WO2011121055A1 - Pyridinyl derivatives comprising a cyanoguanidine or squaric acid moiety - Google Patents

Abstract

The present application discloses compounds of the formula (I) wherein X = opt.subst. pyrid-3-yl or pyrid-4-yl; Q = opt.subst. Ci-6 alkylene or a single bond; Y is formula (i) wherein D is = N-CN, or formula (ii) B = is opt.subst. C1-6 alkylene; A = (formula) Z = -J-V, wherein J = -C(=0)-, -C(=O)-O, -S(=O)₂-, -P(=O)(OR⁴)-, -C(=O)-NR⁴- and -C(=S)-NR⁴-, and V = opt.subst. C_1-12-alkyl, opt.subst. C_3-12-cycloalkyl, -[CH₂CH₂O]_1-10-( opt.subst. C_1-6-alkyl), opt.subst. C_1-12- alkenyl, opt.subst. aryl, opt.subst. heterocyclyl, or opt.subst. heteroaryl; q = 0-2, and r = 0- 2; and pharmaceutically acceptable salts thereof, and prodrugs thereof. The application also discloses the compound for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPRT), e.g. inflammatory and tissue repair disorders; dermatosis; autoimmune diseases, Alzheimer's disease, stroke, athersclerosis, restenosis, diabetes, glomerulonephritis, cancer, cachexia, inflammation associated with infection and certain viral infections, including Acquired Immune Deficiency Syndrome (AIDS), adult respiratory distress syndrome, ataxia telengiectasia.

Description

PYRIDINYL DERIVATIVES COMPRISING A CYANOGUANIDINE OR SQUARIC ACID MOIETY

FIELD OF THE INVENTION

The present invention relates to pyridinyl derivatives which are useful for the inhibiting of the 5 enzyme nicotinamide phosphoribosyltransferase (NAMPRT), and to medical use of such

pyridinyl derivatives.

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

0 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 high5 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. 0 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 mononucletide5 (dNAM) using the enzyme quinolinic acid phosphoribosyltransferase Θ which is found in liver kidney and brain.

Nicotinic acid (niacin) reacts with PRPP to form niacin mononucleotide (dNAM), using the enzyme niacin phosphoribosyltransferase Θ 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 ©.

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 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) . 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 AP0866. (see Hasmann and Schemainda, Cancer Res 63(21) : 7463-7442.) Antiproliferative compounds comprising a cyanoguanidine moiety have been described in WO 09/086835, WO 06/066584, WO 03/097662, WO 03/097601, WO 02/094813 and WO 02/042265. Furthermore, antiproliferative compounds comprising a squaric acid moiety have been described in WO 09/086835, WO 00/061561 and WO 0061559. Inhibitors of the enzyme NAMPRT may be used in the treatment of cancer (WO 97/48696), to cause immuno-suppression (WO 97/48397), for the treatment of diseases involving angiogenesis (WO 03/80054), for the treatment of rheumatoid arthritis or septic shock (WO 08/025857), or for the prophylaxis and treatment of ischaemia (WO 09/109610).

SUMMARY 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 claims 1-14, and the utilization of these compounds in medicine, cf. claims 15-21.

LEGENDS TO THE FIGURE

Figure 1 illustrates the pathway of NAD biosynthesis (from Biedermann E. et al, WO

00/50399).

DETAILED DISCLOSURE OF THE INVENTION Compounds of the invention

The present invention I. a. relates to particular pyridinyl derivatives which are useful for the inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPRT), and which are antiproliferative.

The present invention relates to compounds of the formula (I)

wherein:

X is selected from optionally substituted pyrid-3-yl and optionally substituted pyrid-4-yl;

Q is selected from optionally substituted Ci-₆ alkylene and a single bond; Y is selected from (i) and (ii); where (i) is

D

R¹ R²

(i) , wherein D is =N-CN, and R¹ and R² are independently selected from hydrogen, optionally substituted Ci-i₂-alkyl, optionally substituted C₃-i₂-cycloalkyl, - [CH₂CH₂0]i.io-(optionally substituted Ci_₅-alkyl), optionally substituted Ci_i₂-alkenyl, optionally substituted aryl, optionally substituted heterocydyl, and optionally substituted heteroaryl; and where (ii) is

wherein R⁵ and R⁵ are independently selected from hydrogen, optionally substituted Ci_i₂- alkyl, optionally substituted C₃-i₂-cycloalkyl, -[CH₂CH₂O]i-i₀-(optionally substituted Ci-₆-alkyl), optionally substituted Ci_i₂-alkenyl, optionally substituted aryl, optionally substituted heterocydyl, and optionally substituted heteroaryl;

B is optionally substituted Ci_₅ alkylene;

A is selected from and , wherein R³ is selected from hydrogen, optionally substituted Ci-i₂-alkyl, optionally substituted C₃.i₂-cycloalkyl, -[CH₂CH₂0]i.io-(optionally substituted Ci_₅-alkyl), optionally substituted Ci_i₂-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; Z is -J-V, wherein J is selected from -C(=0)-, -C(=0)-O, -S(=0)₂-, -P(=0)(OR⁴)-, -C(=0)-NR⁴- and - C(=S)-NR⁴-, V is selected from optionally substituted Ci_i₂-alkyl, optionally substituted C₃_i₂- cycloalkyl, -[CH₂CH₂O]i-i₀-(optionally substituted Ci_₅-alkyl), optionally substituted Ci_i₂- alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, and R⁴ is selected from hydrogen, optionally substituted Ci_i₂-alkyl, optionally substituted C₃-i₂-cycloalkyl, -[CH₂CH₂O]i-i₀-(optionally substituted Ci-₆-alkyl), optionally substituted Ci_i₂-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; q = 0-2, and r = 0-2. Definitions

In the present context, the terms "Ci_i₂-alkyl" and "Ci_₅-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-cycloalkyl" 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_₅-alkoxycarbonyl, d_-6- alkylcarbonyl, 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_₅- alkyl)amino, -N(Ci.₄-alkyl)₃ ⁺, carbamoyl, mono- and di(Ci_₅-alkyl)aminocarbonyl, Ci_₅-alkyl- carbonylamino, cyano, guanidino, carbamido, Ci_₅-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_₅-alkoxy, amino, mono- and di(Ci_₅-alkyl)amino, carboxy, Ci_₅-alkylcarbonylamino, Ci_₅-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_₅-alkyl)amino; carbamoyl, mono- and di(Ci_₅-alkyl)aminocarbonyl, amino-Ci-₅-alkyl-aminocarbonyl, mono- and di(Ci_₅-alkyl)amino-Ci.₅-alkyl-aminocarbonyl, Ci-6-alkylcarbonylamino, 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, Ci-6-alkylcarbonylamino, Ci-6-alkylaminocarbonyl, 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, benzo- thiazolyl, 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, hexahydro- pyrimidine, 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 "Ν,Ο-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 "pyrid-3-yl", "pyrid-4-yl", "aryl", "heteroaryl", "heterocyclyl", "Ν,Ο-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_₅-alkyl, Ci_₅-alkoxy, C₂-_&- 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_₅-alkyl)amino-Ci.₅-alkyl-aminocarbonyl, Ci_₅-alkylcarbony- lamino, cyano, guanidino, carbamido, Ci_₅-alkanoyloxy, Ci_₅-alkyl-sulphonyl-amino, aryl- sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci_₅-alkyl-suphonyl, Ci_₅-alkyl-sulphinyl, d_-6- alkylsulphonyloxy, nitro, sulphanyl, amino, amino-sulfonyl, mono- and di(Ci_₅-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_₅-alkoxy, C₂-6-alkenyloxy, amino, mono- and di(Ci_₅- alkyl)amino, carboxy, Ci_₅-alkylcarbonylamino, halogen, Ci_₅-alkylthio, Ci_₅-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, Ci-₆-alkylcarbonyl, formyl, amino, mono- and di(Ci-6-alkyl)amino; carbamoyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino- Ci-₅-alkyl-aminocarbonyl, Ci_₅-alkylcarbonylamino, guanidino, carbamido, Ci_₅-alkyl- sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci_₅-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_₅-alkoxy, C₂-6-alkenyloxy, amino, mono- and di(Ci-₅-alkyl)amino, carboxy, Ci_₅-alkylcarbonylamino, halogen, Ci_₅-alkylthio, Ci_₅-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_₅-alkylthio, Ci_₅-alkyl-sulphonyl-amino, or guanidino. Groups (e.g. R². R⁵ 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. V) 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 (⁺N(R)₃R', where R and R' 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 primary embodiment, X is optionally substituted pyrid-4-yl, in particular pyrid-4-yl . In another embodiment, X is optionally substituted pyrid-3-yl, in particular pyrid-3-yl.

In one embodiment, J is -C(=0)-O, -S(=0)₂- or -C(=0)-.

In one embodiment, J is -S(=0)₂- or -C(=0)-.

In one embodiment, J is -S(=0)₂-.

In one embodiment, J is -C(=0)-. In one embodiment, V is optionally substituted Ci-i₂-alkyl or optionally substituted aryl such as phenyl or naphtyl .

In one embodiment, Z is optionally substituted benzoyl, in particular unsubstituted benzoyl.

In one embodiment A

,CR³ ^CFV

In one em bbooddiimmeenntt AA = . In one embodiment A = , wherein R

hydrogen .

In one embodiment Y is D

, wherein D is = N-CN, and wherein R¹ and R² are hydrogen.

In one embodiment Y is

, wherein R⁵ and R⁵ are hydrogen.

In one embodiment Q is a single bond .

In one embodiment B is Ci-i₂-alkyl, such as Ci_₅-alkyl.

This being said the currently most preferred compounds are selected from the following list tert-butyl 4-(4-(2-cyano-3-(pyridin-4-yl)guanidino)butyl)piperazine-l-carboxylate l-(4-(4-benzoylpiperazin-l-yl)butyl)-2-cyano-3-(pyridin-4-yl)guanidine 3-(4-(4-benzoylpiperazin-l-yl)butylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-l,2-dione

1- (4-(l-benzoylpiperidin-4-yl)butyl)-2-cyano-3-(pyridin-4-yl)guanidine 3-(4-(l-benzoylpiperidin-4-yl)butylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-l,2-dione tert-butyl 4-(5-(2-cyano-3-(pyridin-4-yl)guanidino)pentyl)piperazine-l-carboxylate

2- cyano-l-(5-(4-(phenylsulfonyl)piperazin-l-yl)pentyl)-3-(pyridin-4-yl)guanidine

3- (5-(4-(phenylsulfonyl)piperazin- l-yl)pentylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione l-(5-(4-benzoylpiperazin-l-yl)pentyl)-2-cyano-3-(pyridin-4-yl)guanidine 3-(5-(4-benzoylpiperazin-l-yl)pentylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-l,2-dione General Syntheses

The compounds of the present invention can be synthesized using the methods outlined below, together with methods known in the art of 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 (I) according to the present invention which are cyanoguanidines (la) can be prepared from dimethyl cyanocarbonimidodithioate and amines of general formula (II) followed by reaction with amines of general formula (IV). Diphenyl cyanocarbonimidate may be employed instead of dimethyl cyanocarbonimidodithioate.

Compounds (I) of the present invention which are thioureas (lb) can be prepared by reaction of isothiocyanates of general formula (V), 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 : Tet. Lett. (1985) 26, 1661) and amines of general formula (IV) .

Compounds (I) of the present invention which are cyanoguanidines (la) can also be prepared from thioureas (lb) as described in the literature {e.g. S. K. Hamilton et ai : Org. Lett. (2005) 7 (12)2429-2431 ; Bioorg. Med. Chem. Lett. (1997) (24) 3095-3100; J .K. Lynch et

ai : 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.

Compounds of general formula (I) which are cyclobut-3-ene-l,2-diones (squaric acids) (Id) can be prepared from reaction of amines (II) and 3,4-diethoxycyclobut-3-ene-l,2-dione to yield intermediates of general formula (VI) followed by reaction with amines of general formula (IV) .

Amines of general formula (IV), which are piperazine-derivatives or its ring-analogues (IVa), can be prepared by alkylation of mono-protected piperazine or its ring-analogues (VIII) (protecting group (Pg) e.g. Boc or benzyl) using alkylbromides of general formula (IX) (protecting group (Pg) e.g. phthalimido or Boc) followed by deprotection (by e.g. HCI or hydrogenation, respectively) . If Z is different from H, it can be introduced by derivatization with the relevant reagent (sulfonylchlorides for sulphonamides, carbonyl chlorides or coupling with an acid and a peptide coupling reagent for amides, reaction with isocyanates or isothiocyanates for ureas or thioureas, respectively, alkylation with an alkylbromide for amines, phosphinic chlorides for phosphinic amides). Finally, the second protecting group can be removed (by e.g. hydrazine hydrate or HCI, respectively) to yield amines of general formula (IVa).

(VIII) (IX) (IVa)

Alternatively, mono-protected piperazine or its ring-analogues (VIII) (protecting group (Pg) e.g. Boc or benzyl) can be derivatized as described above, followed by deprotection (by e.g. HCI or hydrogenation, respectively) and alkylation using alkylbromides of general formula (IX) (protecting group (Pg) e.g. phtalimido or Boc). Finally, the second protecting group can be removed (by e.g. hydrazine hydrate or HCI, respectively) to yield amines of general formula (IVa).

_H¾^P9 _tion deprotection

(VIII) (IX) C^Va)

The alkylbromides (IX) are commercially available or can be prepared e.g. from

dibromoalkyls by reaction with phthalimide or by reaction of potassium phthalimide with an aminoalcohol followed by bromination according to literature procedures (Hou et al: JOC (2004) (69) 6094-6099).

Amines of general formula (IV), which are piperidine-derivatives or its ring-analogues (IVb), can be prepared by reduction of 3-(piperidin-4-yl)alkanoic acid hydrochlorides or its ring- analogues using e.g. lithium aluminium hydride to yield amino alcohols (X). Z can subsequently be introduced by derivatization of amino alcohols (X) with the relevant reagent (sulfonylchlorides for sulphonamides, carbonylchlorides or coupling with an acid and a peptide coupling reagent for amides, reaction with isocyanates or isotiocyanates for ureas or thioureas, respectively, alkylation with an alkylbromide for amines, phosphinic chlorides for phosphinic amides). The resulting alcohols of general formula (XI) can then be transformed into azides of general formula (XII) using e.g. diphenylphosphoryl azide, sodium azide and DBU. Finally, Staudinger azide-amine reduction yields amines of general formula (IVb). Alternatively, alcohols of general formula (XI) can be converted into the phtalimide protected amines (XIII) by a Mitsunobu reaction (using e.g. DEAD and phtalimide) followed by deprotection using hydrazine hydrate (see e.g. U.Galli et al. ChemMedChem. (2008) 3(5) 771-779; W097/48696).

Alternatively, amines of general formula (IV), which are piperidine-derivatives or ring analogues (IVb), can be prepared by a Wittig reaction of protected piperidin-4-one or its ring analogues (XIV) (protecting group Pg e.g. benzyl) followed by hydrogenation to yield intermediates of general formula (XV). If the protecting group is not benzyl, a further deprotecting step will have to be employed. Z can subsequently be introduced by

derivatization of intermediates of general formula (XV) with the relevant reagent

(sulfonylchlorides for sulphonamides, carbonylchlorides or coupling with an acid and a peptide coupling reagent for amides, reaction with isocyanates or isotiocyanates for ureas or thioureas, respectively, alkylation with an alkylbromide for amines, phosphinic chlorides for phosphinic amides). Finally, the nitril moiety can be hydrogenated using e.g. 5% Rh-C as the catalyst to yield amines of general formula (IVb). Alternatively, Z can be introduced at an earlier step in place of the protecting group, thus employing intermediate of general formula (IXX) instead of intermediate of general formula (XIV).

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-κΒ 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 ¹ 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), (bd) and (bt) indicate a broad singlet, a broad dublet or a broad triplet, respectively.

MS was performed using an LC-MS using a Bruker Esquire 3000+ ESI lontrap with an Agilent 1200 HPLC-system .

S-Methyl /V-cyano-/V ^'-4-pyridylisothiourea was prepared as described in

Bioorg. Med. Chem. Lett. ( 1997) 7 (24), 3095-3100.

3- Ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-2,3-dione and 3-ethoxy-4-(pyridin-3- ylamino)cyclobut-3-ene-2,3-dione were prepared as described in J. Med. Chem. (2000) 43 1187- 1202.

/V-Benzoyl-4-piperidinebutanamine was prepared as described in ChemMedChem. (2008) 3(5) 771-779.

4- Piperidin-4-yl-butan-l-ol was prepared as described in ChemMedChem. (2008) 3(5) 771- 779. The following abbreviations have been used throughout:

CDI 1,1 ^' -carbonyldiimidazole

DBU l,8-diazabicyclo[5.4.0]undec-7-en

DCM dichloromethane

DCE 1,2-dichloroethane

DIEA diisopropylethylamine

DMF Λ ,/V-dimthylformamide

DMAP N,N dimethylaminopryridine

DPT di(2-pyridyl) thionocarbonate

EDC /V-(dimethylaminopropyl)-N ^' -ethylcarbodiimide hydrochloride

EtOAc ethyl acetate HATU 0- (7-Azabenzotriazol-l-yl)-/V,/\ ,/\ ',/\ '-tetramethyluronium hexafluorophosphate

HOBt 1- hydroxybenzotriazole

MS mass spectroscopy

NMM /V-methylmorpholine

NMR nuclear magnetic resonance

rt room temperature

THF tetrahydrofurane

TLC thin layer chromatography

General procedure 1 : Reaction of phthalic anhydride with aminoalcohols. Phtalic anhydride (1 eq) and an aminoalcohol (1.05 eq) were heated with stirring at 140°C overnight. The reaction mixture was cooled to rt, extracted with EtOAc and NaHC0₃

(aqueous, saturated). The organic phase was subsequently washed with H₂0, 10% citric acid, brine, dried (MgS0₄) and concentrated to yield a pthalimide protected aminoalkanol.

General procedure 2: Bromination of phtalimide protected aminoalkanols to give

alkylbromides (IX).

To a solution of a phtalimide protected aminalkanol (1 eq) in CH₃CN (3 ml/mmol) was added PPh₃ (1 eq) and CBr₄ (1 eq) and the mixture was stirred at rt for 2¹ _ h or until consumption of starting material. The reaction mixture was concentrated and purified by chromatography (mixtures of petroleum ether and EtOAc) to afford the corresponding alkylbromide (IX). General procedure 3: Alkylation of amines of general formula (VIII) using alkylbromides of general formula (IX), followed by deprotection, derivatization and deprotection to give amines of general formula (IVa).

Alkylation: Cs₂C0₃ (2 eq) was added to a solution of an alkyl bromide of general formula (IX) (1 eq) and amine of general formula (VIII) (1.1 eq.) in dry DMF with stirring. The mixture was stirred at 70°C overnight or until consumption of the alkyl bromide. The reaction mixture was concentrated, extracted with EtOAc/H₂0. The organic phase was washed with brine, dried (MgS0₄), concentrated and purified by chromatography (mixtures of petroleum ether and EtOAc) to afford the bis-protected intermediate.

Deprotection (Boc) : The bis-protected intermediate was dissolved in methanol, and 3N HCI in methanol was added with stirring. After 1-1/2 h the mixture was concentrated to yield the mono-protected intermediate as a hydrochloride. Derivatization (amide): The mono-protected intermediate hydrochloride (1 eq.) was suspended in DCM, NEt₃ (2.2 eq.) was added with stirring followed by the carbonyl chloride. The mixture was stirred at rt overnight, extracted with H₂0, brine and the organic phase was dried (MgS0₄) and concentrated to yield the mono-protected, derivatized intermediate. Derivatization (sulfonamide): The mono-protected intermediate hydrochloride (1 eq.) was suspended in DCM, NEt₃ (2.2 eq.) was added with stirring followed by the sulfonyl chloride. The mixture was stirred at rt overnight, extracted with H₂0, brine and the organic phase was dried (MgS0₄) and concentrated to yield the protected, derivatized intermediate.

Deprotection (phtalimide): A solution in ethanol of the protected, derivatized intermediate (1 eq.) was added to a flask suited for microwave heating. Hydrazine hydrate (5 eq) was added and the mixture heated in microwave oven at 120°C for 20 min. After cooling the white precipitate formed was removed by filtration. The filtercake was washed with ethanol and the filtrate was concentrated. The residue was purified by chromatography using the appropriate mixture of MeOH:CHCI₃:NH₃ (25% aq.) to afford amines of general formula (IVa). General procedure 4: Preparation of cvanoauanidines of general formula (la) by reaction of intermediates of general formula (III) with amines of general formula (IV).

Intermediate of general formula (III) (1.0 eq.) was dissolved in pyridine, amine of general formula (XXII) (1.05eq.), triethylamine (1.1 eq.) and polystyrene-supported DMAP (catalytic amount) were added and the mixture heated with stirring at 80 °C overnight or until consumption of starting material (III). The reaction mixture was concentrated twice with toluene, the residue purified by chromatography (chloroform:methanol:NH₃ (25% aq.) 98:2:0.2 to 95:5:1) to afford cyanoguanidine of general formula (la).

General procedure 5: Reaction of amines of general formula (IV) with 3-ethoxy-cvclobut-3- ene-l,2-diones of general formula (VI) to yield cvclobut-3-ene-l,2-diones of general formula (Id).

Amine of general formula (IV) (1.02 eq) and 3-ethoxy-cyclobut-3-ene-l,2-dione of general formula (VI) (1.0 eq) were dissolved in acetonitrile (if the amine is a salt, 1.0 eq. of triethylamine is added) and stirred at rt until consumption of starting material as judged by TLC. The product was either purified by crystallization or chromatography

(chloroform: methanol :NH₃ (25% aq.) 98:2:0.2 to 95:5:1) to afford cyclobut-3-ene-l,2-dione of general formula (Id).

General procedure 6: Formation of alcohols of general formula (XI). Sulfonamides: Under nitrogen, triethylamine (1.1 eq.) and a sulfonyl chloride (1.05 eq.) were added to a cooled (0°C) solution or suspension of alcohol of general formula (X) (1.0 eq) in DCM. The reaction mixture was gradually allowed to reach rt, stirred overnight, concentrated and purified by chromatography (mixtures of petroleum ether and EtOAc) to afford alcohols of general formula (XI).

General procedure 7: Formation of azides of general formula (XII).

Under nitrogen, diphenylphosphoryl azide (3 eq.) and DBU (3 eq.) were added dropwise to a cooled (0°C) solution of alcohol of general formula (XI) (1 eq.) in DMF. After 30 min, NaN₃ (3 eq.) was added. After the addition the cooling bath was removed and the resulting solution was heated to 100°C for 4 h. After cooling to rt, the reaction mixture was diluted with diethyl ether. The organic layer was washed twice with water. The aqueous layer was back-extracted with diethyl ether. The combined organic extracts were washed with brine, dried (MgS0₄), concentrated and purified by chromatography (mixtures of petroleum ether and EtOAc) to afford azides of general formula (XII). General procedure 8: Reduction of azides of general formula (XII) to yield amines of general formula flVb).

Water (6 eq.) and tripehenylphosphine (1.5 eq.) were added to a solution of azide of general formula (XII) (1 eq.) in THF, and the reaction mixture stirred at rt overnight, concentrated and purified by chromatography (chloroform : methanol : NH₃ (25% aq.) 95: 5 : 0.5 to 90: 10: 1) to afford amines of general formula (IVb).

PREPARATIONS

Preparation 1 : 2-(4-hvdroxybutyl)isoindoline-l,3-dione (compound 1).

General procedure 1. Starting material : 4-amino-butan-l-ol. ^-NMR (CDCI₃) : δ 7.83 (m, 2H), 7.71 (m, 2H), 3.71 (m, 4H), 1.78 (m, 2H), 1.63 (m, 3H). Preparation 2: 2-(4-bromobutynisoindoline-l,3-dione (compound 2).

General procedure 2. Starting material : compound 1. ^-NMR (CDCI₃) : δ 7.85 (m, 2H), 7.72 (m, 2H), 3.72 (t, 2H), 3.44 (t, 2H), 1.89 (m, 4H). Preparation 3: 2-(5-hvdroxypentyl^')isoindoline-l,3-dione (compound 3).

General procedure 1. Starting material : 5-amino-pentan-l-ol.

^-NMR (CDCI₃) : δ 7.83 (m, 2H), 7.70 (m, 2H), 3.66 (m, 4H), 1.71 (m, 2H), 1.61 (m, 3H), 1.41 (m, 2H).

Preparation 4: 2-(5-bromopentyl^')isoindoline-l,3-dione (compound 4).

General procedure 2. Starting material : compound 3. ^-NMR (CDCI₃) : δ 7.84 (m, 2H), 7.71 (m, 2H), 3.69 (t, 2H), 3.39 (t, 2H), 1.91 (m, 2H), 1.71 (m, 2H), 1.49 (m, 2H). Preparation 5: ferf-butyl 4(4-(l,3-dioxoisoindolin-2-ynbutylpiperazine-l-carboxylate (compound 5).

General procedure 3 (alkylation). Starting materials: compound 2 and tert-butyl piperazine- 1-carboxylate.

^-NMR (CDCI₃) : δ 7.84 (m, 2H), 7.71 (m, 2H), 3.71 (t, 2H), 3.41 (t, 4H), 2.37 (m, 6H), 1.71 (m, 2H), 1.53 (m, 2H), 1.45 (s, 9H).

Preparation 6: ferf-butyl 4-(4-aminobutynpiperazine-l-carboxylate (compound 6).

A solution in ethanol the compound 5 (38 mg, 0.1 mmol) was added to a flask suited for microwave heating. Hydrazine hydrate (0.025 ml, 0.5 mmol) was added and the mixture heated in microwave oven at 120°C for 20 min. After cooling the white precipitate formed was removed by filtration. The filtercake was washed with ethanol and the filtrate was concentrated. The residue was purified by chromatography (MeOH:CHCI_3:NH₃ (25% aq.) 90: 10: 1) to yield compound 6.

^-NMR (CD₃OD) : δ 3.45 (t, 4H), 2.68 (t, 2H), 2.44 (t, 4H), 2.40 (t, 2H), 1.55 (m, 4H), 1.47 (s, 9H).

Preparation 7: 2-(4-(piperazin-l-yl)butyl)isoindoline-l,3-dione hydrochloride (compound 7)

General procedure 3 (deprotection (Boc)). Starting material: compound 5.

'H-NMR (DMSO-d₅): δ 9.65 (bs, 2H), 7.87 (m, 4H), 3.11 (t, 2H), 3.48 (m, 4H), 3.25 (bs, 2H), 3.14 (t, 4H), 1.69 (m, 4H). Preparation 8: 2-(4-(4-benzoylpiperazin-l-yl)butyl)isoindoline-l,3-dione (compound 8).

General procedure 3 (derivatization (amide)). Starting materials: compound 7 and benzoyl chloride.

^XH-NMR (CDCI₃) : δ 7.85 (m, 2H), 7.74 (m, 2H), 7.44 (m, 5H), 3.91 (bs, 2H), 3.72 (t, 2H), 3.50 (bs, 2H), 3.10 (m, 2H), 2.75 (bs, 4H), 1.96 (m, 2H), 1.80 (m, 2H).

Preparation 9: l-(4-aminobutyl)-4-benzoylpiperazine (compound 9)

General procedure 3 (deprotection (phtalimide)). Starting material: compound 8.

^XH-NMR (CD₃OD) : δ 7.49 (m, 3H), 7.43 (m, 2H), 3.79 (bs, 2H), 3.48 (bs, 2H), 2.73 (t, 2H), 2.57 (bs, 2H), 2.46 (m, 4H), 1.57 (m, 4H).

Preparation 10: terf-butyl 4-(5-(l,3-dioxoisoindolin-2-yl)pentylpiperazine-l-carboxylate (compound 10).

General procedure 3 (alkylation). Starting materials: compound 4 and tert-butyl piperazine- 1-carboxylate.

^-NMR (CDCI₃) : δ 7.84 (m, 2H), 7.70 (m, 2H), 3.68 (t, 2H), 3.40 (t, 4H), 2.34 (m, 6H), 1.70 (m, 2H), 1.53 (m, 2H), 1.45 (s, 9H), 1.36 (m, 2H).

Preparation 11 : ferf-butyl 4-(5-aminopentvnpiperazine-l-carboxylate (compound 11).

A solution in ethanol of the compound 10 (55 mg, 0.14 mmol) was added to a flask suited for microwave heating. Hydrazine hydrate (0.033 ml, 0.7 mmol) was added and the mixture heated in microwave oven at 120°C for 20 min. After cooling the white precipitate formed was removed by filtration. The filtercake was washed with ethanol and the filtrate was concentrated. The residue was purified by chromatography (MeOH:CHCI_3:NH₃(25% aq.) 90: 10: 1) to yield compound 11.

^-NMR (CD₃OD) : δ 3.45 (t, 4H), 2.73 (t, 2H), 2.42 (m, 6H), 1.57 (m, 4H), 1.47 (s, 9H), 1.40 (m, 2H).

Preparation 12: 2-(5-(piperazin-l-yl)pentyl)isoindoline-l,3-dione hydrochloride (compound

121

General procedure 3 (deprotection (Boc)). Starting material: compound 10. 'H-NMR (CD₃OD) : δ 7.84 (m, 4H), 3.89 (bs, 2H), 3.73 (t, 4H), 3.6 (bs, 2H), 3.45 (bs, 3.28 (t, 2H), 1.90 (m, 2H), 1.78 (m, 2H), 1.46 (m, 2H).

Preparation 13: 2-(5-i4-(phenylsulfonyl)piperazin-l-yl)pentyl)isoindoline-l,3-dione (compound 13).

General procedure 3 (derivatization (sulphonamide)). Starting materials: compound 12 and benzenesulfonyl chloride.

'H-NMR (CDCI₃) : δ 7.83 (m, 2H), 7.75 (m, 2H), 7.71 (m, 2H), 7.54 (m, 3H), 3.64 (t, 2H), 3.02 (bt, 4H), 2.49 (t, 4H), 2.30 (t, 2H), 1.65 (m, 2H), 1.46 (m, 2H), 1.30 (m, 2H). Preparation 14: 5-(4-(phenylsulfonyl)piperazin-l-yl)pentan-l-amine (compound 14).

General procedure 3 (deprotection (phtalimide)). Starting material: compound 13.

'H-NMR (CD₃OD) : δ 7.81 (m, 2H), 7.66 (m, 3H), 3.03 (t, 4H), 2.61 (t, 2H), 2.54 (t, 4H), 2.36 (t, 2H), 1.47 (m, 4H), 1.32 (m, 2H).

Preparation 15: 2-(5-(4-benzoylpiperazin-l-yl)pentyl)isoindoline-l,3-dione (compound 15).

General procedure 3 (derivatization (amide)). Starting materials: compound 12 and benzoyl chloride.

'H-NMR (CDCI₃) : δ 7.84 (m, 2H), 7.71 (m, 2H), 7.40 (m, 5H), 3.80 (bs, 2H), 3.68 (t, 2H), 3.46 (bs, 2H), 2.50 (bs 2H), 2.40 (bt, 4H), 1.70 (m, 2H), 1.58 (m, 2H), 1.39 (m, 2H). Preparation 16: l-(5-aminopentyl)-4-benzoylpiperazine (compound 16)

General procedure 3 (deprotection (phtalimide)). Starting material: compound 15.

'H-NMR (CD₃OD) : δ 7.49 (m, 3H), 7.43 (m, 2H), 3.78 (bs, 2H), 3.48 (bs, 2H), 2.66 (t, 2H), 2.56 (bs, 2H), 2.45 (m, 4H), 1.54 (m, 4H), 1.39 (m, 2H). Preparation 17: 4-(l-(naphtalen-2-ylsulfonyl)piperidin-4-yl)butan-l-ol (compound 17)

General procedure 6. Starting materials: 4-piperidin-4-yl-butan-l-ol and naphthalene-2- sulfonyl chloride.

'H-NMR (CDCI₃) : δ 8.33 (d, IH), 7.95 (m, 3H), 7.75 (dd, IH), 7.63 (m, 2H), 3.84 (m, 2H), 3.59 (m, 2H), 2.28 (t, 2H), 1.69 (m, 2H), 1.47 (m, 2H), 1.4-1.0 (m, 8H).

Preparation 18: 4-(4-azidobutyl)-l-(naphtalen-2-ylsulfonyl)piperidine (compound 18).

General procedure 7. Starting material : compound 17.

'H-NMR (CDCI₃) : δ 8.33 (d, IH), 7.95 (m, 3H), 7.76 (dd, IH), 7.64 (m, 2H), 3.86 (m, 2H), 3.22 (t, 2H), 2.29 (m, 2H), 1.71 (m, 2H), 1.53 (m, 2H), 1.4-1.0 (m, 7H).

Preparation 19: 4-(l-(naphtalen-2-ylsulfonv0piperidin-4-vnbutan-l-amine (compound 19).

General procedure 8. Starting material : compound 18.

^XH-NMR (CDCI₃) : δ 8.33 (d, IH), 7.95 (m, 3H), 7.75 (dd, IH), 7.63 (m, 2H), 3.85 (m, 2H), 2.64 (t, 2H), 2.28 (m, 2H), 1.71 (m, 2H), 1.45-1.0 (m, 11H).

EXAMPLES Example 1 : terf-butyl 4-(4-(2-cyano-3-(pyridin-4-yl^')quanidino^')butyl^')piperazine-l- carboxylate (compound 1001).

General procedure 4. Starting materials: S-Methyl /V-cyano-/V ^'-4-pyridylisothiourea and compound 6. ^XH-NMR (CD₃OD) : δ 8.40 (m, 2H), 7.34 (m, 2H), 3.44 (m, 6H), 2.44 (m, 6H), 1.64 (m, 4H), 1.47 (s, 9H).

Example 2: l-(4-(4-benzoylpiperazin-l-yl^')butyl^')-2-cvano-3-(pyridin-4-yl^')auanidine

(compound 1002)

General procedure 4. Starting materials: S-Methyl /V-cyano-/V ^'-4-pyridylisothiourea and compound 9. ^-NMR (CD₃OD) : δ 8.39 (m, 2H), 7.48 (m, 3H), 7.42 (m, 2H), 7.34 (m, 2H), 3.79 (bs, 2H), 3.45 (m, 2H), 2.57 (bs, 2H), 2.46 (t, 4H), 1.65 (m, 4H) .

Example 3 : 3-(4-(4-benzoylpiperazin-l-yl^')butylamino^')-4-(pyridin-4-ylamino^')cyclobut-3-ene- 1 ,2-dione (compound 1003) .

General procedure 5. Starting materials: 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-2,3- dione and compound 9.

'H-NMR (DMSO-d₅) : δ 9.89 (bs, IH), 8.41 (d, 2H), 7.81 (t, IH), 7.45 (m, 5H), 7.37 ( 3.62 (m, 4H), 3.34 (bs, 2H), 2.38 (bs, 2H), 2.34 (t, 4H), 1.54 (m, 4H) .

Example 4: l-(4-(l-benzoylpiperidin-4-yl^')butyl^')-2-cvano-3-(pyridin-4-yl^')auanidine

(compound 1004) .

General procedure 4. Starting materials: S-Methyl /V-cyano-/V ^'-4-pyridylisothiourea and N- benzoyl-4-piperidinebutanamine. ^XH-NMR (CD₃OD) : δ 8.39 (m, 2H), 7.48 (m, 3H), 7.40 (m, 2H), 7.34 (m, 2H), 4.62 (bd, IH), 3.72 (bd, IH), 3.41 (t, 2H), 3.09 (bt, IH), 2.85 (bt, IH), 1.87 (bd, IH), 1.65 (m, 4H), 1.40 (m, 4H), 1.19 (m, 2H).

Example 5: 3-(4-(l-benzoylpiperidin-4-vnbutylamino^')-4-(pyridin-4-ylamino^')cvclobut-3-ene- 1,2-dione (compound 1005)

General procedure 5. Starting materials: 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-2,3- dione and /V-benzoyl-4-piperidinebutanamine. 'H-NMR (DMSO-dg): δ 9.86 (bs, IH), 8.41 (d, 2H), 7.79 (t, IH), 7.43 (m, 5H), 7.35 (m, 2H), 4.45 (bs, IH), 3.61 (q, 2H), 3.53 (bs, IH), 2.98 (bs, IH), 2.76 (bs, IH), 1.60 (m, 5H), 1.30 (m, 4H), 1.06 (m, 2H).

Example 6: terf-butyl 4-(5-(2-cyano-3-(pyridin-4-yl)quanidino)pentyl)piperazine-l- carboxylate (compound 1006)

General procedure 4. Starting materials: S-Methyl /V-cyano-/V ^'-4-pyridylisothiourea and compound 11.

'H-NMR (CD₃OD) : δ 8.39 (m, 2H), 7.34 (m, 2H), 3.43 (m, 6H), 2.43 (m, 6H), 1.68 (m, 2H), 1.60 (m, 2H), 1.47 (s, 9H), 1.42 (m, 2H). Example 7: 2-cyano-l-(5-(4-(phenylsulfonynpiperazin-l-ynpentyn-3-(pyridin-4-ynauanidine

(compound 1007)

General procedure 4. Starting materials: S-Methyl /V-cyano-/V ^'-4-pyridylisothiourea and compound 14.

^-NMR (CD₃OD) : δ 8.38 (m, 2H), 7.79 (m, 2H), 7.66 (m, 3H), 7.32 (m, 2H), 3.37 (t, 2H), 3.02 (m, 4H), 2.53 (m, 4H), 2.36 (t, 2H), 1.63 (m, 2H), 1.49 (m, 2H), 1.36 (m, 2H).

Example 8: 3-(5-(4-(phenylsulfonyl)piperazin-l-yl)pentylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-l,2-dione (compound 1008).

General procedure 5. Starting materials: 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-2,3- dione and compound 14.

'H-NMR (DMSO-dg): δ 8.40 (d, 2H), 7.68 (m, 5H), 7.41 (d, 2H), 3.56 (t, 2H), 2.86 (t, 4H), 2.39 (t, 4H), 2.24 (t, 2H), 1.53 (m, 2H), 1.38 (m, 2H), 1.25 (m, 2H).

Example 9: l-(5-(4-benzoylpiperazin-l-yl)pentyl)-2-cyano-3-(pyridin-4-yl)quanidine

(compound 1009)

General procedure 4. Starting materials: S-Methyl /V-cyano-/V ^'-4-pyridylisothiourea and compound 16.

^-NMR (CD₃OD) : δ 8.39 (m, 2H), 7.48 (m, 3H), 7.43 (m, 2H), 7.34 (m, 2H), 3.79 (bs, 2H) 3.47 (bs, 2H), 3.41 (t, 2H), 2.56 (bs, 2H), 2.46 (bs, 2H), 2.44 (t, 2H), 1.64 (m, 4H), 1.44 (m, 2H).

Example 10: 3-(5-(4-benzoylpiperazin-l-yl^')pentylamino^')-4-(pyridin-4-ylamino^')cvclobut-3- ene-l,2-dione (compound 1010)

General procedure 5. Starting materials: 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-2,3 dione and compound 16.

'H-NMR (DMSO-dg): δ 9.89 (bs, 1H), 8.40 (d, 2H), 7.79 (bt, 1H), 7.43 (m, 5H), 7.35 (m, 2H), 3.61 (m, 4H), 3.40 (bs, 2H), 2.37 (bs, 2H), 2.31 (t, 4H), 1.59 (m, 2H), 1.46 (, 2H), 1.35 (m, 2H).

Example 11 : 2-cyano-l-(4-(l-naphtalen-2-ylsulfonyl)piperidin-4-yl)butyl)-3-(pyridin-4- yPauanidine (compound 1011)

General procedure 4. Starting materials: S-Methyl /V-cyano-/V ^'-4-pyridylisothiourea and compound 19.

'H-NMR (CD₃OD) : δ 8.35 (m, 3H), 8.07 (m, 2H), 7.99 (m, 1H), 7.75 (dd, 1H), 7.67 (m, 2H), 7.30 (d, 2H), 3.80 (m, 2H), 3.34 (m, 2H), 2.27 (t, 2H), 1.72 (m, 2H), 1.55 (m, 2H), 1.4-1.05 (m, 7H).

Example 12: 3-i4-il-inahtalen-2-ylsulfonyl)piperidin-4-yl)butylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-l,2-dione (compound 1012)

General procedure 5. Starting materials: 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-2,3- dione and compound 19.

'H-NMR (DMSO-d₅): δ 9.85 (bs, 1H), 8.40 (m, 3H), 8.20 (m, 2H), 8.08 (d, 1H), 7.73 (m, 4H), 7.41 (d, 2H), 3.70 (d, 2H), 3.56 (q, 2H), 2.24 (t, 2H), 1.69 (m, 2H), 1.50 (m, 2H), 1.35-1.0 (m, 7H).

Example 13: In vitro cell proliferation assay (WST-1 assay) A2780 cells were seeded in 96-well plates at 3 x 10³ cells/well in 100 μΙ_ 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 μΙ_ 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 37°C in a C0₂ 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 μΙ_ of media was then added to all wells, followed by 100 μΙ_ of each compound dilution. The plates were incubated for a further 48 h at 37°C in a C0₂ incubator (total incubation time 72 h). The number of viable cells was then assessed using Cell Proliferation Reagent WST-1. 10 μΙ_ of WST-1 reagent added to each well and incubated for one to four hours at 37°C in C0₂ 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 = [(S^c-B)/(S°-B)]xl00

S^c denotes signal measured in the presence of test compound, S° denotes signal detected in the absence of compound, and B denotes background signal, measured in blank wells containing medium only. Analysed data using GraphPad Prism .

Results can be seen in Table 1.

Table 1 - In vitro cell proliferation assay (WST-1 assay as described in Example 13)

Claims

1. A compound of the formula (I)

wherein:

X is selected from optionally substituted pyrid-3-yl and optionally substituted pyrid-4-yl; Q is selected from optionally substituted Ci-₆ alkylene and a single bond; Y is selected from (i) and (ii); where (i) is

D

R¹ R²

(i) , wherein D is = N-CN, and wherein R¹ and R² are independently selected from hydrogen, optionally substituted Ci-i₂-alkyl, optionally substituted C₃.i₂-cycloalkyl, - [CH₂CH₂0]i.io-(optionally substituted Ci_₅-alkyl), optionally substituted Ci_i₂-alkenyl, optionally substituted aryl, optionally substituted heterocydyl, and optionally substituted heteroaryl; and where (ii) is

wherein R⁵ and R⁵ are independently selected from hydrogen, optionally substituted Ci_i₂- alkyl, optionally substituted C₃-i₂-cycloalkyl, -[CH₂CH₂O]i-i₀-(optionally substituted Ci-₆-alkyl), optionally substituted Ci-i₂-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

B is optionally substituted Ci_₅ alkylene;

A is selected from and , wherein R³ is selected from hydrogen, optionally substituted Ci-i₂-alkyl, optionally substituted C₃-i₂-cycloalkyl, -[CH₂CH₂0]i-io-(optionally substituted Ci-₆-alkyl), optionally substituted Ci_i₂-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl;

Z is -J-V, wherein J is selected from -C(=0)-, -C(=0)-O, -S(=0)₂-, -P(=0)(OR⁴)-, -C(=0)-NR⁴- and - C(=S)-NR⁴-, V is selected from optionally substituted Ci_i₂-alkyl, optionally substituted C₃_i₂- cycloalkyl, -[CH₂CH₂O]i-i₀-(optionally substituted Ci-₆-alkyl), optionally substituted Ci_i₂- alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, and R⁴ is selected from hydrogen, optionally substituted Ci_i₂-alkyl, optionally substituted C₃_i₂-cycloalkyl, -[CH₂CH₂O]i-i₀-(optionally substituted Ci_₅-alkyl), optionally substituted Ci_i₂-alkenyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; q = 0-2, and r = 0-2.

2. The compound according to claim 1, wherein X is optionally substituted pyrid-4-yl.

3. The compound according to claim 2, wherein X is pyrid-4-yl.

4. The compound according to claim 1, wherein X is optionally substituted pyrid-3-yl.

5. The compound according to claim 4, wherein X is pyrid-3-yl.

6. The compound according to any one of the preceding claims, wherein J is -S(=0)₂- or - C(=0)-.

7. The compound according to claim 6, wherein J is -S(=0)₂-.

8. The compound according to claim 6, wherein J is -C(=0)-.

9. The compound according to any one of the preceding claims, wherein Z is optionally substituted benzoyl.

10. The compound according to claim 9, wherein Z is unsubstituted benzoyl.

11. The compound according to any one of the preceding claims, wherein A is

12. The compound according to any one of the preceding claims, wherein A is

13. The compound according to claim 1, which is selected from examples 1-12 described herein.

14. The compound according to claim 1, which is selected from tert-butyl 4-(4-(2-cyano-3-(pyridin-4-yl)guanidino)butyl)piperazine-l-carboxylate, l-(4-(4-benzoylpiperazin-l-yl)butyl)-2-cyano-3-(pyridin-4-yl)guanidine,

3-(4-(4-benzoylpiperazin-l-yl)butylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-l,2-dione,

1- (4-(l-benzoylpiperidin-4-yl)butyl)-2-cyano-3-(pyridin-4-yl)guanidine, 3-(4-(l-benzoylpiperidin-4-yl)butylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-l,2-dione, tert-butyl 4-(5-(2-cyano-3-(pyridin-4-yl)guanidino)pentyl)piperazine-l-carboxylate,

2- cyano-l-(5-(4-(phenylsulfonyl)piperazin-l-yl)pentyl)-3-(pyridin-4-yl)guanidine,

3- (5-(4-(phenylsulfonyl)piperazin-l-yl)pentylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione, l-(5-(4-benzoylpiperazin-l-yl)pentyl)-2-cyano-3-(pyridin-4-yl)guanidine, and 3-(5-(4-benzoylpiperazin-l-yl)pentylamino)-4-(pyridin-4-ylamino)cyclobut-3-e^

15. The compound according to any one of the preceding claims for use as a medicament.

16. The compound according to any one of the claims 1-14 for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide

phosphoribosyltransferase (NAMPRT).

17. The compound according to claims 16, 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.

18. 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 1-14.

19. 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 1-14.

20. The method according to claim 19, wherein the compound is administered in combination with a DNA damaging agent.

21. The method according to any one of the claims 19-20, 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.