WO2005102318A1

WO2005102318A1 - Use of c-kit inhibitors for treating hiv related diseases

Info

Publication number: WO2005102318A1
Application number: PCT/IB2005/001433
Authority: WO
Inventors: Alain Moussy; Jean-Pierre Kinet
Original assignee: Ab Science
Priority date: 2004-04-20
Filing date: 2005-04-19
Publication date: 2005-11-03

Abstract

The present invention relates to a method for treating HIV related diseases comprising administering a compound capable of depleting mast cells or a compound inhibiting mast cell degranulatioin, to a human in need of such treatment. Such compounds can be chosen from c-kit inhibitors and more particularly non-toxic, selective and potent c-kit inhibitors. Preferably, said inhibitors is unable to promote death of IL-3 dependent cells cultured in presence of IL-3.

Description

Use of c-kit inhibitors for treating HIV related diseases

The present invention relates to a method for treating HIV related diseases comprising administering a compound capable of depleting mast cells or a compound inhibiting mast cell degranulation, to a human in need of such treatment. Such compounds can be chosen from c-kit inhibitors and more particularly non-toxic, selective and potent c-kit inhibitors. Preferably, said inhibitor is unable to promote death of IL-3 dependent cells cultured in presence of IL-3.

AIDS was reported in the early eighties as resulting from progressive human immunodeficiency virus (HIV) infection. In infected subjects, HIV progressively destroys or damages cells of the body's immune system. Gradually, immune responses to diseases and pathogens infection deteriorate. As of today, it is estimated that more than 900,000 Americans may be infected with HIV.

Approved drugs for treating HIV infection include nucleoside reverse transcriptase (RT) inhibitors, such as AZT, ddC, ddl, d4T, and 3TC. The aim of these nucleotide analogs is to slow the spread of HIV in the body and delay the onset of opportunistic infections. More recently, protease inhibitors have been approved for blocking virus cycles at a later step. In addition, combination treatment using both drugs is necessary to avoid HIV become resistant. However, these treatments do not represent a cure and severe side effects are commonly observed.

Furthermore, these medications are active when the virus is replicating but are inefficient while the virus is dormant. A report in the Journal of Virology (2000;74:7824-7833) reveals that latent HIV reservoirs form when the virus infects activated T cells and when these cells enter a resting state. For example, the half-life of replication-competent HIV in the pool of latently infected resting CD4+ T cells has been estimated to be about 44 months. There are other CD34+ cells that may serve as a reservoir for HIV. Among these cells, it was found that mast cell progenitors can be infected and can retain the virus in vitro (Bannert et al, Journal of Virology, November 2001, p. 10808-10814, Vol. 75, No. 22). Furthermore, Marone reported that there is evidence that human Fc epsilon RI(+) cells could be infected in vitro by M-tropic HTV-1 strains. (Marone G, de Paulis A, Florio G, Petraroli A, Rossi FW, Triggiani M. Int Arch Allergy Immunol. 2001 Jun; 125 (2): 89-95). There is only few data available concerning the role of mast cells in defence against viral pathogens, however, mast cells have been demonstrated to be a potential reservoir of infection for several pathogens, such as HIV-1 and dengue, and capable of producing mediators following challenge with a number of viral products. (Marshall JS, King CA, McCurdy JD. Mast cell cytokine and chemokine responses to bacterial and viral infection. Curr Pharm Des. 2003;9(1): 11-24).

Mast cells (MC) are tissue elements derived from a particular subset of hematopoietic stem cells that express CD34, c-kit and CD 13 antigens (Kirshenbaum, 1999 and Isbizaka, 1993). Immature MC progenitors circulate in the bloodstream and differentiate in tissues. These differentiation and proliferation processes are under the influence of cytokines, one of utmost importance being Stem Cell Factor (SCF), also termed Kit ligand (KL), Steel factor (SL) or Mast Cell Growth Factor (MCGF). SCF receptor is encoded by the proto-oncogene c-kit, that belongs to type UI receptor tyrosine kinase subfamily (Boissan, 2000). This receptor is also expressed on others hematopoietic or non hematopoietic cells. Mast cells are characterized by their heterogeneity, not only regarding tissue location and structure but also at the functional and histochemical levels (Aldenborg, 1994 ; Bradding, 1995 ; Irani, 1991 , 1989 and Welle, 1997). Li and al, demonstrated that many patients with acquired immunodeficiency syndrome have HIV- 1 -infected MCsT-tasophils in their peripheral blood using a population of metachromatic cells with mast cell (MC) and basophil features. These metachromatic cells express on their surface the gh-affinity IgE receptor (FcepsilonRI), CD4, and the chemokine receptors CCR3, CCR5, and CXCR4, but not the T-cell surface protein CD3 and the monocyte/macrophage surface protein CD68. This lead to susceptibility of mast cells (MCs)/basophils to revirus. (Li Y, Li L, Wadley R, Reddel SW, Qi JC, Archis C, Collins A, Clark E, Cooley M, Kouts S, Naif HM, Alali M, Cunningham A, Wong GW, Stevens RL, Krilis SA. Mast cells/lDasophils in the peripheral blood of allergic individuals who are HIV-1 susceptible due to their surface expression of CD4 and the chemokine receptors CCR3, CCR5, and CXCR4. Blood. 2001 Jun l;97(l l):3484-90.) Qi and al confirmed that AIDS patients often contain HIV-1 -infected mast cells (MCsVbasophils in their peripheral blood. (Qi JC, Stevens RL, Wadley R, Collins A, Cooley M, Naif HM, Nasr N, Cunningham A, Katsoulotos G, Wanigasek Y, Roufogalis B, Krilis SA. E - 16 regulation of human mast ceh^asophils and their susceptibility to HIV-1. J Immunol. 2002 Apr 15;168(8):4127-34).

When infected in vitro with viruses pseudotyped with different HIV and simian immunodeficiency virus envelope glycoproteins, only M-tropic and dualtropic, but not T-tropic, viruses were able to enter mast cell progenitors. Cultures infected with replication-competent virus produced progressively increasing amounts of virus for 21 days as indicated by p24 antigen detection. Mast cell progenitors that were exposed to an M-tropic, green fluorescent protein-expressing HIV-1 strain exhibited fluorescence indicative of viral entry and replication on a single-cell level and retained virus production during differentiation. We postulate here that mast cells may play a larger role in HIV infection than previously thought. Indeed, mast cells can contain and continue to produce large amounts of an HIV-like virus even after the virus depletes CD4+T cells. This discovery provides an explanation on how the virus might survive despites the use of reverse transcriptase and protease inhibitors. Moreover, we have observed that MC has a long life and can migrate throughout the body.

As a consequence, we propose to deplete mast cells to eradicate latent HIV virus in the course of reverse transcriptase and protease inhibitors therapy. In connection with the present invention, we have discovered that c-kit inhibitors are particularly suited for depleting HIV infected mast cells and could be a new route for treating HIV infection and related diseases as well as delaying the onset of AIDS through inhibition of mast cells.

Description

The present invention relates to a method for treating HIV infection and related diseases, including human immunodeficiency virus type 1 and 2, or delaying the onset of acquired immunodeficiency syndrome (AIDS), comprising administering a compound capable of depleting mast cells or a compound inhibiting mast cells degranulation in a human in need of such treatment.

Said method for treating HIV infection and related diseases or delaying the onset of AIDS can comprise administering a c-kit inhibitor to a human in need of such treatment.

Preferred compounds are c-kit inhibitor, more particularly a non-toxic, selective and potent c-kit inhibitor. Such inhibitors can be selected from the group consisting of 2-(3- Substitutedaryl)amino-4-aryl-thiazoles such as 2-(3-amino)arylamino-4-aryl-thiazoles, 2- ammoaryloxazoles, pyrimidme derivatives, pyrrolopyrimidine derivatives, quinazoline derivatives, quinoxaline derivatives, pyrazoles derivatives, bis monocyclic, bicyclic or heterocyclic aryl compounds, vinylene-azaindole derivatives and pyridyl-quinolones derivatives, styryl compounds, styryl-substituted pyridyl compounds, seleoindoles, selenides, tricyclic polyhydroxylic compounds and benzylphosphonic acid compounds.

Among prefereed compounds, it is of interest to focus on pyrimidine derivatives such as N-phenyl-2-pyrimidine-amine derivatives (US 5,521,184 and WO 99/03854), indolinone derivatives and pyrrol-substituted indolinones (US 5,792,783, EP 934 931, US 5,834,504), US 5,883,116, US 5,883,113, US 5, 886,020, WO 96/40116 and WO 00/38519), as well as bis monocyclic, bicyclic aryl and heteroaryl compounds (EP 584 222, US 5,656,643 and WO 92/20642), quinazoline derivatives (EP 602 851, EP 520 722, US 3,772,295 and US 4,343,940), 4-amino-substituted quinazolines (US 3,470,182), 4-thienyl-2-(lH)-quinazolones, 6,7-dialkoxyquinazolines (US 3,800,039), aryl and heteroaryl quinazoline (US 5,721,237, US 5,714,493, US 5,710,158 and WO 95/15758), 4-anilinoquinazoline compounds (US 4,464,375), and 4-thienyl-2-(lH)- quinazolones (US 3,551,427).

So, preferably, the invention relates to a method for treating HIV related diseases and related disorders comprising administering a non toxic, potent and selective c-kit inhibitor is a pyrimidine derivatives, more particularly N-phenyl-2-pyrimidine-amine derivatives of formula I :

wherein the Rl, R2, R3, R13 to R17 groups have the meanings depicted in EP 564 409 Bl, incorporated herein in the description. Preferably, the N-phenyl-2-pyrimidine-amine derivative is selected from the compounds corresponding to formula π :

Wherein Rl, R2 and R3 are independently chosen from H, F, Cl, Br, I, a C1-C5 alkyl or a cyclic or heterocyclic group, especially a pyridyl group;

R4, R5 and R6 are independently chosen from H, F, Cl, Br, I, a C1-C5 alkyl, especially a methyl group; and R7 is a phenyl group bearing at least one substituent, which in turn possesses at least one basic site, such as an amino function. Preferably, R7 is the following group :

Among these compounds, the preferred are defined as follows :

Rl is a heterocyclic group, especially a pyridyl group,

R2 and R3 are H,

R4 is a C1-C3 alkyl, especially a methyl group,

R5 and R6 are H, and R7 is a phenyl group bearing at least one substituent, which in turn possesses at least one basic site, such as an amino function, for example the group :

Therefore, in a preferred embodiment, the invention relates to a method for treating HIV related disorders comprising the administration of an effective amount of the compound known in the art as CGP57148B :

4-(4-mehylpiperazine-l-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-yl)pyrimidine-2 ylamino)phenyl]-benzamide corresponding to the following formula :

The preparation of this compound is described in example 21 of EP 564409 and the β- form, which is particularly useful is described in WO 99/03854.

In another preferred embodiment, the invention contemplates the method mentioned above, wherein said c-kit inhibitor is selected from 2-(3-SubstitutedaryI)amino-4-aryl- thiazoles such as those for which the applicant filed PCT/IB2005/000401, incorporated herein by reference, especially compounds of formula III :

FORMULA III wherein

R⁶ and R⁷ are independently from each other chosen from one of the following: i) hydrogen, a halogen (selected from F, Cl, Br or 1), ii) an alkyl¹ group defined as a linear, branched or cycloalkyl group containing from 1 to 10 carbon atoms, or from 2 or 3 to 10 carbon atoms, (for example methyl, ethyl, propyl, butyl, pentyl, hexyl...) and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (the latter optionally in the form of a pendant basic nitrogen functionality); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl;

(iii) an aryl¹ group defined as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as - halogen(selected from I, F, Cl or Br); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality; - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the fonn of a basic nitrogen functionality; (iv) a heteroaryl¹ group defined as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl , triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as - halogen (selected from F, Cl, Br or I); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality, - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; (v) trifluoromethyl, carboxyl, cyano, nitro, formyl, hydroxy, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality.

R⁸ is one of the following:

(i) hydrogen, or (ii) a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as. halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or

(iii) CO-R8 or COOR8 or CONHR8 or S02R8 wherein R8 maybe - a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F,

Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or - an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen

(selected from F, Cl, Br or I), alkyl groups containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, -βalkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, Cι-₆alkylamino, di(Cι-₆alkyl)amino, and amino, the latter nitrogen substituents optionally in the form of a pendant basic nitrogen functionality; as well as CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or - a heteroaryl group such as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as halogen (selected from F, Cl, Br or I), alkyl groups containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Cι-₆alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, Cι-₆alkylamino, di(C₁.₆alkyl)amino, and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; as well as CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality.

R2, R3, R4 and R5 each independently are selected from hydrogen, halogen (selected from F, Cl, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Cι-₆alkyloxy, amino, Ci- ₆alkylamino, di(C₁-₆alkyl)amino, carboxyl, cyano, nitro, formyl, hydroxy, and CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality. A is : CH2, O, S, SO2, CO, or COO,

B is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, SO2, CO, or COO, JEV is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, SO2, CO or COO; R* being an alkyl¹, aryl¹ or heteroaryl¹ W is a bond or a linker selected from NH, NHCO, NHCOO, NHCONH, NHSO2, NHSO2NH, CO, CONH, COO, COCH2, (CH2)n (n is 0, 1 or 2), CH2-CO, CH2COO, CH2-NH, O, OCH2, S, S02, and SO2NH

R^s : a) a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; b) an aryl or heteroaryl group optionally substituted by an alkyl or aryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality c) an alkyl¹, aryl¹ or heteroaryl¹.

It will be understood that a C1-C10 alkyl encompasses a methyl, ethyl, propyl, and a C2 to C4 alkyl or a C2 to C 10 alkyl.

For example, a subset of compounds may correspond to

Wherein Rl, R4 and R6 have the meaning as defined above.

It will be understood that A-B-B' includes but is not limited to CH2, CH2-CO, CH2-CO-CH2, CH2COO, CH2-CH2-CO, CH2-CH2-COO, CH2-NH, CH2-CH2-NH, CH2-NH-CH2 or CH2-NH-CO or CH2-CO-NH It will be understood that A-B-B' also includes but is not limited to : CO-CH2, COO-CH2, CO-CH2-CH2, CO-NH, or CO-NH-CH2 as well as O-CH2

It will also be understood that NH in B or B' can also be NCH3

In the above formula UI, when W is other than a single bond, it will be understood that A can be also be NH or NCH3.

In the above formula, the following combinations are contemplated :

- R6 is (iv), R4 is H or CH3, A-B-B' is CO-NH and Rl is as defined above.

- R6 is (iv), R4 is H or CH3, A-B-B' is CH2-CO-NH and Rl is as defined above. - R6 is (iv), R4 is H or CH3, A-B-B' is CH2-CO and Rl is as defined above.

- R6 is (iv), R4 is H or CH3, A-B-B' is CH2-NH-CO and Rl is as defined above.

- R6 is (iv), R4 is H or CH3, A-B-B' is CH2-NH and Rl is as defined above.

- R6 is (iv), R4 is H or CH3, A-B-B' is CH2 and Rl is as defined above.

- R6 is W-(iv), R4 is a C1-C2 alkyl, A-B-B' is CO-NH and Rl is as defined above. - R6 is (iv), R4 is a C1-C2 alkyl, A-B-B' is CH2-CO-NH and Rl is as defined above.

- R6 is (iv), R4 is a C1-C2 alkyl, A-B-B' is CH2-CO and Rl is as defined above.

- R6 is a pyridyl according to (iv), R4 is a C1-C2 alkyl, A-B-B' is CO-NH, CH2-CO-NH, CH2-CO, CH2-NH, CH2-NH-CO and Rl is as defined above.

In the above combination, Rl can be an alkyl¹. In the above combination, Rl can be an aryl¹. In the above combination, Rl can be an heteroaryl¹. In another preferred embodiment, the invention contemplated the method mentioned above, wherein said c-kit inhibitor is selected from 2-(3-amino)arylamino-4-aryl- thiazoles such as those for which the applicant filed WO 2004/014903, incorporated herein in the description, especially compounds of formula IN :

FORMULA IV and wherein R¹ is : a) a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; b) an aryl or heteroaryl group optionally substituted by an alkyl or aryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; c) a -CO-NH-R, -CO-R, -CO-OR or a -CO-NRR' group, wherein R and R' are independently chosen from H or an aryl, heteroaryl, alkyl and cycloalkyl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;

R² is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R³ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁴ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁵ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁶ is one of the following:

(i) an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy;

(ii) a heteroaryl group such as a 2,.3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; (iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from

1 to 10 carbon atoms, trifluoromethyl, and alkoxy, iv) H, a halogen selected from I, F, Cl or Br; NH2, NO2 or SO2-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl,

Br and F, and / or bearing a pendant basic nitrogen functionality; and R⁷ is one of the following:

(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; (iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from

1 to 10 carbon atoms, trifluoromethyl, and alkoxy. iv) H, a halogen selected from I, F, Cl or Br; NH2, NO2 or.SO2-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality.

In another preferred embodiment, when R¹ has the meaning depicted in c) above, the invention is directed to compounds of the following formulas:

wherein R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted by an 'alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F and / or bearing a pendant basic nitrogen functionality.

Among the particular compounds in which Rl has the meaning as depicted in c) above, the invention is directed to amide-aniline, amide-benzylamine, amide-phenol, urea compounds of the following formulas respectively :

wherein R is H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F and / or bearing a pendant basic nitrogen functionality; or a a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F and / or bearing a pendant basic nitrogen functionality; a -SO2-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F and / or bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR' group, wherein R and R' are independently chosen from H, an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality.

Among the particular compounds in which Rl has the meaning as depicted in a) and b) above, the invention is directed to N-Ammodkyl-N'-tiιiazol-2-yl-benzene-l,3-diamine compounds of the following formula IVbis:

wherein Y is a linear or branched alkyl group containing from 1 to 10 carbon atoms; wherein Z represents an aryl or heteroaryl group, optionally substituted at one or more ring position with any permutation of the following groups: - a halogen such as F, Cl, Br, I; - a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; - an O-R, where R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one li heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;

- an NRaRb, where Ra and Rb represents a hydrogen, or a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality or a cycle; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;

- a COOR, where R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; - a CONRaRb, where Ra and Rb are a hydrogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;

- an NHCOR, where R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; - an NHCOOR, where R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;

- an NHCONRaRb, where Ra and Rb are a hydrogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; - an OSO₂R, where R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; - an NRaOSO₂Rb, where Ra and Rb are a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom (for example a halogen) and / or bearing a pendant basic nitrogen functionality; Ra can also be a hydrogen; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality;

R³ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁴ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁵ is hydrogen, halogen or a linear or branched alkyl group contaimng from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁶ is one of the following:

(i) an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy; (ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

(iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy. iv) H, a halogen selected from I, F, Cl or Br; NH2, NO2 or SO2-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; and R⁷ is one of the following:

(iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy. iv) H, an halogen selected from I, F, Cl or Br; NH2, NO2 or SO2-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality. It will be understood that a C1-C10 alkyl encompasses a methyl, ethyl, propyl, and a C2 to C4 alkyl or a C2 to CIO alkyl.

An example of preferred compounds of the above formula is depicted below:

4-{[4-Methyl-3-(4-pvridm-3-yl-tMazol-2-ylamino)-phenylamino]-methyl}-benzoic acid methyl ester

Among the compounds of formula nj or IV, the invention is particularly embodied by the compounds of the following formula V:

FORMULA V wherein X is R or NRR' and wherein R and R' are independently chosen from H, an aryl, a heteroaryl, an alkyl , or a cycloalkyl group optionally substituted with at least one heteroatom, such as for example a halogen chosen from F, I, Cl and Br and optionally bearing a pendant basic nitrogen functionality; or an aryl, a heteroaryl, an alkyl or a cycloalkyl group substituted with an aryl, a heteroaryl, an alkyl or a cycloalkyl group optionally substituted with at least one heteroatom, such as for example a halogen chosen from F, I, Cl and Br and optionally bearing a pendant basic nitrogen functionality,

R² is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R³ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁴ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁵ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁶ is one of the following:

(iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from

1 to 10 carbon atoms, trifluoromethyl, and alkoxy. iv) H, a halogen selected from I, F, Cl or Br; NH2, NO2 or SO2-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon, atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality.

In another alternative, substituent R6, which in the formula JJ is connected to position 4 of the thiazole ring, may instead occupy position 5 of the thiazole ring. Among the preferred compounds corresponding formula in, IV or V, the invention is directed to compounds in which Rl or X is a substituted alkyl, aryl or heteroaryl group bearing a pendant basic nitrogen functionality represented for example by the structures a to f and g to m shown below, wherein the wavy line corresponds to the point of attachment to core structure of formula ILL IV or V:

Among group a to f, is preferentially group d. Also, for g to m, the arrow may include a point of attachment to the core structure via a phenyl group.

Furthermore, among the prefened compounds of formula III, IV or V, the invention concerns the compounds in which R² and R³ are hydrogen. Preferentially, R⁴ is a methyl group and R⁵ is H. In addition, R⁶ is preferentially a 3 -pyridyl group (cf. structure g below), or a 4-pyridyl group (cf. structure h below) or a benzonitrile group. The wavy line in structure g and h coreespond to the point of attachment to the core structure of formula III, IV or V.

g

Alternatively, among the preferred compounds of formula HI, IV or V, the invention concerns the compounds in which R6 or R7 is preferentially a cyanophenyl group as shown below, wherein the wavy line in structure p and q correspond to the point of attachment to the core structure of formula III, IV or V:

p q

In one particular embodiment, Rl in formula III and IV, X in formula V and Z in formula IVbis can be :

wherein Ri, Rj, Rk, Rl, Rm, Ro, and Rp are independently chosen from :

- H, an halogen such as Cl, F, Br, I ; a trifluoromethyl group, a CN group, SO2, OH, or a group selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality;

- a NRR', NRCOR, NRCONR'R", NROSO₂R', SO2-R, COOR, CONRR', NHCOOR, CO-R, CO-NRR', OR or OSO₂R group where R and R' are idenpendently chosen from H or a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality.

For example, one of Ri, Rj, Rk, Rl, Rm, Ro or Rp is selected from group a, b, c, g, h, i, j, k, 1, m as defined above such as Rk is one of a, b, c, g, h, i, j, k, 1, m and Ri, Rj, Rl, Rm is H.

Thus, the invention contemplates: 1 - A compound of formula V as depicted above, wherein X is group d and R⁶ is a 3- pyridyl group. 2- A compound of formula V as depicted above, wherein X is group d and R⁴ is a methyl group. 3- A compound of formula HE or IV as depicted above, wherein R¹ is group d and R² and/or R³ and/or R⁵ is H. 4- A compound of formula JJI or TV as depicted above, wherein R⁶ is a 3-pyridyl group and R⁴ is a methyl group. 5- A compound of formula HI or IV as depicted above, wherein R² and/or R³ and/or R⁵ is H and R⁴ is a methyl group. 6- A compound of formula 111 or IV as depicted above wherein R² and or R³ and/or R⁵ is H, R⁴ is a methyl group and R⁶ is a 3-pyridyl group.

Among the compounds of formula IV, the invention is particularly embodied by the compounds wherein R2, R3, R5 are hydrogen, corresponding to the following formula

wherein X is R or NRR' and wherein R and R' are independently chosen from H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; or a a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; a -SO2-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR' group, wherein R and

R' are independently chosen from H, an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality. R is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy;

R⁶ is one of the following:

(ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

1 to 10 carbon atoms, trifluoromethyl, and alkoxy. iv) H, a halogen selected from I, F, Cl or Br; NH2, N02 or SO2-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl,

Br and F, and / or bearing a pendant basic nitrogen functionality.

In another alternative, substituent R6, which in the formula III is connected to position 4 of the thiazole ring, may instead occupy position 5 of the thiazole ring.

Examples :

2-(2-methyl-5-a ino)phenyl-4-(3-pyridyl)-tlιiazole

4-(4-Methyl-piperazin-l-ylmethyl)-N-[3-(4-p ridin-3-yl-tiιiazol-2-ylamino)-phenyl]-berιzamide N-[4-Methyl-3-(4-phenyl-thiazol-2-ylamino)-phenyl]-4-(4-methyl-piperazin-l-ylmethyl)- benzamide

N-[3-([2,4']Bithiazolyl-2'-ylaιr no)-4-methyl-phenyl]-4-(4-methyl-piperazin-l-ylmetlαyl)- benzamide 4-(4-Methyl-piperazin-l-yl ethyl)-N-[4-methyl-3-(4-pyrazin-2-yl-thiazol-2-ylamino)-phenyl]- benzamide

2-[5-(3-Iodo-benzoylamino)-2-methyl-phenylamino]-thiazole-4-carboxylic acid ethyl ester

2-{2-Methyl-5-[4-(4-methyl-piperazin-l-ylmethyl)-benzoylaιnino]-phenylamino}-thiazole-4- carboxylic acid ethyl ester 2-(2-chloro-5-amino)phenyl-4-(3-pyridyl)-thiazole

3-Bromo-N-{3-[4-(4_:chloro-phenyl)-5-methyl-thiazol-2-ylamino]-4-methyl-plιenyl}-benzamide

{3-[4-(4-Chloro-phenyl)-5-methyl-thiazol-2-ylamino]-4-methyl-phenyl}-carbamic acid isobutyl ester

2-[5-(3-Bromo-benzoylamino)-2-methyl-phenylamino]-5-(4-chloro-phenyl)-thiazole-4- carboxylic acid ethyl ester

2-[5-(3-Bromo-benzoylamino)-2-methyl-phenylamino]-5-(4-chloro-phenyl)-thiazole-4- carboxylic acid (2-dimemylamino-ethyl)-amide

N-{3-[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-l ylmethyl)-benzamide 4-(4-Methyl-piperazin-l-ylmethyl)-N-{4-methyl-3-[4-(3-trifluoromethyl-phenyl)-thiazol-2- ylamino]-phenyl} -benzamide

N-{4-Methyl-3-[4-(3-nitro-phenyl)-thiazol-2-ylamino]-phenyl}-4-(4-methyl-piperazin-l- ylmethyl)-benzamide

N-{3-[4-(2,5-Dimethyl-phenyl)-thiazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-l- ylmethyl)-benzamide

N-{3-[4-(4-Chloro-phenyl)-thiazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-l- ylmethyl)-benzamide

N-{3-[4-(3-Methoxy-phenyl)-tWazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-l- ylmethyl)-benzamide N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-isonicotinamide 2,6-Dichloro-N-[4-me1hyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-isonicotinamide 3-Phenyl-propynoic acid [4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)-phenyl]-amide Cyclohexanecarboxylic acid [4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylmethyl)-phenyl]-amide 5-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenylcarbamoyl]-pentanoic acid ethyl ester 1-Methyl-cyclohexanecarboxylic acid [4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylmethyl)-phenyl]- amide

4-tert-Butyl-cyclohexanecarboxylic acid [4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl]-amide N-[4-Methyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)-phenyl]-4-morpholin-4-yl-butyr amide

Among the compounds of formula IV, the invention is particularly embodied by the compounds wherein X is a urea group, a -CO-NRR' group, corresponding to the [3- (thiazol-2-ylamino)-phenyl]-urea family and the following formula:

wherein Ra, Rb are independently chosen from Y-Z as defined above or

H or an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; a -SO2-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR' group, wherein R and R' are independently chosen from H, an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably selected from I, Cl, Br and F, or bearing a pendant basic nitrogen functionality. R⁴ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; R⁶ is one of the following:

(iii) a five-membered ring aromatic heterocyclic group such as for example 2-thienyl, 3- thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, which may additionally bear any combination of one or more substituents such as halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy. iv) H, a halogen selected from I, F, Cl or Br; NH2, NO2 or SO2-R, wherein R is a linear or branched alkyl goup contaimng one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality.

Example 1 l-(4-Methoxy-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-urea l-(4-Bromo-phenyl)-3-[4-melhyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-ιιrea l-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-3-(4-trifluoromethyl-phenyl)-tιrea l-(4-Fluoro-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-urea l-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-urea 4-{3-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-ureido}-benzoic acid ethyl ester l-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-3-thiophen-2-yl-urea l-Cyclohexyl-l-(N-Cyclohexyl-foπnamide)-3-[4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)- phenyl]-urea l-(2,4-Dimethoxy-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-urea l-(2-Iodo-phenyl)-l-(N-(2-Iodo-phenyl)-foιmamide)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2- ylamino)-phenyl]-urea l-(3,5-Dimethyl-isoxazol-4-yl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-urea l-(2-Iodo-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl^Wazol-2-ylamino)-phenyl]-urea l-(4-Difluorome oxy-phenyl)-3-[4-methyl-3-(4-p5τidin-3-yl-thiazol-2-ylamino)-phenyl]-urea l-(4-Dimethylaιmno-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-ιιrea 1 -(2-Fluoro-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-urea l-(2-Chloro-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-urea l-(3-Fluoro-phenyl)-3-[4-methyl-3-(4-pyridm-3-yl-thiazol-2-ylamino)-phenyl]-urea l-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-3-p-tolyl-urea 3-Bromo-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide 3-Iodo-N-[4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

4-Hydroxymemyl-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-yla₁iiirio)-phenyl]-berizamide 4-Amino-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylarnino)-phenyl]-benzamide 2-Iodo-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide 4-Iodo-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide 4-(3- {4-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenylcarbamoyl]-phenyl} -ureido)- benzoic acid ethyl ester

N-[4-Melhyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)-phenyl]-4-[3-(4-trifluoromethyl-phenyl)- ureidoj-benzamide 4-[3-(4-Bromo-phenyl)-ureido]-N-[4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide

4-Hydroxy-N-[4-me1hyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-(3-thiophen-2-yl-ureido)- benzamide 4-[3-(3,5-Dime yl-isoxazol-4-yl)-ureido]-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenylj-benzamide 4-[3-(4-Me1hoxy-phenyl)-ιιreido]-N-[4-methyl-3-(4-pyridm-3-yl-thiazol-2-ylamino)-phenyl]- benzamide

4-[3-(4-Difluoromethoxy-phenyl)-ureido]-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl]-benzamide Thiophene-2-sulfonic acid 4-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenylcarbamoyl]- phenyl ester

4-Iodo-benzenesulfonic acid 4-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenylcarbamoyl]-phenyl ester

N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-(thiophene-2-sulfonylamino)- benzamide

3-Fluoro-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-p ridin-4-yl-benzamide

4-Dimethylamino-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzaιnide

2-Fluoro-5-methyl-N-[4-methyl-3-(4-pyridm-3-yl-thiazol-2-ylamino)-phenyl]-benzamide 4-tert-Butyl-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-beιιzamide

4-Isopropoxy-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmemyl)-phenyl]-benzamide

Benzo[l ,3]dioxole-5-carboxylic acid [4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)-phenyl]- amide

N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-3-(2-morpholin-4-yl-ethoxy)- benzamide

N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)-phenyl]-4-p ridin-4-yl-benzamide

3-Cyano-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

2-Fluoro-N-[4-me yl-3-(4-pyridin-3-yl-1hiazol-2-ylamino)-phenyl]-3-trifluoromethyl- benzamide 3-Fluoro-benzenesulfo^'nic acid 4-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenylcarbamoyl]-phenyl ester

4-Aminomethyl-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylaιnino)-phenyl]-benzamide

2-Fluoro-benzenesulfonic acid 4-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenylcarbamoyl]-phenyl ester 3-Methoxy-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)-phenyl]-beιιzamide 4-(4-Methyl-ρiperazin-l-yl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)-ρhenyl]- benzamide

3-Methyl-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylammo)-phenyl]-benzamide

Biphenyl-3-carboxylic acid [4-methyl-3-(4-pyridin-3-yl-tMazol-2-ylamino)-phenyl]-amide N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-3-1rifluoromethyl-benzamide

N-[4-Methyl-3-(4-pyridm-3-yl-thiazol-2-ylamino)-phenyl]-4-p rrolidin-l-ylmethyl-benzamide

4-[3-(2,4-Dimethoxy-phenyl)-ureido]-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl]-benzamide

4-[3-(2-Iodo-phenyl)-ureido]-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide

4-[3-(4-Fluoro-phenyl)-ureido]-N-[4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide

3-Bromo-4-methyl-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

4-Fluoro-N-[4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide 4-Cyano-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

4-Fluoro-N-[4-methyl-3-(4-pyridin-3-yl-miazol-2-ylamino)-phenyl]-benzamide

Example 2

4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide

3,5-Dibromo-4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2- ylamino)-phenyl] -benzamide

4-Diemylaπιinomethyl-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-morpholin-4-ylmethyl-benzamide 4-Dipropylaminomethyl-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide

N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-piperidin-l-ylmethyl-benzamide

4-[(Diisopropylamino)-methyl]-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide

{4-[4-Methyl-3-(4-pyridin-3-yl-tlιiazol-2-ylaιnino)-phenylcarbamoyl]-benzyl}-carbamic acid tert-butyl ester 3-Fluoro-4-(4-methyl-piperazin-l-ylmemyl)-N-[4-memyl-3-(4-p ridin-3-yl-thiazol-2-ylamino)- phenylj-benzamide

4-(4-Methyl-piperazin-l-ylmethyl)-N-[4- ιethyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)-phenyl]- 3-trifluoromethyl-benzamide 2,3,5,6-Tetrafluoro-4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2- ylamino)-phenyl]-benzamide

N- {3-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-4-methyl-phenyl} -4-(4-methyl-piperazin- 1 - ylmethyl)-benzamide 3-Bromo-4-(4-memyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl]-benzamide

3-Chloro-4-(4-me yl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)- phenyl]-benzamide

4-(4-Methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-phenyl]- benzamide

N-{3-[4-(4-Cyano-phenyl)-thiazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-l- ylmethyl)-benzamide

4-[l-(4-Methyl-piperazin-l-yl)-ethyl]-N-[4-methyl-3-(4-pyridm-3-yl-thiazol-2-ylmethyl)-^ phenyl]-benzamide 4-(l-Methoxy-ethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)-phenyl]-benzamide

N-{4-Methyl-3-[4-(5-methyl-pyridin-3-yl)-thiazol-2-ylamino]-phenyl}-4-(4-methyl-piperazin-l- ylmethyl)-benzamide 3-Iodo-4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylmethyl)- phenyl]-benzamide N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-[3-(4-trifluoromethyl-phenyl)- ureidomethyl]-benzamide

3,5-Dibromo-N-[4-memyl-3-(4-pyridin-3-yl-tMazol-2-ylamino)-phenyl]-4-[(3-morpholin-4-yl- propylamino)-methyl]-benzamide

3,5-Dibromo-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-4-piperidin-l-ylmethyl- benzamide 4-(4-Methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(4-p ridin-2-yl-thiazol-2-ylammo)-phenyl]- benzamide

N-{3-[4-(3-Fluoro-phenyl)-thiazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-l- ylmethyl)-benzaroide N-{3-[4-(2-Fluoro-phenyl)-thiazol-2-ylamino]-4-methyl-phenyl}-4-(4-methyl-piperazin-l- ylmethyl)-benzamides

Example 3

3-Dimethylamino-N-[4-memyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-benzamide 3-(4-Methyl-piperazin-l-yl)-N-[4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]- benzamide N-[4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-phenyl]-3-morpholin-4-yl-benzamide

Among the compounds of formula IV, the invention is particularly embodied by the compounds wherein X is a -OR group, corresponding to the family [3-(Thiazol-2- ylamino)-phenyl]-carbamate and the following formula IV-6

FORMULA IV-6

wherein R is independently chosen from an organic group that can be selected for example from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, Cl, Br and F and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F and / or bearing a pendant basic nitrogen functionality; R4 and R6 are as defined above.

In still another preferred embodiment, the invention contemplated the method mentioned above, wherein said c-kit inhibitor is selected from 2-aminoaryloxazoles of formula X :

FORMULA X

wherein substituents Rl - R7 and X are defined as follows:

Rl, R2, R3 and R4 each independently are selected from hydrogen, halogen (selected from F, Cl, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Cι-₆alkyloxy, amino, Ci- ₆alkylamino,

carboxyl, cyano, nitro, formyl, hydroxy, and CO-R, COO-R, CONH-R, SO2-R, and S02NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality. R5 is one of the following: (i) hydrogen, or

(ii) a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and mtrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or (iii) CO-R8 or COOR8 or CONHR8 or SO2R8 wherein R8 maybe - a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or - an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen (selected from F, Cl, Br or I), alkyl groups containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, -βalkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, Cι-₆alkylamino, di(Cι-₆allyι)amino, and amino, the latter nitrogen substituents optionally in the form of a pendant basic nitrogen functionality; as well as CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and mtrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or - a heteroaryl group such as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as halogen (selected from F, Cl, Br or I), alkyl groups containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, C ealkylo y, carboxyl, cyano, nitro, formyl, hydroxy, -_όalkylamino, di(Ci-₆alkyl)amino, and amino, the latter mtrogen substituents optionally in the form of a basic nitrogen functionality; as well as CO-R, COO-R, CONH-R, S02-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality.

R6 and R7 each independently are selected from: i) hydrogen, a halogen (selected from F, Cl, Br or I), or ii) an alkyl¹ group defined as a linear, branched or cycloalkyl group containing from 1 to

10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (the latter optionally in the form of a pendant basic nitrogen functionality); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; as well as CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality ; as well as a cycloalkyl or aryl or heteroaryl group optionally substituted by a a pendant basic nitrogen functionality, or

(iii) an aryl¹ group defined as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as - halogen(selected from I, F, Cl or Br); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality; - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; - NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R corresponds to hydrogen, alkyl¹, aryl or heteroaryl, or (iv) a heteroaryl¹ group defined as a pyridyl, pyrimidinyl, pyrazmyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl , triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as - halogen (selected from F, Cl, Br or I); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality, - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; , - NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R conesponds to hydrogern, alkyl¹, or

(v) an O-aryl¹, or NH-aryl¹, or O-heteroaryl¹ or NH-heteroaryl¹ group (vi) trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality, or (vi) NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R corresponds to hydrogen, alkyl¹, aryl or heteroaryl. X is:

-NR9R10, wherein R9 and / or RIO are hydrogen or: i) an alkyl¹ group, CF3 or ii) an aryl¹, heteroaryl¹ or cycloalkyl group optionally substituted by a a pendant basic mtrogen functionality, or iii) a CO-R, COO-R, CON-RR'or SO2-R, where R and R' are a hydrogen, alkyl¹, aryl¹ or heteroaryl¹, optionally substituted by a a pendant basic nitrogen functionality; or:

-CO-NR9R10, wherein R9 and / or RIO are hydrogen or: i) an alkyl¹ group, CF3 or ii) an aryl¹, heteroaryl¹ or cycloalkyl group optionally substituted by a a pendant basic nitrogen functionality.

Such compound may be selected from N-Aminoalkyl-N'-oxazol-2-yl-benzene-l,3- diamines of the following formula:

wherein R5 = H, Y is a linear or branched alkyl group contaimng from 1 to 10 carbon atoms and Z represents an aryl or a heteroaryl group, optionally substituted by a pendant basic nitrogen functionality.

For example, it is the 4-{[4-Methyl-3-(4-pyridin-3-yl-oxazol-2-ylamino)-phenylamino]- methyl}-benzoic acid methyl ester. The above 2-aminoaryloxazoles compounds may have the formula XI:

FORMULA XI

Wherein R5 is H, Y is selected from O, S and Z corresponds to H, alkyl, or NRR', wherein R and R' are independently chosen from H or alkyl¹ or aryl¹ or heteroaryl¹, optionally substituted by a pendant basic nitrogen functionality, for example :

or a compound of formula XI- 1 :

FORMULA XI- 1

wherein Ra, Rb are independently chosen from H or alkyl¹ or aryl¹ or heteroaryl¹, optionally substituted by a pendant basic nitrogen functionality, for example :

or a compoimd of formula XI-2:

FORMULA XI-2

wherein R5 = H, Z is an aryl¹ group, aryl¹ being selected from : a phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as - halogen(selected from I, F, Cl or Br); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality; - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality;

NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or S02-R or SO2NH-R wherein R conesponds to hydrogen, alkyl¹, aryl or heteroaryl, for example

or a compound of formula XI-3 :

FORMULA XI-3

wherein R5 = H and R is independently alkyl¹, aryl¹ or heteroaryl¹ as defined above.

Examples of compounds of Formula X : 4-{[4-Methyl-3-(4-pyridin-3-yl-oxazol-2-ylamino)-phenylamino]-methyl}-benzoic acid methyl ester

4-Methyl-Nl-(5-pyridin-3-yl-oxazol-2-yl)--V3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-l,3-diamine m.p. 4-Methyl- -(5-phenyl-oxazol-2-yl)-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-l,3-diamine 4-Methyl- -(5-phenyl-[l,3,4]oxadiazol-2-yl)-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene-l,3- diamine

Nl -Benzooxazol-2-yl-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benzene- 1 ,3-diamine N-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-C-phenyl-methanesulfon -amide N-[4-Methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-acetamide

2-Cyano-N-[4-memyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-acetamide 2-Ethoxy-N-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-acetamide 3-Methoxy-N-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-propionamide l-(4-Cyano-phenyl)-3-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-urea l-(4-Fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-iirea l-(2-Fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-urea l-[4-Methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea l-(4-Chloro-phenyl)-3-[4-methyl-3-(5-p ridin-3-yl-oxazol-2-ylaιnino)-phenyl]-urea l-[4-Methyl-3-(5-phenyl-oxazol-2-ylamino)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea l-(4-Cyano-phenyl)-3-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-thiourea l-(4-Cyano-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-thiourea (2-{2-Methyl-5-[3-(4-trifluoromethyl-phenyl)-ureido]-phenylamino}-oxazol-5-yl)-acetic acid ethyl ester l-Benzyl-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-thiourea 4-(4-Methyl-piperazin-l-ylmethyl)-Ν-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]- benzamide

3-Dimethylarmno-N-[4-me yl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-benzamide 3-Bromo-Ν-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-benzamide N-[4-Me1hoxy-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide 4-(3-Dime ylaιmno-propylamino)-N-[4-memyl-3-(5-pyridin-3-yl-oxazol-2-ylanιino)-phenyl]-3- trifluoromethyl-benzamide

N-[4-Fluoro-3-(5-p ridin-3-yl-oxazol-2-ylar-ιino)-phenyl]-3-trifluoromethyl-benzamide lH-Indole-6-carboxylic acid [4-memyl-3-(5-pyridm-4-yl-oxazol-2-ylarnino)-phenyl]-amide 3-Isopropoxy-N-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-benzamide N-[4-Methyl-3-(5-pyridin-2-yl-oxazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide 3,5-Dimethoxy-N-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-benzamide N-[3-(5-Pyridin-3-yl-oxazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide N-[4-Methyl-3-(5-phenyl-oxazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide 3-Fluoro-4-(4-methyl-piperazin-l-ylmethyl)-N-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)- phenyl]-benzamide

N-[4-Chloro-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide N-[4-Methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-terephthalamide 5-Methyl-isoxazole-4-carboxylic acid [4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]- amide

4-Cyano-N-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-benzamide N-[4-Methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-isonicotinamide N-[4-Methyl-3-(4-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-3-trifluoromethyl-benzamide [4-Methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-carbamic acid isobutyl ester (5-Isobutoxycarbonylamino-2-methyl-phenyl)-(5-p ridin-3-yl-oxazol-2-yl)-carbamic acid isobutyl ester [4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-carbamic acid isobutyl ester N-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylaιιιino)-phenyl]-2-m-tolyl-acetamide 2-(4-Fluoro-phenyl)-N-[4-methoxy-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-acetamide 2-(2,4-Difluoro-phenyl)-N-[4-methyl-3-(5-phenyl-oxazol-2-ylamino)-phenyl]-acetamide 2-(3-Bromo-phenyl)-N-[4-methyl-3-(5-pyridin-2-yl-oxazol-2-ylamino)-phenyl]-acetamide 3-(4-Fluoro-phenyl)-N-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylarr-ino)-phenyl]-propionamide N-{3-[5-(4-Cyano-phenyl)-oxazol-2-ylamino]-4-methyl-phenyl}-2-(2,4-difluoro-phenyl)- acetamide 4-Methyl-pentanoic acid [4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-amide N-[4-Methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-2-piperazin-l-yl-acetamide N-[4-Methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-3-piperazin-l-yl-propionamide 2-(2,6-Dichloro-phenyl)-N-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-acetamide N-[4-Methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-3-pyrrolidin-l-yl-propionamide N-[4-Methoxy-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-2-(4-trifluoromethyl-phenyl)- acetamide

2-(4-Methoxy-phenyl)-N-[4-memyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-acetamide N-(4-Cyano-phenyl)-4-memyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-benzamide N-(3-Dimethylamino-phenyl)-4-methyl-3-(5-p ridin-4-yl-oxazol-2-ylamino)-benzamide N-(2-Dimethylamino-ethyl)-4-methyl-3 -(5 -pyridin-3 -yl-oxazol-2-ylamino)-benzamide N-(3-Fluoro-4-methyl-phenyl)-4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-benzamide N-(3-Chloro-phenyl)-4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-benzamide N-Benzyl-4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-benzamide N-(4-Methoxy-benzyl)-4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-benzamide [4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-morpholin-4-yl-methanone [4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-piperazin-l-yl-methanone N-(4-Fluoro-phenyl)-2-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-acetamide

Process for manufacturing a compound of formula III depicted above. This entails the condensation of a substrate of general formula 10 with a thiourea of the type 11.

l l a: X = ΝH-Rl 10 l l b: X = NH2 ll c: X = NH-PG ll d: X = NO2

Substituent "L" in formula 10 is a nucleofugal leaving group in nucleophilic substitution reactions (for example, L can be selected from chloro, bromo, iodo, toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, etc., with L being preferentially a bromo group).

Group Rl in formula 11a corresponds to group Rl as described in formula in.

Group "PG" in formula 1 lc is a suitable protecting group of a type commonly utilized by the person skilled in the art.

The reaction of 10 with 1 a-d leads to a thiozole-type product of formula 12a-d.

12 b: X = NH2 12 c: X = NH-PG 12 d: X = NO2 Formula 12a is the same as formula I. Therefore, Rl in 12a corresponds to Rl in formula m.

Formula 12b describes a precursor to compounds of formula UI which lack substituent Rl. Therefore, in a second phase of the synthesis, substituent Rl is connected to the free amine group in 12b, leading to the complete structure embodied by formula J-U: 12b + "Rl" ^ m The introduction of Rl, the nature of which is as described on page 3 for the general formula HI, is achieved by the use of standard reactions that are well known to the person skilled in the art, such as alkylation, acylation, sulfonylation, formation of ureas, etc.

Formula 12c describes an N-protected variant of compound 12b. Group "PG" in formula 12c represents a protecting group of the type commonly utilized by the person skilled in the art. Therefore, in a second phase of the synthesis, group PG is cleaved to transform compoimd 12c into compound 12b. Compound 12b is subsequently advanced to structures of formula I as detailed above.

Formula 12d describes a nitro analogue of compound 12b. In a second phase of the synthesis, the nitro group of compound 12d is reduced by any of the several methods utilized by the person skilled in the art to produce the corresponding amino group, namely compound 12b. Compound 12b thus obtained is subsequently advanced to structures of formula πT as detailed above.

Examples of compound synthesis is found in our previous applications WO 2004/014903 and US 60/513,214, incorporated herein by reference.

The expression HIV related diseases as refened herein includes the following therapeutic applications: all forms of human immunodeficiency virus type 1, type 2, acquired immunodeficiency syndrome, AIDS-related non-Hodgkin's lymphomas including aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, immunoblastic lymphomas and Kaposi's sarcoma, neurological disorders such as dementia, opportunistic infections such as Candida, oral hairy leukoplakia, herpes zoster (shingles), bacilliary angiomatosis and tuberculosis, bone disorders such as osteoporosis and osteopenia, progressive cytopenias (anemia, thrombocytopenia, leukopenia). In a further embodiment, c-kit inhibitors as mentioned above are inhibitors of wild type or mutant activated c-kit. In this regard, the invention contemplates a method for treating HIV infection and related diseases as defined above comprising administering to a human in need of such treatment a compound that is a selective, potent and non toxic inhibitor of c-kit obtainable by a screening method which comprises : a) bringing into contact (i) activated c-kit and (ii) at least one compound to be tested; under conditions allowing the components (i) and (ii) to form a complex, b) selecting compounds that inhibit activated c-kit, c) testing and selecting a subset of compounds identified in step b), which are unable to promote death of IL-3 dependent cells cultured in presence of IL-3.

This screening method can further comprise the step consisting of testing and selecting a subset of compounds identified in step b) that are inhibitors of mutant activated c-kit (for example in the transphosphorylase domain), which are also capable of inhibiting SCF- activated c-kit wild. Alternatively, in step a) activated c-kit is SCF-activated c-kit wild.

A best mode for practicing this method consists of testing putative inhibitors at a concentration above 10 μM in step a). In step c), IL-3 is preferably present in the culture media of IL-3 dependent cells at a concentration comprised between 0.5 and 10 ng/ml, preferably between 1 to 5 ng/ml. These screening may be performed following our previous applcation WO 03/003006, which is incorporated herein by reference.

Therefore, the invention embraces the use of the compounds defined above to manufacture a medicament for treating of all forms of human immunodeficiency virus type 1, type 2, treating or delaying the onset of acquired immunodeficiency syndrome, including ATDS-related non-Hodgkin's lymphomas including aggressive monoclonal B- cell Burkitt's lymphomas, large cell lymphomas, immunoblastic lymphomas and Kaposi's sarcoma, neurological disorders such as dementia, opportunistic infections such as Candida, oral hairy leukoplakia, herpes zoster (shingles), bacilliary angiomatosis and tuberculosis, bone disorders such as osteoporosis and osteopenia, progressive cytopenias (anemia, thrombocytopenia, leukopenia).

The pharmaceutical compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra- arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, sublingual, or rectal means.

h addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically-acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

Pharmaceutical compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.

More particularly, the invention relates to a pharmaceutical composition intended for oral administration.

Pharmaceutical compositions suitable for use in the invention include compositions wherein compounds for depleting mast cells, such as c-kit inhibitors, or compounds inhibiting mast cells degranulation are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art. A therapeutically effective dose refers to that amount of active ingredient, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 ED50. Pharmaceutical compositions which exhibit large therapeutic indices are preferred.

Example 1 : AB compounds of formula III, IV, V and X are selective and potent c- Kit and mast cell inhibitors. The specific compounds as listed above are non limitative illustrative examples of AB compounds. They display IC50 below 5 μM, 1 μM. or even 0.1 μM on different forms of c-KIT (Figure 1). Also, these AB compounds are selective for c-KIT versus other tyrosine kinases (Table 1). Table 1 : Inhibition of various protein tyrosine kinases by the AB compound in vitro

addition, the AB compounds potently and dose-dependently inhibited the growth of the mast cells (MC) when they were cultured in the presence of SCF (with an IC50 of <0.1 μM). Again these in vitro data confirmed the potent and selective inhibitory activity of c-Kit tyrosine kinase activity as well as the ability of the AB compound to inliibit almost completely the survival of MC population at concentration lower than 0.1 μM. AB compounds have also been shown to deplete mast cells in vivo. The AB compound has successfully completed preclinical development in September 2003. Safety pharmacology studies revealed no significant effects of the AB compound on the central nervous, cardiovascular and respiratory systems.

Claims

1. A method for treating HIV infection and related diseases, including human immunodeficiency virus type 1 and 2, or delaying the onset of acquired immunodeficiency syndrome (AIDS), comprising administering a compound capable of depleting mast cells or a compound inhibiting mast cells degranulation in a human in need of such treatment.

2. The method according to claim 1 for treating patients suffering from HIV infection and related diseases comprising administering a c-kit inhibitor, to a human in need of such treatment.

3. The method according to claim 2, wherein said c-kit inhibitor is a non-toxic, selective and potent c-kit inhibitor wherein it is unable to promote death of JJL-3 dependent cells cultured in presence of IL-3.

4. The method according to claim 1 or 3 wherein said inhibitor is selected from the group consisting of :

- 2-(3-Substitutedaryl)amino-4-aryl-thiazoles such as 2-(3-amino)arylamino-4-aryl- thiazoles,

- 2-aminoaryloxazoles,

- pyrimidine derivatives, more particularly N-phenyl-2-pyrimidine-amine derivatives, - indolinone derivatives, more particularly pyrrol-substituted indolinones,

- monocyclic, bicyclic aryl and heteroaryl compounds,

- and quinazoline derivatives.

5. The method according to claim 4, wherein said c-kit inhibitor is selected from compounds belonging to the 2-(3-Substitutedaryl)amino-4-aryl-thiazoles of formula III:

FORMULA III

wherein

R⁶ and R⁷ are independently from each other chosen from one of the following: i) hydrogen, a halogen (selected from F, Cl, Br or I), ii) an alkyl¹ group defined as a linear, branched or cycloalkyl group containing from 1 to 10 carbon atoms, or from 2 or 3 to 10 carbon atoms, (for example methyl, ethyl, propyl, butyl, pentyl, hexyl...) and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (the latter optionally in the form of a pendant basic nitrogen functionality); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; (iii) an aryl¹ group defined as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as - halogen(selected from I, F, Cl or Br); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality; - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; (iv) a heteroaryl¹ group defined as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, fiiranyl, oxazolyl, isoxazolyl , triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as - halogen (selected from F, Cl, Br or I); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality, - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; (v) trifluoromethyl, carboxyl, cyano, nitro, formyl, hydroxy, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality.

R⁸ is one of the following:

(i) hydrogen, or

(ii) a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or

(iii) CO-R8 or COOR8 or CONHR8 or SO2R8 wherein R8 maybe - a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or - an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen (selected from F, Cl, Br or I), alkyl groups containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Cι-₆alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, Cι-₆alkylamino, di(Cι-₆alkyl)amino, and amino, the latter nitrogen substituents optionally in the form of a pendant basic nitrogen functionality; as well as CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or - a heteroaryl group such as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as halogen (selected from F, Cl, Br or I), alkyl groups containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Cι-₆alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, Cι-₆alkylamino, di(C₁-₆alkyl)amino, and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; as well as CO-R, COO-R, CONH-R, SO2-R, and S02NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality.

R2, R3, R4 and R5 each independently are selected from hydrogen, halogen (selected from F, Cl, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Cι-₆alkyloxy, amino, . ₆alkylamino, di(Ci-₆alkyl)amino, carboxyl, cyano, nitro, formyl, hydroxy, and CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality.

A is : CH2, O, S, SO2, CO, or COO, B is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, SO2, CO, or COO,

B' is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, SO2, CO or COO;

R* being an alkyl¹, aryl¹ or heteroaryl¹

W is a bond or a linker selected from NH, NHCO, NHCOO, NHCONH, NHSO2,

NHSO2NH, CO, CONH, COO, COCH2, (CH2)n (n is 0, 1 or 2), CH2-CO, CH2COO, CH2-NH, O, OCH2, S, SO2, and SO2NH

R¹ is : a) a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl, Br and F, and / or bearing a pendant basic nitrogen functionality; b) an aryl or heteroaryl group optionally substituted by an alkyl or aryl group optionally substituted with a heteroatom, notably a halogen selected from I, Cl, Br and F or bearing a pendant basic nitrogen functionality c) an alkyl¹, aryl¹ or heteroaryl¹.

6. A method according to claim 5, wherein said c-kit inhibitor is selected from compounds of formula V :

FORMULA V

wherein X is R or NRR' and wherein R and R' are independently chosen from H, an aryl, a heteroaryl, an alkyl , or a cycloalkyl group optionally substituted with at least one heteroatom, such as for example a halogen chosen from F, I, Cl and Br and optionally bearing a pendant basic nitrogen functionality; or an aryl, a heteroaryl, an alkyl or a cycloalkyl group substituted with an aryl, a heteroaryl, an alkyl or a cycloalkyl group optionally substituted with at least one heteroatom, such as for example a halogen chosen from F, I, Cl and Br and optionally bearing a pendant basic nitrogen functionality,

R⁶ is one of the following: (i) an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl, and alkoxy; (ii) a heteroaryl group such as a 2, 3, or 4-pyridyl group, which may additionally bear any combination of one or more substituents such as halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy;

1 to 10 carbon atoms, trifluoromethyl, and alkoxy. iv) H, a halogen selected from I, F, Cl or Br; NH2, NO2 or SO2-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and optionally substituted with at least one heteroatom, notably a halogen selected from I, Cl,

Br and F, and / or bearing a pendant basic nitrogen functionality.

7. The method according to claim 4, wherein said c-kit inhibitor is selected from 2- aminoaryloxazoles of formula X :

FORMULA X

wherein substituents Rl - R7 and X are defined as follows:

Rl, R2, R3 and R4 each independently are selected from hydrogen, halogen (selected from F, Cl, Br or I), a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic mtrogen functionality; as well as trifluoromethyl, Cι-₆alkyloxy, amino, - ₆alkylamino, di(Cι-₆alkyl)ammo, carboxyl, cyano, nitro, formyl, hydroxy, and CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality.

R5 is one of the following: (i) hydrogen, or (ii) a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or (iii) CO-R8 or COOR8 or CONHR8 or SO2R8 wherein R8 maybe - a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or - an aryl group such as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as halogen (selected from F, Cl, Br or I), alkyl groups containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Cι-₆alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, Cι-₆alkylamino,

and amino, the latter nitrogen substituents optionally in the form of a pendant basic nitrogen functionality; as well as CO-R, COO-R, CONH-R, S02-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and mtrogen, the latter optionally in the form of a pendant basic nitrogen functionality, or - a heteroaryl group such as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as halogen (selected from F, Cl, Br or I), alkyl groups contaimng from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, -ealkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, -ealkylamino,

and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; as well as CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality.

R6 and R7 each independently are selected from: i) hydrogen, a halogen (selected from F, Cl, Br or I), or ii) an alkyl¹ group defined as a linear-, branched or cycloalkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen (the latter optionally in the form of a pendant basic nitrogen functionality); as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; as well as CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R wherein R is a linear or branched alkyl group containing 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality ; as well as a cycloalkyl or aryl or heteroaryl group optionally substituted by a a pendant basic nitrogen functionality, or

(iii) an aryl¹ group defined as phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents such as - halogen(selected from I, F, Cl or Br); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality; - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the fonn of a basic nifrogen functionality; - NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R corresponds to hydrogen, alkyl¹, aryl or heteroaryl, or (iv) a heteroaryl¹ group defined as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl , triazolyl, tetrazolyl, indolyl, benzimidazole, quinolinyl group, which may additionally bear any combination, at any one ring position, of one or more substituents such as - halogen (selected from F, Cl, Br or I); - an alkyl¹ group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant basic nitrogen functionality, - trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹, N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nifrogen functionality; - NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R conesponds to hydrogern, alkyl¹, or (v) an O-aryl¹, or NH-aryl¹, or O-heteroaryl¹ or NH-heteroaryl¹ group (vi) trifluoromethyl, O-alkyl¹, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl¹,' N(alkyl¹)(alkyl¹), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality, or (vi) NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NH-R wherein R corresponds to hydrogen, alkyl¹, aryl or heteroaryl.

X is: -NR9R10, wherein R9 and / or Rl 0 are hydrogen or: i) an alkyl¹ group, CF3 or ii) an aryl¹, heteroaryl¹ or cycloalkyl group optionally substituted by a a pendant basic nitrogen functionality, or iii) a CO-R, COO-R, CON-RR'or SO2-R, where R and R' are a hydrogen, alkyl¹, aryl¹ or heteroaryl¹, optionally substituted by a a pendant basic nitrogen functionality; or:

8. The method according to claim 4, wherein said inhibitor is selected from the group consisting of N-phenyl-2-pyrimidine-amine derivatives having the formula II :

R4, R5 and R6 are independently chosen from H, F, Cl, Br, I, a C1-C5 alkyl, especially a methyl group; and R7 is a phenyl group bearing at least one substituent, which in turn possesses at least one basic site, such as an amino function.

9. The method according to claim 8, wherein said inhibitor is the 4-(4-mehylpiperazine- l-yhnethyl)-N-[4-methyl-3-(4-pyridine-3-yl)pyrimidine-2 ylamino)phenyl]-benzamide.

10. A method for treating HIV infection or delaying the onset of AIDS comprising administering to a human in need of such treatment a compound that is a selective, potent and non toxic inhibitor of activated c-kit obtainable by a screening method which comprises : a) bringing into contact (i) activated c-kit and (ii) at least one compound to be tested; under conditions allowing the components (i) and (ii) to form a complex, b) selecting compounds that inhibit activated c-kit, c) testing and selecting a subset of compounds identified in step b), which are unable to promote death of IL-3 dependent cells cultured in presence of IL-3.

11. The method according to one of claims 1 to 10 for treating of all forms of human immunodeficiency virus type 1, type 2, for treating or. delaying the onset of acquired immunodeficiency syndrome, including AJ-DS-related non-Hodgkin's lymphomas including aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, immunoblastic lymphomas and Kaposi's sarcoma, neurological disorders such as dementia, opportunistic infections such as Candida, oral hairy leukoplakia, herpes zoster (shingles), bacilliary angiomatosis and tuberculosis, bone disorders such as osteoporosis and osteopenia, progressive cytopenias (anemia, thrombocytopenia, leukopenia).

12. The use of a compound as defined in one of claims 1 to 9 or obtainable by the method of claim 10 to manufacture a medicament for treating of all forms of human immunodeficiency virus type 1, type 2, treating or delaying the onset of acquired immunodeficiency syndrome, including ATDS-related non-Hodgkin's lymphomas including aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, immunoblastic lymphomas and Kaposi's sarcoma, neurological disorders such as dementia, opportunistic infections such as Candida, oral hairy leukoplakia, herpes zoster (shingles), bacilliary angiomatosis and tuberculosis, bone disorders such as osteoporosis and osteopenia, progressive cytopenias (anemia, thrombocytopenia, leukopenia).