Hellebrin derivatives Field of the invention

The present invention relates to new cardiotonic steroids and their use in the treatment of cancer. In particular, the present invention provides new hellebrin derivatives and their use as anticancer agent. The present invention also relates to a method for the preparation of said compounds. The invention further relates to a pharmaceutical composition comprising an effective amount of said compounds and to the use of said compounds as a medicament and/or for the treatment of diseases associated with cell proliferation, and even in particular in the treatment of cancer. Background of the invention

Cardiotonic steroids (CS) or cardiotonic glycosides represent a group of compounds that share the capacity to bind to the extra-cellular surface of the main ion transport protein in the cell, the membrane-inserted sodium pump (Na+/K+-ATPase) (Schatzmann HeIv. Physiol. Pharmacol. Acta 1 1 (1953) 346-354; Xie & Askari Eur J Biochem. 269 (2002) 2434-2439). These compounds have long been and continue to be used in the treatment of congestive heart failure as positive inotropic agents (Gheorghiade et al., Circulation 109 (2004) 2959-2964). Retrospective epidemiological studies conducted during the late 20th century revealed intriguing results: very few patients maintained on CS treatment for heart problems died from cancer [Stenkvist Anti-Cancer Drugs 12 (2001 ) 635-636]. CSs act by binding to the extra-cellular surface of Na+/K+-ATPase. This fact plus the altered expression of sodium pump subunits in different cancers strongly suggest that targeting Na+/K+-ATPase could represent a novel means to combat a growing number of malignancies. The foregoing evidence suggests that the sodium pump is a relevant molecular target for the prevention and treatment of proliferative diseases. However, the battery of substances useful to impinge on this molecule is presently somewhat restricted. Consequently, there exists a need for further reagents which target the sodium pump and, in particular, for such reagents having advantageous properties, such as, for example, reagents that are increasingly effective and/or decrease unwanted side-effects, and/or are more selective for cancerous cells, and/or are less erosive for healthy cells, and/or are comparably specific for particular cancer types, and/or are less toxic, etc.

Chemically, glycosylated CSs are compounds presenting a steroid nucleus with a lactone moiety at position 17 and a sugar moiety at position 3 (Figure 1 ). The aglycone moiety is composed of the steroid nucleus (Figure 1 ) and the lactone ring at position 17 that defines the class of cardiac glycoside. Two classes have been observed: the cardenolides (with an unsaturated butyrolactone ring) and the bufadienolides (with an α-pyrone ring).

Several plants (more particularly those belonging to Asclepiadacea, Apocynaceae, Ranunculaceae and Scrophulaήaceae families) are recognized to contain CSs. CSs are also extensively found in animal species and occur mainly in toads (species of the Bufo genera). Several independent investigators have also found that mammalian tissues and body fluids (including brain, adrenal glands, heart, blood plasma, cerebrospinal fluid and urine) contain digitalis-like compounds.

The bufadienolide class of CSs remains largely unexplored despite their structural abundance and great natural profusion. Plants of the family Ranunculaceae (mainly Helleborus species) are known to contain several bufadienolides, like hellebrin, helleborein, helleborin.

Hellebrin

A well-known representatives of the Ranunculaceae are Helleborus niger (known as Christmas rose; formerly used in palsy, insanity, apoplexy, dropsy, epilepsy, etc), Helleborus foetidus (has been used in powder and decoction to expel tapeworm, and in asthma, hypochondriasis, and hysteria) and Helleborus viridis (its rhizome and rootlets were used as drug; the commercial name of the drug is Radix hellebori viridis, or green hellebore root). The entire Helleborus plant is toxic. Helleborus poisoning includes vomiting, diarrhea, and nervous system disturbances such as delirium, convulsions, and death due to respiratory collapse. Both animals and humans are affected by this poisonous plant. When eaten, the hellebores are said to have a "burning taste." Cardiac glycosides are responsible for poisonings. Hellebrin is a cardiac stimulant found in these plants.

Most chemotherapeutic agents currently used in the clinic for the treatment of cancer aim to take advantage of cell division itself and gain much of their selectivity from the fact that cancer cells divide more rapidly than their normal counterparts. In addition, the life duration of cancer cells is longer than that of normal cells in the tissue of which the cancer arose. A major problem with the currently used cytotoxic molecules reside in their lack of

specificity: normal cells are themselves being injured. As a consequence, these drugs share in common an elevated toxicity.

It is a general object of the present invention to provide novel hellebrin derivatives, which have a cytotoxic activity with reduced general toxicity. It is another general object of the present invention to provide novel hellebrin derivatives, which can be exploited in medical applications.

Summary of the invention

The present invention provides to compounds of the Formula I, a stereoisomer, tautomer, racemate, prodrug, metabolite, or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

I wherein R ¹ is selected from the group comprising alkyl, hydroxyalkyl, aminoalkyl, thioalkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylaminoalkyl, alkylhydrazinoalkyl, alkylthioalkyl, alkyloxyalkenyl, alkylaminoalkenyl, alkylhydrazinoalkenyl, alkylthioalkynyl, alkanoyl, alkyloxycarbonyl, alkylaminocarbonyl, alkylthiocarbonyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylaminocarbonyl, cycloalkylthiocarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkylaminocarbonyl, cycloalkylalkoxythiocarbonyl, cycloalkylaminoalkyl, cycloalkylhydrazinoalkyl, cycloalkylaminoalkenyl, cycloalkylthioalkyl, cycloalkylthioalkenyl, alkylcarbonyloxyalkyl, alkylcarbonyloxyalkenyl, alkylcarbonylaminoalkyl, alkylcarbonylhydrazinoalkyl, alkylcarbonylaminoalkenyl, arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkenyl, cycloalkylcarbonylaminoalkyl, cycloalkylcarbonylhydrazinoalkyl, silyloxyalkyl, aralkyl, arylalkenyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl, aralkylaminocarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, aryloxyalkenyl, arylaminoalkyl, arylhydrazinoalkyl, arylaminoalkenyl, arylthioalkyl, arylthioalkenyl, haloalkyl, haloalkenyl, aralkanoyl, aroyl, aryloxyalkanoyl, carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl, Het ¹ alkyl, Het ¹ alkenyl, Het ¹ oxyalkyl, Het ¹ aminoalkyl, Het ¹ hydrazinoalkyl, Het ¹ aminoalkenyl, Het ¹ aralkyl, Het ¹ aralkenyl, Het ¹ cycloalkyl, Het ¹ cycloalkenyl, Het ¹ carbonyl, Het ¹ aminocarbonyl,

Het ¹ alkoxycarbonyl, Het ¹ alkylaminocarbonyl, Het ¹ alkylthiocarbonyl, Het ¹ oxycarbonyl, Het ¹ thiocarbonyl, Het ¹ alkanoyl, Het ¹ aralkanoyl, Het ¹ aryloxyalkyl, Het ¹ arylaminoalkyl, Het ¹ arylhydrazinoalkyl, Het ¹ arylaminoalkenyl, Het ¹ aryloxyalkenyl, Het ¹ alkyloxyalkyl, Het ¹ alkyloxyalkenyl, Het ¹ arylthioalkyl, Het ¹ arylthioalkenyl, Het ¹ aryloxycarbonyl, Het ¹ arylaminocarbonyl, Het ¹ aralkoxycarbonyl, Het ¹ aralkylaminocarbonyl, Het ¹ aroyl, Het ¹ oxyalkylcarbonyl, Het ¹ aminoalkylcarbonyl, Het ¹ thioalkylcarbonyl,

Het ¹ alkyloxyalkylcarbonyl, Het ¹ alkylaminoalkylcarbonyl, Het ¹ aryloxyalkylcarbonyl, Het ¹ arylaminoalkylcarbonyl, Het ¹ carbonyloxyalkyl, Het ¹ carbonylaminoalkyl,

Het ¹ carbonyloxyalkenyl, Het ¹ carbonylaminoalkenyl, Het ¹ alkylcarbonyloxyalkyl, Het ¹ alkylcarbonyloxyalkenyl, Het ¹ alkylcarbonylaminoalkyl,

Het ¹ alkylcarbonylhydrazinoalkyl, Het ¹ alkylcarbonylaminoalkenyl,

Het ¹ aralkylcarbonyloxyalkyl, Het ¹ aralkylcarbonyloxyalkenyl,

Het ¹ aralkylcarbonylaminoalkyl, Het ¹ aralkylcarbonylhydrazinoalkyl,

Het ¹ aralkylcarbonylaminoalkenyl, Het ² alkyl; Het ² alkenyl; Het ² oxyalkyl, Het ² oxyalkenyl, Het ² aminoalkyl, Het ² hydrazinoalkyl, Het ² aminoalkenyl, Het ² alkyloxyalkyl,

Het ² alkyloxyalkenyl, Het ² alkylaminoalkyl, Het ² alkylaminoalkenyl, Het ² aralkyl, Het ² aralkenyl, Het ² carbonyl, Het ² oxycarbonyl, Het ² aminocarbonyl, Het ² thiocarbonyl, Het ² alkanoyl, Het ² alkylthiocarbonyl, Het ² alkoxycarbonyl, Het ² alkylaminocarbonyl, Het ² aralkanoyl, Het ² aralkoxycarbonyl, Het ² aralkylaminocarbonyl, Het ² aryloxycarbonyl, Het ² arylaminocarbonyl, Het ² aroyl, Het ² aryloxyalkyl, Het ² aryloxyalkenyl,

Het ² arylaminoalkyl, Het ² arylhydrazinoalkyl, Het ² arylaminoalkenyl, Het ² arylthioalkyl, Het ² arylthioalkenyl, Het ² oxyalkylcarbonyl, Het ² thioalkylcarbonyl, Het ² aminoalkylcarbonyl, Het ² alkyloxyalkylcarbonyl, Het ² alkylthioalkylcarbonyl, Het ² alkylaminoalkylcarbonyl, Het ² aryloxyalkylcarbonyl, Het ² arylaminoalkylcarbonyl, Het ² arylthioalkylcarbonyl, Het ² carbonyloxyalkyl, Het ² carbonylaminoalkyl, Het ² carbonylhydrazinoalkyl,

Het ² carbonylthioalkyl, Het ² carbonyloxyalkenyl, Het ² alkylcarbonyloxyalkyl,

Het ² alkylcarbonyloxyalkenyl, Het ² aralkylcarbonyloxyalkyl, Het ² aralkylcarbonyloxyalkenyl, cyano, aminocarbonyl, aminoalkanoyl, alkylamino, wherein R ² and R ³ are each independently selected from the group comprising hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy, alkyloxyalkyloxy, cycloalkyloxy cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy, haloalkyloxy, hydroxyalkyloxy, aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy, formyloxy, Het ¹ alkyloxy, Het ¹ oxy, Het ¹ oxyalkyloxy, Het ¹ aryloxy,

Het ¹ aralkyloxy, Het ¹ cycloalkyloxy, Het ¹ carbonyloxy, Het ¹ oxycarbonyloxy, Het ¹ alkanoyloxy, Het ¹ aralkanoyloxy, Het ¹ aryloxyalkyloxy, Het ¹ aroyl, Het ² oxy, Het ² alkyloxy; Het ² oxyalkyloxy,

Het ² aralkyloxy, Het ² cycloalkyloxy, Het ² alkanoyloxy, Het ² aralkanoyloxy, Het ² carbonyloxyl, Het ² aryloxy, Het ² aryloxyalkyloxy; wherein R ¹ , R ² and R ³ are each optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy, or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het ¹ , Het ² , Het ¹ alkyl, Het ² alkyl, Het ¹ amino, Het ² amino, Het ¹ alkylamino, Het ² alkylamino, Het ¹ thio, Het ² thio, Het ¹ alkylthio, Het ² alkylthio, Het ¹ oxy and Het ² oxy, OR ⁶ , SR ⁶ , SO ₂ NR ⁶ R ⁷ , SO ₂ N(OH)R ⁶ , CN, CR ⁶ =NR ⁷ , S(O)R ⁶ , SO ₂ R ⁶ , CR ⁶ =N(OR ⁷ ), N ₃ , NO ₂ , NR ⁶ R ⁷ , N(OH)R ⁶ , C(O)R ⁶ , C(S)R ⁶ , CO ₂ R ⁶ , C(O)SR ⁶ , C(O)NR ⁶ R ⁷ , C(S)NR ⁶ R ⁷ , C(O)N(OH)R ⁷ , C(S)N(OH)R ⁶ , NR ⁶ C(O)R ⁷ , NR ⁶ C(S)R ⁷ , N(OH)C(O)R ⁷ , N(OH)C(S)R ⁶ , NR ⁶ CO ₂ R ⁷ , NR ⁶ C(O)NR ⁷ R ⁸ , and NR ⁶ C(S)NR ⁷ R ⁸ , N(OH)CO ₂ R ⁶ , NR ⁶ C(O)SR ⁷ , N(OH)C(O)NR ⁶ R ⁷ , N(OH)C(S)NR ⁶ R ⁷ , NR ⁶ C(O)N(OH)R ⁷ , NR ⁶ C(S)N(OH)R ⁷ , NR ⁶ SO ₂ R ⁷ , NHSO ₂ NR ⁶ R ⁷ , NR ⁶ SO ₂ NHR ⁷ , P(O)(OR ⁶ XOR ⁷ ), with t being an integer selected from 1 or 2, and R ⁶ , R ⁷ and R ⁸ being each independently selected from the group comprising hydrogen, hydroxyl, alkyl, aryl, Het ¹ , Het ¹ alkyl, Het ¹ aryl, Het ² , alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino; wherein R ⁴ is selected from the group comprising hydroxyl, amino, thio, oxo, alkynyl, alkyloxy, alkylamino, alkylthio, alkyloxyalkenyl, alkylaminoalkenyl, alkylhydrazino cycloalkylamino, cycloalkylhydrazino, cycloalkylthio, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylhydrazinoalkyl, arylcarbonyloxy, alkylcarbonylhydrazino, cycloalkylcarbonyloxy, cycloalkylcarbonylamino, cycloalkylcarbonylhydrazino, silyloxy, arylalkenyl, aryloxyalkenyl, arylamino, arylhydrazino, arylthio, arylthioalkenyl, halo, haloalkenyl, Het ¹ alkenyl, Het ¹ oxy, Het ¹ amino, Het ¹ hydrazino, Het ¹ aminoalkenyl,

Het ¹ aryloxy, Het ¹ aralkenyl, Het ¹ cycloalkyloxy, Het ¹ cycloalkenyl, Het ¹ arylamino,

Het ¹ arylhydrazino, Het ¹ arylaminoalkenyl, Het ¹ aryloxyalkenyl, Het ¹ alkyloxy,

Het ¹ alkyloxyalkenyl, Het ¹ arylthio, Het ¹ carbonyloxy, Het ¹ carbonylamino,

Het ¹ carbonyloxyalkenyl, Het ¹ carbonylaminoalkenyl, Het ¹ alkylcarbonyloxy, Het ¹ alkylcarbonyloxyalkenyl, Het ¹ alkylcarbonylamino, Het ¹ alkylcarbonylhydrazino,

Het ¹ alkylcarbonylaminoalkenyl, Het ¹ aralkylcarbonyloxy, Het ¹ aralkylcarbonyloxyalkenyl, Het ¹ aralkylcarbonylamino, Het ¹ aralkylcarbonylhydrazino,

Het ¹ aralkylcarbonylaminoalkenyl, Het ² oxy, Het ² amino, Het ² hydrazino, Het ² aminoalkenyl, Het ² alkyloxy, Het ² alkyloxyalkenyl, Het ¹ alkylamino, Het ² alkylamino, Het ² aralkenyl, Het ² aryloxy, Het ² aryloxyalkenyl, Het ² arylamino, Het ² arylhydrazino, Het ² arylaminoalkenyl, Het ² arylthio, Het ² arylthioalkenyl, Het ² carbonyloxy, Het ² carbonylamino,

Het ² carbonylhydrazino, Het ² carbonylthio, Het ² carbonyloxyalkenyl, Het ² alkylcarbonyloxy, Het ² alkylcarbonyloxyalkenyl, Het ² aralkylcarbonyloxy, Het ² aralkylcarbonyloxyalkenyl, cyano, wherein R ⁴ is optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy, or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het ¹ , Het ² , Het ¹ alkyl, Het ² alkyl, Het ¹ amino, Het ² amino, Het ¹ alkylamino, Het ² alkylamino, Het ¹ thio, Het ² thio, Het ¹ alkylthio, Het ² alkylthio, Het ¹ oxy and Het ² oxy, OR ⁹ , SR ⁹ , SO ₂ NR ⁹ R ¹⁰ , SO ₂ N(OH)R ⁹ , CN, CR ⁹ =NR ¹⁰ , S(O)R ⁹ , SO ₂ R ⁹ , CR ⁹ =N(OR ¹⁰ ), N ₃ , NO ₂ , NR ⁹ R ¹⁰ , N(OH)R ⁹ , C(O)R ⁹ , C(S)R ⁹ , CO ₂ R ⁹ , C(O)SR ⁹ , C(O)NR ⁹ R ¹⁰ , C(S)NR ⁹ R ¹⁰ , C(O)N(OH)R ⁹ , C(S)N(OH)R ⁹ , NR ⁹ C(O)R ¹⁰ , NR ⁹ C(S)R ¹⁰ , N(OH)C(O)R ⁹ , N(OH)C(S)R ⁹ , NR ⁹ CO ₂ R ¹⁰ , NR ⁹ C(O)NR ¹⁰ R ¹¹ , and NR ⁹ C(S)NR ¹⁰ R ¹¹ , N(OH)CO ₂ R ⁹ , NR ⁹ C(O)SR ¹⁰ , N(OH)C(O)NR ⁹ R ¹⁰ , N(OH)C(S)NR ⁹ R ¹⁰ , NR ⁹ C(O)N(OH)R ¹⁰ , NR ⁹ C(S)N(OH)R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , NHSO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ NHR ¹⁰ , P(O)(OR ⁹ )(OR ¹⁰ ), with t being an integer between 1 and 2, and R ⁹ , R ¹⁰ and R ¹¹ being each independently selected from the group comprising hydrogen, hydroxyl, alkyl, aryl, Het ¹ , Het ¹ alkyl, Het ¹ aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino; or wherein R ⁴ is selected from the group comprising glucosyloxy, fructosyloxy, galactosyloxy, mannosyloxy, ribosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, rhamnosyloxy, threosyloxy, sorbosyloxy, psicosyloxy, tagatosyloxy, fucosyloxy, arabinosyloxy, xylofuranosyloxy, lyxosyloxy, talosyloxy, psicosyloxy, idosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, abequosyloxy, isomaltosyloxy, kojibiosyloxy, laminaribiosyloxy, nigerosyloxy,

primeverosyloxy, rutinosyloxy, tyvelosyloxy, maltosyloxy, lactosyloxy, sucrosyloxy, cellobiosyloxy, trehalosyloxy, gentiobiosyloxy, melibiosyloxy, turanosyloxy, sophorosyloxy, isosucrosyloxy, raffinosyloxy, palatinosyloxy, lactulosyloxy, gentianosyloxy, 3- mannobiosyloxy, 6-mannobiosyloxy, 3-galactobiosyloxy, 4-galactobiosyloxy, maltotriosyloxy, maltotetraosyloxy, isomaltotriosyloxy, maltopentaosyloxy, maltohexaosyloxy, maltoheptaosyloxy, sicosyloxy, panosyloxy, isopanosyloxy, inosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, globotriosyloxy, erlosyloxy, neotrehalosyloxy, chitobiosyloxy, chitobiosemannosyloxy, glucosaminyl(2-amino-2-deoxy- D-glucosyloxy), N-acetyl-glucosaminyl(2-(acetylamino)-2-deoxy-D-glucosyloxy) , octylglucopyranosyloxy, octylribofuranosyloxy, cyclohexylglucopyranosyloxy, cyclohexylxylofuranosyloxy, benzylglucopyranosyloxy, benzylarabinofuranosyloxy, N- acetyl-lactosaminyl-oxy, acosaminyl-oxy, amicetosyloxy, amylosyloxy, apiosyloxy, arcanosyloxy, ascarylosyloxy, bacillosaminyl-oxy, boivinosyloxy, cellotriosyloxy, chacotriosyloxy, chalcosyloxy, cladinosyloxy, colitosyloxy, cymarosyloxy, daunosaminyl- oxy, desosaminyl-oxy, d-glycero-L-gulo-heptosyloxy, diginosyloxy, digitalosyloxy, digitoxosyloxy, evalosyloxy, evernitrosyloxy, forosaminyl-oxy, fucosaminyl-oxy, garosaminyl-oxy, hamamelosyloxy, isolevoglucosyl-oxy, kanosaminyl-oxy, kansosaminyl- oxy, lactosaminyl-oxy, lactosediaminyl-oxy, fucitolyl-oxy, maltulosyloxy, mannosaminyl- oxy, melezitosyloxy, mycaminosyloxy, mycarosyloxy, mycinosyloxy, mycosaminyl-oxy, noviosyloxy, oleandrosyloxy, paratosyloxy, perosaminyl-oxy, planteosyloxy, pneumosaminyl-oxy, purpurosaminyloxy, quinovosaminyl-oxy, quinovosyloxy, rhamnitolyl- oxy, rhamnosaminyl-oxy, rhodinosyloxy, rhodosaminyl-oxy, sarmentosyloxy, solatriosyloxy, stachyosyloxy, streptosyloxy, umbelliferosyloxy, trehalosaminyl-oxy, D- glucopyranosyl-α-L-rhamnosyloxy, 1 ,6-anhydro-D-glucopyranosyloxy, 1-hydroxy-α-D- allopyranosyloxy, 2,3:5,6-di-O-isopropylidene-D-mannofuranosyloxy, 2-amino-2-deoxy-D- galactitolyl-oxy, 2-deoxyribosyloxy, 2-deoxyglucosyloxy, 5-amino-5-deoxy-D- glucopyranosyloxy, 6-deoxy-D-galactitolyl-oxy, 2-amino-2-deoxyglucosyloxy, 2-acetamido- 2-deoxy-glucosyloxy, 2-amino-2-deoxy galactosyloxy, 2-acetamido-2-deoxy- galactosyloxy, 2-amino-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-mannosyloxy, 2- acetamido^-deoxy^-O-β-D-galactosyl-D-glucosyloxy, 2-amino-2-deoxy-4-O-β-D- galactosyl-D-glucosyloxy, θ'-N-acetylglucosaminyllactosyloxy, 2-acetamido-2-deoxy-3-O- α-L-fucosyl-D-glucosyloxy, 6-O(2-acetamido-2-deoxy-β-D-glucosyl)-D-galactosyloxy, 2- acetamido^-deoxy-S-O-β-D-galactosyl-D-glucosyloxy, 2'-acetamido-2'-deoxy-3-O-β-D- glucosyl-D-galactosyloxy, S-fucosyl-D-lactosyloxy, 3-fucosyl-2-acetamido-2-deoxy-4-O-β- D-galactosyl-D-glucosyloxy, L or D isomers thereof, a or b form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy

derivatives thereof, hydroxyl-protected acetate or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxy, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, and cycloalkylalkyl; wherein R ⁵ is hydrogen or R ⁵ and R ² together with the carbon atom to which they are attached form a double bond, With the proviso that when R ¹ is formyl, and R ² , R ³ are hydroxyl, and R ⁵ is hydrogen, R ⁴ is not D-glucopyranosyl-α-L-rhamnosyloxy, D-glucopyranosyl-α-L- rhamnosyloxyhexaacetate, or 4-O-(6-deoxy-α-L-mannopyranosyl)-β-D- galactopyranosyloxy, 2-4-di-O-acetyl-6-deoxy-3-O-methyl-α-D-galactopyranosyloxy, 6- deoxy-3-O-methyl-α-D-galactopyranosyloxy, 2,3,4,6-tetra-O-acetyl-β-D- glucopyranosyloxy, β-D-glucopyranosyloxy, 6-deoxy-3-O-methyl-α-L-glucopyranosyloxy, 6-deoxy-α-L-annopyranosyloxyl, or 6-deoxy-4-O-β-D-glucopyranosyl-α-L- mannopyranosyloxy.

The invention further provides the use of the compounds of Formula I as a medicament. The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of at least one compound of Formula I.

The invention further provides for the use of a compound according to the invention for the preparation of a medicament for the prevention and/or treatment of cancer, and/or for preventing, treating and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith.

The invention also provides a method for treating cancer comprising administering at least one compound of formula I in an individual in need thereof.

The present invention further provides kits for use in treating cancer and related disorders in an individual in need thereof comprising a therapeutically effective amount of a

pharmaceutical composition comprising at least one compound of formula I, optionally, in combination with a pharmaceutically acceptable carrier.

Other aspects, embodiments, uses and advantages of the invention will become clear from the further description below. Brief description of the drawings

Figure 1 represents some examples Cardiotonic steroids' structure. Detailed description

The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

In an embodiment, the present invention provides compounds of Formula I,

I wherein R ¹ is selected from the group comprising Ci _-6 alkyl, hydroxyCi _-6 alkyl, aminoCi. ₆ alkyl, thioCi _-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ci _-6 alkyloxyCi. ₆ alkyl, Ci _-6 alkylaminoCi. ₆ alkyl, d-ealkylhydrazinoCi-ealkyl, Ci _-6 alkylthioCi. ₆ alkyl, Ci _-6 alkyloxyC ₂ - ₆ alkenyl, Ci _-6 alkylaminoC ₂ - ₆ alkenyl, Ci _-6 alkylhydrazinoC ₂ - ₆ alkenyl, Ci _-6 alkylthioC ₂ - ₆ alkynyl, Ci _-6 alkanoyl, Ci- ₆ alkyloxycarbonyl, Ci _-6 alkylaminocarbonyl, Ci _-6 alkylthiocarbonyl, Cs-ecycloalkyld-ealkyl, C ₃ - ₆ cycloalkylC ₂ - ₆ alkenyl, C _3-6 cycloalkylcarbonyl, Cs-βcycloalkyld-ealkanoyl, C _{3- 6} cycloalkylaminocarbonyl, Cs-ecycloalkylthiocarbonyl, C _3-6 cycloalkylCi. ₆ alkoxycarbonyl, C _{3- 6} cycloalkylCi _-6 alkylaminocarbonyl, C _3-6 cycloalkylCi _-6 alkoxythiocarbonyl, C _3-

₆ cycloalkylaminoCi _-6 alkyl, Cs-βcycloalkylhydrazinod-ealkyl, C _3-6 cycloalkylaminoC ₂ - ₆ alkenyl, Cs-ecycloalkylthiod-ealkyl, C _3-6 cycloalkylthioC ₂ - ₆ alkenyl, d-ealkylcarbonyloxyd-ealkyl, Ci- ₆ alkylcarbonyloxyC ₂ - ₆ alkenyl, d-ealkylcarbonylaminod-ealkyl, Ci-

₆ alkylcarbonylhydrazinoCi _-6 alkyl, Ci _-6 alkylcarbonylaminoC ₂ - ₆ alkenyl, C _6- ioarylcarbonyloxyCi- ₆ alkyl, Cs-βcycloalkylcarbonyloxyd-ealkyl, C _3-6 cycloalkylcarbonyloxyC ₂ -

₆ alkenyl, C ₃ - ₆ cycloalkylcarbonylaminoCi. ₆ alkyl, C ₃ - ₆ cycloalkylcarbonylhydrazinoCi. ₆ alkyl, silyloxyCi _-6 alkyl, C _6- ioaralkyl, C ₆ -ioarylC ₂ - ₆ alkenyl, C _6- ioaryloxycarbonyl, C _6- i ₀ arylthiocarbonyl, C _6- ioaralkoxycarbonyl, di-ioaralkylaminocarbonyl, C _6- i ₀ arylalkylthiocarbonyl, d;-ioaryloxyd- ₆ alkyl, C ₆ -ioaryloxyC ₂ - ₆ alkenyl, C ₆ -ioarylaminoCi. ₆ alkyl, d;-ioarylhydrazinod- ₆ alkyl, C ₆ -ioarylaminoC ₂ - ₆ alkenyl, d;-ioarylthiod- ₆ alkyl, C _6- ioarylthioC ₂ - ₆ alkenyl, haloCi _-6 alkyl, haloC ₂ - ₆ alkenyl, C _6- ioaralkanoyl, C ₆ -ioaroyl, C _6- ioaryloxyCi _-6 alkanoyl, carboxyl, formyl, C ₂ - ₆ alkenylcarbonyl, C ₂ - ₆ alkynylcarbonyl, Het ¹ d- ₆ alkyl, Het ¹ C _2-6 alkenyl, Het ¹ oxyCi _-6 alkyl, Het ¹ aminoCi. ₆ alkyl, Het ¹ hydrazinoCi _-6 alkyl, Het ¹ aminoC _2-6 alkenyl, Het ¹ C ₆ -ioaralkyl, Het ¹ C ₆ -ioaralkenyl, Het ¹ C _3-6 cycloalkyl, Het ¹ C _5- βcycloalkenyl, Het ¹ carbonyl, Het ¹ aminocarbonyl, Het ¹ Ci- ₆ alkoxycarbonyl, Het ¹ d- ₆ alkylaminocarbonyl, Het ¹ Ci _-6 alkylthiocarbonyl, Het ¹ oxycarbonyl, Het ¹ thiocarbonyl, Het ¹ d- ₆ alkanoyl, Het ¹ C ₆ -ioaralkanoyl, Het ¹ C ₆ -ioaryloxyCi _-6 alkyl, Het ¹ C ₆ -ioarylaminoCi. ₆ alkyl, Het ¹ C ₆ -ioarylhydrazinoCi _-6 alkyl, Het ¹ C ₆ -ioarylaminoC _2-6 alkenyl, Het ¹ C ₆ -ioaryloxyC _2-6 alkenyl, Het ¹ Ci _-6 alkyloxyCi _-6 alkyl, Het ¹ Ci. ₆ alkyloxyC _2-6 alkenyl, Het ¹ C _6- ioarylthioCi _-6 alkyl, Het ¹ C _6- ioarylthioC _2-6 alkenyl, Het ¹ C ₆ -ioaryloxycarbonyl, Het ¹ C ₆ -ioarylaminocarbonyl, Het ¹ C _6- i ₀ aralkoxycarbonyl, Het ¹ C ₆ -ioaralkylaminocarbonyl, Het ¹ C ₆ -ioaroyl, Het ¹ oxyd- ₆ alkylcarbonyl, Het ¹ aminoCi. ₆ alkylcarbonyl, Het ¹ thioCi _-6 alkylcarbonyl, Het ¹ Ci _-6 alkyloxyCi. ₆ alkylcarbonyl, Het ¹ d- ₆ alkylaminod- ₆ alkylcarbonyl, Het ¹ C ₆ -ioaryloxyd- ₆ alkylcarbonyl, Het ¹ d;-ioarylaminod- ₆ alkylcarbonyl, Het ¹ carbonyloxyd- ₆ alkyl, Het ¹ carbonylaminoCi. ₆ alkyl, Het ¹ carbonyloxyC _2-6 alkenyl, Het ¹ carbonylaminoC _2-6 alkenyl, Het ¹ Ci_

6alkylcarbonyloxyCi-6alkyl, Het ¹ d-6alkylcarbonyloxyC _2- 6alkenyl, Het ¹ Ci_

₆ alkylcarbonylaminoCi. ₆ alkyl, Het^i-ealkylcarbonylhydrazinod-ealkyl, Het ¹ Ci_

₆ alkylcarbonylaminoC _2-6 alkenyl, Het^e-ioaralkylcarbonyloxyd-ealkyl, Het ¹ C _6- ioaralkylcarbonyloxyC _2-6 alkenyl, Het^e-ioaralkylcarbonylaminod-ealkyl, Het ¹ C _{6- l} oaralkylcarbonylhydrazinod-ealkyl, Het ¹ C ₆ -ioaralkylcarbonylaminoC _2-6 alkenyl, Het ² d_ ₆ alkyl; Het ² alkenyl; Het ² oxyd- ₆ alkyl, Het ² oxyC _2-6 alkenyl, Het ² aminoCi. ₆ alkyl, Het ² hydrazinod _-6 alkyl, Het ² aminoC _2- 6alkenyl, He^d-ealkyloxyd-ealkyl, Het ² d_ 6alkyloxyC _2-6 alkenyl, Het ² d.6alkylaminod.6alkyl, Het ² Ci.6alkylaminoC _2- 6alkenyl, Het ² C _6- i _O aralkyl, Het ² C ₆ -ioaralkenyl, Het ² carbonyl, Het ² oxycarbonyl, Het ² aminocarbonyl, Het ² thiocarbonyl, Het ² d _-6 alkanoyl, Het ² d- ₆ alkylthiocarbonyl, Het ² d- ₆ alkoxycarbonyl, Het ² Ci. ₆ alkylaminocarbonyl, Het ² C ₆ -ioaralkanoyl, Het ² C ₆ -ioaralkoxycarbonyl, Het ² C _6- i ₀ aralkylaminocarbonyl, Het ² C ₆ -ioaryloxycarbonyl, Het ² C ₆ -ioarylaminocarbonyl, Het ² C _6- i ₀ aroyl, Het ² C ₆ -ioaryloxyd- ₆ alkyl, Het ² C ₆ -ioaryloxyC _2-6 alkenyl, Het ² C ₆ -ioarylaminoCi. ₆ alkyl, Het ² C ₆ -ioarylhydrazinod- ₆ alkyl, Het ² C ₆ -ioarylaminoC _2-6 alkenyl, Het ² C ₆ -ioarylthioCi. ₆ alkyl, Het ² C6-ioarylthioC _2-6 alkenyl, Het ² oxyd _-6 alkylcarbonyl, Het ² thioCi.6alkylcarbonyl,

Het ² aminoCi. ₆ alkylcarbonyl, He^d-ealkyloxyd-ealkylcarbonyl, Het ² Ci _-6 alkylthioCi. ₆ alkylcarbonyl, He^d-ealkylaminod-ealkylcarbonyl, He^Ce-ioaryloxyd-ealkylcarbonyl, Het ² d3-ioai"ylaminod.6alkylcarbonyl, He^Ce-ioarylthiod-ealkylcarbonyl, Het ² carbonyloxyd_ ₆ alkyl, Het ² carbonylaminoCi.6alkyl, Het ² carbonylhydrazinod-6alkyl, Het ² carbonylthioCi_ ₆ alkyl, Het ² carbonyloxyC ₂ -6alkenyl, Het ² d.6alkylcarbonyloxyd.6alkyl, Het ² Ci_ ₆ alkylcarbonyloxyalkenyl, He^Ce-ioaralkylcarbonyloxyd-ealkyl, Het ² C _6- ioaralkylcarbonyloxyC ₂ - ₆ alkenyl, cyano, aminocarbonyl, aminoCi. ₆ alkanoyl, d- ₆ alkylamino, wherein R ² and R ³ are each independently selected from the group comprising hydroxyl, d _-6 alkyloxy, d _-6 alkylsilyloxy, C _6- ioarylsilyloxy, d-ealkyloxyd^alkyloxy, C _{3- 6} cycloalkyloxy, Cs-βcycloalkyld-ealkyloxy, C _6- ioaralkyloxy, Cβ-ioaryloxyd-ealkyloxy, silyloxy, Ci-6alkylcarbonyloxy, Cβ-ioarylcarbonyloxy, Cs-ecycloalkylcarbonyloxy, haloCi-6alkyloxy, hydroxyCi-6alkyloxy, C _6- ioaralkanoyloxy, C _6- ioaroyloxy, Cβ-ioaryloxycarbonyld-ealkyloxy, formyloxy, Het ¹ d-6alkyloxy, Het ¹ oxy, Het ¹ oxyd _-6 alkyloxy, Het ¹ C _6- ioaryloxy, Het ¹ C _6- i ₀ aralkyloxy, Het ¹ C _3- 6cycloalkyloxy, Het ¹ carbonyloxy, Het ¹ oxycarbonyloxy, Het ¹ d_ ₆ alkanoyloxy, Het ¹ C _6- ioaralkanoyloxy, Het ¹ C6-ioaryloxyd.6alkyloxy, Het ¹ C _6- ioaroyl, Het ² oxy, Het ² Ci _-6 alkyloxy; Het ² oxyd _-6 alkyloxy, Het ² C _6- ioaralkyloxy, Het ² C _3- 6cycloalkyloxy, Het ² d_ ₆ alkanoyloxy, Het ² C _6- ioaralkanoyloxy, Het ² carbonyloxyl, Het ² C6-ioaryloxy, Het ² C _6- ioaryloxyCi-6alkyloxy; wherein R ¹ , R ² and R ³ are each optionally substituted by one or more substituents independently selected from the group comprising d _-6 alkyl, C _6- ioaralkyl, C _6- ioaryl, Het ¹ , Het ² , C _3-6 cycloalkyl, d- ₆ alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(d_ ₆ alkyl)aminocarbonyl, aminosulfonyl, d.6alkylS(=O) _t , hydroxy, cyano, halogen, haloCi. ₆ alkyl, haloCi-βalkoxy, or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising d _-6 alkyl, C _6- ioaryl, C _6- ioaralkyl, C _{6- l} oaryloxy, C ₆ -ioarylamino, C _6- ioarylthio, Cβ-ioaryloxyd-ealkyl, Cβ-ioarylaminod-ealkyl, C _6- i ₀ aralkoxy, d _-6 alkylthio, Ci _-6 alkoxy, Cβ-ioaryloxyd-ealkoxy, Cβ-ioarylaminod-ealkoxy, C _6- i ₀ aralkylamino, Cβ-ioaryloxyd-ealkylamino, Cβ-ioarylaminod-ealkylamino, Cβ-ioarylthiod. ₆ alkoxy, Cβ-ioarylthiod-ealkylamino, C _6- ioaralkylthio, Cβ-ioaryloxyd-ealkylthio, C _6- ioarylaminoCi-6alkylthio, C6-ioarylthiod _-6 alkylthio, Ci _-6 alkylamino, C _3-6 cycloalkyl, C _3- ecycloalkyld-ealkyl, Het ¹ , Het ² , Het ¹ d _-6 alkyl, Het ² d _-6 alkyl, Het ¹ amino, Het ² amino, Het ¹ d_ ₆ alkylamino, Het ² d-6alkylamino, Het ¹ thio, Het ² thio, Het ¹ Ci-6alkylthio, Het ² d-6alkylthio, Het ¹ oxy and Het ² oxy, OR ⁶ , SR ⁶ , SO ₂ NR ⁶ R ⁷ , SO ₂ N(OH)R ⁶ , CN, CR ⁶ =NR ⁷ , S(O)R ⁶ , SO ₂ R ⁶ , CR ⁶ =N(OR ⁷ ), N ₃ , NO ₂ , NR ⁶ R ⁷ , N(OH)R ⁶ , C(O)R ⁶ , C(S)R ⁶ , CO ₂ R ⁶ , C(O)SR ⁶ , C(O)NR ⁶ R ⁷ , C(S)NR ⁶ R ⁷ , C(O)N(OH)R ⁷ , C(S)N(OH)R ⁶ , NR ⁶ C(O)R ⁷ , NR ⁶ C(S)R ⁷ , N(OH)C(O)R ⁷ , N(OH)C(S)R ⁶ , NR ⁶ CO ₂ R ⁷ , NR ⁶ C(O)NR ⁷ R ⁸ , and NR ⁶ C(S)NR ⁷ R ⁸ , N(OH)CO ₂ R ⁶ ,

NR ⁶ C(O)SR ⁷ , N(OH)C(O)NR ⁶ R ⁷ , N(OH)C(S)NR ⁶ R ⁷ , NR ⁶ C(O)N(OH)R ⁷ , NR ⁶ C(S)N(OH)R ⁷ , NR ⁶ SO ₂ R ⁷ , NHSO ₂ NR ⁶ R ⁷ , NR ⁶ SO ₂ NHR ⁷ , P(O)(OR ⁶ )(OR ⁷ ), with t being an integer selected from 1 or 2, and R ⁶ , R ⁷ and R ⁸ being each independently selected from the group comprising hydrogen, hydroxyl, Ci _-6 alkyl, C _6- ioaryl, Het ¹ , Het ¹ Ci _-6 alkyl, Het ¹ aC6-ioryl, Het ² , C _2-6 alkenyl, C _2-6 alkynyl, aminoCi _-6 alkyl, aminoC ₆ . i _O aryl, Ci _-6 alkylcarbonylamino, Cβ-ioarylcarbonylamino, Ci _-6 alkylthiocarbonylamino and C _{6- l} oarylthiocarbonylamino; wherein R ⁴ is selected from the group comprising hydroxyl, amino, thio, oxo, C _{2- 6} alkynyl, Ci _-6 alkyloxy, Ci _-6 alkylamino, Ci _-6 alkylthio, Ci _-6 alkyloxyC _2- 6alkenyl, Ci- 6alkylaminoC _2-6 alkenyl, Ci _-6 alkylhydrazino Cs-ecycloalkylamino, Cs-ecycloalkylhydrazino, Cs-βcycloalkylthio, Ci _-6 alkylcarbonyloxy, Ci _-6 alkylcarbonylamino, Ci-

₆ alkylcarbonylhydrazinoCi _-6 alkyl, C _6- ioarylcarbonyloxy, d-ealkylcarbonylhydrazino, C _{3- 6} cycloalkylcarbonyloxy, Cs-βcycloalkylcarbonylamino, Cs-βcycloalkylcarbonylhydrazino, silyloxy, C6-ioarylC _2- 6alkenyl, C6-ioaryloxyC _2-6 alkenyl, C ₆ -ioarylamino, C _6- ioarylhydrazino, C _{6- l} oarylthio, C ₆ -ioarylthioC _2-6 alkenyl, halo, haloC _2-6 alkenyl, Het ¹ C _2-6 alkenyl, Het ¹ oxy, Het ¹ amino, Het ¹ hydrazino, Het ¹ aminoC _2- 6alkenyl, Het ¹ C6-ioaryloxy, Het ¹ C6-ioaralkenyl, Het ¹ C _3-6 cycloalkyloxy, Het ¹ C _5-6 cycloalkenyl, Het ¹ C ₆ -ioarylamino, Het ¹ C _6- ioarylhydrazino, Het ¹ C ₆ -ioarylaminoC _2-6 alkenyl, Het ¹ C ₆ -ioaryloxyC _2-6 alkenyl, Het ¹ Ci _-6 alkyloxy, Het ¹ Ci_ ₆ alkyloxyC _2-6 alkenyl, Het ¹ C _6- ioarylthio, Het ¹ carbonyloxy, Het ¹ carbonylamino, Het ¹ carbonyloxyC _2-6 alkenyl, Het ¹ carbonylaminoC _2-6 alkenyl, Het ¹ Ci _-6 alkylcarbonyloxy, Het ¹ Ci _-6 alkylcarbonyloxyC _2-6 alkenyl, Het ¹ Ci _-6 alkylcarbonylamino, Het ¹ Ci_

₆ alkylcarbonylhydrazino, Het ¹ Ci _-6 alkylcarbonylaminoC _2- 6alkenyl, Het ¹ C _6- i ₀ aralkylcarbonyloxy, Het ¹ C6-ioaralkylcarbonyloxyC _2-6 alkenyl, Het ¹ C _6- i ₀ aralkylcarbonylamino, Het ¹ C _6- ioaralkylcarbonylhydrazino, Het ¹ C _{6- 10} aralkylcarbonylaminoC _2- 6alkenyl, Het ² oxy, Het ² amino, Het ² hydrazino, Het ² aminoC _{2- 6} alkenyl, Het ² Ci _-6 alkyloxy, Het ² Ci _-6 alkyloxyC _2- 6alkenyl, Het ¹ Ci _-6 alkylamino, Het ² d. ₆ alkylamino, Het ² C _6- ioaralkenyl, Het ² C _6- ioaryloxy, Het ² C6-ioaryloxyC _2- 6alkenyl, Het ² C _{6- l} oarylamino, Het ² C _6- ioarylhydrazino, Het ² C6-ioarylaminoC _2- 6alkenyl, Het ² C _6- ioarylthio, Het ² C6-ioarylthioC _2- 6alkenyl, Het ² carbonyloxy, Het ² carbonylamino, Het ² carbonylhydrazino, Het ² carbonylthio, Het ² carbonyloxyC _2-6 alkenyl, Het ² Ci _-6 alkylcarbonyloxy, Het ² Ci_ ₆ alkylcarbonyloxyC _2-6 alkenyl, Het ² C _6- ioaralkylcarbonyloxy, Het ² C _6- ioaralkylcarbonyloxyC _{2- 6} alkenyl, cyano, wherein R ⁴ is optionally substituted by one or more substituents independently selected from the group comprising Ci _-6 alkyl, C _6- ioaralkyl, C _6- ioaryl, Het ¹ , Het ² , C _{6- 6} cycloalkyl, Ci _-6 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci_

₆ alkyl)aminocarbonyl, aminosulfonyl, Ci.6alkylS(=O) _t , hydroxy, cyano, halogen, haloCi. ₆ alkyl, haloCi _-6 alkoxy, or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising Ci _-6 alkyl, C _6- ioaryl, C _6- ioaralkyl, C _{6- l} oaryloxy, C ₆ -ioarylamino, C _6- ioarylthio, C6-ioaryloxyCi _-6 alkyl, Cβ-ioarylaminod-ealkyl, C _{6- l} oaralkoxy, Ci _-6 alkylthio, Ci _-6 alkoxy, Cβ-ioaryloxyd-ealkoxy, C6-ioarylaminoCi _-6 alkoxy, C _6- i ₀ aralkylamino, Cβ-ioaryloxyd-ealkylamino, Cβ-ioarylaminod-ealkylamino, Cβ-ioarylthiod. ₆ alkoxy, Cβ-ioarylthiod-ealkylamino, C _6- ioaralkylthio, Cβ-ioaryloxyd-ealkylthio, C _6- ioarylaminoCi-6alkylthio, C6-ioarylthioCi.6alkylt.hio, Ci _-6 alkylamino, C _3-6 cycloalkyl, C _3- ecycloalkylalkyl, Het ¹ , Het ² , Het ¹ d _-6 alkyl, Het ² d _-6 alkyl, Het ¹ amino, Het ² amino, Het ¹ d_ ₆ alkylamino, Het ² d _-6 alkylamino, Het ¹ thio, Het ² thio, Het ¹ d _-6 alkylthio, Het ² d _-6 alkylthio, Het ¹ oxy and Het ² oxy, OR ⁹ , SR ⁹ , SO ₂ NR ⁹ R ¹⁰ , SO ₂ N(OH)R ⁹ , CN, CR ⁹ =NR ¹⁰ , S(O)R ⁹ , SO ₂ R ⁹ , CR ⁹ =N(OR ¹⁰ ), N ₃ , NO ₂ , NR ⁹ R ¹⁰ , N(OH)R ⁹ , C(O)R ⁹ , C(S)R ⁹ , CO ₂ R ⁹ , C(O)SR ⁹ , C(O)NR ⁹ R ¹⁰ , C(S)NR ⁹ R ¹⁰ , C(O)N(OH)R ⁹ , C(S)N(OH)R ⁹ , NR ⁹ C(O)R ¹⁰ , NR ⁹ C(S)R ¹⁰ , N(OH)C(O)R ⁹ , N(OH)C(S)R ⁹ , NR ⁹ CO ₂ R ¹⁰ , NR ⁹ C(O)NR ¹⁰ R ¹¹ , and NR ⁹ C(S)NR ¹⁰ R ¹¹ , N(OH)CO ₂ R ⁹ , NR ⁹ C(O)SR ¹⁰ , N(OH)C(O)NR ⁹ R ¹⁰ , N(OH)C(S)NR ⁹ R ¹⁰ , NR ⁹ C(O)N(OH)R ¹⁰ , NR ⁹ C(S)N(OH)R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , NHSO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ NHR ¹⁰ , P(O)(OR ⁹ )(OR ¹⁰ ), with t being an integer between 1 and 2, and R ⁹ , R ¹⁰ and R ¹¹ being each independently selected from the group comprising hydrogen, hydroxyl, Ci _-6 alkyl, C _6- ioaryl, Het ¹ , Het ¹ d _-6 alkyl, Het ¹ C ₆ -ioaryl, C _2-6 alkenyl, C _2-6 alkynyl, aminoCi _-6 alkyl, aminoC ₆ -ioaryl, Ci- ₆ alkylcarbonylamino, Cβ-ioarylcarbonylamino, d _-6 alkylthiocarbonylamino and C _{6- l} oarylthiocarbonylamino; or wherein R ⁴ is selected from the group comprising glucosyloxy, fructosyloxy, galactosyloxy, mannosyloxy, ribosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, rhamnosyloxy, threosyloxy, sorbosyloxy, psicosyloxy, tagatosyloxy, fucosyloxy, arabinosyloxy, xylofuranosyloxy, lyxosyloxy, talosyloxy, psicosyloxy, idosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, abequosyloxy, isomaltosyloxy, kojibiosyloxy, laminaribiosyloxy, nigerosyloxy, primeverosyloxy, rutinosyloxy, tyvelosyloxy, maltosyloxy, lactosyloxy, sucrosyloxy, cellobiosyloxy, trehalosyloxy, gentiobiosyloxy, melibiosyloxy, turanosyloxy, sophorosyloxy, isosucrosyloxy, raffinosyloxy, palatinosyloxy, lactulosyloxy, gentianosyloxy, 3- mannobiosyloxy, 6-mannobiosyloxy, 3-galactobiosyloxy, 4-galactobiosyloxy, maltotriosyloxy, maltotetraosyloxy, isomaltotriosyloxy, maltopentaosyloxy, maltohexaosyloxy, maltoheptaosyloxy, sicosyloxy, panosyloxy, isopanosyloxy, inosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, globotriosyloxy, erlosyloxy, neotrehalosyloxy, chitobiosyloxy, chitobiosemannosyloxy, glucosaminyl(2-amino-2-deoxy- D-glucosyloxy), N-acetyl-glucosaminyl(2-(acetylamino)-2-deoxy-D-glucosyloxy) ,

octylglucopyranosyloxy, octylribofuranosyloxy, cyclohexylglucopyranosyloxy, cyclohexylxylofuranosyloxy, benzylglucopyranosyloxy, benzylarabinofuranosyloxy, N- acetyl-lactosaminyl-oxy, acosaminyl-oxy, amicetosyloxy, amylosyloxy, apiosyloxy, arcanosyloxy, ascarylosyloxy, bacillosaminyl-oxy, boivinosyloxy, cellotriosyloxy, chacotriosyloxy, chalcosyloxy, cladinosyloxy, colitosyloxy, cymarosyloxy, daunosaminyl- oxy, desosaminyl-oxy, d-glycero-L-gulo-heptosyloxy, diginosyloxy, digitalosyloxy, digitoxosyloxy, evalosyloxy, evernitrosyloxy, forosaminyl-oxy, fucosaminyl-oxy, garosaminyl-oxy, hamamelosyloxy, isolevoglucosyl-oxy, kanosaminyl-oxy, kansosaminyl- oxy, lactosaminyl-oxy, lactosediaminyl-oxy, fucitolyl-oxy, maltulosyloxy, mannosaminyl- oxy, melezitosyloxy, mycaminosyloxy, mycarosyloxy, mycinosyloxy, mycosaminyl-oxy, noviosyloxy, oleandrosyloxy, paratosyloxy, perosaminyl-oxy, planteosyloxy, pneumosaminyl-oxy, purpurosaminyloxy, quinovosaminyl-oxy, quinovosyloxy, rhamnitolyl- oxy, rhamnosaminyl-oxy, rhodinosyloxy, rhodosaminyl-oxy, sarmentosyloxy, solatriosyloxy, stachyosyloxy, streptosyloxy, umbelliferosyloxy, trehalosaminyl-oxy, D- glucopyranosyl-α-L-rhamnosyloxy, 1 ,6-anhydro-D-glucopyranosyloxy, 1-hydroxy-α-D- allopyranosyloxy, 2,3:5,6-di-O-isopropylidene-D-mannofuranosyloxy, 2-amino-2-deoxy-D- galactitolyl-oxy, 2-deoxyribosyloxy, 2-deoxyglucosyloxy, 5-amino-5-deoxy-D- glucopyranosyloxy, 6-deoxy-D-galactitolyl-oxy, 2-amino-2-deoxyglucosyloxy, 2-acetamido- 2-deoxy-glucosyloxy, 2-amino-2-deoxy galactosyloxy, 2-acetamido-2-deoxy- galactosyloxy, 2-amino-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-mannosyloxy, 2- acetamido^-deoxy^-O-β-D-galactosyl-D-glucosyloxy, 2-amino-2-deoxy-4-O-β-D- galactosyl-D-glucosyloxy, θ'-N-acetylglucosaminyllactosyloxy, 2-acetamido-2-deoxy-3-O- α-L-fucosyl-D-glucosyloxy, 6-O(2-acetamido-2-deoxy-β-D-glucosyl)-D-galactosyloxy, 2- acetamido^-deoxy-S-O-β-D-galactosyl-D-glucosyloxy, 2'-acetamido-2'-deoxy-3-O-β-D- glucosyl-D-galactosyloxy, S-fucosyl-D-lactosyloxy, 3-fucosyl-2-acetamido-2-deoxy-4-O-β- D-galactosyl-D-glucosyloxy, L or D isomers thereof, α or β form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, hydroxyl-protected acetate or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof optionally substituted by one or more substituents independently selected from the group comprising Ci _-6 alkyl, C _6- ioaralkyl, C _6- ioaryl, Het ¹ , Het ² , C _{3- 6} cycloalkyl, Ci _-6 alkyloxy, Ci _-6 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci_ ₆ alkyl)aminocarbonyl, aminosulfonyl, Ci _-6 alkylS(=O) _t , hydroxy, cyano, halogen or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising Ci _-6 alkyl, C _6- ioaryl, C _6- ioaralkyl, C _6- ioaryloxy, C _6- ioarylamino, C _{6- l} oarylthio, C _6- ioaryloxyalkyl, Cβ-ioarylaminod-ealkyl, C _6- ioaralkoxy, Ci _-6 alkylthio, Ci _-6 alkoxy,

C6-ioaryloxyCi.6alkoxy, C6-ioarylaminod-6alkoxy, C ₆ -ioaralkylamino, C _6- ioaryloxyd- ₆ alkylamino, Ce-ioarylaminod-ealkylamino, C _6- ioarylthiod-6alkoxy, C _6- ioarylthiod- ₆ alkylamino, C _6- ioaralkylthio, Cβ-ioaryloxyd-ealkylthio, Cβ-ioarylaminod-ealkylthio, C _6- i ₀ arylthioCi _-6 alkylthio, C ₆ -ioalkylamino, C _3-6 cycloalkyl, and Cs-ecycloalkyld-ealkyl; wherein t is 1 or 2, wherein R ⁵ is hydrogen or R ⁵ and R ² together with the carbon atom to which they are attached form a double bond, with the proviso that when R ¹ is formyl, and R ² , R ³ are hydroxyl, and R ⁵ is hydrogen, R ⁴ is not D-glucopyranosyl-α-L-rhamnosyloxy, D-glucopyranosyl-α-L- rhamnosyloxyhexaacetate, or 4-O-(6-deoxy-α-L-mannopyranosyl)-β-D- galactopyranosyloxy, 2-4-di-O-acetyl-6-deoxy-3-O-methyl-α-D-galactopyranosyloxy, 6- deoxy-3-O-methyl-α-D-galactopyranosyloxy, 2,3,4,6-tetra-O-acetyl-β-D- glucopyranosyloxy, β-D-glucopyranosyloxy, θ-deoxy-S-O-methyl-α-L-glucopyranosyloxy, 6-deoxy-α-L-annopyranosyloxyl, or 6-deoxy-4-O-β-D-glucopyranosyl-α-L- mannopyranosyloxy.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.

Whenever the term "substituted" is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.

Where groups may be optionally substituted, such groups may be substituted with once or more, and preferably once, twice or thrice. Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.

As used herein, the term "halo" or "halogen", as a group or part of a group, is generic for fluoro, chloro, bromo or iodo. The term "nitro" as used herein refers to the group -NO ₂ . The term "cyano" as used herein refers to the group -CN.

The term "alkyl", alone or in combination, means straight and branched chained saturated hydrocarbon radicals Formula C _n H _2n +i wherein n is a number greater than or equal to 1 , containing from 1 to 10 carbon atoms, preferably from 1 to 8 carbon atoms, more

preferably 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, means an alkyl of one to four carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, pentyl, iso-amyl, hexyl, 3-methylpentyl, octyl and the like.

The term "alkenyl", alone or in combination, defines straight and branched chained hydrocarbon radicals containing from 2 to about 18 carbon atoms, preferably from 2 to 8 carbon atoms, more preferably 2-6 carbon atoms containing at least one double bond such as, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.

The term "alkynyl", alone or in combination, defines straight and branched chained hydrocarbon radicals having from 2 to 10 carbon atoms containing at least one triple bond, more preferably from 2 to about 6 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, (propargyl), butynyl, pentynyl, hexynyl and the like.

The term "cycloalkyl" alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or polycyclic alkyl radical wherein each cyclic moiety contains from about 3 to about 8 carbon atoms, more preferably from about 3 to about 7 carbon atoms. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of polycyclic cycloalkyl radicals include decahydronaphthyl, bicyclo [5.4.0] undecyl, adamantyl, and the like.

The term "cycloalkenyl" alone or in combination, means a partially saturated monocyclic, bicyclic or polycyclic alkyl radical wherein each cyclic moiety contains from about 5 to about 8 carbon atoms, more preferably from about 5 to about 7 carbon atoms. The term "cycloalkylalkyl", as a group or part of a group, means an alkyl radical as defined herein, in which at least one hydrogen atom on the alkyl radical is replaced by a cycloalkyl radical as defined herein. Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1- cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, 3-cyclopentylbutyl, cyclohexylbutyl and the like.

The term "aryl", as a group or part of a group , is meant to include phenyl and naphtyl which both may be optionally substituted with one or more substituents independently selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, Het ¹ , amido, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, and phenyl optionally substituted with one or more substituents

selected from Ci _-6 alkyl, Ci _-6 alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCi _-6 alkyl, carboxyl, Ci _-6 alkoxycarbonyl, C _3-7 cycloalkyl, Het ¹ , optionally mono- or disubstituted aminocarbonyl, methylthio and methylsulfonyl; whereby the optional substituents on any amino function are independently selected from alkyl, alkyloxy, Het ¹ , Het ¹ alkyl, Het ¹ alkyl, Het ¹ oxy, Het ¹ oxyalkyl, phenyl, phenyloxy, phenyloxyalkyl, phenylalkyl, alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the amino groups may optionally be mono- or where possible di-substituted with alkyl. Examples of aryl includes phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 3- methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3- acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl, 2-methyl-3- aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl, 2,4-dimethyl-3- aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, 3- amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl, 4,6-dimethoxy-2- naphthyl and the like. The term "aralkyl" alone or in combination, means an alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein. Examples of aralkyl radicals include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3- (2-naphthyl)-butyl, and the like.

As used herein, the term "oxo" or "=O" forms a carbonyl moiety with the carbon atom to which it is attached.

The term "formyl" or "-CHO", as a group or part of a group, is an aldehyde moiety whereby the C atom binds to the carbon atom to which it is attached. As used herein, the term "formyloxy" or "-OCHO" forms a formic ester moiety whereby the oxygen atom binds to the carbon atom to which it is attached. The term "carboxyl" or "-COOH", as a group or part of a group, is an acid moiety whereby the carbon atom binds to the carbon atom to which it is attached.

The term "haloalkyl" alone or in combination, means an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen, preferably, chloro or fluoro atoms, more preferably fluoro atoms. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1- trifluoroethyl and the like.

The terms "Het ¹ " or "heterocyclyl" alone or in combination, is defined as a saturated or partially unsaturated monocyclic, bicyclic or polycyclic heterocycle having preferably 3 to

12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen,

oxygen or sulfur and which is optionally substituted on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are independently selected from alkyl, alkyloxy, Het ² , Het ² alkyl, Het ² oxy, Het ² oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl, alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the amino groups may optionally be mono- or where possible di-substituted with alkyl. Non limiting exemplary Het ¹ groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H- pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,4- dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1 -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide, thiomorpholin-4- ylsulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 1 H-pyrrolizinyl, tetrahydro-1 ,1-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl.

The terms "Het ² " or "heteroaryl", as a group or part of a group, is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl, cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het ¹ and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are independently selected from alkyl, alkyloxy, Het ¹ , Het ¹ alkyl, Het ¹ oxy, Het ¹ oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl, alkyloxycarbonylamino, amino, and aminoalkyl whereby each of the amino groups may optionally be mono- or where possible di-substituted with alkyl. Non- limiting examples of a Het ² include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,

oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1- benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1 ,2-a]pyridinyl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, The term "alkoxy" or "alkyloxy", alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, hexanoxy and the like.

The term "arylthioalkoxy" , as a group or part of a group, means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein. Examples of (arylthio) alkoxy radicals include 2- (phenylthio)-ethoxy, and the like.

The term "alkanoyl" or "alkylcarbonyl", alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. The term "alkenylcarbonyl", alone or in combination, means a radical derived from an alkenylcarboxylic acid.

The term "alkylamino", as a group or part of a group, means an alkyl amine radical, wherein the term "alkyl" is defined as above, i.e. refers to a group of formula a -N(R ^a )(R ^b ) wherein R ^a and R ^b are each independently selected from hydrogen or alkyl. Alkylamino include mono-lower alkyl amino group (e.g. mono-C1-6alkylamino group such as methylamino and ethylamino), di-lower alkylamino group (e.g. di-Ci _-6 alkylamino group such as dimethylamino and diethylamino). Examples of alkylamino radicals include methylamino (NHCH ₃ ), ethylamino (NHCH ₂ CH ₃ ), n-propylamino, isopropylamino, n- butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-hexylamino, and the like. The term "alkylthio" as a group or part of a group means an alkyl thioether radical, wherein the term "alkyl" is defined as above. Examples of alkylthio radicals include methylthio (SCH ₃ ), ethylthio (SCH ₂ CH ₃ ), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-hexylthio, and the like.

The term "aminoalkanoyl", as a group or part of a group, means an acyl group derived from an amino-substituted alkylcarboxylic acid wherein the amino group can be a primary,

secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.

The term "aminocarbonyl" alone or in combination, means an amino-substituted carbonyl (carbamoyl) group wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.

The term "aralkanoyl", as a group or part of a group, means an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4- aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like.

The term "aralkoxy", as a group or part of a group, means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein. Examples of aralkoxy radicals include 2-phenylethoxy, 2-phenyl-1-propoxy, and the like.

The term "aralkoxycarbonyl", alone or in combination, means a radical of the formula aralkyl-O-C(O)- in which the term "aralkyl" has the significance given above. Examples of an aralkoxycarbonyl radical are benzyloxycarbonyl and 4- methoxyphenylmethoxycarbonyl.

The term "aralkylamino", as a group or part of a group, means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein. Examples of aralkylamino radicals include 2-phenethylamino, 4-phenyl-n-butylamino, and the like.

The term "aralkylthio", as a group or part of a group, means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an aryl as defined herein. Examples of aralkylthio radicals include 3-phenyl-2-propylthio, 2- (2-naphthyl)-ethylthio, and the like. The term "aroyl" or "arylcarbonyl", as a group or part of a group, means an acyl radical derived from an arylcarboxylic acid, aryl having the meaning given above. Examples of such arylcarboxylic acid radicals include substituted and unsubstituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6- (benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxyformamidol-2-naphthoyl, and the like.

The term "arylaminoalkoxy", as a group or part of a group, means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein. Examples of (arylamino) alkoxy radicals include 2- (phenylamino)-ethoxy, 2- (2- naphthylamino)-1-butoxy, and the like.

The term "arylaminoalkyl", as a group or part of a group, means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein. Examples of arylaminoalkyl radicals include phenylaminoethyl, 4- (3-methoxyphenylamino)- 1 -butyl, and the like. The term "arylaminoalkylamino", as a group or part of a group, means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein. Examples of (arylamino) alkylamino radicals include 3- (naphthylamino)- propylamino, 4- (phenylamino)-i-butylamino, and the like.

The term "arylaminoalkylthio", as a group or part of a group, means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an arylamino as defined herein. Examples of (arylamino) alkylthio radicals include 2- (phenylamino)- ethylthio, 3- (2- naphthylamino)-n-propylthio, and the like.

The term "aryloxy", as a group or part of a group, means a radical of the formula aryl-O- in which the term aryl has the significance given above. The term "aryloxyalkanoyl", as a group or part of a group, means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above.

The term "aryloxyalkoxy", as a group or part of a group, means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of (aryloxy) alkoxy radicals include 2-phenoxyethoxy, 4- (3-aminophenoxy)-1- butoxy, and the like.

The term "aryloxyalkyl", as a group or part of a group, means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of aryloxyalkyl radicals include phenoxyethyl, 4- (3-aminophenoxy)-l-butyl, and the like.

The term "aryloxyalkylamino", as a group or part of a group, means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of (aryloxy) alkylamino radicals include 3-phenoxy-npropylamino, 4- phenoxybutylamino, and the like.

The term "aryloxyalkylthio", as a group or part of a group, means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an aryloxy as defined herein. Examples of (aryloxy) alkylthio radicals include 3-phenoxypropylthio, 4 (2-fluorophenoxy)- butylthio, and the like.

The term "arylthioalkylamino", as a group or part of a group, means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein. Examples of (arylthio) alkylamino radicals include 2- (phenylthio)- ethylamino, and the like.

The term "arylthioalkylthio", as a group or part of a group, means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by an arylthio as defined herein. Examples of (arylthio) alkylthio radicals include 2- (naphthylthio)- ethylthio, 3- (phenylthio)- propylthio, and the like. The term "cycloalkylalkoxycarbonyl", as a group or part of a group, means an acyl group of formula cycloalkylalkyl-O-CO- derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O-COOH wherein cycloalkylalkyl has the meaning given above.

The term "cycloalkylcarbonyl", as a group or part of a group, means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropylcarbonyl, cyclohexylcarbonyl, adamantylcarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, alkanoylamino, amido, mono and dialkyl substituted amino, mono and dialkyl substituted amido and the like, such as 1 ,2,3,4- tetrahydro-2-naphthoyl, 2-acetamido-1 ,2,3,4-tetrahydro-2-naphthoyl.

The term "Het ² alkoxy", as a group or part of a group, means alkoxy as defined herein, wherein an alkyl hydrogen atom is replaced by a Het ² as defined herein. Examples of Het ² alkoxy radicals include 2-pyridylmethoxy, 4- (l-imidazolyl)-butoxy, and the like.

The term "Het ² alkyl", as a group or part of a group, means alkyl as defined herein, wherein an alkyl hydrogen atom is replaced by a Het ² as defined herein. Examples of Het ² alkyl radicals include 2-pyridylmethyl, 3- (4-thiazolyl)-propyl, and the like.

The term "Het ² alkylamino", as a group or part of a group, means alkylamino as defined herein, wherein an alkyl hydrogen atom is replaced by a Het ² as defined herein. Examples of Het ² alkylamino radicals include 4-pyridylmethylamino, 3 (2-furanyl)-propylamino, and the like.

The term "Het ² alkylthio", as a group or part of a group, means alkylthio as defined herein, wherein an alkyl hydrogen atom is replaced by a Het ² as defined herein. Examples of Het ² alkylthio radicals include 3-pyridylmethylthio, 3 (4-thiazolyl)-propylthio, and the like.

The term "Het ² amino", as a group or part of a group, means Het ² as defined herein, wherein a hydrogen atom on the Het ² ring is replaced by a nitrogen. Het ² amino radicals include, for example, 4-thiazolylamino, 2-pyridylamino, and the like.

The term "Het ² oxy", as a group or part of a group, means Het ² as defined herein, wherein a hydrogen atom on the Het ² ring is replaced by an oxygen. Het ² oxy radicals include, for example, 4-pyridyloxy, 5-quinolyloxy, and the like.

The term "Het ² oxycarbonyl", as a group or part of a group, means an acyl radical derived from a carbonic acid represented by Het ² -O-COOH, i.e. a group of formula Het ¹ -O-CO-, wherein Het ² has the meaning given above.

The term "Het ² thio", as a group or part of a group, means Het ² as defined herein, wherein a hydrogen atom on the Het ² ring is replaced by a sulfur. Het ² thio radicals include, for example, 3-pyridylthio, 3-quinolylthio, 4-imidazolylthio, and the like.

The term "Het ¹ alkanoyl" , as a group or part of a group, is an acyl radical derived from a Het ¹ -substituted alkylcarboxylic acid, i.e. a group of formula Het ¹ -alkylene-CO-, wherein Het ¹ has the meaning given above. The term "Het ¹ alkoxycarbonyl", as a group or part of a group, means an acyl group derived from Het ¹ -O-COOH, i.e. a group of formula Het ¹ -alkylene-O-CO-, wherein Het ¹ is as defined above.

The term "hydrazino", as a group or part of a group, refers to a group of formula NH ₂ -NH-.

The glycosyl terms such as "glucosyl" (also named "glucopyranosyl") "rhamnosyl" etc refer to the residue formed by detaching the anomeric hydroxy group from a saccharide. For instance, the term "rhamnosyl" refers to the residue formed by detaching the anomeric hydroxyl group from rhamnose. The term "glycosyloxy" includes the oxygen of the glycosidic bond.

As used herein before, the term "one or more" covers the possibility of all the available C- atoms, where appropriate, to be substituted, preferably, one, two or three. When any variable, e.g. halogen or alkyl, occurs more than one time in any constituent, each definition is independent.

As used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

In an embodiment, Het ¹ as a group or part of a group is selected from piperidinyl, 2- imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 2- oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H- pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,4-dioxanyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl,1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, and morpholin-4-yl.

In an embodiment, Het ² as a group or part of a group is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2- b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2- benzisoxazolyl, 2,1-benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1- benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1 ,2,3- benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, purinyl, imidazo[1 ,2-a]pyridinyl, 1 (6H)-yl, 1 ,3- benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl.

In an embodiment, the present invention provides compounds of Formula I, wherein R ¹ is selected from the group comprising alkyl, hydroxyalkyl, aminoalkyl, thioalkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylaminoalkyl, alkylhydrazinoalkyl, alkylthioalkyl, alkyloxyalkenyl, alkylaminoalkenyl, alkylhydrazinoalkenyl, alkylthioalkynyl, alkanoyl, alkyloxycarbonyl, alkylaminocarbonyl, alkylthiocarbonyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylaminocarbonyl, cycloalkylthiocarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkylaminocarbonyl, cycloalkylalkoxythiocarbonyl, cycloalkylaminoalkyl, cycloalkylhydrazinoalkyl, cycloalkylaminoalkenyl, cycloalkylthioalkyl, cycloalkylthioalkenyl, alkylcarbonyloxyalkyl, alkylcarbonyloxyalkenyl, alkylcarbonylaminoalkyl, alkylcarbonylhydrazinoalkyl, alkylcarbonylaminoalkenyl, arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkenyl, cycloalkylcarbonylaminoalkyl, cycloalkylcarbonylhydrazinoalkyl, silyloxyalkyl, aralkyl, arylalkenyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl, aralkylaminocarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, aryloxyalkenyl, arylaminoalkyl, arylhydrazinoalkyl, arylaminoalkenyl, arylthioalkyl, arylthioalkenyl, haloalkyl, haloalkenyl, aralkanoyl, aroyl, aryloxyalkanoyl, carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl, Het ¹ alkyl, Het ¹ alkenyl, Het ¹ oxyalkyl, Het ¹ aminoalkyl, Het ¹ hydrazinoalkyl, Het ¹ aminoalkenyl, Het ¹ cycloalkyl, Het ¹ cycloalkenyl, Het ¹ carbonyl, Het ¹ aminocarbonyl, Het ¹ alkoxycarbonyl, Het ¹ alkylaminocarbonyl, Het ¹ alkylthiocarbonyl, Het ¹ oxycarbonyl, Het ¹ thiocarbonyl, Het ¹ alkanoyl, Het ¹ alkyloxyalkyl, Het ¹ alkyloxyalkenyl, Het ¹ oxyalkylcarbonyl, Het ¹ aminoalkylcarbonyl, Het ¹ thioalkylcarbonyl, Het ¹ alkyloxyalkylcarbonyl,

Het ¹ alkylaminoalkylcarbonyl, Het ¹ carbonyloxyalkyl, Het ¹ carbonylaminoalkyl,

Het ¹ carbonyloxyalkenyl, Het ¹ carbonylaminoalkenyl, Het ¹ alkylcarbonyloxyalkyl, Het ¹ alkylcarbonyloxyalkenyl, Het ¹ alkylcarbonylaminoalkyl,

Het ¹ alkylcarbonylhydrazinoalkyl, Het ¹ alkylcarbonylaminoalkenyl, Het ² alkyl; Het ² alkenyl;

Het ² oxyalkyl, Het ² oxyalkenyl, Het ² aminoalkyl, Het ² hydrazinoalkyl, Het ² aminoalkenyl, Het ² alkyloxyalkyl, Het ² alkyloxyalkenyl, Het ² alkylaminoalkyl, Het ² alkylaminoalkenyl, Het ² carbonyl, Het ² oxycarbonyl, Het ² aminocarbonyl, Het ² thiocarbonyl, Het ² alkanoyl, Het ² alkylthiocarbonyl, Het ² alkoxycarbonyl, Het ² alkylaminocarbonyl, Het ² oxyalkylcarbonyl, Het ² thioalkylcarbonyl, Het ² aminoalkylcarbonyl, Het ² alkyloxyalkylcarbonyl,

Het ² alkylthioalkylcarbonyl, Het ² alkylaminoalkylcarbonyl, Het ² carbonyloxyalkyl,

Het ² carbonylaminoalkyl, Het ² carbonylhydrazinoalkyl, Het ² carbonylthioalkyl,

Het ² carbonyloxyalkenyl, Het ² alkylcarbonyloxyalkyl, Het ² alkylcarbonyloxyalkenyl, cyano, aminocarbonyl, aminoalkanoyl, alkylamino, wherein R ¹ is optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy, or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het ¹ , Het ² , Het ¹ alkyl, Het ² alkyl, Het ¹ amino, Het ² amino, Het ¹ alkylamino, Het ² alkylamino, Het ¹ thio, Het ² thio, Het ¹ alkylthio, Het ² alkylthio, Het ¹ oxy and Het ² oxy, OR ⁶ , SR ⁶ , SO ₂ NR ⁶ R ⁷ , SO ₂ N(OH)R ⁶ , CN, CR ⁶ =NR ⁷ , S(O)R ⁶ , SO ₂ R ⁶ , CR ⁶ =N(OR ⁷ ), N ₃ , NO ₂ , NR ⁶ R ⁷ , N(OH)R ⁶ , C(O)R ⁶ , C(S)R ⁶ , CO ₂ R ⁶ , C(O)SR ⁶ , C(O)NR ⁶ R ⁷ , C(S)NR ⁶ R ⁷ , C(O)N(OH)R ⁷ , C(S)N(OH)R ⁶ , NR ⁶ C(O)R ⁷ , NR ⁶ C(S)R ⁷ , N(OH)C(O)R ⁷ , N(OH)C(S)R ⁶ , NR ⁶ CO ₂ R ⁷ , NR ⁶ C(O)NR ⁷ R ⁸ , and NR ⁶ C(S)NR ⁷ R ⁸ , N(OH)CO ₂ R ⁶ , NR ⁶ C(O)SR ⁷ , N(OH)C(O)NR ⁶ R ⁷ , N(OH)C(S)NR ⁶ R ⁷ , NR ⁶ C(O)N(OH)R ⁷ , NR ⁶ C(S)N(OH)R ⁷ , NR ⁶ SO ₂ R ⁷ , NHSO ₂ NR ⁶ R ⁷ , NR ⁶ SO ₂ NHR ⁷ , P(O)(OR ⁶ )(OR ⁷ ), with t being an integer selected from 1 or 2, and R ⁶ , R ⁷ and R ⁸ being each independently selected from the group comprising hydrogen, hydroxyl, alkyl, aryl, Het ¹ , Het ¹ alkyl, Het ¹ aryl, Het ² , alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino; and wherein R ² , R ³ , R ⁴ , and R ⁵ have the same meaning as that defined above. Preferably, R ¹ is selected from the group comprising alkyl, hydroxyalkyl, aminoalkyl, thioalkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylaminoalkyl, alkylhydrazinoalkyl, alkylthioalkyl, alkyloxyalkenyl, alkylaminoalkenyl, alkylhydrazinoalkenyl, alkylthioalkynyl, alkanoyl, alkyloxycarbonyl, alkylaminocarbonyl, alkylthiocarbonyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkylaminocarbonyl, cycloalkylthiocarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkylaminocarbonyl, cycloalkylalkoxythiocarbonyl,

cycloalkylaminoalkyl, cycloalkylthioalkyl, alkylcarbonyloxyalkyl, alkylcarbonyloxyalkenyl, alkylcarbonylaminoalkyl, alkylcarbonylaminoalkenyl, arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl, cycloalkylcarbonylaminoalkyl, silyloxyalkyl, aralkyl, arylalkenyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl, aralkylaminocarbonyl, arylalkylthiocarbonyl, aryloxyalkyl, arylaminoalkyl, arylhydrazinoalkyl, arylaminoalkenyl, arylthioalkyl, haloalkyl, aralkanoyl, aroyl, aryloxyalkanoyl, carboxyl, formyl, alkenylcarbonyl, alkynylcarbonyl, Het ¹ alkyl, Het ¹ alkenyl, Het ¹ oxyalkyl, Het ¹ aminoalkyl, Het ¹ cycloalkyl, Het ¹ carbonyl, Het ¹ aminocarbonyl, Het ¹ alkoxycarbonyl,

Het ¹ alkylaminocarbonyl, Het ¹ alkylthiocarbonyl, Het ¹ oxycarbonyl, Het ¹ thiocarbonyl, Het ¹ alkanoyl, Het ¹ alkyloxyalkyl, Het ¹ oxyalkylcarbonyl, Het ¹ aminoalkylcarbonyl, Het ¹ thioalkylcarbonyl, Het ¹ alkyloxyalkylcarbonyl, Het ¹ alkylaminoalkylcarbonyl,

Het ¹ carbonyloxyalkyl, Het ¹ carbonylaminoalkyl, Het ¹ alkylcarbonyloxyalkyl,

Het ¹ alkylcarbonylaminoalkyl, Het ² alkyl; Het ² alkenyl; Het ² oxyalkyl, Het ² aminoalkyl, Het ² alkyloxyalkyl, Het ² alkylaminoalkyl, Het ² carbonyl, Het ² oxycarbonyl, Het ² aminocarbonyl, Het ² thiocarbonyl, Het ² alkanoyl, Het ² alkylthiocarbonyl,

Het ² alkoxycarbonyl, Het ² alkylaminocarbonyl, Het ² oxyalkylcarbonyl, Het ² thioalkylcarbonyl, Het ² aminoalkylcarbonyl, Het ² alkyloxyalkylcarbonyl, Het ² alkylthioalkylcarbonyl,

Het ² alkylaminoalkylcarbonyl, Het ² carbonyloxyalkyl, Het ² carbonylaminoalkyl,

Het ² carbonylhydrazinoalkyl, Het ² carbonylthioalkyl, Het ² alkylcarbonyloxyalkyl, cyano, aminocarbonyl, aminoalkanoyl, alkylamino, wherein R ¹ is optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, wherein t is 1 or 2, wherein Het ¹ as a group or part of a group is selected from piperidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H- indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H- pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1 ,4-dioxanyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholin-4-yl,1 ,3- dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, and morpholin-4-yl, and Het ² as a group or part of a group is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl,

indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1- benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, purinyl, imidazo[1 ,2-a]pyridinyl.

In an embodiment, the present invention provides compounds of Formula I wherein R ² and R ³ are each independently selected from the group comprising hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy, alkyloxyalkyloxy, cycloalkyloxy cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy, haloalkyloxy, hydroxyalkyloxy, aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy, formyloxy, Het ¹ alkyloxy, Het ¹ oxy, Het ¹ oxyalkyloxy, Het ¹ cycloalkyloxy, Het ¹ carbonyloxy, Het ¹ oxycarbonyloxy, Het ¹ alkanoyloxy, Het ² oxy, Het ² alkyloxy; Het ² oxyalkyloxy, Het ² cycloalkyloxy, Het ² alkanoyloxy, Het ² carbonyloxyl, wherein R ² and R ³ are each optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy, or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het ¹ , Het ² , Het ¹ alkyl, Het ² alkyl, Het ¹ amino, Het ² amino, Het ¹ alkylamino, Het ² alkylamino, Het ¹ thio, Het ² thio, Het ¹ alkylthio, Het ² alkylthio, Het ¹ oxy and Het ² oxy, OR ⁶ , SR ⁶ , SO ₂ NR ⁶ R ⁷ , SO ₂ N(OH)R ⁶ , CN, CR ⁶ =NR ⁷ , S(O)R ⁶ , SO ₂ R ⁶ , CR ⁶ =N(OR ⁷ ), N ₃ , NO ₂ , NR ⁶ R ⁷ , N(OH)R ⁶ , C(O)R ⁶ , C(S)R ⁶ , CO ₂ R ⁶ , C(O)SR ⁶ , C(O)NR ⁶ R ⁷ , C(S)NR ⁶ R ⁷ , C(O)N(OH)R ⁷ , C(S)N(OH)R ⁶ , NR ⁶ C(O)R ⁷ , NR ⁶ C(S)R ⁷ , N(OH)C(O)R ⁷ , N(OH)C(S)R ⁶ , NR ⁶ CO ₂ R ⁷ , NR ⁶ C(O)NR ⁷ R ⁸ , and NR ⁶ C(S)NR ⁷ R ⁸ , N(OH)CO ₂ R ⁶ , NR ⁶ C(O)SR ⁷ , N(OH)C(O)NR ⁶ R ⁷ , N(OH)C(S)NR ⁶ R ⁷ , NR ⁶ C(O)N(OH)R ⁷ , NR ⁶ C(S)N(OH)R ⁷ , NR ⁶ SO ₂ R ⁷ , NHSO ₂ NR ⁶ R ⁷ , NR ⁶ SO ₂ NHR ⁷ , P(O)(OR ⁶ XOR ⁷ ), with t being an integer selected from 1 or 2, and R ⁶ , R ⁷ and R ⁸ being each independently selected from the group comprising hydrogen, hydroxyl, alkyl, aryl, Het ¹ , Het ¹ alkyl, Het ¹ aryl, Het ² , alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino; and wherein R ¹ , R ⁴ and R ⁵ have the same meaning as that defined above. Preferably, R ² and R ³ are each independently selected from the group comprising hydroxyl, alkyloxy, alkylsilyloxy,

arylsilyloxy, alkyloxyalkyloxy, cycloalkyloxy cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy, haloalkyloxy, hydroxyalkyloxy, aralkanoyloxy, aroyloxy, formyloxy, Het ¹ alkyloxy, Het ¹ oxy, Het ¹ cycloalkyloxy, Het ¹ carbonyloxy, Het ¹ alkanoyloxy, Het ² oxy, Het ² alkyloxy; Het ² cycloalkyloxy, Het ² alkanoyloxy, Het ² carbonyloxyl, wherein R ² and R ³ are each optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy, or amino, aminoalkyl, or alkylamino, wherein t is 1 or 2, wherein Het ¹ as a group or part of a group is selected from piperidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3- pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3- dioxolanyl, 1 ,4-dioxanyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholin-4-yl,1 ,3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5- trioxanyl, and morpholin-4-yl, and Het ² as a group or part of a group is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3- d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1 ,3- benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3- benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, purinyl, imidazo[1 ,2-a]pyridinyl.

In an embodiment, the present invention provides compounds of Formula I wherein R ⁴ is selected from the group comprising hydroxyl, amino, thio, oxo, alkynyl, alkyloxy, alkylamino, alkylthio, alkyloxyalkenyl, alkylaminoalkenyl, alkylhydrazino cycloalkylamino, cycloalkylhydrazino, cycloalkylthio, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylhydrazinoalkyl, arylcarbonyloxy, alkylcarbonylhydrazino, cycloalkylcarbonyloxy, cycloalkylcarbonylamino, cycloalkylcarbonylhydrazino, silyloxy, arylalkenyl, aryloxyalkenyl, arylamino, arylhydrazino, arylthio, arylthioalkenyl, halo, haloalkenyl, Het ¹ alkenyl, Het ¹ oxy, Het ¹ amino, Het ¹ hydrazino, Het ¹ aminoalkenyl, Het ¹ cycloalkyloxy, Het ¹ cycloalkenyl, Het ¹ alkyloxy, Het ¹ alkyloxyalkenyl, Het ¹ carbonyloxy,

Het ¹ carbonylamino, Het ¹ carbonyloxyalkenyl, Het ¹ carbonylaminoalkenyl,

Het ¹ alkylcarbonyloxy, Het ¹ alkylcarbonyloxyalkenyl, Het ¹ alkylcarbonylamino,

Het ¹ alkylcarbonylhydrazino, Het ¹ alkylcarbonylaminoalkenyl, Het ² oxy, Het ² amino, Het ² hydrazino, Het ² aminoalkenyl, Het ² alkyloxy, Het ² alkyloxyalkenyl, Het ¹ alkylamino, Het ² alkylamino, Het ² carbonyloxy, Het ² carbonylamino, Het ² carbonylhydrazino, Het ² carbonylthio, Het ² carbonyloxyalkenyl, Het ² alkylcarbonyloxy,

Het ² alkylcarbonyloxyalkenyl, cyano, wherein R ⁴ is optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy, or amino optionally mono- or disubstituted wherein the substituents are independently selected from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het ¹ , Het ² , Het ¹ alkyl, Het ² alkyl, Het ¹ amino, Het ² amino, Het ¹ alkylamino, Het ² alkylamino, Het ¹ thio, Het ² thio, Het ¹ alkylthio, Het ² alkylthio, Het ¹ oxy and Het ² oxy, OR ⁹ , SR ⁹ , SO ₂ NR ⁹ R ¹⁰ , SO ₂ N(OH)R ⁹ , CN, CR ⁹ =NR ¹⁰ , S(O)R ⁹ , SO ₂ R ⁹ , CR ⁹ =N(OR ¹⁰ ), N ₃ , NO ₂ , NR ⁹ R ¹⁰ , N(OH)R ⁹ , C(O)R ⁹ , C(S)R ⁹ , CO ₂ R ⁹ , C(O)SR ⁹ , C(O)NR ⁹ R ¹⁰ , C(S)NR ⁹ R ¹⁰ , C(O)N(OH)R ⁹ , C(S)N(OH)R ⁹ , NR ⁹ C(O)R ¹⁰ , NR ⁹ C(S)R ¹⁰ , N(OH)C(O)R ⁹ , N(OH)C(S)R ⁹ , NR ⁹ CO ₂ R ¹⁰ , NR ⁹ C(O)NR ¹⁰ R ¹¹ , and NR ⁹ C(S)NR ¹⁰ R ¹¹ , N(OH)CO ₂ R ⁹ , NR ⁹ C(O)SR ¹⁰ , N(OH)C(O)NR ⁹ R ¹⁰ , N(OH)C(S)NR ⁹ R ¹⁰ , NR ⁹ C(O)N(OH)R ¹⁰ , NR ⁹ C(S)N(OH)R ¹⁰ , NR ⁹ SO ₂ R ¹⁰ , NHSO ₂ NR ⁹ R ¹⁰ , NR ⁹ SO ₂ NHR ¹⁰ , P(O)(OR ⁹ )(OR ¹⁰ ), with t being an integer between 1 and 2, and R ⁹ , R ¹⁰ and R ¹¹ being each independently selected from the group comprising hydrogen, hydroxyl, alkyl, aryl, Het ¹ , Het ¹ alkyl, Het ¹ aryl, alkenyl, alkynyl, aminoalkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino; and wherein R ¹ , R ² , R ³ and R ⁵ have the same meaning as that defined above. Preferably, R ⁴ is selected from the group comprising hydroxyl, amino, thio, oxo, alkynyl, alkyloxy, alkylamino, alkylthio, alkyloxyalkenyl, alkylaminoalkenyl, alkylhydrazino cycloalkylamino, cycloalkylhydrazino, cycloalkylthio, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonylhydrazinoalkyl, arylcarbonyloxy, alkylcarbonylhydrazino, cycloalkylcarbonyloxy, cycloalkylcarbonylamino, cycloalkylcarbonylhydrazino, silyloxy, arylalkenyl, aryloxyalkenyl, arylamino, arylhydrazino, arylthio, arylthioalkenyl, halo, haloalkenyl, Het ¹ oxy, Het ¹ amino, Het ¹ cycloalkyloxy, Het ¹ alkyloxy, Het ¹ carbonyloxy,

Het ¹ carbonylamino, Het ¹ alkylcarbonyloxy, Het ¹ alkylcarbonylamino, Het ² amino, Het ² hydrazino, Het ² alkyloxy, Het ¹ alkylamino, Het ² alkylamino, Het ² carbonyloxy, Het ² carbonylamino, Het ² carbonylthio, Het ² alkylcarbonyloxy, cyano, wherein R ⁴ is optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy or amino, aminoalkyl, or alkylamino, wherein t is 1 or 2, wherein Het ¹ as a group or part of a group is selected from piperidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3- pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3- dioxolanyl, 1 ,4-dioxanyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholin-4-yl,1 ,3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5- trioxanyl, and morpholin-4-yl, and Het ² as a group or part of a group is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3- d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1 ,3- benzothiazolyl, 1 ,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3- benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, purinyl, imidazo[1 ,2-a]pyridinyl.

In another embodiment, the present invention provides compounds of Formula I wherein R ⁴ is selected from the group comprising glucosyloxy, fructosyloxy, galactosyloxy, mannosyloxy, ribosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, rhamnosyloxy, threosyloxy, sorbosyloxy, psicosyloxy, tagatosyloxy, fucosyloxy, arabinosyloxy, xylofuranosyloxy, lyxosyloxy, talosyloxy, psicosyloxy, idosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, abequosyloxy, isomaltosyloxy, kojibiosyloxy, laminaribiosyloxy, nigerosyloxy, primeverosyloxy, rutinosyloxy, tyvelosyloxy, maltosyloxy, lactosyloxy, sucrosyloxy, cellobiosyloxy, trehalosyloxy, gentiobiosyloxy, melibiosyloxy, turanosyloxy, sophorosyloxy, isosucrosyloxy, raffinosyloxy, palatinosyloxy, lactulosyloxy, gentianosyloxy, 3- mannobiosyloxy, 6-mannobiosyloxy, 3-galactobiosyloxy, 4-galactobiosyloxy,

maltotriosyloxy, maltotetraosyloxy, isomaltotriosyloxy, maltopentaosyloxy, maltohexaosyloxy, maltoheptaosyloxy, sicosyloxy, panosyloxy, isopanosyloxy, inosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, globotriosyloxy, erlosyloxy, neotrehalosyloxy, chitobiosyloxy, chitobiosemannosyloxy, glucosaminyl(2-amino-2-deoxy- D-glucosyloxy), N-acetyl-glucosaminyl(2-(acetylamino)-2-deoxy-D-glucosyloxy) , octylglucopyranosyloxy, octylribofuranosyloxy, cyclohexylglucopyranosyloxy, cyclohexylxylofuranosyloxy, benzylglucopyranosyloxy, benzylarabinofuranosyloxy, N- acetyl-lactosaminyl-oxy, acosaminyl-oxy, amicetosyloxy, amylosyloxy, apiosyloxy, arcanosyloxy, ascarylosyloxy, cellotriosyloxy, d-glycero-L-gulo-heptosyloxy, evalosyloxy, evernitrosyloxy, forosaminyl-oxy, fucosaminyl-oxy, kansosaminyl-oxy, lactosaminyl-oxy, lactosediaminyl-oxy, fucitolyl-oxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyl-oxy, rhamnosaminyl-oxy, rhodinosyloxy, rhodosaminyl-oxy, sarmentosyloxy, solatriosyloxy, stachyosyloxy, streptosyloxy, umbelliferosyloxy, trehalosaminyl-oxy, D-glucopyranosyl-α- L-rhamnosyloxy, 1 ,6-anhydro-D-glucopyranosyloxy, 1-hydroxy-α-D-allopyranosyloxy, 2,3:5,6-di-O-isopropylidene-D-mannofuranosyloxy, 2-amino-2-deoxy-D-galactitolyl-oxy, 2- deoxyribosyloxy, 2-deoxyglucosyloxy, δ-amino-S-deoxy-D-glucopyranosyloxy, 6-deoxy-D- galactitolyl-oxy, 2-amino-2-deoxyglucosyloxy, 2-acetamido-2-deoxy-glucosyloxy, 2-amino- 2-deoxygalactosyloxy, 2-acetamido-2-deoxy-galactosyloxy, 2-amino-2-deoxy- mannosyloxy, 2-acetamido-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-4-O-β-D- galactosyl-D-glucosyloxy, 2-amino-2-deoxy-4-O-β-D-galactosyl-D-glucosyloxy, 6'-N- acetylglucosaminyllactosyloxy, 2-acetamido-2-deoxy-3-O-α-L-fucosyl-D-glucosyloxy, 6- O(2-acetamido-2-deoxy-β-D-glucosyl)-D-galactosyloxy, 2-acetamido-2-deoxy-3-O-β-D- galactosyl-D-glucosyloxy, 2'-acetamido-2'-deoxy-3-O-β-D-glucosyl-D-galactosyloxy, 3- fucosyl-D-lactosyloxy, 3-fucosyl-2-acetamido-2-deoxy-4-O-β-D-galactosyl-D-glucosyl oxy, L or D isomers thereof, a or b form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, hydroxyl-protected acetate or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof, each optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxy, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted, wherein the substituents are independently selected from the group comprising alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio, alkoxy,

aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino, aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, and cycloalkylalkyl; wherein t is 1 or 2, and wherein R ¹ , R ² , R ³ and R ⁵ have the same meaning as that defined above. Preferably, R ⁴ is selected from the group comprising glucosyloxy, fructosyloxy, galactosyloxy, mannosyloxy, ribosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, rhamnosyloxy, threosyloxy, sorbosyloxy, psicosyloxy, tagatosyloxy, fucosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, sedoheptulosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, sucrosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, isosucrosyloxy, lactulosyloxy, gentianosyloxy, 3-mannobiosyloxy, 6-mannobiosyloxy, 3-galactobiosyloxy, 4- galactobiosyloxy, maltotriosyloxy, maltotetraosyloxy, isomaltotriosyloxy, maltopentaosyloxy, maltohexaosyloxy, maltoheptaosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, neotrehalosyloxy, chitobiosyloxy, chitobiosemannosyloxy, glucosaminyl(2-amino-2-deoxy-D-glucosyloxy), N-acetyl-glucosaminyl(2-(acetylamino)-2- deoxy-D-glucosyloxy), octylglucopyranosyloxy, octylribofuranosyloxy, cyclohexylglucopyranosyloxy, cyclohexylxylofuranosyloxy, benzylglucopyranosyloxy, benzylarabinofuranosyloxy, N-acetyl-lactosaminyl-oxy, acosaminyl-oxy, amicetosyloxy, amylosyloxy, apiosyloxy, arcanosyloxy, ascarylosyloxy, cellotriosyloxy, d-glycero-L-gulo- heptosyloxy, fucosaminyl-oxy, lactosaminyl-oxy, lactosediaminyl-oxy, fucitolyl-oxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyl-oxy, rhamnosaminyl-oxy, trehalosaminyl- oxy, D-glucopyranosyl-α-L-rhamnosyloxy, 1 ,6-anhydro-D-glucopyranosyloxy, 1-hydroxy- α-D-allopyranosyloxy, 2,3:5,6-di-O-isopropylidene-D-mannofuranosyloxy, 2-amino-2- deoxy-D-galactitolyl-oxy, 2-deoxyribosyloxy, 2-deoxyglucosyloxy, 5-amino-5-deoxy-D- glucopyranosyloxy, 6-deoxy-D-galactitolyl-oxy, 2-amino-2-deoxyglucosyloxy, 2-acetamido- 2-deoxy-glucosyloxy, 2-amino-2-deoxy galactosyloxy, 2-acetamido-2-deoxy- galactosyloxy, 2-amino-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-mannosyloxy, 2- acetamido^-deoxy^-O-β-D-galactosyl-D-glucosyloxy, 2-amino-2-deoxy-4-O-β-D- galactosyl-D-glucosyloxy, θ'-N-acetylglucosaminyllactosyloxy, 2-acetamido-2-deoxy-3-O- α-L-fucosyl-D-glucosyloxy, 6-O(2-acetamido-2-deoxy-β-D-glucosyl)-D-galactosyloxy, 2- acetamido^-deoxy-S-O-β-D-galactosyl-D-glucosyloxy, 2'-acetamido-2'-deoxy-3-O-β-D- glucosyl-D-galactosyloxy, 3-fucosyl-D-lactosyloxy, 3-fucosyl-2-acetamido-2-deoxy-4-O-β- D-galactosyl-D-glucosyloxy, L or D isomers thereof, a or b form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, hydroxyl-protected acetate or benzoyl derivatives thereof, amino

derivatives thereof, amido derivatives thereof, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof, each glycosyl moiety being optionally substituted by one or more substituents independently selected from the group comprising alkyl, aralkyl, aryl, Het ¹ , Het ² , cycloalkyl, alkyloxy, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(=O) _t , hydroxy, cyano, halogen, haloalkyl, haloalkoxy, or amino, alkylamino, aminoalkyl, wherein t is 1 or 2, wherein Het ¹ is selected from piperidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H- pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1 ,4-dioxanyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholin-4-yl,1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, and morpholin-4-yl, and Het ² is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3- d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3- benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2- benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3- benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, purinyl, imidazo[1 ,2- a]pyridinyl. Whenever used hereinafter, the term "compounds of the invention" or "derivatives" or "analogues" or a similar term is meant to include the compounds of general formula I, i.e. the hellebrin and hellebrigenin derivatives and any subgroup thereof. This term also refers to the compounds as depicted in Table 1 and their N-oxides, salts, stereoisomeric forms, racemic mixtures, pro-drugs, esters and metabolites, as well as their quaternized nitrogen derivatives. The N-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.

The compounds according to the invention contain one or more asymmetric carbon atoms that serve as chiral center, which may lead to different optical forms (e.g. enantiomers or diastereoisomers). The invention comprises all such optical forms in all possible configurations, as well as mixtures thereof.

More generally, from the above, it will be clear to the skilled person that the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers, and mixtures thereof are included within the scope of the invention.

The term stereochemically isomeric forms of the compounds according to the invention, as used herein, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound herein encompasses the mixture of all possible stereochemically isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the invention either in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

For instance, the present invention also provides compound the structural Formula II, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as that defined above.

The present invention also provides compound the structural Formula III, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as that defined above.

The present invention also provides compound the structural Formula IV, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as that defined above.

IV

The present invention also provides compound the structural Formula V, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as that defined above.

V

In an embodiment, the present invention provides compounds of Formula I, II, III, IV or V, wherein R ¹ is selected from the group comprising Ci _-4 alkyl, hydroxyCi _-4 alkyl, aminoCi. ₄ alkyl, thioCi _-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Ci _-4 alkyloxyCi _-4 alkyl, Ci _-4 alkylaminoCi _-4 alkyl, Ci _-4 alkylhydrazinoCi _-4 alkyl, Ci _-4 alkylthioCi _-4 alkyl, Ci _-4 alkanoyl, Ci _-4 alkyloxycarbonyl, Ci- ₄ alkylaminocarbonyl, Ci _-4 alkylthiocarbonyl, C _3-6 cycloalkylCi _-4 alkyl, C _3-6 cycloalkylcarbonyl, C _3-6 cycloalkylCi _-4 alkanoyl, Cs-ecycloalkylaminocarbonyl, Cs-ecycloalkylthiocarbonyl, C _3-

₆ cycloalkylCi _-4 alkoxycarbonyl, C ₃ - ₆ cycloalkylCi. ₄ alkylaminocarbonyl, C _3-6 cycloalkylCi. ₄ alkoxythiocarbonyl, Cs-ecycloalkylaminod^alkyl, Cs-ecycloalkylthiod^alkyl, Ci- ₄ alkylcarbonyloxyCi _-4 alkyl, Ci^alkylcarbonylaminoCi^alkyl, arylcarbonyloxyCi _-4 alkyl, C _{3- 6} cycloalkylcarbonyloxyCi _-4 alkyl, C ₃ - ₆ cycloalkylcarbonylaminoCi. ₄ alkyl, silyloxyCi _-4 alkyl, aralkyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl, aralkylaminocarbonyl, arylCi. ₂ alkylthiocarbonyl, aryloxyCi _-4 alkyl, arylhydrazinoCi _-4 alkyl, arylthioC-i. ₄ alkyl, haloCi _-4 alkyl, aralkanoyl, aroyl, aryloxyCi _-4 alkanoyl, carboxyl, formyl, Het ¹ Ci _-4 alkyl, Het ¹ C _3-6 cycloalkyl, Het ¹ carbonyl, Het ¹ aminocarbonyl, Het ¹ Ci _-4 alkoxycarbonyl, Het ¹ Ci_ ₄ alkylaminocarbonyl, Het ¹ Ci _-4 alkylthiocarbonyl, Het ¹ oxycarbonyl, Het ¹ thiocarbonyl, Het ¹ Ci_ ₄ alkanoyl, Het ¹ Ci. ₄ alkyloxyCi. ₄ alkyl, Het ¹ aminoCi. ₄ alkylcarbonyl, Het ¹ Ci- ₄ alkyloxyCi. ₄ alkylcarbonyl, He^Ci^alkylaminoCi^alkylcarbonyl, Het ¹ carbonyloxyCi _-4 alkyl,

Het ¹ carbonylaminoCi. ₄ alkyl, Het ¹ alkylcarbonyloxyCi _-4 alkyl, Het ¹ Ci. ₄ alkylcarbonylaminoCi. ₄ alkyl, Het ² Ci _-4 alkyl; Het ² aminoCi. ₄ alkyl, Het ² Ci. ₄ alkylaminoCi. ₄ alkyl, Het ² carbonyl, Het ² aminocarbonyl, Het ² thiocarbonyl, Het ² Ci _-4 alkanoyl, Het ² Ci_ ₄ alkylthiocarbonyl, Het ² Ci- ₄ alkoxycarbonyl, Het ² Ci- ₄ alkylaminocarbonyl, Het ² aminoCi. ₄ alkylcarbonyl, He^Ci^alkyloxyCi^alkylcarbonyl, He^Ci^alkylthioCi^alkylcarbonyl, Het ² Ci. ₄ alkylaminoCi. ₄ alkylcarbonyl, Het ² carbonyloxyCi _-4 alkyl, Het ² carbonylaminoCi. ₄ alkyl, Het ² carbonylthioCi _-4 alkyl, He^Ci^alkylcarbonyloxyCi^alkyl, cyano, aminocarbonyl, aminoCi _-4 alkanoyl, Ci _-4 alkylamino, wherein R ¹ is optionally substituted by one or more substituents independently selected from the group comprising Ci _-4 alkyl, aralkyl, aryl, Het ¹ , Het ² , C _3-6 cycloalkyl, Ci _-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci_ ₄ alkyl)aminocarbonyl, aminosulfonyl, Ci _-4 alkylS(=O) _t , hydroxy, cyano, halogen, haloCi. ₄ alkyl, haloCi _-4 alkoxy, amino, aminoCi _-4 alkyl, Ci _-4 alkylamino, wherein t is 1 or 2, wherein Het ¹ as a group or part of a group is selected from piperidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, pyrrolinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholin-4-yl, and morpholin-4-yl, aryl as a group or part of a group is phenyl or naphthyl, and Het ² as a group or part of a group is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, benzisoxazolyl, 1 ,3- benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, purinyl, and wherein R ² , R ³ , R ⁴ , and R ⁵ have the same meaning as that defined herein.

In an embodiment, the present invention provides compounds of Formula I, II, III, IV, or V, wherein R ² and R ³ are each independently selected from the group comprising hydroxyl, Ci _-4 alkyloxy, Ci _-4 alkylsilyloxy, arylsilyloxy, Ci _-4 alkyloxyCi _-4 alkyloxy, C _3- 6cycloalkyloxy C _{3- 6} cycloalkylCi _-4 alkyloxy, aralkyloxy, aryloxyCi _-4 alkyloxy, silyloxy, Ci _-4 alkylcarbonyloxy, arylcarbonyloxy, Cs-ecycloalkylcarbonyloxy, haloCi _-4 alkyloxy, hydroxyCi _-4 alkyloxy, aralkanoyloxy, aroyloxy, formyloxy, Het ¹ Ci _-4 alkyloxy, Het ¹ oxy, Het ¹ C _3- 6cycloalkyloxy, Het ¹ carbonyloxy, Het ¹ Ci _-4 alkanoyloxy, Het ² oxy, Het ² Ci _-4 alkyloxy; Het ² C _3-6 cycloalkyloxy, Het ² Ci _-4 alkanoyloxy, Het ² carbonyloxyl, wherein R ² and R ³ are each optionally substituted by one or more substituents independently selected from the group comprising Ci _-4 alkyl, aralkyl, aryl, Het ¹ , Het ² , C _3-6 cycloalkyl, Ci _-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci _-4 alkyl)aminocarbonyl, aminosulfonyl, Ci _-4 alkylS(=O) _t , hydroxy, cyano, halogen, haloCi _-4 alkyl, haloCi _-4 alkoxy, or amino, aminoCi _-4 alkyl, or Ci _-4 alkylamino, wherein t is 1 or 2, wherein Het ¹ as a group or part of a group is selected from piperidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, pyrrolinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholin-4-yl, and morpholin-4-yl, aryl as a group or part of a group is phenyl or naphthyl, and Het ² as a group or part of a group is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, benzisoxazolyl, 1 ,3-benzothiazolyl, benzoisothiazolyl, benzotriazolyl, 1 ,2,3- benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, benzothiadiazolyl, purinyl, and wherein R ¹ , R ⁴ and R ⁵ have the same meaning as that defined herein.

In an embodiment, the present invention provides compounds of Formula I, II, III, IV, or V, wherein R ⁴ is selected from the group comprising hydroxyl, amino, thio, oxo, C _{2- 4} alkynyl, Ci _-4 alkyloxy, Ci _-4 alkylamino, Ci _-4 alkylthio, Ci _-4 alkylhydrazino, C _3-6 cycloalkylamino, Cs-ecycloalkylhydrazino, C _3-6 cycloalkylthio, Ci _-4 alkylcarbonyloxy, Ci _-4 alkylcarbonylamino, Ci _-4 alkylcarbonylhydrazinoCi _-4 alkyl, arylcarbonyloxy, Ci _-4 alkylcarbonylhydrazino, C _{3- 6} cycloalkylcarbonyloxy, cycloalkylcarbonylamino, C _3-6 cycloalkylcarbonylhydrazino, silyloxy, arylamino, arylhydrazino, arylthio, halo, Het ¹ oxy, Het ¹ amino, Het ¹ C _3- βcycloalkyloxy, Het ¹ Ci _-4 alkyloxy, Het ¹ carbonyloxy, Het ¹ carbonylamino, Het ¹ Ci_ ₄ alkylcarbonyloxy, Het ¹ Ci _-4 alkylcarbonylamino, Het ² amino, Het ² hydrazino, Het ² Ci_ ₄ alkyloxy, Het ¹ alkylamino, Het ² alkylamino, Het ² carbonyloxy, Het ² carbonylamino,

Het ² carbonylthio, Het ² Ci- ₄ alkylcarbonyloxy, cyano, wherein R ⁴ is optionally substituted by one or more substituents independently selected from the group comprising C-^alkyl, aralkyl, aryl, Het ¹ , Het ² , C _3-6 cycloalkyl, Ci _-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci _-4 alkyl)aminocarbonyl, aminosulfonyl, Ci. ₄ alkylS(=O) _t , hydroxy, cyano, halogen, haloCi _-4 alkyl, haloCi _-4 alkoxy, amino, aminoCi _-4 alkyl, or Ci _-4 alkylamino, wherein t is 1 or 2, wherein Het ¹ as a group or part of a group is selected from piperidinyl, 2- imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, pyrrolinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholin-4-yl, and morpholin-4-yl, aryl as a group or part of a group is phenyl or naphthyl, and Het ² as a group or part of a group is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, benzisoxazolyl, 1 ,3-benzothiazolyl, benzoisothiazolyl, benzotriazolyl, 1 ,2,3- benzoxadiazolyl, 2,1 ,3-benzoxadiazolyl, benzothiadiazolyl, purinyl, and wherein R ¹ , R ² , R ³ and R ⁵ have the same meaning as that defined herein. In another embodiment, the present invention provides compounds of Formula I, II, III, IV, or V, wherein R ⁴ is selected from the group comprising glucosyloxy, fructosyloxy, galactosyloxy, mannosyloxy, ribosyloxy, ribulosyloxy, xylulosyloxy, erythrosyloxy, erythrulosyloxy, rhamnosyloxy, threosyloxy, fucosyloxy, arabinosyloxy, xylofuranosyloxy, talosyloxy, gulosyloxy, altrosyloxy, allosyloxy, mannoheptulosyloxy, isomaltosyloxy, maltosyloxy, lactosyloxy, sucrosyloxy, cellobiosyloxy, trehalosyloxy, melibiosyloxy, isosucrosyloxy, lactulosyloxy, 3-mannobiosyloxy, 6-mannobiosyloxy, 3-galactobiosyloxy, 4-galactobiosyloxy, maltotriosyloxy, maltotetraosyloxy, isomaltotriosyloxy, maltopentaosyloxy, maltohexaosyloxy, maltoheptaosyloxy, N-acetylgalactosaminyloxy, mannotriosyloxy, glucosaminyl(2-amino-2-deoxy-D-glucosyloxy), N-acetyl-glucosaminyl(2- (acetylamino)-2-deoxy-D-glucosyloxy), octylglucopyranosyloxy, octylribofuranosyloxy, cyclohexylglucopyranosyloxy, cyclohexylxylofuranosyloxy, benzylglucopyranosyloxy, benzylarabinofuranosyloxy, N-acetyl-lactosaminyl-oxy, d-glycero-L-gulo-heptosyloxy, fucosaminyl-oxy, lactosaminyl-oxy, lactosediaminyl-oxy, fucitolyl-oxy, maltulosyloxy, mannosaminyl-oxy, rhamnitolyl-oxy, rhamnosaminyl-oxy, trehalosaminyl-oxy, D- glucopyranosyl-α-L-rhamnosyloxy, 1 ,6-anhydro-D-glucopyranosyloxy, 1-hydroxy-α-D- allopyranosyloxy, 2,3:5,6-di-O-isopropylidene-D-mannofuranosyloxy, 2-amino-2-deoxy-D-

galactitolyl-oxy, 2-deoxyribosyloxy, 2-deoxyglucosyloxy, 5-amino-5-deoxy-D- glucopyranosyloxy, 6-deoxy-D-galactitolyl-oxy, 2-amino-2-deoxyglucosyloxy, 2-acetamido- 2-deoxy-glucosyloxy, 2-amino-2-deoxy galactosyloxy, 2-acetamido-2-deoxy- galactosyloxy, 2-amino-2-deoxy-mannosyloxy, 2-acetamido-2-deoxy-mannosyloxy, 2- acetamido^-deoxy^-O-β-D-galactosyl-D-glucosyloxy, 2-amino-2-deoxy-4-O-β-D- galactosyl-D-glucosyloxy, θ'-N-acetylglucosaminyllactosyloxy, 2-acetamido-2-deoxy-3-O- α-L-fucosyl-D-glucosyloxy, 6-O(2-acetamido-2-deoxy-β-D-glucosyl)-D-galactosyloxy, 2- acetamido^-deoxy-S-O-β-D-galactosyl-D-glucosyloxy, 2'-acetamido-2'-deoxy-3-O-β-D- glucosyl-D-galactosyloxy, 3-fucosyl-D-lactosyloxy, 3-fucosyl-2-acetamido-2-deoxy-4-O-β- D-galactosyl-D-glucosyloxy, L or D isomers thereof, α or β form thereof, pyranuronic or furanuronic form thereof, pyranose or furanose form thereof, combination thereof, deoxy derivatives thereof, hydroxyl-protected acetate or benzoyl derivatives thereof, amino derivatives thereof, amido derivatives thereof, thio derivatives thereof, di-, tri-, oligo- and polysaccharide thereof, each glycosyl moiety being optionally substituted by one or more substituents independently selected from the group comprising Ci _-4 alkyl, aralkyl, aryl, Het ¹ , Het ² , C _{3- 6} cycloalkyl, Ci _-4 alkyloxy, Ci _-4 alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci_ ₄ alkyl)aminocarbonyl, aminosulfonyl, Ci _-4 alkylS(=O) _t , hydroxy, cyano, halogen, haloCi. ₄ alkyl, haloCi _-4 alkoxy, amino, Ci _-4 alkylamino, Ci _-4 aminoalkyl, wherein t is 1 or 2, wherein Het ¹ is selected from piperidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, pyrrolinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholin-4-yl, and morpholin-4-yl, aryl as a group or part of a group is phenyl or naphthyl, and Het ² is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, benzisoxazolyl, 1 ,3- benzothiazolyl, benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3- benzoxadiazolyl, benzothiadiazolyl, purinyl, and wherein R ¹ , R ² , R ³ and R ⁵ have the same meaning as that defined herein.

In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for

example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above. The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I, II, III, IV and V, for which general reference is made to the prior art cited hereinbelow.

The term "pro-drug" as used herein means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated. Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component. Typical examples of pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Pro-drugs are characterized by increased bioavailability and are readily metabolized into the active inhibitors in vivo. The term "pre-drug", as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the pre-drug reaches the area of the body where administration of the drug is indicated.

For pharmaceutical use, the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base- addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form of a pro-drug or pre-drug, such as an ester. As used herein and unless otherwise stated, the term "solvate" includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, and the like. Such salts, hydrates, solvates, etc., and the preparation thereof will be clear to the skilled person; reference is for instance made to the salts, hydrates, solvates, etc. described in US-A-6,372,778, US-A-6,369,086, US-A-6,369,087, and US-A-6,372,733.

For therapeutic use, the salts of the compounds according to the invention are those wherein the counterion is pharmaceutically or physiologically acceptable.

The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D- glucamine, and salts with amino acids such a sarginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.

The pharmaceutically acceptable esters of the compounds according to the invention refer to non-toxic esters, preferably the alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters, of which the methyl ester is preferred. However, other esters such as phenyl-alkyl may be employed if desired. The compounds of the invention are particularly useful as medicament. The compounds according to the invention show cytotoxic activities, which implies that they may be used in various medical applications. As is demonstrated in the examples given below, the compounds according to the invention have in vitro anti-tumor activity.

The compounds according to the invention bind to the alpha-1 subunit and/or to the alpha- 3 subunit of Na ⁺ ,K ⁺ -ATPase.

The term "binding" as used herein generally refers to a physical association, preferably herein a non-covalent physical association, between molecular entities, e.g., between a "ligand" (generally referring to any agent, e.g., a substance or molecule) and a "receptor" (generally referring to any molecule). Preferably, a "receptor" may be a polypeptide or protein, such as, e.g., the alpha-1 subunit or the alpha-3 subunit of NKA, or variants or

fragments thereof, or a nucleic acid encoding such, etc. Preferably, a "ligand" may be, e.g., a polypeptide or protein, an antibody, a peptide, a peptidomimetic, an aptamer, a chemical substance (preferably an organic molecule, more preferably a small organic molecule), a lipid, a carbohydrate, a nucleic acid, etc. Furthermore, the compounds according to the invention exhibit a low toxicity level. "Toxicity" is related to the detrimental effect a compound may exhibit on healthy cells, tissues or organs. The toxicity level of the compounds according to the invention is surprisingly low. The compounds according to the invention combine the essential features of a good anti-tumor activity and a low level of toxicity. Consequently the compounds according to the invention may be used in pharmaceutical compositions for the treatment of various diseases. In addition, because they have a low level of toxicity the compounds according to the invention may be used during longer periods of treatments.

The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutic effective amount of at least one compound according to the invention.

The term "therapeutically effective amount" as used herein means that amount of compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.

The pharmaceutical composition can be prepared in a manner known per se to one of skill in the art. For this purpose, at least one compound according to the invention having formula I or any subgroup or derivative thereof, one or more solid or liquid pharmaceutical excipients and, if desired, in combination with other pharmaceutical active compounds, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human medicine or veterinary medicine.

Particular forms of the pharmaceutical composition may be, for example, solutions, suspensions, emulsions, creams, tablets, pills, capsules, nasal sprays, liposomes or micro-reservoirs, especially compositions in orally ingestible or sterile injectable form, for example, as sterile injectable aqueous or oleaginous suspensions or suppositories and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration. The solid carrier may comprise one or more excipients, e.g. lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, fillers, disintegrating agents, binders,

e.g. cellulose, carboxymethylcellulose or starch or anti-stick agents, e.g. magnesium stearate, to prevent tablets from adhering to tabletting equipment, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. Tablets, pills and boluses may be formed so as to disintegrate rapidly or to provide slow release of the active ingredient. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying, and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained, or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ o, β- or γ-cyclodextrins or their derivatives. In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention are obviously more suitable due to their increased water solubility.

Appropriate cyclodextrins are o, β- or γ-cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl, particularly carboxymethyl or carboxyethyl; alkylcarbonyl, particularly acetyl; alkyloxycarbonylalkyl or carboxyalkyloxyalkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; alkylcarbonyloxyalkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6- dimethyl- β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2- carboxymethoxy)propyl- β-CD, and in particular 2-hydroxypropyl- β-CD (2-HP- β-CD). The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. An interesting way of formulating the compounds according to the invention in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331. Although the formulations described therein are with antifungal active ingredients, they are equally interesting for formulating the compounds according to the

invention. Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavors.

More in particular, the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water- soluble polymers.

The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. The term "a solid dispersion" also comprises dispersions that are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.

The water-soluble polymer is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 20 ⁰ C solution. Preferred water- soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule. The compounds according to the invention as defined hereinabove can be prepared by first preparing a solid dispersion of the compounds according to the invention, and then optionally grinding or milling that dispersion. Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution- evaporation, melt-extrusion being preferred. It may further be convenient to formulate the compounds according to the invention in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular

weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal-coating polymer layer. Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.

The preparations may be prepared in a manner known per se, which usually involves mixing the at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. Reference is again made to US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule, or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300, or 400 mg per unit dosage.

Another important feature attributed to the compounds according to the invention is their broad application possibility. The compounds according to the invention are highly active against several types of cancers. As will be shown in the examples described below, the compounds according to the invention exert significant anti-tumor effects on several tumor models tested, including glioma, colon, lung and bladder cancer (see examples). Importantly, the compounds according to the invention exhibit anti-tumor activity on a broad panel of histological tumor types. In addition, the compounds according to the

invention bind to the alpha-1 subunit and/or to the alpha-3 subunit of Na ⁺ ,K ⁺ -ATPase and they exhibit a low toxicity level.

Therefore, due to their favorable pharmacological properties the compounds according to the present invention are particularly suitable for use as medicaments in the treatment of individuals suffering from diseases associated with cell proliferation. In another embodiment, the compounds according to the present invention are used as a medicament, in particular for the prevention and/or treatment of cancer, and/or for preventing, treating, and/or alleviating complications, and/or symptoms, and/or inflammatory responses associated therewith. In yet another embodiment, the compounds according to the present invention are used in the preparation of a medicament for treating diseases associated with cell proliferation. In particular the compounds according to the present invention are used in the preparation of a medicament for treating cancer.

The term "treating" as used herein includes treating any one or more of the conditions underlying or characteristic of cancer. Treatment of cancer means administration of a medicament with the result that cancer is reduced or the patient is cured.

The term "individual," as used herein refers to an animal, preferably a mammal such a human or an animal, and most preferably a human, who has been the object of treatment, observation or experiment.

The term "diseases associated with cell proliferation"' as used herein refers to, but is not limited to, any type of cancer or condition involving cell proliferation.

The compounds of the invention may be especially used in (the preparation of a medicament for) the treatment of cancers such as, but not limited to, leukemia, non-small cell lung cancer, small cell lung cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, breast cancer, glioma, colon cancer, bladder cancer, head and neck cancer, pancreas cancer, sarcoma, pancreatic cancer, colorectal cancer, skin cancer, liver cancer, bone cancer, bone marrow cancer, stomach cancer, duodenum cancer, oesophageal cancer, thyroid cancer, hematological cancer, and lymphoma.

Accordingly, the present invention provides a method for the treatment and/or prevention of cancer comprising administering to an individual an effective amount of at least one compound of formula I as defined above. By way of example, in an embodiment of the invention, cancer is treated in a subject in need of treatment by administering to the subject a therapeutically effective amount of at least one compound of formula I, effective to treat the cancer. The subject is preferably a mammal (e.g., humans, domestic animals, and commercial animals, including cows, dogs, monkeys, mice, pigs, and rats), and is most preferably a human.

In addition, the compounds according to the invention may also be very suitable in the treatment of scar tissue and wounds. It is believed that most, if not all, of the compounds of the present invention can act as active ingredients in treating scar tissue and in promoting wound healing and tissue regeneration. In another embodiment, the invention relates to a method of treatment of diseases associated with cell proliferation comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention. In particular, the invention relates to a method of treating cancer comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention. For these purposes, the compounds or the pharmaceutical composition of the present invention may be administered orally, parenterally, i.e. including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques, by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of the Formula I above that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200, or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to US-A-6,372,778, US-A- 6,369,086, US-A-6,369,087, and US-A-6,372,733, and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

In accordance with the method of the present invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

Essentially, the primary modes of treatment of solid tumor cancers comprise surgery, radiation therapy and chemotherapy, separately and in combination. The compounds according to the invention are suitable for use in combination with these medicinal techniques. The compounds of the invention may be useful in increasing the sensitivity of tumor cells to radiation in radiotherapy and also in potentiating or enhancing damage to tumors by chemotherapeutic agents. The compounds and their pharmaceutically acceptable salts and/or solvates may also be useful for sensitizing multidrug-resistant tumor cells. The compounds according to the invention are useful therapeutic compounds for administration in conjunction with DNA-damaging cytotoxic drugs or radiation used in radiotherapy to potentiate their effect.

In another embodiment of the method of the invention, the administration may be performed with food, e.g., a high-fat meal. The term "with food" means the consumption of a meal either during or no more than about one hour before or after administration of a pharmaceutical composition according to the invention. For an oral administration form, the compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

The oral administration of a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt or ester or solvate thereof, is suitably accomplished by uniformly and intimately blending together a suitable amount of said compound in the form of a powder, optionally also including a finely divided solid carrier, and encapsulating the blend in, for example, a hard gelatin capsule. The solid carrier can include one or more substances, which act as binders, lubricants, disintegrating agents, coloring agents, and the like. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose,

dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Oral administration of a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt or ester and/or solvate thereof can also be accomplished by preparing capsules or tablets containing the desired amount of said compound, optionally blended with a solid carrier as described above. Compressed tablets containing the pharmaceutical composition of the invention can be prepared by uniformly and intimately mixing the active ingredient with a solid carrier such as described above to provide a mixture having the necessary compression properties, and then compacting the mixture in a suitable machine to the shape and size desired. Molded tablets maybe made by molding in a suitable machine, a mixture of powdered compound according to the invention moistened with an inert liquid diluent.

When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous or intravenous administration, the compounds of the invention, if desired with the substances customary therefor such as solubilizers, emulsifiers or further auxiliaries, are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.

The pharmaceutical compositions of this invention can be administered to humans in dosage ranges specific for each compound comprised in said compositions. The compounds comprised in said composition can be administered together or separately.

It will be understood, however, that specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound of the invention employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. The compounds according to the invention may be prepared by a method of chemical synthesis, starting from Hellebrin or other compounds. The methods of synthesis of the compounds according to the invention involve chemical modifications of Hellebrin or derivatives thereof. Hellebrin can be obtained by any convenient method, for example by chemical synthesis. Alternatively, it may also be obtained from extraction and purification from e.g. plants of the Ranunculaceae family, which produce Hellebrin naturally, e.g. Helleborus foetidus, Helleborus orientalis or Helleborus niger.

It will also be clear that when the desired compounds of the invention, and/or the starting materials, precursors, and/or intermediates used in the preparation thereof, contain functional groups that are sensitive to the reaction conditions used in the preparation of the compounds of the invention (i.e. that would undergo undesired reactions under those conditions if they were not suitably protected) can be protected during said reaction with one or more suitable protective group, which protective group can then be suitably removed after either completion of said reaction and/or as a later or final step in the preparation of the compounds of the invention. Protected forms of the inventive compounds are included within the scope of the present invention. Suitable protective groups, as well as methods and conditions for inserting them and removing them, will be clear to the skilled person and are generally described in the standard handbooks of organic chemistry, such as Greene and Wuts, "Protective groups in organic synthesis", 3rd Edition, Wiley and Sons, 1999, which is incorporated herein by reference in its entirety. It will also be clear to the skilled person that compounds of the invention in which

one or more functional groups have been protected with suitable functional groups can find use as intermediates in the production and/or synthesis of the compounds of the invention, and as such form a further aspect of the invention.

The following examples are meant to illustrate the present invention. These examples are presented to exemplify the invention and are not to be considered as limiting the scope of the invention.

Examples

Example 1 : Compound according to the invention:

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of synthetic organic chemistry, biological testing, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

The compounds according to the invention are prepared by a method of chemical synthesis, starting from Hellebrin or other compounds. Hellebrin can be obtained by any convenient method, for example by chemical synthesis or from extraction and purification from e.g. plants of the Ranunculaceae family, for e.g. Helleborus foetidus, Helleborus oriental is or Helleborus niger.

In particular compounds of formula IV can be prepared according to the general procedure shown hereunder in scheme 1.

Reduction

Scheme 1

Preparation of Compound 1 :

100.3 mg of Hellebrin (1.38 10 ^"4 mol, Mw = 724.81 g/mol) and 13.0 mg of NaBH ₄ (3.44 10 ^"4 mol, M = 37.82 g/mol, 2.7 eq) were added to 6 ml. of methanol (previously distilled on Na). The mixture was stirred at 0 ⁰ C during 1 h 15 until the total disappearance of the starting product (followed on CCM). Then 0.2 ml. was added to quench the excess of NaBH ₄ . And the solvent was evaporated under reduced pressure. The residue was then submitted to a reverse phase flash chromatography (RP-C18): MeOH/H ₂ 0 (5/5).

48.0 mg of compound 1 was isolated after evaporation and drying of the compound on P ₂ O ₅ at 40 ⁰ C during 16 hours.

Compound 1 was characterized by:

¹ H NMR (300 MHz, DMSO) as follows : 7.92 (1 H, dd, J = 2.4 and 9.9); 7.52 (1 H, d, J = 1.2); 6.28 (1 H, d, J = 9.6); 5.48 (1 H, bs); 5.05 (3H, m); 4.72 (1 H, s); 4.39 (1 H, bs); 4.37 (1 H, d, J = 8.1 ); 4.29 (1 H, bs); 4.15 (2H, d, J = 13.5); 3.98 (1 H, bs); 3.80 (1 H, d, J = 11.1 ); 3.65 (2H, m); 3.50 (3H, m), 2.80-3.20 (5H); 2.46 (1 H, m); 1.25-2.15 (22H); 1.22 (2H, d, J = 5.7); 1.10 (1 H, m) and 0.60 (3H, s). carbon nuclear magnetic resonance ( ¹³ C NMR) performed at 300 MHz in DMSO, as follows : 161.3; 149.1 ; 147.3; 122.7; 114.1 ; 104.5; 98.9; 83.5; 82.0; 76.9; 76.4; 74.4; 74.3; 73.3; 70.6; 70.2; 69.9; 67.4; 62.5; 61.0; 49.9; 48.5; 47.8; 42.7; 38.1 ; 35.2; 34.5; 31.6; 28.3; 25.0; 23.5; 21.8; 19.2; 17.6; 16.6. mass spectra, ionization by electrospray, positive mode (ESI-MS (+)) as follows: 727.4 (M+H, 10); 565.4 (18); 419.3 (100); 401.3 (22); 383.3 (28); 371.3 (20) and 353.3 (26).

In Table 1 which is set forth below, compounds of the invention are set out in tabulated form. In Table 1 , an arbitrarily assigned compound number and structural information are set out.

^** : refers to fact that R ⁵ and R ² together with the carbon atom to which they are attached form a double bond

The present invention encompasses the compounds of Formula I as well as all those listed in Table 1 as well as stereoisomers, tautomers, racemates, prodrugs, metabolites thereof, or a pharmaceutically acceptable salt and/or solvate thereof.

Example 2: In vitro characterization of the biological effects of the compound according to the invention - Effect on overall cell growth

MTT tests were performed in order to rapidly, i.e. within 5 days, measure the effect of compounds of this invention on the overall cell growth. The test measured the number of metabolically active living cells that were able to transform the yellow product 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (herein referred as MTT) into the blue product formazan dye by mitochondrial reduction. The amount of formazan obtained at the end of the experiment, measured by means of a spectrophotometer, is directly proportional to the number of living cells. Optical density determination thus enabled a quantitative measurement of the effect of the investigated compounds as compared to the control condition (untreated cells) and/or to other reference compounds such as Hellebrin. Six human cancer cell lines described in table 2 were used in the following MTT tests. These cancer cell lines cover six histological cancer types, being prostate, glioma, pancreas, colon, lung, and breast cancers.

To perform the assay, cells were allowed to grow in 96-well micro-wells with a flat bottom with an amount of 100 μl of cell suspension per well with 1 ,000 to 4,000 cells/well depending on the cell type used. Each cell line was seeded in a well known MEM 10 % serum culture medium.

Table 2

The detailed experimental procedure was the following: after a 24-hour period of incubation at 37°C, the culture medium was replaced by 100 μl of fresh medium in which the tested compound was previously dissolved, at the following molar concentrations: 10 ^"9 M, 5.10 ^"9 M, 10 ^"8 M, 5.10 ^"8 M, 10 ^"7 M, 5.10 ^"7 M, 10 ^"6 M, 5.10 ^"6 M, and 10 ^"5 M. Each experimental condition was repeated 6 times.

After 72 hours of incubation at 37°C with (experimental conditions) or without (control condition) the compound to be tested, the medium was replaced by 100 μl MTT dissolved in RPMI (1640 without phenol red) at a concentration of 1 mg/ml. The micro-wells were subsequently incubated during 3 hours at 37° C and centrifuged at 400 g during 10 minutes. MTT was removed and formazan crystals formed were dissolved in 100 μl DMSO. The micro-wells were shaken for 5 minutes and read on a spectrophotometer at wavelengths of 570 nm (maximum formazan absorbance) and 630 nm (background noise).

For each experimental condition, the mean optical density was calculated, allowing the determination of the percentage of remaining living cells in comparison to the control.

Table 3 shows for compound n°1 (UNBS5194) according to the invention, and a reference compound hellebrin, the IC ₅ O obtained for the human cancer cell lines (mean of the six cell lines). The IC ₅₀ represents the range of nanomolar concentrations of the compound tested that resulted in a 50% inhibition of overall tumor cells growth.

Table 3

Example 3 In vitro characterization of the biological effects of the compound according to the invention - Compound 1 Displays Inhibitory Action on the Na+/K+- ATPase

The effects of the tested compounds on Na7K ⁺ -ATPase activity are evaluated by a colorimetric assay, based on the increase of color intensity resulting from the formation of a complex between orthophosphate and Biomolgreen. The color intensity is proportional to the amount of orthophosphate released and so to the activity of sodium pump.

The assay is performed on 96 well microplates and in quadruplicates. The enzyme and the potential inhibitors are incubated together to allow the eventual interactions and bindings for 20 min. ATP is then added. The reaction is allowed to proceed for 15 min, afterwards it is stopped by biomolgreen and the DO are read with a microplate reader. The mean of the quadruplicats are calculated and the mean of the values obtained with ouabain is taken as the 100 % inhibition.

The percentage of Na7K ⁺ -ATPase activity is calculated as:

(100 ^* mean of one quadruplicat)/(mean of the 4 values obtained with ouabain)-100. The most important parameter is the concentration at which 50 % of the Na7K ⁺ -ATPase activity is inhibited.

This assay showed that Compound 1 keep the inhibitory activity of the sodium pump (IC50~309nM) similarly to that observed with hellebrin (IC ₅₀ about193nM).

Example 4: In vivo characterization of the anti-tumour effects of the compound according to the invention - Determination of the acute toxicity in female mice (B6D2F1):

The maximum tolerated dose (herein after MTD) is defined as the maximum amount of a given drug which can be administered acutely (i.e. in one intraperitoneal, intravenous, subcutaneous or oral single dose) to healthy animals, i.e. animals not grafted with tumors. In this assay, compounds were dissolved in 5% hydroxypropyl-β-cyclodextrine (HPBCD) and administered intravenously as a single slow bolus (-60 seconds) in the tail vein. Mice were carefully observed over the first 4 hours after administration to record clinical signs. They were then monitored daily over 14 days for clinical signs and body weight. Five different doses of each compound were tested on three mice each to determine the NOEL (No-Observed Effect Level), the MTD (Maximal Tolerated Dose) and the lethal dose (LD). Using this methodology, the following data were obtained and reported in table 4:

Table 4 In vivo toxicity of compounds according to the invention

It can be seen from Table 4, that compound of the invention is more advantageous since it is less toxic in vivo than hellebrin, while being as potent as hellebrin in vitro (examples 2-

3). Also, compound 1 offered better safety margin based on the clinical signs monitored after an acute intravenous administration.

All patents, patent applications, and published references cited herein are hereby incorporated by reference in their entirety. While this invention has been particularly shown and described with references to preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope of the invention encompassed by the claims.