BACKGROUND OF THE INVENTION Non-cancerous pathogenic cellular proliferation has wide-ranging clinical implications. Such proliferation can be due to an abnormal cell proliferation or hyperproliferation, which is defined by an abnormally high rate of cell division, resulting in a rapid proliferation of the cells. Non- cancerous hyperproliferating cells typically resemble normal cells and function like normal cells.

In contrast, malignant hyperproliferating cells are typically anaplastic and are capable of invasion and metastasis.

The pathogenesis of diseases involving non-cancerous cellular proliferation often include cellular migration and inflammation. For example, angiogenesis associated with disease states, involves migration of endothelial cells in addition to endothelial cell proliferation. Moreover, immunological mechanisms play a role in the pathogenesis of a number of diseases associated with cellular proliferation and, therefore, such disease states are associated with inflammation.

For example, it has been suggested that immunologic mechanisms play a role in the pathogenesis of psoriasis. Specifically, it has been suggested that cytokines produced during immune activation and other inflammatory processes may lead to epidermal hyperplasia observed in psoriasis (Gottlieb J Invest Dermatol. 95 (5): 18S-19S (1990) ).

A number of diseases and disorders are associated with such non-cancerous pathogenic cellular proliferation including, but not limited to, psoriasis, blood vessel proliferative disorders, fibrotic disorders, arteriosclerotic disorders, restenosis, neointimal hyperplasia, endometriosis and lymphoproliferative disorders.

One example of non-cancerous pathogenic cellular proliferation is psoriasis, which is a common skin disease resulting in thickening of the epidermis and the presence of red scaly plaques.

Hyperproliferation of keratinocytes is a key feature of psoriasis along with epidermal inflammation and reduced differentiation of keratinocytes. Multiple mechanisms have been invoked to explain the keratinocyte hyperproliferation that characterizes psoriasis, but no single mechanism has been definitively implicated. Activation of epidermal growth factor receptors, alterations in protein kinase C signal transduction pathways, and the attendant changes in intracellular calcium metabolism may play a role in psoriatic epidermal hyperplasia. Disordered cellular immunity has also been implicated in the pathogenesis of psoriasis. However, the exact mechanisms of keratinocyte hyperproliferation and epidermal inflammation remain unclear and, because of the multifactorial nature of psoriasis, it is difficult to predict whether pharmacologic manipulation of complex signal transduction pathways, growth factor receptors, or cellular immune functions will attenuate the hyperproliferation of keratinocytes.

Topical treatments, either alone or as an adjunct to other therapies for those patients with moderate to severe psoriasis, are widely used in the treatment of psoriasis. Topical therapies include, for example, coal tar preparation (1-5% by weight), topical steroids, anthralin cream (1%) and synthetic retinoid tazarotene. Various side-effects are associated with the use of such therapies, for example, coal tar has a bad odour and stains clothing; long term use of fluorinated corticosteroids (which are more effective than hydrocortisone) may lead to striae, telangiectasis and ecchythmosis, and antbralin cream or synthetic retinoid tazarotene are often irritating. Other topical agents such as calcipotriene and vitamin D analogues (vitamin D3 or calcipotriol) may also provide temporary relief, while keratolytics such as salicylic acid can help in removing the thick scales from the psoriatic plaques. Natural sunlight may be beneficial for treatment of psoriasis, and this has led to the use of W radiation therapy (see, for example, U. S. Patent Nos. 4,153, 572 and 4,558, 700). WB radiation (280-320 nm) of affected areas is one of the most common treatments for moderate to severe psoriasis, with its efficacy enhanced by coating the skin with a tar containing emollient prior to the radiation.

The use of oral corticosteroids, which have an immunosuppressive effect on cytotoxic T lymphocytes, is also common. Other frequently used oral therapeutic agents include methotrexate, cyclosporin, hydroxyurea and acitretin. As with topical treatments, various side- effects are associated with prolonged use of these compounds, for example, methotrexate can lead to leukopenia and cumulative hepatic toxicity, cyclosporin may result in hypertension and nephrotoxicity, hydroxyurea use is limited by hematologic side effects and patients using acitretin may experience extreme dryness of mucous membranes, an increase in arthralgias and increased blood triglycerides.

A second example of non-cancerous pathogenic cellular proliferation are fibrotic disorders.

Fibrotic disorders result in whole or in part from the proliferation of fibroblasts. Fibrotic disorders include but are not limited to fibrosis, cirrhosis and arteriosclerotic conditions.

Another example of non-cancerous pathogenic cellular proliferation is unregulated angiogenesis, and/or angiogenesis involved in the pathogenesis of disease. Under normal physiological conditions, humans or animals undergo angiogenesis only in very specific restricted situations, for example, during wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. Persistent, unregulated angiogenesis, however, occurs in a multiplicity of disease states and supports the pathological damage seen in these disease states.

For example, while cornea and cartilage are avascular in healthy situations, several diseases involving these tissues are complicated by the massive arrival of new blood vessels. Eye angiogenic diseases include neovascular glaucoma, retrolental fibroplasia, macular degeneration and neovascularization of corneal grafts. Joint angiogenic diseases include rheumatoid arthritis and arthrosis. Psoriasis also exhibits hypervascularization at the surface of the skin. Solid tumour growth is also critically dependent upon the formation of new blood vessels to progress locally and spread throughout the body. Regulation of cell replication and/or differentiation is important in the maintenance of existing blood vessels, for example, acute and chronic pathological processes, such as atherosclerosis, post-angioplastic restenosis and hypertension, involve the proliferation of different cellular components of mature blood vessels (endothelial cells, smooth muscle cells, myocytes and fibroblasts).

Several kinds of compounds have been proposed for the prevention or inhibition of angiogenesis involved in disease states, for example, protamine (see Taylor et al. , (1982) Nature 297: 307), heparin (see Folkman et al., Science 221: 719 (1983) and U. S. Patent Nos. 5,001, 116 and 4,994, 443) and certain steroids, such as tetrahydrocortisol, which lack gluco and mineral corticoid activity. The toxicity of protamine, however, limits its practical use as a therapeutic.

Other factors found endogenously in animals, such as a 4 kDa glycoprotein from bovine vitreous humour and a cartilage derived factor, have been used to inhibit angiogenesis. Cellular factors such as interferon inhibit angiogenesis. For example, interferon-a or human interferon-P has been shown to inhibit tumour-induced angiogenesis in mouse dermis stimulated by human neoplastic cells. Interferon- (3 is also a potent inhibitor of angiogenesis induced by allogeneic spleen cells (Sidky et al., (1987) Cancer Research 47: 5155-5161). The use of human recombinant interferon-a (alphalA) in the treatment of pulmonary hemangiomatosis, an angiogenesis-induced disease, has been reported (White et al., (1989) New England J. Med.

320: 1197-1200).

Urea-based compounds have been described for diverse indications, including as herbicides (U. S. Patent No. 3, 885, 954), as prophylactics against gastrointestinal and cardiovascular disorders (U. S. Patent No. 4,707, 478), as anti-parasitic agents (U. S. Patent No. 4,707, 478), as anti-athersclerotic agents (U. S. Patent No. 4,623, 662), as treatments for gastrointestinal, spasmolytic and ulcerogenic disorders (U. S. Patent No. 4,304, 786) and as anti-cancer agents (for example, U. S. Patent Nos. 3,968, 249; 4,973, 675 and 4,803, 223). A class of l-aryl-3-(2- chloroethyl) urea derivatives have been described as anti-cancer agents (U. S. Patent Nos.

5,530, 026 and 5,750, 547, and International Patent Application WO 00/61546) and as p-tubulin inhibitors (International Patent Application WO 01/447504).

This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.

SUMMARY OF THE INVENTION An object of the present invention is to provide haloethyl urea compounds and their use as anti- proliferative agent in the attenuation, inhibition, or prevention of non-cancerous cellular proliferation. In accordance with one aspect of the present invention there is provided a method of attenuating, inhibiting, or preventing non-cancerous cellular proliferation comprising contacting cells with an effective amount of a compound having structural formula (I) : or a pharmaceutically acceptable salt thereof, wherein: X is F, Cl, Br or I ; R1 and R2 are each independently selected from the group of H,-R,-halo,-OR, -SR,-NRR,-CN,-C (O) R, -C (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-C (O) NRR, - C (S) NRR,-C (O) NR (SR), -C (S) NR (SR),-CH (CN) 2,-CH [C (O) R] 2, -CH [C (S) R] 2, - CH [C (O) OR] 2,-CH [C (S) OR] 2, -CH [C (O) SR] 2, -CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, or RI and R2 when taken together form =O, =S or a C3-C6 spiro group; B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine; wherein: B is substituted with one or more substituents selected from the group of (C1-C16) alkyl, (C2-C16) alkenyl, (C2-Cl6) alkynyl, aryl,-O-(Cl-Cl6) alkyl,-O-(C2-Cl6) alkenyl,-O-(C2-Cl6) alkynyl, -O-aryl, -O-CH2-aryl, -S-(C1-C16)alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S- aryl,-S-CH2-aryl, (C3-C8) cycloalkyl,-O- (C3-C8) cycloalkyl,-S- (C3-C8) cycloalkyl,-halo,-NRR, - ONRR-N02,-CN,-C (O) R, -C (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R,- SC (O) R, -SC (S) R, -OC (S) R,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),- C (O) NR (SR), -C (S) NR (SR),-CH (CN) 2,-CH [C (O) R] 2, -CH [C (S) R] 2,-CH [C (O) OR] 2,- CH [C (S) OR] 2, -CH [C (O) SR] 2,-CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, - S (O) 2OR,-S (O) NRR, -S (O) ONRR; wherein: each R is independently selected from-H, (C1-C16) alkyl, substituted (C1-C16) alkyl, (C2- C16) alkenyl, substituted (C2-C16) alkenyl, (C2-C16) alkynyl, substituted (C2-Cl6) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cycloalkyl, aryl or substituted aryl; the alkyl, alkenyl, alkynyl and aryl are optionally substituted with one or more substituents independently selected from the group of-halo, trihalomethyl,-R',-OR',-SR',-NR'R',-NO2,- CN, -OC (O) R', -OC (S) R',-SC (O) R, -SC (S) R-C (O) R', -C (S) R',-C (O) OR', -C (S) OR',-C (O) SR', -C (S) SR',-C (O) NR'R',-C (S) NR'R',-NR'C (O) R' and -NR'C(O)OR'; the cycloalkyl is optionally substituted with one or more substituents independently selected from the group of R',-halo, OR', -SR', -NR'R', -ONR'R', -NO2, -CN, -C (O) R', -C (S) R',- OC (O) R',-SC (O) R', -SC (S) R',-OC (S) R',-C (O) OR',-C (S) OR',-C (O) SR',-C (S) SR',- C (O) NR'R',-C (S) NR'R',-C (O) NR'(OR'), -C (S) NR'-(OR'),-C (O) NR'(SR'),-C (S) NR'(SR'),- CH (CN) 2,-CH [C (O) R'] 2,-CH [C (S) R']2, -CH [C (O) OR'] 2, -CH [C (S) OR] 2,-CH [C (O) SR'] 2, - CH [C (S) SR'] 2,-NR'C (O) R',-NR'C (O) OR', -S (O)-R', -S(O)OR', -S(O)2OR', -S(O)NR'R', - S (O) ONRR', and each R'is independently selected from the group of-H, (C1-C6) alkyl, substituted (Cl-Cl6) alkyl, (C2-Cl6) alkenyl, substituted (C2-C16) alkenyl, (C2-C16) alkynyl, substituted (C2-Cl6) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl.

In accordance with another aspect of the invention compounds of formula (I) are provided for use as anti-proliferative agent in the attenuation, inhibition, or prevention of non-cancerous cellular proliferation. for use as a therapeutic agent in the treatment of a disease or disorder, wherein pathogenesis of said disease or disorder is associated with non-cancerous pathogenic cellular proliferation.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 presents a graph illustrating the ability of compound 1 to inhibit human foreskin fibroblast cell proliferation (* Number of untreated cells were arbitrary assign to 100%).

Figure 2 presents a graph illustrating the ability of compound 1 to inhibit human umbilical vein endothelial cell (HUVEC) proliferation (* Number of untreated cells were arbitrary assign to 100%).

Figure 3 presents graphs illustrating the ability of compound 1 (A); compound 5 (B); 1- (4-t- butyl-phenyl) -3-ethyl urea (tBEU) (C) aand cDDP to inhibit human umbilical vein endothelial cell (HUVEC) proliferation.

Figure 4 presents a graph illustrating the ability of compounds 1,2 and 3 to affect the inhibition of IL-2 production of PMA-stimulated Jurkat cells. The graph further illustrates that the compounds do not stimulate IL-2 production in non-stimulated (control) Jurkat cells.

Figures 5A and 5B present graphs illustrating the ability of compounds 1,2, 3 and 88 to affect the inhibition of IL-2 production of PMA-stimulated Jurkat cells. The graphs further illustrate that the compounds do not stimulate IL-2 production in non-stimulated (control) Jurkat cells.

Figure 6a-c present graphs illustrating the ability of compounds of the invention to inhibit IL-2 production of PMA/PHA stimulated human lympho-mono cells and the cytotoxicity of the compounds in PMA/PHA stimulated lympho-mono cells. Figure 7 presents a graph illustrating the ability of compound 1 to inhibit growth of immortalized human keratinocytes (HaCat cells) (*Number of untreated cells were arbitrary assign to 100% growth).

Figures 8A-H present graphs illustrating the effect of various compounds of the invention and control compounds on immortalized human keratinocytes (HaCat cells). 8A compound 1; 8B compound 2; 8C compound 3; 8D compound 17; 8E 5-FU; 8F colchicine; 8G taxol, and 8H vinblastine.

Figure 9 presents graphs illustrating the cytotoxic activity of compounds 1 (9A), 2 (9B), 3 (9C), 22 (9D) and tB-CEU (9E) on HaCat cells.

Figure 10 presents the results of a Matrigel plug assay using compound 5.

Figure 11 presents the results of a Matrigel plug assay using compound 1, compound 1, compound 5 or tBEU.

Figure 12 presents graphs illustrating the effects of compound 1 (A) and compound 5 (B) on cell migration.

Figure 13 presents graphs illustrating the effects of compounds 1 (A); 5 (B) and tBEU (C) on endothelial cell migration.

Figure 14 presents a histogram depicting the effect of compound 1 on tumour growth in the chick CAM assay.

Figure 15 presents graphs depicting the effect of compounds 1 (A); 5 (B); tBEU (C) and cDDP (D) of the invention on tumour growth in the CAM assay.

Figure 16 presents graphs depicting the effect of compounds 1 (A); 5 (B); 2 (C) and 22 (D) of the invention on tumour growth in the CAM assay.

Figure 17 depicts the microtubule depolymerization and cytoskeleton disruption in HUVECs induced by compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION The invention provides for the use of haloethyl urea derivatives of Formula I for the attenuation, inhibition or prevention of non-cancerous pathogenic cellular proliferation and diseases associated therewith.

Defitzitions The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. For example"°C"refers to degrees Celsius;"N"refers to normal or normality;"mmol"and"mM"refer to millimole or millimoles ;"pM"refers to micromole or micromoles;"g"refers to gram or grams;"mL"means milliliter or milliliters;"M"refers to molar or molarity ;"p-"refers to para, "MS"refers to mass spectrometry ; "IR"refers to infrared spectroscopy; and"NMR"refers to nuclear magnetic resonance spectroscopy.

The terms are defined as follows: The term"halogen"refers to fluorine, bromine, chlorine, and iodine atoms.

The term"hydroxyl"refers to the group-OH.

The tenn"thiol"or"mercapto"refers to the group-SH, and-S (O) 02.

The term"lower alkyl"refers to a straight chain or branched, or cyclic, alkyl group of 1 to 16 carbon atoms. This term is further exemplified by such groups as methyl, ethyl, n-propyl, i- propyl, n-butyl, t-butyl, 1-butyl (or 2-methylpropyl), cyclopropylmethyl, i-amyl, n-amyl, hexyl and the like.

The term"substituted lower alkyl"refers to lower alkyl as just described including one or more groups such as hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, carboxyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, alkyl cycloheteroalkyl, cyano. These groups may be attached to any carbon atom of the lower alkyl moiety.

The term"lower alkenyl"refers to a straight chain or branched hydrocarbon of 2 to 16 carbon atoms having at least one carbon to carbon double bond.

The term"substituted lower alkenyl"refers to lower alkenyl as just described including one or more groups such as hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, carboxyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkyl, alkenyl, alkynyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, alkyl cycloheteroalkyl, cyano. These groups may be attached to any carbon atom to produce a stable compound.

The term"lower alkynyl"refers to a straight chain or branched hydrocarbon of 2 to 16 carbon atoms having at least one carbon to carbon triple bond.

The term"substituted lower alkynyl"refers to lower alkynyl as just described including one or more groups such as hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, carboxyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkyl, alkenyl, alkynyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, alkyl cycloheteroalkyl, cyano. These groups may be attached to any carbon atom to produce a stable compound. The term"alkyl alkenyl"refers to a group-R-CR'=CR"'R"", where R is lower alkyl, or substituted lower alkyl, R', R"', R""are each independently selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

The term"alkyl alkynyl"refers to a group-R-C=-CR'where R is lower alkyl or substituted lower alkyl, R'is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined below.

The term"alkoxy"refers to the group-OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl as defined below.

The term"alkylthio"denotes the group-SR,-S (O) -1-2-R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl aralkyl or substituted aralkyl as defined below.

The term"acyl"refers to groups-C (O) R, where R is hydrogen, lower alkyl substituted lower alkyl, aryl, substituted aryl.

The term"aryloxy"refers to groups-OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group as defined below.

The term"amino"refers to the group NRR', where R and R'may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, cycloalkyl, or substituted hetaryl as defined below or acyl.

The term"amido"or"amide"refers to the group-C (O) NRR', where R and R'may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined below.

The term"carboxyl"refers to the group-C (O) OR, where R may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl and the like as defined.

The terms"aryl"or"Ar"refer to an aromatic carbocyclic group having at least one aromatic ring (e. g. , phenyl or biphenyl) or multiple condensed rings in which at least one ring is aromatic, (e. g. , 1,2, 3, 4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl, 9-fluorenyl etc. ).

The term"substituted aryl"refers to aryl optionally substituted with one or more functional groups, e. g. , halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, trifluoromethyl, alkenyl, alkenyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, sulfamido or cyano.

The term"heterocycle"refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring (e. g. , morpholino, pyridyl or furyl) or multiple condensed rings (e. g. , naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl, indanyl or benzo [b] thienyl) and having at least one hetero atom, such as N, O or S, within the ring.

The term"substituted heterocycle"refers to heterocycle optionally substituted with, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, trifluoromethyl, alkenyl, alkenyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, sulfamido or cyano and the like.

The terms"heteroaryl"or"hetar"refer to a heterocycle in which at least one heterocyclic ring is aromatic.

The term"substituted heteroaryl"refers to a heterocycle optionally mono or poly substituted with one or more functional groups, e. g. , halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, trifluoromethyl, alkenyl, alkenyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, sulfamido or cyano and the like.

The term"aralkyl"refers to the group-R-Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group. Aryl groups can optionally be unsubstituted or substituted with, e. g. , halogen, lower alkyl, alkoxy, alkyl thio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term"heteroalkyl"refers to the group-R-Het where Het is a heterocycle group and R is a lower alkyl group. Heteroalkyl groups can optionally be unsubstituted or substituted with e. g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term"heteroarylalkyl"refers to the group-R-HetAr where HetAr is an heteroaryl group and R lower alkyl or substituted loweralkyl. Heteroarylalkyl groups can optionally be unsubstituted or substituted with, e. g. , halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term"cycloalkyl"refers to a cyclic or polycyclic alkyl group containing 3 to 15 carbon. For polycyclic groups, these may be multiple condensed rings in which one of the distal rings may be aromatic (e. g. tetrahydronaphthalene, etc. ).

The term"substituted cycloalkyl"refers to a cycloalkyl group comprising one or more substituents with, e. g halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, trifluoromethyl, alkenyl, alkenyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, sulfamido or cyano and the like.

The term"cycloheteroalkyl"refers to a cycloalkyl group wherein one or more of the ring carbon atoms is replaced with a heteroatom (e. g. , N, O, S or P).

The term"substituted cycloheteroalkyl"refers to a cycloheteroalkyl group as herein defined which contains one or more substituents, such as halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The term"alkyl cycloalkyl"refers to the group-R-cycloalkyl where cycloalkyl is a cycloalkyl group and R is a lower alkyl or substituted lower alkyl. Cycloalkyl groups can optionally be unsubstituted or substituted with e. g. halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.

The terms"treatment,""therapy"and the like refer to improvement in the recipient's status as well as prophylaxis. The improvement can be subjective or objective and related to features such as symptoms or signs of the disease or condition being treated. Prevention of deterioration of the recipient's status is also encompassed by the term.

The term"non-cancerous pathogenic cellular proliferation"refers to excessive or abnormal cell proliferation or hyperproliferation. "Non-cancerous pathogenic cellular proliferation"may include proliferation of a wide variety of cell types, including but not limited to keratinocytes and endothelial cells. "Non-cancerous pathogenic cellular proliferation"includes unregulated angiogenesis which may or may not be associated with cancer.

The term"inhibit"or"inhibition"as it refers to non-cancerous pathogenic cellular proliferation includes the arrest, prevention or decrease in non-cancerous pathogenic cellular proliferation, both temporary and long-term. The term"ameliorate"or"amelioration"includes the arrest, prevention, decrease, or improvement in one or more the symptoms, signs, and features of the disease being treated, both temporary and long-term.

The compounds according to the instant invention include compounds of the following general formula: or a pharmaceutically acceptable salt thereof, wherein: X is F, Cl, Br or I; R1 and R2 are each independently selected from the group of H,-R,-halo,-OR, -SR, -NRR, -CN, -C(O) R, -C (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-C (O) NRR, - C (S) NRR,-C (O) NR (SR), -C (S) NR (SR), -CH (CN) 2,-CH [C (O) R] 2,-CH [C (S) R] 2, - CH [C (O) OR] 2, -CH [C (S) OR] 2,-CH [C (O) SR] 2,-CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, or RI and R2 when taken together form =O, =S or a C3-C6 spiro group; B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine; wherein: B is substituted with one or more substituents selected from the group of (C1-C16) alkyl, (C2-C16) alkenyl, (C2-Cl6) alkynyl, aryl,-O-(Cl-Cl6) alkyl,-O-(C2-Cl6) alkenyl,-O-(C2-Cl6) alkynyl,-O- aryl, -O-CH2-aryl, -S- (C1-C16)alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S-aryl, -S-CH2- aryl, (C3-Cg) cycloalkyl,-O- (C3-C8) cycloalkyl,-S- (C3-Cs) cycloalkyl,-halo,-NRR,-ONRR- NO2, -CN, -C (O) R, -C (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, - SC (S) R,-OC (S) R,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), - C (S) NR (SR),-CH (CN) 2,-CH [C (O) R] 2, -CH [C (S) R] 2, -CH [C (O) OR] 2,-CH [C (S) OR] 2, - CH [C (O) SR] 2,-CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (0) 20R,- S (O) NRR, -S (O) ONRR; wherein: each R is independently selected from-H, (C1-C16) alkyl, substituted (Cl-Cl6) alkyl, (C2- C16) alkenyl, substituted (C2-Cl6) alkenyl, (C2-C16) alkynyl, substituted (C2-Cl6) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cycloalkyl, aryl or substituted aryl; the alkyl, alkenyl, alkynyl and aryl are optionally substituted with one or more substituents independently selected from the group of-halo, trihalomethyl,-R',-OR',-SR',-NR'R',-N02,- CN, -OC (O) R', -OC (S) R',-SC (O) R, -SC (S) R-C (O) R', -C (S) R',-C (O) OR', -C (S) OR',-C (O) SR', -C (S) SR',-C (O) NR'R', -C (S) NR'R',-NR'C (O) R' and -NR'C(O)OR'; the cycloalkyl is optionally substituted with one or more substituents independently selected from the group of R',-halo, OR', -SR', -NR'R', -ONR'R', -NO2, -CN, -C (O) R',-C (S) R',- OC (O) R',-SC (O) R', -SC (S) R', -OC (S) R',-C (O) OR',-C (S) OR',-C (O) SR', -C (S) SR',- C (O) NR'R',-C (S) NRR',-C (O) NR' (OR),-C (S) NR' -(OR'), -C(O)NR'(SR'), -C (S) NR'(SR'), - CH (CN) 2,-CH [C (O) R2,-CH [C (S) R']2, -CH [C (O) OR'] 2,-CH [C (S) OR']2, -CH [C (O) SRg2,- CH [C (S) SR] 2,-NRC (O) R,-NRC (O) OR,-S (O)-R',-S (O) OR', -S (0) 20R',-S (O) NR'R',- S (O) ONR'R', and each R'is independently selected from the group of-H, (C1-C16) alkyl, substituted (Cl- C16) alkyl, (C2-Cl6) alkenyl, substituted (C2-C16) alkenyl, (C2-C16) alkynyl, substituted (C2-Ci6) alkynyl, (C3-Cs) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl.

In one embodiment, the compound of the invention is one in which RI and R2 are each independently selected from H, (C1-C6) alkyl and (Ci-Ce) alkoxy.

In a specific embodiment in the compound of formula (I) B is phenyl, substituted with one or more substituents indepnednetly selected from the list as shown above.

In another embodiment in the compound of formula (I), B is phenyl substituted with halo,-CN, -C(O) R, -C (O) OR, -OC (O) R, -C (O) NRR, -OR, (C1-C16) alkyl, (C2-C16) alkenyl, (C2-C16) alkynyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted with-CN,-C (O) R', - C (O) OR', -OC (O) R', -C (O) NR'R',-OR', wherein R and R'are as defined above.

In another embodiment the substituents of the compounds of formula (I) are as follows: X is F, Cl, Br or I ; R1 and R2 are as defined above, and B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine; and substituted with at least one substituent selected from, (Cl-Cl6) alkyl, (C2-Cl6) alkenyl, (Ca-Cis) alkynyl,-O-(Cl-Cl6) alkyl,-O-(C2-Cl6) alkenyl,-O-(C2-Cl6) alkynyl, aryl, substituted aryl,-0- aryl, -O-CH2-aryl, -S- (C1-C16) alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S-aryl, -S-CH2- aryl, (C3-Cs) cycloalkyl,-O-(C3-C8) cycloalkyl,-S-(C3-C8) cycloalkyl,-ONRR,-C (O) R, -C (S) R -C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, -SC (S) R, -OC (S) R,-C (O) NRR, - C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), -C (S) NR (SR),-CH (CN) 2, - CH [C (O) R] 2,-CH [C (S) R] 2,-CH [C (O) OR] 2, -CH [C (S) OR] 2,-CH [C (O) SR] 2,-CH [C (S) SR] 2, -NRC(O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (0) 20R, -S (O) NRR, -S (O) ONRR; wherein: said alkyl is substituted with at least one substituent selected from the group of halo,-CN,-NO2, -NR'R', -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -OC(O)R', -OC (S) R',-C (O) R', -C (S) R',- C (O) NR'R' and-C (S) NR'R' ; said alkenyl, alkylnyl,-O-alkyl,-S-alkyl, are each independently substituted with at least one group selected from halo, -CN, -NO2, -NR'R', -OH, -OR', -O-aryl, -OC (O) R', -OC (S) R',-C (O) R', - C (S) R',-C (O) OR', -C (O) NR'R' and-C (S) NR'R' ; said-O-alkenyl,-O-alkynyl,-S-alkenyl,-S-alkynyl, cycloalkyl, -O-cycloalkyl are are each optionally and independently substituted with at least one group selected from halo, -CN, -NO2, - NR'R',-OH,-OR',-O-aryl,-OC (O) R', -OC (S) R',-C (O) R', -C (S) R',-C (O) OR',-C (O) NR'R' and- C (S) NR'R', and wherein R, R'and aryl are as defined above and their substituents are as defined above.

In another embodiment the substituents of the compounds of formula (I) are as follows: X is F, Cl, Br or I ; Rl and R2 are as defined above, and B is phenyl substituted with at least one substituent selected from, (Cl-Cl6) alkyl, (C2-Ci6) alkenyl, (C2-C16) alkynyl, -O-(C1-C16) alkyl, -O-(C2-C16) alkenyl, -O-(C2-C16) alkynyl, aryl, substituted aryl, -O-aryl, -O-CH2-aryl, -S-(C1-C6) alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S-aryl,-S-CH2-aryl, (C3-Cg) cycloalkyl,-O- (C3-C8) cycloalkyl,-S- (C3-C8) cycloalkyl,- ONRR, -C (O) R, -C (S) R-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, -SC (S) R, - (S) R,-C (O) NRR,-C (S) NRR,-C (O) NR (OR),-C (S) NR (OR),-C (O) NR (SR),-C (S) NR (SR),- CH (CN) 2,-CH [C (O) R] 2, -CH [C (S) R] 2,-CH [C (O) OR] 2,-CH [C (S) OR] 2, -CH [C (O) SR] 2, - CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (0) 20R, -S (O) NRR,- S (O) ONRR; wherein: said alkyl is substituted with at least one substituent selected from the group of halo, -CN, -NO2, -NR'R', -O-alkyl, -O-alkenyl, -O-alkynal, -O-aryl, -OC(O) R', -OC (S) R',-C (O) R', -C (S) R', - C (O) NR'R' and-C (S) NR'R' ; said alkenyl, alkylnyl,-O-alkyl,-S-alkyl, are each independently substituted with at least one group selected from halo,-CN,-NO2,-NR'R',-OH,-OR',-O-aryl,-OC (O) R', -OC (S) R',-C (O) R', - C (S) R',-C (O) OR',-C (O) NR'R' and -C (S) NR'R' ; said-O-alkenyl,-O-alkynyl,-S-alkenyl,-S-alkynyl, cycloalkyl,-O-cycloalkyl are are each optionally and independently substituted with at least one group selected from halo,-CN,-N02,- NR'R', -OH, -OR', -O-aryl, -OC (O) R', -OC (S) R',-C (O) R', -C (S) R',-C (O) OR', -C (O) NR'R' and - C (S) NR'R', and wherein R, R'and aryl are as defined above and their substituents are as defined above.

In another embodiment the substituents of the of the compounds of formula (I) are as follows: X is F, Cl, Br or I ; R1 and R2 are as defined above, and B is phenyl substituted with at least one group selected from, (C1-C6) alkyl, (C2-C16) alkenyl, (C2-Ci6) alkynyl,-O- (CI-C16) alkyl,-O- (C2-Ci6) alkenyl,-O- (C2-Ci6) alkynyl,-aryl,-O-aryl,-O- CH2-aryl,-OC (O) R, -C (O) R, -C (O) OR, -C (O) NR'R', -NRC (O) R, -NRC (O) OR, -S (O)-R, - S (O) OR, -S (O) NRR, -S (O) ONRR; wherein: said alkyl is substituted with at least one group selected from halo,-CN,-O-alkyl,-O-alkenyl, -O-alkylnyl, -O-aryl, -OC(O) R', -C (O) R', and-C (O) NR'R' : said alkenyl, alkynyl,-O-alkyl,-O-alkenyl and-O-alkynyl are each independently substituted with at least one group selected from halo, -CN, -OH, -OR', -O-aryl, -OC (O) R', -C (O) R', - C (O) OR'and-C (O) NR'R', and R and R'are as defined above.

In another embodiment, the substituents of the of the compounds of formula (I) are as follows: XisFCl, BrorI ; RI and R2 are each independently selected from the group of H, (Cl-C6) alkyl, (Cl-C6) hydroxy alkyl, or R1 and R2 when taken together form =O ; B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine; and substituted with at least one substituent selected from (Cl-Cl6) alkyl, (C2-Cl6) alkenyl, (C2-Cl6) alkynyl, -O-(C1-C16) alkyl, -O-(C2-16) alkenyl, -O-(C2-C16) alkynyl, aryl, substituted aryl,-0- aryl, -O-CH2-aryl, -S-(C1-C16) alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S-aryl,-S-CH2- aryl, (C3-C8) cycloalkyl, -O-(C3-C8) cycloalkyl, -S-(C3-C8) cycloalkyl, -ONRR, -C(O) R, -C (S) R -C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, -SC (S) R, -OC (S) R,-C (O) NRR, - C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), -C (S) NR (SR),-CH (CN) 2, -CH [C (O) R] 2, -CH [C (S) R] 2, -CH [C (O) OR] 2,-CH [C (S) OR] 2, -CH [C (O) SR] 2,-CH [C (S) SR] 2, -NRC(O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (O) 2OR,-S (O) NRR, -S (O) ONRR; wherein: said alkyl is substituted with at least one substituent selected from the group of halo,-CN,-NO2, -NR'R', -O-alkyl, -O-alkenyl, -O-alkyyl, -O-aryl, -OC(O) R', -OC (S) R',-C (O) R', -C (S) R',- C (O) NR'R' and-C (S) NR'R'; said alkenyl, alkylnyl,-O-alkyl,-S-alkyl, are each independently substituted with at least one group selected from halo, -CN, -NO2, -NR'R', -OH, -OR', -O-aryl, -OC (O) R', -OC (S) R',-C (O) R', - C (S) R',-C (O) OR', -C (O) NR'R' and-C (S) NR'R' ; said-O-alkenyl,-O-allcynyl,-S-alkenyl,-S-alkynyl, cycloalkyl,-O-cycloalkyl are are each optionally and independently substituted with at least one group selected from halo, -CH, -NO2, - NR'R',-OH,-OR',-O-aryl,-OC (O) R', -OC (S) R',-C (O) R', -C (S) R',-C (O) OR', -C (O) NR'R' and- C (S) NR'R', and wherein R, R'and aryl are as defined above and their substituents are as defined above.

In another embodiment, the compounds of formula (I) include the compounds of formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is F Cl, Br or I; B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine; wherein: B is substituted with one or more substituents selected from the group of (Ci-Cl6) alkyl, (C2-C16) alkenyl, (C2-C16) alkynyl, aryl, -O-(C1-C16) alkyl, -O-(C2-C16) alkenyl, -O-(C2-C16) alkynyl,-O-aryl,-O-CH2-aryl,-S-(Cl-Cl6) alkyl,-S-(C2-Cl6) alkenyl,-S-(C2-Cl6) alkynyl, -S- aryl, -S-CH2-aryl, (C3-C8) cycloalkyl,-0- (C3-C8) cycloalkyl,-S- (C3-C8) cycloalkyl,-halo,-NRR, -ONRR -NO2, -CN, -C(O) R, -C (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R,- SC (O) R, -SC (S) R, -OC (S) R,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),- C (O) NR (SR), -C (S) NR (SR), -CH (CN) 2, -CH [C (O) R] 2,-CH [C (S) R] 2,-CH [C (O) OR] 2,- CH [C (S) OR] 2,-CH [C (O) SR] 2, -CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR,- S (0) 20R, -S (O) NRR, -S (O) ONRR ; wherein: each R is independently selected from-H, (Cl-Cl6) alkyl, substituted (Cl-Cl6) alkyl, (C2- C16) alkenyl, substituted (C2-Cl6) alkenyl, (C2-C16) alkynyl, substituted (C2-C16) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cycloalkyl, aryl or substituted aryl; the alkyl, alkenyl, alkynyl and aryl are optionally substituted with one or more substituents independently selected from the group of-halo, trihalomethyl,-R',-OR',-SR',- NR'R',-N02,-CN,-OC (O) R', -OC (S) R',-SC (O) R, -SC (S) R-C (O) R', -C (S) R',-C (O) OR', - C (S) OR',-C (O) SR', -C (S) SR',-C (O) NR'R',-C (S) NR'R',-NR'C (O) R' and -NR'C(O)OR'; the cycloalkyl is optionally substituted with one or more substituents independently selected from the group of R', -halo, OR', -SR', -NR'R', -ONR'R', -NO2, -CN, -C(O)R', -C (S) R', -OC(O) R', -SC (O) R',-SC (S) R',-OC (S) R',-C (O) OR',-C (S) OR',-C (O) SR', -C (S) SR',- C (O) NRR',-C (S) NR'R',-C (O) NR' (OR),-C (S) NR' -(OR'), -C(O)NR'(SR'), -C (S) NR' (SR'),- CH (CN) 2,-CH [C (O) R'] 2,-CH [C (S) R']2, -CH [C (O) OR']2, -CH [C (S) OR12,-CH [C (O) SR']2, - CH [C (S) SR12,-NR'C (O) R',-NR'C (O) OR',-S (O)-R',-S (O) OR', -S (0) 20R', -S (O) NRR',- S (O) ONR'R, and each R'is independently selected from the group of-H, (C1-C16) alkyl, substituted (Cl-Cl6) alkyl, (C2-Cl6) alkenyl, substituted (C2-C16) alkenyl, (C2-CI6) alkynyl, substituted (C2-C16) alkynyl, (C3-Cg) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl.

In a specific embodiment in the compound of formula (II) B is phenyl, substituted with one or more substituents indepnednetly selected from the list as shown above.

In another embodiment, in the compounds of formula II, X is Cl or Br.

In another embodiment the substituents of the compounds of formula (II) are as follows: XisF, Cl, Br or I ; B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine; and substituted with at least one substituent selected from (C1-C6) alkyl, (C2-C16) alkenyl, (C2-CI6) alkynyl, -O-(C1-C16) alkyl, -O-(C2-C16) alkenyl, -O-(C2-C16) alkynyl, aryl, substituted aryl,-0- aryl, -O-CH2-aryl, -S-(C1-C16) alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S-aryl,-S-CH2- aryl, (C3-Cg) cycloalkyl, -O-(C3-C8) cycloalkyl, -S-(C3-C8) cycloalkyl, -ONRR, -C(O) R, -C (S) R -C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, -SC (S) R, -OC (S) R,-C (O) NRR, - C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), -C (S) NR (SR),-CH (CN) 2, - CH [C (O) R] 2, -CH [C (S) R] 2, -CH [C (O) OR] 2,-CH [C (S) OR] 2, -CH [C (O) SR] 2, -CH [C (S) SR] 2, -NRC(O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (O) 2OR,-S (O) NRR, -S (O) ONRR; wherein: said alkyl is substituted with at least one substituent selected from the group of halo, -CN, -NO2, -NR'R', -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -OC(O) R', -OC (S) R',-C (O) R', -C (S) R',- C (O) NR'R' and -C (S) NR'R' ; said alkenyl, alkylnyl,-O-alkyl,-S-alkyl, are each independently substituted with at least one group selected from halo,-CN,-N02,-NR'R',-OH,-OR',-0-aryl,-OC (O) R',-OC (S) R',-C (O) R', - C (S) R',-C (O) OR', -C (O) NR'R' and-C (S) NR'R' ; said-O-alkenyl,-O-alkynyl,-S-alkenyl,-S-alkynyl, cycloalkyl,-O-cycloalkyl are are each optionally and independently substituted with at least one group selected from halo,-CN,-NO2,- NR'R',-OH,-OR',-O-aryl,-OC (O) R', -OC (S) R',-C (O) R', -C (S) R',-C (O) OR', -C (O) NR'R' and- C (S) NR'R', and wherein R, R'and aryl are as defined above and their substituents are as defined above.

In another embodiment the substituents of the compounds of formula (I) are as follows: X is F, Cl, Br or I ; B is phenyl substituted with at least one substituent selected from (Cl-C16) alkyl, (C2-C16) alkenyl, (C2-C16) alkynyl,-O-(Cl-Cl6) alkyl,-O-(C2-Cl6) alkenyl,-O-(C2-Cl6) alkynyl, aryl, substituted aryl, -O-aryl, -O-CH2-aryl, -S-(C1-C16) alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl,-S-aryl,-S-CH2-aryl, (C3-Cg) cycloalkyl,-O- (C3-C8) cycloalkyl,-S- (C3-C8) cycloalkyl,- ONRR, -C (O) R, -C (S) R-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, -SC (S) R, -OC (S) R,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), -C (S) NR (SR),- CH (CN) 2,-CH [C (O) R] 2,-CH [C (S) R] 2, -CH [C (O) OR] 2, -CH [C (S) OR] 2, -CH [C (O) SR] 2,- CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (0) 20R,-S (O) NRR, - S (O) ONRR; wherein: said alkyl is substituted with at least one substituent selected from the group of halo,-CN,-N02, -NR'R', -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -OC(O) R', -OC (S) R',-C (O) R', -C (S) R',- C (O) NR'R' and-C (S) NR'R' ; said alkenyl, alkylnyl,-O-alkyl,-S-alkyl, are each independently substituted with at least one group selected from halo, -CN, -NO2, -NR'R', -OH, -OR', -O-aryl, -OC (O) R', -OC (S) R',-C (O) R', - C (S) R',-C (O) OR', -C (O) NR'R' and-C (S) NR'R'; said-O-alkenyl,-O-alkynyl,-S-alkenyl,-S-alkynyl, cycloalkyl,-O-cycloalkyl are are each optionally and independently substituted with at least one group selected from halo, -CN, -NO2, - NR'R',-OH,-OR',-O-aryl,-OC (O) R',-OC (S) R',-C (O) R', -C (S) R',-C (O) OR', -C (O) NR'R' and- C (S) NR'R', and wherein R, R'and aryl are as defined above and their substituents are as defined above.

In another embodiment the substituents of the of the compounds of formula (I) are as follows: X is F, Cl, Br or I ; B is phenyl substituted with at least one group selected from (Cl-Cl6) alkyl, (C2-C16) alkenyl, (C2-C16) alkynyl, -O-(C1-C16) alkyl, -O-(C2-C16) alkenyl, -O-(C2-C16) alkynyl, -aryl, -O-aryl, -O- CH2-aryl,-OC (O) R, -C (O) R, -C (O) OR, -C (O) NR'R', -NRC (O) R, -NRC (O) OR, -S (O)-R, - S (O) OR, -S (O) NRR, -S (O) ONRR ; wherein: said alkyl is substituted with at least one group selected from halo,-CN,-O-alkyl,-O-alkenyl, -O-alkynyl, -O-aryl, -OC(O) R', -C (O) R', and-C (O) NR'R' : said alkenyl, alkynyl,-O-alkyl,-O-alkenyl and-O-alkynyl are each independently substituted with at least one group selected from halo,-CN,-OH,-OR',-O-aryl,-OC (O) R', -C (O) R', - C (O) OR'and-C (O) NR'R', and R and R'are as defined above.

In another embodiment the substituents of the of the compounds of formula (II) are as follows: X is F, Cl, Br or I ; and B is substituted with at least one group selected from aryl,-O-aryl,-O-CH2-aryl and halo.

In another embodiment the substituents of the of the compounds of formula (II) are as follows: X is F, Cl, Br or I ; B is substituted with at least one substituent selected from the group of (Cl-Cl6) alkyl, (Cl-Cl6) alkynyl or-O-alkyl ; wherein: said alkyl is substituted with at least one substituent selected from the group of-CN,-O-alkyl,- OC (O) R', -C (O) R', ,-C (O) NR'R' or halo; said alkyny and-O-alkyl are are substituted with at least one substituent selected from-CN,- OH,-O-alkyl,-OC (O) R', -C (O) R', -C (O) OR', -C (O) NR'R' or halo; and R'is as defined above.

In another embodiment the substituents of the of the compounds of formula (II) are as follows: X is F, Cl, Br or I ; B is substituted with at least one group selected from-NRC (O) R, -NRC (O) OR, -S (O)-R, -S(O) OR, -S (0) 20R,-S (O) NRR, -S (O) ONRR, -C (O) R, -C (O) OR, -OC (O) R, -C (O) NRR; wherein R is as defined above.

In another embodiment, the compounds of formula (I) include the compounds of formula (III): or a pharmaceutically acceptable salt thereof, wherein: X is F, Cl, Br or I ; B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine; wherein: B is substituted with one or more substituents selected from the group of (Cl-Cl6) alkyl, (C2-Cl6) alkenyl, (C2-C16) alkynyl, aryl, -O-(C1-C16) alkyl, -O-(C2-C16) alkenyl, -O-(C2-C16) alkynyl, -O- aryl, -O-CH2-aryl, -S-(C1-C16)alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S-aryl,-S-CH2- aryl, (C3-C8) cycloalkyl,-O-(C3-Cg) cycloalkyl,-S-(C3-C8) cycloalkyl,-halo,-NRR,-ONRR- NO2, -CN, -C (O) R, -C (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, - SC (S) R, -OC (S) R,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), - C (S) NR (SR), -CH (CN) 2,-CH [C (O) R] 2, -CH [C (S) R] 2, -CH [C (O) OR] 2,-CH [C (S) OR] 2, - CH [C (O) SR] 2, -CH [C (S) SR] 2,-NRC (O) R,-NRC (O) OR, -S (O)-R,-S (O) OR, -S (O) 20R, - S (O) NRR, -S (O) ONRR; wherein: each R is independently selected from-H, (C1-C6) alkyl, substituted (Cl-Cl6) alkyl, (C2- C16) alkenyl, substituted (C2-C16) alkenyl, (C2-Ci6) alkynyl, substituted (C2-C61) alkynyl, (C3-Cs) cycloalkyl, substituted (C3-Cg) cycloalkyl, aryl or substituted aryl; the alkyl, alkenyl, alkynyl and aryl are optionally substituted with one or more substituents independently selected from the group of-halo, trihalomethyl,-R',-OR',-SR',-NR'R',-N02,- CN, -OC (O) R', -OC (S) R',-SC (O) R, -SC (S) R-C (O) R', -C (S) R',-C (O) OR', -C (S) OR',-C (O) SR', - C (S) SR',-C (O) NR'R', -C (S) NR'R',-NR'C (O) R' and -NR'C(O)OR'; the cycloalkyl is optionally substituted with one or more substituents independently selected from the group of R',-halo, OR', -SR', -NR'R', -ONR'R', -NO2, -CN, -C (O) R',-C (S) R',- OC (O) R', -SC(O) R', -SC (S) R',-OC (S) R', -C(O) OR', -C (S) OR',-C (O) SR', -C (S) SR',- C (O) NR'R',-C (S) NRR',-C (O) NR' (OR),-C (S) NR'- (OR),-C (O) NR (SR),-C (S) NR (SR),- CH (CN) 2,-CH [C (O) R'] 2,-CH [C (S) R']2, -CH [C (O) OR']2, -CH [C (S) OR']2, -CH [C (O) SR']2, - CH [C (S) SR] 2,-NRC (O) R',-NRC (O) OR', -S (O)-R',-S (O) OR',-S (0) 20R', -S (O) NRR',- S (O) ONR'R', and each R'is independently selected from the group of-H, (C1-C16) alkyl, substituted (Cl-Cl6) alkyl, (C2-C16) alkenyl, substituted (C2-C16) alkenyl, (C2-Cl6) alkynyl, substituted (C2-Cl6) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl.

In a specific embodiment in the compound of formula (III) B is phenyl, substituted with one or more substituents indepnednetly selected from the list as shown above.

In another specific embodiment, the substitutents of formula (I) are as follows: XisFCl, BrorI ; R1 and R2 are each independently selected from the group of H, (C1-C6) alkyl, (C1-C6) hydroxy alkyl, (C1-C6) alkoxy, (C3-C7) cycloalkyl, halo substituted (Cl-C6) alkyl, halo di- substituted (Cl-C6) alkyl, halo tri-substituted (Cl-C6) alkyl and halo; B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine; wherein: B is substituted with one or more substituents selected from the group of (C1-C16) alkyl, (C2-C16) alkenyl, (C2-C16) alkynyl, aryl, -O-(C1-C16) alkyl, -O-(C2-C16) alkenyl, -O-(C2-C16) alkynyl, -O- aryl, -O-CH2-aryl, -S-(C1-C16)alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S-aryl,-S-CH2- aryl, (C3-C8) cycloalkyl, -O-(C3-C8) cycloalkyl, -S-(C3-C8) cycloalkyl, -halo, -NRR, -ONRR, - N02,-CN,-C (O) R, -C (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, - SC (S) R, -OC (S) R,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), - C (S) NR (SR),-CH (CN) 2,-CH [C (O) R] 2,-CH [C (S) R] 2,-CH [C (O) OR] 2, -CH [C (S) OR] 2, - CH [C (O) SR] 2, -CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (O) 2OR, -S(O) NRR, -S (O) ONRR; wherein: each R is independently selected from-H, (C1-C16) alkyl, substituted (C1-C16) alkyl, (C2- C16) alkenyl, substituted (C2-C16) alkenyl, (C2-C16) alkynyl, substituted (C2-C16) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cycloalkyl, aryl or substituted aryl; the alkyl, alkenyl, alkynyl and aryl are optionally substituted with one or more substituents independently selected from the group of-halo, trihalometliyl,-R',-OR',-SR',-NR'R',-N02,- CN, -OC (O) R', -OC (S) R',-SC (O) R, -SC (S) R-C (O) R', -C (S) R',-C (O) OR', -C (S) OR',-C (O) SR', - C (S) SR',-C (O) NR'R',-C (S) NR'R',-NR'C (O) R' and -NR'C(O)OR'; the cycloalkyl is optionally substituted with one or more substituents independently selected from the group of R',-halo, OR', -SR', -NR'R', -ONR'R', -NO2, -CN, -C (O) R',-C (S) R',- OC (O) R', -SC (O) R', -SC (S) R', -OC (S) R',-C (O) OR', -C (S) OR',-C (O) SR', -C (S) SR',- C (O) NR'R',-C (S) NR'R',-C (O) NR' (OR),-C (S) NR' -(OR'), -C(O)NR'(SR'), -C (S) NR' (SR'),- CH (CN) 2,-CH [C (O) R'] 2, -CH [C (S) R'] 2, -CH [C (O) OR'] 2, -CH [C (S) OR'] 2, -CH [C (O) SR'] 2, - CH [C (S) SR'] 2,-NR'C (O) R',-NR'C (O) OR', -S (O)-R',-S (O) OR',-S (O) 2OR',-S (O) NR'R', - S (O) ONR'R', and each R'is independently selected from the group of-H, (C1-C16) alkyl, substituted (Cl-Cl6) alkyl, (C2-C16) alkenyl, substituted (C2-Cl6) alkenyl, (C2-C16) alkynyl, substituted (C2-C16) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl.

In another specific embodiment the substituents of the compounds of formula (I) are as follows: X is F, Cl, Br or I ; Rl and R2 are each independently selected from the group of H, (C1-C6) alkyl, (C1-C6) hydroxy alkyl, (CI-C6) alkoxy, (C3-C7) cycloalkyl, halo substituted (Cl-C6) alkyl, halo di-substituted (Cl- C6) alkyl, halo tri-substituted (C1-C6) alkyl and halo; B is an aryl group selected from phenyl, indane, fluorene, indazole, indole, and pyridine ; and substituted with at least one substituent selected from (Cl-Cl6) alkyl, (C2-Ci6) alkenyl, (C2-C16) alkynyl, -O-(C1-C16) alkyl, -O-(C2-C16) alkenyl, -O-(C2-C16) alkynyl, aryl, substituted aryl,-0- aryl, -O-CH2-aryl, -S-(C1-C16) alkyl, -S-(C2-C16) alkenyl, -S-(C2-C16) alkynyl, -S-aryl,-S-CH2- aryl, (C3-C8) cycloalkyl, -O-(C3-C8) cycloalkyl, -S-(C3-C8) cycloalkyl, -ONRR, -C(O) R, -C (S) R -C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, -SC (S) R,-OC (S) R,-C (O) NRR, - C (S) NRR,-C (O) NR (OR), -C (S) NR (OR), -C (O) NR (SR), -C (S) NR (SR),-CH (CN) 2, - CH [C (O) R] 2,-CH [C (S) R] 2,-CH [C (O) OR] 2,-CH [C (S) OR] 2, -CH [C (O) SR] 2, -CH [C (S) SR] 2, -NRC(O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (0) 20R,-S (O) NRR, -S (O) ONRR; wherein: said alkyl is substituted with at least one substituent selected from the group of halo,-CN,-N02, -NR'R', -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -OC(O) R', -OC (S) R',-C (O) R', -C (S) R', - C (O) NR'R' and -C (S) NR'R'; said alkenyl, alkylnyl,-O-alkyl,-S-alkyl, are each independently substituted with at least one group selected from halo,-CN,-N02,-NR'R',-OH,-OR',-0-aryl,-OC (O) R', -OC (S) R',-C (O) R', - C (S) R',-C (O) OR', -C (O) NR'R' and-C (S) NR'R'; said-O-alkenyl,-O-alkynyl,-S-alkenyl,-S-alkynyl, cycloalkyl,-O-cycloalkyl are are each optionally and independently substituted with at least one group selected from halo, -CN, -NO2, - NR'R',-OH,-OR',-O-aryl,-OC (O) R', -OC (S) R',-C (O) R', -C (S) R',-C (O) OR', -C (O) NR'R' and- C (S) NR'R', and wherein R, R'and aryl are as defined above and their substituents are as defined above.

In another embodiment, the substituents of the compounds of formula (I) are as follows: X is F, Cl, Br or I ; RI and R2 are each independently selected from the group of H, (Cl-C6) alkyl, (Cl-C6) hydroxy alkyl, (Cl-C6) alkoxy, (C3-C7) cycloalkyl, halo substituted (Cl-C6) alkyl, halo di-substituted (Cl- C6) alkyl, halo tri-substituted (Cl-C6) alkyl and halo, B is phenyl substituted with at least one group selected from (Cl-Cl6) alkyl, (C2-Cl6) alkenyl, (C2-Ci6) alkynyl, -O-(C1-C16) alkyl, -O-(C2-C16) alkenyl, -O-(C2-C16) alkynyl, -aryl, -O-aryl, -O- CH2-aryl, -OC (O) R, -C (O) R, -C (O) OR, -C (O) NR'R', -NRC (O) R, -NRC (O) OR, -S (O)-R,- S (O) OR, -S (O) NRR, -S (O) ONRR; wherein: said alkyl is substituted with at least one group selected from halo,-CN,-O-alkyl,-O-alkenyl, -O-alkynyl, -O-aryl, -OC(O)R', -C(O) R', and-C (O) NR'R': said alkenyl, alkynyl,-O-alkyl,-O-alkenyl and-O-alkynyl are each independently substituted with at least one group selected from halo,-CN,-OH,-OR',-O-aryl,-OC (O) R', -C (O) R', - C (O) OR'and-C (O) NR'R', and R and R'are as defined above.

In an another embodiment, the compounds of formula (I) include the compounds of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from the group of H, R, -halo, OR, -SR, -NRR, -ONRR, -NO2, -CN, -C(O) R, -C (S) R, -OC (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, - SC (S) R,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), -C (S) NR (SR), -CH(CN)2, -CH [C (O) R] 2, -CH [C (S) R] 2, -CH [C (O) OR] 2, -CH [C (S) OR] 2, -CH [C (O) SR] 2, - CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (0) 20R,-S (O) NRR, -S(O) ONRR; each R is independently selected from-H, (Cl-Cl6) alkyl, substituted (Cl-Cl6) alkyl, (C2- C16) alkenyl, substituted (C2-C16) alkenyl, (C2-C16) alkynyl, substituted (C2-Ci6) alkynyl, (C3-Cg) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl; the alkyl, alkenyl, alkynyl and aryl substituents are each independently selected from the group of-halo, trihalomethyl,-R',-OR',-SR',-NR'R',-N02,-CN,-OC (O) R', -OC (S) R',- SC (O) R', -SC (S) R'-C (O) R', -C (S) R',-C (O) OR', -C (S) OR',-C (O) SR', -C (S) SR',-C (O) NR'R', -C (S) NR'R',-NR'C (O) R', -NR'C (O) OR'and aryl; the cycloalkyl substituents are each independently selected from the group of H, R,-halo, OR,-SR,-NRR,-ONRR-N02,-CN,-C (O) R, -C (S) R,-OC (O) R, -SC (O) R, -SC (S) R, -OC (S) R,- C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),- C (O) NR (SR), -C (S) NR (SR),-CH (CN) 2,-CH [C (O) R] 2,-CH [C (S) R] 2, -CH [C (O) OR] 2,- CH [C (S) OR] 2,-CH [C (O) SR] 2,-CH [C (S) SR] 2,-NRC (O) R,-NRC (O) OR,-S (O)-R,-S (O) OR,- S (0) 20R, -S (O) NRR, -S (O) ONRR', and each R'is independently selected from the group-H, (Cl-Cl6) alkyl, substituted (Cl-Cl6) alkyl, (C2-C16) alkenyl, substituted (C2-Cl6) alkenyl, (C2-C16) alkynyl, substituted (C2-Cl6) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl.

In another embodiment in the compoundof formula (IV), R3 is selected from halo,-CN, -C(O) R, -C (O) OR, -OC (O) R, -C (O) NRR, -OR, (CI-C16) alkyl, (C2-CI6) alkenyl, (C2-CI6) alkynyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted with-CN,-C (O) R', - C (O) OR', -OC(O) R', -C (O) NR'R',-OR', wherein R and R'are as defined above.

In an another embodiment, the compounds of formula (1) include the compounds of formula (V): or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from the group of H, R, -halo, OR,-SR,-NRR,-ONRR,-NO2,-CN, -C(O) R, -C (S) R, -OC (S) R,-C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-OC (O) R, -SC (O) R, - SC (S) R,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),-C (O) NR (SR), -C (S) NR (SR), -CH (CN) 2,-CH [C (O) R] 2, -CH [C (S) R] 2,-CH [C (O) OR] 2, -CH [C (S) OR] 2,-CH [C (O) SR] 2, - CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, -S (0) 20R, -S (O) NRR, -S(O) ONRR; each R is independently selected from-H, (Ci-Cl6) alkyl, substituted (Cl-Cl6) alkyl, (C2- C16) alkenyl, substituted (C2-Ci6) alkenyl, (C2-Cl6) alkynyl, substituted (C2-Cl6) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl; the aryl substituents are each independently selected from the group of-halo, trihalomethyl,-R',-OR',-SR',-NR'R',-N02,-CN,-C (O) R', -C (S) R',-OC (O) R', -OC (S) R', -SC(O) R', -SC (S) R',-C (O) OR', -C (S) OR',-C (O) SR',-C (S) SR',-C (O) NR'R', -C (S) NR'R', NR'C (O)R', -NR'C(O)OR'; the alkyl, alkenyl and alkynyl substituents are each independently selected from the group of -halo, trihalomethyl,-R',-OR',-SR',-NR'R',-NO2,-CN,-OC (O) R', -OC (S) R',-SC (O) R', -SC (S) R'-C (O) R', -C (S) R',-C (O) OR', -C (S) OR',-C (O) SR',-C (S) SR',-C (O) NR'R', -C (S) NR'R',-NR'C (O) R',-NR'C (O) OR'and aryl; the cycloalkyl substituents are each independently selected from the group of H, R,-halo, OR,-SR,-NRR,-ONRR-NO2,-CN,-C (O) R, -C (S) R,-OC (O) R, -SC (O) R, -SC (S) R, -OC (S) R,- C (O) OR, -C (S) OR,-C (O) SR, -C (S) SR,-C (O) NRR, -C (S) NRR,-C (O) NR (OR), -C (S) NR (OR),- C (O) NR (SR), -C (S) NR (SR),-CH (CN) 2,-CH [C (O) R] 2, -CH [C (S) R] 2,-CH [C (O) OR] 2,- CH [C (S) OR] 2,-CH [C (O) SR] 2, -CH [C (S) SR] 2,-NRC (O) R, -NRC (O) OR, -S (O)-R,-S (O) OR, - S (0) 20R,-S (O) NRR, -S (O) ONRR', and each R'is independently selected from the group-H, (Cl-Cl6) alkyl, substituted (Cl-Cl6) alkyl, (C2-Cl6) alkenyl, substituted (C2-C16) alkenyl, (C2-C16) alkynyl, substituted (C2-Cl6) alkynyl, (C3-C8) cycloalkyl, substituted (C3-C8) cyloalkyl, aryl or substituted aryl.

In another embodiment in the compoundof formula (V), R3 is selected from halo,-CN, -C(O) R, -C (O) OR, -OC (O) R, -C (O) NRR, -OR, (Ci-Cl6) alkyl, (C2-C16) alkenyl, (C2-C16) alkynyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted with-CN,-C (O) R',- C (O) OR', -OC(O) R', -C (O) NR'R',-OR', wherein R and R'are as defined above.

In an illustrative embodiment, the compounds according to formula (I) include those listed below: 4-iodo-1-[3-(2-chloroethyl) ureido] benzene; 4-tert-butyl-1-[3-(2-chloroethyl) ureido] benzene; 4-sec-butyl-1- [3- (2-chloroethyl) ureido] benzene; 4-isopropyl-1- [3- (2-chloroethyl) ureido] benzene ; 4- (p- [3- (2-chloroethyl) ureido] phenyl) butanol; 4-pentyl-1- [3- (2-chloroethyl) ureido] benzene; 4-hexyl-l- [3- (2-chloroethyl) ureido] benzene; 4-cyclohexyl-l- [3- (2-chloroethyl) ureido] benzene; 4-heptyl-1-[3-(2-chloroethyl)ureido] benzene; 4-octyl-1- [3- (2-chloroethyl) ureido) benzene; 4-decyl-1- [3- (2-chloroethyl) ureido) benzene; 4-dodecyl-1-[3-(2-chloroethyl) ureido] benzene; 3-ethoxy-1- [3- (2-chloroethyl) ureido] benzene; 4-pentoxy-1- [3- (2-chloroethyl) ureido] benzene; 4-hexyloxy-1- [3- (2-chloroethyl) ureido] benzene; 2,4, 6-trimethyl-l- [3- (2-chloroethyl) ureido] benzene; 2-ethyl-1-[3-(2-chlorothyl) ureido] benzene; 2, 4-diethyl-1-[3-(2-chloroethyl) ureido] benzene; 2-propyl-1-[3-(2-chloroethyl) ureido] benzene; 2, 6-diisopropyl-1-[3-2-chloroethyl) ureido] benzene; 2-isopropyl-6-methyl-1-[3-(2-chloroethyl) ureido] benzene; 2,5-ditert butyl-1-[3-(2-chloroethyl) ureido] benzene; 2-methoxy-5-methyl-1- [3- (2-chloroethyl) ureido] benzene; 2-methoxy-6-methyl-1- [3- (2-chloroethyl) ureido] benzene; 2-methyl-5-methoxy-1-[3-(2-chloroethyl) ureido] benzene; 2-methyl-4-methoxy-1- [3- (2-chloroethyl) ureido] benzene; 2-ethoxy-1-[3-(2-chloroethyl) ureido] benzene; 4-ethoxy-1- (3- (2-chloroethyl) ureido] benzene; 4-butoxy-1-(3-(2-chloroethyl) ureido] benzene; 1,4-di [3- (2-chloroethyl) ureido] benzene; 2-cyano-1-[3-(2-chloroethyl) ureido] benzene; 4-(3-hydroxypropyl)-1-[3-(2-chloroethyl) ureido] benzene; 4- (2-hydroxybutyl)-1- [3- (2-chloroethyl) ureido] benzene; 4- (4- (2-butyrate ethanoic acid))-1-[3-(2-chloroethyl) ureido] benzene; 4- (3- (2-propylate ethanoic acid))-1- [3- (2-chloroethyl) ureido] benzene; 4-ethylthio-1-[3-(2-chloroethyl) ureido] benzene; 2- [3- (2-chloroethyl) ureido] fluorene ; 5- [3- (2-chloroethyl) ureido] indane ; 6-[3-(2-chloroethyl) ureido] indazole; 5- [3- (2-chloroethyl) ureido] 4, 6-dimethyl pyridine ; 5- [3- (2-chloroethyl) ureido] indole ; 1- (4-tert-Butyl-phenyl)-3- (2-chloro-ethyl)-urea ; 1- (2-Chloro-ethyl)-3- (4-cyclohexyl-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- (4-heptyl-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- [3- (5-hydroxy-pentyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- (4-methoxy-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- (4-iodo-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- (4-phenoxy-phenyl)-urea ; 1- (4-Benzyloxy-phenyl)-3- (2-chloro-ethyl)-urea ; 1-(2-Chloro-ethyl)-3-[4-(2-methoxy-ethyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- [4- (4-ethoxy-butyl)-phenyl]-urea ; 1-Biphenyl-4-yl-3- (2-chloro-ethyl)-urea ; 1- (2-Chloro-acetyl)-3- (4-iodo-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- [4- (4-fluoro-butyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- [3- (5-hydroxy-pent-1-ynyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- (4-hydroxy-phenyl)-urea ; Acetic acid 5- {4- [3- (2-chloro-ethyl)-urcido]-phcnyl}-pentyl ester; N- 3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-acetamide ; N-Butyl-4- (5-chloro-1, 3-dimethyl-2-oxo-pentyl)-benzenesulfonamide ; 1- (2-Chloro-ethyl)-3- [3- (1-hydroxy-ethyl)-phenyl]-urea ; 1-(2-Chloro-ethyl)-3-[3-(1-hydroxy-ethyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- (2-heptyl-phenyl)-urea ; 1- (2-Chloro-acetyl)-3- [3- (5-hydroxy-pentyl)-phenyl]-urea ; R-1- (4-tert-Butyl-phenyl)-3- (2-chloro-1-methyl-ethyl)-urea ; S-1- (4-tert-Butyl-phenyl)-3- (2-chloro-1-methyl-ethyl)-urea ; 1- (4-tert-Butyl-phenyl)-3- (2-chloro-1, 1-dimethyl-ethyl)-urea ; 1- (2-Bromo-ethyl)-3- (3-iodo-phenyl)-urea ; 3- [3- (2-Bromo-ethyl)-ureido]-benzoic acid ethyl ester.

In another illustrative embodiment, the compounds according to formula (I) include those listed below: 4-iodo-3- (2-chloro-ethyl)-urea ; 1- (2-Chloro-ethyl)-3- (4-iodo-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- (4-phenoxy-phenyl)-urea ; 1- (4-Benzyloxy-phenyl)-3- (2-chloro-ethyl)-urea ; 1- (2-Chloro-ethyl)-3- [4- (2-methoxy-ethyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- [4- (4-ethoxy-butyl)-phenyl]-urea ; 1-Biphenyl-4-yl-3-(2-chloro-ethyl)-urea ; 1- (2-Chloro-acetyl)-3- (4-iodo-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- [4- (4-fluoro-butyl)-phenyl]-urea ; 1-(2-Chloro-ethyl)-3-[3-(5-hydroxy-pent-1-ynyl)-phenyl]-urea ; Acetic acid 5-{4-[3-(2-chloro-etyl)-ureido]-phenyl}-pentyl ester; n- 3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-acetamide ; n-Butyl-4- (5-chloro-1, 3-dimethyl-2-oxo-pentyl)-benzenesulfonamide ; 1-(2-Chloro-ethyl)-3-[3-(1-hydroxy-ethyl)-phenyl]-urea ;? 1- (2-Bromo-ethyl)-3- (3-iodo-phenyl)-urea ; 3- [3- (2-Bromo-ethyl)-ureido]-benzoic acid ethyl ester; 1- (4-n-hexyl-phenyl)-3- (2-chloro-1-methyl-ethyl) urea; 1- (4-iodo-phenyl)-3- (2-bromo-1-methyl-ethyl) urea; (R) 1- (4-iodo-phenyl)-3- (2-bromo-1-methyl-ethyl) urea; (S) 1-(4-iodo-phenyl)-3-(2-bromo-1-methyl-ethyl)urea.

In another illustrative embodiment, the compounds according to formula (I) include those listed below: 1-(4-tert-butylphenyl)-3-(2-chloroethyl)urea ; 1- (2-chloroethyl)-3- (4-cyclohexylphenyl) urea; 1- (2-chloroethyl)-3- (4-hepthylphenyl) urea; 1- (2-chloroethyl)-3- (4-iodophenyl) urea; 1- (2-chloroethyl)-3- (4-phenoxyphenyl) urea; 1- (4-benzyloxyphenyl)-3- (2-chloroethyl) urea; 1- (biphenyl-4-yl)-3- (2-chloroethyl) urea ; 1- (2-chloroethyl)-3- (4-hydroxyphenyl) urea; N-f 3- [3- (2-chloroethyl) ureido] phenyl} acetamide; N-Butyl-3- [3- (2-chloroethyl) ureido] benzenesulfonamide ; 1-(2-chloroethyl)-3-[3-(1-hydroxyethyl) phenyl] urea; 1-(2-chlorotheyl)-3-[4-(2-methoxyethyl) phenyl) urea; 1- (2-chloroethyl)-3- [4- (4-ethoxybutyl) phenyl) urea; 1- (2-chloroethyl)-3- [4- (4-fluorobutyl) phenyl] urea; 1-(2-chloroethyl)-3-[3-(5-hydroxypent-1-ynyl) phenyl) urea; 1- (2-chloroethyl)-3- [3- (5-hydroxypentyl) phenyl) urea ; Acetic acid 5- {4- [3- (2-chloroethyl) ureido] phenyl} pentyl ester; 6- {3- [3- (2-chloroethyl) ureido] phenoxy} hexanoic acid ethyl ester; 1- (2-chloroethyl)-2- (2-heptylphenyl) urea; 1- (2-Chloroacetyl)-3- (4-iodophenyl) urea; 1- (2-chloroacetyl)-3- [3- (5-hydroxypentyl) phenyl] urea; (R)-1-(2-chloro-1-methylethyl)-3-(4-iodophenyl) urea; (S)-1-(2-chloro-1-methylethyl)-3-(4-iodophenyl) urea; (R)-1-(4-tert-Butylphenyl)-3-(2-chloro-1-methylethyl) urea; (S)-1-(4-tert-Butylphenyl)-3-(2-chloro-1-methylethyl) urea; 1-(4-tert-Butylphenyl)-3-(2-chloro-1,1-dimethylethyl) urea; 1- (2-Bromoethyl)-3- (3-iodophenyl) urea; 4-tert-Butylphenyl (4,5-dihydrooxazol-2-yl) amine; In another illustrative embodiment, the compounds according to formula (I) include those listed below: 1-(2-Chloro-ethyl)-3-m-tolyl-urea ; 1- (2-Chloro-ethyl)-3- (3-ethyl-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- (3-methoxy-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- [4- (4-hydroxy-butyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- [4- (3-hydroxy-propyl)-phenyl]-urea ; 1- (2-Chloro-etliyl)-3- (3-iodo-phenyl)-urea ; 1-(2-Chloro-ethyl)-3-[4-(5-hydroxy-pentyl)-phenyl]-urea ; 1-(2-Chloro-ethyl)-3-[3-(5-hydroxy-pent-1-ynyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- [3- (5-hydroxy-pentyl)-phenyl]-urea ; 3- [3- (2-Chloro-ethyl)-ureido]-benzoic acid ethyl ester; 1- (2-Chloro-ethyl)-3- [3- (5-methoxy-pentyl)-phenyl]-urea ; {3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-acetic acid; 1-(2-Bromo-ethyl)-3-[3-(5-hydroxy-pentyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- (3-heptyl-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- [3- (6-hydroxy-hexyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- [3- (4-hydroxy-butyl)-phenyl]-urea ; 1-(2-Bromo-ethyl)-3-[3-(3-hydroxy-pentyl)-phenyl]-urea ; 5- 3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-pentanoic acid amide; 1- (3-Bromo-phenyl)-3- (2-chloro-ethyl)-urea ; 1- (2-Chloro-ethyl)-3- (3-chloro-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- (3-hydroxy-phenyl)-urea ; Acetic acid 3- [3- (2-chloro-ethyl)-ureido]-phenyl ester; 1-(2-Bromo-ethyl)-3-(5-hydroxy-pentyl)-phenyl]-urea ; Acetic acid 5-{3-[3-(2-chloro-ethyl)-ureido]-phenyl}-pentyl ester; Acetic acid 4- {3- [3- (2-chloro-etliyl)-ureido]-phenyl}-butyl ester; Acetic acid 3- [3- (2-chloro-cthyl)-ureido]-benzyl ester; Acetic acid 3- {3- [3- (2-chloro-ethyl)-ureido]-phenyl}-propyl ester; 1-(2-Bromo-ethyl)-3-[3-(2-hydroxy-entyl)-phenyl]-urea ; Acetic acid 2- {3- [3- (2-chloro-ethyl)-ureido]-phenyl}-ethyl ester; Acetic acid 6- {3- [3- (2-chloro-ethyl)-ureido]-phenyl}-hexyl ester; Pentanedioic acid mono- {3- [3-(2-chloro-ethyl)-ureido]-phenyl} ester; 1- (2-Chloro-ethyl)-3- [3- (7-hydroxy-heptyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- (3-cyano-phenyl)-urea ; 3- [3- (2-Chloro-ethyl)-ureido]-benzoic acid ; 1- (2-Chloro-ethyl)-3- [3- (3-methoxy-propyl)-phenyl]-urea ; 1- (3-pentyl-phenyl)-3- (2-chloro-ethyl)-urea ; 5- {3- [3- (2-Chloro-cthyl)-ureido]-phenyl}-pentanoic acid ethyl ester; 5- {3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-pentanoic acid; 5- {3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-pentanoic acid methyl ester; 1- (2-Chloro-ethyl)-3- (3-hexyl-phenyl)-urea ; 1- (2-Chloro-ethyl)-3- (3-hexyl-phenyl)-urea ; 6- {3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-hexanoic acid ethyl ester; 6-{3-[3-(2-Chloro-ethyl)-ureido]-phenyl}-hexanoic acid ; 6- 3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-hexanoic acid methyl ester; 3- [3- (2-Chloro-ethyl)-ureido]-benzoic acid methyl ester; 1- (2-Chloro-etliyl)-3- [3- (4-hydroxy-but-1-ynyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- [3- (3-hydroxy-prop-1-ynyl)-phenyl]-urea ; 1- (2-Chloro-ethyl)-3- (3-cyanomethyl-phenyl)-urea ; 2- {3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-acetamide ; 3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-acetic acid ethyl ester; Acetic acid 3-f 3- [3- (2-chloro-ethyl)-ureido]-phenyl}-propyl ester.

Compounds of Formula I wherein X is Br or I may undergo rearrangement to provide a rearrangement product. Such rearrangement products are considered to be within the scope of the present invention. Thus, the present invention contemplates the compounds of Formula I wherein X is Br or I as a form of pro-drugs, for which both the pro-drug form and the rearrangement product may have activity in inhibiting proliferation of cells.

As noted supra, this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I, II, III, IV or V. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

The term"pharmaceutically acceptable salt, "as used herein, refers to salts of the compounds of the above formulae, which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.

Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, y-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like.

In one embodiment of the invention, the pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.

Salts of amine groups may also comprise quarternary ammonium salts wherein the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. In one embodiment, the base addition salt is a potassium or sodium salt.

It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, as long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formula I, II, III, IV or V. Many of these compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.

The compounds of the present invention have multiple asymmetric (chiral) centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.

The prefixes"R"and"S"are used herein as commonly used in organic chemistry to denote the absolute configuration of a chiral center, according to the Cahn-Ingold-Prelog system. The stereochemical descriptor R (rectus) refers to that configuration of a chiral center with a clockwise relationship of groups tracing the path from highest to second-lowest priorities when viewed from the side opposite to that of the lowest priority group. The stereochemical descriptor S (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of groups tracing the path from highest to second-lowest priority when viewed from the side opposite to the lowest priority group. The priority of groups is decided using sequence rules as described by Cahn et al., Ange. Chem., 78, 413-447,1966 and Prelog, V. and Helmchen, G.; Ange. Chem. Int. Ed. Erg., 21, 567-583, 1982).

In addition to the R, S system used to designate the absolute configuration of a chiral center, the older D-L system is also used in this document to denote relative configuration, especially with reference to amino acids and amino acid derivatives. In this system a Fischer projection of the compound is oriented so that carbon-1 of the parent chain is at the top. The prefix"D"is used to represent the relative configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and"L", that of the isomer in which it is on the left.

As would be expected, the stereochemistry of the Formula I II, III, IV and V compounds may be critical to their potency as agonists or antagonists. The relative stereochemistry is preferably established early during synthesis, which avoids stereoisomer separation problems later in the process. Subsequent synthetic steps then employ stereospecific procedures so as to maintain the preferred configuration.

Non-toxic metabolically labile esters and amides of compounds of Formula I II, III, IV or V are ester or amide derivatives that are hydrolyzed in vivo to afford said compounds of Formula I II, III, IV or V and a pharmaceutically acceptable alcohol or amine. Examples of metabolically labile esters include esters formed with (Cl-C6) alkanols in which the alkanol moiety may be optionally substituted by a (Cl-C8) alkoxy group, for example, methanol, ethanol, propanol and methoxyethanol. Examples of metabolically labile amides include amides formed with amines such as methylamine.

Therapeutic Uses of Compou1zds of Formula (I) The compounds of Formula I can be used to attenuate, inhibit and/or prevent non-cancerous cellular proliferation in a patient in need of such therapy. The compounds of the invention are also for use in the treatment of diseases and disorders associated with non-cancerous pathogenic cellular proliferation, the pathogenesis of which, may include cell migration and/or inflammation. The compounds can be used alone or they can be used as part of a multi-drug regimen in combination with known therapeutics.

In one embodiment, the compounds of Formula I can be used to attenuate, inhibit or prevent non- cancerous cell proliferation of keratinocytes. In another embodiment diseases or disorders that can be treated with the compounds of Formula I include those associated with hyperproliferation and/or migration of keratinocytes and/or epidermal or epithelial cells. Typically, such diseases and disorders are dermatological and include psoriasis, eczema, lupus-associated skin lesions, dermatitides (such as seborrheic dermatitis and solar dermatitis), keratoses (such as seborrheic keratosis, senile keratosis, actinic keratosis, photo-induced keratosis, and keratosis follicularis), scars and prophylaxis against scar formation (including hypertrophic scars), acne vulgaris, keloids and prophylaxis against keloid formation, nevi, warts (including verruca, condyloma or condyloma acuminatum), human papilloma viral (HPV) infections (such as venereal warts), leukoplakia, lichen planus, and keratitis.

In one embodiment, the compounds of Formula I can be used to attenuate, inhibit or prevent non- cancerous cell proliferation of fibroblasts. In another embodiment, the compounds of the invention are also useful for the treatment of fibrotic disorders such as arteriosclerotic conditions, fibrosis and other medical complications of fibrosis, which result in whole or in part from the proliferation of fibroblasts. An arteriosclerotic condition refers to classical atherosclerosis, accelerated atherosclerosis, atherosclerotic lesions and other arteriosclerotic conditions characterized by undesirable endothelial and/or vascular smooth muscle cell proliferation, including vascular complications of diabetes. Proliferation of vascular smooth muscle cells produces accelerated atherosclerosis, which is the main reason for failure of heart transplants that are not rejected. The compounds of Formula I can, therefore, be used to inhibit such obstruction and reduce the risk of, or even prevent, such failures.

In one embodiment, the compounds of Formula I can be used to attenuate, inhibit or prevent non- cancerous cell proliferation of endothelial and smooth muscle cells. Proliferation of endothelial and vascular smooth muscle cells is the main feature of neovascularization. Abnormal neovascularization has long been associated with solid tumour growth and metastasis.

Accordingly, in one embodiment of the present invention, the compounds are used to attenuate, inhibit or prevent angiogenesis associated with cancer. Abnormal neovascularization also plays a pivotal role in a variety of other diseases and disorders. In another embodiment, the compounds of Formula I can be used in the treatment of such diseases and disorders, which include, rheumatoid arthritis, psoriatic arthritis, diabetic retinopathy, diabetic glomerulosclerosis, neovascular glaucoma, macular degeneration, Crohn's disease, endometriosis, psoriasis and atherosclerosis.

In another embodiment, the compounds of Formula I can be used to treat vascular injury which is associated with endothelial and vascular smooth muscle cell proliferation. The injury can be caused by a number of traumatic events or interventions, including vascular surgery and balloon angioplasty. Restenosis is the main complication of successful balloon angioplasty of the coronary arteries. Thus, by inhibiting unwanted endothelial and smooth muscle cell proliferation, the compounds of the present invention can be used to delay, or even avoid, the onset of restenosis.

In another embodiment, the compounds of the invention are also useful for the treatment of inflammatory dermatosis, rosacea, prerosacea. Another example of an angiogenesis associated disorder is Rosacea. Rosacea is a common, chronic, progressive inflammatory dermatosis based upon vascular instability. It primarily affects the central part of the face. Rosacea is characterized by facial flushing/blushing, facial erythema, papules, pustules, and telangiectasia.

In one embodiment, the compounds of Formula I can be used to attenuate, inhibit or prevent non- cancerous cell proliferation of endothelial cells. In another embodiment, the compounds of Formula I can be used to treat angiogenesis-associated diseases and disorders. As is known in the art, endothelial cell proliferation and/or migration are key features of neovascularisation and angiogenesis. Thus, one embodiment of the invention contemplates the use of the compounds in the treatment of angiogenesis-associated diseases and disorders. As used herein, the terms angiogenesis-associated disease and angiogenesis-associated disorder refer to a disease or disorder which occurs as a consequence of, or which results in, increased vascularization in a tissue. Angiogenesis may be an actual cause of the disease or a condition resulting from of the disease. Examples of angiogenesis-associated diseases and disorders include, but are not limited to, immune disorders such as inflammation, chronic articular rheumatism and psoriasis, disorders associated with inappropriate or inopportune invasion of vessels such as diabetic retinopathy, neovascular glaucoma, restenosis, capillary proliferation in atherosclerotic plaques and osteoporosis, cancer, cancer associated disorders, such as solid tumors, solid tumor metastases, angiofibromas, retrolental fibroplasia, hemangiomas, Kaposi sarcoma, psoriasis, acne, rosacea, warts, eczema, hemangiomas, lymphangiogenesis, Sturge-Weber syndrome, neurofibromatosis, tuberous sclerosis, chronic inflammatory disease, arthritis, chronic articular rheumatism and psoriasis. Skin disorders which have as a primary or secondary characterisation, increased vascularization, are considered to be angiogenesis-associated disorders for purposes of the present invention.

Thus, methods which inhibit angiogenesis in a diseased tissue ameliorates symptoms of the disease and, depending upon the disease, can contribute to cure of the disease. The compounds of the present invention are suitable for use in a variety of tissues that can be invaded by blood vessels upon angiogenic stimuli including skin, muscle, gut, connective tissue, joints, bones and the like.

In one embodiment the compounds of Formula I can be used to attenuate, inhibit or prevent IL-2 production in order to ameliorate inflammation associated with angiogenesis-associated diseases and disorders, as well as inflammatory conditions not associated with angiogenesis. The present invention, therefore, further contemplates that the compounds can be used in the treatment of diseases such as, inflammatory arthritis (including rheumatoid arthritis), psoriasis, rheumatism.

Efficacy of the Therapeutic Compounds In accordance with the present invention, the therapeutic compounds of Formula I are capable of attenuating, inhibiting, or preventing non-cancerous cellular proliferation in vivo. One skilled in the art will appreciate that compounds within Formula I will demonstrate different activities in their ability to attenuate, inhibit, or prevent non-cancerous cellular proliferation and to treat the diseases associated with such proliferation, the pathogenesis of which, may include the cellular migration and/or inflammation. The ability of the compounds to attenuate, inhibit, or prevent non-cancerous cellular proliferation, cellular migration and/or inflammation can be initially determined in vitro if desired. The present invention thus contemplates a preliminary in vitro screening step to further characterize compounds suitable for incorporation into the therapeutic compositions. A number of standard tests to determine the ability of a compound to attenuate, inhibit, or prevent proliferation, cellular migration and/or inflammation are known in the art and can be employed to test the compounds of Formula I. Exemplary procedures are described herein.

Functional Assays Candidate compounds of Formula I can be tested in vitro and in vivo to determine their activity in inhibiting non-cancerous cellular proliferation and/or cell migration. The compounds can also be tested for their ability to inhibit production of pro-inflammatory cytokines, such as IL-2.

1. In vitro Testing Cell Proliferation Assays The compounds can be assayed initially for their ability to inhibit the growth of cells, such as endothelial cells or keratinocytes, (i. e. their cytotoxicity) in vitro using standard techniques. In general, cells of a specific test cell line are grown to an appropriate density (e. g. approximately 1 x 104) and the candidate compound is added. After an appropriate incubation time (for example 48 to 74 hours), the cell density is assessed. Methods of measuring cell density are known in the art, for example, the cell density can be assessed under a light inverted microscope by measuring the surface of the culture plate covered by the cell monolayer ; or by using the resazurin reduction test (see Fields & Lancaster (1993) Am. Biotechnol. Lab. 11: 48-50; O'Brien et al., (2000) Eur. J Bioclzem. 267: 5421-5426 and U. S. Patent No. 5,501, 959), the sulforhodamine assay (Rubinstein et al., (1990) J. Natl. CancerInst. 82: 113-118) or the neutral red dye test (Kitano et al., (1991) Euro. J. Clin. Investg. 21: 53-58; West et al., (1992) J Investigative Derm. 99: 95-100).

Alternatively, the cells can be detached from the plate, for example, by incubation with trypsin and then counted in an hemocytometer. Percent inhibition of proliferation of the cells is calculated by comparison of the cell density in the treated culture with the cell density in control cultures, for example, cultures not pre-treated with the candidate compound and/or those pre- treated with a control compound (typically a known therapeutic). Cells may be treated with a mitogen prior to addition of the candidate compound to assess the ability of the compounds to inhibit proliferation of stimulated cells as opposed to unstimulated, or quiescent cells.

DNA synthesis can be also assessed and used as an indication of cell proliferation. For example, by the uptake of [3H] thymidine. Typically cells are grown to an appropriate density (generally to confluence) at which point the growth medium is replaced with a medium that renders the cells quiescent (for example, DME 0.5% serum). The quiescent cells are exposed to a mitogenic stimulus, such as 10% serum, PDGF, bFGF, or other appropriate mitogen according to the cell line, at a suitable interval after the medium replacement. [3H] thymidine is subsequently added to the cells, and the cells are maintained at 37°C. After an appropriate incubation time, the cells are washed, the acid-precipitable radioactivity is extracted and the amount of radioactivity determined, for example, by using a scintillation counter.

Cell Migration Assays In general, the ability of a compound to inhibit migration of cells, such as endothelial cells and keratinocytes, can be assessed in vitro using standard cell migration assays. Typically, such assays are conducted in multi-well plates, the wells of the plate being separated by a suitable membrane into top and bottom sections. The membrane can be coated with an appropriate compound, the selection of which is dependent on the type of cell being assessed and can be readily determined by one skilled in the art. Examples include but are not limited to fibronectin, collagen, gelatine or Matrigel. An appropriate chemo-attractant, the selectin of which is dependent on the type of cell being assessed and can readily be determined by one skilled in the art. Examples include but are not limited to EGM-2, IL-8, a-FGF, P-FGF, EGF and the like, is added to the bottom chamber as a chemo-attractant. An aliquot of the test cells together with the test compound is added to the upper chamber, typically various dilutions of the test compound are tested. After a suitable incubation time, the membrane is rinsed, fixed and stained. The cells on the upper side of the membrane are wiped off, and then randomly selected fields on the bottom side are counted. Cell (for example, keratinocyte or endothelial cell) migration can also be assessed in vitro by monitoring the closure of a denuded area scratched in a confluent monolayer in the presence or absence of test compound (see Phan et al., Wound Repair Regen 9 (4): 305-313).

The migration and differentiation of endothelial cells during angiogenesis can also be studied in vitro using the Matrigel tube formation assay (see Grant et al., (1992) J. Cell. Physiol. 153: 614).

In general, cell culture plates are coated with a Matrigel solution and then incubated at 37°C to promote gelling. HUVECs or other suitable cells are resuspended in growth media and added to each well. The candidate compound, positive control compound (s) (for example, aFGF and/or bFGF) and/or media alone (as a second control) are also added to the wells at this time. After an appropriate incubation time, the plates are fixed and the length of the tubes measured by microscopy.

Examples of suitable cell lines to assess the anti-angiogenic properties of candidate compounds include, but are not limited to, human umbilical vein endothelial cells (HUVECs), bovine aortic endothelial cells (BAECs), human coronary artery endothelial cells (HCAECs) and vascular smooth muscle cells. HUVECs can be isolated from umbilical cords using standard methods (see, for example, Jaffe et al. (1973) J. Clin. Invest. 52: 2745), or they can be obtained from the ATCC or various commercial sources, as can other suitable endothelial cell lines. Suitable cell lines to assess the anti-psoriasis properties of candidate compounds include, but are not limited to, keratinocytes (e. g. HaCat cells). The use of proliferating keratinocytes in culture as a test system for determining the utility of a compound for treating psoriasis is well documented (see, for example, Kitano et al., (1991) Euro. J. Clin. Investg. 21: 53-58; West et al., (1992) J Investigative Derm. 99: 95-100).

Cytokine Assays A number of assays, including but not limited to enzyme immunoassay systems such as ELISA, ELISPOT, are known in the art to measure cytokine concentrations in a sample. Accordingly, in one embodiment of the invention, the ability of a candidate compound to inhibit IL-2 production in cells is determined by treating a T cell culture with candidate compound and quantifying IL-2 production using an IL-2 ELISA and comparing to control treated cultures. Alternatively, IL-2 concentration can be examined in samples, including but not limited to serum, isolated from mammals treated with the compounds of the invention.

2. In vivo Testing A number of assays are known in the art for testing the ability of candidate compounds to inhibit angiogenesis in vivo. For example, the ability of the candidate compounds to inhibit endothelial cell migration can be determined using the chick chorioallantoic membrane (CAM) assay, Matrigel plug assay and/or corneal micropocket assay. In addition, the ability of the compositions to inhibit psorasis can be assessed using various murine models of psorasis.

The CAM assay is a standard assay that is used to evaluate the ability of a test compound to inhibit the growth of blood vessels into various tissues, i. e. both angiogenesis and neovascularization (see Brooks et al., in Methods in Molecular Biology, Vol. 129, pp. 257-269 (2000), ed. A. R. Howlett, Humana Press Inc., Totowa, NJ; Ausprunk et al., (1975) Am. J : Pathol., 79: 597-618; Ossonski et al., (1980) CancerRes., 40: 2300-2309). Since the CAM assay measures neovascularization of whole tissue, wherein chick embryo blood vessels grow into the chorioallantoic membrane (CAM) or into the tissue transplanted on the CAM, it is a well- recognised assay model for in vivo angiogenesis.

The Matrigel plug assay is also a standard method for evaluating the anti-angiogenic properties of compounds in vivo (see, for example, Passaniti, et al., (1992) Lab. Invest. 67: 519-528). In this assay, a test compound is introduced into cold liquid Matrigel which, after subcutaneous injection into a suitable animal model, solidifies and permits penetration by host cells and the formation of new blood vessels. After a suitable period of time, the animal is sacrificed and the Matrigel plug is recovered, usually together with the adjacent subcutaneous tissues. Assessment of angiogenesis in the Matrigel plug is achieved either by measuring haemoglobin or by scoring selected regions of histological sections for vascular density, for example by immunohistochemistry techniques identifying specific factors such as hemagglutinin (HA), CD31 (platelet endothelial cell adhesion molecule-1) or Factor VIII. Modifications of this assay have also been described (see, for example, Akhtar et al., (2002) Angiogenesis 5: 75-80; Kragh et al., (2003) IntJOncol. 22: 305-11).

The comeal micropocket assay is usually conducted in mice, rats or rabbits and has been described in detail by others (see D'Amato, et al., (1994) Proc. Natl, Acad. Sci. USA, 91: 4082- 4085; Koch et al., (1991) Agents Actions, 34: 350-7; Kenyon, et al., (1996) Invest. Ophthalmol.

Vis. Sci. 37: 1625-1632). Briefly, pellets for implantation are prepared from sterile hydron polymer containing a suitable amount of the test compound. The pellets are surgically implanted into corneal stromal micropockets created at an appropriate distance medial to the lateral corneal limbus of the animal. Angiogenesis can be quantitated at various times after pellet implantation through the use of stereomicroscopy. Typically, the length of neovessels generated from the limbal vessel ring toward the centre of the cornea and the width of the neovessels are measured.

The efficacy of the compounds of Formula I in the treatment of various diseases and disorders associated with angiogenesis can be tested initially in an appropriate animal model. Accepted animal models are available for a number of diseases (see, for example, Enna et al., (Eds. ) Current Protocols in Pharmacology, J. Wiley & Sons, New York, NY).

As indicated above, the compounds of the invention can be used in the treatment of psoriasis. A number of murine psoriasis models are known in the art and can be used initially to assess the ability of the candidate compounds to treat psoriasis. Murine psoriasis models include immune comprised mice injected with CD45Rb positive cells (U. S. Patent No 64,10, 824). Alternatively a human psoriasis xenograft model (Sugai et al. (1998) J Dermatol Sci 17: 85-92) or transgenic mouse models (Xia et al. Blood 102 (1) : 161-168 can be used.

Additional Tests In addition to the above tests, the compounds of the invention can be submitted to other standard tests, such as cytotoxicity tests, stability tests, bioavailability tests and the like. As will be readily apparent to one skilled in the art, the therapeutic compositions of the invention will need to meet certain criteria in order to be suitable for human use and to meet regulatory requirements. Thus, once a compound of the invention has been found to be suitable for animal administration, standard in vitro and in vivo tests can be conducted to determine information about the metabolism and pharmacokinetic (PK) of the compositions and combinations (including data on drug-drug interactions where appropriate) which can be used to design human clinical trials.

Clinical Trials One skilled in the art will appreciate that, following the demonstrated effectiveness of the compounds of the present invention in vitro and in animal models (i. e. pre-clinical efficacy), the safety profile of the compounds can be determined in at least two non-human species and then the compositions will progress into Clinical Trials in order to further evaluate their efficacy in the treatment of non-cancerous pathogenic cellular proliferation and the diseases and disorders associated therewith in order to obtain regulatory approval for therapeutic use. As is known in the art, clinical trials progress through phases of testing, which are identified as Phases I, II, III, and IV. In vitro and in vivo information about the metabolism and pharmacokinetic (PK) of the compounds of the invention determined from pre-clinical studies facilitates the design of initial Phase I and Phase II clinical studies.

Phase I These studies are conducted to investigate the safety, tolerability and PK of the compounds and to help design Phase II studies, for example, in terms of appropriate doses, routes of administration, administration protocols.

Phase II Phase I studies allow the selection of safe dose levels for Phase II studies. An important factor in the protocol design of the Phase II studies is the adequate recruitment of the patient population to be studied based on stringent selection criteria defining the demographics (age, race and sex) of the study and the previous medical history of the patient. A protocol for Phase II studies typically specifies baseline data that can be used to characterise the population, to evaluate the success of randomization in achieving balance of important prognostic factors, and to allow for consideration of adjusted analyses.

Clinical biomarkers can be defined as follows (Atkinson A et al : Clin. Pharinacol. Ther. 69, 89- 95 (2001): Biological marker (biomarker) : a characteristic that is objectively measured and evaluated as an indicator of normal biological process, pathogenic process, or pharmacological response to a therapeutic intervention.

Clinical endpoint : a characteristic or variable that reflects how a patient feels or functions, or how long a patient survives.

Surrogate endpoint : biomarker intended to substitute for a clinical endpoint. A clinical investigator uses epidemiological, therapeutic, pathophysiological, or other scientific evidence to select a surrogate endpoint that is expected to predict benefit, harm or the lack of benefit or harm. The FDA defines a surrogate endpoint, or marker, as a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions or survive and is expected to predict the effect of the therapy.

Phase III Phase III trials focus on determining how the compound compares to the standard, or most widely accepted, treatment. In Phase III trials, patients are randomly assigned to one of two or more"arms". In a trial with two arms, for example, one arm will receive the standard treatment (control group) and the other arm will be treated with the therapeutic composition/combination (investigational group).

Phase IV Phase IV trials can be used to further evaluate the long-term safety and effectiveness of the compound. Phase IV trials are less common than Phase I, II and III trials and would take place after the therapeutic composition has been approved for standard use.

Preparation of Compounds of Formula I In one embodiment of the present invention, compounds of Formula I wherein Rl and R2 are both H are prepared by the general method provided below.

An amine derivative of Formula IV wherein B is as defined for compound of formula (I) is reacted with an isocyanate of Formula V in anhydrous ether under nitrogen atmosphere at room temperature for 2 to 16 hours or until the disappearance on thin layer chromatography (TLC) of the starting amine of Formula II. The solid residue obtained is filtered and dried in vacuo, the filtrate is evaporated under reduced pressure, and the solid remaining therein is also dried in vacuo. Both solids are independently recrystallized with suitable organic solvents and the final crystals are pooled after evaluation of their purity by chromatography, IR, IH NMR and MS.

Where the crystallization is difficult, purification by column chromatography on silica gel may be required prior to the final crystallization. The compounds of Formula IV are either commercially available or can be prepared with the standard procedures known to a worker skilled in the relevant art.

In another embodiment of the invention, compounds of formula I, wherein B is a substituted phenyl, Rl and/or R2 are other than H and X is Cl, are prepared by the general method provided below. a = Boc20, DMAP, CH2C12 ; b = (R) or (S) NH2CR2R3CH20H, CH2C12 ; c = PPh3, CC14/CH2C12 Formation of the urea moiety is achieved using the 4-dimethylaminopyridine-catalyzed reaction of the relevant 4-alkylaniline (VI) with di-tert-butyldicarbonate in dichloromethane followed by the trapping of the in situ generated isocyanate with the appropriate (R)-or ()-2-aminoalcohol (see Knolker, et al., Synlett (1996) 502-504 and Journal of Medicinal Chemistry, 46,2003, 5055- 5063). This procedure ensures a racemization-free synthesis of urea under mild conditions and circumvents side reactions such as the formation of symmetrical disubstituted urea (see Knolker, et al., Synlett (1997) 925-928). Subsequently, chloration of the chiral 2-hydroxyethylureas (VII) is achieved using triphenylphosphine in a mixture of carbon tetrachloride and dichloromethane at room temperature, affording the final enantiomerically pure (R)-or (59-(1-alkyl-2- chloro) ethylurea derivative.

Other methods of preparing compounds of Formula I are known and can be readily employed by one skilled in the art to obtain the compounds of the invention. Certain compounds of Formula I are also available commercially. Further exemplary methods of preparing the compounds are provided by the Examples. These methods are provided by means of example only and are not intended to limit the scope of the invention in any way.

Administration of Therapeutic Compounds and Pharamceutical Compositions The present invention provides methods of attenuating, inhibiting or preventing non-cancerous pathogenic cellular proliferation in a mammal comprising administering an effective amount of one or more compounds of Formula I, or non-toxic metabolically-labile esters or amides thereof, or pharmaceutically acceptable salts thereof. Accordingly, the present invention provides methods for the treatment of diseases and disorders associated with non-cancerous pathogenic cellular proliferation, the pathogenesis of which, may include cell migration and/or inflammation. In one embodiment of the invention, methods for the treatment of diseases and disorders characterised by endothelial cell proliferation and/or migration, keratinocyte proliferation and/or migration, inflammation, or combinations thereof are provided. In another embodiment of the invention, methods for the amelioration of inflammation associated with IL-2 production are provided.

The compounds of the present invention are typically formulated prior to administration. The present invention thus provides pharmaceutical compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients.

Compounds of the general Formula I or pharmaceutical compositions comprising the compounds may be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. In the usual course of therapy, the active compound is incorporated into an acceptable vehicle to form a composition for topical administration to the affected area, such as hydropohobic or hydrophilic creams or lotions, or into a form suitable for oral, rectal or parenteral administration, such as syrups, elixirs, tablets, troches, lozenges, hard or soft capsules, pills, suppositiories, oily or aqueous suspensions, dispersible powders or granules, emulsions, injectables, or solutions. The term parenteral as used herein includes subcutaneous injections, intradermal, intra-articular, intravenous, intramuscular, intravascular, intrasternal injection or infusion techniques.

Compositions intended for oral use may be prepared in either solid or fluid unit dosage forms.

Fluid unit dosage form can be prepared according to procedures known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. An elixir is prepared by using a hydroalcoholic (e. g. , ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent. Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.

Solid formulations such as tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate : granulating and disintegrating agents for example, corn starch, or alginic acid: binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc and other conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, methylcellulose, and functionally similar materials. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.

Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxylmethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylen oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl-p-hydroxy benzoate, one or more colouring agents, one or more flavouring agents or one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.

The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the- addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.

The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.

The sterile injectable preparation may also be a sterile injectable solution or a suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.

Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Adjuvants such as local anaesthetics, preservatives and buffering agents can also be included in the injectable solution or suspension.

The compound (s) of the general Formula I may be administered, together or separately, in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

For ophthalmic applications, such as treatment of keratitis, the compounds can be formulated into solutions, suspensions, and ointments appropriate for use in the eye (see, for example, Mitra (ed. ), (1993) Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, N. Y.; Havener, (1983) Ocular Pharmacology, C. V. Mosby Co., St. Louis).

Other pharmaceutical compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in"Remington : The Science and Practice of Pharmacy" (formerly"Remingtons Pharmaceutical Sciences"), Gennaro, A. , Lippincott, Williams & Wilkins, Philidelphia, PA (2000).

In general, the route of administration of the compounds of Formula I is topical (including administration to the eye, scalp, and mucous membranes), oral, or parenteral. Topical administration is usually most effective for the treatment of skin lesions, including lesions of the scalp, lesions of the cornea (keratitis), and lesions of mucous membranes where such direct application is practical. Shampoo formulations can be advantageous for treating scalp lesions, such as seborrheic dermatitis and psoriasis of the scalp, and mouthwash and oral paste formulations can be advantageous for mucous membrane lesions, such as oral lesions and leukoplakia. Oral administration is an alternative for treatment of skin lesions and other lesions discussed above where direct topical application is not as practical, as well as for other applications. The present invention contemplates the administration of one or more compounds of Formula I either alone or in combination with other therapeutics.

The dosage to be administered is not subject to defined limits, but it will usually be an effective amount. It will usually be the equivalent, on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active free drug to achieve its desired pharmacological and physiological effects. The compositions may be formulated in a unit dosage form. The term"unit dosage form"refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Examples of ranges for the compound (s) in each dosage unit are from about 0.05 to about 100 mg, or more usually, from about 1.0 to about 30 mg.

Daily dosages of the compounds of the present invention will typically fall within the range of about 0.01 to about 100 mg/kg of body weight, in single or divided dose. However, it will be understood that the actual amount of the compound (s) to be administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. The above dosage range is given by way of example only and is not intended to limit the scope of the invention in any way.

In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing harmful side effects, for example, by first dividing the larger dose into several smaller doses for administration throughout the day.

Pharmaceutical Kits The present invention additionally provides for therapeutic kits containing the therapeutic combinations for use in the treatment of a subject in need of therapy for attenuating non-cancer cell hyperproliferation. Individual components of the kit would be packaged in separate containers and, associated with such containers, can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

When the components of the kit are provided in one or more liquid solutions, the liquid solution can be an aqueous solution, for example a sterile aqueous solution. In this case the container means may itself be an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the composition may be administered to a patient or applied to and mixed with the other components of the kit.

The components of the kit may also be provided in dried or lyophilised form and the kit can additionally contain a suitable solvent for reconstitution of the lyophilised components.

Irrespective of the number or type of containers, the kits of the invention also may comprise an instrument for assisting with the administration of the composition to a patient. Such an instrument may be an inhalant, syringe, pipette, forceps, measured spoon, eye dropper or any such medically approved delivery vehicle.

To gain a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only. Therefore, they should not limit the scope of this invention in any way.

EXAMPLES The following abbreviations are used in the Examples: EtOAc, ethyl acetate; THF, tetrahydrofuran ; EtOH, ethanol; TLC, thin layer chromatography; GC, gas chromatography ; HPLC, high pressure liquid chromatography; m-CPBA, m-chloroperbenzoic acid; Et20, diethyl ether; DMSO, dimethyl sulfoxide ; DBU, 1, 8-diazabicyclo- [5. 4.0] undec-7-ene, MTBE, methyl t-butyl ether; and FDMS, field desorption mass spectrometry.

EXAMPLE 1: Preparation of 1- (4-tert-butylphenyl)-3- (2-chloroethyl) urea [1] 2-Chloroethyl isocyanate (1.15 equiv.) was slowly added dropwise to a magnetically stirred and cooled solution (ice bath) of freshly distilled 4-t-butylaniline (1 equiv.) in dichloromethane (18 mL of solvent/g of aniline). The ice bath was then removed and the reaction mixture was stirred at room temperature for 20 h. After completion of the reaction, the solvent was removed by vacuum distillation to give a white solid, which was purified by recrystallization from dichloromethane/hexane to obtain 88% of 1- (4-tert-butylphenyl)-3- (2-chloroethyl) urea.

NMR 1H (CDC13, 300 MHz) 8 7.28 (d, 2H, J = 8. 5 Hz), 7,17 (d, 2H, J = 8.5 Hz), 3.52 (m, 4H), 1.27 (s, 9H).

EXAMPLE 2: Preparation of 1- (2-chloroethyl)-3- (4-cyclohexylphenyl) urea [2] This compound was prepared according to the process of Example 1, except that 4-cyclohexyl aniline was used instead of 4-t-butyl aniline. The final product was recrystallized from THF/hexane to obtain 82% yield.

'H NMR (CDC13 + MeOD, 300 MHz) 8 7.10 (d, 2H, J = 8. 4 Hz), 6.98 (d, 2H, J = 8. 4 Hz), 3.48 (m, 2H), 3. 38 (m, 2H), 2.31 (m, 1H), 1.6-1. 7 (m, 5H), 1.1-1. 3 (m, 5H).

EXAMPLE 3: Preparation of 1- (2-chloroethyl)-3- (4-hepthylphenyl) urea [3] This compound was prepared according to the process of Example 1, except that 4-heptylaniline was used instead of 4-t-butyl aniline. The final product was recrystallized from THF/hexane to obtain 93% Yield.

'H NMR (CDC13,300 MHz) b 7.15 (d, 2H, J= 8. 4 Hz), 7.01 (d, 2H, J= 8.4 Hz), 3.53 (t, 2H, J= 5.2 Hz), 3.45 (t, 2H, J=5. 2 Hz), 2.46 (t, 2H, J= 7.7 Hz), 1.49 (m, 2H), 1.21 (m, 8H), 0.80 (t, 3H, J= 6. 7 Hz).

EXAMPLE 4 EXAMPLE 5: Preparation of 1- (2-chloroethyl)-3- (4-iodophenyl) urea [5] This compound was prepared according to the process of Example 1, except that 4-iodoaniline was used instead of 4-t-butyl aniline. The final product was recrystallized from THF/hexane.

Yield 60% IH NMR (DMSO, 300 MHz) b 8.80 (s, 1H), 7.53 (d, 2H, J = 8.7 Hz), 7.24 (d, 2H, J = 8. 7 Hz), 6.45 (m, 1H), 3.64 (m, 2H), 3.39 (m, 2H).

EXAMPLE 6: Preparation of 1- (2-chloroethyl)-3- (4-phenoxyphenyl) urea [6] This compound was prepared according to the process of Example 1, except that 4- phenoxyaniline was used instead of 4-t-butyl aniline. IH NMR (CDC13, 300 MHz) b 7.1-7. 3 (m, 5H), 6.96 (m, 4H), 3.63 (m, 2H), 3.58 (m, 2H).

EXAMPLE 7: Preparation of 1- (4-benzyloxyphenyl)-3- (2-chloroethyl) urea [7] This compound was prepared according to the process of Example 1, except that 4- benzyloxyaniline was used instead of 4-t-butyl aniline.

EXAMPLE 8: Preparation of l-(biphenyl-4-yl)-3-(2-chloroethyl) urea [8] This compound was prepared according to the process of Example 1, except that 4- biphenylamine was used instead of 4-t-butyl aniline. The final product was recrystallized from methanol/water. Yield 79%.

'H NMR (CDCl3, 300 MHz) 6 7.44 (m, 4H), 7.2-7. 35 (m, 5H), 3.55 (m, 2H), 3.46 (m, 2H).

EXAMPLE 9: Preparation of 1- (2-chloroethyl)-3- (4-hydroxyphenyl) urea [9] This compound was prepared according to the process of Example 1, except that 4- hydroxyaniline was used instead of 4-t-butyl aniline. The final product was recrystallized from THF/hexane. Yield 30% IH NMR (CDC13, 300 MHz) 8 7.04 (d, 2H, J= 8.7 Hz), 6.69 (d, 2H, J= 8.7 Hz), 3.53 (m, 2H), 3.44 (t, 2H, J= 5. 5 Hz).

EXAMPLE 10: Preparation of N-{3- [3- (2-chloroethyl) ureido] phenyl} acetamide [10] This compound was prepared according to the process of Example 1, except that 3'- aminoacetanilide was used instead of 4-t-butyl aniline. The final product was recrystallized from ethyl acetate/methanol/hexane. Yield 46%.

'H NMR (DMSO, 300 MHz) 8 9.86 (br s, 1H), 8.67 (br s, 1H), 7.66 (br s, 1H), 7.12 (s, 4H), 6.35 (t, 1H, J= 5.7 Hz), 3.65 (t, 2H, J= 6.1 Hz), 3.41 (t, 2H, J= 6.1 Hz), 2.02 (s, 3H).

EXAMPLE 11: Preparation of N-Butyl-3- [3- (2- chloroethyl) ureido] benzenesulfonamide [11] This compound was prepared according to the process of Example 1, except that 3-amino-N- butylbenzenesulfonmide was used instead of 4-t-butyl aniline. The final product was recrystallized from from ethanol/water. Yield 50%.

'H NMR (DMSO, 300 MHz) 8 9.02 (s, 1H), 7.98 (s, 1H), 7.50 (m, 2H), 7.43 (t, 1H, J= 7.9 Hz), 7.30 (d, 1H, J= 7.9 Hz), 6.48 (t, 1H, J= 5.7 Hz), 3.67 (t, 2H, J= 6.0 Hz), 3.43 (q, 2H, J = 6.0 Hz), 2.72 (q, 2H, J= 6.5 Hz), 1.34 (m, 2H), 1.24 (m, 2H), 0.79 (t, 3H, J= 7.1 Hz).

EXAMPLE 12: Preparation of 1- (2-chloroethyl)-3- [3- (l-hydroxyethyl) phenyl] urea [12] This compound was prepared according to the process of Example 1, except that 3- (1- hydroxyethyl) aniline was used instead of 4-t-butyl aniline. The final product was purified by flash chromatography on silica gel (3/2 ethyl acetate/chloroform). Yield 63% 'H NMR (CDC13, 300 MHz) 8 7.1-7. 3 (m, 4H), 4.85 (q, 1H, J = 6.6 Hz), 3.63 (m, 2H), 3.58 (m, 2H), 1.46 (d, 3H, J = 6. 6 Hz).

EXAMPLE 13: Preparation of 1- (2-chloroethyl) 3- [4- (2-methoxyethyl) phenyl) urea [13] To a cold (ice bath) suspension of NaH 60% (483 mg, 12.1 mmol) in dry THF (20 mL) was added a solution of 2- (4-nitrophenyl) ethanol (1.04 g, 6.25 mmol) in dry THF (5 mL). The mixture was stirred at 0 °C for 10 minutes, then methyl iodide (0.50 mL, 8.0 mmol) was added.

The ice bath was removed and the solution was stirred at room temperature for 24 h. Excess of NaH was quenched carefully with water and the solution was poured into brine. The aqueous phase was extracted with ether (3 times). The organic portions were washed with brine, dried over MgS04 and concentrated to give 1- (2-methoxyethyl)-4-nitrobenzene which was purified by flash chromatography on silica gel (ether/petroleum ether 1/1).

1- (2-Methoxyethyl)-4-nitrobenzene was dissolved in a mixture of ethanol (5 mL) and water (0.5 mL) and conc. HC1 (0.25 mL). Iron powder was added (140 mg) and the mixture was refluxed for 2 hours. The solid was removed by filtration on Celite. The solution was neutralized with NaOH 1M (to pH 8) and extracted with ethyl acetate (3 times). The organic portions were reunited, washed with brine, dried over K2CO3 and concentrated to yield 4- (2- methoxyethyl) aniline which was purified by flash chromatography (CH2C12).

4-(2-methoxyethyl) aniline was then reacted with 2-Chloroethyl isocyanate as described in Example 1 to prepare compound 13. The final product was purified by flash chromatography on silica gel (ether/petroleum ether 13/7). Yield 84%.

'H NMR (CDC13, 300 MHz) 8 7.16 (d, 2H, J = 8.5 Hz), 7.11 (d, 2H, J = 8. 5 Hz), 3.5-3. 6 (m, 6H), 3.34 (s, 3H), 2.81 (t, 2H, J= 6.9 Hz).

EXAMPLE 14: Preparation of 1- (2-chloroethyl)-3- [4- (4-ethoxybutyl) phenyl) urea [14] To a suspension of powdered potassium hydroxide (2.42 g, 43.1 mmol) in DMSO (20 mL) was added a solution of 4- (4-nitrophenyl) butanol (2.09 mg, 10.7 mmol) and ethyl iodide (3.4 mL, 42 mmol) in DMSO (10 mL) over a 1 h period while the temperature was maintained below 25 °C.

The resulting mixture was stirred for an additional hour, poured into water (150 mL), and extracted with methylene chloride (3 times). The combined organic extracts were washed with 10% sodium bisulfite (twice), water and brine, dried over MgS04, and concentrated in vacuo to yield 1- (4-ethoxybutyl)-4-nitrobenzene (838 mg, 35%).

A mixture of 1-(4-ethoxybutyl)-4-nikobenzene (838 mg, 3.75 mmol), iron powder (1. 58 g), and concd HC1 (0.05 mL) in of a mixture of EtOH, CH3COOH and H20 (2: 2: 1,25 mL) was refluxed for 4h. The solution was filtered, diluted with H20 (100 mL), and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with a saturated aqueous solution of NaHC03, water, and dried over K2CO3. Evaporation of the solvent afforded 4- (4-ethoxybutyl) aniline which was used without further purification to prepare compound 14 by reacting with 2- Chloroethyl isocyanate as described for compound 1 to 13. The final product was purified by flash chromatography on silica gel (dichloromethane/ether 9/1). Yield 82%.

IH NMR (CDC13, 300 MHz) 8 7.14 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.4 Hz), 3.3-3. 5 (m, 8H), 2.53 (t, 2H, J= 6.8 Hz), 1.60 (m, 4H), 1.18 (t, 3H, J= 6.9 Hz).

EXAMPLE 15: Preparation of 1- (2-chloroethyl)-3- [4- (4-fluorobutyl) phenyl] urea [15] To a cold solution (-12 °C) of 4- (4-nitrophenyl) butanol (788 mg, 4.04 mmol) in dry CH2C12 (8 mL) was slowly added, under nitrogen, bis (2-methoxyethyl) aminosulfur trifluoride (0.8 mL, 4.3 mmol). The reaction was kept at-12 °C for 15 min and warmed up to room temperature. The mixture was stirred for 24 h. The solution was poured into saturated aqueous NaHC03 (25 mL), and after CO2 evolution ceased it was extracted three times with dichloromethane. The organic portions were reunited and washed with brine, dried over Na2S04, filtered, and evaporated in vacuo. Flash chromatography on silica gel (ether/hexane 1/9) afforded 1- (4-fluorobutyl)-4- nitrobenzene (490 mg, 62%).

To a solution of 1- (4-fluorobutyl)-4-nitrobenzene (70 mg, 0.36 mmol) in ethanol (2 mL) was added SnCl2|2 H2O (409 mg, 1. 81 mmol) and the mixture was refluxed for 2 hours. The solution was cooled and poured into chilled water. The aqueous phase was alkalized by adding a solution of NaHC03 and extracted with ethyl acetate (3 times). The organic portions were reunited, washed with brine, dried over K2CO3 and evaporated in vacuo to afford 4- (4-fluorobutyl) aniline which was purified by flash chromatography (CHC13) (53 mg, 88%).

4- (4-fluorobutyl) aniline was then reacted with 2-Chloroethyl isocyanate as described in examples 1-12 to obtain compound 15. Purified by flash chromatography on silica gel (dichloromethane/ether 85/15). Yield 74%.

IH NMR (CDC13, 300 MHz) 8 7.16 (d, 2H, J= 8. 3 Hz), 7.07 (d, 2H, J= 8.3 Hz), 4.43 (dt, 2H, J = 47.4, 5.5 Hz), 3.53 (m, 4H), 2. 58 (t, 2H, J= 7.0 Hz), 1.65-1. 75 (m, 4H).

EXAMPLE 16: Preparation of 1- (2-chloroethyl)-3- [3- (5-hydroxypent-1-ynyl) phenyl) urea [16] 3-Iodoaniline (5.05 g, 23.0 mmol), K2CO3 (7.97 g, 57.7 mmol), Cul (183 mg, 0.96 mmol), PPh3 (499 mg, 1.90 mmol), and 10% Pd/C (492 mg, 0.46 mmol Pd) were mixed in 1,2- dimethoxyethane (30 mL) and water (30 mL) at 25 °C under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes and 4-pentyn-1-ol (4.8 mL, 51.6 mmol) was added. The mixture was heated at 80 °C for 16 hours, cooled to room temperature and filtered through Celite. The organic solvents were removed in vacuo, and the aqueous residue acidified with 1M HC1. This solution was extracted with ethyl acetate, and the aqueous phase basified with KOH.

The water layer was then extracted with ethyl acetate (3X). The organic portions were reunited, washed with brine, dried over Na2S04 and concentrated in vacuo. 3- (5-hydroxypent-l- ynyl) aniline was used for the next reaction without any purification. (5.62 g), which was then reacted with 2-Chloroethyl isocyanate as described in examples 1-12 to obtain compound 16.

Purified by flash chromatography on silica gel (chloroform/ethyl acetate 1/1). Yield 72%.

IH NMR (CDC13, 300 MHz) 8 7.26 (m, 2H), 7.10 (t, 1H, J= 7.9 Hz), 6.94 (d, 1H, J= 7.5 Hz), 3.68 (t, 2H, J = 6.3 Hz), 3.55 (m, 2H), 3.47 (m, 2H), 3.31 (br s, 3H), 2.42 (t, 2H, J= 6.9 Hz), 1.75 (quint, 2H, J= 6.6 Hz).

EXAMPLE 17: Preparation of 1- (2-chloroethyl)-3- [3- (5-hydroxypentyl) phenyl) urea [171 The crude 3- (5-hydroxypent-1-ynyl) aniline (5.62 g, 32.0 mmol) (as prepared in example 16) was dissolved in ethanol (40 mL) and placed in a hydrogenation bottle with 10% Pd/C (604 mg).

The bottle was filled with 40 psi of hydrogen and shaken for 4 h. The product was filtered through Celite, and the solvent was removed in vacuo. The aniline was purified by vacuum distillation to give 3- (5-hydroxypentyl) aniline as a clear oil (3.49 g, 84% for two steps, from 3- iodoaniline). 3- (5-hydroxypentyl) aniline was then reacted with 2-Chloroethyl isocyanate as described in examples 1-12 to obtain compound 17.

Purified by flash chromatography on silica gel (ethyl acetate/hexane 45/55. Yield 36%.

'H NMR (CDC13,300 MHz) 6 7.0-7. 15 (m, 3H), 6.77 (d, 1H, J= 7.2 Hz), 3.45-3. 6 (m, 6H), 3.31 (br s, 3H), 2.50 (t, 2H, J= 7.6 Hz), 1.45-1. 6 (m, 4H), 1.30 (m, 2H).

EXAMPLE 18 : Preparation of Acetic acid 5-f4- [3- (2-chloroethyl) ureido] phenyl} pentyl ester [18] To a cold (0 °C) solution of 3- (5-hydroxypentyl) aniline (708 mg, 3.95 mmol) (as prepared in example 17) in dry dichloromethane (20 mL) was added, under nitrogen, (Boc) 20 (1.00 g, 4.60 mmol). The solution was allowed to warm to room temperature and stirred for 2 days (the reaction was monitored by TLC). The solution was diluted with ethyl acetate. The organic phase was washed with a 5% solution of citric acid (twice), brine, dried over Na2S04 and concentrated under vacuum. [3- (5-Hydroxypentyl) phenyl] carbamic acid tert-butyl ester was used without any further purification.

To a cold (0 °C) solution of [3- (5-Hydroxypentyl) phenyl] carbamic acid tert-butyl ester (112 mg, 0.40 mmol) in dry dichloromethane (3 mL) was added triethylamine (0.06 mL, 0.43 mmol) and acetyl chloride (32 IL- 0.45 mmol) under nitrogen. The solution was allowed to warm to room temperature and stirred for 5 hours. The solution was diluted with ethyl acetate. The organic phase was washed successively with a 5% solution of citric acid (3 times), a saturated solution of NaHC03 (twice), brine, dried over Na2S04 and evaporated to give acetic acid 5- (3-tert- butoxycarbonylaminophenyl) pentyl ester which was purified by flash chromatography on silica gel (ethyl acetate/hexane 15/85) (88 mg, 68 %).

Acetic acid 5- (3-tert-butoxycarbonylamino-phenyl)-pentyl ester (88 mg, 0.27 mmol) was dissolved in a mixture of trifluoroacetic acid (4.5 mL) and water (0.5 mL) and the solution was stirred for 10 min at room temperature. The solvents were evaporated and the residue was taken up in ethyl acetate. The organic phase was washed with a saturated solution of NaHC03 (twice), brine, dried over Na2S04 and concentrated in vacuo to give acetic acid 5- (3-aminophenyl) pentyl ester (36 mg, 60%).

Acetic acid 5- (3-aminophenyl) pentyl ester was then reacted with 2-Chloroethyl isocyanate as described in examples 1-12 to obtain compound 18.

Purified by flash chromatography on silica gel (ethyl acetate/hexane 3/7). Yield 86% 'H NMR (CDC13, 300 MHz) 8 7.19 (d, 2H, J= 8.3 Hz), 7.10 (d, 2H, J= 8.3 Hz), 4.04 (t, 2H, J= 6.7 Hz), 3.60 (m, 2H), 3.55 (m, 2H), 2.56 (t, 2H, J= 7.6 Hz), 2.04 (s, 3H), 1.63 (m, 4H), 1.38 (m, 2H).

EXAMPLE 19: Preparation of 6- {3- [3- (2-chloroethyl) ureido] phenoxy} hexanoic acid ethyl ester [19] To a solution of 3-nitrophenol (1.72 g, 12.3 mmol) and K2CO3 (3.40 g, 24.6 mmol) in acetone (30 mL) was added dropwise 6-bromohexanoic acid ethyl ester (2.3 mL, 15 mmol). The mixture was refluxed under nitrogen for 48 hours. The solution was diluted with ethyl acetate. The organic phase was successively washed with water, a saturated solution of NaHC03 (3 times), brine, dried over MgS04 and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 9/1) to yield 6- (3- nitrophenoxy) hexanoic acid ethyl ester (3.34 g, 48%).

To a solution of 6- (3-nitrophenoxy) hexanoic acid ethyl ester (442 mg, 1.57 mmol) in ethanol (20 mL) was added SnCl2 2 H2O (1.78 g, 7.90 mmol) and the mixture was refluxed for 4 hours.

The solution was cooled and poured into chilled water. The aqueous phase was alkalized by adding a solution of 1M NaOH and extracted with ethyl acetate (3 times). The organic portions were reunited, washed with brine (twice), dried over Na2SO4 and evaporated under reduced pressure to yield 6- (3-aminophenoxy) hexanoic acid ethyl ester which was used without any further purification (371 mg, 94%).

6- (3-aminophenoxy) hexanoic acid ethyl ester was then reacted with 2-Chloroethyl isocyanate as described in examples 1-12 to obtain compound 19. Purified by flash chromatography (hexane/ethyl acetate 3/2). Yield 85%.

IH NMR (CDC13,300 MHz) 8 7.11 (t, 1H, J = 8.1 Hz), 6.96 (t, 1H, J = 2. 1 Hz), 6.77 (dd, 1H, J = 8.1, 1.1 Hz), 6.54 (dd, 1H, J = 8.1, 2.1 Hz), 4.11 (q, 2H, J = 7.1 Hz), 3.86 (t, 2H, J = 6.4 Hz), 3.54 (m, 4H), 2.30 (t, 2H, J = 7.5 Hz), 1.6-1. 8 (m, 4H), 1.4-1. 5 (m, 2H), 1.24 (t, 3H, J = 7.1 Hz).

EXAMPLE 20: Preparation of 1- (2-chloroethyl)-2- (2-heptylphenyl) urea [20] 2-Iodoaniline (1.31 g, 5.97 mmol), K2CO3 (2.07 g, 15.0 mmol), Cul (47 mg, 0.25 mmol), PPh3 (134 mg, 0.51 mmol), and 10% Pd/C (125 mg, 0.12 mmol Pd) were mixed in 1,2- dimethoxyethane (15 mL) and water (15 mL) at 25 °C under a nitrogen atmosphere. This was stirred for 30 minutes and hept-1-yne (2.0 mL, 15 mmol) was added. The mixture was heated at 80 °C for 16 hours, cooled to room temperature and filtered through Celite. The organic solvents were removed in vacuo, and the aqueous residue acidified with 1M HC1. This solution was extracted with ethyl acetate, and the aqueous phase basified with KOH. The water layer was then extracted with ethyl acetate (3X). The organic portions were reunited, washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (THF/hexane 5/95) to yield 2-(hept-1-ynyl) aniline (909 mg, 81%).

2- (hept-1-ynyl) aniline (628 mg, 3.35 mmol) was dissolved in ethanol (20 mL) and placed in a hydrogenation bottle with 10% Pd/C (88 mg). The bottle was filled with 40 psi of hydrogen and shaken for 4 h. The product was filtered through Celite, and the solvent was removed in vacuo to obtain 2-heptanylaniline. The aniline was used without any further purification (602 mg, 94%).

2-heptanylaniline was then reacted with 2-Chloroethyl isocyanate as described in examples 1-12 to obtain compound 20. Purified by flash chromatography (ethyl acetate/hexane 3/7). Yield 83%.

'H NMR (CDC13,300 MHz) 8 7.37 (m, 1H), 7.1-7. 25 (m, 3H), 6.63 (br s, 1H), 5.44 (t, 1H, J = 5.5 Hz), 3.58 (m, 2H), 3.49 (m, 2H), 2.57 (t, 2H, J = 7.7 Hz), 1.52 (m, 2H), 1.25-1. 55 (m, 8H), 0.86 (t, 3H, J=6. 7Hz).

EXAMPLE 21: Preparation of 1- (2-Chloroacetyl)-3- (4-iodophenyl) urea [21] 2-Chloroacetyl isocyanate (1.15 mL, 13.5 mmol) was slowly added dropwise to a magnetically stirred and cooled solution (ice bath) of freshly recrystallized 4-iodoaniline (2.60 g, 11. 8 mmol) in dichloromethane (70 mL). The ice bath was then removed and the reaction mixture was stirred at room temperature for 20 h. After completion of the reaction, the solvent was removed under reduced pressure to give a yellow solid, which was purified by recrystallization (THF/hexane) to give 21 (3.23 g, 81%).

IH NMR (DMSO, 300 MHz) 8 10.93 (br s, 1H), 10.15 (br s, 1H), 7.66 (d, 2H, J= 8.6 Hz), 7.37 (d, 2H, J= 8.6 Hz), 4.38 (s, 2H).

EXAMPLE 22: Preparation of 1- (2-chloroacetyl)-3- (3- (5-hydroxypentyl) phenyl] urea [22] Prepared as described for compound 21 from 3- (5-hydroxypentyl) aniline (see previous example for its preparation).

Purified by flash chromatography (chloroform/ethyl acetate 1/1). Yield 51%.

'H NMR (CDC13,300 MHz) b 7.34 (s, 1H), 7.15 (m, 2H), 6.87 (m, 1H), 4.43 (s, 2H), 4.11 (s, 2H), 4. 08 (m, 2H), 2.55 (t, 2H, J= 7.2 Hz), 1.5-1. 65 (m, 4H), 1.36 (m, 2H).

EXAMPLE 23: Preparation of (R)-l- (2-chloro-l-methylethyl)-3- (4-iodophenyl) urea [(R)- 23] To a stirred solution of phenyl chloroformate (4.04 g, 25.8 mmol) in dry THF (60 mL) at 0 °C and under nitrogen was added 4-iodoaniline (5.59 g, 25.5 mmol) over 5 minutes. After the addition was complete, triethylamine (4.0 mL, 28.7 mmol) was added. The ice bath was removed and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate and the organic solution was washed successively with 1 M HC1 (2X), 1 M NaOH (3X), brine (1X), dried over MgS04 and evaporated down to afford a white solid (6.99 g, 81%) which was used directly.

In a round bottom flask equipped with a drying tube filled with CaCl2, (R)-alaninol (698 mg, 9.17 mmol) was dissolved in acetonitrile (35 mL). To the solution was added the carbamate (2.575 g, 7.59 mmol) and the mixture was stirred at room temperature for 3 days. The solution was then diluted with ethyl acetate (heating might be necessary to dissolve completely the urea).

The organic portion was washed successively with 1M HC1 (2X), 1M NaOH (3X), brine (1X), dried over MgS04 and the solvent was evaporated under reduce pressure. The pure product was obtained after crystallization from CHC13/THF/hexanes (1.542 g, 63%).

To a suspension of the alcohol (1.79 g, 5.61 mmol) in dry THF (30 mL) and under nitrogen was added SOC12 (0.6 mL, 8.2 mmol). The mixture was then heated for 30 min. The cooled solution was poured into brine and the product was extracted three times with ethyl acetate. The organic portions were reunited, washed successively with 1M HC1 (2X), brine, dried over MgS04 and the solvent s were removed under reduced pressure. The residue was purified twice by crystallization from THF/hexane (1.42 g, 75%).

'H NMR (CDC13 + MeOD, 300 MHz) 8 7.44 (d, 2H, J = 8. 8 Hz), 7.07 (d, 2H, J =8. 8 Hz), 4.09 (m, 1H), 3.59 (dd, 1H, J = 11.0, 4.6 Hz), 3.50 (dd, 1H, J = 11. 0, 3.6 Hz), 1.17 (d, 3H, J = 6.8 Hz).

EXAMPLE 24: Preparation of (S)-l- (2-chloro-l-methylethyl)-3- (4-iodophenyl) urea [(S)-23] Prepared as described for (R) -23 using (S)-alaninol instead of (R)-alaninol.

'H NMR (CDC13 + MeOD, 300 MHz) 8 7.44 (d, 2H, J = 8.8 Hz), 7.07 (d, 2H, J = 8. 8 Hz), 4.09 (m, 1H), 3.59 (dd, 1H, J = 11.0, 4.6 Hz), 3.50 (dd, 1H, J = 11.0, 3.6 Hz), 1.17 (d, 3H, J = 6.8 Hz). EXAMPLE 25: Preparation of (R)-1- (4-tert-Butylphenyl)-3- (2-chloro-1-methylethyl) urea [(R)-24] Prepared as described for (R)-23 starting with 4-tert-butylaniline.

EXAMPLE 26: Preparation of (S)-1-(4-tert-Butylphenyl)-3-(2-chloro-1-methylethyl) urea [(S)-24] Prepared as described for (R)-23 starting with 4-tert-butylaniline and using (S)-alaninol instead of (R)-alaninol.

EXAMPLE 27: Preparation of 1- (4-tert-Butylphenyl)-3- (2-chloro-1, 1-dimethylethyl) urea [25] Prepared as described for (R)-23 starting with 4-tert-butylaniline and using 2-amino-2-methyl-1- propanol instead of (R)-alaninol.

EXAMPLE 28: Preparation of 1- (2-Bromoethyl)-3- (3-iodophenyl) urea [26] 2-Bromoethyl isocyanate (0.21 mL, 2.32 mmol) was slowly added dropwise to a magnetically stirred and cooled solution (ice bath) of freshly recrystallized 3-iodoaniline (465 mg, 2.12 mmol) in dichloromethane (10 mL). The ice bath was then removed and the reaction mixture was stirred at room temperature for 20 h. After completion of the reaction, the solvent was removed under reduced pressure to give a solid, which was purified by recrystallization (THF/hexane) to give 26 (650 mg, 83%) 'H NMR (CDC13, 300 MHz) 8 7.72 (d, 1H, J= 2.0 Hz), 7.25 (m, 2H), 6.89 (t, 1H, J= 8. 0 Hz), 3.53 (M, 2H), 3.41 (M, 2H).

EXAMPLE 29: Preparation of 3- [3- (2-bromoethyl) ureido] benzoic acid ethyl ester [27] Prepared as described for compound 26 using 3-aminobenzoic acid ethyl ester.

Purified by flash chromatography on silica gel (ethyl acetate/hexane 2/3). Yield 87%.

'H NMR (CDC13, 300 MHz) 8 7.87 (s, 1H), 7.72 (d, 2H, J= 8. 0 Hz), 7.36 (t, 1H, J= 8.0 Hz), 4.36 (q, 2H, J= 7.1 Hz), 3.67 (m, 2H), 3.51 (m, 2H), 1.38 (t, 3H, J= 7.1 Hz).

EXAMPLE 30: Preparation of 4-tert-Butylphenyl (4, 5-dihydrooxazol-2-yl) amine [27] 4- (tert-Butylphenyl)-3- (2-chloroethyl) urea (102 mg, 0.40 mmol) and KF supported on silica gel 40% (220 mg) were suspended in acetonitrile (5 mL). The mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the solid was purified by flash chromatography on silica gel (methanol/dichloromethane 5/95) to yield the oxazoline (41 mg, 47%).

IH NMR (CDC13, 300 MHz) 8 7.28 (d, 2H, J = 8.7 Hz), 7.18 (d, 2H, J = 8. 7 Hz), 4.37 (t, 2H, J = 8. 4 Hz), 3.80 (t, 2H, J = 8. 4 Hz), 1.27 (s, 9H).

EXAMPLE 31: Preparation of 1-(2-Chloro-ethyl)-3-(3-iodo-phenyl)-urea [28] 2-Chloroethyl isocyanate (1,2 Eq, 1.640 mmol, 0.173 g) was slowly added dropwise to a magnetically stirred and cooled solution (ice bath) of freshly distilled 3-iodobenzenamine (1.0 Eq, 1.370 mmol, 0.300 g) in dichloromethane (15 mL of solvent/g of aniline). The ice bath was then removed and the reaction mixture was kept at room temperature for 20 h. After completion of the reaction, the solvent was removed by vacuum distillation to give a white solid, which was purified by flash chromatography on silica gel: dichloromethane/MeOH (98/2). Yield = 100% NMR'H (Acetone) 8 : 8. 18 (s, NHCONH, 1H), 8.10 (s, Ar, 1H), 7.37 (d, Ar, 1H J = 8,01), 7.30 (d, Ar, 1H, J = 7, 86), 7,02 (t, Ar, 1H, J = 8, 01), 6.17 (s, NHCONH, 1H), 3.68 (m, 2H), 3.53 (q, 2H, J = 5,85) NMR 13c (Acetone): 158. 0,143. 0,131. 1,127. 4,125. 0,118. 0,102. 8, 44.7, 42.4.

EXAMPLE 32: Preparation of 1- (2-Chloro-ethyl)-3- [3- (7-hydroi. y-heptyl)-phenyl]- urea (29) 3-iodonitrobenzene (1.0 Eq, 3.655 mmol, 0.910 g), Pd/C 10% (0.02 Eq, 0.073 mmol, 0.078 g), PPh3 (0.08 Eq, 0.292 mmol, 0.077 g), CuI (0.04 Eq, 0.146 mmol, 0.028 g), K2CO3 (2.52 Eq, 9.212 mmol, 1.273 g), 1,2-DME (5 mL), H20 (5 mL) were mixed at 25 °C under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes and 6-Heptyn-l-ol (1.0 Eq, 3.655 mmol, 0.410 g) was added. The mixture was heated at 80 °C for 16 hours, cooled to room temperature. The organic solvents were removed in vacuo, and the product was purified by flash crhomatographie on silica gel: Hexane/AcOEt (75/25).

7- (3-nitrophenyl) hept-6-yn-1-ol (1.0 Eq, 0.276 mmol, 0.064 g) was dissolved in ethanol (10 mL) and placed in a hydrogenation bottle with 10% Pd/C (0.03 Eq, 0.009 mmol, 0.010 g). The bottle was filled with 38 psi of hydrogen and shaken for 4 h. The product was filtered through Celite, and the solvent was removed in vacuo. The resulting aniline was purified by flash crhomatography on silica gel: Hexane/AcOEt (70/30).

In a round bottom flask equipped with a dry tube filled with CaCl2, 7- (3-aminophenyl) heptan-l- ol (1.0 Eq, 0.060 mmol, 0.012 g) was dissolved in dichloromethane (10 mL). 2-chloroethyl isocyanate (1.1 Eq, 0.067 mmol, 0.007 g) was added and the mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by flash chromatography on silica gel: Dichloromethane/MeOH (98/2).

NMR IH (Acetone) 8 : 8.01 (s, NHCONH, 1H), 7.29 (m, Ar, 3H), 6. 78 (m, Ar, 1H), 6.09 (s, NHCONH, 1H), 3.67 (m, 2H), 3.52 (m, 4H), 2.87 (m, 4H), 2.54 (m, 2H), 1.35 (m, 6H).

EXAMPLE 33: Preparation of 1- (2-Chloro-ethyl)-3- [3- (5-hydroxy-pentyl)-phenyl]-urea (30) 3-iodonitrobenzene (1.0 Eq, 8.010 mmol, 1.995 g), 4-Pentyn-l-ol (2.67 Eq, 21.400 mmol, 1.800 g), Pd/C 10% (0.02 Eq, 0.160 mmol, 0.170 g), PPh3 (0.08 Eq, 0.630 mmol, 0.166 g), Cul (0.04 Eq, 0.320 mmol, 0.061 g), K2CO3 (2.52 Eq, 20.200 mmol, 2.790 g), 1.2-DME (10 mL), H20 (10 mL) were mixed as described in Example 32. The procedure was similar. The purification technique was flash chromatography on silica gel: Hexane/AcOEt (70/30).

5-(3-nitrophenyl)pent-4-yn-1-ol (1.0 Eq, 0. 970 mmol, 0.200 g) in Pd/C 10% (0.05 Eq, 0.047 mmol, 0.050 g), H2 (38 PSI), ETOH (10 mL) was hydrogenated as described in Example 32 to yield 5-(3-aminophenyl)pentan-1-ol. The product was purified by flash chromatography on silica gel: Hexane/AcOEt (70/30).

2-Chloroethyl isocyanate (1.2 Eq, 0.600 mmol, 0.063 g) and 5- (3-aminophenyl) pentan-1-ol (1.0 Eq, 0.500 mmol, 0.090 g) were mixed in dichloromethane (10 mL) as described in Example 31.

The product was purified by flash chromatography on silica gel: dichloromethane/MeOH (98/ 2). Yield =20% 'H NMR (CDC13 and MD30D) 8 : 7.03 (m, Ar, 3H), 6.70 (t, Ar, 1H, J = 6.54) 3. 89 (s, 3H), 4.03 (t, 2H, J = 6.54), 3.45 (m, 6H), 2.45 (t, 2H, J = 7.56), 1.45 (m, 4H), 1.23 (m, 2H). 13C NMR (CDC13 and MD30D) 8 : 156.3, 143.4, 138.9, 128.6, 122. 8, 119.3, 116.6, 62.1, 44.2, 41.6, 35.7, 32.2, 30. 8, 25.2. EXAMPLE 34: Preparation of 1- (2-Chloro-ethyl)-3- [3- (6-hydroxy-hexyl)-phenyl]-urea (31) 3-iodonitrobenzene (1.0 Eq, 8.010 mmol, 1.995 g) was mixed with 5-Hexyn-l-ol (2. 58 Eq, 20.670 mmol, 2.030 g), Pd/C 10% (0.02 Eq, 0.160 mmol, 0.170 g), PPh3 (0.08 Eq, 0.630 mmol, 0.166 g), Cul (0.04 Eq, 0.320 mmol, 0.061 g), K2C03 (2.52 Eq, 20.200 mmol, 2.790 g), 1,2- DME (10 mL), H2O (10 mL) as described in Example 32.

6- (3-nitrophenyl) hex-5-yn-l-ol (1.0 Eq, 0. 958 mmol, 0.210 g) was hydrogenated with Pd/C 10% (0.05 Eq, 0.047 mmol, 0.050 g), H2 (38 PSI), ETOH (10 mL) as described in Example 32.

6- (3-aminophenyl) hexan-l-ol (1.0 Eq, 0.671 mmol, 0.147 g) was mixed with 2-chloroethyl isocyanate (1. 1 Eq, 0.739 mmol, 0.078 g) in dichloromethane (10 mL) as described in Example 31. The product was purified by flash chromatography on silica gel: Dichloromethane/MeOH (97/3). Yield = 42% IH NMR (Acetone) 5 : 8. 17 (s, NHCONH, 1H), 7.20 (m, Ar, 3H), 6.79 (d, Ar, 1H J = 6.42), 6.25 (s, NHCONH, 1H), 3.60 (m, 6H), 2.51 (t, 2H, J = 6,87), 1.48 (m, 8H). 13C NMR (Acetone) 8 : 156.2, 144.1, 141.0, 129.2, 122.7, 119.2, 116.6, 62.4, 44.8, 42.5, 36.5, 33.6, 32.1, 29.7, 26.4.

EXAMPLE 35: Preparation of 1- (2-Chloro-ethyl)-3- [3- (4-hydroxy-butyl)-phenyl]-urea (32) 3-iodonitrobenzene (1.0 Eq, 8. 010 mmol, 1.995 g) was mixed with 3-Butyn-l-ol (2.58 Eq, 20. 670 mmol, 1.449 g), Pd/C 10% (0.02 Eq, 0.160 mmol, 0.170 g), PPh3 (0.08 Eq, 0.630 mmol, 0.166 g), CuI (0.04 Eq, 0.320 mmol, 0.061 g), K2CO3 (2.52 Eq, 20.200 mmol, 2.790 g), 1,2- DME (10 mL), H20 (10 mL) as described in Example 32.

4- (3-nitrophenyl) but-3-yn-l-ol (1.0 Eq, 1.046 mmol, 0.200 g) was hydrogenated with Pd/C 10% (0.05 Eq, 0.047 mmol, 0.050 g), H2 (38 PSI), ETOH (10 mL) as described in Example 32.

4- (3-aminophenyl) butan-l-ol (1.0 Eq, 0.726 mmol, 0.120 g) was mixed with 2-chloroethyl isocyanate (1.2 Eq, 0.870 mmol, 0.091 g) in dichloromethane (10 mL) as described in Example 31. The product was purified by flash chromatography on silica gel: Hexane/AcOEt (65/35).

Yield = 18% 'H NMR (Acetone) 5 : 8.17 (s, NHCONH, 1H), 7.20 (m, Ar, 3H), 6.79 (d, Ar, 1H J = 6.42), 6.25 (s, NHCONH, 1H), 3.60 (m, 6H), 2.51 (t, 2H, J = 6,87), 1.48 (m, 8H). 13C NMR (Acetone) b : 156.2, 144.1, 141.0, 129.2, 122.7, 119. 2, 116. 6,62. 4,44. 8,42. 5,36. 5,33. 6,32. 1,29. 7,26. 4.

EXAMPLE 36: Preparation of 1- (2-Chloro-ethyl)-3- [3- (3-hydroxy-propyl)-phenyl]-urea (33) To a mixture of 3-iodonitrobenzene (7 g, 28. 1 mmoles), K2CO3 (11.63 g, 84.3 mmoles) in 80 mL 1,2-DME/water (1: 1) were added successively Cul (229.50 mg, 1.21 mmoles), PPh3 (591.20 mg, 2.25 mmoles), Pd/C 10% (598.0 mg, 0.562 mmoles). The mixture was stirred at room temperature for 1 hour. 4-butyn-1-ol (5.90 g, 84. 30 mmoles) was added, then the mixture was heated to reflux overnight. After cooling, the mixture was filtered on Celite and the organic layer was evaporated under reduced pressure. Tha aqueous layer was acidified with concentrated Chlorhydric acid and extracted with AcOEt. The organic layer were washed with brine, dried, filtered and evaporated. Purified by flash chrmatography on silica gel AcOEt/Hexanes (35: 65).

Yield: 81% 'H NMR (CDC13, 300 MHz) b : 8. 29 (s, Ar, 1H), 8. 17 (m, Ar, 1H), 7.74 (d, Ar, 1H, J = 8Hz), 7.51 (t, Ar, 1H, J = 8Hz), 4.53 (d, 2H, J = 6Hz).

A mixture of 3- (3-nitrophenyl)-prop-2-yn-l-ol (100 mg, 0.564 mmoles), Pd/C 10% (10 mg, 0.094 mmoles) was hydrogenated under 38 psi overnight. The mixture was filtered on Celite and the filtrate was evaporated to dryness. Purified by flash chrmatography on silica gel AcOEt/Hexanes (25: 75). Yield: 99% 'H NMR (CDC13, 300 MHz) 8 : 7. 08 (t, Ar, 1H, J = 8. 0Hz), 6.61 (d, Ar, 1H, J = 7. 5Hz), 6.53 (m, Ar, 2H), 3.67 (t, 2H, J = 6. 5Hz), 2.84 (s, 3H), 2.62 (t, 2H, J = 8. OHz), 1.87 (m, 2H).

3- (3-aminophenyl) propan-l-ol was then reacted with 2-chloroethylisocyanate as described in examples 1-12 to obtain desired product. Purified by flash chromatography on silica gel EtOH/CH2Cl2 (2: 98). Yield: 28% 'H NMR (Acetone) 8 : 8. 00 (s, NHCONH, 1H), 7.36 (s, Ar ; 1H), 7.29 (d, Ar, 1H J = 8. 01), 7.13 (t, Ar, 1H J = 7. 83), 6. 80 (d, Ar, 1H J = 7.32), 6.09 (s, NHCONH, 1H), 3.68 (m, 2H), 3.55 (m, 4H), 2.63 (t, 2H, J = 7.62), 1.79 (m, 2H). 13C NMR (Acetone) 8 : 155.9, 143.8, 141.2, 129.2, 122.6, 119.1, 116.5, 61.7, 42.6, 42.4, 35. 3, 32. 8.

EXAMPLE 37: Preparation of 1- (3-Sromo-phenyl)-3- (2-chloro-ethyl)-urea (34) 3-bromobenzenamine (1.0 Eq, 1.740 mmol, 0.300 g) was mixed with 2-chlroethyl isocyanate (1,2 Eq, 2.090 mmol, 0.220 g) in dichloromethane (10 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (98/2). Yield = 100% 'H NMR (Acetone) 6 : 8.26 (s, NHCONH, 1H), 7.93 (m, Ar, 1H), 7.31 (m, Ar, 1H), 7.15 (m, Ar, 2H), 6.20 (s, NHCONH, 1H), 3.67 (m, 2H), 3.52 (q, 2H, J = 2, 11). 13C NMR (Acetone) 8 : 155.6, 142.9, 131.0, 125.0, 122.7, 121.3, 117.4, 44.7, 42.5.

EXAMPLE 38: Preparation of 1- (2-Chloro-ethyl)-3- (3-chloro-phenyl)-urea (35) 3-chlorobenzenamine (1.0 Eq, 2.350 mmol, 0.300 g) was mixed with 2-chlroethyl isocyanate (1,2 Eq, 2.820 mmol, 0.298 g) in dichloromethane (15 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (98/2). Yield = 99%.

'H NMR (Acetone) b : 8.28 (s, NHCONH, 1H), 7.76 (m, Ar, 1H), 7.24 (m, Ar, 2H), 6.95 (m, Ar, 1H), 6.21 (s, NHCONH, 1H), 3.68 (m, 2H), 3.54 (q, 2H, J = 2,13). 13C NMR (Acetone) 8 : 155. 6, 142.7, 134.6, 130.7, 122.0, 118.6, 117.0, 44.6, 42.4.

EXAMPLE 39: Preparation of (36) 3-aminophenol (1.0 Eq, 2.740 mmol, 0.300 g) was mixed with 2-chloroethyl isocyanate (1.2 Eq, 3.300 mmol, 0.348 g) in THF (4 mL) and dichloromethane (10 mL) as described in Example 31.

The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (99/1). Yield = 96%.

'H NMR (Acetone) 8 : 8.57 (s, Ph, 1H), 8.23 (s, NHCONH, 1H), 7.25 (s, NHCONH, 1H), 7.06 (m, Ar, 1H), 6. 80 (d, Ar, 1H, J = 7.71), 6. 50 (m, Ar, 1H), 6. 35 (m, Ar, 1H), 3.64 (m, 2H), 3. 55 (q, 2H, J = 5.73). 13C NMR (Acetone) 8 : 158.7, 156. 8, 141.7, 130.4, 110.9, 110.3, 107.0, 44.8, 42.6.

EXAMPLE 40: Preparation of Acetic acid 3- [3- (2-chloro-ethyl)-ureido]-phenyl ester (37) 1- (2-chloroethyl)-3- (3-hydroxyphenyl) urea (IMO-365) was obtained as described in example 39.

1- (2-chloroethyl)-3- (3-hydroxyphenyl) urea (1.0 Eq, 0.326 mmol, 0.070 g) was mixed with triethylamine (3.0 Eq, 0.978 mmol, 0.099 g), acetic anhydride (3.0 Eq, 0.978 mmol, 0.100 g) and 4-pyrrolidinopyridine (0.02 Eq, 0.007 mmol, 0.001 g) at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel, Dichloromethane/ MeOH (98/2). Yield = 27% 'H NMR (Acetone) 8 : 8. 32 (s, NHCONH, 1H), 7. 48 (s, Ar, 1H), 7.20 (m, Ar, 2H), 6.68 (m, Ar, 1H), 6.22 (s, NHCONH, 1H), 3.67 (m, 2H), 3.55 (q, 2H, J = 5. 82). 13C NMR (Acetone) 8 : 169.5, 155.4, 152.2, 142.4, 129. 8, 115.8, 115.5, 112.3, 44.7, 42.4, 20.8.

EXAMPLE 41: Preparation of 1-(2-Chloro-ethyl)-3-(3-hydroxymethyl-phenyl)-urea (38) 3-nitrobenzylalcohol (1.0 Eq, 1.959 mmol, 0.300 g) was reduced on SnCl2. 2H20 (6.0 Eq, 11.750 mmol, 2.650 g) and EtOH (20 mL). (3-aminophenyl) methanol (1.0 Eq, 1.620 mmol, 0.200 g) was mixed with 2-chlroethyl isocyanate (1.2 Eq, 1.940 mmol, 0.206 g) in THF (20 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (98/2). Yield = 56% 'H NMR (Acetone) 8 : 8.09 (s, NHCONH, 1H), 7.46 (s, Ar, 1H), 7.37 (m, Ar, 1H), 7.18 (t, Ar, 1H, J = 7.86), 6.95 (d, Ar, 1H, J = 7, 35), 6.15 (s, NHCONH, 1H), 4.57 (s, 2H), 4.23 (s, OH, 1H), 3.67 (m, 2H), 3.53 (q, 2H, J = 6,00). 13C NMR (Acetone) 8 : 156.0, 143.9, 141.0, 129.2, 120.7, 117.6, 117.3, 64.6, 44.8, 42.4.

EXAMPLE 42: Preparation of Acetic acid 5- {3- [3- (2-chloro-ethyl)-ureido]-phenyl}-pentyl ester (39) 3-iodonitrobenzene (1.0 Eq, 8.010 mmol, 1.995 g) was mixed with 4-pentyn-1-ol (2.67 Eq, 21.400 mmol, 1. 800 g), Pd/C 10% (0.02 Eq, 0.160 mmol, 0.170 g), PPh3 (0.08 Eq, 0.630 mmol, 0.166 g), Cul (0.04 Eq, 0.320 mmol, 0.061 g), K2C03 (2.52 Eq, 20.200 mmol, 2.790 g), 1,2- DME (10 mL), H2O (10 mL) as described in Example 32. The solvent was removed and the residue was purified by flash chromatography on silica gel: hexane/AcOEt (70/30).

5- (3-nitrophenyl) pent-4-yn-l-ol (1.0 Eq, 1.460 mmol, 0.300 g) was mixed with triethylamine (3.0 Eq, 4. 380 mmol, 0.443 g), acetic anhydride (3.0 Eq, 4.380 mmol, 0.447 g) and 4- pyrrolidinopyridine (0.02 Eq, 0.029 mmol, 0.004 g) at room temperature. The solvent was removed and the residue was purified by flash chromatography on silica gel: hexane/AcOEt (75 /25).

5- (3-nitrophenyl) pent-4-ynyl acetate (1.0 Eq, 0. 978 mmol, 0.242 g) in Pd/C 10% (0.05 Eq, 0.047 mmol, 0.050 g), H2 (38 PSI) and EtOH (10 mL) was hydrogenated and purified as described in Example 32. The solvent was removed and the product was purified by flash chromatography on silica gel: hexane/AcOEt (75/25).

5- (3-aminophenyl) pentyl acetate (1.0 Eq, 0.704 mmol, 0.156 g) was mixed with 2-chlroethyl isocyanate (1.2 Eq, 0.808 mmol, 0. 085 g) in dichloromethane (15 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/AcOEt (70/30). Yield = 54% 'H NMR (CDC13) 5 : 7.81 (s, NHCONH, 1H), 7.09 (m, Ar, 3H), 6. 80 (d, Ar, 1H, J = 7.32), 6.07 (s, NHCONH, 1H), 3. 48 (m, 4H), 2.48 (t, 2H, J= 7.68), 2.02 (s, Ac, 3H), 1.56 (m, 4H), 1.31 (m, 2H). 13C NMR (CDC13) 8 : 171.5, 156.4, 143.5, 138. 8,128. 9,123. 3,120. 1,117. 5,64. 5,44. 3, 41.9, 35.7, 30.9, 28.4, 25.5, 21.0.

EXAMPLE 43: Preparation of Acetic acid 4- {3- [3- (2-chloro-ethyl)-ureido]-phenyl}-butyl ester (40) 3-iodonitrobenzene (1.0 Eq, 8.010 mmol, 1.995 g) was mixed with 3-Butyn-l-ol (2.58 Eq, 20.670 mmol, 1.449 g), Pd/C 10% (0.02 Eq, 0.160 mmol, 0.170 g), PPh3 (0.08 Eq, 0.630 mmol, 0.166 g), Cul (0.04 Eq, 0.320 mmol, 0.061 g), K2C03 (2.52 Eq, 20.200 mmol, 2.790 g), 1,2- DME (10 mL), H20 (10 mL) as described in Example 32. The solvent was removed and the residue was purified by flash chromatography on silica gel: Hexane/AcOEt (65/35).

4- (3-nitrophenyl) but-3-yn-l-ol (1.0 Eq, 1.046 mmol, 0.200 g) was mixed with triethylamine (3.0 Eq, 3.1380 mmol, 0.318 g), acetic anhydride (3.0 Eq, 3.138 mmol, 0.320 g), and 4- pyrrolidinopyridine (0.02 Eq, 0.021 mmol, 0.003 g) at room temperature. The solvent was removed.

4- (3-nitrophenyl) but-3-ynyl acetate (1.0 Eq, 0. 988 mmol, 0.231 g) in Pd/C 10% (0.05 Eq, 0.047 mmol, 0.050 g), H2 (38 PSI), ETOH (10 mL) was hydrogenated and purified as described in Example 32. The solvent was removed and the product was purified by flash chromatography on silica gel: hexane/AcOEt (75/25).

4- (3-aminophenyl) butyl acetate (1.0 Eq, 0.471 mmol, 0. 098 g) was mixed with 2-chlroethyl isocyanate (1.2 Eq, 0.539 mmol, 0.057 g) in dichloromethane (15 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: hexane/AcOEt (65/35). Yield = 48% 'H NMR (CDC13) 8 : 7.69 (s, NHCONH, 1H), 7.11 (m, Ar, 3H), 6.83 (d, Ar, 1H, J = 7.32), 6.07 (s, NHCONH, 1H), 4.03 (t, 2H, J = 6.57), 3.53 (m, 4H), 2.52 (t, 2H, J= 7. 89), 2.03 (s, Ac, 3H), 1.60 (m, 4H). 13C NMR (CDC13) 8 : 171.5, 156.3, 143.2, 138. 7,129. 0,123. 5,120. 3,117. 8, 64.4, 44.4, 41.9, 35.4, 28.1, 27.5, 21.0.

EXAMPLE 44: Preparation of Acetic acid 3- [3- (2-chloro-ethyl)-ureido]-benzyl ester (41) 3-nitrobenzylalcohol (1.0 Eq, 1.959 mmol, 0.300 g) was mixed with triethylamine (3.0 Eq, 5. 880 mmol, 0.595 g), acetic anhydride (3.0 Eq, 5.880 mmol, 0.600 g) and 4-pyrrolidinopyridine (0.02 Eq, 0.039 mmol, 0.006 g) at room temperature. The solvent was removed and the product was purified by flash chromatography on silica gel: hexane/AcOEt (75/25).

3-nitrobenzyl acetate (1.0 Eq, 0.649 mmol, 0.127 g) was reduced on SnC12. 2Hz0 (6.0 Eq, 3.890 mmol, 0.879 g) and EtOH (20 mL). The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (95/5). 2- (3-aminophenyl) ethyl acetate (1.0 Eq, 0.352 mmol, 0. 058 g) was mixed with 2-chlroethyl isocyanate (1,2 Eq, 0.422 mmol, 0.045 g) in dichloromethane (10 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (95/5). Yield =31% 'H NMR (CDC13) 8 : 7.79 (s, NHCONH, 1H), 7.23 (m, Ar, 3H), 6.98 (m, Ar, 1H), 6. 08 (s, NHCONH, 1H), 4.98 (s, 2H), 3.53 (m, 4H), 2.05 (s, Ac, 3H). 13C NMR (CDC13) 171.2, 156.2, 139.0, 136.9, 129.3, 122.9, 119.9, 119. 8, 66.1, 44.4, 41.9, 21.0.

EXAMPLE 45: Preparation of Acetic acid 3- {3- [3- (2-chloro-ethyl)-ureido]-phenyl}-propyl ester (42) To a mixture of 3-iodonitrobenzene (1 g, 4.56 mmoles), K2C03 (1.57 g, 11.4 mmoles) in 30 mL 1.2-DME/water (1: 1) were added successively Cul (34.78 mg, 0.18 mmoles), PPh3 (95.80 mg, 0.36 mmoles), Pd/C 10% (97.05 mg, 0.09 mmoles). The mixture was stirred at room temperature for 1 hour. Propargyl alcohol (807 mg, 14.40 mmoles) was added, then the mixture was heated to reflux overnight. After cooling, the mixture was filtered on Celite and the organic layer was evaporated under reduced pressure. Tha aqueous layer was acidified with concentrated Chlorhydric acid and extracted with AcOEt. The combined organic layers were washed with brine, dried, filtered and evaporated. Purified by flash chromatography on silica gel CH2Cl2/EtOH (95: 5). Yield: 81% 'H NMR (CDC13, 300 MHz) 8 : 8.29 (s, Ar, 1H), 8. 17 (m, Ar, 1H), 7.74 (d, Ar, 1H, J = 8Hz), 7.51 (t, Ar, 1H, J = 8Hz), 4.53 (d, 2H, J = 6Hz).

To an ice-cold 3- (3-nitrophenyl)-prop-2-yn-l-ol (150 mg, 0.85 mmoles) in diethylether (10 mL) were added acetic anhydride (254.23 mg, 2.54 mmoles), triethylamine (256.54 mg, 2.54 mmoles), 4-pyrrolidinopyridine (2.52 mg, 0.017 mmoles) and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by saturated solution of Na2C03 and the mixture was extracted with AcOEt. The extracts were washed with brine, dried and evaporated.

Purified by flash chromatography on silica gel AcOEt/Hexanes (8: 2). Yield: 99% 'H NMR (CDC13, 300 MHz) b : 8. 24 (s, Ar, 1H), 8.14 (d, Ar, 1H, J = 8. 5Hz), 7.71 (d, Ar, 1H, J = 7. 5Hz), 7. 48 (t, Ar, 1H, J= 8Hz), 4. 88 (s, 2H), 2.12 (s, 3H).

A mixture of acetic acid 3- (3-nitrophenyl)-prop-2-ynyl ester (100 mg, 0. 48 mmoles), Pd/C 10% (10 mg, 0.094 mmoles) in 30 mL of dry ethanol was hydrogenated under 38 psi overnight. The mixture was filtered on Celite and the filtrate was evaporated to dryness. Purified by flash chromatography on silica gel AcOEt/Hexanes (25: 75). Yield: 81% 'H NMR (CDC13,300 MHz) 5 : 7.08 (m, Ar, 1H), 6.59 (d, Ar, 1H, J = 7. 5Hz), 6.53 (m, Ar, 2H), 4.09 (t, 2H, J = 6. 5Hz), 3.66 (s, 2H), 2.60 (t, 2H, J = 8Hz), 2.06 (s, 3H), 1.93 (m, 2H).

Acetic acid 3- (3-aminophenyl)-prop-2-ynyl ester was then reacted with 2-chloroethylisocyanate as described in examples 1-12 to obtain desired product. Purified by flash chromatography on silica gel AcOEt/CH2Cl2 (2: 8). Yield: 93% 'H NMR (CDC13) b : 7.51 (s, NHCONH, 1H), 7.11 (m, Ar, 3H), 6. 98 (m, Ar, 1H), 6.84 (d, Ar, 1H, J = 7.38) 5.94 (s, NHCONH, 1H), 4.03 (t, 2H, J = 6.54), 3.55 (m, 4H), 2.59 (t, 2H, J = 7.92), 2.04 (s, Ac, 3H), 1. 88 (m, 2H) NMR. 13C (CDC13) 8 : 171.5, 156.2, 142.4, 138.7, 129.2, 123.6, 120.5, 118.1, 63.9, 44.5, 41.9, 32.1, 30.0, 21.0.

EXAMPLE 46: Preparation of 1- (2-Chloro-ethyl)-3- [3- (2-hydroxy-ethyl)-phenyl]-urea (43) 2- (3-nitrophenyl) ethan-l-ol (1.0 Eq, 1.200 mmol, 0.200 g) was reduced on SnC12. 2H20 (6.0 Eq, 7.200 mmol, 1.625 g) and EtOH (20 mL). The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (95/5).

2- (3-aminophenyl) ethan-l-ol (1.0 Eq, 0. 437mmol, 0.060 g) was mixed with 2-chloroethyl isocyanate (1.2 Eq, 0.524 mmol, 0.055 g), in dichloromethane (15 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: Ether/Hexane (90/10). Yield = 20% 'H NMR (Acetone-d6) 8 : 8.08 (brs, NH, 1H), 7.33 (m, Ar, 2H), 7.13 (m, Ar, 1H), 6.82 (d, Ar, 1H, J = 7.44), 6.15 (brs, NH, 1H), 3.69 (m, 4H), 3.53 (m, 2H), 2.93 (s, OH, 1H), 2.74 (t, 2H, J = 7.02). 13C NMR (Acetone-d6) b : 177.3, 155.9, 140.9, 129.2, 123.1, 119.5, 116.7, 63.7, 44. 8, 42.4, 40.3.

EXAMPLE 47: Preparation of Acetic acid 2- {3- [3- (2-chloro-ethyl)-ureido]-phenyl}-ethyl ester (44) 2- (3-nitrophenyl) ethan-1-ol (1.0 Eq, 1.495 mmol, 0.250 g) was mixed with triethylamine (3.0 Eq, 4. 485 mmol, 0.454 g), acetic anhydride (3.0 Eq, 4.485 mmol, 0.457 g) and 4- pyrrolidinopyridine (0.02 Eq, 0.030 mmol, 0.004 g) ) at room temperature. The solvent was removed and the product was purified by flash chromatography on silica gel: Hexane/AcOEt (75/25).

3-nitrophenethyl acetate (1.0 Eq, 0.871 mmol, 0.182 g) in Pd/C 10% (0.05 Eq, 0.047 mmol, 0.050 g), H2 (38 PSI), and ETOH (10 mL) was hydrogenated and purified as described in Example 32. The solvent was removed and the product was purified by flash chromatography on silica gel: hexane/AcOEt (60/40).

2- (3-aminophenyl) ethyl acetate (1.0 Eq, 0.726 mmol, 0.130 g) was mixed with 2-chloroethyl isocyanate (1,2 Eq, 0. 871 mmol, 0.092 g), in dichloromethane (15 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (98/2). Yield = 87% 'H NMR (Acetone) 8 : 7.90 (s, NHCONH, 1H), 7.11 (m, Ar, 3H), 6. 83 (d, Ar, 1H, J = 6.63), 6.21 (s, NHCONH, 1H), 4.18 (t, 2H, J = 6.96), 3.50 (m, 4H), 2.79 (t, 2H, J = 6.99), 1.99 (s, Ac, 3H) NMR 13C (Acetone) 8 : 171.4, 156.5, 138. 9,138. 8, 129.1, 123.8, 120.5, 118.4, 64. 8, 44.3, 41.9, 34.9, 21.0.

EXAMPLE 48: Preparation of Acetic acid 6-13- [3- (2-chloro-ethyl)-ureido]-phenyl}-hexyl ester (45) 3-iodonitrobenzene (1.0 Eq, 8.010 mmol, 1.995 g) was mixed with 5-Hexyn-l-ol (2.58 Eq, 20.670 mmol, 2.030 g), Pd/C 10% (0.02 Eq, 0.160 mmol, 0.170 g), PPh3 (0.08 Eq, 0.630 mmol, 0.166 g), Cul (0.04 Eq, 0.320 mmol, 0.061 g), K2CO3 (2.52 Eq, 20.200 mmol, 2.790 g), 1,2- DME (10 mL), H20 (10 mL) under a nitrogen atmosphere. The reaction was carried out as described in Example 32. The organic portion was purified by flash chromatography on silica gel : Hexane/AcOEt (75/25).

6- (3-nitrophenyl) hex-5-yn-l-ol (1.0 Eq, 1.140 mmol, 0.255 g) was mixed with triethylamine (3.0 Eq, 3.420 mmol, 0.346 g), acetic anhydride (3.0 Eq, 3.420 mmol, 0.349 g) and 4- pyrrolidinopyridine (0.02 Eq, 0.023 mmol, 0.003 g) ) at room temperature. The solvent was removed and the product was purified by flash chromatography on silica gel: Hexane/AcOEt (75/25).

6- (3-aminophenyl) hex-5-ynyl acetate (1.0 Eq, 0.643 mmol, 0.168 g) in Pd/C 10% (0.07 Eq, 0.047 mmol, 0.050 g), H2 (38 PSI), and ETOH (10 mL) was hydrogenated and purified as described in Example 32. The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (99/1).

6- (3-aminophenyl) hexyl acetate (1.0 Eq, 0.348 mmol, 0.082 g) was mixed with 2-chloroethyl isocyanate (1.2 Eq, 0.418 mmol, 0.0446 g), in dichloromethane (15 mL) as described in Example 31. The solvent was removed and the product was purified by flash chromatography on silica gel: dichloromethane/MeOH (98/2). Yield = 64% 'H NMR (Acetone) 8 : 7. 80 (s, NHCONH, 1H), 7.12 (m, Ar, 3H), 6.84 (m, Ar, 1H), 6.15 (s, NHCONH, 1H), 4.05 (m, 2H), 3.51 (m, 4H), 2.42 (m, 2H), 2.08 (s, Ac, 3H) 1.56 (m, 4H), 1.32 (m, 4H). 13C NMR (Acetone) 8 : 171.7, 156.4, 143.8, 138. 8, 128. 9,123. 4,120. 2,117. 6,64. 7, 44.4, 41.9, 35. 8,31. 2,28. 9,28. 8,25. 7, 21. 0.

EXAMPLE 49: Preparation ofl- (2-ChIoro-ethyI)-3- [3- (3-methoxy-propy !)-phenyl]-urea (46) NaH (60%) (97.40 mg, 4.06 mmoles) was suspended in dry THF (8 mL) and 3- (3-nitrophenyl)- pent-4-yn-1-ol (see synthesis of IM0-371) (200 mg, 0.98 mmoles) in dry THF (3 Ml) was added dropwide at 0°C. The mixture was stirred for 15 minutes at 0°C. The MeI (332.5 mg, 2.34 mmoles) was added dropwise and the mixture was stirred at room temperature for 3 hours.

Saturated solution of NaHC03 (10 mL) and MeOH (10 mL) were added. The mixture was extracted with AcOEt, dried, filtered and evaporated to dryness. Purified by flash chromatography on silica gel AcOEt. Yield: 58% 'H NMR (CDC13, 300 MHz) 8 : 8. 17 (s, 1H), 8. 07 (d, 1H, J = 8Hz), 7.64 (d, 1H, J = 7. 5Hz), 7.42 (m, 1H), 3.49 (t, 2H, J = 6Hz), 3.34 (s, 3H), 2.49 (t, 2H, J = 6Hz), 1. 86 (t, 2H, J = 6Hz), 1.22 (m, 2H).

A mixture of 1- (5-methoxypent-1-ynyl)-3-nitrobenzene (100 mg, 0.425 mmoles), Pd/C 10% (10 mg, 0.094 mmoles), dry ehtanol was hydrogenated under 38 psi overnight. The mixture was filtered on Celite and the filtrate was evaporated to dryness. Purified by flash chrmatography on silica gel AcOEt. Yield: 85% 'H NMR (DMSO-d6, 300MHz) 5 : 7.17 (m, 1H), 6.55 (m, 3H), 3.37 (m, 5H), 2.51 (m, 2H), 1.61 (m, 2H).

3- (5-methoxypentyl) phenylamine was then reacted with 2-chloroethylisocyanate as described in examples 1-12 to obtain desired product. Purified by flash chromatography on silica gel AcOEt.

Yield: 87% 'H NMR (CDC13,300 MHz) 8 : 8, 18 (brs, NH, 1H), 7,14 (m, 3H), 6,86 (d, Ar, 1H, J = 7, 2Hz), 3,57 (m, 4H), 3,33 (m, 4H), 2,55 (t, 2H, J = 7Hz), 1,59 (m, 4H).

EXAMPLE 50: Preparation of (47) 1- (3-pentyl-phenyl)-3- (2-chloro-ethyl)-urea (47) To a mixture of 3-iodonitrobenzene (1 g, 4.01 mmoles), K2CO3 (1.38 g, 10.0 mmoles) in 20 mL 1,2-DME/water (1: 1) were added successively CuI (30.54 mg, 0.16 mmoles), PPh3 (84.14 mg, 0.32 mmoles), Pd/C 10% (85.35 mg, 0.080 mmoles). The mixture was stirred at room temperature for 1 hour. 1-pentyne (725.40 mg, 84.30 mmoles) was added, then the mixture was heated to reflux overnight. After cooling, the mixture was filtered on Celite and the organic layer was evaporated under reduced pressure. Tha aqueous layer was acidified with concentrated Chlorhydric acid and extracted with AcOEt. The organic layer were washed with brine, dried, filtered and evaporated. Purified by flash chrmatography on silica gel Hexanes/AcOEt (60: 40).

Yield: 58% 'H NMR (CDC13, 300 MHz) 5 : 8.17 (s, 1H), 8.06 (d, 1H, J = 8Hz), 7.63 (d, 1H, J = 7. 5Hz), 7.41 (m, 1H), 2.37 (m, 2H), 1.02 (m, 2H).

A mixture of l-nitro-3-pentynylbenzene (100 mg, 0.523 mmoles), Pd/C 10% (10 mg, 0.094 mmoles) in 30 mL of dry ethanol was hydrogenated under 38 psi overnight. The mixture was filtered on Celite and the filtrate was evaporated to dryness. Purified by flash chrmatography on silica gel CH2Cl2/EtOH (95: 5). Yield: 97% 'H NMR (DMSO-d6, 300MHz) 6 : 7.09 (m, 1H), 6.63 (d, 1H, J = 7. 5Hz), 6.53 (m, 2H), 3.55 (brs, 2H), 2.54 (m, 2H), 1.63 (m, 2H), 1.37 (m, 4H), 0.93 (m, 2H).

3-pentylphenylamine was then reacted with 2-chloroethylisocyanate as described in examples 1- 12 to obtain desired product. Purified by flash chrmatography on silica gel CH2Cl2/EtOH (95: 5). Yield: 91% 'H NMR (CDC13, 300 MHz) 8 : 7,94 (brs, NH, 1H), 7,01 (m, Ar, 1H), 6,77 (brs, Nh, 1H), 3,47 (m, CH2, 8H), 2,45 (t, CH2,2H, J = 7), 1,21 (m, CH2, 4H).

EXAMPLE 51: Preparation of 5- {3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-pentanoic acid (48) To a mixture of 3-iodonitrobenzene (5 g, 20.3 mmoles), K2CO3 (7.03 g, 50.9 mmoles) in 80 mL 1,2-DME/water (1: 1) were added successively CuI (166.0 mg, 0. 87 mmoles), PPh3 (427.11 mg, 1.82 mmoles), Pd/C 10% (432.06 mg, 0.406 mmoles). The mixture was stirred at room temperature for 1 hour. 5-pentanoic acid (5.90 g, 84. 30 mmoles) was added, then the mixture was heated to reflux overnight. After cooling, the mixture was filtered on Celite and the organic layer was evaporated under reduced pressure. Tha aqueous layer was acidified with concentrated Chlorhydric acid and extracted with AcOEt. The organic layer were washed with brine, dried, filtered and evaporated.

Purified by flash chromatography on silica gel CH2Cl2/EtOH (95: 5). Yield: 45% 'H NMR (DMSO-d6,300 MHz) 8 : 12.39 (brs, 1H), 8. 19 (d, 1H, J = 8Hz), 8.13 (s, 1H), 7. 82 (d, 1H, J = 7. 5Hz), 7.66 (t, 1H, J = 8Hz), 2.63 (m, 4H).

A mixture of 5- (3-nitrophenyl)-pent-4-ynoic acid (100 mg, 0.456 mmoles), Pd/C 10% (10 mg, 0.094 mmoles) was hydrogenated under 38 psi overnight. The mixture was filtered on Celite and the filtrate was evaporated to dryness.

Purified by flash chromatography on silica gel EtOH/CH2Cl2 (2: 98). Yield: 57% IH NMR (DMSO-d6, 300 MHz) 8 : 7.08 (t, 1H, J = 8Hz), 6.61 (d, 1H, J = 7Hz), 6.54 (m, 2H), 6.17 (m, 2H), 2.56 (m, 2H), 2.36 (m, 2H), 1.67 (m, 4H).

5- (3-aminophenyl) pent-4-ynoic acid was then reacted with 2-chloroethylisocyanate as described in examples 1-12 to obtain desired product.

Purified by flash chromatography on silica gel EtOH/CH2Cl2 (5: 95). Yield: 37% IH NMR (Acetone-d6, 300MHz) 8 : 7.57 (brs, NH, 1H), 7.36 (m, Ar, 2H), 7.07 (m, Ar, 2H), 6.87 (d, Ar, 1H, J =, 0), 6.74 (brs, NH, 1H), 3.66 (m, CH2,4H), 3.46 (m, CH2, 4H), 2.59 (m, CH2, 2H), 1.63 (m, CH2, 2H).

EXAMPLE 52: Preparation of 5- {3- [3- (2-CMoro-ethyt)-ureido]-phenyI}-pentanoic acid ethyl ester (49) To a mixture of 3-iodonitrobenzene (5 g, 20.3 mmoles), K2CO3 (7.03 g, 50.9 mmoles) in 80 mL 1,2-DME/water (1: 1) were added successively Cul (166.0 mg, 0. 87 mmoles), PPh3 (427.11 mg, 1.82 mmoles), Pd/C 10% (432.06 mg, 0.406 mmoles). The mixture was stirred at room temperature for 1 hour. 5-pentanoic acid (5.90 g, 84.30 mmoles) was added, then the mixture was heated to reflux overnight. After cooling, the mixture was filtered on Celite and the organic layer was evaporated under reduced pressure. Tha aqueous layer was acidified with concentrated Chlorhydric acid and extracted with AcOEt. The organic layer were washed with brine, dried, filtered and evaporated.

Purified by flash chromatography on silica gel CH2Cl2/EtOH (95: 5). Yield: 45% 'H NMR (DMSO-d6, 300 MHz) 8 : 12.39 (brs, 1H), 8.19 (d, 1H, J = 8Hz), 8.13 (s, 1H), 7.82 (d, 1H, J = 7. 5Hz), 7.66 (t, 1H, J = 8Hz), 2.63 (m, 4H).

A mixture of 5- (3-nitrophenyl)-pent-4-ynoic acid (250 mg, 1.14 mmoles), 4 mL of dry EtOH, 8.5 mL of dry CHzClz and 8 mg of APTS was stirred at reflux for 12 hours. After cooling, the mixture was evaporated under reduce pressure. The residue was dissolved in saturated solution Na2CO3 and extracted with CH2C12. The organic layer was dried, filtered and evaporated to dryness. Purified by flash chromatography on silica gel CH2Cl2/EtOH (98: 2). Yield: 87% 'H NMR (CDC13, 300 MHz) 8 : 8.14 (s, 1H), 8.05 (d, 1H, J = 8Hz), 7.61 (d, 1H, J = 8Hz), 7.41 (m, 1H), 4.15 (q, 2H, J = 7Hz), 2.71 (m, 2H), 2.59 (m, 2H), 1.23 (q, 3H, J = 7Hz).

A mixture of 5-ethyl- (3-nitrophenyl)-pent-4-ynoic acid ester (100 mg, 0.404 mmoles), Pd/C 10% (10 mg, 0.094 mmoles) was hydrogenated under 38 psi overnight. The mixture was filtered on Celite and the filtrate was evaporated to dryness. Purified by flash chromatography on silica gel EtOH/CH2Cl2 (2: 98). Yield: 57% 'H NMR (CDC13, 300 MHz) 8 : 7.06 (m, 1H), 6.58 (d, 1H, J = 7. 5Hz), 6.50 (m, 2H), 4.11 (q, 2H, J = 7Hz), 2.54 (m, 2H), 2.32 (m, 2H), 1.64 (m, 4H), 1.26 (t, 3H, J = 7Hz).

5-ethyl- (3-aminophenyl) pent-4-ynoic acid ester was then reacted with 2-chloroethylisocyanate as described in examples 1-12 to obtain desired product. Purified by flash chromatography on silica gel EtOH/CH2Cl2 (5: 95). Yield: 77% 'H NMR (CDC13, 300 MHz) 8 : 7.23 (m, Ar, 3H), 6.89 (m, Ar, 2H), 5.63 (brs, NH, 1H), 4.31 (q, CH2,2H, J = 7,0), 2.56 (m, CH2,2H), 2.39 (m, CH2,2H), 1.81 (m, CH2,4H), 1.23 (t, CH3, 3H, J = 7. 0).

EXAMPLE 53: Preparation of 1- (2-Chloro-ethyl)-3- (3-cyanomethyl-phenyl)-urea (50) A mixture of nitrobenzene acetic acid (1 g, 5.52 mmoles), 1.66 mL of SOC12, 10 mL dry CHC13 was refluxed for 14 hours. CHC13 and excess thionyl chlorid were removed in vacuo, and the residue was evaporated twice with 25 mL of toluene to remove traces of thionyl chlorid. The residue was taken into 10 mL of toluene and 30 mL of cold concentrated ammonium hydroxyde were added. The white solid formed was collected and dried with etanol in vacuo. Yield: 79 %.

'H NMR (DMSO-d6, 300MHz) 8 : 8.14 (m, 2H), 7.71 (m, 2H), 7.06 (brs, 2H), 3.58 (s, 2H).

2- (3-nitrophenyl) acetamide was added with 10 mL of POC13 and the mixture was heated at reflux for 2 hours. After cooling, the mixture was poured into ice, basified with Na2CO3 and extracted with CH2C12. The organic layer was dried over Na2S04, filtered and evaporated.

Purified by flash chromatography on silica gel CH2C12. Yield : 41% 'H NMR (CDC13,300 MHz) 5 : 8. 14 (m, 2H), 7.69 (d, 1H, J = 8Hz), 7.56 (m, 1H), 3.88 (s, 2H).

A solution of 15 mL HBr 48% was cooled to 0°C. (430 mg, 2.65 mmoles) of 3-nitrobenzonitrile, (574 mg, 4. 85 mmoles) of Sn were added successively. The mixture was stirred at room temperature for 3 hours, then poured into ice. The solution was basified with Na2C03, extracted with CH2C12, dried, filtered and evaporated. Purified by flash chromatography on silica gel EtOH/CH2Cl2 (2: 98). Yield: 32% 'H NMR (DMSO-d6, 300MHz) 8 : 7.37 (m, 2H), 6.81 (m, 2H), 3.86 (s, 2H).

3-aminobenzonitrile was then reacted with 2-chloroethylisocyanate as described in examples 1- 12 to obtain desired product. Purified by flash chrmatography on silica gel EtOH/CH2Cl2 (5: 95). Yield: 78% 'H NMR (CDCl3, 300 MHz) 8 : 8.12 (brs, NH, 1H), 7.26 (m, Ar, 4H), 6.97 (brs, NH, 1H), 3.63 (m, CH2,6H).

EXAMPLE 54: Preparation of2- {3- [3- (2-Ch ! oro-ethyt)-ureido]-phenyI}-acetamide (51) A mixture of 2- (3-nitrophenyl) acetamide (510 mg, 2. 83 mmoles), Pd/C 10% (29 mg, 0.272 mmoles), dry ehtanol was hydrogenated under 38 psi overnight. The mixture was filtered on Celite and the filtrate was evaporated to dryness. The crude product was then reacted with 2- chloroethylisocyanate as described in examples 1-12 to obtain desired product. Purified by flash chromatography on silica gel EtOH/CH2CI2 (10: 90). bYield : 37%.

'H NMR (DMSO-d6, 300MHz) 5 : 8.17 (brs, NH, 1H), 8.12 (d, Ar, 1H, J = 8. 2Hz), 7.65 (m, Ar, 3H), 7.03 (brs, NH, 1H), 3. 68 (s, CH2,2H), 3.45 (m, CH2, 4H).

The following exemplary compounds were also prepared.

Example 55: 1- (2-Chloro-ethyl)-3-m-tolyl-urea (52): 'H NMR (CDC13) 8 : 7.20-7, 12 (m, Ar, 3H), 6.90 (d, Ar, 1H, J = 7), 3.57 (m, Ch2,4H), 2.29 (s, CH3, 3H). 13C NMR a : 156.1, 139.4, 138.0, 129.2, 125.1, 122.1, 118.4, 44.5, 42.1, 21,4.

Example 56: 1- (2-Chloro-ethyl)-3- (3-ethyl-phenyl)-urea (53); 'H NMR (Acetone-d6) 8 : 8.09 (brs, NH, 1H), 7.29 (m, Ar, 2H), 7.13 (t, Ar, 1H, J = 7.8), 6. 80 (d, Ar, J = 7.8), 6.20 (brs, NH, 1H), 2.54 (q, CH2,2H, J = 7.1), 3.57 (m, CH2,4H), 1.19 (t, CH3, 3H, J = 7). 13C NMR 8 : 156.2, 145.5, 141.0, 129.3, 122.1, 118. 7,116. 7,44. 8,42. 5,29. 0,14. 9.

Example 57: 1- (2-Chloro-ethyl)-3- (3-methoxy-phenyl)-urea (54); 'H NMR (CDCl3) 8 : 8.12 (brs, NH, 1H), 7.21 (m, Ar, 3H), 6.87 (d, Ar, 1H, J = 7), 3.97 (s, CH3, 3H), 3.57 (m, CH2,4H). 13C NMR # : 156.1, 139.4, 138. 0,129. 2,125. 1,122. 1,118. 4,57. 8,44. 5, 42.1.

Example 58: 1- (2-Chloro-ethyl)-3- [4- (4-hydroxy-butyl)-phenyl]-urea (55); 'H NMR (Acetone-d6) 6 : 8.00 (brs, NH, 1H), 7.39 (d, CH2,2H, J = 8. 2), 7.07 (d, CH2,2H, J = 8. 2), 6.50 ( (brs, NH, 1H), 3.51 (m, 8H), 2.57 (t, 2H, J = 7.5), 1. 58 (m, 2H). 13C NMR 8 : 155.9, 139.0, 136.3, 130.0, 119.2, 64.8, 42.8, 42.5, 42.4, 35.2.

Example 59: 1- (2-Chloro-ethyl)-3- [4- (3-hydroxy-propyl)-phenyl]-urea (56); 1H NMR: 8.23 (brs, NH, 1H), 7.30 (d, Ar, 1H, J = 7.9), 7.06 (d, Ar, 1H, J = 8.2), 6.36 (brs, Nh, 1H), 3. 58 (m, 4H), 3.42 (m, 6H). 13CNMR5 : 155.2, 138.2, 134.0, 128.5, 118.0, 63.3, 44.5, 43.1, 35.7, 30.4.

Example 60: 1- (2-Chloro-ethyl)-3- [4- (5-hydroxy-pentyl)-phenyl]-urea (57); 'H NMR: 8.63 (brs, NH, 1H), 7.36 (d, 2H, J = 7.9), 7.13 (d, 2H, J = 7.9), 6.43 (brs, NH, 1H), 3.96 (t, 2H, J = 6.5), 3.57 (m, 6H), 2.57 (t, 2H, J = 7.5), 1.54 (m, 2H), 1.42 (m, 2H). 13C NMR 5 : 155.2, 129.5, 128.4, 123.2, 117.9, 60.6, 43.4, 40.9, 34.4, 32.7, 25.0.

Example 61: 1- (2-Chloro-ethyl)-3- [3- (5-hydroxy-pent-1-ynyl)-phenyl]-urea (58); H NMR (acetone-d6) 8 : 8. 12 (brs, Nh, 1H), 7.03 (m, 1H), 6.79 (d, Ar, 1H, J=7), 6.69 (brs, Ar, 1H), 6. 57 (d, Ar, 1H,j=8. 0), 3.74 (t, 2H, j = 7), 3.49 (m, 4H), 2.47 (t, 2H, J = 7), 1. 81 (t, 2H, J = 7), 1.23 (t, 2H, j=7). 13C NMR 8 : 156.1, 146.3, 129.2, 125.3, 124.4, 122.0, 118. 0,114. 9, 88. 9, 81.3, 61.6, 45.1, 42.8, 31.4, 16.0.

Example 62: 3- [3- (2-Chloro-ethyl)-ureido]-benzoic acid ethyl ester (59); 'H NMR (CDC13) S : 8. 22 (brs, Nh, 1H), 7.93 (s, Ar, 1H), 7.63 (d, Ar, 1H, J = 7,8), 7.57 (d, Ar, 1H, J = 7), 7.30 (m, 1H), 6.35 (brs, Nh, 1H), 4.31 (q, CH2,2H, J = 7), 3.57 (m, 4H), 1.34 (t, CH3,3H, J = 7). 13C NMR 8 : 166.7, 156.0, 139.1, 131.0, 129.1, 124.3, 124.1, 120.5, 61.2, 44.5, 42.0, 14.2.

Example 63: 1- (2-Chloro-ethyl)-3- [3- (5-methoxy-pentyl)-phenyl]-urea (60); 'H NMR (CDC13) 5 : 8. 18 (brs, Nh, 1H), 7.14 (m, 3H), 6.86 (d, Ar, 1H, J = 7,2), 3.57 (m, 4H), 3.33 (m, 4H), 2.55 (t, 2h, J = 7), 1.59 (m, 4H). 13C NMR 8 : 156.0, 144.0, 138. 4,129. 1,123. 9, 120.8, 118.2, 58. 5,44. 6,42. 0,35. 9,31. 2,29. 5,25. 9.

Example 64: {3- [3- (2-Chloro-ethyI)-ureido]-phenyI}-acetic acid (61); 'H NMR (DMSO-d6) 8 : 8.95 (brs, OH), 7.89 (s, 1H, Ar), 7.61 (d, 1H, J = 8.0), 7.41 (d, 1H, J = 7.9), 7.29m, 1H, Ar), 6.61 (brs, NH, 1H), 3.68 (m, 4H), 3.34 (s, 2H). 13C NMR 8 : 168. 8,155. 7, 148. 6,135. 2, 128. 5,116. 5,114. 7,113. 2,47. 3,44. 8,38. 2.

Example 65: 3- [3- (2-Chloro-ethyl)-ureido]-phenyl]-carboxamide (62); 'H NMR (DMSO-d6) b : 8. 92 (brs, NH2,2H), 7.89 (brs, 1H, NH), 7.83 (s, 1H, Ar), 7.40 (d, 1H, J = 7.9), 7.32 (m, 2H), 6.57 (brs, NH, 1H), 3.69 (m, 4H). 13C NMR# : 168.1, 155.1, 140.4, 135.1, 128. 5,120. 5,120. 1,117. 3,44. 4,41. 3.

Example 66: 1- (2-Chloro-ethyl)-3- (3-heptyl-phenyl)-urea (63); 'H NMR: 7.83 (brs, NH, 1H), 7.08 (m, 3H), 6.79 (d, Ar, 1H, J = 7), 6.23 (brs, NH, 1H), 3.50 (m, 6H), 2. 48 (t, Ar, 2H, J = 7), 1.21 (m, 8H). l3C NMR 8 : 156.0, 144.0, 138. 9,128. 8, 123.3, 120.0, 117.2, 61.1, 44.7, 43.9, 42.7, 41.9, 36.0, 31.7, 31.4, 29.3.

Example 67: 5- {3- [3- (2-ChIoro-ethyt)-ureido]-phenyl}-pentanoic acid amide (64); 'H NMR (DMSO-d6) 8 : 8.03 (brs, NH, 1H, 7.11 (m, Ar, 3H), 6.69 (d, Ar, 1H, J = 7), 6.21 (brs, NH, 1H), 3.47 (m, 4H), 3.34 (m, 2H), 2.67 (t, CH2,2H, J = 7), 2.53 (m, 2H), 2.39 (t, CH2,2H, J = 7). 13C NMR 8 : 172.3, 155.8, 147.9, 137.5, 130.3, 125.6, 124.7, 122.9, 58. 3,44. 9,41. 2,33. 9, 29.3, 15.0.

Example 68: Pentanedioic acid mono-{3-[3-(2-chloro-ethyl)-ureido]-phenyl} ester (65); 'H NMR (Acetone-d6) 8 : 8.23 (brs, NH, 1H), 7.23 (m, Ar, 3H), 6.69 (m, Ar, 1H), 6.20 (brs, NH, 1H), 3.67 (m, 2H), 3.52 (m, 2H), 2.66 (m, 2H), 2.44 (m, 2H), 2.04 (m, 2H). 13C NMR (Acetone- d6) 8 : 174.1, 171.9, 155.7, 152.2, 142.3, 129.9, 115.8, 115.6, 112.4, 44.7, 42.4, 33.6, 33.0, 20. 8.

Example 69: 1- (2-Chloro-ethyl)-3- (3-cyano-phenyl)-urea (66); 'H NMR (DMSO-d6) b : 8.92 (brs, NH, 1H), 7.76 (s, Ar, 1H), 7.40 (d, Ar, 1H, j = 6.7), 7. 18 (d, Ar, 1H, J = 7.2), 6.43 (brs, Nli, 1H), 3.51 (t, CH2,2H, J = 7.0), 3.47 (t, CH2,2H, J = 7. 0). 13C NMR 8 : 154. 8, 141.2, 130. 0,123. 9,122. 6,120. 8, 118.9, 111.4, 44. 8, 41.4.

Example 70: 3- [3- (2-Chloro-ethyl)-ureido]-benzoic acid (67); 'H NMR (DMSO-d6) 8 : 12. 87 (brs, OH, 1H), 8. 91 (brs, NH, 1H), 8. 08 (s, Ar, 1H), 7. 68 (d, Ar, 1H, J = 7.3), 7.61 (d, Ar, 1H, J = 7.5), 7.36 (m, Ar, 1H), 6.48 (brs, Nh, 1H), 3.68 (m, CH2,2H), 3. 45 m, CH2,2H. 13C NMR 8 : 167.4, 155. 0,140. 6,131. 3,128. 9,122. 1,121. 9,118. 5,44. 3,41. 3.

Example 71: 5- {3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-pentanoic acid methyl ester (68); 'H NMR (CDC13) 8 : 8.21 (brs, NH, 1H), 7.07 (m, Ar, 1H), 6.57 (m, Ar, 3H), 6.17 (brs, NH, 1H), 3.66, (s, CH3,3H), 3.51 (m, CH2,4H), 2. 58 (m, CH2,2H), 2. 33 (t, CH2,2H, J = 7.0), 1.65 (m, CH2,2H), 1.25 (m, CH2, 2H). 13C NMR 8 : 174.1, 155.3, 146.3, 1434,129. 2, 118. 8,115. 3, 112. 8, 51.3, 44.7, 41.8, 35.5, 34.2, 30.4, 24.6.

Example 72: 1- (2-Chloro-ethyl)-3- (3-hexyl-phenyl)-urea (69); 'H NMR (CDC13) 8 : 7.58 (brs, NH, 1H), 7.11 (m, Ar, 3H), 6.79 (d, Ar, 1H, J = 69), 3.53 (m, CH2,4H), 3.46 (m, CH2,4H), 2.48 (m, CH2,2H), 1.20 (m, CH2, 8H). 13C NMR 8 : 156.6, 144.0, 138. 8,128. 8, 123.3, 120.0, 117.2, 61.1, 44.7, 43.9, 42.7, 41.9, 36.0, 31.8, 31.4, 29.3, 29.1, 22.6.

Example 73: 6-f 3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-hexanoic acid amide (70); 'H NMR (DMSO-d6) 8 : 8.21 (brs, NH, 1H), 7.38 (m, Ar, 2H), 6.55 (m, Ar, 2H), 6.38 (brs, NH, 1H), 3.45 (m, CH2,6H), 2.56 (m, CH2,2H), 2.23 (m, CH2, 4H). 13C NMR 8 : 172.3, 154.8, 137.4, 129.2, 123.7, 121.1, 117.2, 60.1, 44.7, 42.1, 35.9, 32.4, 30.9, 23.8.

Example 74: 6-{3-[3-(2-Chloro-ethyl)-ureido]-phenyl}-hexanoic acid ethyl ester (71); 'H NMR (CDC13) 8 : 7.14 (m, Ar, NH, 4H), 6.86 (d, Ar, 1H, J = 7,2), 5.66 (brs, NH, 1H), 4.10 (q, CH2,2H, J = 7.0), 3.59 (m, CH2,4H), 2.54 (m, CH2, 2H), 2.27 (m, CH2,2H), 1.62 (m, CH2, 4H), 135 (m, CH2, CH3, 5H). 13C NMR 8 : 174.9, 155.9, 143.9, 138.4, 129.1, 124.0, 120.9, 118. 3,60. 3,44. 8,42. 0,35. 6,34. 3,30. 9,29. 7, 28. 7,24. 8,14. 2.

Example 75: 6-f 3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-hexanoic acid (72); 'H NMR (Acetone-d6) 8 : 8.17 (brs, NH, 1H), 7.31 (m, Ar, 1H), 7.12 (m, Ar, 2H), 6.79 (d, Ar, 1H, J = 7.4), 6.23 (brs, Nh, 1H), 3.64 (m, CH2,2H), 3.54 (m, CH2,2H), 2.55 (m, CH2,2H), 2.20 (m, CH2,2H), 1.71 (m, CH2,4H), 1.22 (m, CH2, 2H). 13C NMR 8 : 174.1, 156.1, 143.9, 141.1, 129.2, 122.6, 119.2, 116.8, 44.9, 44.8, 42.5, 36.3, 34.1, 31.8, 30.6, 30.2, 25.4.

Example 76: 6-3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-hexanoic acid methyl ester (73); 'H NMR (CDC13) 8 : 8. 11 (brs, Nh, 1H), 7.48 (m, Ar, 2H), 6.51 (m, Ar, 2H), 6.38, (brs, Nh, 1H), 3.57 (m, CH2,6H), 3.81 (s, CH3,3H), 2.51 (m, CH2,2H), 2.17 (m, CH2, 4H). 13C NMR 8 : 174.1, 155.3, 138.3, 131.7, 124.2, 121.1, 116.8, 51.4, 44.6, 41.9, 35.9, 32.6, 30.8, 23.6.

Example 77: 3- [3- (2-Chloro-ethyl)-ureido]-benzoic acid methyl ester (74); 'H NMR (CDC13) 8 : 8.21 (brs, NH, 1H), 7.87 (s, Ar, 1H), 7. 61, Ar, 1H, J = 7.0), 7.58 (d, Ar, 1H, J = 7. ), 7.21 brs, Nh, 1H), 3.76 (s, CH3,3H), 3.57 (m, CH2, 4H). 13C NMR 8 : 167.1, 156.2, 139.3, 131.1, 129.0, 125.0, 123.9, 120.4, 52.2, 46.4, 42.0.

Example 78: 1- (2-Chloro-ethyl)-3- [3- (4-hydroxy-but-1-ynyl)-phenyl]-urea (75); 'H NMR (Acetone-d6) 3 : 8.21 (brs, NH, 1H), 7.03 (m, Ar, 1H), 6.79 (d, Ar, 1H, J = 7.0), 6.71 (s, Ar, 1H), 6.57 (d, Ar, 1H, J = 7.9), 6.23 (brs, NH, 1H), 3.71 (m, CH2,6H), 3.45 (m, CH2,2H) 2.601 (t, CH2,2H, J = 7. 0)."C NMR b : 155. 8, 146.3, 129.3, 124.1, 122.1, 118. 2,115. 2,86. 2, 82. 5,61. 1,44. 7,42. 3,23. 7.

Example 79: 1- (2-Chloro-ethyl)-3- [3- (3-hydroxy-prop-1-ynyl)-phenyl]-urea (76); 'H NMR (Acetone-d6) 8 : 8.06 (brs, NH, 1H), 7.08 (m, Ar, 1H), 6.83 (d, Ar, 1H, J = 7.5), 6.75 (s, Ar, 1H), 6.63 (d, Ar, 1H J = 7.9), 3.57 (m, CH2,4H), 2.04 (s, CH2, 2H). 13C NMR 5 : 155.2, 129. 8, 123.3, 123.1, 118. 0,115. 6,86. 7,85. 9,51. 6,44. 8,42. 3.

Example 80: 3- [3- (2-Chloro-ethyl)-ureido]-phenyl}-acetic acid ethyl ester (77); 'H NMR (CDC13) 8 : 7.89 (brs, NH, 1H), 7.17 (s, Ar, 1H), 7.08 (m, Ar, 2H), 6.81 (d, Ar, 1H, J = 7.9), 4.09 (q, CH2,2H, J = 7,0), 3.46 (m, CH2,6H), 1.21 (t, CH3,3H, J = 7.0). 13C NMR 8 : 172.1, 156.2, 139.2, 134.9, 129.7, 123.8, 120.8, 118.6, 61.1, 44.4, 42.0, 41.8, 14.1.

Example 81: Acetic acid 3-f 3- [3- (2-chloro-ethyl)-ureido]-phenyl}-propyl ester (78).

'H NMR (CDC13) 8 : 7.57 (brs, NH, 1H), 7.21 (m, Ar, 3H), 6.79 (m, Ar, 1H), 5.91 (m, Ar, 1H), 3.57 (m, CH2, CH3, 9H). 13C NMR b : 172.5, 156.0, 139.1, 134.7, 129.2, 124.0, 120.9, 118.8, 52.1, 44.4, 40.9, 40. 3.

EXAMPLE 82: Inhibition of Proliferation of Fibroblasts by Compound 1 Human foreskin fibroblasts, obtained by biopsy, were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum. Cytotoxicity was assessed using a modified Alamar Blue assay as described by Lancaster et al. (U. S. Patent No. 5,501, 959). Briefly, 2 x 103 cells in 100 ul were seeded in 96-well plates and preincubated for 24 hours. After addition of 100 1 fresh medium containing increasing concentrations of compound 1, cells were incubated at 37°C for 72 hours. The culture medium was removed, cells were washed with a phosphate-buffered saline (PBS) solution and replaced by 50 1 of a resazurin solution (resazurin 125 llg/ml in PBS: serum free RPMI 1: 4). Cell survival was calculated from fluorescence (exitation 485 nm ; emission 590 nm) measured with a FL 600 Reader (BioTek Instruments). Cytotoxicity was expressed as the dose required to inhibit cell growth by 50% (GIso). Values are the means of at least three independent determinations. GI50 of compound 1 on human foreskin fibroblasts was 12.5 pM. Results of this assay are shown in Figure 1.

EXAMPLE 83: Inhibition of Proliferation of HUVECs by Compound 1 Human umbilical vein endothelial cells, isolated from umbilical cord, were cultured in M199 medium supplemented with Endothelial Cell Growth Supplement (ECGS, 20 pg/ml), heparin (0.09 g/1), L-glutamine (0.292 g/1), 1% antibiotic-antimycotic, and 10% fetal calf serum.

Cytotoxicity was assessed using a modified Alamar Blue assay as described by Lancaster et al.

(U. S. Patent No. 5,501, 959). Briefly, 2 x 103 cells in 100 ul were seeded in gelatine-coated 96- well plates and preincubated for 24 hours. After addition of 100 tl fresh medium containing increasing concentrations of compound 1, cells were incubated at 37°C for 72 hours. The culture medium was removed, cells were washed with a phosphate-buffered saline (PBS) solution and replaced by 50 1 of a resazurin solution (resazurin 125 J. gel in PBS: serum free RPMI 1: 4).

Cell survival was calculated from fluorescence (exitation 485 nm; emission 590 nm) measured with a FL 600 Reader (BioTek Instruments). Cytotoxicity was expressed as the dose required to inhibit cell growth by 50% (GI50). Values are the means of at least three independent determinations. GIso of compound 1 on HUVECs was 3.1 uM. Results of this assay are shown in Figure 2.

EXAMPLE 84: Inhibition of Proliferation of HUVECs by Various Compounds of Formula I Inhibition of HUVEC Proliferation by Various Compounds of Formula I was determined as outlined in Example 83.

Table 1: Inhibition of HUVEC Proliferation by Various Compounds of Formula I Compound # GIso 1 6.3 2 8.4 3 7. 8 4 72. 6 5 17. 1 Compound # GI50 6 5. 4 8 15. 3 13 63. 0 14 18. 8 21 1. 6 (R)-24 27. 2 1 0150 is the dose required to inhibit cell growth by 50%.

Table 2: Inhibition of HUVEC Proliferation by Various compounds of Formula I Compound R R2 R3 R4 R5 X Y Z GI501 (R)-79 H methoxy methoxy H H H methyl (R-Cl 30.7 isomer) (S)-80 H methoxy methoxy H H H methyl (S- C1 >100 isomer) (R)-81 H H I H H H methyl (R-Br 1. 8 isomer) (S)-82 H H n-heptyl H H H n-propyl C1 8. 5 (S-isomer) (S)-83 H H n-heptyl H H H i-propyl (S-Cl 10.4 isomer) (14.02) 84 H H n-heptyl H H H Methyl3 C1 18.4 (R)-85 H H n-butyl H H H methyl (R- Cl 9.5 Compound RI R2 R3 R4 Rs X Z GIso isomer) 1 GI50 is the dose required to inhibit cell growth by 50%.

2 Different values obtained in separate experiments.

Racemic mixture.

Example 85: Inhibition of HUVECs by CEUs in a dose-and time-dependent manner.

Human umbilical vein endothelial cells (HUVECs) were isolated as previously described.

HUVECs were maintained in a gelatin-coated 75-cm2 flask in M199 (Invitrogen, Burlington, ON) supplemented with 20 % fetal bovine serum (FBS), 100 units/ml penicillin, 100 J. gel streptomycin, 3 ng/ml basic fibroblast growth factor (bFGF) (Invitrogen, Burlington, ON) and 5 units/ml heparin (Invitrogen, Burlington, ON).

HUVECs were inoculated into 96 well tissue culture plates in 100 uL containing 2 X 103 cells and were incubated at 37 °C. After 24 h, freshly solubilized drugs in DMSO were diluted in fresh medium. Aliquots of 100 ul containing escalating concentration of drugs (0.3 uM to 100 uM) were added to the appropriate microtiter wells already containing 100 ul of culture medium.

The cells were incubated for different period of time ranging from 3 h to 48 h. The supernatant was removed, the cells were washed and incubated with fresh medium to complete the total incubation time to 48 h for each condition. Assays were stopped by addition of cold TCA to the wells (final concentration, 10 %), followed by their incubation for 60 min at 4 °C. The supernatant was discarded and the plates were washed five times with tap water and air-dried.

Sulforhodamine B solution (50 1li) at 0.1 % (w/v) in 1 % acetic acid was added to each well, and plates were incubated for 15 min at room temperature. After staining, unbound dye was removed by washing five times with 1 % acetic acid and the plates were air-dried. Bound stain was solubilized with 10 mM trizma base, and the absorbance was read using a quant Universal Microplate Spectrophotometer (Biotek, Winooski, VT) at 585 nm. The results were compared with those of a control reference plate fixed on the treatment day and the growth inhibition percentage was calculated for each drug contact period. The growth inhibition percentage is expressed as the mean of triplicates for each drug contact period, compared with those of a control reference plate fixed on the day of the treatment.

The cytotoxicity of soft alkylant compound 1 its bioisosteric derivative, compound 5 and its non- alkylating counterpart, tBEU, was compared with that of a classical and strong alkylating agent, namely cisplatin (cDDP). The antimicrotubule agents colchicine, vinblastin and paclitaxel were also tested in this assay but was found not cytotoxic until they reach 48 h of exposure (data not shown). When they were in contact for less than 6 h with either cell lines, virtually none of the tested compounds (CEUs) showed inhibition of tumor cell growth and proliferation. However, as the time of contact between the tested compounds (CEUs) and tumor cells was increased from 6 to 48 h, the comparable GIso of compound 1 and compound 5 markedly shifted to the left hand- side of the graph Figure 3A and B and this was shown in the low micromolar range for all tumor cell lines tested. These was strikingly different from the cDDP effect, which displayed cytotoxicity after only 3 h of treatment, with a GI50 that was essentially in the same range for all time of contact tested (Figure 3D). Interestingly, at all concentrations tested, the non-alkylating tBEU showed no apparent cytotoxicity (Figure 3C), suggesting that the chemical alkylating property of candidate compounds was essential for their cytotoxicity. Overall, soft alkylating CEUs were as much cytotoxic as cDDP. However they require a longer time of contact to display their proliferative inhibitory activity, which is compatible to the incubation time of other anti-antimicrotubule agents tested, such as colchicine and paclitaxel (data not shown).

EXAMPLE 86: Inhibition of IL-2 Production in Jurkat Cells by Compounds of Formula I #1 The human leukemic T-cell line Jurkat was maintained in suspension culture in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum. The cultures were kept at 37°C in a humidified 95% air, 5% C02 atmosphere.

Quantification of IL-2 production from Jurkat T lymphocytes was performed using a commercial enzyme immunoassay (EIA) system (Cayman Chemical Company, USA). Cells were grown to log phase, harvested by centrifugation, counted with a hemacytometer, and resuspended in fresh media at 106 cells/ml. Then 96-well culture plates were prepared with 50uM of inhibitor (compounds 1,2 or 3 in dimethyl sulfoxide) alone or either T-cell receptor (TCR)-independent stimulants (80 nM phorbol myristate acetate (PMA) and 10 llg/ml phytohemagglutinin (PHA)) or TCR-independent stimulants (80 nM PMA and 1 M ionomycin). Cells suspension (150 ! was added to each well and incubated for 24 h at 37°C. Culture supernatants were harvested and diluted 1: 22 and 1: 220 to bring the IL-2 concentrations within the linear range of the EIA. EIA detection was performed as suggested by manufacturer (Cayman Chemical) and colormetric reading determined on automatic plate reader. The results are presented in Figure 4 and Table 3.

Autonomous cell growth has been shown to be regulated in part by IL-2. The ability of compounds of Formula I to affect the inhibition of IL-2 production, therefore, can help to control cell proliferation.

Table 3: Effect of Compound of Formula I on IL-2 production on stimulated Jurkat cells PMA + PMA + Compound # Ioizonaycin PHA DMSO (control) 100% 100% 1 67% 47% 2 40% 33% 3 6% 24% EXAMPLE 87: Inhibition of IL-2 Production in Jurkat Cells by Compounds of Formula I #2 The ability of compounds 1,2, 3 and 86 to inhibit IL-2 production in Jurkat cells was assayed as described above (Example 86). The results are presented in Figures 5A and 5B.

EXAMPLE 88: Effect of haloethyl urea derivatives on IL-2 production on human lympho- mono cells.

Lympho-mono cells were isolated from human blood, and kept in suspension culture in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum. The cultures were kept at 37°C in a humidified 95% air, 5% C02 atmosphere for 24 hours.

Quantification of IL-2 production from human lympho-mono cells was performed using a commercial EIA system (eBiosciences, USA). Cells were counted with a hemacytometer, and resuspended in fresh media at 106 cells/mL. Cell suspension (150 gel) was added to each well of a 96-well culture plates. IMO compounds were dissolved in dimethyl sulfoxide. 50uL of inhibitor (compouns 1,2, 3,86, 5,30, 87 was added to each well to yield a final concentration of 3,10 and 30gM. The control consisted of the blank solution used to dissolve the test compounds, added to the cell suspension. The mixture of cell suspension and inhibitor was incubated for 24 h at 37°C. On the second day, stimulant (80 nM PMA and 10pg/mL PHA) was added to each well and incubated for 24 h at 37°C. Culture supernatants were harvested and diluted 1: 22 and 1: 220 to bring the IL-2 concentrations within the linear range of the EIA. EIA detection was performed as suggested by manufacturer (eBiosciences) and colorimetric reading determined on automatic plate reader. The cells, from which the supernatant was collected, were exposed to resazurin (Alamard blue) to measure the number of cells alive. This measurement is performed to discriminate between cell death (cell toxicity) and IL-2 decrease after exposure to the different compounds of the invention. Normally, at 3011M, all the compounds of the invention tested here are non toxic. (The compounds toxicity arises solely with dividing cells). Nevertheless, the addition of PMA and PHA to the mixture of compounds of the invention and cell suspension made some compounds of the invention toxic for the non-dividing lympho-mono cells.

The results are shown in Figure 6. Figure 6a illustrates the total amount of IL-2 measured in the culture supernatant. Figure 6b illustrates number of cells alive as determined by exposure to resazurin. While Figure 6c illustrates Normalized amount of IL-2 measured in the supernatant.

The normalization procedure consisted in the ratio of total IL-2 value (Figure 6a) by the number of live cells (Figure 6b).

EXAMPLE 89: Inhibition of Proliferation of Keratinocytes by Compound 1 Cells from the human immortalized keratinocyte cell line HaCat were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum Cytotoxicity was assessed using a modified sulforhodamine B assay as described by Rubinstein et al (JNatl Cancer Inst 82 : 113-118,1990). Briefly, 2 x 103 cells in 100 u. L were seeded in 96- well plates and preincubated for 24h. After that, 100 J. L of fresh medium containing increasing concentration of compound 1 were added. Cells were incubated at 37°C for 72 hours. Cells were then fixed in situ by the gentle addition of 50 al of cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at 4°C. The supernatant was discarded, and the plates were washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (50 gl at 0.2 % (w/v) in 1 % acetic acid) was added to each well, and plates were incubated for 30 minutes at room temperature. After staining, unbound dye was removed by washing five times with 1 % acetic acid and the plates were air dried. Bound stain was subsequently solubilized with 10 mM Trizma base, and the absorbance was read on an automated plate reader at a wavelength of 580 nm. Cytotoxicity was expressed as the dose of drug required to inhibit cell growth by 50% (GI50). Values are the means of at least three independent determinations. GI50 of compound 1 on HaCat cells was 11.1 I1M. The results of this assay are presented in Figure 7.

EXAMPLE 90: Inhibition of Proliferation o fKeratinocytes by Compounds of the Invention The ability of other compounds to inhibit the proliferation of kerationocytes was assayed as described above (Example 89). The results are presented in Table 4.

Table 4: Cytotoxicity of compounds of the invention on proliferative HaCat cells Compound # GI50 1 11. 1 2 25.6 3 15.0 5 6.9 R-23 3.0 S-23 78. 0 27 6.2 88 6.7 89 13.2 30 0.9 14 22.5 1 GI50 is the dose required to inhibit cell growth by 50%.

Compound 30 in the above Table is 4-ter-butyl-C (K-E) U.

EXAMPLE 91: The Effect of Compounds of Formula I on Proliferating and Non- proliferating Keratinocytes by Compounds of Formula I The effect of compounds 1,2, 3 and 17 on the growth of proliferating and non-proliferating HaCat cells was studied and compared to control compounds (5-FU, colchicine, taxol and vinblastine). The results are presented in Figures 8A-H.

EXAMPLE 92: Effect of 1- (4-tert-butyl-phenyl)-3-3 (2-chloro-ethyl) -urea (tB-CEU) on growth of the human immortalized keratinocyte cell line HaCat Cells from the human immortalized keratinocyte cell line HaCat were cultured in RPMI-1640 medium supplemented with 10% fetal calf serum Growth inhibition was assessed using a modified sulforhodamine B assay as described by Rubinstein et all. Briefly, 2 x 103 cells in 100pL were seeded in 96-well plates and preincubated for 24h. After that, 100tL of fresh medium containing increasing concentration of the test drugs were added. Cells were incubated at 37°C for 72 hours. Cells are then fixed in situ by the gentle addition of 50 1 of cold 50 % (w/v) TCA (final concentration, 10 % TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (50 ul at 0.2 % (w/v) in 1 % acetic acid) is added to each well, and plates are incubated for 30 minutes at room temperature. After staining, unbound dye is removed by washing five times with 1 % acetic acid and the plates are air dried.

Bound stain is subsequently solubilized with 10 mM trizma base, and the absorbance is read on an automated plate reader at a wavelength of 580 nm. Growth Inhibition was expressed as the dose of drug required to inhibit cell growth by 50% (GIso). Number of untreated cells were arbitrary assign to 100% growth. Values are the means of at least three independent determinations.

Results are presented in Table 5 and Figure 9 Table 5 Growth Inhibition of haloethyl urea derivatives on proliferative HaCat cells Compound Gogo 1 11.1 2 25.6 3 15.0 5 6. 9 (R) 23 3. 0 (S)23 78.0 90 6.7 91 13.2 92 0. 9 93 22. 5 EXAMPLE 93: Matrigel Plug Assay The Matrigel plug assay was conducted to determine the ability of compound 5 to inhibit angiogenesis using known procedures and suriname as a control. The results are shown in Figure 10.

EXAMPLE 94: Figure 6. CEUs inhibit the bFGF-induced angiogenesis in the mice Matrigel plug assay.

The experimental protocol was conducted as previously described Auerbach et al. Pharmacol Ther. 51: 1-11 (1991); Ribatti et al. Int. J. Biol. Markers 14: 207-213 (1999); Stefansson et al. J.

Biol. Chem. 276: 8135-8141) ). Briefly, the liquid Matrigel (Becton Dickinson, Bedford, Mass.) was kept on ice until the injection to avoid gelling of the colloid. The Matrigel solution was either loaded with bFGF (250 ng/ml) to induce angiogenesis, or left unloaded to be used as negative controls. Five hundreds microliters of cold Matrigels were injected subcutaneously on the ventral line of mice. After the injection, the Matrigel preparation was allowed to polymerize for 5 min. The drugs (50 and 100 mg/kg; in DMA: transcutol: chremophor; Tween20 [1: 3: 3: 3] ) was then administered intraperitoneally, according to the method described by Stefansson et al.

(J. Biol. Chem. 276: 8135-8141)). After 5 to 7 days, the mice were euthanized by C02 asphyxiation, the Matrigelw plugs were excised and only those that did not show any sign of hematoma were solubilized in PBS-Triton X-100 (0.1 %). The hemoglobin content of Matrigel plugs was compared to a hemoglobin standard-curve (405 nm) to evaluate the level of vascularization Stefansson et al. J. Biol. Chem. 276: 8135-8141) ). The results are normalized according to the Matrigel total dry weight. The results are representative of three independent experiments. The hemoglobin content of bFGF-containing Matrigel was used as the 100 % reference. ANOVA test revealed a significant difference between the groups (p < 0.05) and the Dunnett test was performed (t p < 0.05, when compared to Matrigel alone, *p< 0.05 when compared to bFGF-containing plugs). For the sake of clarity, the results corresponding to the Matrigel without bFGF are not shown but revealed that a significant vascularization was induced by bFGF, after its addition to the Matrigel plugs.

Matrigel plugs containing bFGF induced a significant two-fold increase in hemoglobin content over Matrigel alone (Figure 11). When compound 1 and compound 5 were administrated at 100 mg/kg, they were potent inhibitors of bFGF-induced blood vessel formation (Figure 11), causing a significant reduction of the hemoglobin content of 62 % and 58 %, respectively. At the same dose, tBEU clearly failed to reduce bFGF-induced vascularization, rather showing an hemoglobin content statistically similar to that from mice injected with the vehicle or not (untreated). Accordingly, the holoethyl urea compounds of the instant invention have antiangiogenic action in vivo. The mice injected with the test compounds of the instant invention showed no sign of toxicity EXAMPLE 95: Cell Migration Assay The ability of compound 1 and compound 5 to inhibit the migration of endothelial cells (HUVECs) through an artificial membrane when submitted to the influence of a chemoattractant molecule was evaluated using Boyden's chambers and following published protocols (see the website for National Cancer Institute, Developmental Therapeutic Program, Angiogenesis Resource Center). Generally, a 48-well plate was fitted with collagen coated membrane inserts (8 uM pore size). The lower chamber of each well contained culture medium (29 pl) with or without the chemoattractant bFGF (250 ng/ml). HUVECs in culture medium plus BSA (45 il) were added to the upper chamber. Once the cells had attached to the membrane, the test compound was added. After a five-hour incubation at 37°C, the migrating cells were fixed and labelled. The results are presented in Figures 12A and B.

Example 96: Inhibition of endothelial cell migration by compounds 1 and 5 The chemotaxis motility of HUVECS was assessed using Boyden chambers. Briefly, the underside of TranswellTM migration chamber membranes (8. 0- mm pore size) were coated with collagen IV as described previously (Filardo et al. J. Cell Biol. 130: 441-450 (1995); Klemke et al. J. Cell Biol. 127: 859-866 (1994) ) and as modified by Petitclerc et al. (J. Biol. Chem.

275: 8051-8061 (2000). The HUVECs (A, B, C) were pre-treated () or not (O) for 16 h with escalating concentrations of different drugs, then they were added to the top of the TranswellTM in a DMEM medium containing 0.1 % BSA, in the presence of drugs. Soluble fibronectin (25 , ug/ml) was added to the lower chamber to induce chemotaxis. The cells were allowed to migrate for 4-6 h at 37 °C, fixed and stained for quatification. The number of migrating cells per well were counted. The results expressed the mean s. e. of triplicates.

CEUs abrogate the motogenic potential of endothelial cells. Figure 13 demonstrates that the CEUs inhibited HUVEC cell migration with an overall efficiency of 30-40 %. Because the antiproliferative effect of CEUs depends on the time of contact, the migration assays were conducted with either 0 or 16 hours pretreatments.

EXAMPLE 97: Chick Embryo Chorioallantoic Membrane (CAM) Assay The ability of compound 1 to inhibit formation of a solid tumour was assessed in the chick CAM assay using published protocols (Brooks et al., in Methods in Molecular Biology, Vol. 129, pp.

257-269 (2000), ed. A. R. Howlett, Humana Press Inc., Totowa, NJ). 10-day old chick embryos were inoculated with cells from the hamster melanoma cell line. After 11 days, the test compound was injected intravenously and the eggs were incubated for a further 6 days. Tumours were then harvested and weighed. The results are presented in Figure 14. Inhibition of tumour growth by compound 1 appears to be mediated by inhibition of formation of a vascular network.

EXAMPLE 98 : Compounds of the instant invention impede the growth of two unrelated tumor cell lines in the chick chorioallantoic membrane (CAM) assay.

Human HT1080 fibrosarcoma and hamster CS1 melanoma cell lines were used to assess the antitumoral activity of CEUs in the chick chorioallantoic assay (Petitclerc et al. J. Biol. Chem.

275: 8051-9061 (2000); Kim et al. Cell 94: 353-362 (1998); Lyu et al. Int. J. Cancer 77: 257-263 (1998) ). In brief, day-0 fertilized chicken eggs were purchased from Couvoirs Victoriaville (Victoriaville, QC, Canada). The eggs were incubated for 10 days in a Pro-FI egg incubator fitted with an automatic egg turner, before being transferred to a Roll-X static incubator for the rest of the incubation time (incubators were purchased from Lyon Electric, Chula Vista, San Diego).

The eggs were kept at 37 °C in a 60 % humidity atmosphere for the whole incubation period.

Using a hobby drill (Dremel; Racine, WI), a hole was drilled on the side of the egg, and a negative pressure was applied to create a new air sac. A window was opened on this new air sac and was covered with transparent adhesive tape to prevent contamination. A freshly prepared cell suspension (40 gel) of either HT1080 (3.5 x 105 cells/egg) or CS1 (5 x 106 cells/egg) cells was applied directly on the freshly exposed CAM tissue through the window. On day 11, the tested drugs were injected intravenously in 10-12 eggs in a small volume (100 ul). The eggs were incubated until day 17, at which time the embryos were euthanized at 4 °C, followed by decapitation. Tumors were collected, pictures were taken to illustrate the different groups and the tumor-wet weights were recorded. In all experiments, the number of dead embryos from the different groups was monitored for any sign of toxicity.

Panel A and B of Figure 15 show that incubation of CS1-derived tumors on the CAM with compounds 1 and 5 resulted in a significant dose-dependent reduction of the tumors size, as observed also with cDDP (Figure 15D). Moreover, both CEUs also inhibited the formation of HT1080 tumor mass in the same concentration range (data not shown). It is noteworthy that the non-alkylating homologue tBEU failed to influence the growth of CS1 tumors (Figure 15C), supporting the assumption that the antitumoral effect of the compounds 1 and 5 was dependent on their alkylating activity. In the same experimental settings, only 10 llg/egg of cDDP was sufficient to inhibit tumor cell growth. However, a high level of chick embryo toxicity was observed at higher concentration, since 95 to 100 % of embryos died at a cDDP concentration reaching 50, ug/egg (Figure 15). By contrast, the antitumoral effect of tBCEU and COMPOUND 5 was shown at doses that were well tolerated by the chick embryo, as we monitored by chick necropsy (up to 150 ug/egg, data not shown).

Cumulative results are shown from three independent experiments. ANOVA test showed a significant difference between doses (p< 0.01). Dunnett test was performed (* p < 0.05, ** p< 0.01). t indicates 95-100 % chick embryos mortality in the group when using 25 ug/ml cDDP.

In panel A), the black circle corresponds to the injection of the solvent used to solubilize the drugs.

EXAMPLE 99: Compounds 1,5, 2 and 22 impede the growth of CS1 tumor cell line in the chick chorioallantoic membrane (CAM) assay.

The ability of compounds 1,5, 2 and 30 to impede the growth of CS1 tumor cell line was determined using the chick chorioallantoic membrane (CAM) assay as described in Example 98.

The results are present in Figure 16.

Example 99: Microtubule depolymerization and cytoskeleton disruption induced by CEUs.

Morphological analysis of microtubules, actin cytoskeleton and nucleus by immunocytochemistry.

Human umbilical vein endothelial cells (HUVECs) were as previously described. HUVECs were maintained in a gelatin-coated 75-cm2 flask in M199 (Invitrogen, Burlington, ON) supplemented with 20 % fetal bovine serum (FBS), 100 units/ml penicillin, 100 llg/ml streptomycin, 3 ng/ml basic fibroblast growth factor (bFGF) (Invitrogen, Burlington, ON) and 5 units/ml heparin (Invitrogen, Burlington, ON).

HUVECs were seeded at 1x105 cells in in 35-mm Petri dishes and incubated for 16. h at 37 °C.

After treatments with either the test compounds of the instant invention or classical antimicrotubule agents, the cells were washed twice with phosphate-buffered saline (PBS, pH 7.4) and then fixed with 3.7 % formaldehyde in PBS for 20 min. After two washes, the cells were permeabilized and blocked with 0.1 % saponin and 3 % (w/v) BSA in PBS, during 1 h at 37 °C. The cells were then further incubated during 1 h at 37 °C with anti-tubulin (clone TUB2.1, that is specific to p-tubulin and does not cross-react with other-tubulin isoforms ; Sigma-Aldrich; St-Louis, MO) (1 : 200) in 0.1 % saponin and 3 % BSA in PBS. The cells were washed three times with PBS containing 0.05 % of Tween 20 and incubated 1 h at 37 °C in blocking buffer containing anti-mouse IgG Alexa-488 (1: 1000), DAPI (2.5 pg/ml in PBS) to stain nuclei and Rhodamine-labeled phalloidin (1 : 600) to stain the actin cytoskeleton. The observations were made using a Nikon Eclipse E800 microscope (Tokyo, Japan) equipped with a 40X objective.

Images were captured as 16 bit TIFF files with a Hamamatsu ORCA ER cooled (-20°C) digital camera (Photonics Management Management Corp. , Bridgewater, N. J. ) driven by SimplePCI AIC software (Compix Inc. C Imaging systems, Pennsylvania).

The effect of compounds 1,5 and tBEU on the microtubule network was compared by an immunofluorescence staining of p-tubulin (Figure 17) In comparison with untreated cells, 100 I1M of tBCEU during 24 h considerably affected the p-tubulin fibers (Figure 17), showing a punctated p-tubulin staining that lead to a microtubule depolymerization phenotype. This was established by a comparison with a 24 h cells exposure to paclitaxel (50, uM), colchicine (25 , uM), or to vinblastine (5 uM), classical antimicrotubule agents having opposite effect on microtubule network by their non-covalent binding to p-tubulin. Paclitaxel stabilizes the microtubules, thus inhibiting their depolymerization, whereas the others rather blocking their polymerization, inducing therefore a depolymerization phenotype (Figure 17). In fact, the tBCEU effect on p-tubulin was indeed drastically different from what was observed after paclitaxel treatment, not as severe as vinblastine, but rather similar to that observed after colchicine cell exposure. As expected, the bioisosteric derivative compound 5 showed a similar microtubule dissolution activity as tBCEU. On the contrary, tBEU did not exhibit any effect on the microtubule network nor did affected the filamentous structure of actin. However, tBCEU, compound 5, colchicine and vinblastine considerably decreased the amounts of filamentous actin in both cell lines, presumably as an indirect consequence of p-tubulin depolymerization, showing a more punctate actin distribution. This collapse of the actin structure was not observed in response to paclitaxel. Interestingly, the toxic effect of cDDP on p-tubulin and on actin filaments seemed rather associated to its pro-apoptotic mechanism, actin and microtubules being dissolved only in cells showing a typical apoptotic nuclear fragmentation phenotype Deschesnes et al., Mol. Biol. Cell. 12: 1569-1582 (1996); Desbiens et al. , Biochem. J. 372: 631-641 (2003). Stress fibers were rather observed in cDDP-treated cells that are still non-apoptotic. This was still contrasting with CEUs that were rather inducing a non-classical nuclear condensation phenotype consequently or in parallel to their microtubules disruption effect.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.