCM and added dropwise to a solution of cyclohexylamine (0.12 ml, 1.07 mmol) and triethylamine (0.17 ml, 1.23 mmol) in DCM at O0C with stirring. Gradually allowed to reach rt and stirred overnight, washed with NaHCO3 (10%), H2O, IN HCI, H2O, brine, dried (MgSO4), concentrated and purified by chromatography (1-2% ethanol in DCM) to afford ethyl /V-cyclohexyl-P-(6-(l,3- dioxoisoindolin-2-yl)hexyl)phosphonamidate.
Ethyl Λ/-cyclohexyl-P-(6-(l,3-dioxoisoindolin-2-yl)hexyl)phosphonamidate (0.23 g, 0.54 mmol) was dissolved in ethanol, hydrazine hydrate (0.13 ml, 2.7 mmol)) was added and the mixture heated in a microwave oven at 13O0C for 20min. The mixture was cooled to rt, filtered, filtercake washed with ethanol, the filtrate was concentrated and purifed by chromatography (chloroform:ethanol:NH3 (25% aq.) 80:20:0.5) to afford compound 124. 1H-NMR (CDCI3): δ 3.99 (m, 2H), 2.97 (m, IH), 2.66 (t, 2H), 1.89 (m, 2H), 1.8-1.1 (m, 18H), 1.30 (t, 3H). Preparation 125: Ethyl 6-(l,3-dioxoisoindolin-2-v0hexylfmethv0phosphinate (compound 1251.
Figure imgf000102_0001
Compound 122 (2.33 g, 7.5 mmol) and diethyl methylphosphonate (2.62 ml, 15 mmol) were heated with stirring at 170 0C for 3h, cooled to rt and purified by chromatography (1% ethanol in DCM) to afford compound 125. 1H-NMR (CDCI3): δ 7.84 (m, 2H), 7.71 (m, 2H), 4.03 (m, 2H), 3.67 (t, 2H), 1.8-1.25 (m, 10H), 1.43 (d, 3H), 1.30 (t, 3H).
Preparation 126: P-(6-aminohexyO-Λ/-cvclohexyl-P-methylphosphinic amide f compound 1261.
Figure imgf000102_0002
Compound 125 (0.41 g, 1.22 mmol) was dissolved in toluene, PCI5 (0.28g, 1.34 mmol) was added and the reaction mixture refluxed overnight, concentrated, redissolved in DCM and added dropwise to a solution of cyclohexylamine (0.14 ml, 1.22 mmol) and triethylamine (0.34 ml, 2.44 mmol) in DCM at O0C with stirring. Gradually allowed to reach rt and stirred overnight, washed with NaHCO3 (10%), H2O, IN HCI, H2O, brine, dried (MgSO4), concentrated and purified by chromatography (1-5% MeOH in DCM) to afford /V-cyclohexyl-P-(6-(l,3- dioxoisoindolin-2-yl)hexyl)-P-methylphosphinic amide.
Λ/-cyclohexyl-P-(6-(l,3-dioxoisoindolin-2-yl)hexyl)-P-methylphosphinic amide (45 mg, 0.12 mmol) was dissolved in ethanol, hydrazine hydrate (28 μl, 0.6 mmol)) was added and the mixture heated in a microwave oven at 13O0C for 20min. The mixture was cooled to rt, filtered, filtercake washed with ethanol, the filtrate was concentrated and purifed by chromatography (chloroform: methanol: NH3 (25% aq.) 80:20:1) to afford compound 126. 1H-NMR (CDCI3): δ 2.95 (m, IH), 2.89 (t, 2H), 1.90 (m, 2H), 1.85-1.1 (m, 18H), 1.44 (d, 3H).
Preparation 127: 6-f3,4-dihvdroisoquinolin-2dH)-ylsulfonvnhexan-l-amine (compound 1127").
Figure imgf000103_0001
General procedure 8. Starting materials: 1,2,3,4-tetrahydroisoquinoline and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 3.70 (m, 4H), 3.53 (m, IH), 3.35 (m, 2H), 3.12 (m, 2H), 2.68 (t, 2H), 2.55 (m, 6H), 1.83 (m, 6H), 1.75-1.25 (m, HH), 1.18 (m, IH).
Preparation 128: Ethyl 6-aminohexylfmorpholino')phosphinate (compound 1281.
Figure imgf000103_0002
Compound 123 (0.42 g, 1.15 mmol) was dissolved in toluene, PCI5 (0.72g, 3.45 mmol) was added and the reaction mixture refluxed overnight, concentrated, redissolved in DCM and added dropwise to a solution of tetra hydro- 1,2-oxazinium hydrochloride (J.Chem.Soc, Pekin Trans 2 (2000), 1435-144) (0.14 mg, 1.1 mmol) and triethylamine (0.34 ml, 2.3 mmol) in DCM at O0C with stirring. Gradually allowed to reach rt and stirred overnight, concentrated and purified by chromatography (1-2% ethanol in DCM) to afford ethyl 6-(l,3-dioxoisoindolin-2- yl)hexyl)(morpholino)phosphinate.
Ethyl 6-(l,3-dioxoisoindolin-2-yl)hexyl)(morpholino)phosphinate (0.22 g, 0.54 mmol) was dissolved in ethanol, hydrazine hydrate (0.13 ml, 2.7 mmol)) was added and the mixture heated in a microwave oven at 13O0C for 20min. The mixture was cooled to rt, filtered, filtercake washed with ethanol, the filtrate was concentrated and purifed by chromatography (chloroform :ethanol: NH3 (25% aq.) 80:20:0.5) to afford compound 128. 1H-NMR (CDCI3): δ 4.11 (m, 2H), 3.97 (t, 2H), 3.37 (m, 2H), 2.67 (t, 2H), 1.95 1.3 (m, 14H), 1.33 (t, 3H).
Preparation 129: 5-amino-Λ/-cyclobutyl-ΛH2-morpholinoethoxy')pentane-l- sulfonamide ("compound 129").
Figure imgf000104_0001
General procedure 8. Starting materials: compound 113 and 5-(l,3-dioxoisoindolin- 2-yl)pentane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.20 (m, 3H), 3.72 (m, 4H), 3.08 (t, 2H), 2.68 (m, 4H), 2.57 (m, 4H), 2.42 (m, 2H), 2.15 (m, 2H), 1.86 (m, 2H), 1.76 (m, 2H), 1.52 (m, 4H).
Preparation 130: 5-amino-Λ/-cvclopentyl-/V-f3-morpholinopropyQpentane-l- sulfonamide (compound 130").
General procedure 8. Starting materials: compound 102 and 5-(l,3-dioxoisoindolin- 2-yl)pentane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.07 (m, IH), 3.71 (m, 4H), 3.18 (m, 2H), 3.04 (m, 2H), 2.66 (t, 2H), 2.47 (m, 4H), 2.39 (t, 2H), 1.95-1.4 (m, 16H).
Preparation 131: l-f4-(6-aminohexylsulfonv0piperazin-l-yl)ethanone (compound 13JΛ.
Figure imgf000105_0001
General procedure 8. Starting materials: 1-acetylpiperazine and 6-(l,3- dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD) : δ 3.50 (m, 4H), 3.4-2.8 (m, 10H), 2.01 (s, 3H), 1.65 (m, 2H), 1.33 (m, 6H).
Preparation 132: 5-amino-Λ/-cyclopentyl-Λ/-(2-morpholinoethoxy')pentane-l- sulfonamide fcompound 132).
Figure imgf000105_0002
General procedure 8. Starting materials: compound 107 and 5-(l,3-dioxoisoindolin- 2-yl)pentane-l-sulfonyl chloride. The product was used without identification.
Preparation 133: 6-amino-Λ/-phenylhexane-l-sulfonamide ("compound 1331.
Figure imgf000105_0003
General procedure 8. Starting materials: aniline and 6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 7.34 (m, 2H), 7.25 (m 2H), 7.14 (m, IH), 3.08 (m, 2H), 2.90 (m, 2H), 1.81 (m, 2H), 1.64 (m, 2H), 1.43 (m, 4H).
Preparation 134: 6-amino-Λ/-rbenzyloxyVΛ/-methylhexane-l-sulfonamide (compound 134).
Figure imgf000105_0004
General procedure 9. Starting materials: Λ/-(benzyloxy)-6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonamide and methyl iodide. MS [M+H]+= 301.1
Preparation 135: 6-amino-Λ/-fbenzyloxyVΛ/-f2-morpholinoethyπhexane-l- sulfonamide fcompound 1351.
Figure imgf000106_0001
General procedure 9. Starting materials: Λ/-(benzyloxy)-6-(l,3-dioxoisoindolin-2- yl)hexane-l-sulfonamide and 4-(2-chloroethyl)-morpholine hydrochloride. MS [M+H]+= 400.2
Preparation 136: 5-amino-Λ/-cvclobutyl-Λ/-(3-morpholinopropyπpentane-l- sulfonamide fcompound 136^.
Figure imgf000106_0002
General procedure 8. Starting materials: compound 115 and 5-(l,3-dioxoisoindolin- 2-yl)pentane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.22 (m, IH), 3.72 (m, 4H), 3.30 (t, 2H), 2.99 (m, 2H), 2.66 (m, 2H), 2.49 (m, 4H), 2.42 (m, 2H), 2.22 (m, 4H), 1.9-1.4 (m, 10H).
Preparation 137: 4-amino-Λ/-cvclobutyl-ΛK3-morpholinopropyl)butane-l- sulfonamide f compound 137").
Figure imgf000107_0001
General procedure 8. Starting materials: compound 115 and 4-(l,3-dioxoisoindolin- 2-yl)butane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.22 (m, IH), 3.71 (m, 4H), 3.30 (m, 2H), 2.99 (m, 2H), 2.67 (t, 2H), 2.48 (m, 4H), 2.41 (m, 2H), 2.21 (m, 4H), 1.9-1.5 (m, 8H).
Preparation 138: 4-amino-Λ/-cyclopentyl-Λ/-(3-morpholinopropyl)butane-l- sulfonamide (compound 138^.
Figure imgf000107_0002
General procedure 8. Starting materials: compound 102 and 4-(l,3-dioxoisoindolin- 2-yl)butane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 4.07 (m, IH), 3.71 (m, 4H), 3.19 (m, 2H), 3.05 (m, 2H), 2.68 (t, 2H), 2.48 (m, 4H), 2.39 (t, 2H), 2.0-1.5 (m, 14H).
Preparation 139: 6-amino-ΛH4-chlorophenyl)hexane-l-sulfonamide (compound 1391.
Figure imgf000107_0003
General procedure 8. Starting materials: 4-chloroaniline and 6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonyl chloride. 1H-NMR (CD3OD): δ 7.22 (m, 4H), 3.06 (m, 2H), 2.67 (t, 2H), 1.79 (m, 2H), 1.6-1.25 (m, 6H).
Preparation 140: 6-amino-/V-f4-chlorophenvO-Λ/-methylhexane-l-sulfonamide (compound 140).
Figure imgf000108_0001
General procedure 9. Starting materials: /V-(4-chlorophenyl)-6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonamide and methyl iodide. 1H-NMR (CD3OD): δ 7.43 (m, 4H), 3.32 (s, 3H), 3.10 (m, 2H), 2.63 (t, 2H), 1.77 (m, 2H), 1.55-1.25 (m, 6H).
Preparation 141 : 6-amino-Λ/-(4-chlorophenyl)-ΛH 2-morpholinoethvOhexane-l- sulfonamide fcompound 1411.
Figure imgf000108_0002
General procedure 9. Starting materials: Λ/-(4-chlorophenyl)-6-(l,3-dioxoisoindolin- 2-yl)hexane-l-sulfonamide and 4-(2-chloroethyl)-morpholine hydrochloride. 1H-NMR (CD3OD): δ 7.45 (m, 4H), 3.85 (m, 2H), 3.64 (m, 4H), 3.15 (m, 2H), 2.64 (t, 2H), 2.44 (m, 6H), 1.81 (m, 2H), 1.55-1.25 (m, 6H).
Examples
Example 1 : 6-f 2-Cyano-3-f pyridin^-yPauanidinoV/V-f tetrahvdro-2/-7-pyran-2- yloxyihexanamide fcompound 10011
Figure imgf000108_0003
General procedure 4. Starting materials: compound 2 and O-(tetrahydro-2W-pyran- 2-yl)hydroxylamine. 1H-NMR (DMSO-Cy6): δ 10.91 (s, IH), 9.36 (br s, IH), 8.41-8.39 (m, 2H), 7.84 (br s, IH), 7.24 (s, 2H), 4.80 (br s, IH), 3.95-3.87 (m, IH), 3.52- 3.46 (m, IH), 3.29-3.22 (m, 2H), 2.00 (t, 2H), 1.66-1.48 (m, 10H), 1.32-1.24 (m, 2H).
Example 2: 6-f2-Cyano-3-fpyridin-4-yQquanidinoyΛ/-phenoxyhexanamide (compound 1002)
Figure imgf000109_0001
General procedure 4. Starting materials: compound 2 and O-phenylhydroxylamine hydrochloride. 1H-NMR (DMSO-CZ6): δ 11.66 (s, IH), 9.34 (br s, IH), 8.40 (d, 2H), 7.83 (br s, IH), 7.32 (t, 2H), 7.23 (d, 2H), 7.04-6.98 (m, 3H), 3.29-3.26 (m, 2H), 2.19 (t, 2H), 1.64-1.52 (m, 4H), 1.39-1.24 (m, 2H).
Example 3: Λ/-(2-(4-Chlorophenoxy')ethoxy)-6-f2-cvano-3-(pyridin-4- vOαuanidinoihexanamide (compound 10031.
Figure imgf000109_0002
General procedure 4. Starting materials: compound 2 and O-(2-(4- chlorophenoxy)ethyl)hydroxylamine. 1H-NMR (DMSO-Of6) : δ 11.05 (s, IH), 9.35 (br s, IH), 8.39 (s, 2H), 7.81 (br s, IH), 7.33 (d, 2H), 7.22 (br s, 2H), 6.98 (d, 2H), 4.15-4.08 (m, 4H), 3.27-3.25 (m, 2H), 1.98 (br s, 2H), 1.55-1.25 (m, 6H).
Example 4: Λ/-(4-ChlorobenzyloxyV6-(2-cvano-3-(pyridin-4- vπquanidino")hexanamide (compound 10041L
Figure imgf000109_0003
General procedure 4. Starting materials: compound 2 and O-(4- chlorophenoxy)methyl)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.94 (s, IH), 9.34 (br s, IH), 8.41-8.39 (d, 2H), 7.81 (br s, IH), 7.46-7.40 (m, 4H), 7.23 (br s, 2H), 4.77 (s, 2H), 3.31-3.22 (m, 2H), 1.96 (t, 2H), 1.55-1.46 (m, 4H), 1.30-1.22 (m, 2H).
Example 5: 7-f2-Cyano-3-fpyridin-4-vπαuanidino')-/V-('tetrahydro-2A7-pyran-2- yloxy'lheptanamide (compound 10051.
Figure imgf000110_0001
General procedure 4. Starting materials: compound 1 and O-(tetrahydro-2H-pyran- 2-yl)hydroxylamine. 1H-NMR (DMSO-Of6): δ 10.87 (s, IH), 9.39 (br s, IH), 8.39 (d, 2H), 7.81 (t, IH), 7.22 (br s, 2H), 4.80 (br s, IH), 4.10-4.05 (m, IH), 3.96-3.88 (m, IH), 3.52-3.23 (m, 4H), 1.99 (t, 2H), 1.68-1.45 (m, 8H), 1.31-1.22 (m, 4H).
Example 6: Λ/-f4-Chlorobenzyloxy')-7-f2-cvano-3-('pyridin-4- vQquanidino)heptanamide (compound 1006I.
Figure imgf000110_0002
General procedure 4. Starting materials: compound 1 and O-(4- chlorophenoxy)rnethyl)hydroxylamine. 1H-NMR (DMSO-CZ6): δ 10.93 (s, IH), 9.34 (br s, IH), 8.41-8.39 (m, 2H), 7.82 (br s, IH), 7.46-7.39 (m, 4H), 7.21 (br s, 2H), 4.77 (s, 2H), 3.29-3.22 (m, 2H), 1.94 (t, 2H), 1.53-1.46 (m, 4H), 1.26-1.22 (m, 4H).
Example 7: Λ/-(4-Chlorobenzyloxy")-5-f2-cvano-3-(pyridin-4- vπαuanidinoloentanamide ( compound 1007I.
Figure imgf000111_0001
General procedure 4. Starting materials: compound 3 and O-(4- chlorophenoxy)methyl)hydroxylamine. 1H-NMR (DMSO-d6): δ 10.97 (s, IH), 9.36 (br s, IH), 8.39 (d, 2H), 7.83 (br s, IH), 7.46-7.40 (m, 4H), 7.23 (br s, 2H), 4.77 (s, 2H), 3.30-3.25 (m, 2H), 2.01-1.96 (m, 2H), 1.56-1.47 (m, 4H).
Example 8: /V-(4-Chlorobenzyloxy)-8-(2-cvano-3-(pyridin-4- vQquanidinoioctanamide (compound 10081.
Figure imgf000111_0002
General procedure 4. Starting materials: compound 4 and O-(4- chlorophenoxy)methyl)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.92 (s, IH), 9.33 (br s, IH), 8.40 (d, 2H), 7.82 (br s, IH), 7.46-7.39 (m, 4H), 7.23-7.21 (m, 2H), 4.77 (s, 2H), 3.30-3.23 (m, 2H), 1.94 (t, 2H), 1.55-1.45 (m, 4H), 1.30-1.21 (m, 6H).
Example 9: 7-(2-Cvano-3-(pyridin-4-yl)quanidino>Λ/-(2-(2-(2- methoXyethoXViethoXVtethoXViheptanamide (compound 1009).
Figure imgf000111_0003
General procedure 4. Starting materials: compound 1 and O-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.92 (s, IH), 9.34 (br s, IH), 8.41-8.39 (m, 2H), 7.81 (br S, IH), 7.23 (br s, 2H), 3.86 (t, 2H), 3.59-3.50 (m, 8H), 3.45-3.42 (m, 2H), 3.27-3.24 (m, 5H), 1.95 (t, 2H), 1.54-1.47 (m, 4H), 1.33-1.25 (m, 4H). Example 10: 7-f2-Cvano-3-fpyridin-4-vπquanidino')-Λ/-phenoxyheptanamide fcompound 1010).
Figure imgf000112_0001
General procedure 4. Starting materials: compound 1 and O-phenylhydroxylamine hydrochloride. 1H-NMR (DMSO-Gf6): δ 11.67 (s, IH), 9.38 (br s, IH), 8.40-8.38 (m, 2H), 7.84 (br s, IH), 7.32 (t, 2H), 7.22 (br s, 2H), 7.04-6.98 (m, 3H), 3.31-3.24 (2H), 2.18 (t, 2H), 1.62-1.48 (m, 4H), 1.38-1.27 (m, 4H).
Example 11 : Λ/-(2-f4-chlorophenoxy')ethoxy')-7-f2-cvano-3-fpyridin-4- yhguanidinoiheptanamide fcompound 1011V
Figure imgf000112_0002
General procedure 4. Starting materials: compound 1 and O-(2-(4- chlorophenoxy)ethyl)hydroxylamine. 1H-NMR (DMSO-CZ6): δ 11.03 (s, IH), 9.34 (br s, IH), 8.40 (d, 2H), 7.82 (br s, IH), 7.34 (d, 2H), 7.23 (br s, 2H), 6.98 (d, 2H), 4.17-4.06 (m, 4H), 3.28-3.22 (m, 2H), 1.96 (t, 2H), 1.57-1.45 (m, 4H), 1.32-1.24 (m, 4H).
Example 12: 5-f2-Cvano-3-fpyridin-4-yπαuanidino')-Λ/-rtetrahvdro-2AV-pyran-2- yloxylpentanamide fcompound 10121.
Figure imgf000112_0003
General procedure 4. Starting materials: compound 3 and O-(tetrahydro-2AY-pyran- 2-y|)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.92 (s, IH), 9.34 (br s, IH), 8.41 (br s, 2H), 7.84 (br s, IH), 7.23 (br s, 2H), 4.81 (br s, IH), 3.94-3.88 (m, IH), 3.53- 3.44 (m, IH), 3.30-3.21 (m, 2H), 2.05-2.00 (m, 2H), 1.70-1.44 (m, 10H).
Example 13: 5-r2-Cvano-3-rpyridin-4-vπαuanidino')-Λ/-r2-f2-f2- methoxyethoxy'jethoxy^ethoxylpentanamide fcompound 10131.
Figure imgf000113_0001
General procedure 4. Starting materials: compound 3 and O-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)hydroxylamine. 1H-NMR (DMSOd6) : δ 10.96 (s, IH), 9.36 (br s, IH), 8.41-8.39 (m, 2H), 7.85 (br s, IH), 7.23 (br s, 2H), 3.89-3.85 (m, 2H), 3.59-3.50 (m, 8H), 3.45-3.42 (m, 2H), 3.29-3.24 (m, 5H), 2.01-1.96 (m, 2H), 1.57-1.49 (m, H).
Example 14: 8-(2-Cvano-3-fpyridin-4-yl)quanidinoy/\Htetrahvdro-2rt-pyran-2- yloxyioctanamide fcompound 1014").
General procedure 4. Starting materials: compound 4 and O-(tetrahydro-2W-pyran- 2-yl)hydroxylamine. 1H-NMR (DMSOd6): δ 10.87 (s, IH), 9.32 (br s, IH), 8.40 (d, 2H), 7.82 (br s, IH), 7.23-7.21 (m, 2H), 4.80 (br s, IH), 3.96-3.87 (m, IH), 3.52- 3.46 (m, IH), 3.31-3.23 (m, 2H), 2.00 (t, 2H), 1.69-1.45 (m, 1OH), 1.32-1.22 (m, 6H).
Example 15: 8-f2-Cvano-3-(pyridin-4-ynαuanidinoVΛ/-f2-(r2-f2- methoxyethoxyiethoxyiethoxyioctanamide (compound 1015).
Figure imgf000114_0001
General procedure 4. Starting materials: compound 4 and O-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)hydroxylamine. 1H-NMR (DMSOd6): δ 10.91 (s, IH), 9.33 (br s, IH), 8.40 (d, 2H), 7.82 (br s, IH), 7.22 (br s, 2H), 3.88-3.85 (m, 2H), 3.59-3.50 (m, 8H), 3.45-3.42 (m, 2H), 3.34-3.26 (m, 5H), 1.94 (t, 2H), 1.54-1.44 (m, 4H), 1.33-1.22 (m, 6H).
Example 16: 5-f2-Cvano-3-fpyridin-4-vπαuanidino')-Λ/-phenoxypentanamide fcompound 10161.
Figure imgf000114_0002
General procedure 4. Starting materials: compound 3 and O-phenylhydroxylamine hydrochloride. 1H-NMR (DMSO-Cf6) : δ 8.38 (d, 2H), 7.92 (br s, IH), 7.32 (t, 2H), 7.23-7.18 (m, 3H), 7.08-6.98 (m, 4H), 3.11-3.01 (m, 2H), 2.32-2.13 (m, 2H), 1.69- 1.54 (m, 4H).
Example 17: /\H2-(4-chlorophenoxy')ethoxy>5-f2-cyano-3-fpyridin-4- vOquanidino")pentanamide fcompound 10171.
Figure imgf000114_0003
General procedure 4. Starting materials: compound 3 and O-(2-(4- chlorophenoxy)ethyl)hydroxylamine. 1H-NMR (DMSO-CZ6): δ 11.07 (s, IH), 9.36 (br s, IH), 8.40 (br s, 2H), 7.85 (br s, IH), 7.35-7.31 (m, 3H), 7.23 (br s, IH), 6.98 (d, 2H), 4.15-4.08 (m, 4H), 3.41-3.24 (m, 2H), 2.00 (br s, 2H), 1.54-1.48 (m, 4H). Example 18: 6-(2-Cvano-3-(pyridin-4-vπαuanidinoVΛ/-(2-(2-(2- methoxyethoxyiethoxyiethoxyihexanamide (compound 10181.
Figure imgf000115_0001
General procedure 4. Starting materials: compound 2 and O-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)hydroxylamine. 1H-NMR (DMSO-cfe): δ 10.93 (s, IH), 9.33 (br s, IH), 8.40 (d, 2H), 7.82 (br S, IH), 7.22 (br s, 2H), 3.88-3.85 (m, 2H), 3.58-3.50 (m, 8H), 3.45-3.42 (m, 2H), 3.27-3.23 (m, 5H), 1.96 (t, 2H), 1.56-1.46 (m, 4H), 1.32-1.25 (m, 2H).
Example 19: 8-f2-Cvano-3-rpyridin-4-vπquanidino')-Λ/-phenoxyoctanamide (compound 10191.
Figure imgf000115_0002
General procedure 4. Starting materials: compound 4 and O-phenylhydroxylamine hydrochloride. 1H-NMR (DMSO-Cf6): δ 11.65 (s, IH), 9.32 (br s, IH), 8.38 (br s, 2H), 7.82 (br s, IH), 7.32 (t, 2H), 7.22 (br s, 2H), 7.04-6.97 (m, 3H), 3.31-3.25 (m, 2H), 2.17 (t, 2h), 1.61-1.48 (m, 4H), 1.37-1.26 (m, 6H).
Example 20 : Λ/-(2-(4-Chlorophenoxy)ethoxy')-8-(2-cvano-3-(pyridin-4- vπαuanidinoioctanamide (com pound 1020").
Figure imgf000115_0003
General procedure 4. Starting materials: compound 4 and O-(2-(4- chlorophenoxy)ethyl)hydroxylamine. 1H-NMR (DMSO-CZ6): δ 9.32 (s, IH), 8.40 (br s, 2H), 7.32 (d, 2H), 7.22 (br s, 2H), 6.95 (d, 2H), 4.18-4.03 (m, 4H), 3.31-3.21 (m, 2H), 1.97 (t, 2H), 1.55-1.42 (m, 4H), 1.30-1.20 (m, 6H).
Example 21: 7-(2-Cvano-3-(pyridin-4-vDαuanidino')-Λ/-(pyridin-4- ylmethoxyiheptanamide (compound 10211.
Figure imgf000116_0001
General procedure 4. Starting materials: compound 1 and 0-(pyridin-4- yloxy)methyl)hydroxylamine. 1H-NMR (DMSO-c/6): δ 11.04 (s, IH), 9.34 (br s, IH), 8.57 (d, 2H), 8.40 (d, 2H), 7.82 (br s, IH), 7.39 (d, 2H), 7.22 (br s, 2H), 4.85 (s, 2H), 3.32-3.22 (m, 2H), 1.95 (t, 2H), 1.53-1.45 (m, 4H), 1.31-1.22 (m, 4H).
Example 22: 7-(2-Cvano-3-(pyridin-4-vπquanidinoVΛ/-(pyridin-3- ylmethoxyiheptanamide (compound 10221.
Figure imgf000116_0002
General procedure 4. Starting materials: compound 1 and 0-(pyridin-3- yloxy)methyl)hydroxylamine. 1H-NMR (DMSO-CZ6): δ 10.98 (s, IH), 9.37 (br s, IH), 8.58-8.54 (m, 2H), 8.40 (d, 2H), 7.88-7.79 (m, 2H), 7.44-7.40 (m, IH), 7.22 (d, 2H), 4.83 (s, 2H), 3.28-3.21 (m, 2H), 1.94 (t, 2H), 1.52-1.43 (m, 4H), 1.30-1.20 (m, 4H).
Example 23: 7-(2-Cvano-3-(pyridin-4-v0αuanidino')-Λ/-(2- morpholinoethoxyiheptanamide (compound 10231.
Figure imgf000117_0001
General procedure 4. Starting materials: compound 1 and O-(2- morpholinoethyl)hydroxylamine. 1H-NMR (DMSO-CZ6) : δ 10.88 (s, IH), 9.33 (br s, IH), 8.38 (br s, 2H), 7.81 (br s, IH), 7.22 (br s, 2H), 3.86 (t, 2H), 3.56 (t, 4H), 3.32-3.23 (m, 2H), 2.43-2.40 (m, 6H), 1.95 (t, 2H), 1.54-1.48 (m, 4H), 1.34-1.22 (m, 4H).
Example 24: 5-f2-Cvano-3-rpyridin-4-vπαuanidino")-Λ/-rpyridin-4- ylmethoxyipentanamide (compound 1024^.
Figure imgf000117_0002
General procedure 4. Starting materials: compound 3 and 0-(pyridin-4- yloxy)methyl)hydroxylamine. 1H-NMR (DMSO-Cf6) : δ 11.08 (s, IH), 9.35 (br s, IH), 8.57 (d, 2H), 8.40 (d, 2H), 7.83 (br s, IH), 7.39 (d, 2H), 7.24 (br s, 2H), 4.85 (s, 2H), 3.32-3.23 (m, 2H), 2.92-1.97 (m, 2H), 1.57-1.47 (m, 4H).
Example 25: 5-r2-Cvano-3-fpyridin-4-vπαuanidinoVΛ/-fpyridin-3- ylmethoxyipentanamide (compound 10251.
Figure imgf000117_0003
General procedure 4. Starting materials: compound 3 and 0-(pyridin-3- yloxy)methyl)hydroxylamine. 1H-NMR (DMSO-Cf6) : δ 11.02 (s, IH), 9.38 (br s, IH), 8.59-8.54 (m, 2H), 8.40 (d, 2H), 7.89-7.80 (m, 2H), 7.44-7.40 (m, IH), 7.23 (d, 2H), 4.83 (s, 2H), 3.29-3.21 (m, 2H), 2.01-1.96 (m, 2H), 1.55-1.46 (m, 4H). Example 26: 5-r2-Cvano-3-fpyridin-4-vπquanidino')-Λ/-f2- morpholinoethoxyipentanamide (compound 1026).
Figure imgf000118_0001
General procedure 4. Starting materials: compound 3 and O-(2- morpholinoethyl)hydroxylamine. 1H-NMR (DMSO-CZ6): δ 10.94 (s, IH), 9.37 (br s, IH), 8.40 (d, 2H), 7.87 (br s, IH), 7.23 (br s, 2H), 3.86 (t, 2H), 3.56 (t, 4H), 3.30- 3.23 (m, 2H), 2.50-2.37 (m, 6H), 2.01-1.96 (m, 2H), 1.56-1.47 (m, 4H).
Example 27: 8-(2-Cvano-3-(pyridin-4-v0quanidinoVΛ/-(pyridin-4- ylmethoxyioctanamide (compound 10271.
Figure imgf000118_0002
General procedure 4. Starting materials: compound 4 and 0-(pyridin-4- yloxy)methyl)hydroxylamine. 1H-NMR (DMSO-Of6): δ 11.30 (s, IH), 9.38 (br s, IH), 8.56 (d, 2H), 8.40 (br s, 2H), 7.82 (br s, IH), 7.39 (d, 2H), 7.22 (br s, 2H), 4.85 (s, 2H), 3.31-3.21 (m, 2H), 1.95 (t, 2H), 1.57-1.42 (m, 4H), 1.30-1.20 (m, 6H).
Example 28: 8-(2-Cvano-3-(pyridin-4-yl')quanidino')-Λ/-(2- morpholinoethoxy)octanamide (compound 10281.
Figure imgf000118_0003
General procedure 4. Starting materials: compound 4 and O-(2- morpholinoethyl)hydroxylamine. 1H-NMR (DMSO-CZ6): δ 10.87 (s, IH), 9.34 (br s, IH), 8.39 (br s, 2H), 7.83-7.79 (m, IH), 7.22 (br s, 2H), 3.86 (t, 2H), 3.58-3.55 (m, 6H), 3.31-3.23 (m, 2H), 2.46-2.37 (m, 4H), 1.94 (t, 2H), 1.54-1.47 (m, 4H), 1.30-1.23 (m, 6H).
Example 29: 6-(2-Cvano-3-(pyridin-4-vnquanidinoV/V-(pyridin-4- ylmethoxyihexanamide ("compound 1029).
Figure imgf000119_0001
General procedure 4. Starting materials: compound 2 and 0-(pyridin-4- yloxy)methyl)hydroxylamine. 1H-NMR (DMSO-CZ6): δ 11.08 (s, IH), 9.38 (br s, IH), 8.57 (d, 2H), 8.40 (d, 2H), 7.84 (br s, IH), 7.38 (d, 2H), 7.23 (br s, 2H), 4.85 (s, 2H), 3.28-3.21 (m, 2H), 1.96 (t, 2H), 1.55-1.46 (m, 4H), 1.31-1.19 (m, 2H).
Example 30: 7-(2-Cvano-3-(pyridin-4-v0quanidino)-/V-(ftetrahvdrofuran-2- vπmethoxy")heptanamide (compound 1030).
Figure imgf000119_0002
General procedure 4. Starting materials: compound 1 and O-((tetrahydrofuran-2- yl)methyl)hydroxylamine. 1H-NMR (DMSO-c/6): δ 10.96 (s, IH), 9.36 (br s, IH), 8.40 (d, 2H), 7.85 (br s, IH), 7.22 (br s, 2H), 4.03-3.95 (m, IH), 3.76-3.59 (m, 4H), 3.33-3.22 (m, 4H), 1.96-1.74 (m, 4H), 1.61-1.44 (m, 4H), 1.32-1.23 (m, 4H).
Example 31: 8-(2-Cyano-3-(pyridin-4-yl)quanidinoV/V-(pyridin-3- ylmethoxy)octanamide (compound 10311.
Figure imgf000119_0003
General procedure 4. Starting materials: compound 4 and 0-(pyridin-3- yloxy)methyl)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.96 (s, IH), 9.35 (br s, IH), 8.58-8.54 (m, 2H), 8.40-8.38 (m, 2H), 7.86-7.79 (m, 2H), 7.44-7.39 (m, IH), 7.22 (br s, 2H), 4.83 (s, 2H), 3.31-3.23 (m, 2H), 1.94 (t, 2H), 1.54-1.44 (m, 4H), 1.30- 1.19 (m, 6H).
Example 32: 8-(2-Cvano-3-(pyridin-4-vπquanidinoV/V-fftetrahvdrofuran-2- vπmethoxy'ϊoctanamide (compound 1032").
Figure imgf000120_0001
General procedure 4. Starting materials: compound 4 and 0-((tetrahydrofuran-2- yl)methyl)hydroxylamine. 1H-NMR (DMSO-Gf6): δ 10.95 (s, IH), 9.37 (br s, IH), 8.39 (d, 2H), 7.84 (br s, IH), 7.21 (br s, 2H), 4.03-3.95 (m, IH), 3.76-3.59 (m, 4H), 3.30-3.23 (m, 4H), 1.98-1.74 (m, 4H), 1.59-1.44 (m, 4H), 1.32-1.22 (m, 6H).
Example 33:6-f2-Cvano-3-(pyridin-4-vπαuanidinoVΛ/-fpyridin-3- ylmethoxyihexanamide (compound 1033").
Figure imgf000120_0002
General procedure 4. Starting materials: compound 2 and 0-(pyridin-3- yloxy)methyl)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.96 (s, IH), 9.34 (br s, IH), 8.58-8.54 (m, 2H), 8.41-8.38 (m, 2H), 7.82-7.80 (m, 2H), 7.44-7.39 (m, IH), 7.23 (br s, 2H), 4.83 (s, 2H), 3.19-3.17 (m, 2H), 1.97 (t, 2H), 1.56-1.46 (m, 4H), 1.31- 1.22 (m, 2H).
Example 34: 6-f2-Cvano-3-(pyridin-4-v0αuanidino")-ΛH2- morpholinoethoxvihexanamide (compound 10341.
Figure imgf000121_0001
General procedure 4. Starting materials: compound 2 and O-(2- morpholinoethyl)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.90 (s, IH), 9.34 (br s, IH), 8.39 (d, 2H), 7.83 (br s, IH), 7.23 (br s, 2H), 3.86 (t, 2H), 3.57-3.54 (m, 4H), 3.33-3.23 (m, 2H), 2.45-2.37 (m, 6H), 1.96 (t, 2H), 1.57-1.47 (m, 4H), 1.32-1.22 (m, 2H).
Example 35: 7-f2-Cyano-3-(pyridin-4-y0quanidino1-Λ/-ftetrahydro-2AY-pyran-4- yloxyiheptanamide (compound 10351.
Figure imgf000121_0002
General procedure 4. Starting materials: compound 1 and 0-(tetrahydro-2H-pyran- 4-yl)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.77 (s, IH), 9.41 (br s, IH), 8.38 (d, 2H), 7.84 (br s, IH), 7.20 (br s, 2H), 4.13-4.07 (m, IH), 3.95-3.87 (m, IH), 3.84- 3.77 (m, 2H), 3.37-3.23 (m, 3H), 1.97 (t, 2H), 1.86-1.79 (m, 2H), 1.52-1.41 (m, 6H), 1.34-1.22 (m, 4H).
Example 36: 7-f2-Cyano-3-fpyridin-4-vπαuanidinoVΛ/-('cvclohexyloxy1heptanannide (compound 10361.
Figure imgf000121_0003
General procedure 4. Starting materials: compound 1 and O- cyclohexylhydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.67 (s, IH), 9.34 (br s, IH), 8.39 (br s, 2H), 7.84 (br s, IH), 7.21 (br s, 2H), 3.72-3.63 (m, IH), 3.32-3.23 (m, 2H), 1.96 (t, 2H), 1.85-1.76 (m, 2H), 1.71-1.63 (m, 2H), 1.55-1.45 (m, 5H), 1.34-1.18 (m, 9H).
Example 37: 8-(2-Cvano-3-(Pyridin-4-vnαuanidino')-/V-(cvclohexyloxy')octanamide (compound 10371.
Figure imgf000122_0001
General procedure 4. Starting materials: compound 4 and O- cyclohexylhydroxylamine. 1H-NMR (DMSO-c/6) : δ 10.66 (s, IH), 9.39 (br s, IH), 8.38 (d, 2H), 7.82 (br s, IH), 7.20 (br s, 2H), 3.71-3.63 (m, IH), 3.31-3.21 (m, 2H), 1.95 (t, 2H), 1.84-1.77 (m, 2H), 1.72-1.63 (m, 2H), 1.55-1.41 (m, 5H), 1.34-1.18 (m, HH).
Example 38: 8-(2-Cvano-3-fpyridin-4-vπαuanidino)-/V-0:etrahydrofuran-3- yloxyloctanamide (compound 10381.
Figure imgf000122_0002
General procedure 4. Starting materials: compound 4 and O-(tetrahydrofuran-3- yl)hydroxylamine. 1H-NMR (DMSO-Cf6): δ 10.92 (br s, IH), 9.37 (br s, IH), 8.38 (d, 2H), 7.81 (br s, IH), 7.20 (br s, 2H), 4.57-4.53 (m, IH), 3.83-3.58 (m, 4H), 3.31- 3.23 (m, 2H), 1.96 (t, 4H), 1.53-1.47 (m, 4H), 1.32-1.22 (m, 6H).
Example 39: 7-(2-Cvano-3-(pyridin-4-vnquanidinoVΛ/-(tetrahvdrofuran-3- yloxylheptanamide (compound 1039T.
Figure imgf000122_0003
General procedure 4. Starting materials: compound 1 and O-(tetrahydrofuran-3- yl)hydroxylamine. 1H-NMR (DMSOd6): δ 10.90 (s, IH), 9.37 (br s, IH), 8.38 (d, 2H), 7.79 (br s, IH), 7.20 (d, 2H), 4.58-4.52 (m, IH), 3.84-3.58 (m, 4H), 3.31-3.23 (m, 2H), 1.97 (t, 4H), 1.55-1.48 (m, 4H), 1.32-1.23 (m, 4H).
Example 40: 8-f2-Cvano-3-fpyridin-4-y0quanidino')-Λ/-(tetrahydro-2H-pyran-4- yloxyioctanamide ("compound 104O-).
Figure imgf000123_0001
General procedure 4. Starting materials: compound 4 and O-(tetrahydro-2W-pyran- 4-yl)hydroxylamine. 1H-NMR (DMSOd6): δ 10.74 (s, IH), 9.33 (br s, IH), 8.40 (d, 2H), 7.82 (t, IH), 7.22 (d, 2H), 3.95-3.78 (m, 3H), 3.38-3.23 (m, 4H), 1.97 (t, 2H), 1.87-1.78 (m, 2H), 1.55-1.41 (m, 6H), 1.32-1.23 (m, 6H).
Example 41 : 7-( 3-f 2-chloropyridin-4-vπ-2-cyanoαuanidino1-Λ/-f tetra hydro- 2/f- pyran-2-yloxy')heptanamide (compound 1041").
Figure imgf000123_0002
General procedure 4. Starting materials: compound 7 and O-(tetrahydro-2H-pyran- 2-yl)hydroxylamine. 1H-NMR (DMSOd6): δ 10.89 (s, IH), 9.58 (br s, IH), 8.21 (d, IH), 8.00 (br s, IH), 7.26 (d, 2H), 4.81-4.78 (m, IH), 3.96-3.87 (m, IH), 3.51-3.46 (m, IH), 3.32-3.23 (m, 2H), 1.99 (t, 2H), 1.72-1.46 (m, 1OH), 1.32-1.23 (m, 4H).
Example 42:7-f2-Cyano-3-fpyridin-4-yπquanidinoVΛ/-methoxyheptanamide ("compound 10421.
Figure imgf000124_0001
General procedure 4. Starting materials: compound 1 and O-methylhydroxylamine hydrochloride. 1H-NMR (DMSO-c/6): δ 10.94 (s, IH), 9.38 (br s, IH), 8.39 (d, 2H), 7.85 (t, IH), 7.21 (br s, 2H), 3.56 (s, 3H), 3.29-3.22 (m, 2H), 1.94 (t, 2H), 1.54- 1.45 (m, 4H), 1.32-1.25 (m, 4H).
Example 43 : N-( Benzyloxy')-7-f 2-cvano-3-f pyridin-4-vQquanidino)heptanamide (compound 1043L
Figure imgf000124_0002
General procedure 4. Starting materials: compound 1 and O-benzylhydroxylamine hydrochloride. 1H-NMR (DMSO-Cf6): δ 10.87 (s, IH), 9.29 (br s, IH), 8.33 (d, 2H), 7.78 (t, IH), 7.32-7.28 (m, 5H), 7.15 (br s, 2H), 4.71 (s, 2H), 3.21-3.15 (m, 2H), 1.88 (t, 2H), 1.46-1.46 (m, 4H), 1.23-1.14 (m, 4H).
Example 44: 7-f2-Cvano-3-(pyridin-4-v0quanidinoVΛHcycloheptyloxy')heptanamide (compound 10441.
Figure imgf000124_0003
General procedure 4. Starting materials: compound 1 and O- cycloheptylhydroxylamine. 1H-NMR (DMSO-d6): δ 10.66 (s, IH), 9.16 (br s, IH), 8.38 (d, 2H), 7.85 (br s, IH), 7.21 (br s, 2H), 3.88-3.79 (m, IH), 3.27-3.22 (m, 2H), 1.97-1.81 (m, 4H), 1.64-1.47 (m, 12H), 1.36-1.23 (m, 6H). Example 45: 7-f2-Cvano-3-fpyridin-4-vQquanidino1-/V-(2- cvclohexvlethoxviheptanamide (compound 10451.
Figure imgf000125_0001
General procedure 4. Starting materials: compound 1 and O-(2- cyclohexylethyl)hydroxylamine. 1H-NMR (DMSO-Cy6): δ 10.80 (s, IH), 9.35 (br s, IH), 8.40 (s, 2H), 7.82 (br s, IH), 7.22 (br s, 2H), 3.76 (t, 2H), 3.29-3.22 (m, 2H), 1.94(t, 2H), 1.71-1.09 (m, 19H), 0.93-0.81 (m, 2H).
Example 46: 7-(2-Cyano-3-(pyridin-4-vQquanidino1-/V- (cvclohexylmethoxyiheptanamide (compound 10461.
Figure imgf000125_0002
General procedure 4. Starting materials: compound 1 and O-(2- cyclohexylmethyl)hydroxylamine. 1H-NMR (DMSO-c/6): δ 10.82 (s, IH), 9.36 (br s, IH), 8.40 (d, 2H), 7.84 (br s, IH), 7.22 (br s, 2H), 3.54 (d, 2H), 3.29-3.22 (m, 2H), 1.93 (t, 2H), 1.73-1.44 (m, 9H), 1.32-1.10 (m, 8H), 0.98-0.85 (m, 2H).
Example 47: 7-(2-Cyano-3-(pyrdin-4-yl1quanidino1-Λ/-(cvclopentyloxy1heptanamide (compound 10471.
Figure imgf000125_0003
General procedure 4. Starting materials: compound 1 and O- cyclopentylhydroxylamine. 1H-NMR (DMSO-Cl6): δ 10.67 (s, IH), 9.33 (br s, IH), 8.39 (d, 2H), 7.81 (t, IH), 7.22 (br s, 2H), 4.37-4.31 (m, IH), 3.29-3.23 (m, 2H), 1.95 (t, 2H), 1.73-1.46 (m, 12H), 1.32-1.22 (m, 4H).
Example 48: 7-(2-Cvano-3-(pyridin-4-vπαuanidino')-Λ/-methoxy-Λ/- methylheptanamide (compound 1048").
Figure imgf000126_0001
General procedure 4. Starting materials: compound 1 and N,O- dimethylhydroxylamine hydrochloride. 1H-NMR (DMSO-c/6): δ 9.33 (br s, IH), 8.39 (br s, 2H), 7.82 (br s, IH), 7.22 (br s, 2H), 3.65 (s, 3H), 3.31-3.23 (m, 2H), 3.08 (s, 3H), 2.36 (t, 2H), 1.55-1.46 (m, 4H), 1.33-1.24 (m, 4H).
Example 49: Λ/-ter£-Butoxy-7-(2-cvano-3-(pyridin-4-vQquanidino')heptanamide (compound 1049).
Figure imgf000126_0002
General procedure 4. Starting materials: compound 1 and O-tert- butylhydroxylamine hydrochloride. 1H-NMR (DMSO-^6): δ 10.20 (s, IH), 9.34 (br s, IH), 8.40 (s, 2H), 7.82 (br s, IH), 7.20 (br S, 2H), 3.30-3.22 (m, 2H), 1.99 (t, 2H), 1.58-1.44 (m, 4H), 1.30-1.22 (m, 4H), 1.18 (s, 9H).
Example 50: /V-Benzyl-7-(2-cvano-3-(pyridin-4-v0αuanidino)-Λ/- (cvclohexyloxyiheptanamide (compound 1050).
Figure imgf000126_0003
General procedure 4. Starting materials: compound 1 and compound 12. 1H-NMR (DMSO-Gf6): δ 9.36 (br s, IH), 8.39 (d, 2H), 7.84 (br s, IH), 7.34-7.21 (m, 7H), 4.75 (s, 2H), 3.91-3.84 (m, IH), 3.30-3.22 (m, 2H), 2.42 (t, 2H), 1.90-1.84 (m, 2H), 1.72-1.65 (m, 2H), 1.56-1.46 (m, 4H), 1.28-1.15 (m, 1OH).
Example 51 : 7-(2-Cyano-3-( pyridin-4-vπαuanidino>/V-('cyclohexyloxy')-/V- methylheptanamide (compound 1051).
Figure imgf000127_0001
General procedure 4. Starting materials: compound 1 and compound 13. 1H-NMR (DMSO-Gf6): δ 9.36 (br s, IH), 8.40 (d, 2H), 7.84 (br s, IH), 7.23 (br s, 2H), 3.86- 3.78 (m, IH), 3.30-3.23 (m, 2H), 3.09 (s, 3H), 2.37 (t, 2H), 1.92-1.86 (m, 2H), 1.75-1.67 (m, 2H), 1.54-1.45 (m, 5H), 1.33-1.16 (m, 9H).
Example 52: Λ/-Benzyl-6-f2-cvano-3-fpyridin-4-vπαuanidino)hexane-2-sulfonamide (compound 10521.
Figure imgf000127_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 35. 1H-NMR (DMSO-Gf6): δ 9.40 (br s, IH), 8.39 (d, 2H), 7.86 (br s, IH), 7.63 (t, IH), 7.36-7.19 (m, 7H), 4.13 (d, 2H), 3.28- 3.22(m, 2H), 2.91-2.85 (m, 2H), 1.65-1.45 (m, 4H), 1.31-1.23 (m, 4H).
Example 53: 2-Cvano-l-(7-(2-cvclohexylhvdraziny0-7-oxoheptvπ-3-(pyridin-4- vDαuanidine (compound 1053T.
Figure imgf000128_0001
General procedure 4. Starting materials: compound 1 and cycloheylhydrazine hydrochloride. 1H-NMR (DMSO-CZ6): δ 9.40 (br s, IH), 9.20 (s, IH), 8.39 (d, 2H), 7.85 (br s, IH), 7.21 (br s, 2H), 3.27-3.23 (m, 2H), 2.62-2.53 (m, IH), 2.03 (t, 2H), 1.69 (t, 4H), 1.57-1.45 (m, 4H), 1.32-0.96 (m, 10H).
Example 54: 6-(2-Cyano-3-(pyridin-4-ynquanidino')-/V-cvclohexylhexane-l- sulfonamide (compound 1054").
Figure imgf000128_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 36. 1H-NMR (CD3OD): δ 8.39-8.37 (m, 2H), 7.34 (d, 2H), 3.40 (t, 2H), 3.20-3.11 (m, IH), 3.05-3.00 (m, 2H), 1.94-1.10 (m, 10H).
Example 55: 6-r2-Cyano-3-pyridin-4-vπquanidino')-/V-('cvclohexylmethvπhexane-l- sulfonamide (compound 1055^.
Figure imgf000128_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 38. 1H-NMR (DMSO-cfe): δ 9.38 (br s, IH), 8.40 (br s, 2H), 7.86 (br s, IH), 7.23 (br s, 2H), 6.97 (t, IH), 3.31-3.24 (m, 2H), 2.98- 2.93 (m, 2H), 2.74 (t, 2H), 1.73-1.07 (m, 17H), 0.91-0.78 (m, 2H).
Example 56: Λ/-rBenzyloxy')-6-(2-cyano-3-rpyridin-4-yπαuanidino')hexane-l- sulfonamide (compound 10561.
Figure imgf000129_0001
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ ' -4- pyridylisothiourea and compound 34. 1H-NMR (DMSO-Gf6): δ 10.10 (br s, IH), 9.35 (br s, IH), 8.39 (d, 2H), 7.85 (br S, IH), 7.42-7.33 (m, 5H), 7.21 (br s, 2H), 4.88 (s, 2H), 3.29-3.22 (m, 2H), 3.18-3.13 (m, 2H), 1.74-1.63 (m, 2H), 1.56-1.24 (m, 6H).
Example 57: 6-f2-Cvano-3-fpyridin-4-yl1αuanidino1-Λ/-(tetrahydro-2/-y-pyran-2- yloxyihexane-1-sulfonamide (compound 10571.
Figure imgf000129_0002
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea and compound 40. 1H-NMR (CD3OD): δ 8.39-8.37 (m, 2H), 7.33 (d, 2H), 5.01 (t, IH), 3.97-3.89 (m, IH), 3.63-3.56 (m, IH), 3.40 (t, 2H), 3.25-3.20 (m, 2H), 1.87-1.41 (m, 4H).
Example 58: 6-f2-Cvano-3-fpyridin-4-yl)quanidino')-/\/-(cvcloheptyloxy")hexane-l- sulfonamide (compound 10581.
Figure imgf000129_0003
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea and compound 41. 1H-NMR (CD3OD): δ 3.38 (d, 2H), 7.34 (d, 2H), 4.08-4.00 (m, IH), 3.40 (t, 2H), 3.21-3.16 (m, 2H), 2.02-1.93 (m, 2H), 1.86- 1.76 (m, 2H), 1.70-1.37 (m, 16H). Example 59: 6-r2-Cvano-3-fpyridin-4-vπquanidino')-Λ/-fcvclohexylmethoxy')hexane- 1-sulfonamide (compound 10593.
Figure imgf000130_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 39. 1H-NMR (CD3OD): δ 8.39 (d, 2H), 7.35 (br s, 2H), 3.75 (d, 2H), 3.41 (t, 2H), 3.22-3.17 (m, 2H), 1.88-1.17 (m, 17H), 1.05-0.92 (m, 2H).
Example 60: 6-(2-Cvano-3-fpyridin-4-vπquanidinoV/V-f2-cvclohexylethoxy1hexane- 1-sulfonamide (compound 10601.
Figure imgf000130_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 42. 1H-NMR (CD3OD): δ 8.38 (d, 2H), 7.33 (d, 2H), 3.97 (t, 2H), 3.40 (t, 2H), 3.21-3.16 (m, 2H), 1.87-1.15 (m, 19H), 0.99-0.86 (m, 2H).
Example 61 : 6-(2-Cvano-3-(pyridin-4-v0quanidinoVΛ/-(cvclopentyloxy')hexane-l- sulfonamide (compound 10611.
Figure imgf000130_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 43. 1H-NMR (CD3OD): δ 8.37 (d, 2H), 7.33 (d, 2H), 4.53-4.48 (m, IH), 3.40 (t, 2H), 3.19-3.14 (m, 2H), 1.89-1.27 (m, 16H). Example 62: 6-f2-Cvano-3-(-pyridin-4-vπquanidino1-Λ/-rcvclohexyloxy")hexane-l- sulfoπamide ("compound 1062).
Figure imgf000131_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea and compound 44. 1H-NMR (CD3OD): δ 3.38 (d, 2H), 7.33 (d, 2H), 3.90-3.82 (m, IH), 3.40 (t, 2H), 3.21-3.16 (m, 2H), 1.96-1.26 (m, 18H).
Example 63: 6-(2-Cvano-3-(pyridin-4-vQquanidino')-ΛH2- morpholinoethoxy)hexane-l-sulfonamide (compound 10637).
Figure imgf000131_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 45. 1H-NMR (CD3OD): δ 8.39-8.37 (m, 2H), 7.33 (d, 2H), 4.10 (t, 2H), 3.71-3.68 (m, 4H), 3.40 (t, 2H), 3.25-3.20 (m, 2H), 2.66 (t, 2H), 2.54-2.51 (m, 4H), 1.87-1.77 (m, 2H), 1.71-1.61 (m, 2H), 1.58-1.41 (m, 4H).
Example 64: 6-f2-Cvano-3-(pyridin-4-yQquanidino)-Λ/-methoxy-Λ/-methylhexane-l- sulfonamide (compound 1064).
Figure imgf000131_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea and compound 46. 1H-NMR (CD3OD): δ 7.38 (d, 2H), 7.34 (br s, 2H), 3.75 (s, 3H), 3.40 (t, 2H), 3.19-3.13 (m, 2H), 3.00 (s, 3H), 1.93-1.83 (m, 2H), 1.71-1.42 (m, 6H). Example 65: (RV7-(2-Cvano-3-(rpyridin-4-vπαuanidino')-Λ/-fcvclohexyloxy')-2- methylheptanamide (compound 1065").
Figure imgf000132_0001
General procedure 4. Starting materials: compound 11 and O- cyclohexylhydroxylamine. H-NMR (CD3OD): δ 8.40-8.38 (m, 2H), 7.34 (d, 2H), 3.82-3.74 (m, IH), 3.39 (t, 2H), 1.98-1.90 (m, 2H), 1.83-1.75 (m, 2H), 1.69-1.55 (m, 4H), 1.48-1.27 (m, HH), 1.13 (d, 3H).
Example 66: (S)-7-(2-Cvano-3-(pyridin-4-vnquanidino')-/V-(2-cvclohexylethoxy')-2- methylheptanamide (compound 10661.
Figure imgf000132_0002
General procedure 4. Starting materials: compound 10 and O- (cyclohexylethyl)hydroxylamine. 1H-NMR (CD3OD): δ 8.39 (d, 2H), 7.35 (br s, 2H), 3.89 (t, 2H), 3.39 (t, 2H) 2.20-2.11 (m, IH), 1.78-1.21 (m, 18H), 1.12 (d, 3H), 1.01-0.88 (m, 3H).
Example 67: (S1-2-Benzyl-7-(2-cyano-3-(pyridin-4-vnquanidino)-/V- (cvclohexyloxyiheptanamide (compound 10671.
Figure imgf000132_0003
General procedure 4. Starting materials: compound 8 and O- cyclohexylhydroxylamine. 1H-NMR (CD3OD): δ 8.40-8.38 (m, 2H), 7.35-7.17 (m, 7H), 3.49-3.37 (m, 3H), 2.81-2.78 (m, 2H), 2.42-2.32 (m, IH), 1.80-1.04 (m, 18H).
Example 68: (S")-2-Benzyl-7-f2-cvano-3-fpyridin-4-vπαuanidino")-Λ/-(2- cvclohexylethoxy'jheptanamide (compound 1068^.
Figure imgf000133_0001
General procedure 4. Starting materials: compound 8 and O- (cyclohexylethyl)hydroxylamine. 1H-NMR (CD3OD): δ 8.39 (d, 2H), 7.37-7.16 (m, 7H), 3.69-3.62 (m, IH), 3.55-3.48 (m, IH), 3.39 (t, 2H), 2.86-2.72 (m, 2H), 2.38- 2.27 (m, IH), 1.75-1.14 (m, 19H), 0.94-0.82 (m, 2H).
Example 69: f/?V2-Benzyl-7-r2-cvano-3-fpyridin-4-yπαuanidino')-Λ/-f2- cvclohexylethoxy'jheptanamide (compound 1069V
Figure imgf000133_0002
General procedure 4. Starting materials: compound 9 and O-
(cyclohexylethyl)hydroxylamine. 1H-NMR (CD3OD): δ 8.37 (d, 2H), 7.34-7.16 (m, 7H), 3.68-3.60 (m, IH), 3.54-3.46 (m, IH), 3.37 (t, 2H), 2.80-2.71 (m, 2H), 2.36- 2.25 (m, IH), 1.72-1.13 (m, 18H), 0.92-0.80 (m, 3H).
Example 70 : fS)-7-(2-Cvano-3-f pyridin-4-yl)quanidinoVΛ/-f cvclohexyloxy')-2- methylheptanamide (compound 1070).
Figure imgf000134_0001
General procedure 4. Starting materials: compound 10 and O- cyclohexylhydroxylamine. 1H-NMR (CD3OD): δ 8.39 (d, 2H), 7.34 (d, 2H), 3.82-3.74 (m, IH), 3.39 (t, 2H), 2.25-2.15 (m, IH), 1.99-1.24 (m, 18H), 1.13 (d, 3H).
Example 71 : ( RV2-Benzyl-7-( 2-Cvano-3-( pyridin-4-vnquanidinoV/V- Ccvclohexyloxy'JheDtanamide (compound 1071L
Figure imgf000134_0002
General procedure 4. Starting materials: compound 9 and O- cyclohexylhydroxylamine. 1H-NMR (CD3OD): δ 8.39 (d, 2H), 7.35-7.17 (m, 7H), 3.48-3.37 (m, 3H), 2.81-2.78 (m, 2H), 2.42-2.32 (m, IH), 1.76-1.05 (m, 18H).
Example 72: 7-f2-Cvano-3-fpyridin-4-y0quanidino')-Λ/-(cvclohexyloxy')-ΛH2-(2-(2- methoxyethoxy'tethoxy'ϊetrivOheptanamide (compound 10721.
Figure imgf000134_0003
General procedure 4. Starting materials: compound 1 and compound 14. 1H-NMR (CD3OD): δ 8.40-8.38 (m, 2H), 7.36 (d, 2H), 3.94-3.80 (m, 4H), 3.67-3.58 (m, 8H), 3.54-3.50 (m, 2H), 3.42-3.35 (m, 5H), 2.49 (t, 2H), 2.00-1.94 (m, 2H), 1.85-1.75 (m, 2H), 1.70-1.59 (m, 5H), 1.48-1.27 (m, 8H).
Example 73:Λ/-Benzyl-7-(2-cvano-3-(pyridin-4-v0quanidino)-Λ/-(2- morpholinoethoxy^heptanamide (compound 1073").
Figure imgf000135_0001
General procedure 4. Starting materials: compound 1 and compound 21. 1H-NMR (CD3OD): δ 8.40-8.37 (m, 2H), 7.38-7.26 (m, 7H), 4.85 (s, 2H), 4.03 (t, 2H), 3.66- 3.63 (m, 4H), 3.39 (t, 2H), 2.61-2.55 (m, 4H), 2.45-2.42 (m, 4H), 1.72-1.60 (m, 4H), 1.46-1.39 (m, 4H).
Example 74: 7-(2-Cvano-3-(pyridin-4-yl)quanidino')-Λ/-(cvclohexyloxy')-Λ/-(3,3- dimethylbutvOheptanamide (compound 1074).
Figure imgf000135_0002
General procedure 4. Starting materials: compound 1 and compound 20. 1H-NMR (CD3OD): δ 8.40 (d, 2H), 8.35 (d, 2H), 3.90-3.82 (m, IH), 3.69-3.59 (m, 3H), 3.41 (t, 2H), 2.47 (t, 2H), 2.02-1.95 (m, 2H), 1.86-1.78 (m, 2H), 1.69-1.31 (m, 15H), 0.95 (s, 9H).
Example 75: 7-(2-Cvano-3-(Dyridin-4-v0quanidino')-/V-(cyclohexyloxyVΛ/-(3- hvdroxvpropvltheptanamide (compound 1075).
Figure imgf000136_0001
General procedure 4. Starting materials: compound 1 and compound 15. 1H-NMR (CD3OD): δ 8.41-8.38 (m, 2H), 7.35 (d, 2H), 3.93-3.85 (m, IH), 3.75 (t, 2H), 3.57 (t, 2H), 3.41 (t, 2H), 2.50 (t, 2H), 2.02-1.95 (m, 2H), 1.88-1.79 (m, 4H), 1.70-1.59 (m, 5H), 1.48-1.30 (m, 9H).
Example 76: 7-f2-Cvano-3-(pyridin-4-v0αuanidino>Λ/-(cvclohexyloxy)-ΛHpyridin-3- ylmethvOheptanamide fcompound 1076").
Figure imgf000136_0002
General procedure 4. Starting materials: compound 1 and compound 16. 1H-NMR (CD3OD): δ 8.50-8.36 (m, 4H), 7.81-7.77 (m, IH), 7.42-7.34 (m, 3H), 4.86 (s, 2H), 4.00-3.93 (m, IH), 3.37-3.30 (m, 3H), 2.56-2.48 (m, 2H), 2.00-1.94 (m, 2H), 1.85- 1.75 (m, 2H), 1.67-1.51 (m, 4H), 1.44-1.24 (m, 9H).
Example 77: 7-f2-Cvano-3-(pyridin-4-vDquanidino)-/\HcvclohexyloxyV/V- isopropylheptanamide fcompound 10771.
Figure imgf000136_0003
General procedure 4. Starting materials: compound 1 and compound 22. 1H-NMR (CD3OD): δ 8.40 (d, 2H), 7.35 (br s, 2H), 4.35-4.26 (m, IH), 3.88-3.80 (m, IH), 3.40 (t, 2H), 2.47 (t, 2H), 2.08-2.02 (m, 2H), 1.87-1.79 (m, 2H), 1.70-1.58 (m, 4H), 1.45-1.28 (m, 16H).
Example 78: 7-(2-Cvano-3-(pyridin-4-vQquanidino')-Λ/-(cvclohexyloxyV/\/-(2- hvdroxyethvπheptanamide (compound 1078).
Figure imgf000137_0001
General procedure 4. Starting materials: compound 1 and compound 17. 1H-NMR (CD3OD): δ 8.39 (d, 2H), 7.35 (br s, 2H), 3.94-3.88 (m, IH), 3.79-3.72 (m, 4H), 3.41 (t, 2H), 2.57-2.50 (m, 2H), 2.43-2.38 (m, 2H), 2.03-1.98 (m, 2H), 1.85-1.79 (m, 2H), 1.70-1.61 (m, 4H), 1.48-1.27 (m, 7H).
Example 79: 7-(2-Cvano-3-(pyridin-4-vQquanidino')-Λ/-(cyclohexyloxyVΛ/-(3- phenylpropyπheptanamide (compound 1079").
Figure imgf000137_0002
General procedure 4. Starting materials: compound 1 and compound 24. 1H-NMR (CD3OD): δ 8.39-8.37 (m, 2H), 7.35-7.14 (m, 7H), 3.85-3.77 (m, IH), 3.67 (t, 2H), 3.39 (t, 2H), 2.61 (t, 2H), 2.54-2.45 (m, 2H), 1.98-1.88 (m, 4H), 1.83-1.74 (m, 2H), 1.70-1.58 (m, 5H), 1.47-1.26 (m, 9H).
Example 80: 7-(2-Cvano-3-(pyridin-4-vπquanidinoVΛ/-(cvclohexyloxy)-/V- phenvlethvlheptanamide (compound 1080).
Figure imgf000138_0001
General procedure 4. Starting materials: compound 1 and compound 23. 1H-NMR (CD3OD): δ 8.39 (d, 2H), 7.35-7.17 (m, 7H), 3.91-3.77 (m, 3H), 3.39 (t, 2H), 2.93- 2.88 (m, 2H), 2.46-2.38 (m, IH), 1.97-1.93 (m, 2H), 1.83-1.76 (m, 2H), 1.67-1.19 (m, 15H).
Example 81: /V-Butyl-7-f2-cvano-3-fpyridin-4-yQquanidino')-/\/- fcvclohexyloxy'lheptanamide (compound 1081).
Figure imgf000138_0002
General procedure 4. Starting materials: compound 1 and compound 25. 1H-NMR (CD3OD): δ 8.40-8.38 (m, 2H), 7.35 (d, 2H), 3.91-3.82 (m, IH), 3.66 (t, 2H), 3.41 (t, 2H), 2.49 (t, 2H), 2.03-1.92 (m, 2H), 1.87-1.77 (m, 2H), 1.65-1.55 (m, 7H), 1.43-1.19 (m, HH), 0.94 (t, 3H).
Example 82: 7-f2-Cvano-3-fpyridin-4-v0αuanidino)-Λ/-(cvclohexyloxy')-Λ/- (naphtalen-2-ylmethyl)heptanamide (compound 1082").
Figure imgf000138_0003
General procedure 4. Starting materials: compound 1 and compound 27. 1H-NMR (CD3OD): δ 8.36 (d, 2H), 7.85-7.77 (m, 4H), 7.51-7.41 (m, 3H), 7.33 (br s, 2H), 4.99 (s, 2H), 4.02-3.93 (m, IH), 3.29 (t, 2H), 2.55 (t, 2H), 2.03-1.95 (m, 2H), 1.81-1.74 (m, 2H), 1.66-1.50 (m, 5H), 1.45-1.19 (m, 9H).
Example 83 : 7-f 2-Cyano-3-(pyridin-4-yl1quanidino1-Λ/-( cvclohexyloxy1-/V- ethvlheptanamide (compound 10831.
Figure imgf000139_0001
General procedure 4. Starting materials: compound 1 and compound 26. 1H-NMR (CD3OD): δ 8.40-8.38 (m, 2H), 7.35 (d, 2H), 3.89-3.83 (m, IH), 3.68 (q, 2H), 3.41 (t, 2H), 2.48 (t, 2H), 2.02-1.95 (m, 2H), 1.87-1.76 (m, 2H), 1.72-1.56 (m, 4H), 1.49-1.13 (m, 13H).
Example 84: 7-(2-Cvano-3-(pyridin-4-yl1quanidino1-/V-(cvclohexyloxy1-/V-(pyridin-2- ylmethvπheptanamide (compound 10841.
Figure imgf000139_0002
General procedure 4. Starting materials: compound 1 and compound 29. 1H-NMR (CD3OD): δ 8.50-8.48 (m, IH), 8.39-8.37 (m, 2H), 7.84-7.78 (m, IH), 7.36-7.30 (m, 4H), 4.97 (s, 2H), 3.97-3.89 (m, IH), 3.40 (t, 2H), 2.61 (t, 2H), 1.97-1.19 (m, 18H).
Example 85: 7-(2-Cvano-3-(pyridin-4-yl1αuanidino1-/V-cyclohexyl-Λ/-(2- morpholinoethoxviheptanamide (compound 10851.
Figure imgf000140_0001
General procedure 5. Starting materials: compound 1 and compound 30. 1H-NMR (CD3OD): δ 8.41 -8.39 (m, 2H), 7.35 (br s, 2H), 4.08 (t, 2H), 3.73-3.70 (m, 4H), 3.41 (t, 2H), 2.68 (t, 2H), 2.58-2.49 (m, 6H), 1.88-1.15 (m, 19H).
Example 86: Λ/-Benzyl-6-("2-cvano-3-(pyridin-4-vπquanidinoVΛ/-f2- morpholinoethoxy'lhexane-l-sulfonamide (compound 1086").
Figure imgf000140_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 47. 1H-NMR (CD3OD): δ 8.41-8.38 (m, 2H), 7.49- 7.34 (m, 7H), 4.40 (s, 2H), 3.81 (t, 2H), 3.61-3.58 (m, 4H), 3.43 (t, 2H), 3.31-3.26 (m, 2H), 2.35 (t, 2H), 2.28-2.25 (m, 4H), 2.00-1.89 (m, 2H), 1.74-1.42 (m, 6H).
Example 87: 7-f2-Cvano-3-(pyridin-4-yl)quanidino')-Λ/-(cvclohexyloxy')-Λ/-f2- morpholinoethvπheptanamide (compound 10871.
Figure imgf000140_0003
General procedure 4. Starting materials: compound 1 and compound 18. 1H-NMR (CD3OD): δ 8.39 (d, 2H9, 7.35 (d, 2H), 3.93-3.77 (m, 3H), 3.67-3.64 (m, 4H), 3.41 (t, 2H), 2.60-2.50 (m, 8H), 2.02-1.96 (m, 2H), 1.86-1.79 (m, 2H), 1.72-1.59 (m, 5H), 1.50-1.24 (m, 9H).
Example 88: 7-f2-Cvano-3-(pyridin-4-v0quanidinoVΛ/-(rcvclohexyloxyVΛ/- fnaphtalen-l-ylmethvDheptanamide (compound 1088").
Figure imgf000141_0001
General procedure 4. Starting materials: compound 1 and compound 28. 1H-NMR (CD3OD): δ 3.37 (d, 2H), 8.14-8.10 (m, IH), 7.92-7.83 (m, 2H), 7.57-7.42 (m, 4H), 7.35-7.31 (m, 2H), 5.34 (s, 2H), 3.90-3.81 (m, IH), 2.57 (t, 2H), 1.93-1.15 (m, 20H).
Example 89: Λ/-Benzyl-6-f2-cvano-3-fpyridin-4-vπquanidino1-/V- (cvclohexylmethoxy^hexane-1-sulfonamide (compound 10891.
Figure imgf000141_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 48. 1H-NMR (CD3OD): δ 8.40-8.38 (m, 2H), 7.46- 7.34 (m, 7H), 4.37 (s, 2H), 3.45-3.40 (m, 4H), 3.24-3.19 (m, 2H), 1.99-1.89 (m, 2H), 1.74-1.09 (m, 15H), 0.83-0.71 (m, 2H). Example 90: 2-Cvano-l-(7-morpholino-7-oxoheptvO-3-(pyridin-4-vπαuanidine (compound 10901.
Figure imgf000142_0001
General procedure 4. Starting materials: compound 1 and tetrahydro-l,2-oxazin-2- ium chloride (J.Chem.Soc, Pekin Trans 2 (2000), 1435-144). 1H-NMR (CD3OD): δ 8.39 (d, 2H), 7.36 (br s, 2H), 4.01 (t, 2H), 3.75 (t, 2H), 3.41 (t, 2H), 2.46 (t, 2H), 1.88-1.81 (m, 2H), 1.76-1.60 (m, 6H), 1.48-1.39 (m, 4H).
Example 91 : 7-( 2-Cyano-3-( pyridin^-vOguanidinoV/V-f cvclohexyloxy")-/V- octylheptanamide (compound 1091).
Figure imgf000142_0002
General procedure 4. Starting materials: compound 1 and compound 31. 1H-NMR (CD3OD): δ 8.40-8.38 (m, 2H), 7.35 (br s, 2H), 3.91-3.82 (m, IH), 3.65 (t, 2H), 3.41 (t, 2H), 2.49 (t, 2H), 2.02-1.94 (m, 2H), 1.87-1.77 (m, 2H), 1.72-1.56 (m, 7H), 1.43-1.31 (m, 19H), 0.93-0.89 (m, 3H).
Example 92: Λ/-(3-aminopropyπ-7-(2-cvano-3-(pyridin-4-vπαuanidinoVΛ/- (cvclohexyloxylheptanamide (compound 1092).
Figure imgf000143_0001
Compound 1075 (0.20 mmol) was dissolved in DCM (5 ml_), triethylamine (0.22 mmol) was added, the mixture was cooled on an ice bath, methansulfonyl chloride (0.21 mmol) was added with stirring and the mixture gradually allowed to reach it and stirred overnight, concentrated, re-dissolved in DMF (1 mL), sodium azide (2.0 mmol) was added, and the mixture stirred at rt for 3 days, concentrated and the residue purified by chromatography (chloroform: methanol: NH3 (25% aq.) 95:5:0.5) to afford the azide. The azide (0.11 mmol) was dissolved in THF (2 mL), H2O (0.5 mL), the reaction vessel was evacuated and filled with N2, triphenylphosphine (0.15 mmol) was added and the mixture was stirred for 7 h, concentrated and the residue purified by chromatography (chloroform: methanol: NH3 (25% aq.) 95:5:0.5) to afford compound 1092. 1H-NMR (CD3OD): δ 8.40 (d, 2H), 7.35 (br s, 2H), 3.58-3.51 (m, IH), 3.42-3.35 (m, 4H), 3.25 (t, 2H), 2.88 (t, 2H), 2.21 (t, 2H), 1.97-1.88 (m, 2H), 1.77-1.24 (m, 16H).
Example 93 : /V-f 3-Acetamidopropyn-7-f 2-cvano-3-f pyridin^-yliquanidinoV/V- (cvclohexyloxyiheptanamide (compound 1093").
Figure imgf000143_0002
Compound 1092 (0.03 mmol) was dissolved in pyridine (1 ml) and acetic acid anhydride (0.033 mmol) was added with stirring and the reaction mixture was stirred at rt overnight, concentrated twice with toluene and the residue purified by chromatography (chloroform:methanol:NH3 (25% aq.) 95:5:0.5) to afford compound 1093. 1H-NMR (CD3OD): δ 8.41-8.37 (m, 2H), 7.35-7.30 (m, 2H), 3.96- 3.85 (m, IH), 3.69 (t, 2H), 3.40 (t, 2H), 3.19 (t, 2H), 2.21 (t, 2H), 2.13 (s, 3H), 2.30-1.95 (m, 2H), 1.88-1.75 (m, 4H), 1.71-1.58 (m, 5H), 1.49-1.20 (m, 9H).
Example 94: 2-Cvano-l-(7-(isoxazolidin-2-yn-7-oxohepty0-3-(pyridin-4- vQquanidine (compound 1094).
Figure imgf000144_0001
General procedure 4. Starting materials: compound 1 and isoxazolidinium chloride (J.Chem.Soc, Pekin Trans 2 (2000), 1435-144). 1H-NMR (CD3OD): δ 8.41-8.38 (m, 2H), 7.36-7.34 (m, 2H), 4.03 (t, 2H), 3.72-3.65 (m, 2H), 3.40 (t, 2H), 2.49-2.31 (m, 4H), 1.68-1.61 (m, 4H), 1.45-1.40 (m, 4H).
Example 95: 2-Cvano-l-(6-(morpholinosulfonvπhexy0-3-(pyridin-4-v0quanidine (compound 1095).
Figure imgf000144_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea and compound 50. 1H-NMR (CD3OD): δ 8.38 (d, 2H), 7.33 (d, 2H), 4.09 (t, 2H), 3.42-3.33 (m, 4H), 3.23-3.18 (M, 2H), 1.91-1.80 (m, 4H), 1.74- 1.61 (m, 4H), 1.56-1.40 (m, 4H).
Example 96:2-Cvano-l-(6-(isoxazolidin-2-ylsulfOnv0hexyπ-3-(pyridin-4- vπαuanidine (compound 1096).
Figure imgf000144_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 51. 1H-NMR (CD3OD): δ 8.40 (d, 2H), 7.35 (s, 2H), 4.15 (t, 2H), 3.65-3.61 (m, 2H), 3.41 (t, 2H), 3.34-3.28 (m, 2H), 2.40-2.30 (m, 2H), 1.93-1.82 (m, 2H), 1.72-1.62 (m, 2H), 1.58-1.41 (m, 4H).
Example 97: 6-f2-Cyano-3-pyridin-4-yπαuanidino')-/\/-cvclohexyl-ΛH2- morpholinoethoxyihexane-l-sulfonamide (compound 10971.
Figure imgf000145_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea and compound 49. 1H-NMR (CD3OD): δ 8.41-8.38 (m, 2H), 7.35- 7.33 (m, 2H), 4.18-4.14 (m, 2H), 3.72-3.69 (m, 4H), 3.64-3.54 (m, IH), 3.42 (t,
2H), 3.24 (br s, 2H), 2.65 (t, 2H), 2.56-2.53 (m, 4H), 1.98-1.82 (m, 6H), 1.70-1.14 (m, 14H).
Example 98: 7-(2-cvano-3-fpyridin-4-v0αuanidino')-Λ/-(cyclohexyloxy1-Λπ2-f2-(2- hvdroxyethoxyiethoxyiethvOheptanamide (compound 10981.
Figure imgf000145_0002
General procedure 4. Starting materials: compound 1 and compound 19. 1H-NMR (CD3OD): δ 8.41-8.39 (m, 2H), 7.38-7.34 (m, 2H), 3.94-3.82 (m, 2H), 3.70-3.54 (m, 8H), 3.43-3.37 (m, 3H), 2.51 (t, 2H), 2.01-1.95 (m, 2H), 1.84-1.78 (m, 2H), 1.69-1.59 (m, 6H), 1.45-1.23 (m, 10H).
Example 99: 7-(2-Cvano-3-(pyridin-4-v0quanidinoV/V-(l-methylpiperidin-4-yl)-/V- (2-morpholinoethoxy')heptanamide (compound 1099).
Figure imgf000146_0001
General procedure 5. Starting materials: compound 1 and compound 32. 1H-NMR (CD3OD): δ 8.41-8.38 (m, 2H), 7.35-7.33 (m, 2H), 4.09 (t, 2H), 3.73-3.70 (m, 4H), 3.41 (t, 2H), 2.99-2.94 (m, 2H), 2.69 (t, 2H), 2.57-2.51 (m, 6H), 2.29 (s, 4H), 2.15-1.97 (m, 4H), 1.79-1.62 (m, 6H), 1.47-1.41 (m, 4H).
Example 100: 7-(2-Cvano-3-(pyridin-4-v0quanidino')-/V-(2-morpholinoethoxy')-/V- (tetrahvdro-2/-/-Pyran-4-vπheptanamide (compound 11001.
Figure imgf000146_0002
General procedure 4. Starting materials: compound 1 and compound 33. 1H-NMR (CD3OD): δ 8.41-8.39 (m, 2H), 7.36-7.34 (m, 2H), 4.39 (br s, IH), 4.10 (t, 2H), 4.04-4.98 (m, 2H), 3.74-3.71 (m, 4H), 3.51-3.37 (m, 4H), 2.69 (t, 2H), 2.58-2.52 (m, 6H), 2.09-1.93 (m, 2H), 1.73-1.63 (m, 6H), 1.46-1.41 (m, 4H).
Example 101 : 6-(2-Cyano-3-f pyridin-4-v0αuanidino)-Λ/-(2-morpholinoethv0rιexane- 1-sulfonamide (compound 1101").
Figure imgf000147_0001
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea and compound 52. 1H-NMR (CD3OD): δ 8.29-8.27 (m, 2H), 7.23- 7.21 (m, 2H), 3.61-3.57 (m, 4H), 3.30 (t, 2H), 3.09 (t, 2H), 3.03-2.98 (m, 2H), 2.43-2.38 (m, 6H), 1.76-1.66 (m, 2H), 1.61-1.52 (m, 2H), 1.47-1.30 (m, 4H).
Example 102: 6-r2-Cvano-3-fpyridin-4-vπαuanidino')-/V-cvcloheptylhexane-l- sulfonamide ("compound 11021.
Figure imgf000147_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea and compound 53. 1H-NMR (CD3OD): δ 8.40-8.38 (m, 2H), 7.36- 7.34 (m, 2H), 3.44-3.37 (m, 4H), 3.06-3.01 (m, 2H), 2.02-1.94 (m, 2H), 1.86-1.76 (m, 2H), 1.72-1.44 (m, 15H).
Example 103: 6-r2-Cvano-3-fpyridin-4-vπquanidino')-Λ/-f3- morpholinopropyOhexane-1-sulfonamide ("compound 11031.
Figure imgf000147_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea and compound 54. 1H-NMR (CD3OD): δ 8.41-8.39 (m, 2H), 7.35- 7.33 (m, 2H), 3.72-3.69 (m, 4H), 3.42 (t, 2H), 3.14-3.04 (m, 4H), 2.50-2.44 (m, 6H), 1.86-1.63 (m, 6H), 1.58-1.42 (m, 4H). Example 104: Λ/-f2-f2-f2-Aminoethoxy')ethoxy)ethvπ-7-f2-cvano-3-fPyridin-4- vQquanidino')-/\Hcvclohexyloxy)heptanamide (compound 1104).
Figure imgf000148_0001
Compound 1098 (0.20 mmol) was dissolved in DCM (5 ml_), triethylamine (0.22 mmol) was added, the mixture was cooled on an ice bath, methansulfonyl chloride (0.21 mmol) was added with stirring and the mixture gradually allowed to reach rt and stirred overnight, concentrated, re-dissolved in DMF (1 ml_), sodium azide (2.0 mmol) was added, and the mixture stirred at rt for 3 days, concentrated and the residue purified by chromatography (chloroform:methanol:NH3 (25% aq.) 95:5:0.5) to afford the azide. The azide (0.11 mmol) was dissolved in THF (2 ml_), H2O (0.5 mL), the reaction vessel was evacuated and filled with N2, triphenylphosphine (0.15 mmol) was added and the mixture was stirred for 7 h, concentrated and the residue purified by chromatography (chloroform: methanol: NH3 (25% aq.) 95:5:0.5) to afford compound 1104. 1H-NMR (CD3OD): δ 8.40-8-38 (m, 2H), 7.35-7.33 (m, 2H), 3.94-3.82 (m, 3H), 3.68 (t, 2H), 3.62-3.59 (m, 4H), 3.52 (t, 2H), 3.41 (t, 2H), 2.81 (t, 2H), 2.51 (t, 2H), 2.02-1.96 (m, 2H), 1.85-1.78 (m, 2H), 1.70-1.58 (m, 4H), 1.46-1.29 (m, 10H).
Example 105: /V-f2-(2-f2-acetamidoethoxy')ethoxy')ethy0-7-('2-cvano-3-fpyridin-4- yl')quanidino'>-/V-fcvclohexyloxy)heptanamide fcompound HOST.
Figure imgf000149_0001
Compound 1104 (0.03 mmol) was dissolved in pyridine (1 ml) and acetic acid anhydride (0.033 mmol) was added with stirring and the reaction mixture was stirred at rt overnight, concentrated twice with toluene and the residue purified by chromatography (chloroform: methanol: NH3 (25% aq.) 95:5:0.5) to afford compound 1105. 1H-NMR (CD3OD): δ 8.40-8.39 (m, 2H), 7.37-7.34 (m, 2H), 3.92- 3.81 (m, 3H), 3.68 (t, 2H), 3.62-3.51 (m, 6H), 3.41 (t, 2H), 2.51 (t, 2H), 2.02-1.93 (m, 4H), 1.85-1.78 (m, 2H), 1.69-1.57 (m, 4H), 1.45-1.21 (m, 13 H).
Example 106: 6-f2-Cvano-3-fpyridin-4-yπquanidinoVΛ/-f2-cvclohexylethyπhexane- 1-sulfonamide (compound 1106).
Figure imgf000149_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg.Med.Chem.Lett. (1997) 7 (24), 3095-3100) and compound 55. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.42 (t, 2H), 3.06 (m, 4H), 1.9-1.1 (m, 19H), 0.94 (m, 2H).
Example 107: 6-(2-Cvano-3-rpyridin-4-vπαuanidino")-Λ/-f2-cvclohexylethoxy')-Λ/-f2- (2-(2-methoxyethoxy')ethoxy')ethv0hexane-l-sulfonamide (compound 1107).
Figure imgf000150_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 56. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.35 (m, 2H), 4.09 (t, 2H), 3.73 (t, 2H), 3.65 (m, 6H), 3.56 (m, 2H), 3.44 (m, 4H), 3.36 (s, 3H), 3.21 (m, 2H), 1.76 (m, 2H), 1.7-1.0 (m, 17H), 0.81 (m, 2H).
Example 108: 6-(3-(2-chloropyridin-4-y0-2-cyanoquanidinoVΛ/-(2- cvclohexylmethoxy)-hexane-l-sulfonamide (compound 11081.
Figure imgf000150_0002
General procedure 10. Starting materials: compound 6 and compound 39. 1H-NMR (CD3OD): δ 8.21 (dd, IH), 7.41 bs, IH), 7.29 (bs, IH), 3.75 (d, 2H), 3.42 (t, 2H), 3.20 (m, 2H), 1.9-1.15 (m, 17H), 1.00 (m, 2H).
Example 109: 7-(3-(2-chloropyridin-4-y0-2-cvanoquanidinoVΛ/-cvclohexyl-Λ/-(2- morpholinoethoxyiheptanamide (compound 1109\
Figure imgf000151_0001
General procedure 10. Starting materials: compound 6 and compound 58. 1H-NMR (CD3OD): δ 8.20 (dd, IH), 7.40 bs, IH), 7.29 (bs, IH), 4.09 (m, 3H), 3.70 (m, 4H), 3.4 (t, 2H), 2.66 (t, 2H), 2.55 (m, 4H), 2.40 (m, 2H), 1.8-1.15 (m, 18H).
Example 110: 6-r2-cvano-3-rpyridin-4-vπαuanidino')-Λ/-f2-cvclohexylethoxy')-Λ/-f2- morpholinoethvπhexane-1-sulfonamide (compound lllO').
Figure imgf000151_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 59. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.34 (m, 2H), 4.12 (t, 2H), 3.72 (m, 4H), 3.42 (m, 4H), 3.21 (m, 2H), 2.68 (d, 2H), 2.54 (m, 4H), 1.91 (m, 2H), 1.8-1.1 (m, 17H), 0.95 (m, 2H).
Example 111: 7-f2-cvano-3-(2,6-dichloropyridin-4-vπαuanidinoVΛ/-cyclohexyl-/\/-f2- morpholinoethoxyiheptanamide fcompound 1111).
Figure imgf000151_0003
General procedure 10. Starting materials: compound 60 and compound 58. 1H-NMR (CD3OD): δ 7.36 (bs, 2H), 4.11 (m, 3H), 3.72 (m, 4H), 3.42 (t, 2H), 2.69 (t, 2H), 2.58 (m, 4H), 2.51 (m, 2H), 1.9-1.1 (m, 18H).
Example 112: Λ/-benzyl-6-f2-cvano-3-fpyridin-4-vπquanidino')-Λ/-(2- cvclohexylethoxy^hexane-l-sulfonamide (compound 1112^.
Figure imgf000152_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 61. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.50-7.32 (m, 7H), 4.36 (s, 2H), 3.66 (t, 2H), 3.43 (t, 2H), 3.23 (m, 2H), 1.94 (m, 2H), 1.75-1.06 (m, 17H), 0.71 (m, 2H).
Example 113: 6-r2-cyano-3-fpyridin-4-vπquanidino')-Λ/-('2-cvclohexylethoxy')-Λ/- methylhexane-1-sulfonamide (compound 1113).
Figure imgf000152_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 62. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 7H), 4.01 (t, 2H), 3.42 (t, 2H), 3.18 (m, 2H), 3.02 (s, 3H), 1.90 (m, 2H), 1.55-1.15 (m, 17H), 0.95 (m, 2H).
Example 114: 6-(2-cyano-3-f2.6-dichloropyridin-4-v0quanidinoV/V-f2- cyclohexylmethoxyihexane-l-sulfonamide (compound 1114).
Figure imgf000153_0001
General procedure 10. Starting materials: compound 60 and compound 39. MS [M+H]+= 505.2, [M-H]-= 503.4.
Example 115: 6-("2-cvano-3-fpyridin-4-vπαuanidinoVΛ/-rcvclohexylmethoxy)-Λ/-f2- f2-(2-methoxyethoxy')ethoxy)ethv0hexane-l-sulfonamide (compound Ills').
Figure imgf000153_0002
General procedure 10. Starting materials: S-methyl N-cyano-N '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 63. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.87 (d, 2H), 3.73 (m, 2H), 3.66 (m, 6H), 3.55 (m, 2H), 3.43 (m, 4H), 3.38 (s, 3H), 3.19 (m, 2H), 1.90 (m, 2H), 1.85-1.15 (m, 15H), 1.03 (m, 2H).
Example 116: Λ/-benzyl-8-(2-cvano-3-(pyridin-4-yπquanidinoVΛ/-(2- morpholinoethoxyVoctanamide (compound 1116^.
Figure imgf000153_0003
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 65. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.33 (m, 7H), 4.86 (s, 2H), 4.03 (t, 2H), 3.65 (m, 4H), 3.39 (t, 2H), 2.58 (m, 4H), 2.44 (m, 4H), 1.65 (m, 4H), 1.39 (m, 6H).
Example 117: Λ/-benzyl-6-f2-cyano-3-fpyridin-4-vnquanidino)-Λ/-f2- morpholinoethoxy)-hexanamide fcompound 11171.
Figure imgf000154_0001
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 67. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.33 (m, 7H), 4.86 (s, 2H), 4.04 (t, 2H), 3.65 (m, 4H), 3.40 (t, 2H), 2.61 (m, 4H), 2.45 (m, 4H), 1.69 (m, 4H), 1.44 (m, 2H).
Example 118: 6-(2-cvano-3-(pyridin-4-y0quanidinoVΛ/-cvcloheptyl-Λ/-methylhexan- 1-sulfonamide fcompound Ills').
Figure imgf000154_0002
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 68. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.81 (m, IH), 3.41 (t, 2H), 3.01 (m, 2H), 2.79 (s, 3H), 1.9-1.3 (m, 20H).
Example 119: 6-f2-cvano-3-(pyridin-4-v0quanidinoVΛ/-f3-morpholinopropy0-Λ/- fpyridin-3-ylmethyl)hexan-l-sulfonamide fcompound 11191.
Figure imgf000155_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 69. 1H-NMR (CD3OD): δ 8.61 (m, IH), 8.51 (dd IH), 8.39 (m, 2H), 7.96 (dt, IH), 7.48 (m, IH), 7.34 (m, 2H), 4.50 (s, 2H), 3.64 (m, 4H), 3.42 (t, 2H), 3.31 (m, 2H), 3.15 (m, 2H), 2.32 (m, 4H), 2.26 (t, 2H), 1.86 (m, 2H), 1.75-1.35 (m, 8H).
Example 120: 6-f2-cvano-3-fpyridin-4-v0quanidinoVΛ/-f2-morpholinoethy0-/V-f3- morpholinopropyπhexan-1-sulfonamide fcompound 11201.
Figure imgf000155_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 70. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.70 (m, 8H), 3.41 (q, 4H), 3.31 (m, 2H), 3.18 (m, 2H), 2.58 (t, 2H), 2.52 (m, 8H), 2.43 (t, 2H), 1.84 (m, 4H), 1.68 (m, 2H), 1.50 (m, 4H).
Example 121 : 6-f 2-cvano-3-fpyridin-4-vπαuanidino)-ΛK cvclohexylmethoxyV/V-f 2- morpholinoethvπhexan-1-sulfonamide fcompound 11211.
Figure imgf000156_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 71. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.90 (d, 2H), 3.72 (m, 4H), 3.42 (t, 4H), 3.21 (t, 2H), 2.68 (m, 2H), 2.58 (t, 2H), 2.54 (m, 4H), 1.91 (m, 2H), 1.85-0.95 (m, 17H).
Example 122: 7-(2-cyano-3-(pyridin-3-vnquanidino")-Λ/-cvclohexyl-Λ/-(2- morpholinoethoxy'ϊheptanamide (compound 11221.
Figure imgf000156_0002
General procedure 10. Starting materials: compound 72 and compound 58. 1H-NMR (CD3OD): δ 8.50 (d, IH), 8.38 (dd, IH), 7.81 (m, IH), 7.46 (m, IH), 4.09 (m, 3H), 3.72 (m, 4H), 3.34 (m, 2H), 2.68 (t, 2H), 2.56 (m, 4H), 2.51 (m, 2H), 1.9-1.05 (m, 18H).
Example 123: 6-r2-cvano-3-rpyridin-3-vπαuanidinoVΛ/-fcyclohexylmethoxy')hexane- 1-sulfonamide (compound 1123").
Figure imgf000156_0003
General procedure 10. Starting materials: compound 72 and compound 39. 1H-NMR (CD3OD): δ 8.50 (d, IH), 8.38 (dd, IH), 7.81 (m, IH), 7.46 (m, IH), 3.75 (d, 2H), 3.35 (m, 2H), 3.20 (m, 2H), 1.9-1.15 (m, 17H), 1.00 (m, 2H).
Example 124: 6-f2-cvano-3-(pyridin-4-v0αuanidino')-/V-cvcloheptyl-/V-f2- morpholinoethvπ hexane-1-sulfonamide (compound 1124").
Figure imgf000157_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea {Bioorg.Med.Chem.Lett. (1997) 7 (24), 3095-3100) and compound 73. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.68 (m, 5H), 3.42 (t, 2H), 3.34 (m, 2H), 3.10 (m, 2H), 2.59 (t, 2H), 2.52 (m, 4H), 2.0-1.3 (m, 21H).
Example 125: 6-f2-cvano-3-(pyridin-4-yπquanidinoVΛ/-methyl-ΛH2- morpholinoethoxy) hexane-1-sulfonamide fcompound 1125).
Figure imgf000157_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg.Med.Chem.Lett. (1997) 7 (24), 3095-3100) and compound 74. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.34 (m, 2H), 4.14 (t, 2H), 3.71 (m, 4H), 3.42 (t, 2H), 3.22 (m, 2H), 3.06 (s, 3H), 2.65 (t, 2H), 2.53 (m, 4H), 1.90 (m, 2H), 1.68 (m, 2H), 1.57 (m, 2H), 1.48 (m, 2H). Example 126: 2-cvano-l-(6-fmorpholinosulfonyπhexyO-3-(pyridin-4-vQquanidine (compound 1126").
Figure imgf000158_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 75. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.73 (m, 4H), 3.41 (t, 2H), 3.25 (m, 4H), 3.05 (m, 2H), 1.83 (m, 2H), 1.67 (m, 2H), 1.6-1.4 (m, 4H).
Example 127: l-(6-(azapan-l-ylsulfonvπhexyπ-2-cvano-3-(pyridin-4-yl)quanidine (compound 1127^.
Figure imgf000158_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett (1997) 7 (24), 3095-3100) and compound 76. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.41 (t, 2H), 3.35 (m, 4H), 3.05 (m, 2H), 1.85-1.6 (m, 12H), 1.47 (m, 4H).
Example 128: 6-(2-cvano-3-(pyridin-4-yπquanidino')-Λ/-(2-morpholinoethoxyVΛ/- (pyridin-3-ylmethvπhexane-l-sulfonamide (compound 1128").
Figure imgf000158_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 77. 1H-NMR (CD3OD): δ 8.63 (d, IH), 8.56 (dd, IH), 8.40 (m, 2H), 8.00 (m, IH), 7.52 (m, IH), 7.34 (m, 2H), 4.49 (s, 2H), 3.83 (m, 2H), 3.62 (m, 4H), 3.43 (t, 2H), 3.34 (m, 2H), 2.38 (t, 2H), 2.31 (m, 4H) 1.96 (m, 2H), 1.75-1.40 (m, 6H).
Example 129:6-(2-cvano-3-(2-fluoropyridin-4-yl1quanidino1-/V- fcvclohexvlmethoxvihexane-1-sulfonamide (compound 11291.
Figure imgf000159_0001
General procedure 10. Starting materials: compound 78 and compound 39. 1H-NMR (CD3OD): δ 8.06 (m, IH), 7.20 (m, IH), 7.02 (bs, IH), 3.75 (d, 2H), 3.43 (t, 2H), 3.20 (m, 2H), 1.9-1.15 (m, 17H), 1.00 (m, 2H).
Example 130:7-f2-cyano-3-(2-fluoropyridin-4-yπquanidinoVΛ/-cyclohexyl-/V-(2- morpholinethoxy)heptanamide (compound 11301.
Figure imgf000159_0002
General procedure 10. Starting materials: compound 78 and compound 58. 1H-NMR (CD3OD): δ 8.06 (m, IH), 7.20 (m, IH), 7.02 (bs, IH), 4.09 (m, 3H), 3.72 (m, 4H), 3.42 (m, 2H), 2.68 (t, 2H), 2.56 (m, 4H), 2.51 (m, 2H), 1.9-1.1 (m, 18H).
Example 131 :6-(2-cvano-3-(pyridin-4-yl1quanidino1-/V-(2-morpholinoethoxy1-/V-f2- morpholinethvDhexan-1-sulfonamide ("compound 11311.
Figure imgf000160_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 79. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 4.24 (t, 2H), 3.71 (m, 8H), 3.42 (m, 4H), 3.27 (m, 2H), 2.71 (t, 2H), 2.65 (t, 2H), 2.54 (m, 8H) 1.91 (m, 2H), 1.68 (m, 2H), 1.56 (m, 2H), 1.47 (m, 2H).
Example 132: 2-cvano-l-fpyridin-4-vO-3-f6-pyrrolidine-l- ylsulfonvOhexynquanidine (compound 1132^.
Figure imgf000160_0002
General procedure 10. Starting materials: S-methyl N-cyano-N ' -4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 80. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.41 (t, 2H), 3.34 (m, 4H), 3.07 (m, 2H), 1.95 (m, 4H), 1.83 (m, 2H), 1.67 (m, 2H), 1.49 (m, 4H).
Example 133: 2-cyano-l-f6-morpholinosulfonv0hexy0-3-fpyridin-3-v0αuanidine (compound 1133^.
Figure imgf000160_0003
General procedure 10. Starting materials: compound 72 and compound 50. 1H-NMR (CD3OD): δ 8.50 (d, IH), 8.38 (dd, IH), 7.81 (dt, IH), 7.47 (m, IH), 4.11 (m, 2H), 3.33 (m, 4H), 3.22 (m, 2H), 1.88 (m, 4H), 1.72 (m, 2H), 1.65 (m, 2H), 1.54 (m, 2H), 1.44 (m, 2H).
Example 134: 2-cyano-l-("6-piperidin-l-ylsuHOnv0hexy0-3-(pyridin-4-vπαuanidine (compound 1134).
Figure imgf000161_0001
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 81. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.41 (t, 2H), 3.23 (m, 4H), 3.00 (m, 2H), 1.81 (m, 2H), 1.73-1.37 (m, 12H).
Example 135: 6-(2-cyano-3-pyridin-4-vπquanidino')-/\/-fcyclohexylmethoxyVΛ/-(2- fluoroethyl)hexane-l-sulfonamide (compound 1135).
Figure imgf000161_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 82. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.34 (m, 2H), 4.63 (dt, 2H), 3.88 (d, 2H), 3.55 (dt, 2H), 3.42 (t, 2H), 3.21 (t, 2H), 1.91 (m, 2H), 1.8-1.1 (m, 15H), 1.04 (m, 2H).
Example 136: 6-r2-cvano-3-pyridin-3-vπquanidino)-Λ/-(cvclohexylmethoxyVΛ/-C2- f2-(2-methoxvethoxv')ethoxv)ethvDhexane-l-sulfonamide f compound 11361.
Figure imgf000162_0001
General procedure 10. Starting materials: compound 72 and compound 63. 1H-NMR (CD3OD): δ 8.50 (m, IH), 8.38 (m, IH), 7.81 (m, IH), 7.47 (m, IH), 3.87 (d, 2H), 3.73 (m, 2H), 3.66 (m, 6H), 3.55 (m, 2H), 3.44 (m, 2H), 3.37 (s, 3H), 3.35 (m,2H), 3.20 (m, 2H), 1.90 (m, 2H), 1.85-1.15 (m, 15H), 1.05 (m, 2H).
Example 137: 6-f2-cvano-3-f2-fluoropyridin-4-yliQuanidino)-/V- (cvdohexylmethoxyV/V-f2-f2-f2-methoxyethoxy)ethoxy)ethv0hexane-l- sulfonamide (compound 1137).
Figure imgf000162_0002
General procedure 10. Starting materials: compound 78 and compound 63. 1H-NMR (CD3OD): ): δ 8.05 (m, IH), 7.20 (m, IH), 7.02 (bs, IH), 3.87 (d, 2H), 3.73 (m, 2H), 3.66 (m, 6H), 3.55 (m, 2H), 3.44 (m, 4H), 3.38 (s, 3H), 3.20 (m, 2H), 1.90 (m, 2H), 1.85-1.15 (m, 15H), 1.05 (m, 2H).
Example 138: 2-cyano-l-(6-f4-methylpiperazin-l-ylsulfony0hexy0-3-fpyridin-4- vDguanidine (compound 1138).
Figure imgf000163_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 84. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.41 (t, 2H), 3.30 (m, 4H), 3.05 (m, 2H), 2.52 (m, 4H), 2.34 (s, 3H), 1.82 (m, 2H), 1.67 (m, 2H), 1.49 (m, 4H).
Example 139: 4-f2-cvano-3-(6-(N- cvclohexylmethoxy^sulfamovπhexyOαuanidinoipyridin-l-oxide (compound 1139").
Figure imgf000163_0002
Compound 1059 (57 mg, 0.13 mmol) was dissolved in DCM, peracetic acid (39% in acetic acd, 212 μl) was added and the mixture stirred at rt overnight, concentrated to dryness and purified by chromatography (chloroform:methanol:NH3 (25% aq.) 98:2:02 to 90: 10:1) to afford compound 1139. 1H-NMR (CD3OD): δ 8.25 (m, 2H), 7.55 (m, 2H), 3.75 (d, 2H), 3.43 (t, 2H), 3.20 (m, 2H), 1.95-1.1 (m, 17H), 1.01 (m, 2H).
Example 140: 7-f2-cvano-3-fpyridin-4-vπαuanidino")-Λ/-isopropyl-Λ/-(tetrahvdro-2H- Pyran-4-yloxyiheptanamide (compound 1140).
Figure imgf000163_0003
General procedure 4. Starting materials: compound 1 and 85. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.32 (m, IH), 4.09 (m, IH), 4.00 (m, 2H), 3.42 (m, 4H), 2.48 (t, 2H), 2.00 (m, 2H), 1.66 (m, 6H), 1.42 (m, 4H), 1.31 (d, 6H).
Example 141 : 6-f 2-cvano-3-f pyridin^-vOquanidinoVΛHcvclohexylmethoxyVΛH 2- hvdroxyethvπhexane-1-sulfonamide (compound 1141).
Figure imgf000164_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/'-4- pyridylisothiourea (Bioorg. Med, Chem. Lett. (1997) 7 (24), 3095-3100) and compound 86. 1H-NMR (DMSO-Cf6): δ 9.36 (br s, IH), 8.39 (m, 2H), 7.85 (t, IH), 7.21 (m, 2H), 4.85 (t, IH), 3.77 (d, 2H), 3.60 (q, 2H), 3.3-3.1 (m, 6H), 1.85-1.05 (m, 17H), 0.96 (m, 2H).
Example 142: 6-f2-cvano-3-fpyridin-3-yl)quanidino)-Λ/-cvclohexyl-Λ/-(2- morpholinoethoxy^hexane-l-sulfonamide oxalatefcompound 1142").
Figure imgf000164_0002
General procedure 10. Starting materials: compound 72 and compound 49. 1H-NMR 200 MHz (DMSO-de): δ 9.11 (bs, IH), 8.45 (d, IH), 8.33 (dd, IH), 7.66 (m, IH), 7.45 (t, IH), 7.37 (dd, IH), 4.10 (t, 2H), 4.02-3.33 (m, 5H), 3.31-3.13 (m, 4H), 2.98-2.82 (m, 2H), 2.82-2.64 (m, 4H), 1.96-1.65 (m, 6H), 1.65-0.96 (m, 12H).
Example 143: 2-cvano-l-f6-morpholinosulfOnynhexyO-3-(pyridin-3-vπαuanidine oxalate (compound 1143L
Figure imgf000165_0001
General procedure 10. Starting materials: compound 72 and compound 50. 1H-NMR 200 MHz (DMSO-d6): δ 9.07 (s, IH), 8.46 (d, IH), 8.34 (dd, IH), 7.67 (m, IH), 7.44 (t, IH), 7.38 (dd, IH), 4.03 (t, 2H), 3.33-3.13 (m, 6H), 1.89-1.19 (m, 12H).
Example 144: 6-f2-cvano-3-fpyridin-4-vπquanidino')-/\/-πsopropyπ-Λ/-f2- morpholinoethoxy)hexane-l-sulfonamide ("compound 1144).
Figure imgf000165_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 88. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.19 (t, 2H), 3.99 (m, IH), 3.71 (m, 4H), 3.42 (t, 2H), 3.23 (m, 2H), 2.67 (t, 2H), 2.55 (m, 4H), 1.91 (m, 2H), 1.68 (m, 2H), 1.52 (m, 4), 1.30 (d, 6H).
Example 145: Λ/-(benzylcarbamoyπ-6-f2-cvano-3-(rpyridin-4-v0quanidino')hexane-l- sufonamide (compound 1145^.
Figure imgf000165_0003
Compound 90 (35 mg, 0.1 mmol) was suspended in DCM, benzylisocyanate (40 μl, 0.33 mmol) and DMAP (15 mg, 0.12 mmol) were added and the mixture heated at reflux for 7 days, concentrated and purified by chromatography ( gradient of chloroform: methanol: NH3 (25% aq.) 98:2:0.2 to 80:20:1) to afford compound 1145. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.39-7.22 (m, 7H), 4.36 (s, 2H), 3.40 (m, 4H), 1.82 (m, 2H), 1.65 (m, 2H), 1.46 (m, 4H).
Example 146: 6-(2-cyano-3-fpyridin-4-y0quanidinoV/V-cvclohexyl-ΛH3- morpholinopropyπhexane-1-sufonamide (compound 11461.
Figure imgf000166_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 92. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.71 (m, 4H), 3.52 (m, IH), 3.42 (m, 2H), 3.24 (m, 2H), 3.04 (m, 2H), 2.47 (m, 4H), 2.38 (t, 2H), 1.95-1.25 (m, 19H), 1.17 (m, IH).
Example 147: 7-(2-cyano-3-(rpyridin-4-vnαuanidino')-Λ/-cvclohexyl-Λ/-f2- morpholinoethoxy')heptane-l-sufonamide f compound 1147I.
Figure imgf000166_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 93. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.17 (m, 2H), 3.71 (m, 4H), 3.59 (m, IH), 3.41 (t, 2H), 3.23 (bs, 2H), 2.67 (t, 2H), 2.55 (m, 4H), 2.0- 1.25 (m, 19H), 1.20 (m, IH).
Example 148: 5-f2-cvano-3-(pyridin-4-y0quanidino1-Λ/-cvclohexyl-Λ/-f2- morpholinoethoxyipentane-1-sufonamide fcompound 1148").
Figure imgf000167_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 94. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.17 (m, 2H), 3.71 (m, 4H), 3.59 (m, IH), 3.42 (t, 2H), 3.24 (bs, 2H), 2.66 (t, 2H), 2.55 (m, 4H), 2.0- 1.5 (m, 13H), 1.36 (m, 2H), 1.19 (m, IH).
Example 149: 5-f2-cvano-3-fpyridin-4-vQquanidinoV/V- fcvclohexylmethoxyipentane-l-sufonamide (compound 1149").
Figure imgf000167_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 95. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.34 (m, 2H), 3.74 (d, 2H), 3.42 (t, 2H), 3.22 (t, 2H), 2.0-1.45 (m, 14H), 1.28 (m, 2H), 1.00 (m, IH).
Example 150: 7-f2-cvano-3-(pyridin-4-vπαuanidino")-/V- fcvclohexylmethoxylheptane-l-sufonamide (compound 11501.
Figure imgf000167_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 96. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.35 (m, 2H), 3.75 (d, 2H), 3.41 (t, 2H), 3.19 (m, 2H), 1.9-1.1 (m, 19H), 1.00 (m, 2H). Example 151 : 2-cvano-l-(7-(morpholinosulfonv0heptyn-3-(pyridin-4-v0αuanidine (compound 1151").
Figure imgf000168_0001
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 97. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.11 (t, 2H), 3.39 (m, 4H), 3.21 (m, 2H), 1.95-1.3 (m, 14H).
Example 152: 6-f2-cvano-3-fpyridin-4-ylVαuanidinoV/V- (cyclohexylcarbamovOhexane-1-sufonamide (compound 1152^.
Figure imgf000168_0002
Compound 90 (42 mg, 0.13 mmol) and compound 98 (102 mg, 0.39 mmol), were dissolved in DMF, K2CO3 (18 mg, 0.13 mmol) was added and the mixture heated at 7O0C for 2 days, concentrated and purified by chromatography (1-6% methanol in DCM) to afford compound 1152. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.54 (m, IH), 3.41 (m, 4H), 1.95-1.15 (m, 17H), 0.91 (m, IH).
Example 153: 6-(2-cvano-3-(pyridin-4-vπ-αuanidino")-Λ/- fcvcloheptvlcarbamovπhexane-l-sufonamide (compound 1153).
Figure imgf000168_0003
Compound 90 (37 mg, 0.11 mmol) and compound 99 (96 mg, 0.33 mmol), were dissolved in DMF, Cs2CO3 (37 mg, 0.11 mmol) was added and the mixture heated at 7O0C for 2 days, concentrated and purified by chromatography (1-6% methanol in DCM) to afford compound 1153. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.36 (m, 2H), 3.75 (m, IH), 3.41 (m, 4H), 2.0-1.3 (m, 20H).
Example 154: 6-f2-cvano-3-('pyridin-4-vO-αuanidino')-Λ/-isopropyl-Λ/-f3- morpholinopropyπhexane-l-sufonamide (compound 11541.
Figure imgf000169_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett (1997) 7 (24), 3095-3100) and compound 101. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.99 (m, IH), 3.71 (m, 4H), 3.41 (t, IH), 3.22 (m, 2H), 3.04 (m, 2H), 2.48 (m, 4H), 2.39 (t, 2H), 1.82 (m, 4H), 1.67 (m, 2H), 1.49 (m, 4H), 1.26 (d, 6H).
Example 155: 6-f2-cvano-3-fpyridin-4-vO-αuanidino')-/V-cvclopentyl-ΛH3- morpholinopropyOhexane-1-sufonamide (compound 11551.
Figure imgf000169_0002
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-A- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 103. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.07 (m, IH), 3.70 (m, 4H), 3.41 (t, IH), 3.19 (m, 2H), 3.05 (m, 2H), 2.47 (m, 4H), 2.39 (t, 2H), 2.0- 1.35 (m, 18H).
Example 156: 2-cvano-l-f5-(moψholinosulfony0pentvπ-3-fpyridin-4-y0quanidine (compound 1157").
Figure imgf000170_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-/V '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 104. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.11 (t, 2H), 3.39 (m, 4H), 3.24 (m, 2H), 1.89 (m, 4H), 1.70 (m, 4H), 1.56 (m, 2H).
Example 157: Λ/-benzyl-6-f2-cvano-3-(pyridin-4-vπαuanidinoVΛ/-f3- morpholinipropyOhexane-1-sulfonamide (compound 1157").
Figure imgf000170_0002
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 105. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.38 (m, 7H), 4.42 (s, 2H), 3.62 (m, 4H), 3.41 (t, 2H), 3.27 (t, 2H), 3.09 (m, 2H), 2.29 (m, 4H), 2.23 (t, 2H), 1.82 (m, 2H), 1.64 (m, 4H), 1.47 (m, 4H).
Example 158: 6-f2-cvano-3-(pyridin-4-y0quanidinoVΛ/-ethyl-ΛH3- morpholinopropyπhexane-1-sulfonamide (compound 11581.
Figure imgf000170_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 106. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.71 (m, 4H), 3.41 (t, 2H), 3.29 (m, 4H), 3.05 (m, 2H), 2.48 (m, 4H), 2.41 (t, 2H), 1.81 (m, 4H), 1.67 (m, 2H), 1.48 (m, 4H), 1.22 (t, 3H).
Example 159: 6-(2-cvano-3-(pyridin-4-yl1quanidino1-/V-cvclopentyl-Λ/-(2- morpholinoethoxyihexane-1-sulfonamide (compound 11591.
Figure imgf000171_0001
General procedure 10. Starting materials: S-methyl N-cyano-N ' -4- pyridylisothiourea (Bioorg. Med. Chem. Lett (1997) 7 (24), 3095-3100) and compound 108. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.21 (bs, 2H), 4.04 (m, IH), 3.70 (m, 4H), 3.42 (t, 2H), 3.19 (bs 2H), 2.65 (t, 2H), 2.54 (m, 4H), 2.0-1.35 (m, 16H).
Example 160: 6-(2-cvano-3-(pyridin-4-yl1αuanidino1-/\/-cvcloheptyl-Λ/-(3- morpholinopropylihexane-l-sulfonamide ("compound 11601.
Figure imgf000171_0002
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea [Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 110. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.71 (m, 4H), 3.66 (m, IH), 3.41 (t, 2H), 3.23 (t, 2H), 3.02 (m, 2H), 2.47 (m, 4H), 2.38 (t, 2H), 2.0- 1.35 (m, 22H).
Example 161 : 6-f 2-cvano-3-(pyridin-4-yl1quanidino1-Λ/-cvcloheptyl-/V-(2- morpholinoethoxyihexane-1-sulfonamide (compound 11611.
Figure imgf000172_0001
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 112. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.19 (t, 2H), 3.83 (m, IH), 3.71 (m, 4H), 3.42 (t, 2H), 3.21 (bs, 2H), 2.65 (t, 2H), 2.55 (m, 4H), 2.1- 1.3 (m, 20H).
Example 162: 6-f2-cvano-3-fpyridin-4-yπquanidinoVΛ/-cvclobutyl-Λ/-f2- morpholinoethoxyihexane-l-sulfonamide (compound 1162).
Figure imgf000172_0002
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett (1997) 7 (24), 3095-3100) and compound 114. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.20 (m, 3H), 3.71 (m, 4H), 3.40 (m, 2H), 3.08 (bs, 2H), 2.70 (t, 2H), 2.55 (m, 4H), 2.40 (m, 2H), 2.14 (m, 2H), 1.87 (m, 2H), 1.71 (m, 4H), 1.49 (m, 4H).
Example 163 : 6-(2-cvano-3-f pyridin-4-v0quanidinoVΛ/-cyclobutyl-ΛH 3- morpholinopropyπhexane-1-sulfonamide (compound 1163").
Figure imgf000172_0003
General procedure 10. Starting materials: S-methyl N-cyano-N '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 116. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.21 (m, IH), 3.71 (m, 4H), 3.41 (t, 2H), 3.30 (m, 2H), 2.99 (m, 2H), 2.48 (m, 4H), 2.41 (m, 2H), 2.21 (m, 4H), 1.78 (m, 4H), 1.66 (m, 4H), 1.47 (m, 4H).
Example 164: 6-(2-cvano-3-(pyridin-4-y0αuanidino>Λ/-cyclohexyl-ΛH3- fdimethylamino'jpropyπhexane-l-sulfonamide fcompound 11641.
Figure imgf000173_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 118. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.52 (m, IH), 3.41 (t, 2H), 3.21 (m, 2H), 3.04 (m, 2H), 2.35 (m, 2H), 2.26 (s, 6H), 1.80 (m, 8H), 1.75-1.25 (m, HH), 1.18 (m, IH).
Example 165 : 6-f 2-cvano-3-(pyridin-4-v0αuanidino')-Λ/-cvclohexyl-Λ/-(2- morpholinoethvOhexane-l-sulfonamide fcompound 1165).
Figure imgf000173_0002
General procedure 10. Starting materials: S-methyl N-cyano-N ' -4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 120. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.68 (m, 4H), 3.52 (m, 2H), 3.41 (t, 2H), 3.12 (m, 2H), 2.53 (m, 6H), 1.95-1.25 (m, 17H), 1.18 (m, IH). Example 166: 6-f2-cvano-3-fpyridin-4-yl)quanidino')-Λ/-fcvclohexylmethvO-Λ/-f3- morpholinopropyπhexane-1-sulfoπamide fcompound 1166I.
Figure imgf000174_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg.Med.Chem.Lett. (1997) 7 (24), 3095-3100) and compound 121. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.71 (m, 4H), 3.41 (t, 2H), 3.25 (t, 2H), 3.05 (m, 4H), 2.48 (m, 4H), 2.39 (t, 2H), 1.9-1.1 (m, 19H), 0.93 (m, 2H).
Example 167: Ethyl P-6-f2-cyano-3-fpyridin-4-vnquanidino1hexyl-/V- cyclohexylphosphonamidate fcompound 1167).
Figure imgf000174_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 124. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.35 (m, 2H), 4.00 (m, 2H), 3.41 (t, 2H), 2.96 (m, IH), 1.89 (m, 2H), 1.85-1.05 (m, 23H).
Example 168: 2-Cvano-l-f6-ffcydohexylamino')fmethvnphosphory0hexy0-3- fpyridin-4-yl)quanidine') fcompound 1168^.
Figure imgf000174_0003
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 126. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.41 (t, 2H), 2.96 (m, IH), 2.0-0.8 (m, 2H), 1.85-1.05 (m, 23H). MS [M+H]+= 405.3 [M-H]+= 403.3
Example 169: 2-Cvano-l-f6-f3,4-dihydroisoquinolin-2flH)-ylsulfony0hexyn-3- (pyridin-4-vQquanidine (compound 11691.
Figure imgf000175_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 127. 1H-NMR (CD3OD): δ 8.38 (m, 2H), 7.34 (m, 2H), 7.15 (m, 4H), 4.46 (s, 2H), 3.56 (t, 2H), 3.38 (t, 2H), 3.09 (t, 2H), 2.94 (t, 2H), 1.81 (m, 2H), 1.62 (m, 2H), 1.45 (m, 4H).
Example 170: Ethyl 6-f2-cvano-3-(pyridin-4- vOαuanidinoihexylfmorpholinoiphosphinate (compound 11701.
Figure imgf000175_0002
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 128. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.10 (m, 2H), 3.97 (m, 2H), 3.38 (m, 4H), 1.95-1.55 (m, 10H), 1.47 (m, 4H), 1.33 (t, 3H).
Example 171 : 5-f 2-cvano-3-f pyridin-4-vπαuanidino)-Λ/-cvclobutyl-Λ/-f 2- morpholinoethoxyipentane-l-sulfonamide fcompound 1171").
Figure imgf000176_0001
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 129. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.21 (m, 3H), 3.71 (m, 4H), 3.41 (t, 2H), 3.11 (t, 2H), 2.70 (t, 2H), 2.56 (m, 4H), 2.41 (m, 2H), 2.15 (m, 2H), 1.91 (m, 2H), 1.71 (m, 4H), 1.57 (m, 2H).
Example 172: 5-(2-cvano-3-fpyridin-4-yQquanidino')-Λ/-cvclopentyl-ΛH3- morpholinopropyθpentane-1-sulfonamide (compound 11721.
Figure imgf000176_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 130. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.07 (m, IH), 3.70 (m, 4H), 3.41 (t, 2H), 3.18 (m, 2H), 3.07 (m, 2H), 2.47 (m, 4H), 2.39 (t, 2H), 2.06 (m, 2H), 2.0-1.4 (m, 16).
Example 173: l-f6-(r4-acetylpiperazin-l-ylsulfonyπhexyπ-2-cyano-3-fpyridin-4- yHauanidine (compound 11731.
Figure imgf000176_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea {Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 131. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 3.67 (m, 2H), 3.63 (m, 2H), 3.41 (t, 2H), 3.32 (m, 2H), 3.26 (m, 2H), 3.06 (m, 2H), 2.14 (s, 3H), 1.82 (m, 2H), 1.67 (m, 2H), 1.49 (m, 4).
Example 174: 5-(2-cvano-3-(pyridin-4-vQquanidino')-Λ/-cvclopentyl-Λ/-(2- morpholinoethoxyipentane-l-sulfonamide (compound 11741.
Figure imgf000177_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 132. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.21 (bs, 2H), 4.04 (m, IH), 3.71 (m, 4H), 3.42 (t, 2H), 3.22 (bs, 2H), 2.65 (t, 2H), 2.54 (m, 4H), 05-1.5 (m, 14H).
Example 175: 6-(2-cyano-3-(pyridin-4-yl)quanidino')-/\/-phenylhexane-l-sulfOnamide (compound 1175).
Figure imgf000177_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 133. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.4-7.2 (m, 6H), 7.12 (m, IH), 3.36 (t, 2H), 3.09 (m, 2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.40 (m, 4H).
Example 176: Λ/-fbenzyloxyV6-(2-cvano-3-(pyridin-4-yπquanidinoV/V- methvlhexane-1-sulfonamide (compound 11761.
Figure imgf000178_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 134. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.39 (m, 7H), 4.95 (s, 2H), 3.40 (t, 2H), 3.18 (m, 2H), 2.92 (s, 3H), 1.89 (m, 2H), 1.65 (m, 2H), 1.48 (m, 4H).
Example 177: Λ/-("benzyloxyV6-f2-cvano-3-fpyridin-4-vπquanidino')-Λ/-(2- morpholinoethvOhexane-1-sulfonamide (compound 1177).
Figure imgf000178_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 135. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.38 (m, 7H), 5.06 (s, 2H), 3.68 (m, 4H), 3.40 (m, 4H), 3.24 (m, 2H), 2.53 (t, 2H), 2.46 (m, 4H), 1.92 (m, 2H), 1.66 (m, 2H), 1.51 (m, 4H).
Example 178: 5-f2-cvano-3-(pyridin-4-yQquanidino')-/\/-cyclobutyl-/V-f3- morpholinopropyQpentane-1-sulfonamide (compound 11781.
Figure imgf000178_0003
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 136. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.21 (m, IH), 3.71 (m, 4H), 3.41 (t, 2H), 3.30 (m, 2H), 3.01 (m, 2H), 2.48 (m, 4H), 2.41 (t, 2H), 2.21 (m, 4H), 1.81 (m, 4H), 1.68 (m, 4H), 1.55 (m, 2H).
Example 179: 4-(2-cvano-3-(pyridin-4-v0αuanidinoVΛ/-cvclobutyl-Λ/-(3- morpholinopropyObutane-l-sulfonarnide (compound 1179").
Figure imgf000179_0001
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 137. 1H-NMR (CD3OD): δ 8.41 (m, 2H), 7.35 (m, 2H), 4.22 (m, IH), 3.71 (m, 4H), 3.44 (t, 2H), 3.31 (m, 2H), 3.06 (m, 2H), 2.48 (m, 4H), 2.41 (m, 2H), 2.22 (m, 4H), 1.95-1.55 (m, 8H).
Example 180: 4-(2-cyano-3-(pyridin-4-v0αuanidinoV/V-cvclopentyl-Λ/-(3- morpholinopropyObutane-1-sulfonamide (compound 1180).
Figure imgf000179_0002
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett (1997) 7 (24), 3095-3100) and compound 138. 1H-NMR (CD3OD): δ 8.40 (m, 2H), 7.35 (m, 2H), 4.09 (m, IH), 3.70 (m, 4H), 3.45 (t, 2H), 3.19 (m, 2H), 3.12 (m, 2H), 2.47 (m, 4H), 2.38 (m, 2H), 2.0- 1.5 (m, 14H).
Example 181 : /V-(4-chlorophenvn-6-(2-cvano-3-(pyridin-4-vQquanidino')hexane-l- sulfonamide (compound 1181").
General procedure 10. Starting materials: S-methyl Λ/-cyano-Λ/ '-4- pyridylisothiourea (Bioorg.Med.Chem.Lett. (1997) 7 (24), 3095-3100) and compound 139. 1H-NMR (DMSO-c/6): δ 9.9 (bs, IH), 9.4 (bs, IH), 8.38 (m, 2H), 7.83 (t, IH), 7.39 (m, 2H), 7.21 (m, 4H), 3.23 (m, 2H), 3.09 (t, 2H), 1.65 (m, 2H), 1.45 (m, 2H), 1.30 (m, 4H).
Example 182: ΛH4-chlorophenyl)-6-f2-cvano-3-('pyridin-4-v0quanidino')-Λ/- methylhexane-1-sulfonamide (compound 1182").
Figure imgf000180_0002
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea (Bioorg. Med. Chem. Lett. (1997) 7 (24), 3095-3100) and compound 140. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.42 (m, 4H), 7.33 (m, 2H), 3.38 (t, 2H), 3.32 (s, 3H), 3.11 (m, 2H), 1.79 (m, 2H), 1.63 (m, 2H), 1.44 (m, 4H).
Example 183 : Λ/-(4-chlorophenyl)-6-f 2-cvano-3-fpyridin-4-vπαuanidino')-Λ/-('2- morpholinoethvπhexane-1-sulfonamide (compound 1183).
Figure imgf000180_0003
General procedure 10. Starting materials: S-methyl /V-cyano-Λ/ '-4- pyridylisothiourea {Bioorg.Med.Chem.Lett. (1997) 7 (24), 3095-3100) and compound 141. 1H-NMR (CD3OD): δ 8.39 (m, 2H), 7.44 (m, 4H), 7.33 (m, 2H), 3.85 (t, 2H), 3.63 (m, 4H), 3.40 (t, 2H), 3.16 (m, 2H), 2.44 (m, 6H), 1.83 (m, 2H), 1.65 (m, 2H), 1.46 (m, 4H).
Example 184: In vitro cell proliferation assay fSRB assay1)
A2780 cells were seeded in 96-well plates at 2000 cells/well in 100 μl_ of culture medium, 4 wells were left empty for media only controls.
After 24 h the compound titrations were performed, in a separate dilution plate, by serially diluting the compounds of general formula (I) in culture medium. A 100 μl_ of each dilution was added to the plated cells, this was done in quadruplicate, and controls {e.g. DMSO and blanks) were included. The plates were incubated for 72 h at 370C in a CO2 incubator. 50 μl_ cold 50% trichloroacetic acid was then added to each well. After 1 h the supernatant was discarded and the wells were washed 5 times with tap water and dried at room temperature. 50 μl_ 0.4 % Sulpho-Rodamine B (SRB) solution in 1 % acetic acid was added to each well, and after 30 minutes the supernatant was removed and the wells washed 4 times with 1% acetic acid and dried at room temperature. Bound stain was subsequently solubilized by addition of 200 μL 10 mM Tris pH 10.5 to each well, and the plates were shaken for at least 30 minutes, and the absorbance read on an automated plate reader at 515 nm. Using the nine absorbance measurements [time zero, (Tz), control growth, (C), and test growth in the presence of drug at the seven concentration levels (Ti)], the percentage growth is calculated at each of the drug concentrations levels after averaging the quadruplet wells. Percentage growth inhibition is calculated as:
[(Ti-Tz)/(C-Tz)] x 100 for concentrations for which Ti>/=Tz
[(Ti-Tz)/Tz] x 100 for concentrations for which Ti<Tz.
Growth inhibition of 50 % (GI50) is calculated from [(Ti-TzV(C-Tz)] x 100 = 50, which is the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation.
Results can be seen in Table 1. Example 185: In vitro cell proliferation assay (WST-I assavi
A2780 cells were seeded in 96-well plates at 3 x 103 cells/well in 100 μl_ of culture medium, 8 wells were left empty for media only controls.
After 24 h the compound titrations were performed, in a separate dilution plate, by serially diluting the compounds of general formula (I) in culture medium. A 100 μl_ of each dilution was added to the plated cells, this was done in triplicate, and controls {e.g. DMSO and blanks) were included. The plates were incubated for 24 h at 370C in a CO2 incubator. The compound titrations were repeated in a separate dilution plate after 24 h. The media plus compound from the assay plates were then aspirated. A 100 μl_ of media was then added to all wells, followed by 100 μl_ of each compound dilution. The plates were incubated for a further 48 h at 370C in a CO2 incubator (total incubation time 72 h). The number of viable cells was then assessed using Cell Proliferation Reagent WST-I. 10 μl_ of WST-I reagent added to each well and incubated for one to four hours at 370C in CO2 incubator. The absorbance was measured (450 nm/690 nm).
The activity of compounds of general formula (I) in reducing the number of viable cells was calculated as:
% activity = [(Sc-B)/(S°-B)]xl00
Sc denotes signal measured in the presence of test compound, S0 denotes signal detected in the absence of compound, and B denotes background signal, measured in blank wells containing medium only. Analyse data using GraphPad Prism.
Results can be seen in Table 1.
Table 1 - In vitro cell proliferation assay (SRB or WST-assay as described in Examples 184 and 185)
Figure imgf000182_0001
Figure imgf000183_0001

Claims

1. A compound of the formula (I)
Figure imgf000184_0001
(I)
wherein
A is selected from -C(=O)-, -S(=O)2-, -C(=S)-, and -P(=O)(R5)-, wherein R5 is selected from Ci-6-alkyl, Ci-6-alkoxy, and hydroxy;
B is selected from a single bond, -O-, -NR6- and -C(=O)-NR6-, wherein R6 is selected from hydrogen, optionally substituted Ci-12-alkyl, optionally substituted Ci- 12-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;
m is an integer of 0-12 and n is an integer of 0-12, wherein the sum m+n is 1-20;
R1 is selected from optionally substituted heteroaryl;
R2 is selected from hydrogen, optionally substituted
Figure imgf000184_0002
optionally substituted C3-i2-cycloalkyl, -[CH2CH2O]I-I0-(OPtJOnBlIy substituted Ci-6-alkyl), optionally substituted Ci-i2-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; and R3 is selected from optionally substituted Ci-12-alkyl, optionally substituted C3-i2-cycloalkyl, - [CH2CH2θ]i-10-(optionally substituted Ci-6-alkyl), optionally substituted
Figure imgf000184_0003
optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or R2 and R3 together with the intervening atoms {i.e. -N-B-) form an optionally substituted N-containing heterocyclic or heteroaromatic ring; each of R4 and R4* independently is independently selected from hydrogen, optionally substituted Ci-12-alkyl and optionally substituted Ci-i2-alkenyl;
and pharmaceutically acceptable salts thereof, and prodrugs thereof;
with the proviso that when B is a single bond, then A is selected from -S(=O)2-, - C(=S)-, and -P(=O)(R5)-.
2. The compound according to claim 1, wherein B is selected from -O- and -NR6-, in particular B is -O-.
3. The compound according to claim 2, wherein A is -S(=O)2- and B is -O-.
4. The compound according to claim 2, wherein A is-C(=O)- and B is -O-.
5. The compound according to claim 1, wherein B is a single bond.
6. The compound according to claim 5, wherein A is -S(=O)2-.
7. The compound according to claim 1, wherein B is -C(=O)-NR6-.
8. The compound according to any one of the preceding claims, wherein R1 is optionally substituted pyridinyl, in particular optionally substituted pyridin-4-yl.
9. The compound according to any one of the preceding claims, wherein m is an integer of 0-10 and n is an integer of 0-10, wherein the sum m+n is 1-12; in particular m is an integer of 1-8 and n is an integer of 0-3, wherein the sum m+n is 3-8.
10. The compound according to claim 9, wherein m is an integer of 2-8 and n is 0.
11. The compound according to any one of the preceding claims, wherein at least one of R2 and R3 includes a carbocyclic ring, heterocyclic ring or a heteroaromatic ring, or R2 and R3 together with the intervening atoms form an optionally substituted N-containing heterocyclic or heteroaromatic ring.
12. The compound according to claim 11, wherein R2 and R3 together with the intervening atoms form an optionally substituted N,O-containing heterocyclic or heteroaromatic ring.
13. The compound according to any one of the preceding claims, wherein R4 is selected from hydrogen, Ci-6-alkyl and optionally substituted benzyl; and R4* is hydrogen.
14. The compound according to claim 1, wherein
A is selected from -C(=O)- and -S(=O)2-;
B is -O-;
m is an integer of 2-8 and n is 0;
R2 is selected from hydrogen, optionally substituted C3-i2-cycloalkyl, -[CH2CH2θ]i-io- (optionally substituted Ci-6-alkyl), -(CH2)o-2-(optionally substituted aryl), -(CH2)o-2-(optionally substituted heteroaryl) and -(CH2)o-2-(optionally substituted heterocyclyl);
R3 is selected from optionally substituted C3-i2-cycloalkyl, -[CH2CH2θ]i-io-(optionally substituted Ci-6-alkyl), optionally substituted Ci-12-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;
R4 is selected from hydrogen, optionally substituted C3-i2-cycloalkyl, -(CH2)o-2-(optionally substituted aryl), -(CH2)o-2-(optionally substituted heteroaryl) and -(CH2)o-2-(optionally substituted heterocyclyl); and
R4* is hydrogen;
with the proviso that at least one of R2 and R4 is not hydrogen.
15. The compound according to claim 1, which is selected from compounds 1001- 1183 described herein.
16. The compound according to any one of the preceding claims for use as a medicament.
17. The compound according to any one of the claims 1-15 for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT).
18. The compound according to claims 17, wherein said disease or condition is one or more selected from the group consisting of inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and CPOD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukaemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telengiectasia.
19. A method of inhibiting the enzymatic activity of nicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said method comprising the step of administering to said mammal a pharmaceutically relevant amount of a compound as defined in any of claims 1-15.
20. A method of treating a disease or condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT) in a mammal, said method comprising the step of administering to said mammal a pharmaceutically relevant amount of a compound as defined in any of claims 1-15.
21. The method according to claim 20, wherein the compound is administered in combination with a DNA damaging agent.
22. The method according to any one of the claims 20-21, wherein said disease or condition is one or more selected from the group consisting of inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultra-violet induced skin damage; autoimmune diseases including systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, particularly wherein the cancer is selected from breast, prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukaemia, lymphoma or Hodgkin's disease, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telengiectasia.
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US11638762B2 (en) 2016-10-18 2023-05-02 Seagen Inc. Targeted delivery of nicotinamide adenine dinucleotide salvage pathway inhibitors
US11931414B2 (en) 2017-04-27 2024-03-19 Seagen Inc. Quaternized nicotinamide adenine dinucleotide salvage pathway inhibitor conjugates
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