NZ548884A

NZ548884A - 2-(3-substituted-aryl)amino-4-aryl-thiazoles as tyrosine kinase inhibitors

Info

Publication number: NZ548884A
Application number: NZ548884A
Authority: NZ
Inventors: Alain Moussy; Camille Wermuth; Bruno Giethlen; Marco Ciufolini
Original assignee: Ab Science
Priority date: 2004-01-30
Filing date: 2005-01-28
Publication date: 2010-06-25
Also published as: BRPI0507271A; IL177007A0; ZA200606152B; CN1934107A; CA2554925A1; KR20060129413A; WO2005073225A1; NO20063861L; EP1711497A1; JP2007519711A; AU2005209485A1

Abstract

Disclosed are compounds of formula II, wherein R6 is aryl, heteroaryl or heterocyclic, and the remaining substituents are as defined in the specification. The compounds selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant tyrosine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. More particularly, the compounds are potent and selective c-kit inhibitors.

Description

New Zealand Paient Spedficaiion for Paient Number 548884 RECEIVED at IPONZ on 11 February 2010 548884 1 2- (3-STJBSTITUTED-ARYL) AMIN0-4-ARYL-THIAZ0IiES AS TYROSINE KINASE INHIBITORS The present invention relates to novel compounds selected from 2-(3-substitutedaryl)an;3ino-4-aryl-tliiazoIes that selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant tyrosine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. More particularly, these compounds are potent and selective ofcit inhibitors.

Tyrosine kinases are receptor type or non-receptor type proteins, which transfer the terminal phosphate of ATP to tyrosine residues of proteins thereby activating or inactivating signal transduction pathways. These proteins are involved in many cellular mechanisms, which in case of disruption, lead to disorders such as abnormal cell proliferation and migration as well as inflammation.

As of today, there are about 58 known receptor tyrosine kinases. Other tyrosine kinases are the VEGF receptors (Kin et al., Nature 362, pp. 841-844, 1993), PDGF receptors, c-kit and the FLK family. These receptors can transmit signals to other tyrosine kinases including Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps, Fak, Jak, Ack. etc.

Among tyrosine kinase receptors, c-kit is of special interest Indeed, c-kit is a .key receptor activating mast cells, which have proved to be directly or indirectly implicated in numerous pathologies for which the Applicant filed WO 03/004007, WO 03/004006, WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109, WO 03/002108, WO 03/002107, WO 03/002106, WO 03/002105, WO 03/039550, WO 03/035050, WO 03/035049, US 60/359,652 and US 60/359651.

C:\poflvw/tft$Pec-NZl4WS-oe.ctoe l0/02/t0 548884 2 It was found that mast cells present in tissues of patients are implicated in or contribute to the genesis of diseases such as autoimmune diseases (rheumatoid arthritis, inflammatory bowel diseases (IBD)) allergic diseases, tumor angiogenesis, inflammatory 5 diseases, and interstitial cystitis. In these diseases, it has been shown that mast cells participate in the destruction of tissues by releasing a cocktail of different proteases and mediators such as histamine, neutral proteases, lipid-derived mediators (prostaglandins, thromboxanes and leucotrienes), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, EL-6, IL-8, TNF-a, GM-CSF, MEM a, MlP-lb, MIP-2 and IFN-y).

The c-kit receptor also can be constitutively activated by mutations leading to abnormal cell proliferation and development of diseases such as mastocytosis and various cancers.

For this reason, it has been proposed to target c-kit to deplete the mast cells responsible for these disorders.

The main objective underlying the present invention is therefore to find potent and selective compounds capable of inhibiting wild type and/or mutated c-kit.

Many different compounds have been described as tyrosine kinase inhibitors, for example, bis monocyclic, bicyclic or heterocyclic aryl compounds (WO 92/20642), vinylene-azaindole derivatives (WO 94/14808) and l-cycloproppyl-4-pyridyl-quinolones (US 5,330,992), styryl compounds (US 5,217,999), styryl-substituted pyridyl compounds 25 (US 5,302,606), selenoindoles and selenides (WO 94/03427), tricyclic polyhydroxylic compounds (WO 92/21660) and benzylphosphonic acid compounds (WO 91/15495), pyrimidine derivatives (US 5,521,184 and WO 99/03854), indolinone derivatives and RECEIVED at IPONZ on 11 February 2010 548884 3 pyrrole-substituted indolinoncs (US 5,792,783, BP 934 931, US 5,834,504, US 5,883,116, US 5,883,113, US 5, 886,020, WO 96/401J6 and'WO 00/38519), as well as bis monocyclic, bicyclic aryl and fieteroaryl compounds (BP 584 222, US 5,656,643 and WO 92/20642), quinazoline derivatives (BP 602 851, EP 520 722, US 3,772,295 and US 4,343,940) and aryl aid heteroaryl quinazoline (US 5,721,237, US 5,714,493, US 5,710,158 and WO 95/15758).

However, none of these compounds have been described as potent and selective inhibitors of c-kit or of the c-kit pathway. in connection with our previous invention which is described in W02Q04Q14903, we found that compounds corresponding to the 2-(3-ananoaryl)amino-4-aiyl-thiazoles are potent and selective inhibitors of c-kit or c-kit pathway. These compounds are good candidates for treating diseases such as autoimmunes diseases, inflammatoiy diseases, cancer and mastocytosis.

We now have determined that other 2-(3-substitutedaryi)amino-4~aryl-thiazole derivatives display very strong inhibitory activity on several forms of c-kit The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof.

C:\poftword\SPEC-NZ14949-06.doc 10/02/10 RECEIVED at IPONZ on 11 February 2010 548884 3a Description Therefore, the present invention, relates to compounds belonging to fee 2-(3-keioai^amiao-4-aryl-thiazole8. These compounds are capable of selectively inhibiting signal transduction involving the tyrosine phosphokinase c-kit and mutant forms thereof. In a first embodiment, the invention is aimed at compounds of formula I, which may represent either free base forms of the substances or pharmaceutically acceptable salts thereof: C:\poftWQrcftSPEC-NZl4949-QG doc 10/02/10 548884 4 R3 R8 R5 FORMULA I and wherein R6 and R7 are independently from each other chosen from one of the following: i) hydrogen, a halogen (selected from F, CI, Br or I), ii) an alkyl1 group defined as a linear, branched or cycloalkyl group containing from 1 to 10 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, CI, 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, CI or Br); - an alkyl1 group; - a cycloalkyl, aryl or heteroaryl group optionally substituted by a pendant 20 basic nitrogen functionality; - trifluoromethyl, O-allcyl1, 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; 548884 (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, CI, 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, 10 N(alkyl')(allcyl1), 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, CI, 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 may be - 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, CI, 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 548884 (selected from F, CI, 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, CI, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Ci.6alkyloxy, carboxyl, cyano, nitro, 5 formyl, hydroxy, Ci^allcylamino, di(Ci.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, S02-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, CI, Br or I), oxygen, and 10 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 15 (selected from F, CI, 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, CI, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Ci_6alkyloxy, carboxyl, cyano, nitro, formyl, hydroxy, Ci-galkylamino, di(Ci.6alkyl)amino, and amino, the latter nitrogen 20 substituents optionally in the form of a basic nitrogen functionality, as well as CO-R, COO-R, CONH-R, S02-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, CI, 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, CI, 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 548884 7 (selected from F. CI, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality; as well as trifluoromethyl, Ci^alkyloxv, amino, Q_ 6alkylamino, di(Ci-6alkyl)amino, carboxyl, cyano, nitro, formyl, hydroxy, and CO-R, COO-R, CONH-R, S02-R, and S02NH-R wherein R is a linear or branched alkyl group 5 containing from 1 to 10 carbon atoms and optionally substituted with at least one heteroatom, notably a halogen (selected from F, CI, Br or I), oxygen, and nitrogen, the latter optionally in the form of a pendant basic nitrogen functionality.

A is : CH2, O, S, S02, CO, or COO, B is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, S02, CO, or COO, B' is a bond or NH, NCH3, NR*, (CH2)n (n is 0, 1 or 2), O, S, S02, CO or COO; R ' being an alkyl1, aryl1 or heteroaiyl1 W is a bond or a linker selected from NH, NHCO, NHCOO, NHCONH, NHS02, NHS02NH, CO, CONH, COO, COCII2, (CII2)n (n is 0, 1 or 2), CII2-CO, CH2COO, 15 CH2-NH, O, OCH2, S, S02, and S02NH 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, CI, 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, CI, 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 C10 alkyl. 548884 8 For example, a subset of compounds may correspond to R6 B' H 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-NII 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 0-CH2 It will also be understood that NH in B or B' can also be NCH3 In the above formula I, 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. 548884 9 - 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 one preferred embodiment, when ABB' is CONH, the invention is directed to 10 compounds of the following formula 1-1: wherein R is H or an organic group that can be selected for example from a linear or 15 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 aiyl 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, CI, Br and F and / or bearing a pendant basic nitrogen functionality.

In one other preferred embodiment, the invention is directed to amide-aniline compounds of the following formula 1-2: 548884 1-2 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 5 aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, 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, CI, Br and F and / or bearing a pendant 10 basic nitrogen functionality; - a S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality; - a CO-R or a CO-NRR' group, wherein R and R' are independently chosen from H, an 15 alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom, notably selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

Among the particular compounds in which Rl has the meaning as depicted above, the 20 invention is directed to amide-benzylamine compounds of the following formula 1-3: 548884 11 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, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, aryl or heteroaryl group optionally 5 substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or an alkyl, cycloalkyl, aryl or heteroaryl group substituted by a alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, 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 or an aryl heteroaryl, alkyl and cycloalkyl group optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality.

Among the particular compounds in which Rl has the meaning as depicted above, the invention is directed to amide-phenol compounds of the following formula 1-4: 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, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; 548884 12 a cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality; or an alkyl, cycloalkyl, aryl or heteroaryl group substituted by a alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with a heteroatom, notably a 5 halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality; a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F and / or bearing a pendant basic nitrogen functionality; or a -CO-R or a -CO-NRR' group, 10 wherein R and R' are independently chosen from H or an aryl, heteroaryl, alkyl and cycloalkyl group optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality.

Among compounds of formula I, the invention is particularly directed to 3-(thiazol-2-15 ylamino)-benzamide compounds of the following formula 1-5: wherein Y is a single bond, a linear or branched alkyl group containing from 1 to 10 20 carbon atoms, especially CH2 or CH2-CH2; or NH 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, CI, Br, I; a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally 25 substituted with at least one heteroatom (for example a halogen) and / or bearing 1-5 548884 13 a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaiyl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aiyl or heteroaryl group substituted by an alkyl, a cycloalkyl, an 5 aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, 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 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, CI, 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 heteroaiyl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, 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 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, CI, 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, CI, 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, cyano or alkoxy; 548884 14 R3 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, cyano or alkoxy; R4 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, cyano or alkoxy; R5 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl, cyano 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, 3-15 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, CI or Br; NH2, N02 or S02-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and 20 optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; andR7 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; 548884 (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, CI or Br; NH2, N02 or S02-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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

An example of preferred compounds of the above formula is depicted below: 001 : 4-[4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzoylamino]-benzoic acid 2-diethylamino-ethyl ester Among the compounds of formula I, the invention is particularly embodied by the compounds of the following formula II: 548884 16 FORMULA II wherein X is R or NRR' and wherein R and R' are independently chosen from H, an 5 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, CI 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 10 chosen from F, I, CI 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; RJ is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 15 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 25 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 548884 17 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, CI or Br; NH2, N02 or S02-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and 5 optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

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

Among the preferred compounds corresponding formulas I and II, the invention is directed to compounds in which Rl and X, respectively, is a substituted alkyl, aryl or heteroaryl group bearing a pendant basic nitrogen fiinctionality represented for example by the structures a to m shown below, wherein the wavy line and the arrow line 15 correspond to the point of attachment to core structure of formula I or II. 548884 18 N h j k I m Among group a to f and g to m Rl of formula I and X of formula II is preferentially group d. Also, for g to m, the arrow includes a point of attachment to the core structure via a phenyl group.

Furthermore, among the preferred compounds of formula I or II, the invention concerns 10 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). The wavy line in structure g and h correspond to the point of attachment to the core structure of formula I or II.

Thus, the invention contemplates: 1- A compound of formula n as depicted above, wherein X is group d and R6 is a 3-pyridyl group. 2- A compound of formula II as depicted above, wherein X is group d and R4 is a 20 methyl group. g h 548884 19 3- A compound of formula I or II as depicted above, wherein R1 is group d and R2 is H. 4- A compound of formula I or II as depicted above, wherein R1 is group d and R3 is H. 5- A compound of formula I or II as depicted above, wherein R1 is group d and R2 and/or R3 and/or R5 is H. 6- A compound of formula I or II as depicted above, wherein R6 is a 3-pyridyl group and R3 is a methyl group. 7- A compound of formula I or II as depicted above, wherein R6 is a 3-pyridyl group 10 andR2isH. 8- A compound of formula I or II as depicted above, wherein R2 and/or R3 and/or R5 is H and R4 is a methyl group. 9- A compound of fonnula I or II 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 H, the invention is particularly embodied by the compounds wherein R2, R3, R5 are hydrogen, corresponding to the following formula III : FORMULA n-1 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 25 or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl 548884 group optionally substituted with an heteroatom, notably a halogen selected from I, CI, 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 aiyl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, 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: (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, CI or Br; NH2, N02 or S02-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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

Examples: 002 : N-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-3 -(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 548884 21 *H NMR (DMSO-d6) 5 = 2.36 (s, 3H, ArCH3); 7.43 (d, IH, J = 7.5Hz, Ar-H); 7.68 (dd, IH, J= 7.5, 1.5Hz, Ar-H); 7.73 (s, IH, thiazol-H) ; 7.82 (m, 3H, pyridyl-H+Ar-H); 8.54 5 (m, 4H, pyridyl-H+2xAr-H); 8.85 (br s, IH, Ar-H) ; 9.67 (s, IH. NH), 10.84 (s, IH, NH). 003 : N-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylaimno)-benzamide lH NMR (DMSO-d6) 5 = 1.00-1.40 (m, 5H, cyclo-H); 1.50-1.85 (m, 5H, cyclo-H); 2.34 15 (s, 3H, AxCHj); 7.28 (d, IH, J = 7.9Hz, Ar-H); 7.48 (dd, IH, J = 7.9, 1.5Hz, Ar-H); 7.67 (s, IH, thiazol-H) ; 7.82 (d, 2H, J = 6.0Hz, pyridyl-H); 8.57 (d, 2H, J = 6.0Hz, pyridyl-H); 8.63 (d, IH, J = 1.5Hz, Ar-H); 9.55 (s, IH, NH). 092: N-Cyclohexyl-4-methyl-3-(4-pyiidin-4-yl-thiazol-2-ylamino)-benzamide 548884 WO 2005/073225 PCT/IB2005/000401 22 093: 4-Methyl-N-( 1 -methyl-1 H-indol-6-yl)-3-(4-pyridin-3-yl-tMazol-2-ylamino)- benzamide 094: N-(2-Methoxy-ethyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 096: N-(2-Cyano-ethyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-bcnzamidc CT CN H Among the compounds of formula II, the invention is particularly embodied by the compounds wherein X is a -substituted Aryl group, corresponding to the N-[3-(Thiazol-2-ylamino)-phenyl]-amide family and the following formula II-3 : 548884 23 Rb Rc FORMULA II-3 Rd wherein Ra, Rb, Rc, Rd, Re 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 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, CI, 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, CI, Br and F or bearing a pendant basic nitrogen functionality; a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, notably a halogen selected from I, CI, 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 aiyl or heteroaryl group optionally substituted with at least one heteroatom, notably selected from I, CI, Br and F, and or bearing a pendant basic nitrogen functionality; Ra, Rb, Rc, Rd, Re may also be - a halogen such as I, CI, Br and F - a NRR' group where R and R' are 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, CI, 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 548884 24 optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; - an OR group where R is 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, CI, 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, CI, Br and F or 10 bearing a pendant basic nitrogen functionality; a -S02-R' group wherein R' is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted witli a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen'functionality; - a NRaCORb group where Ra and Rb are 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, CI, 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, CI, Br and 20 F or bearing a pendant basic nitrogen functionality; - a NRaCONRbRc group where Ra and Rb are 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, CI, 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, CI, Br and F or bearing a pendant basic nitrogen functionality; 548884 - 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 5 selected from I, CI, 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, CI, 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 10 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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group 15 substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, 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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aiyl or heteroaryl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected 25 from I, CI, 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 548884 26 heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aiyl or heteroaryl, group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected 5 from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - an NRaOSC^Rb, 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, CI, 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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - a CN group - a trifluoromethyl group 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: (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 25 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 548884 27 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, CI or Br; NH2, N02 or S02-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and 5 optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

Examples 028: N-(2-Fluoro-3 -trifhaoromethyl-phenyl)-4-methyl-3 -(4-pyridin-4-yl-thiazol-2- ylamino)-benzamide 029: N-(3-Fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-tliiazol-2-ylamiiio)-benzamide 030: 4-Methyl-3-(4-pyridin-4-yI-thiazol-2-ylamino)-N-(3-trifluoromethyl-phenyl)-benzamide 548884 031: 4-Methyl-N-(4-methyl-3-trifhioromethyl-phenyl)-3-(4-pyridin-4-yl-thiazol-2-yl am i no )-benzami de 032: N-(2-Fluoro-5-trifluoromcthyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2- ylamino)-benzamide lR NMR (DMSO-d6) 8 = 2.39 (s, 3H, ArCH3); 7.41 (d, IH, J = 7.9Hz, Ar-H); 7.54-7.70 (m, 3H, Ar-H); 7.72 (s, IH, thiazol-H); 7.82 (d, 2H, J = 6.0Hz, pyridyl-H); 8.10 (dd, IH, J = 6.8, 2.2Hz, Ar-H); 8.55 (d, 2H, J = 6.0Hz, pyridyl-H) ; 8.84 (d, IH, J = 1.8Hz, Ar-H) ; 9.65 (s, IH, NH); 10.31 (s, IH, NH). 15 033: N-(4-Cyaao-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 548884 29 034: N-(4-Fluoro-phenyl)-4-methyl-3-(4-pyridm-4-yl-thiazol-2-ylamino)-benzamide 035: N-(3-Fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-5 benzamide 036:N-(4-tert-Butyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 038: N-(3-Cyano-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide I N 039: N-(3 -Cyano-4-methyl-phenyl)-4-methyl-3 -(4-pyridin-4-yl-thiazol-2-ylamiiio)-benzamide 548884 lH NMR (DMSO-d6) 5 = 2.37 (s, 3H, ArCH3); 2.46 (s, 3H, ArCH3); 7.43 (m, 2H, Ar-H); 7.63 (dd, IH, J = 7.9, 1.8Hz, Ar-H) ; 7.72 (s, IH, thiazol-H); 7.83 (d, 2H, J = 6.0Hz, 5 pyridyl-H); 7.96 (dd, IH, J - 8.3, 1.8Hz, Ar-H); 8.19 (d, IH, J = 2.3Hz, Ar-H); 8.55 (d, 2H, J = 6.0Hz, pyridyl-H); 8.81 (d, IH, J = 1.5Hz, Ar-H) ; 9.65 (s, IH, NH); 10.46 (s, IH, NH). 040: N-(3 -Bromo-phenyl)-4-methyl-3 -(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 041: N-(3-Bromo-4-methyl-phenyl)-4-metliyI-3-('4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 042: N-(3,5-Dibromo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)- benzamide 548884 31 043: N-(3 -Cliloro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 044: N-(3-CMoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 045: N-(3-Methoxy~phenyl)-4-methyl-3-(4-pyMm-4-yl-thiazol-2-ylamino)-bcnzamide 046: 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-N-m-tolyl-benzamide 548884 32 047:N-(4-Fluoro-3-methyl-phenyl)-4-metliyl-3-(4-pyridm-4-yl~thiazol-2-ylamino)-benzamide 048: N-(3-Iodo-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)- benzamide 049: 4-Methyl-N-(3-nitro-phenyl)-3-(4-pyridin-4-yl-thiazol-2-ylamiiio)-benzamide 050: 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-N-p-tolyl-benzamide 051:4-Methyl-N-pheiiyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 548884 33 052: N-(3,4-Dimethyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 053: 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-N-(3-trifluoromcthoxy-phenyl)-benzamide OCF3 054: N-(3.4-Dicyano-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazo1-2-yla:mino)-benz amide Q 0 H 055: N-(2-Fluoro-5-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 548884 34 056: N-(2,4-Difluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide /V N " F 057: N-(4-Cyan<)-2-fluoro-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)- benzamide 058: N-(2-Fluoro-4-methyl-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 059: N-(2,4-Difluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide H [ w 548884 060: N-(4-Cyano-2-fluoro-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino) benzamide N 061: X-(2-Fluoro-4-metliyl-plienyl)-4-metliyl-3-(4-pyridin-3-yl-lhiazoI-2-y]amino) benzamide 062: N-(4-Cyano-phenyl)-4-methyl-3-(4-pyridm-3-yl-thiazol-2-ylammo)-benzamide 065: N- (4-Fluoro-phenyl)-4-methyl-3 -(4-pyridin-3 -yl-thiazol-2-ylamino)-benzamide 099: 4-Methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-N-m-tolyl-benzamide 548884 36 100: 4-Methvl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-N-(3-trifluoromcthyl-phenyl)-benzamide 101: 4-Methyl-N-(4-methyl-3-trifluoromethyl-phenyl)-3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide 102: N-(2-Fluoro-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide 105: N-(4-Cyano-3-trifluoromethyl-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2- ylamino)-benzamide 548884 37 106: N-(4-Cyano-3-methyl-phenyl)-4-methyl-3~(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide Among compounds of formula n, the invention is particularly embodied by the compounds wherein X is a -substituted-aryl group, corresponding to the 4-(4-substituted-l-ylmethyl)-N-[3-(thiazol-2-ylamino)-phenyl]-bcnzamide family and the following formula II-4 ; FORMULA II-4 wherein X is a heteroatom, such as O or N 15 wherein Ra, Rb, Rd, Re, Rf, Rg, Rli 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 and / or 548884 38 bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, notably a halogen, selected from. I, CI, 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 5 substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; - or a NRR' group where R and R' are 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 10 optionally substituted with a heteroatom, notably a halogen selected from I, CI, 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, CI, Br and F or bearing a pendant basic nitrogen functionality; - or an OR group where R is 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, CI, Br and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group 20 optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; a -S02-R' group wherein R' is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; 25 - or a NRaCORb group where Ra and Rb are 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, CI, Br 548884 39 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, CI, Br and F or bearing a pendant basic nitrogen functionality; - or a NRaCONRbRc group where Ra and Rb are 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, CI, Br and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or 10 heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; - or 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 heteroaiyl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, 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 20 from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - or 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 aiyl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, 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 548884 40 with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - or 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, CI, 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 10 from I, CI, 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, CI, 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 aiyl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - or an NRa0S02Rb, where Ra and Rb are a linear or branched alkyl group containing 20 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 aiyl or heteroaryl group optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group 25 substituted by an alkyl, a cycloalkyl, an aiyl or heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; 548884 41 - or a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with an heteroatom, notably a halogen selected from I, CI, 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 5 heteroaiyl group optionally substituted with at least one heteroatom, notably selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

Ra, Rb, Rd, Re can also be halogen such as CI, F, Br, I or trifluoromethyl; 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: (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 heteroaiyl 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, 3-20 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, CI or Br; NH2, N02 or S02-R, wherein R is a linear or branched alkyl goup containing one or more group such as 1 to 10 carbon atoms, and 25 optionally substituted with at least one heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

Examples 548884 42 004 : 4-Methyl-N-[4-(4-methyl-piperazin~l-yhnethyl)-3-trifluoromethyl-phenyl]-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 'H NMR (MeOH-cU) 6 = 2.41 (s, 6H, NCH3+ArCH3); 2.50-2.70 (m, 4H, pyperazine-H); 2.90 (m, 4H, pyperazine-H); 3.68 (br s, 2H, CH2-piperazine); 7.38 (d, IH, J = 7.9Hz, Ar-H); 7.50 (m, IH, thiazol-H) ; 7.60 (m, IH, Ar-H); 7.76 (d, IH, J = 8.3Hz, Ar-H); 7.90 (m, 2H, pyridyl-H); 8.00 (m, IH, Ar-H); 8.12 (m, IH, Ar-H); 8.46 (m, 2H, pyridyl-10 H); 8.90 (m, IH, Ar-H). 005 : 4-Methyl-N- {4-[ 1 -(4-methyl-piperazin-1 -yl)-ethyl]-phenyl} -3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide Among compounds of formula n, the invention is particularly embodied by the compounds wherein X is a -aryl-substituted group, corresponding to the 3-Disubstituted-amino-N-[3-(thiazol-2-ylamino)-phenyl]-benzamide family and the following formula H-5: 548884 43 R6 Rb Rc Rg" Rf FORMULA II-5 wherein Ra, Rb, Rc, Re, Rf, Rg 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 5 to 10 carbon atoms optionally substituted with at least one heteroatom and / or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaiyl group optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaiyl group optionally substituted with a cycloalkyl, an aryl or heteroaryl group optionally 10 substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; - or a NRR' group where R and R' are 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 15 optionally substituted with a heteroatom, notably a halogen selected from I, CI, 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, CI, Br and F or bearing a pendant basic nitrogen functionality; - or an OR group where R is 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 aiyl or heteroaryl group optionally substituted with a heteroatom, notably a halogen selected from 1, CI, Br and F or bearing 548884 44 a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a cycloalkyl, an aryl or heteroaiyl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; a -S02-R' group wherein R' is an alkyl, 5 cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, notably a halogen selected from I, CI, Br and F or bearing a pendant basic nitrogen functionality; - or a NRaCORb group where Ra and Rb are 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, CI, 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, CI, Br and F or bearing a pendant basic nitrogen functionality; - or a NRaCONRbRc group where Ra and Rb are 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, CI, 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, CI, Br and F or bearing a pendant basic nitrogen functionality; - or 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, CI, 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 548884 45 heteroaryl group optionally substituted with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - or 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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaiyl group substituted by an alkyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted 10 with an heteroatom, notably a halogen selected from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - or 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, CI, 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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; 20 - an OSOoR, 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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; or a 25 cycloalkyl, an aiyl 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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; 548884 46 - or an NRaOSCbRb, 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 5 least one heteroatom, notably a halogen selected from I, CI, 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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality; - or a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with an heteroatom, notably a halogen selected from I, CI, 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 15 from I, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

Ra, Rb, Rc, Re can also be halogen such as CI, F, Br, I or trifluoromethyl; R4 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 20 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; 548884 47 (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, CI or Br; NH2, N02 or S02-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, CI, Br and F, and / or bearing a pendant basic nitrogen functionality.

Examples 089: N-(3-Dimethylamino-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)- JH NMR (DMSO-d6) 8 = 2.36 (s, 3H, ArCH3); 2.88 (s, 6H, 2xCH3); 6.50 (d, IH, J = 7.9Hz, Ar-H); 7.10-7.30 (m, 3 H, Ar-H); 7.38 (d, IH, J = 7.9Hz, Ar-H); 7.62 (dd, IH, J = 7.9, 1.5Hz, Ar-H) ; 7.70 (s, IH, thiazol-H); 7.85 (d, 2H, J - 6.4Hz, pyridyl-H) ; 8.54 (d, IH, J = 6.4Hz, pyridyl-H) ; 8.78 (br s, IH, Ar-H) ; 9.63 (s, IH, NH), 10.04 (s, IH, NH). benzamide 090: N-(3-Dimethylamino-phenyl)-4-methyl-3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide 548884 In a second embodiment, the invention is directed to a process for manufacturing a 5 compound of formula I depicted above. This entails the condensation of a substrate of general formula 10 with a thiourea of the type 11.

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, 15 methanesulfonyloxy, trifluoromethanesulfonyloxy, etc., with L being preferentially a bromo group).

Group Rl in formula 1 la corresponds to an alkoxy group.

The reaction of 10 with 1 a-d leads to a thiozole-type product of formula 12a-d. 548884 49 R3 R7 .R1 R8 R5 12 a Fomiula 12a is the same as formula I. Therefore, Rl in 12a corresponds to Rl in formula I.

Examples of Compound synthesis General: All chemicals used were commercial reagent grade products. Dimethylformamide (DMF), methanol (MeOH) were of anhydrous commercial grade and were used without further purification. Dichloromethane and tetrahydrofuran (THF) 10 were freshly distilled under a stream of argon before use. The progress of the reactions was monitored by thin layer chromatography using precoated silica gel 60F 254, Fluka TLC plates, which were visualized under UV light. Multiplicities in *H NMR spectra are indicated as singlet (s), broad singlet (br s), doublet (d), triplet (t), quadruplet (q), and multiplet (m) and the NMR spectrum were realized on a 300MHz Bruker spectrometer. 4-Bromoacetyl-pyridine, HBr salt O Dibromine (17.2g, 108 mmol) was added dropwise to a cold (0°C) solution of 4-acetyl-20 pyridine (12 g, 99 mmol) in acetic acid containing 33% of HBr (165 mL) under vigourous stirring. The vigorously stirred mixture was warmed to 40°C for 2h and then to 75°C. After 2h at 75°C, the mixture was cooled and diluted with ether (400 mL) to 548884 50 precipitate the product, which was recovered by filtration and washed with ether and acetone to give white crystals (100%). This material may be recrystallised from methanol and ether.

JH NMR (DMSO-d6) 5 = 5.09 (s, 2H, CH2Br); 8.62 (m, 2H, pyridyl-H) ; 9.07 (m, 2H, pyridyl-H). 4-Methyl-3-thioureido-benzoic acid methyl ester Benzoyl chloride (5.64 g, 80 mmol) was added dropwise to a well-stirred solution of ammonium thiocyanate (3.54 g, 88 mmol) in acetone (50 mL). The mixture was refluxed for 15 min, then, the 3-amino-4-methyl-benzoic acid methyl ester(13.2 g, 80 mmol) was added slowly portionswise. After lh, the reaction mixture was poured into water (350 mL) and the bright yellow precipitate was isolated by filtration. This crude solid was stirred at room temperature with an excess anhydrous potassium carbonate in 200 mL of methanol for 2 hours. Then, the solvent was removed under reduced pressure and the crude product wax extracted with ethyl acetate and washed with water. The organic layer was dried over Na2S04 and concentrated to give a white solid. The solid was stirred in ether for 15 min and filtered to give the final product as a white solid.

'HNMR (DMSO-d6) 5 = 2.22 (s, 3H, ArCH3); 3.81 (s5 3H, C02CH3); 7.38 (d, IH, J = 7.9Hz, Ar-H); 7.70 (dd, IH, J = 7.9, 1.5Hz, Ar-H); 7.82 (d, IH, J = 1.8Hz, Ar-H). 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzoic acid methyl ester 548884 51 A mixture of 4-bromoacetyl-pyridine, HBr salt (0.40g, 1.43 mmol), 4-methyl-3-thiourcido-benzoic acid methyl ester (0.32g, 1.43 mmol) and KHCO3 (~0.4g) in ethanol (10 mL) was heated at 75°C for 20h. The mixture was cooled, filtered (removal of 5 KHCO3) and evaporated under reduced pressure. The residue was dissolved in CHC13 (40 mL) and washed with saturated aqueous sodium hydrogen carbonate solution and with water. The organic layer was dried over Na2S04 and concentrated. The crude product was triturated in small amount of ethyl acetate and filtered to give the final product as an orange solid.

]II NMR (DMSO-d6) 5 = 2.38 (s, 3H, ArCH,); 3.88 (s, 3H, CO2CH3); 7.58 (dd, IH, J = 7.9, 1.8Hz, Ar-H); 7.75 (s, IH, thiazol-H); 7.85 (d, 2H, J = 6.0Hz, pyridyl-H); 8.62 (d, IH, J = 6.0Hz, pyridyl-H); 9.12 (d, IH, J = 1.8Hz, Ar-H) ; 9.63 (s, IH, NH).

N-(4-Cyano-phenyl)-4-metkyI-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide 4-Methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzoic acid methyl ester 548884 52 A 2M solution of trimethyl aluminium in hexane (1.9 mL) was added dropwise to a cold (0° C) solution of 4-amino-benzonitrile (0.29 g, 2.46 mmol) in anhydrous dichloromethane (30 mL) under argon atmosphere. The mixture was warmed to room 5 temperature and stirred at room temperature for 30 min. A solution of 4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzoic acid methyl ester (0.80 g, 2.46 mmol) in anhydrous dichloromethane (30 mL) and added slowly, and the resulting mixture was heated at reflux for 5h. The mixture was cooled to 0°C and quenched by dropwise addition of a 4N aqueous sodium hydroxide solution (3 mL). The mixture was extracted with dichloromethane (3x20 mL). The combined organic layers were washed with brine (3x20 mL) and dried over anhydrous MgSCU. N-(4-Cyano-phenyl)-4-methyl-3-(4-pyridin-4-yl-thiazol-2-ylamino)-benzamide is obtained in 98% after trituration of the crude product in methanol.

NMR (CDC13) 5 = 2.40 (s, 3H, ArCH3); 7.40 ( d, IH, J - 7.9Hz, Ar-H); 7.63 (dd, IH, J - 7.9, 1.5Hz, Ar-H); 7.72 (s, IH, thiazole-H); 7.80-7.88 (m, 4H, Ar-H); 8.10 (d, 2H, J = 8.6Hz, Ar-H) ; 8.56 (m, 2H, Ar-H); 8.86 (d, IH, J = 1.8Hz, Ar-H); 9.66 (br s, IH, NH).

Examples: 548884 53 548884 54 In a third embodiment, the invention relates to a pharmaceutical composition comprising a compound as depicted above.

Such medicament can take the form of a pharmaceutical composition adapted for oral 5 administration, which can be formulated using pharmaceutically acceptable carriers well known in the art in suitable dosages. 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. In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically-10 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.).

The composition of the invention can also take the form of a pharmaceutical or cosmetic composition for topical administration.

Such compositions may be presented in the form of a gel, paste, ointment, cream, lotion, liquid suspension aqueous, aqueous-alcoholic or, oily solutions, or dispersions of the 20 lotion or serum type, or anhydrous or lipophilic gels, or emulsions of liquid or semi-solid consistency of the milk type, obtained by dispersing a fatty phase in an aqueous phase or vice versa, or of suspensions or emulsions of soft, semi-solid consistency of the cream or gel type, or alternatively of microemulsions, of microcapsules, of microparticles or of vesicular dispersions to the ionic and/or nonionic type. These compositions are prepared 25 according to standard methods.

The composition according to the invention comprises any ingredient commonly used in dermatology and cosmetic. It may comprise at least one ingredient selected from 548884 55 hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, emollients, viscosity enhancing polymers, humectants, surfactants, preservatives, antioxidants, solvents, and fillers, antioxidants, solvents, perfumes, fillers, screening agents, bactericides, odor absorbers and coloring matter.

As oils which can be used in the invention, mineral oils (liquid paraffin), vegetable oils (liquid fraction of shea butter, sunflower oil), animal oils, synthetic oils, silicone oils (cyclomethicone) and fluorinated oils may be mentioned. Fatty alcohols, fatty acids (stearic acid) and waxes (paraffin, carnauba, beeswax) may also be used as fatty 10 substances.

As emulsifiers which can be used in the invention, glycerol stearate, polysorbate 60 and the PEG-6/PEG-32/glycol stearate mixture are contemplated.

As hydrophilic gelling agents, carboxyvinyl polymers (carbomer), acrylic copolymers 15 such as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose. clays and natural gums may be mentioned, and as lipophilic gelling agents, modified clays such as bentones, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, or alternatively ethylcellulose and polyethylene may be mentioned.

As hydrophilic active agents, proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, vitamins, starch and plant extracts, in particular those of Aloe vera may be used.

As lipophilic active, agents, retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides and essential oils may be used. These agents add extra moisturizing or skin softening features when utilized. 548884 56 In addition, a surfactant can be included in the composition so as to provide deeper penetration of the compound capable of depleting mast cells, such as a tyrosine kinase inhibitor, preferably a c-kit inhibitor.

Among the contemplated ingredients, the invention embraces penetration enhancing agents selected for example from the group consisting of mineral oil, water, ethanol, triacetin, glycerin and propylene glycol; cohesion agents selected for example from the group consisting of polyisobutylene, polyvinyl acetate and polyvinyl alcohol, and thickening agents.

Chemical methods of enhancing topical absorption of drugs are well known in the art. For example, compounds with penetration enhancing properties include sodium lauryl sulfate (Dugard, P. H. and Sheuplein, R. J., "Effects of Ionic Surfactants on the Permeability of Human Epidermis: An Electrometric Study," J. Ivest. Dermatol., V.60, 15 pp. 263-69, 1973), lauryl amine oxide (Johnson et. al., US 4,411,893), azone (Rajadhyaksha, US 4,405,616 and 3,989,816) and decylmethyl sulfoxide (Sekura, D. L. and Scala, J., "The Percutaneous Absorption of Alkylmethyl Sulfides," Pharmacology of the Skin, Advances In Biolocy of Skin, (Appleton-Century Craft) V. 12, pp. 257-69, 1972), It has been observed that increasing the polarity of the head group in amphoteric 20 molecules increases their penetration-enhancing properties but at the expense of increasing their skin irritating properties (Cooper, E. R. and Berner, B., "Interaction of Surfactants with Epidermal Tissues: Physiochemical Aspects," Surfactant Science Series, V. 16, Reiger, M. M. ed. (Marcel Dekker, Inc.) pp. 195-210, 1987).

A second class of chemical enhancers are generally referred to as co-solvents. These materials are absorbed topically relatively easily, and, by a variety of mechanisms, achieve permeation enhancement for some drugs. Ethanol (Gale et. al., U.S. Pat. No. 4,615,699 and Campbell et. al., U.S. Pat. Nos. 4,460,372 and 4,379,454), dimethyl 548884 57 sulfoxide (US 3,740,420 and 3,743,727, and US 4,575,515), and glycerine derivatives (US 4,322,433) are a few examples of compounds which have shown an ability to enhance the absorption of various compounds.

The pharmaceutical compositions of the invention can also be intended for administration with aerosolized formulation to target areas of a patient's respiratory tract.

Devices and methodologies for delivering aerosolized bursts of a formulation of a drug is disclosed in US 5,906,202. Formulations are preferably solutions, e.g. aqueous 10 solutions, ethanoic solutions, aqueous/ethanoic solutions, saline solutions, colloidal suspensions and microcrystalline suspensions. For example aerosolized particles comprise the active ingredient mentioned above and a carrier, (e.g., a pharmaceutically active respiratory drug and carrier) which are formed upon forcing the formulation through a nozzle which nozzle is preferably in the form of a flexible porous membrane. 15 The particles have a size which is sufficiently small such that when the particles are formed they remain suspended in the air for a sufficient amount of time such that the patient can inhale the particles into the patient's lungs.

The invention encompasses the systems described in US 5,556,611: - liquid gas systems (a liquefied gas is used as propellent gas (e.g. low-boiling FCHC or 20 propane, butane) in a pressure container, - suspension aerosol (the active substance particles are suspended in solid form in the liquid propellent phase), - pressurized gas system (a compressed gas such as nitrogen, carbon dioxide, dinitrogen monoxide, air is used.

Thus, according to the invention the pharmaceutical preparation is made in that the active substance is dissolved or dispersed in a suitable nontoxic medium and said solution or dispersion atomized to an aerosol, i.e. distributed extremely finely in a carrier gas. This is technically possible for example in the form of aerosol propellent gas packs, 548884 58 pump aerosols or other devices known per se for liquid misting and solid atomizing which in particular permit an exact individual dosage.

Therefore, the invention is also directed to aerosol devices comprising the compound as defined above and such a formulation, preferably with metered dose valves.

The pharmaceutical compositions of the invention can also be intended for intranasal administration. hi this regard, pharmaceutically acceptable carriers for administering the compound to the nasal mucosal surfaces will be readily appreciated by the ordinary artisan. These carriers are described in the Remington's Pharmaceutical Sciences" 16th edition, 1980, Ed. By Arthur Osol, the disclosure of which is incorporated herein by reference.

The selection of appropriate carriers depends upon the particular type of administration that is contemplated. For administration via the upper respiratory tract, the composition can be formulated into a solution, e.g., water or isotonic saline, buffered or unbuffered, or as a suspension, for intranasal administration as drops or as a spray. Preferably, such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers. For example, a representative nasal decongestant is described as being buffered to apH of about 6.2 (Remington's, Id. at page 1445). Of course, the ordinary artisan can readily determine a suitable saline content and pH for an innocuous aqueous carrier for nasal and/or upper respiratory administration.

Common intranasal carriers include nasal gels, creams, pastes or ointments with a viscosity of, e.g., from about 10 to about 3000 cps, or from about 2500 to 6500 cps, or greater, may also be used to provide a more sustained contact with the nasal mucosal RECEIVED at IPONZ on 11 February 2010 548884 59 surfaces. Such earner viscous formulations may be based upon, simply by way of example, alkylcelluloses and/or other biocompatible carriers of high viscosity well known to the art (see e.g., Remington's, cited supra, A preferred alkylcellulose is, e.g., roethylcellulose in a concentration ranging from about 5 to about 1000 or more mg per 100 ml of carrier, A more preferred concentration of methyl cellulose is, simply by way of example, from about 25 to about mg par 1 TO ml of carrier.

Other ingredients, such as art known preservatives, colorants, lubricating or viscous mineral or vegetable oils, perfumes, natural or synthetic plant extracts such as aromatic oils, and humectants and viscosity cnhancers such as, e.g., glycerol can also be included to provide additional viscosity, moisture retention aid a pleasant texture and odor for fee formulation. For nasal administration of solutions or suspensions according to the invention, various devices are available in the ait for the generation of drops, droplets and sprays.

A premeasured unit dosage dispenser including a dropper or spray device containing a solution or suspension for delivery as drops or as a spray is prepared containing one or more doses of the drug to be administered and is another aspect of the invention. The invention also includes a kit containing one or more unit dehydrated doses of the compound, together with any required salts and/or buffer agents, preservatives, colorants and the like, ready for preparation of a solution or suspension by flue addition of a suitable amount of water.

-Another aspect of the invention is directed to the use of said compound to manufacture a medicament In other words, the invention embraces a method for treating a disease .related to unregulated c-kit transduction comprising administering an effective amount of a compound as defined above to a mammal in need of such treatment C:\pof\word\8PEC-N214948-0e.doc 10/02/10 548884 60 More particularly, the invention is aimed at a method for treating a disease selected from autoimmune diseases, allergic diseases, bone loss, cancers such as leukemia and GIST, tumor angiogenesis, inflammatory diseases, inflammatory bowel diseases (IBD), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes and CNS disorders comprising administering an effective amount a compound depicted above to a mammal in need of such treatment.

The above described compounds are useful for manufacturing a medicament for the treatment of diseases related to unregulated c-kit transduction, including, but not limited to: - neoplastic diseases such as mastocytosis, canine mastocytoma, human gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal tumors, testicular cancers, glioblastomas, solid tumors and astrocytomas. tumor angiogenesis. - metabolic diseases such as diabetes mellitus and its chronic complications; obesity; diabete type II; hyperlipidemias and dyslipidemias; atherosclerosis; hypertension; and cardiovascular disease. - allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin inflammation and blood sucking parasitic infestation. - interstitial cystitis. bone loss (osteoporosis). - inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions. 2005/073225 548884 61 autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, as well as proliferative glomerulonephritis. graft-versus-host disease or graft rejection in any organ transplantation including kidney, pancreas, liver, heart, lung, and bone marrow.

Other autoimmune diseases embraced by the invention active chronic hepatitis and chronic fatigue syndrome. subepidermal blistering disorders such as pemphigus.

Vasculitis. melanocyte dysfunction associated diseases such as hypermelanosis resulting from melanocyte dysfunction and including lentigines, solar and senile lentigo, Dubreuilh melanosis, moles as well as malignant melanomas. In this regard, the invention embraces the use of the compounds defined above to manufacture a medicament or a cosmetic composition for whitening human skin.

CNS disorders such as psychiatric disorders, migraine, pain, memory loss and nerve cells degeneracy. More particularly, the method according to the invention is useful for the treatment of the following disorders: Depression including dysthymic disorder, cyclothymic disorder, bipolar depression, severe or "melancholic" depression, atypical depression, refractory depression, seasonal depression, anorexia, bulimia, premenstrual syndrome, post-menopause syndrome, other syndromes such as mental slowing and loss of concentration, pessimistic worry, agitation, self-deprecation, decreased libido, pain including, acute pain, postoperative pain, chronic pain, nociceptive pain, cancer pain, neuropathic pain, psychogenic pain syndromes, anxiety disorders including anxiety associated with hyperventilation and cardiac arrhythmias, phobic 548884 62 disorders, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, psychiatric emergencies such as panic attacks, including psychosis, delusional disorders, conversion disorders, phobias, mania, delirium, dissociative episodes including dissociative amnesia, 5 dissociative fugue and dissociative identity disorder, depersonalization, catatonia, seizures, severe psychiatric emergencies including suicidal behaviour, self-neglect, violent or aggressive behaviour, trauma, borderline personality, and acute psychosis, schizophrenia including paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, and undifferentiated schizophrenia, 10 - neurodegenerative diseases including Alzheimer's disease , Parkinson's disease, Huntington's disease, the prion diseases, Motor Neurone Disease (MND), and Amyotrophic Lateral Sclerosis (ALS). substance use disorders as referred herein include but are not limited to drug addiction, drug abuse, drug habituation, drug dependence, withdrawal syndrome 15 and overdose.

Cerebral ischemia Fibrosis Duchenne muscular dystrophy Regarding mastocytosis, the invention contemplates the use of the compounds as defined above for treating the different categories which can be classified as follows: The category I is composed by two sub-categories (IA and IB). Category IA is made by diseases in which mast cell infiltration is strictly localized to the skin. This category represents the most frequent form of the disease and includes : i) urticaria pigmentosa, 25 the most common form of cutaneous mastocytosis, particularly encountered in children, ii) diffuse cutaneous mastocytosis, iii) solitary mastocytoma and iv) some rare subtypes like bullous, erythrodermic and telangiectatic mastocytosis. These forms are characterized by their excellent prognosis with spontaneous remissions in children and a 548884 63 very indolent course in adults. Long term survival of this form of disease is generally comparable to that of the normal population and the translation into another form of mastocytosis is rare. Category IB is represented by indolent systemic disease (SM) with or without cutaneous involvement. These forms are much more usual in adults than in 5 children. The course of the disease is often indolent, but sometimes signs of aggressive or malignant mastocytosis can occur, leading to progressive impaired organ function.

The category II includes mastocytosis with an associated hematological disorder, such as a myeloproliferative or myelodysplastic syndrome, or acute leukemia. These 10 malignant mastocytosis does not usually involve the skin. The progression of the disease depends generally on the type of associated hematological disorder that conditiones the prognosis.

The category 111 is represented by aggressive systemic mastocytosis in which massive 15 infiltration of multiple organs by abnormal mast cells is common. In patients who pursue this kind of aggressive clinical course, peripheral blood features suggestive of a myeloproliferative disorder are more prominent. The progression of the disease can be very rapid, similar to acute leukemia, or some patients can show a longer survival time.

Finally, the category IV of mastocytosis includes the mast cell leukemia, characterized by the presence of circulating mast cells and mast cell progenitors representing more than 10% of the white blood cells. This entity represents probably the rarest type of leukemia in humans, and has a very poor prognosis, similar to the rapidly progressing variant of malignant mastocytosis. Mast cell leukemia can occur either de novo or as the 25 terminal phase of urticaria pigmentosa or systemic mastocytosis. 548884 64 The invention also contemplates the method as depicted for the treatment of recurrent bacterial infections, resurging infections after asymptomatic periods such as bacterial cystitis. More particularly, the invention can be practiced for treating Fimll expressing bacteria infections such as Gram-negative enterobacteria including E. coli, Klebsiella 5 pneumoniae, Serratia marcescens, Citrobactor freudii and Salmonella typhimurium. In this method for treating bacterial infection, separate, sequential or concomitant administration of at least one antibiotic selected bacitracin, the cephalosporins, the penicillins, the aminoglycosides, the tetracyclines, the streptomycins and the macrolide antibiotics such as erythromycin; the fluoroquinolones, actinomycin, the sulfonamides 10 and trimethoprim, is of interest.

In one preferred embodiment, the invention is directed to a method for treating neoplastic diseases such as mastocytosis, canine mastocytoma, human gastrointestinal stromal tumor ("GIST"), small cell lung cancer, non-small cell lung cancer, acute 15 myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, colorectal carcinomas, gastric carcinomas, gastrointestinal stromal tumors, testicular cancers, glioblastomas, and astrocytomas comprising administering a compound as defined herein to a human or mammal, especially dogs and cats, in need of such treatment.

In one other preferred embodiment, the invention is directed to a method for treating allergic diseases such as asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria, angioedema, atopic dermatitis, allergic contact dermatitis, erythema nodosum, erythema multiforme, cutaneous necrotizing venulitis and insect bite skin 25 inflammation, and blood sucking parasitic infestation comprising administering a compound as defined herein to a human or mammal, especially dogs and cats, in need of such treatment. 548884 65 In still another preferred embodiment, the invention is directed to a method for treating inflammatory diseases such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions comprising administering a compound as defined herein to a human in need of such treatment.

In still another preferred embodiment, the invention is directed to a method for treating autoimmune diseases such as multiple sclerosis, psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis and polyarthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus, 10 cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy, as well as proliferative glomerulonephritis comprising administering a compound as defined herein to a human in need of such treatment.

In still another preferred embodiment, the invention is directed to a method for treating graft-versus-host disease or graft rejection in any organ transplantation including kidney, pancreas, liver, heart, lung, and bone marrow comprising administering a compound as defined herein to a human in need of such treatment.

Example 1 : in vitro TK inhibition assays • Procedure Experiments were performed using purified intracellular domain of c-kit expressed in baculovirus. Estimation of the kinase activity was assessed by the phosphorylation of tyrosine containing target peptide estimated by established ELISA assay.

• Experimental results on tested compounds 548884 66 Result in Table 1 shows the potent inhibitory action of the catalytic activity of c-kit with an IC50 <10 jj,M. Further experiments (not shown) indicates that at least one compound acts as perfect competitive inhibitors of ATP.

Example 2 : ex vivo TK inhibition assays • Procedures o C-Kit WT and mutated C-Kit fJM) assay Proliferation assays Cells were washed two times in PBS before plating at 5 x 104 cells per well of 96-well 10 plates in triplicate and stimulated either with hematopoietic growth factors (HGF) or without. After 2 days of culture, 37 Bq (1.78 Tbq/mmol) of [3H] thymidine (Amersham Life Science, UK) was added for 6 hours. Cells were harvested and filtered through glass fiber filters and [3H] thymidine incorporation was measured in a scintillation counter. For proliferation assay, all drugs were prepared as 20mM stock solutions in DMSO and 15 conserved at -80°C. Fresh dilutions in PBS were made before each experiment. DMSO dissolved drugs were added at the beginning of the culture. Control cultures were done with corresponding DMSO dilutions. Results are represented in percentage by talcing the proliferation without inhibitor as 100%.

Cells Ba/F3 murine kit and human kit, Ba/F3 mkitD27 (juxtamembrane deletion) are derived from the murine IL-3 dependent Ba/F3 proB lymphoid cells. The FMA3 and P815 cell lines are mastocytoma cells expressing endogenous mutated forms of Kit, i.e., frame deletion in the murine juxtamembrane coding region of the receptor-codons 573 to 579. The human leulcaemic MC line HMC-1 expresses mutations JM-Y560G; 25 Immunoprecipitation assays and western blotting analysis For each assay, 5.106 Ba/F3 cells and Ba/F3-derived cells with various c-kit mutations were lysed and immunoprecipitated as described (Beslu et al., 1996), excepted that cells were stimulated with 250 ng / ml of rmKL. Cell lysates were immunoprecipitated with a

Claims

WO 2005/073225 548884 PCT/IB2005/000401 67 rabbit immunserum anti murine KIT, directed against the KIT cytoplasmic domain (Rottapel et al., 1991). Western blot was hybridized either with the 4G10 anti-phosphotyrosine antibody (UBI) or with the rabbit immunserum anti-murine KIT or with different antibodies (described in antibodies paragraph). The membrane was then 5 incubated either with HRP-conjugated goat anti mouse IgG antibody or with HRP-conjugated goat anti rabbit IgG antibody (Immunotech), Proteins of interest were then visualized by incubation with ECL reagent (Amersham). • Experimental results 10 The experimental results for various compounds according to the invention using above-described protocols are set forth at Table 2: Table 2: Target IC50 (mM) Compounds c-Kit WT IC50 < 10 mM 001; 002; 003; 004; 005; 028; 029; 030; 031; 032; 033; 034; 35; 036; 038; 039; 040; 041; 042; 043; 044; 045; 046; 047; 048; 049; 050; 051; 052; 053; 054; 055; 056; 057; 058; 059; 060; 061; 062; 0.65; 089; 090; 092; 093; 094; 096; 099; 100; 101; 102; 105; 106 c-Kit JM D27 IC50 < 1 mM 15 RECEIVED at IPONZ on 11 February 2010 548884 68 The Claims Defining The Invention Are As Follows

1. A compound of formula II: 0 n Ra X FORMULA II 5 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 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 and optionally bearing a pendant basic 10 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; K4 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; R* Is one of the following: (i) an aryl group bearing any combination, at any one ring position, of one or more substituents; 15 (ii) a heteroaryl group, which may additionally bear any combination of one or more substituents; (iii) a five-membered ring aromatic heterocyclic group which may additionally bear any combination of one or more substituents. C:\poftworcl\SPEG-NZ14949-06.doc 10/02/10 RECEIVED at IPONZ on 11 February 2010 548884 69

2. A compound according to claim 1, wherein X is a substituted alkyl, aryl or heteroaryl group bearing a pendant basic nitrogen functionality.

3. A compound according to claim 2, wherein X is selected from the structures a to m 5 shown below, wherein the wavy line and the arrow line correspond to the point of attachment to core structure of formula II. jo b c N A/NV^/ I M h2N^ N N" "N -N- SO. -N. ) 10 J I m

4. A compound according to claim 3, wherein the arrow is a point of attachment to the core structure via a phenyl group.

5. A compound according to any one of claims 1 to 4, wherein R is a 3-pyridyl group 15 (structure g below), or a 4-pyridyl group (structure h below), the wavy line in structure g and h correspond to the point of attachment to the core structure of formula II. G:\pof\vvord\SPEC-N2l4949-C6.doc 10/02/10 RECEIVED at IPONZ on 11 February 2010 548884 70 g h

6. A compound according to claim 1 of formula II-3: 5 wherein Ra, Rb, Rc, Rd, Re are independently chosen from H or an organic group; a -S02-R group wherein R is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom 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 and/or bearing a 10 pendant basic nitrogen functionality; Ra, Rb, Rc, Rd, Re may also be - a halogen a NRR' group where R and R' are 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 15 pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, or bearing a pendant basic nitrogen functionality; an OR group where R is H or a linear or branched alkyl group containing from 20 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 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, or bearing a pendant basic C:>pofkWortf\SP£C-NZ14B494)6.dOC 10/02710 RECEIVED at IPONZ on 11 February 2010 548884 71 nitrogen functionality; a -S02-R' group wherein R' is an alkyl, cycloalkyl, aryl or heteroaryl optionally substituted with a heteroatom, or bearing a pendant basic nitrogen functionality; a NRaCORb group where Ra and Rb are H or linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at least one heteroatom 5 and/or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom 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, or bearing a basic nitrogen functionality; 10 - a NRaCONRbRc group where Ra and Rb are 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, or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with a 15 cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom, 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 and/or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally 20 substituted with at least one heteroatom and/or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom 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 25 heteroatom and/or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom 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 and/or bearing a pendant basic nitrogen functionality; 30 - 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 and/or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom 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 C:\poftwoitf\SP5C-NZ14W9-06.doc 10/02/10 RECEIVED at IPONZ on 11 February 2010 548884 72 heteroaryl group optionally substituted with an heteroatom and/or bearing a pendant basic nitrogen functionality; an OSOiR, where R is a linear or branched alkyl group containing from 1 to 10 carbon atoms atoms optionally substituted with at least one heteroatom and/or bearing a 5 pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with at least one heteroatom 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 and/or bearing a pendant basic nitrogen functionality; 10 an NRaOSC>2Rb, 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 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, and/or bearing a pendant basic nitrogen functionality; or a cycloalkyl, an aryl or heteroaryl 15 group substituted by and akyl, a cycloalkyl, an aryl or heteroaryl group optionally substituted with an heteroatom and/or bearing a pendant basic nitrogen functionality; a CN group a trifluoromethyl group R4 is hydrogen, halogen or a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 20 R6 is one of the following: (i) an aryl group bearing any combination, at any one ring position, of one or more substituents; (ii) a heteroaryl group, which may additionally bear any combination of one or more substituents; 25 (iii) a five-membered ring aromatic heterocyclic group, which may additionally bear any combination of one or more substituents.

7. A compound according to claim 6, wherein the organic group is selected from a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with at 30 least one heteroatom and/or bearing a pendant basic nitrogen functionality; a cycloalkyl, an aryl or heteroaryl group optionally substituted with a heteroatom, or bearing a pendant basic C:\pof\word\SPEC-NZ14049-06.doc 10/02/10 RECEIVED at IPONZ on 11 February 2010 548884 73 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 or bearing a pendant basic nitrogen functionality. 5

8. A compound according to any one of claims 1 to 7, wherein at each occurrence, said heteroatom is a halogen selected from I, CI, Br and F.

9. A compound according to claim 1 or 6 wherein in the group R6, said aryl group is selected from a phenyl or a substituted variant thereof. 10

10. A compound according to claim 1 or 6, wherein in the group R6, said heteroaryl group is selected from a 2, 3, or 4-pyridyl group.

11. A compound according to claim 1 or 6, wherein in the group R6, said five-membered 15 ring aromatic heterocyclic group is selected from 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl and 5-thiazolyl.

12. A compound according to any one of claims 1 or 6-11, wherein in the group R6, said aryl group, said heteroaryl group or said five-membered ring aromatic heterocyclic group 20 bears one or more substituents selected from halogen, an alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy.

13. A compound according to claim 1 or 6, wherein it is selected from N-(2-FluorO'3-trifluoromethylphenyl)4methyl3(4pyridin4ytthiazol-2y]ainino)-benzamide, K-(3-Ftuoro-phenyl)-4-methyl-3 -(4-pyridin-4-yl-4hiazol-2-ylarnino)-bciizatoMc, 4-Methyl-3-(4-pyridin-4-yl-tliia2»l-2-ylamiao)-N-(3-tiifl«oi"omet3i;yl-phenyl)~henzamide, 4-Metiiyl-N-(4-metliyl-3-trifluoromethyl-phenyl)-3-(4-pyi'idiii-4-yl-tMazol-2~yiammo>benzafflide, N-(2-Flit0m-54riflu0r0methyl-pliaiyl)-4-i-neth3d--3-(4-pyridln^~yl-tMazol-2-^amino)-bcozamid©, N-(4-Cyano-phenyl)-4-methyl-3-(4-pyridm- C:\poAvwfti\SPEC-NZ14949-00.doc \QtQ2f-\Q 548884 RECEIVED at IPONZ on 06 May 2010 75 Methyi-3--(4-p}Tiditi-3-yl-tbiazol-2-ylamino)-N-(3"trifl,uoromethyl-pbeoyI)-beazamide, 4-Mahyl-N-(4-aiethyi-3-triiluorometiiyl-pheiiyi)-3-(4-pyridia-3-yl-thiazol-2-ylamko)-benzamide, N-(2-Fluoro-3~trifluoroniefliyi-phenyl)-4-fiiethjl-3-(4-pyridin-3-yl-thiazoI-2-ylamino)-benzamide, N-(4-<^iK>-3-trifluoromctifciyl-ph.eDyl)-4-me&)4-3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzmnide, N-(4-Cyano-3-inethyl-phenyl)-4-niethyl-3-(4-pyridin-3-yl-tWa2ol-2-ylamiiio)-bessainide, 4-Methyl-N^4-(4-mcfl]iyi^ipearazin-l-ykaethyl)-3-trifluonMncthyl-pheaylJ-S^^jyridin-^yl-thiazol-i-ylaminoJ-benzamide, 4-MethyI-N-{4-[l -(4-methyl-piperazin-l -yi)-rthyl]-ph<aiyl} -3-{4-pyridin-3-yi-thiaz»l-2-yiammo)-bcnzamidc, N^3~Dlmdliylarnino-phenyl)^mcthyl-3-(4-^yridin-4-yl-thiazol-2- ylamino)4>enzHirude, N-(3-Dimethylamino-ph«iji)-4-meftyi-3-(4-pyridin-3-yl-thiazol-2-ylamino)-benzamide.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13.

15. A pharmaceutical composition according to claim 14 which is suitable for oral administration.

16. A dermopharmaceutic or cosmetic composition comprising a compound according to any one of claims 1 to 13, for topical administration.

17. A vetenary composition comprising a compound according to any one of claims 1 to 13.

18. The use of a compound according to any one of claims 1 to 13 to manufacture a medicament.

19. The use according to claim 18 to manufacture a medicament for treating a disease selected from autoimmune diseases, allergic diseases, bone loss, cancers such, as leukemia and GIST, tumor angiogenesis, inflammatory diseases, such as arthritis, inflammatory bowel diseases (H3D), interstitial cystitis, mastocytosis, infections diseases, metabolic disorders, fibrosis, diabetes and CNS disorders. RECEIVED at IPONZ on 11 February 2010 548884 76

20. A compound according to claim 1, substantially as hereinbefore described with reference to any one of the Examples. C:\pofWwrd\SPEC-NZ1484e-06.ClOC 10/02/10