FR2910895A1 - New imino-tetrahydrobenzothiazole compounds, are Met-receptor inhibitors useful for preventing the migration of metastases or tumor cells - Google Patents

Abstract

2-Phenyl-5,6,7,8-tetrahydro-imidazo-(2,1-b)-benzothiazole derivatives (I) are new. Also new are corresponding amino-substituted intermediates (II) and nitro-substituted intermediates (III). Imino-tetrahydrobenzothiazole compounds of formula (I) (including their enantiomers and analogs with a completely hydrogenated (hexahydro) benzo ring in the benzothiazole part) are new. Z1-Z5 : H, F, Br, alkyl, CF 3, alkoxy, NO 2(provided that 0 or 2-5 NO 2groups are present as Z1-Z5) or NR1R2; R1, R2 : H, alkyl, 3-6C alkenyl, 3-6C alkynyl or 1-6C-alkanoyl; phenyl, 1-3C-alkylphenyl or 1-3C-alkanoylphenyl (where phenyl moieties are optionally substituted (os) by 1 or 2 of F, Cl and Br); or -CO-CHR4-NHCO-X'-Ph', -(CH 2) n-phthalimide, 1-phenyl-1-hydroxy-(1-10C) alkyl, -(CH 2) n-CO-naphthalene, -(CH 2) n-COCH 2Ph', tert. butoxycarbonyl-alanyl, 3-chlorophenylacetyl or -CO-CHR4-NHCO-X'-C 6H 4-Cl (where the Cl may be in any position on the phenyl); X' : O, N, S or 1-10C alkylene (os by OH); R4 : 1-10C alkyl (os by OH) or aryl (os by alkyl); Ph' : 3,5-difluorophenyl; n : 0-10; R3 : H, alkyl, allyl, propargyl, benzyl, chlorobenzyl, ethylphenyl, 5-6C cycloalkyl, os amino, 2-10C alkyl ester residue, COOH, CONH 2, urea, sulfonamide, sulfonyl, hydroxamate, CONHOH, NHSO 3->, NHSO 3R', COO ->, NH3 +>, NHC(=NH)NH 3+>, (CH 2) m-NHC(=NH)NH 3+>, (CH 2) m-COO ->, (CH 2) m-NH 3+>, (CH 2) m-CONH 2or (CH 2) m-COOR''; or two adjacent R3 groups complete a 5-6 membered cycloaliphatic or (optionally hydrogenated and/or fused) aromatic ring (os by alkyl or halo); or at least one CR3 group may be replaced by N, O, S or NQ; R' : alkyl or phenyl; m : 1-10; R'' : alkyl or aryl (os by halo, NO 2, NH 2or alkoxy); Q : H, 1-10C alkyl, 2-10C alkyl ester residue, OH, -(CH 2) m-Ph, sulfonyl (os by alkyl or aryl (os by halo, NO 2, NH 2or alkoxy)) or -CO-CHR4-NHCO-X'-Ph'; alkyl moieties have 1-6C unless specified otherwise. Independent claims are included for new intermediates (II) and (III), which are as defined for (I) except that: (a) in (II) one of Z1 - Z5 = NH 2and the remainder = H, provided that compounds in which all R3 groups = H are excluded; and (b) in (III) one of Z1 - Z5 = NO 2and the others = H, provided that compounds in which all R3 groups = H are excluded. [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Met receptor inhibitor. Met is a tyrosine kinase type heterodimer receptor, the natural ligand for which is hepatocyte growth factor (also known as scatter factor). N-(N-(3,5-Difluorophenylacetyl)-(S)-alanyl)-N-(2-(4-nitrophenyl)-5,6,7,8-tetrahydro-7-(phenylmethyl)-imidazo-(2',1':2,3)-thiazolol-(5,4-c)-pyridine (sic) (Ia) had IC 5030 nM for inhibition of Met-mediated cell migration in assays using MDCK epithelial cells.

Description

The present invention relates to derivatives

  of imino-tetrahydrobenzotriazoles having anti-migratory properties of Met dependent metastases.

  Kinase-like proteins are enzymes that catalyze the phosphorylation of proteins, particularly the hydroxyl groups of tyrosine, serine and threonine thereof. The consequence of this enzymatic activity is cell differentiation and proliferation, i.e. cell life, in some aspects, depends on the activity of these protein kinases. Abnormal activity has been associated with some cancer-like diseases.

  Protein kinases include protein tyrosine kinase (PTK). One of the aspects of protein tyrosine kinase activity is their involvement with growth factor receptors (growth factors). Growth factor receptors are proteins on the surface of cells. When the growth factor receptors are ligated with a growth factor ligand, these receptors are transformed into an active form that interacts with the inner surface proteins of the cell membranes. This leads to phosphorylation of the receptor tyrosine residues, as well as other proteins, and to the formation of complexes with cytoplasmic signaling molecules which, in turn, induce many cellular responses, such as division, differentiation and cell growth etc. Growth factor receptors with PTK activity are known as tyrosine kinase receptors. They constitute an important class of transmembrane receptors, for example of the insulin type, having various biological activities. They consist of a binding domain of an extracellular glycosylated ligand, a transmembrane domain and a cytoplasmic catalytic intracellular domain that allows the phosphorylation of tyrosine residues of proteins.

  Among this class of receptors are Met receptors, or c-Met, which is a kinase member of the family of heterodimeric tyrosine kinase receptors. C-Met receptor expression occurs in a variety of cell types, such as epithelial and endothelial cells, where activation of these receptors causes migration, proliferation, and other cellular activities. Signal transduction via c-Met receptor activation is responsible for certain characteristics of tumor cells. The endogenous ligand for the c-Met receptor is the Hepatocyte Growth Factor (HGF), also called scatter factor (SF). The binding of HGF to c-Met results in activation of the receptor by autophosphorylation resulting in an increase in receptor-dependent signaling, which promotes cell growth. Some authors have shown that anti-HGF antibodies and HGF antagonists inhibit metastasis in vivo (Maulik et al., Cytokine & Growth Factor reviews, 2002, 13, 41-59). Various tumors, such as pulmonary, renal, and colon, overexpress the Met receptor that is associated with increased proliferation of cells in various tumors.

  Therefore, the modulation of Met receptor activity must therefore be able to treat or prevent diseases associated with abnormal cell proliferation or metastasis.

  Indeed, it is known that many cancers, such as gastric and liver carcinomas as well as sarcomas, are dependent on the Met protein and its Hepatocyte Growth Factor (HGF) ligand (Birchmeieir et al., Nature Reviews Molecular Eye Biology , 2003, 4, 915-925). Met dependent cancers favor the risk of metastasis. It has thus been shown that an inhibition of the Met receptor can be effective in the treatment of certain cancers. Such inhibition of this receptor may be effected via pyrroleindolinone derivatives because these are characterized by their ability to inhibit HGF / SF mediated cellular responses. They also inhibit the motility and proliferation of epithelial cells and carcinomas (Wang et al., Mol Cancer Ther, 2003, 11, 1085-1092). Other compounds, such as trastuzumab, a monoclonal antibody, are also Met receptor inhibitors (Christensen et al, Cancers Letters, 2005, 225, 1-26, WO2006 / 124731, WO2006 / 014325).

  One of the aims of the present invention is to provide novel molecules for treating or preventing diseases associated with the proliferation of metastases or, more generally, tumor cells and angiogenesis. The Applicant has developed a new class of molecules as Met receptor inhibitors thus exhibiting antimetastatic properties of Met dependent cells.

  The present invention thus relates to compounds of the imino-tetrahydrobenzothiazole family corresponding to the following general formula (I): ## STR3 ## in which: Z1, Z2, Z3, Z4 and Z5, independently, represent a hydrogen atom, a halogen selected from F and Br, an alkyl group of 1 to 6 carbon atoms, a group -CF3, a group -OR where R is an alkyl group of 1 to 6 carbon atoms, or wherein at least two of Z1 to Z5 represent a group -NO2, or Z1, Z2, Z3, Z4 and Z5 independently represent a group of formula

  Wherein R 1 and R 2, independently of each other, represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, carbon, an alkanoyl group having 1 to 6 carbon atoms, a phenyl, alkylphenyl or alkanoylphenyl group having 1 to 3 carbon atoms in the alkyl part, the phenyl group being unsubstituted or substituted with 1 or 2 halogen atoms selected from F, Br and Cl, or a group selected from groups (I) of formula (A) R 4 O (A) wherein X 'represents a heteroatom selected from the group consisting of O, N and S or a group alkylene having from 1 to 10 carbon atoms unsubstituted or substituted by a hydroxyl group, and R4 represents a linear or branched alkyl group of 1 to 10 carbon atoms unsubstituted or substituted by a hydroxyl group, or an unsubstituted aryl group or substituted with an alkyl group of 1 to 6 atoms s carbon; Of formula (B): - (CH 2) n-phthalimide; of formula (C): 1-phenyl-1- (linear or branched alkanol of 1 to 10 carbon atoms); of formula (D): - (CH 2) n-C = O-naphthalene; of formula (E): - (CH 2) n-3,5-difluorophenylacetyl; Of formula (F): tert-butoxycarbonylalanyl; of formula (G): 3-chlorophenylacetyl, and of formula (H) which is a group of formula (A) in which the two F atoms are replaced by a single chlorine atom in any position of the ring, n is 0 to 10; R3 independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an allyl, propargyl, benzyl, chlorobenzyl, ethylphenyl, cyclopentyl, cyclohexyl, amine, substituted amine, alkyl ester of 2 to 10 carbon atoms, carboxylic acid, -C = O-NH 2 amide, urea, sulfonamide, sulfonyl, hydroxamate, -C = O-NH-OH, -NH-SO 3 -, -NH-SO 3 -R 'where R represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, -COO-, -NH3, -NH-C = NH-NH3 +, - (CH2) n -NH-C = NH-NH3 +, - (CH2 n-COO, - (CH2) n -NH3 +, - (CH2) nC = O-NH2 or - (CH2) n -COO-R "where R" represents an alkyl group of 1 to 6 carbon atoms or a group aryl unsubstituted or substituted by a halogen atom, a nitro group, amino or O-alkyl groups of 1 to 6 carbon atoms, n being from 1 to 10, or two adjacent R3 forming a 5- or 6-membered ring aliphatic, aromatic or condensed aromatic linkages, optionally hydrogenated, non-substituting or substituted with an alkyl group of 1 to 6 carbon atoms or a halogen atom, or, in combination with the above, in the derivative of formula (1), at least one carbon atom of the tetrahydrobenzo ring in position 5, 6, 7 or 8, bearing a group R 3, is replaced by a heteroatom selected from the group consisting of N, O and S, where N is protonated or unsubstituted and unsubstituted or substituted by an alkyl group of 1 to 10 carbon atoms. carbon, alkyl ester of 2 to 10 carbon atoms, hydroxyl, a - (CH 2) n -phenyl group, n being from 1 to 10, unsubstituted or alkyl-substituted sulfonyl of 1 to 6 carbon atoms or an aryl group unsubstituted or substituted with a halogen atom, a nitro group, amino or O-alkyl groups of 1 to 6 carbon atoms, or with the group of formula A defined above, or, in combination with the above, R3 being as defined above, positions 4 and 9 of the tetrahydrobenzo ring are hydrogen es, and their enantiomers.

  According to one embodiment of the invention, the compound of formula (I) in which Z1, Z2, Z3, Z4 and Z5, independently, represent a hydrogen atom, a halogen selected from F and Br, a alkyl group of 1 to 6 carbon atoms, a -CF3 group, a group -OR where R is an alkyl group of 1 to 6 carbon atoms or, wherein at least two of Z1 to Z5 are -NO2, or Z1, Z2, Z3, Z4 and Z5, independently, represent a group of formula N where R1 represents a hydrogen atom; R2 represents a group chosen from groups of formula (A), (B), (C), (D), (E), (F), (G) and (H) as defined above; R 3 each represents a hydrogen atom, or one or more of the R 3 groups carried by a carbon atom of the tetrahydrobenzo ring at the 5, 6, 7 or 8 position is chosen from the group consisting of the benzyl group, the ester group and ethyl, propyl, n-butyl, isopropyl, isobutyl or tert-butyl, -C = O-NH2 amide, -C = O-NH-OH, -NHSO3-, - NH-SO3-R 'wherein R' represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, -COO-, -NH3, -NH-C = NH-NH3 +, - (CH2) -NH-C = NH-NH3 +, - (CH2) -COO-, - (CH2) -NH3 +, - (CH2) -C = O-NH2 and - (CH2) -COO-CH3, the other R3 being a hydrogen atom, or two of the adjacent R 3 together form an aliphatic or aromatic 6-membered ring, unsubstituted or substituted by an alkyl group of 1 to 6 carbon atoms or a halogen atom, or, in combination with the above, in the derivative of formula (I), a carbon atom of the tetrahydrobenzo ring at position 5, 6, 7 or 8, bearing R 3, is substituted by a nitrogen atom, optionally protonated, unsubstituted or substituted with -SO2-, a hydroxyl group, a benzyl group, an alkyl group of 2 to 6 carbon atoms, an ethyl ester group, propyl group, n-butyl, isopropyl, isobutyl or tert-butyl, or by the group of formula A defined above, or, in combination with the above, R3 being as defined above, positions 4 and 9 The tetrahydrobenzo rings are hydrogenated, and their enantiomers.

  According to one embodiment of the invention, the compounds of formula (I) in which Z1, Z2 and Z3 together represent a halogen selected from F and Br, a methyl group, a -CF3 group, are particularly preferred. a group -NO2, a group -O-CH3 and Z4 and Z5 represent a hydrogen atom, or Z1, Z2, Z3, Z4 and Z5 each represent a hydrogen atom, or, wherein, Z1, Z2, Z4 and Z5 represent a hydrogen atom and Z3 represents a group of formula

N ùRI 30 \ R2

  R1 represents a hydrogen atom; R2 represents a group selected from groups of formula (A) wherein R4 is methyl or ethyl optionally substituted with hydroxyl and X 'is methylene; of formula (B): - (CH 2) phthalimide or - (CH 2) 5-phthalimide; of formula (C): 1-phenyl-1- (linear alkanol of 3 carbon atoms); of formula (D): -C = O-naphthalene; of formula (E): -3,5-difluorophenylacetyl; of formula (F): tert-butoxycarbonyl-alanyl; of formula (G): 3-chlorophenylacetyl; three of the four R 3 represent a hydrogen atom and the last R 3 in the 5, 6, 7 or 8 position is chosen from the group consisting of the benzyl group, the ethyl, propyl, n-butyl, isopropyl, isobutyl or tert-butyl amide of type -C = O-NH2, -C = O-NH-OH, -NH-SO3-, -NH-SO3-CH3, -COO-, -NH3 , -NH-C = NH-NH3 +, - (CH2) -NH-C = NH-NH3 +, - (CH2) -000-, - (CH2) -NH3, - (CH2) -C = O-NH2 and - (CH 2) -COO-CH 3, or, in the derivative of formula (I), a carbon atom of the tetrahydrobenzo ring in position 5, 6, 7 or 8 is replaced by a nitrogen atom, optionally protonated, unsubstituted or substituted with -SO3-, a hydroxyl group, a benzyl group or an alkyl group of 2 to 6 carbon atoms, or two of the adjacent R3 together form a 6-membered aliphatic ring, unsubstituted or substituted by an alkyl group of 1 to 6 carbon atoms or a halogen atom, or in the derivative of formula (I), a carbon atom of the tetrahydrobenzo ring in 5, 6, 7 or 8 is replaced by a nitrogen atom, optionally protonated, unsubstituted or substituted with -SO3-, a hydroxyl group, a benzyl group, an alkyl group of 2 to 6 carbon atoms, a group ethyl, propyl, n-butyl, isopropyl, isobutyl or tert-butyl ester, or by the group of formula A defined above, or, in combination with the foregoing, R3 being such as defined above, the 4 and 9 positions of the tetrahydrobenzo ring are hydrogenated, and their enantiomers.

  According to a particularly preferred embodiment of the invention, the compounds of formula (I) are chosen from the group consisting of: 2 - [[[4- (5,6,7,8-tetrahydroimidazo [2,1- b] benzothiazol-2-yl) phenyl] amino] methyl] -1H-isoindole-1,3 (2) -dione,

  1- [2 - [[4- (5,6,7,8-tetrahydroimidazo [2,1b] benzothiazol-2-yl) phenyl] amino] ethyl] -15 benzenemethanol,

  2- (5- {[4- (5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-yl) phenyl] amino} pentyl) -1H-isoindole-1 3 (2H) -dione, N- (N- (naphthyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole,

  N- (N- (3,5-difluorophenylacetyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole),

  N- (N- (tert-butoxycarbonyl- (S) -alanyl) -N- (2 (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydro-benzothiazole),

  N- (N- (3-chlorophenylacetyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole)

  N- (N- (tert-butoxycarbonyl) - (S) -alanyl) - N- (2 (4-aminophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8 8a, 9-octahydro-naphthothiazole, N- (N- (3-chlorophenylacetyl) - (S) -alanyl) -N- (2 (4-aminophenyl) imidazo [2,1-b] -5,6 7,8-tetrahydrobenzothiazole), N- (N (3,5-difluoromandelyl) - (S) -alanyl) -N- (2 (4-aminophenyl) imidazo [2,1-b] -5,6, 7,8-tetrahydrobenzothiazole)

  N- (N- (3,5-difluorophenylacetyl) - (R) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole), N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5, ethyl ester, 6, 7,8-tetrahydrobenzothiazole-5-carboxylic acid,

  N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1b] -5,6,7 ethyl ester of ethyl ester 8-tetrahydrobenzothiazole-6-carboxylic acid

  N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-nitrophenyl) -5,6,7,8-tetrahydro-2-7- (phenylmethyl) imidazo) [2 ', 1': 2,3] thiazolo [5,4-c] pyridine),

  N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole), N (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8 8a, 9-octahydro-naphthothiazole),

  N- (N- (3,5-Difluorophenylacetyl) - (S) -alanyl) -N- (2- (4- (N-nitrophenyl) imidazo [2,1-b]) propyl or isopropyl ester -5,6,7,8-tetrahydrobenzothiazole-5- or 6-carboxylic acid,

  butyl ester of N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,6 7,8-tetrahydrobenzothiazole-5-carboxylic acid N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-nitrophenyl) -5,6,7,8- tetrahydro-2-7- (phenylmethyl) imidazo [2 ', 1', 2,3] thiazolo [5,4-c] pyridine).

  {2- [4- ({N- (3,5-difluorophenyl) acetyl] - (R) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2.1-15 b] [ 1,3] benzothiazole-7-amine,

  N- [4- (tert -butoxycarbonyl) -5,6,7,8-tetrahydro-imidazo [2 ', 1', 2,3] [1,3] thiazolo- [4,5-b] pyridin-2- yl) phenyl] -N-2 - [(3,5-difluorophenyl) acetyl] - (R) -alaninamide,

  2- [4- ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -N-hydroxy-5,6,7,8-tetrahydroimidazo [ 2, 1-b] [1,3] benzothiazole-5,6,7 or 8-carboxamide,

  N2 - [(3,5-difluorophenyl) acetyl] -N- {4- [5-, 6-, 7- or 8- (sulfonatoamino) -5,6,7,8-tetrahydroimidazo [2,1-b] ] [1,3] benzothiazol-2-yl] phenyl} - (R) or (S) -alaninamide,

  {2- [4- (N- [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [ Methyl 2,1-b] [1,3] benzothiazol-5,6,7-or 8-yl} sulfamate;

N- [4- (7-Benzyl-5,6,7,8-tetrahydroimidazo [2 ', 1': 2,3] [1,3] thiazolo [5,4-c] pyridin-7- (2-yl) phenyl] -N- 2 - [(3,5-difluorophenyl) acetyl] - (S) - or - (R) -alaninamide, N2 - [(3,5-difluorophenyl) ) acetyl] -N- {4- (5,6,7,8-tetrahydroimidazo [2 ', 1': 2,3] [1,3] [thia-b] pyridin-2-yl) phenyl] - ( S) -alaninamide, N2 - [(3,5-difluorophenyl) acetyl] -N- {4- [5,6,7,8-tetrahydroimidazo [2 ', 1', 2,3] [1,3]] [thia-c] pyridin-6- or -7-ium-2-yl) phenyl] - (S) or (R) -alaninamide,

  2- [4- (N- [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alanyl) amino) phenyl] -7,8-dihydroimidazo [2 ', 1']: 2, 3] - [1, 3] thiazolo [4,5-b] pyridine-5 (6H) -sulfonate,

  2- [4- ({N - [(3,5-difluorophenyl) acetyl] - (S) - or - (R) -alanyl} amino) phenyl] -7,8-dihydroimidazo [2 ', l': 2 , 3] - [1, 3] thiazolo [4,5-b] -pyridine-6 (5H) -sulfonate,

  2- [4- ({N - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alanyl} amino) phenyl] -7,8-dihydroimidazo [2 ', l': 2 , 3] [1, 3] thiazolo [4,5-b] pyridine-7 (6H) -sulfonate,

  2- [4- (N- [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alanyl) amino) phenyl] -7,8-dihydroimidazo [2 ', 1': 2] , 3] - [1,3] thiazolo [4,5-b] -pyridine-8 (5H) -sulfonate,

  N2 - [(3,5-difluorophenyl) acetyl] -N- [4- (5-, 6-, 7- or 8-hydroxy-5,6,7,8-tetrahydroimidazo [2 ', 1'] 2 , 3] - [1,3] thiazolo [5,4-b] pyridin-2-yl) phenyl] - (S) - or (R) -alaninamide,

  N2 - [(3,5-difluorophenyl) acetyl] -N- [4- (5aR or SaS, 9aR or 9aS)) - 5,5a, 6,8,8,9a, 10-octahydroimidazo [2,1- b] naphtho [2,3-d] [1,3] thiazol-2-yl] phenyl) - (S) - or (R) -ananinamide, N2 - [(3,5-difluorophenyl) acetyl] ] -N- [4- (5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-yl) phenyl) - (S) - or (R) -alaninamide, the N [4- (6-benzyl) -5,6,7,8-tetrahydroimidazo [2 ', 1', 2,3] [1,3] thiazolo [4,5-c] pyridin-6-ium- 2-yl) phenyl] -N 2 - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -ananinamide, N- {4 - [(4aS or 4aR, 6R or 6S, 8aS or 8aR) - (6-Benzyl-4a, 5,6,7,8,8a-hexahydroimidazo [2 ', 1', 2,3] [1,3] thiazolo [4,5-c] pyridin] 6-ium-2-yl] phenyl} -N 2 - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alaninamide, 2- (3,5-difluorophenyl) -N - [( 1R) -1-methyl-2-oxo-2- (2-phenyl-5,8-dihydroimidazo [2 ', 1', 2,3] [1,3] thiazolo [5,4-c] pyridin] 7 (6H) -yl) ethyl] acetamide,

2- (3,5-difluorophenyl) -N - {(1 R) -1-methyl-2-oxo-2- [2- (2,3,4-trifluorophenyl) -5,8-dihydroimidazo [2 1 ', 2,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl] acetamide

2- (3,5-Difluorophenyl) -N - {(1 R) -1-methyl-2-oxo-2- [2- (2,3,4-tribromophenyl) -5,8-dihydroimidazo [2] 1 ', 2,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl] acetamide

2- (3,5-difluorophenyl) -N - {(1R) -1-methyl-2-oxo-2- [2- (2,3,4-trimethylphenyl) -5,8-dihydroimidazo] 2 1 ', 2,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl] acetamide

  2- (3,5-difluorophenyl) -N - {(1 R) -1-methyl-2-oxo-2- [2- [2,3,4-tris (trifluoromethyl) phenyl] -5,8- Dihydroimidazo [2 ', 1', 2,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl] acetamide,

  2- (3,5-difluorophenyl) -N - {(1R) -1-methyl-2-oxo-2- [2- (2,3,4-trimethoxyphenyl) -5,8-dihydroimidazo [2 '] 2,3,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl) acetamide;

2- (3,5-difluorophenyl) -N - {(1R) -1-methyl-2-oxo-2- [2- (2,3,4-trinitrophenyl) -5,8-dihydroimidazo [2 '] 2,3,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl) acetamide;

  N - (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-nitrophenyl) imidazo [2,1-b] -5,6) methyl ester of methyl ester 7,8-tetrahydrobenzothiazole-5-, 6-, 7- or 8-carboxylic acid,

  2- [4- ({N- (3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-b] ] [1,3] benzothiazole-5,6,7- or 8-carboxamide,

  2- [4- ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1- B] [1,3] benzothiazole-5,6,7- or 8-carboxylate,

  2- [4- ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1- b] [1,3] benzothiazol-5-, 6-, 7- or 8-aminium,

  ({2- [4- (N- [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2], 1- [b] [1,3] benzothiazol-5,6-, 7- or 8-yl} amino) (imino) methanaminium,

  [({2- [4- ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2] 1- [35b] [1,3] benzothiazol-5-, 6-, 7- or 8-yl} methyl) amino) (imino) methanaminium,

  {2- [4- (N- [(3,5-difluorophenyl) acetyl] - (R) or (S) -5-alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2], 1-b] [1,3] benzothiazol-5,6,7-or 8-yl} acetate,

  {2- [4- (N- [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2.1 B) [1,3] benzothiazol-5,6,7 or 8-yl} methanaminium

N- {4- [5-, 6-, 7- or 8- (2-amino-2-oxoethyl) -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-yl] phenyl} -N - 2 [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alaninamide,

  {2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazoacetate; [2,1-b] [1,3] benzothiazol-5,6,7 or 8-yl} methyl or ethyl,

  {(7R) -2- [4- (N- [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} aminc) phenyl] -5,6,7 acetate 8-Tetrahydroimidazo [2,1-b] [1,3] benzothiazole-5,6- [7- or 8-yl] methyl,

  N2 - [(3,5-difluorophenyl) acetyl] -N- {4- [5-, 6-, 7- or 8- (hydroxymethyl) -5,6,7,8-tetrahydroimidazo [2,1-b] ] - [1,3] benzothiazol-2-yl) phenyl} - (R) - or (S) -alaninamide,

  N2 - [(3,5-difluorophenyl) acetyl] -N- [4- (5-, 6-, 7- or 8-formyl-5,6,7,8-tetrahydroimidazo [2,1-b] ] [1,3] benzothiazol-2-yl) phenyl] - (R) - or (S) -alaninamide, and N- [4- (5-, 6-, 7- or 8- {[(aminocarbonyl)]; ) amino] methyl} -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-yl) phenyl] -N2 - [(3,5-difluorophenyl) acetyl] - (S) - or (R) - alaninamide.

  The compounds of formula (I) can be prepared in different ways depending on the nature of the substituents present in the compounds of formula (1). In the case where, in the compounds of formula (I), one of the substituents Z1, Z2, Z3, Z4 or Z5 is the N1R1 group R2 in which R1 is a hydrogen atom and R2 is the group - (CH 2) naphthalimide or the 1-phenyl-1- (linear or branched alkanol of 1 to 10 carbon atoms) group and R 3 has the above meanings, these may be prepared in the following manner (compounds of formula la ). The compound of general formula (II) Z4 wherein one of Z1, Z2, Z3, Z4 and Z5 is -RNH2, the others being a hydrogen atom, R3 has the same meanings as for the compound of formula (I), and the corresponding enantiomers, is reacted respectively with either N- (1-bromo- (CH 2) n-phthalimide or with 3-chloro-1-phenyl-1- (linear or branched alkanol) 1 to 10 carbon atoms) with stirring in anhydrous alkaline earth metal carbonate in an anhydrous solvent, preferably acetonitrile, dimethylformamide (DMF) or anhydrous THF The reaction mixture thus obtained is refluxed for a period of one hour. 8-12 hours, preferably 10 hours, under an inert atmosphere, in particular under a nitrogen atmosphere, the solvent is advantageously removed by evaporation under reduced pressure and the product obtained is then preferably purified, for example by gel adsorption chromatography. of silica using eluents based on methanol, ethanol or methylene chloride, or their mixture.

  The compounds of formula (I) in which one of the substituents Z1, Z2, Z3, Z4 or Z5 is the group N1 R1 where R2 is a hydrogen atom and R2 is the group of formula (D): - (CH2) nC = O-naphthalene, n is 0 to 10; of formula (E): - (CH 2) n - 3,5-difluorophenylacetyl, n is 0 to 10; of formula (F): tert-butoxycarbonylalanyl; of formula (G). 3-Chlorophenylacetyl, the others being a hydrogen atom, and wherein R 3 has the above meanings, can be prepared according to a reaction which follows, named Method A (compounds of formula Ib).

  Method A The general principle of preparation of the compounds of formulas (Ib) above is based on a coupling of the compound of general formula (II) above, where R3 has the same meanings as for the compound of formula (I), in the presence of phosphorus oxychloride (POCl 3) and N-Boc-alanine (Boc = butyloxycarbonyl) and respectively - (CH 2) n-naphthoic acid, n is 0 to 10, of - (CH 2) n - acid -3,5-difluorophenylacetic acid, n is 0 to 10, tert-butoxycarbonylalanine and 3-chlorophenylacetic acid. N-Boc-alanine, the compound of formula (II) and each of the above compounds are dissolved in an anhydrous solvent, preferably pyridine, dimethylformamide (DMF) or methylene chloride. In the thus obtained reaction medium cooled to a temperature of between -10 and -20 ° C., preferably at a temperature of -15 ° C., POC13 is added dropwise with vigorous stirring of the reaction medium. Stirring is continued for 24 hours to 48 hours in the above temperature range. The products obtained are then preferably extracted in a solvent, concentrated and purified if necessary by chromatography by techniques known to those skilled in the art.

  Compounds of formula (I) in which one of the substituents Z1, Z2, Z3, Z4 or Z5 is NR1 group R1 where R1 is hydrogen and R2 is the group of formula (A) wherein X 'represents a heteroatom selected from the group consisting of O, N and S or an alkylene group having from 1 to 10 carbon atoms unsubstituted or substituted by a hydroxyl group, and R4 represents a linear or branched alkyl group of 1 to 10 carbon atoms unsubstituted or substituted with a hydroxyl group, or R2 is the group of formula (G). 3-chlorophenylacetyl, the others being a hydrogen atom, and wherein R 3 has the above meanings, can be prepared according to a reaction which follows, named Method B (compounds of formula Ic). Method B The general principle of preparing the compounds of formulas (Ic) above is based on a reaction involving benzotriazol-1-yl-oxy-tris- (dimethylamino) phosphonium hexafluorophosphate (BOP) in the presence of N Boc-alanine dissolved in an anhydrous chlorinated solvent, for example methylene chloride (CH 2 Cl 2), in DMF or anhydrous anhydrous pyridine. Diisopropylethylamine is then added to the reaction medium thus obtained, and the mixture is then all mixed at room temperature. The solution obtained is cooled, typically at 0 ° C., and a compound of formula (II), diisopropylethylamine and a compound of formula A 'are then added dropwise with stirring.

  Wherein X 'represents a heteroatom selected from the group consisting of O, N and S or an alkylene group having from 1 to 10 carbon atoms unsubstituted or substituted by a hydroxyl group, and R4 represents a linear or branched alkyl group of 1 to 10 carbon atoms unsubstituted or substituted by a hydroxyl group, or a compound of formula A "in which the two F atoms are replaced by a single chlorine atom in any position of the ring, the The products obtained are then preferably extracted in a solvent, concentrated and purified if necessary by chromatography by techniques known to those skilled in the art.

  A compound of formula (I) in which one of R3 represents an amide of the type -C = O-NH2, Z1, Z2, Z3, Z4 and Z5 being as defined above, may be obtained by reacting the compound of formula (I), in a suitable solvent, wherein R3 is an ester group with ammonia gas, typically for 1 hour at room temperature.

  A compound of formula (I) in which Z1, Z2 and Z3 together represent a halogen selected from F and Br, a methyl group, a -CF3 group, a -NO2 group, a -O-CH3 group and Z4 and Z5 represent a hydrogen atom, or Z1, Z2, Z3, Z4 and Z5 each represent a hydrogen atom, and in the derivative of formula (I), a carbon atom of the tetrahydrobenzo ring at the 5, 6, 7 or 8 position is replaced by a nitrogen atom substituted by the group of formula A defined above, wherein R4 represents a methyl group and X 'represents a methylene group, can be synthesized in the following manner (compounds Id). The compounds Id are obtained from products of N2 - [(3,5-difluorophenyl) acetyl] -N [4- (5,6,7,8-tetrahydroimidazo [2 ', 1': 2,3] 1,3] thia-b] pyridin-2-yl) phenyl] alaninamide, by coupling thereof with the aid of the BOP reagent with the Bocalanyl derivative or of these homologs 3,5-difluorophenylacetylalanine, in an anhydrous solvent, such as methylene chloride or pyridine. The different products are then classically purified by chromatography.

  The invention also relates to the compounds of formula (II) Z4 wherein one of Z1, Z2, Z3, Z4 and Z5 is -RNH2, the others being hydrogen, R3 has the same meanings as for the compound of formula (I), as well as the corresponding enantiomers, as intermediate compounds for the preparation of compounds of formula (I), excluding compound (I) wherein all R3 substituents are an atom of hydrogen and one of Z1, Z2, Z3, Z4 and Z5 is -RNH2, the others being hydrogen. In particular, the preferred compounds of formula (II) are selected from the group consisting of 5,6,7,8-tetrahydro-2- (4-nitrophenyl) -7- (phenylmethyl) imidazo [2 ', 1 2,3,4-thiazolo [5,4-c] pyridine, 2- (4-aminophenyl) imidazo [2,1-b] -5,6,7-ethyl-ethyl ester; tetrahydro-benzothiazole-5-carboxylic acid, 2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole-4-carboxylic acid ethyl ester and 2 (4-Aminophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8,8a, 9-octahydro-naphthothiazole. These compounds of formula (II) can themselves be prepared for from the compounds of formula (III) Z4 where one of the substituents among Z1, Z2, Z3, Z4 and Z5 is -RNO2, the others being a hydrogen atom, R3 has the same meanings as for the compound of formula (I), as well as the corresponding enantiomers, as intermediates for the preparation of compounds of formula (II), excluding compound (I) wherein all R3 substituents are hydrogen and one of Z1, Z2, Z3, Z4 and Z5 is -RNO2, the others being hydrogen.

  In particular, the preferred compounds of formula (III) are selected from the group consisting of 5,6,7,8-tetrahydro-2- (4-nitrophenyl) -7- (phenylmethyl) imidazo [2 '], 2,3,4-thiazolo [5,4-c] pyridine, 2- (425-nitrophenyl) imidazo [2,1-b] -5,6,7-ethyl-ethyl ester; tetrahydro-benzothiazole-5-carboxylic acid, 2- (4-nitrophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole-4-carboxylic acid and 2- ( 4-nitrophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8,8a., 9octahydro-naphthothiazole. The compounds of formula (III) can be prepared in a conventional manner by -NO2 group of the compounds of formula (II) carried out for example at reflux in the presence of an iron salt, such as the Fe / NH 4 Cl system, present in protic solvents, according to implementations known to those skilled in the art .

  The compounds of formula (II) can be synthesized as follows, with reference to the teaching of the publications of King L.0 et al., J. Am.Chem.Soc., 1950, 72, 3722-3725 and Pietraricosta N. et al., Bioorg.Med.Chem.Lett., 2005, 15, 1561-1564. A cyclohexanone derivative (1 equivalent), substituted with the groups R 3 as defined according to the present invention for the compounds of formula (I), is reacted with thiourea (2 equivalents) in the presence of iodine (1 equivalent ) at a temperature of the order of 110 C for about 10-13 hours, preferably 12 h. This reaction is followed by basic treatment to give the 2-aminothiazole derivatives. These derivatives are then N-alkylated via N in the 3-position with α-bromoacetophenone at room temperature in toluene for 48 hours. The 2-aminothiazole derivatives substituted in the N 3 position are brought into the presence of methanol to yield the compounds of formula (II).

  The invention also relates to the compounds of formula (I) and, preferably, pharmaceutical compositions containing them for use as a medicament.

  The Applicant has therefore found that such compounds have a great capacity to inhibit the Met receptor and to avoid Metastatization of the Met dependent cells. Therefore, the invention relates, in particular, to the use of compounds of formula (I), as defined above, for the manufacture of a medicament for inhibiting Met receptor activity. In particular the invention relates to the use of the compounds of formula (I) above for the manufacture of a medicament for the treatment or prevention of diseases or disorders involving abnormal activation of the Met receptor. Abnormal activation is understood to mean overexpression of the Met receptor and its ligand, then by the appearance of autocrine loops and later by the appearance and development of active mutations.

  The invention also relates to the use of the compounds of formula (I) above for the manufacture of a medicament for preventing the migration of metastases or tumor cells, such as carcinomas, sarcomas, myelomas, melanomas and mesothelioma.

  The Applicant has surprisingly shown that the substituents R 1 and R 2 of the group as defined above, compounds of formula (I) were particularly important for the anti-migratory activity of the resulting compounds. Measurement of the activity of these novel compounds of formula (I) as Met receptor inhibitors was performed in vitro by the use of various tests cited in the literature.

  These include the tests described by Vande Woude (USA) on the basis of Graveel C. et al., (PNAS, 2004, 101, 17198) and Elliott B. (J.Biol.Chem, 2004, 279, 32499 1- Proliferation tests on SK-LMS-1 cells using labeled thymidine. Met kinase activity is measured in the presence or absence of compounds. A specific alkaloid is used as a reference inhibitor. Induction of proliferation is done using HGF / SF. 2- HGF / Met immunoglobulin binding assay (HGF / Met-IgG binding assay) (used for screening the effects of divalent cations); 3- Tests on MDCK cells: Madin-Darby canine kidney cell lines (Madin-Darby canine kidney cell lines), which respond to the induction of HGF / SF and Met by the cell dispersion effect technique ( scattering effect). The cell dispersion is inhibited in the presence of the inhibitor compounds described in this patent. Tests described by Wang X. et al., Molecular Cancer Therapeutics, 2003, 1085-1092. 1- B-cell, HGF / SF-treated PC3 tests, measurement of incorporation of BrdUrd (ligand); 2- scattering effect on MDCK cells stimulated by HGF / SF; 3-A549 cells from American Type Culture Collection (ATCC, USA) stimulated by HGF / SF; measurement of inhibition of Met receptor phosphorylation.

  The evaluation of the activity of the compounds of formula (I) as Met receptor inhibitors was measured by the cell diffusion assay on the basis of the Eliott test but in the absence of cupric ions ( Cu (II)).

  This model uses MDCK cells that have the property of expressing the Met receptor at a physiological level and being very receptive to stimulations by the growth factor HGF, the nature ligand of Met. These cells grow naturally in islets (Figure A), but the addition of the HGF factor causes their diffusion in a manner dependent on the Met receptor signaling pathway (Figure B). (Fig. B) In summary, the Eliott test uses epithelial MDCK cells which are plated in 24-well culture plates and are then incubated in different reaction media containing the compounds (I) of the invention, in concentration. variables, and the HGF ligand. Tests are also performed with cells not treated with the compounds (I). After about 12 to 24 hours, the cells are fixed and treated with a dye, such as crystal violet. The cells are then counted and photographs taken from the cell. It is then determined the concentrations for observing an anti-migratory effect. According to one embodiment, the tests are carried out in the following reaction media: (A): DMEM buffer alone (Dulbecco's modified Eagles Medium to which 10% fetal bovine serum can be added); (B): buffer containing 500 M of compounds of formulas (I). (C): buffer containing 20 ng of HGF; (D): buffer containing 500 M of compounds of formulas (I) and 20 ng of HGF; (E). buffer containing 100 ng of TPA (12-0-tetradacinylphorbol-13-acetate) (F): buffer containing 100 ng of TPA and 500 M of compounds of formulas (I) After 24 hours, the cells were fixed and stained by a modified Harris hematoxylin solution, cell diffusion was measured visually The following figures represent microscopic photographs of the cell diffusion results using the different media cited above, considering, as a for example, the following compounds of the invention:

  Α- [2 - [[4- (5,6,7,8-tetrahydroimidazo [2,1b] benzothiazol-2-yl) phenyl] amino] ethyl] benzenemethanol (Compound II) 2- (5- { [4- (5,6,7,8-tetrahydroimidazo [2,1b] [1,3] benzothiazol-2-yl) phenyl] amino pentyl) -1H-isoindole-1,3 (2H) dione (Compound 12), N- (N- (3,5-difluorophenylacetyl) -N- (2 (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole) I3), N- (N- (tert-butoxycarbonyl) - (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1b] -4,4a, 5,6,7,8 8a, 9-octahydro-naphthothiazole (Compound I4), N- [4- (tertbutoxycarbonyl) -5,6,7,8-tetrahydroimidazo [2 ', l'] 2,3] [1,3 thiazolo- [4,5-b] pyridin-2-yl) phenyl] -N - 2 - [(3,5-difluorophenyl) acetyl] - (R) -alaninamide (Compound I5), A: Buffer (g) Buffer + compounds of formula (1) C: HGF D: HGF + compounds of formula (I) LE: TPA 1F: TPA + Cu (II) These photographic snapshots of the various reaction media show in particular that the cells in question placed in the presence of HGF (middle C) show a much higher diffusion / migration tendency than those containing in addition compounds of formula (I) of the invention (medium D), in particular with the compounds I1, I2, I3, I4 and I5. After the analysis of the results of these various tests, other tests were carried out in order to determine the minimum quantity necessary in these compounds in order to observe an anti-migratory activity as defined previously, in particular by the photographs above. Such minimum amounts have been determined to be between 30 nM and 5M.

  It is also possible to verify that the results of the diffusion tests expressed in the form of IC50 values (concentration required to inhibit cell diffusion activity by 50% compared with the diffusion effect obtained without treatment of the cells) are included. between 30 nM and 15 M.

  It is the same when the reaction medium is based on TPA (medium E), further containing compounds of the invention (medium F).

  The TPA has the effect of producing a non-protein effect specific to TPA-induced cell diffusion and not inhibited by the addition of the compounds (I) of the invention, shows that the activity of the ligand HGF is delayed or prevented at the cellular level by a specific interaction with the compounds (I) of the invention.

  The following examples further illustrate the invention without limiting its scope.

Example 1 Synthesis of compound x- [2 - [[4- (5,6,7,8-tetrahydroimidazo [2,1b] benzothiazol-2-yl) phenyl] amino] ethyl] benzenemethanol (compound II) added 17 mg (0.09 mole) of 3-chloro-1-phenyl-1-propanol to a stirred mixture of 2- (4-aminophenyl) imidazo [2,1-b] -5,6,7 8-tetrahydrobenzothiazole, prepared according to Pietrancosta N. et al cited above, and anhydrous potassium carbonate (31 mg-0.22 mmol) in 5 ml of anhydrous acetonitrile. The suspension was stirred at room temperature for 10 hours under a nitrogen atmosphere. The suspension was then concentrated. The product thus obtained was purified by adsorption chromatography with a mixture of methylene chloride and ethanol (9/1, v / v). The product obtained has the following characteristics. 1H NMR (CDCl3): δ 7.71 (d, 2H, J = 8.0Hz), 7. (s, 1H), 7.10 (m, 5H), 6.64 (d, 2H, J = 8. Hz), 4.92 (m, 1H), 3.21-3.00 (m, 6H), 2.65 (m, 2H), 1.95-1.60 (m, 6H). MS-ES m / z 404 (M + H) +. Example 2 Synthesis of N- (N- (3,5-difluorophenylacetyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole) Compound I3) This compound is synthesized by coupling 2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzo-thiazole with (3,5) -difluorophenyl) acetic acid, using Method A described above. The compound 2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole (1 equivalent, 1.6 3125 moles), 200 mg (1 equivalent) of N-Boc-alanine (Boc = butyloxycarbonyl) and (3,5) -difluorophenylacetic acid are dissolved in 3 ml of anhydrous pyridine. The solution is cooled to -15 C and 110 l POC13 are added dropwise with vigorous stirring. The reaction mixture thus obtained is stirred for 30 minutes at -15 C. Stirring is continued for another 48 hours. Then, the product is extracted with ethyl acetate, which is then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product obtained has the following characteristics. Rf 0.40 (Toluene / EtOAc 1/1). 1H NMR (CDCl3): δ 7.87 (d, 2H, J = 8.0Hz), 7.42 (d, 2H, J = 8.0Hz), 7. 36 (s, 1H), 7.08 (m, 2H); 6.81 (m, 1H), 3.87 (s, 2H), 3.21-2.95 (m, 2H), 2.75-2.60 (m, 2H), 1.98-1.61 (m, 4H). MS-ES m / z 424 (M + H) +.

  Example 3 Synthesis of the compound N- (N- (naphthyl) -N- (2 (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole.

  This compound was prepared in the same manner as in Example 2, except that (3,5) -difluorophenylacetic acid was replaced by 1-naphthoic acid.

Example 4 Synthesis of compound N- (N- (tert-butoxycarbonyl- (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole This compound was prepared in the same manner as in Example 2 except that (3,5) -difluorophenylacetic acid was replaced by tert-butylcarbonyl- (S) -alanine.

Example 5 Synthesis of N- (N- (3-chlorophenylacetyl) - (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7, 8- tetrahydrobenzothiazole)

  Such a compound is prepared on the basis of Method B described above.

  200 mg of N-Boc-alanine are taken which are dissolved in 5 ml of anhydrous DMF. 560 mg of BOP are added thereto and the resulting mixture is cooled to 0 ° C. 184 l of diisopropylethylamine are then added to the reaction medium thus obtained, and the mixture is then all mixed at room temperature for 1 hour. The solution was then cooled to 0 ° C. A solution of 2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole is added dropwise under stirring. (1 equivalent), 552 of diisopropylethylamine (in excess) and 3-chlorophenylacetyl- (S) -alanine (1.2 equivalents) in 1 ml of anhydrous DMF. The resulting solution is brought to ambient temperature and then mixed. The solvent is evaporated under reduced pressure and the residue is dissolved in 20 ml of ethyl acetate. The organic phase was washed with 5% citric acid and dried over magnesium sulfate, filtered and concentrated under reduced pressure.

  The product obtained has the following characteristics. Rf 0.50 (Toluene / EtOAc 1/1). 1H NMR (CDCl3):? 9.24 (s, 2H), 7.71-7.23 (m, 8H), 6.86 (m, 1H), 4.31 (m, 1H), 3.24 (s, 2H), 2.55-2.60 (m, 4H), 1.70-1.85 (m, 4H), 1.28 (d, 3H, 7.2Hz). MS-ES m / z 494 (M + H) +.

  Example 6 Synthesis of the Compound N- (N- (3,5-difluoromandelyl) - (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6) 7,8-tetrahydrobenzothiazole). This compound was prepared in the same manner as in Example 5, except that 3-chlorophenylacetyl- (S) -alanine was replaced by 3,5-difluoromandelyl- (S) -alanine. Example 7 Synthesis of the compound N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) -5,6,7,8-tetrahydro-2-7 (phenylmethyl) imidazo [2 ', 1': 2,3] thiazolo [5,4-c] pyridine).

  This compound was prepared in the same manner as in Example 5, except that 2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole was replaced by 5,6,7,8-Tetrahydro-2- (4-nitrophenyl) -7- (phenylmethyl) imidazo [2 ', 1': 2,3] -thiazolo [5,4-c] pyridine, and 3-chlorophenylacetyl- (S) -alanine has been replaced by 3,5-difluorophenylacetyl- (S) -alanine. Example 8 Synthesis of N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-nitrophenyl) imidazo [2,1-b] - ethyl ester compound 5,6,7,8-tetrahydrobenzothiazole-5-carboxylic

  This compound was prepared in the same manner as in Example 5, except that 2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole was replaced by 2- (4-Aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole-5-carboxylic acid ethyl ester and 3-5-chlorophenylacetyl- (S) -alanine was replaced by 3,5-difluorophenylacetyl- (S) -alanine.

Example 9 Synthesis of N- [4- (terbutoxycarbonyl-5,6,7,8-tetrahydroimidazo [2 ', 1'] 2,3] [1,3] thiazolo- [4: 5-b] ] pyridin-2-yl) phenyl] -N-2- [(3,5-difluorophenyl) acetyl] - (R) -alaninamide, It is synthesized from the compound of Example 7 (N- (N-) (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) -5,6,7,8-tetrahydro-2-7- (phenylmethyl) imidazo [2 ', 1 ': 2, 3] thiazolo [5,4-c] pyridine) which undergoes catalytic debenzylation by hydrogenation over a palladium-based catalyst, and then the free N-amine product thus obtained (1 equivalent) is then treated with the diterbutyl carbonate reagent (1.2 equivalents) in methylene chloride to yield the desired product.

  EXAMPLE 10 This example gives values of the minimal activities for observing the Met receptor inhibitory effect and thus the inhibition of the diffusion / cell migration according to the protocol defined above, by using the different reaction media (A) to (F) . These media contain, where appropriate, varying amounts of compounds (I).

  An anti-migratory activity is observed due to the presence in particular of the compounds (I) of different structures which follow, for concentrations of at least 5 M, according to the photographs of the medium (D) shown previously. 2- [[[4- (5,6,7,8-tetrahydroimidazo [2,1-b] benzothiazol-2-yl) phenyl] amino] methyl] -1H-isoindole-1,3 (2) -donne, α- [2 - [[4- (5,6,7,8-tetrahydroimidazo [2,1b] benzothiazol-2-yl) phenyl] amino] ethyl] benzenemethanol, 2- (5- {[4- 6,8,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-yl) phenyl] amino} pentyl) -1H-isoindole-1,3 (2H) -dione

  N- (N- (naphthyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] 5,6,7,8-tetrahydrobenzothiazole,

  N- (N- (3,5-difluorophenylacetyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole) (Compound I3), N- (N- (tert-butoxycarbonyl- (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole),

  N- (N- (3-chlorophenylacetyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydro-benzothiazole),

  N- (N- (tert-butoxycarbonyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8,8a , 9-25 octahydro-naphthothiazole,

  N- (N- (3-chlorophenylacetyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole), N- ( N (3,5-difluoromandelyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole),

  N- (N- (3,5-difluorophenylacetyl) - (R) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole), N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,6 -ethyl-ethyl ester 7,8-tetrahydro-benzothiazole-5-carboxylic acid

  N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,7,7-ethyl ester of ethyl ester 8-tetrahydrobenzothiazole-6-carboxylic acid

  N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-nitrophenyl) -5,6,7,8-tetrahydro-2-7- (phenylmethyl) imidazo [ 2 ', 1', 2, 3] thiazolo [5,4-c] pyridine), N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-aminophenyl) ) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole),

  N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8 8a, 9-octahydro-naphthothiazole),

  N- (N- (3,5-difluorophenylacetyl) - (R) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,6 -isopropyl ester, 7,8-tetrahydrobenzothiazole-6-carboxylic acid

  N- [4- (7-Benzyl-5,6,7,8-tetrahydroimidazo [2 ', 1': 2,3] -30 [1,3] thiazolo [5,4] pyridin-2-) yl) phenyl] -N-2- [3,5-difluorophenyl) acetyl] -L-alaninamide,

  {2- [4- (N- (3,5-difluorophenyl) acetyl] -D-alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] Benzothiazole-7-amine,

  N- [4- (Terbutoxycarbonyl-5,6,7,8-tetrahydroimidazo-15 [21,1 ', 2,3] [1,3] thiazolo- [4,5-b] pyridin-2-yl) ) phenyl] -N-2 - [(3,5-difluorophenyl) acetyl] - (R) -alaninamide.

  In addition, the following compounds show an IC 50 (concentration required to inhibit cell diffusion activity of 50% relative to the diffusion effect obtained without cell treatment) of between 30 nM and 15 M.

  N- (N- (3,5-Difluorophenylacetyl) - (S) -alanyl) -N (2- (4-nitrophenyl) -5,6,7,8-tetrahydro-2-7- (phenylmethyl) imidazo [ 2 ', 1', 2, 3] thiazolo [5,4-c] pyridine).

  IC 50 = 30 nM, N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8 -tétrahydrobenzothiazole)

IC 50 = 500 nM,

  N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8, 8a, 9-octahydro-naphthothiazole), IC 50 = 5M,

  {2- [4- (N- (3,5-difluorophenyl) acetyl] -D-alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] Benzothiazole-7-amine,

IC50 = 15M,

  N- (N- (3,5-Difluorophenylacetyl) - (R) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,6 -isopropyl ester, 7,8-tetrahydro-benzothiazole-6-carboxylic acid, IC 50 = 15M,

  N- [4- (tertbutylcarbonyl) -5,6,7,8-tetrahydroimidazo [2 ', 1', 2,3] [1,3] thiazolo [4,5-b] pyridin-2-yl ) phenyl] -N-2 - [(3,5-difluorophenyl) acetyl] - (R) -alaninamide,

IC50 = 5 M. 3910

Claims (12)

claims   1. Compounds of the imino-5-tetrahydrobenzothiazole family having the following general formula (I): Z4 (I) wherein: Z1, Z2, Z3, Z4 and Z5, independently, represent a hydrogen atom, a halogen selected from F and Br, an alkyl group of 1 to 6 carbon atoms, a group -CF3, a group -OR where R is an alkyl group of 1 to 6 carbon atoms, or wherein at least two Z1 to Z5 are -NO2, or Z1, Z2, Z3, Z4 and Z5, independently, are a group of the formula ## STR2 ## where R1 and R2 independently of one another represent hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl group, alkylphenyl group or alkanoylphenyl having 1 to 3 carbon atoms in the alkyl part, the phenyl group being unsubstituted or substituted with 1 or 2 halogen moieties selected from F, Br and Cl, or a group selected from the groups of the formula (A) wherein X 'is a heteroatom selected from the group consisting of by O, N and S or an alkylene group having from 1 to 10 carbon atoms unsubstituted or substituted by a hydroxyl group, and R4 represents a linear or branched alkyl group of 1 to 10 carbon atoms unsubstituted or substituted by a hydroxyl group, or an aryl group unsubstituted or substituted by an alkyl group of 1 to 6 carbon atoms; of formula (B): - (CH 2) n-phthalimide; of formula (C): 1-phenyl-1- (linear or branched alkanol of 1 to 10 carbon atoms); of formula (D): - (CH 2) n-C = O-naphthalene; of formula (E): - (CH 2) n-3,5-difluorophenylacetyl; of formula (F): tert-butoxycarbonylalanyl; of formula (G): 3-chlorophenylacetyl, and of formula (H) which is a group of formula (A) in which the two F atoms are replaced by a single chlorine atom in any position of the ring, n is 0 to 10 ; R3 independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an allyl, propargyl, benzyl, chlorobenzyl, ethylphenyl, cyclopentyl, cyclohexyl, amine, substituted amine, alkyl ester of 2 to 10 groups; carbon atoms, carboxylic acid, -C = O-NH 2 type amide, urea, sulfonamide, sulfonyl, hydroxamate, -C = O-NH-OH, -NH-SO 3 -, -NH-SO 3 -R 'where R' represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, -COO-, -NH3 +, -NH-C = NH-NH3 +, - (CH2) n -NH-C = NH-NH3 +, - (CH2) n-COO, - (CH2) -NH3, - (CH2) nC = O-NH2 or - (CH2) n -COO-R "where R" represents an alkyl group of 1 to 6 carbon atoms or a non-aryl group substituted or substituted by a halogen atom, a nitro group, amino or O-alkyl groups of 1 to 6 carbon atoms, n being between 1 and 10, or two adjacent R3 form a 5- or 6-membered aliphatic ring , aromatic or aromatic condensed, optionally hydrogenated, unsubstituted or substituted by an alkyl group of 1 to 6 carbon atoms or a halogen atom, or, in combination with the above, in the derivative of formula (I), at least one carbon atom of the tetrahydrobenzo ring at the 5-position , 6, 7 or 8, bearing a group R3, is replaced by a heteroatom selected from the group consisting of N, O and S, N being protonated or not and not substituted or substituted by an alkyl group of 1 to 10 carbon atoms , alkyl ester of 2 to 10 carbon atoms, hydroxyl, a - (CH 2) n-n-phenyl group, n being from 1 to 10, unsubstituted or alkyl-substituted sulfonyl of 1 to 6 carbon atoms or aryl group which is unsubstituted or substituted by a halogen atom, a nitro group, an amino group or O-alkyl groups of 1 to 6 carbon atoms, or by the group of formula A defined above, or, in combination with this above, R3 being as defined above, positions 4 and 9 of the tetrahydrobenzo ring are hydrogenated , and their enantiomers.   2. Compounds of formula (I) according to claim 1, wherein Z1, Z2, Z3, Z4 and Z5, independently, represent a hydrogen atom, a halogen selected from F and Br, an alkyl group of 1 to 6 carbon atoms, a group -CF3, a group -OR where R is an alkyl group of 1 to 6 carbon atoms or, wherein at least two of Z1 to Z5 represent a group -NO2, or Z1, Z2, Z3, Z4 and Z5, independently, represent a group of the formula ## STR2 ## R1 represents a hydrogen atom; R2 represents a group selected from groups of formula (A), (B), (C), (D), (E), (F), (G) and (H) as defined above; R 3 are each a hydrogen atom, or one or more of the R 3 groups carried by a carbon atom of the tetrahydrobenzo ring at the 5, 6, 7 or 8 position is selected from the group consisting of benzyl, the group ethyl, propyl, n-butyl, isopropyl, isobutyl or tert-butyl ester, -C = O-NH 2 amide, -C = O-NH-OH, -NH -SO 3 Where R 'represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, -000-, -'44 NH3, -NH-C = NH-NH3 +, - (CH2) -NH-S03-R' NH-C = NH-NH3 +, - (CH2) -000, - (CH2) -NH3 +, - (CH2) -C = O-NH2 and - (CH2) -COO-CH3, the other R3 being an atom of hydrogen, or two of the adjacent R 3 together form an aliphatic or aromatic 6-membered ring, unsubstituted or substituted by an alkyl group of 1 to 6 carbon atoms or a halogen atom, or, in combination with the foregoing, in the derivative of formula (I), a carbon atom of the tetrahydrobenzo ring in position 5, 6, 7 or 8, bearing R3, is replaced by a nitrogen atom, optionally protonated, unsubstituted or substituted with -SO3-, a hydroxyl group, a benzyl group, an alkyl group of 2 to 6 carbon atoms, an ethyl ester group of propyl, n-butyl, isopropyl, isobutyl or tert-butyl, or by the group of formula A defined above, or, in combination with the above, R3 being as defined above, the positions 4 and The tetrahydrobenzo rings are hydrogenated, and their enantiomers.   3. Compounds of formula (I) according to claim 1 or 2, wherein Z1, Z2 and Z3 together represent a halogen selected from F and Br, a methyl group, a -CF3 group, a -NO2 group, a group -O- CH 3 and Z 4 and Z 5 represent a hydrogen atom, or Z 1, Z 2, Z 3, Z 4 and Z 5 each represent a hydrogen atom, or, in which, Z 1, Z 2, Z 4 and Z 5 represent a hydrogen atom; and Z3 represents a group of formula ## STR2 ## R1 represents a hydrogen atom; R2 is a group selected from groups of formula (A) wherein R4 is methyl or ethyl optionally substituted with hydroxyl and X 'is methylene; of formula (B): - (CH 2) phthalimide or - (CH 2) 5-phthalimide; of formula (C): 1-phenyl-1- (linear alkanol of 3 carbon atoms) of formula (D): -C = O-naphthalene; of formula (E): -3,5-difluorophenylacetyl; of formula (F): tert-butoxycarbonyl-alanyl of formula (G): 3-chlorophenylacetyl; three of the four R 3 represent a hydrogen atom and the last R 3 in the 5, 6, 7 or 8 position is chosen from the group consisting of the benzyl group, the ethyl, propyl, n-butyl, isopropyl, isobutyl or tert-butyl, amide of the type -C = O-NH2-C = O-NH-OH, -NHSO3, -NH-SO3-CH3, -000, -NH3, -NH-C = NH-NH3 +, - (CH2) -NH-C = NH-NH3 +, (CH2) -COO, - (CH2) -NH3, - (CH2) -C = O-NH2 and - (CH2) -COO-CH3 or, in the derivative of formula (I), a carbon atom of the tetrahydrobenzo ring in position 5, 6, 7 or 8 is replaced by a nitrogen atom, optionally protonated, unsubstituted or substituted with -SO3-, a hydroxyl group, a benzyl group or an alkyl group of 2 to 6 carbon atoms, or two of the adjacent R 3 together form a 6-membered aliphatic ring, unsubstituted or substituted by an alkyl group of 1 to 6 carbon atoms or an atom of halogen, or, in the derivative of formula (I), a carbon atom of the tetrahydrobenzo ring in posi 5, 6, 7 or 8 is replaced by a nitrogen atom, optionally protonated, unsubstituted or substituted with -SO3-, a hydroxyl group, a benzyl group, an alkyl group of 2 to 6 carbon atoms, a group ethyl, propyl, n-butyl, isopropyl, isobutyl or tert-butyl ester, or by the group of formula A defined above, or, in combination with the foregoing, R3 being such that As previously defined, positions 4 and 9 of the 5-tetrahydrobenzo ring are hydrogenated, and their enantiomers.   4. Compounds of formula (I) according to one of claims 1 to 3, selected from the group consisting of: 2 - [[[4- (5,6,7,8-tetrahydroimidazo [2,1-b] benzothiazol-2-yl) phenyl] amino] methyl] -1H-isoindole-1,3 (2) -dione, α- [2 - [[4- (5,6,7,8-tetrahydroimidazo)]; [2,1b] benzothiazol-2-yl) phenyl] amino] ethyl] benzenemethanol, 2- (5 - {[4- (5,6,7,8-tetrahydroimidazo [2,1-20 b] [1 3-Benzothiazol-2-yl) phenyl] amino} pentyl) -1H-isoindole-1,3 (2H) -dione, N- (N- (naphthyl) -N- (2- (4-aminophenyl) imidazo] [2,1-b] -5,6,7,8-tetrahydrobenzothiazole, N- (N- (3,5-difluorophenylacetyl) -N- (2- (4-aminophenyl) imidazo [2,1-- b] -5.6, 7,8-tetrahydrobenzothiazole), N- (N- (tert-butoxycarbonyl- (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] ] -5,6,7,8-tetrahydrobenzothiazole), N- (N- (3-chlorophenylacetyl) -N- (2- (4-aminophenyl) -35-imidazo [2,1-b] -5,6, 7,8-tetrahydrobenzothiazole), N- (N- (tert-butoxycarbonyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -4,4a, , 6,7,8,8a, 9-octahydro-nap htothiazole, N- (N- (3-chlorophenylacetyl) - (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydro- Benzothiazole), N- (N- (3,   5-difluoromandelyl) - (S) -alanyl) -N (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole), N- (N- (3 5-difluorophenylacetyl) - (R) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole), the ethyl ester of N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,6,8,8-tetrahydrobenzothiazole 5-carboxylic acid, N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo] -2- (N- (3,5-difluorophenylacetyl) ethyl ester; b] -5,6,8,8-tetrahydrobenzothiazole-6-carboxylic acid, N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) - 5,6,7,8-tetrahydro-2-7- (phenylmethyl) imidazo [2 ', 1': 2,3] thiazol [5,4-c] pyridine), N- (N-) (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2 (4-aminophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole), N- (N-) (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-aminophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8,8a, 9- Octahydro-naphthothiazole), the propyl ester or N- (N- (3,5-Difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,6,7 isopropyl 8-tetrahydrobenzothiazole-5- or   6-carboxylic acid, butyl ester of N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,6,8,8-tetrahydrobenzothiazole-5-carboxylic acid, N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) -5,6- 7,8-tetrahydro-2-7- (phenylmethyl) imidazo [2 ', 1', 2,3] thiazolo [5,4-c] pyridine) {2- [4 - ({N (3,5-difluorophenyl) acetyl] - (R) -alanyl) amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazole-7-amine, the N- [4- (tert -butoxycarbonyl) -5,6,7,8-tetrahydro-imidazo-20 [2 ', 1': 2,3] [1,3] thiazolo- [4,5-b] pyridin-2- yl) phenyl] -N-2- [3,5-difluorophenyl) acetyl] - (R) -alaninamide, 2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl) amino) phenyl] -N-hydroxy-5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazole-5,6,7 or carboxamide, N2 - [(3,5-difluorophenyl) acetyl] -N- {4- [5-, 6 7- or   8- (sulfonatoamino) -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-yl] phenyl) - (R) or (S) -alaninamide. {2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2] Methyl 1-b] [1,3] benzothiazol-5,6,7- or 8-yl} sulfamate, N- [4- (7-benzyl) -5,6,7,8-tetrahydroimidazo] - [2 ', 1': 2,3] [1,3] thiazolo [5,4-c] pyridin-7-ium-2-yl) phenyl] -N-2 - [(3,5-dif. luorophenyl) acetyl] - (S) - or (R) -alaninamide, N2 - [(3,5-difluorophenyl) acetyl] -N- {4- (5,6,7,8-tetrahydroimidazo [2 ', l] ': 2,3] [1,3] [thia-b] pyridin-2-yl) phenyl] - (S) -alaninamide, N2 - [(3,5-difluorophenyl) acetyl] -N- { 4- [5,6,7,8-Tetrahydroimidazo [2 ', 1': 2,3] [1,3] [thia-c] pyridin-6- or 10 -7-ium-2-yl) phenyl] - (S) or (R) -alaninamide, 2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alanyl} amino) phenyl] - 7,8-dihydroimidazo [2 ', 1': 2,3] - [1,3] thiazolo [4,5-b] -pyridin-5 (6H) -sulfonate, 2- [4 - ({N- [(3,5-difluorophenyl) acetyl] - (S) - or - (R) -alanyl} amin o) phenyl] -7,8-dihydroimidazo [2 ', 1': 2,3] - [1,3] thiazolo [4,5-b] pyridine-6 (5H) -sulfonate, 2- [ 4 - ({N - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alanyl} amino) phenyl] -7,8-dihydroimidazo [2 ', 1': 2,3] - [1,3] thiazolo [4,5-b] -pyridine-7 (6H) -sulfonate, 2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (S) - or ( R) -25 alanyl} amino) phenyl] -7,8-dihydroimidazo [2 ', 1': 2,3] - [1,3] thiazolo [4,5-b] pyridine-8 (5H) -sulfonate N2 - [(3,5-difluorophenyl) acetyl] -N- [4- (5-, 6-7- or 8-hydroxy-5,6,7,8-tetrahydroimidazo [2 ', 1'] 2, 3] [1,3] thiazolo [5,4-b] pyridin-2-yl) phenyl] - (S) - or (R) -alaninamide, N2 [(3,5-difluorophenyl) acetyl] -N- [4- (5aR or 5aS, 9aR or 9aS)) - 5,5a, 6,7,8,9a, 10-octahydroimidazo [2,1b] naphtho [2,3-d] [1,3] thiazol-2 N-[(3,5-difluorophenyl) acetyl] -N- [4- (5,6,7,8-tetrahydroimidazo b) [1,3] benzothiazol-2-yl) phenyl) - (S) - or (R) -alaninamide, N- [4- (6-benzyl-5,6,7,8-tetrahydroimidazo [ 2 ', 1': 2,3] [1,3] thiazolo [4,5-c] pyridin-6-ium-2-yl) phenyl N2 - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alaninamide, N- {4 - [(4aS or 4aR, 6R or 6S, 8aS or 8aR) - (6) benzyl-4α, 5,6,7,8,8a-hexahydroimidazo [2 ', 1': 2,3] [1,3] thiazolo [4,5-c] pyridin-6-ium) 2-yl] phenyl} -N 2 - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alaninamide, 2- (3,5-difluorophenyl) -N - [(1R) - 1-methyl-2-oxo-2- (2-phenyl-5,8-dihydroimidazo [2 ', 1': 2,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) ) -yl) ethyl] acetamide, 2- (3,5-difluorophenyl) -N - {(1R) -1-methyl-2-oxo-2- [2- (2,3,4-trifluorophenyl)] - 5,8-dihydroimidazo [2 ', 1': 2,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl) acetamide, 2- 5-difluorophenyl) -N - {(1R) -1-methyl-2-oxo-2- [2- (2,3,4-tribromophenyl) -5,8-dihydroimidazo [2 ', 1'] 2 3 [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl) acetamide, 2- (3,5-difluorophenyl) -N - ((1 R) -1 1-methyl-2-oxo-2- [2- (2,3,4-trimethylphenyl) -5,8-dihydroimidazo [2 ', 1', 2,3] [1,3] thiazolo [5,4- c] -pyridin-7 (6H) -yl] ethyl) acetamide, 2- (3,5-difluorophenyl) -N - {(1 R) -1-methyl-2-oxo-2- [2- [2,3,4-tris (trifluoromethyl) phenyl] -5,8-dihydroimidazo [2 ', 1': 2,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) ) -yl] ethyl} acetamide, 2- (3,5-difluorophenyl) -N - {(1R) -1-methyl-2-oxo-2- [2- (2,3,4-trimethoxyphenyl)] - 5,8-dihydroimidazo [2 ', 1': 2,3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl) acetamide, 2- (3, 5-difluorophenyl) -N - {(1R) -1-methyl-2-oxo-2- [2- (2,3,4-trinitrophenyl) -5,8-dihydroimidazo [2 ', 1': 2, 3] [1,3] thiazolo [5,4-c] pyridin-7 (6H) -yl] ethyl} acetamide, methyl ester of N- (N- (3,5-difluorophenylacetyl) - (S) -alanyl) -N- (2- (4-nitrophenyl) imidazo [2,1-b] -5,6,8,8-tetrahydrobenzothiazole-5-, 6-, 7- or 8-carboxylic acid, 2- [4 - ((N- (3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazole-5,6-, 7- or 8-carboxamide, 2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-25 b] [1,3] benzothiazole-5,6-, 7- or 8-carboxylate, 2- [4 - ({N - [(3,5-difluorop phenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-5-, 6-, 7 or 8-aminium, ({2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7, 8-Tetrahydroimidazo [2,1-b] [1,3] benzothiazol-5,6- or 7-yl} amino) (imino) methanamine, the [({2- [4 - ({N- [ (3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-35b] [1,3] benzothiazole 5-, 6-, 7- or 8-yl} methyl) amino) (imino) methanaminium, {2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (R) or ( S) -5-alanyl) amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-5,6,7-or 8-yl} acetate, 2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2.1-10] b] [1,3] benzothiazol-5,6,7 or 8-yl} methanaminium, N- {4- [5-, 6-, 7- or 8- (2-amino-2-oxoethyl)} 5,6,7,8-Tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-yl] phenyl} -N - 2 - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alaninamide, {2- [4 - ({N - [(3,5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo acetate [2,1-b] [1,3] benzothiazol-5,6,7 or 8-yl} methyl or ethyl, {(7R) -2- [4 - ({N - [(3 5-difluorophenyl) acetyl] - (R) or (S) -alanyl} amino) phenyl] -5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-5,6 25, 7- or 8-yl} methyl, N2 - [(3,5-difluorophenyl) acetyl] -N- {4- [5-, 6-, 7- or 8- (hydroxymethyl) -5, 6,7,8-tetrahydroimidazo [2,1-b] - [1,3] benzothiazol-2-yl) phenyl} - (R) - or (S) -ananinamide, N 2 - [(3, 5 difluorophenyl) acetyl] -N- [4- (5-, 6-, 7- or 8-formyl-5,6,7,8-tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2- yl) phenyl] (R) - or (S) -alaninamide, and N- [4- (5-, 6-, 7- or 8 - {[(aminocarbonyl) amino] methyl} -5.6, 7,8-Tetrahydroimidazo [2,1-b] [1,3] benzothiazol-2-yl) phenyl] -N 2 - [(3,5-difluorophenyl) acetyl] - (S) - or (R) -alaninamide . 5. Compounds of formula (II) wherein one of the substituents among Z1, Z2, Z3, Z4 and Z5 is -RNH2, the others being a hydrogen atom, R3 has the same meanings as for the compound of formula (I), as well as the corresponding enantiomers, as intermediate compounds for the preparation of the compounds of formula (I), excluding the compound (I) wherein all the substituents R3 are an atom of hydrogen and one of Z1, Z2, Z3, Z4 and Z5 is -RNH2, the others being a hydrogen atom. 6. Compounds of formula (II) according to claim 5, selected from the group consisting of 5,6,7,8-tetrahydro-2- (4-nitrophenyl) -7- (phenylmethyl) imidazo [2 '] , 1 ': 2,3] -thiazolo [5,4-c] pyridine, 2- (4-aminophenyl) imidazo [2,1b] -5,6,7,8-tetrahydrobenzothiazole acid ethyl ester; 5-carboxylic acid, 2- (4-aminophenyl) imidazo [2,1b] -5,6,7,8-tetrahydrobenzothiazole-4-carboxylic acid ethyl ester and 2- (4-aminophenyl) imidazo [ 2,1-b] -4,4a, 5,6,7,8,8a., 9octahydro-naphtothiazole.7. Compounds of formula (III) Z4 where one of the substituents among Z1, Z2, Z3, Z4 and Z5 is -RNO2r the others being a hydrogen atom, R3 has the same meanings as for the compound of formula (I), as well as the corresponding enantiomers, as intermediate compounds for the preparation of compounds of formula (II), excluding compound (I) wherein all R3 substituents are hydrogen and one of Z1 substituents Z2, Z3, Z4 and Z5 are -RNO2, the others being a hydrogen atom. 8. Compounds of formula (III) according to claim 7, selected from the group consisting of 5,6,7,8-tetrahydro-2- (4-nitrophenyl) -7- (phenylmethyl) imidazo [2 ', 1 2,3-thiazolo [5,4-c] pyridine, 2- (4-nitrophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydro- benzothiazole-5-carboxylic acid, 2- (4-nitrophenyl) imidazo [2,1-b] -5,6,7,8-tetrahydrobenzothiazole-4-carboxylic acid ethyl ester and 2- (4- nitrophenyl) imidazo [2,1-b] -4,4a, 5,6,7,8,8a, 9-octahydro-naphthothiazole. R330'55   Compounds of formula (I), as defined in any one of claims 1 to 4, for use as a medicament.   Use of compounds of formula (I), as defined in any one of claims 1 to 4, for the manufacture of a medicament for inhibiting Met receptor activity.   11. Use of the compounds of formula (I), as defined according to any one of claims 1 to 4, for the manufacture of a medicament for the treatment or prevention of diseases or disorders involving abnormal activation of the receptor Met.   12. Use of the compounds of formula (I) as defined in any one of claims 1 to 4, for the manufacture of a medicament for preventing the migration of metastases or tumor cells.