MX2011008319A

MX2011008319A - Derivatives of 6-(6-o-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as met inhibitors.

Info

Publication number: MX2011008319A
Application number: MX2011008319A
Authority: MX
Inventors: Conception Nemecek; Sylvie Wentzler; Eric Bacque; Antonio Ugolini; Dominique Damour
Original assignee: Sanofi Sa
Priority date: 2009-02-06
Filing date: 2010-02-04
Publication date: 2012-01-25
Also published as: AU2010212232A1; FR2941950B1; CN102378759A; AR075249A1; CL2011001879A1; KR20110132560A; EP2393791A1; JP2012517408A; EA201171011A1; CA2750875A1; IL214406A0; MA33107B1; UY32420A; FR2941950A1; SG173559A1; BRPI1008232A2; CO6400223A2; WO2010089507A1; TW201031670A

Abstract

The invention relates to novel products of the formula (I) where: (II) is a single double bond; Ra is -O-Z-Rc with Z being a single bond or optionally substituted alkylene and Rc being optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Rb is H or F; if Rb is H, then Rc is not cycloalkyl when Z is a single bond, and Rc is not heterocycloalkyl when Z is alkylene; X is S, SO or SO2, A is NH or S; W is H, alkyl, cycloalkyl or COR with R being cycloalkyl; alkyl; alkoxy; O- phenyl; -O-(CH2)n-phenyl with n = 1 to 4; or NR1 R2 with R1 is H or alk and R2 is H, cycloalkyl or alkyl; or R1, R2 form a cycle with N optionally containing O, S, N and/or NH; wherein all of these radicals are optionally substituted, and said products are in any isomer or salt form and can be used as drugs, in particular as MET inhibitors.

Description

DERIVATIVES OF 6- (6-O S U ST IT I I-TRI AZO WH P I RL D AZI N A- SULFANIDBENZOTIAZOLES AND BENCIMIDAZOLES: PREPARATION, APPLICATION AS MEDICINES AND USE AS MET INHIBITORS Field of the Invention The present invention relates to new derivatives of 6- (6-0-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, their method of preparation, the new intermediates obtained, their application as medicaments, the pharmaceutical compositions containing them and the new use of such 6-triazolopyridazine-sulfanyl-benzothiazole and benzimidazole derivatives.

The present invention relates more particularly to new derivatives of 6- (6-0-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, which have an anticancer activity, by modulating the activity of proteins, in particular, of kinases .

Background of the Invention Until now, most of the commercial compounds used in chemotherapy are cytotoxic compounds that pose significant problems of side effects and tolerance for patients. These effects could be limited to the extent that the drugs used act selectively on cancer cells, excluding healthy cells.

One of the solutions to limit the undesirable effects of a chemotherapy can consist, therefore, in the use of drugs that act on metabolic routes or on constitutive elements of these routes, expressed mostly in cancer cells, and that are not expressed, or they are poorly expressed in healthy cells. Protein kinases are a family of enzymes that catalyze the phosphorylation of hydroxy groups of specific protein moieties, such as tyrosine, serine or threonine residues. Such phosphorylations can significantly modify the function of proteins: in this way, protein kinases play an important role in the regulation of a wide variety of cellular processes, including mainly metabolism, cell proliferation, adhesion and cellular motility. , cell differentiation or cell survival, with certain protein kinases playing a central role in the initiation, development and termination of cell cycle events.

Among the different cellular functions where the activity of a protein kinase is involved, certain processes represent attractive targets to treat certain diseases. As an example, we can mention mainly the angiogenesis and the control of the cell cycle as well as the cell proliferation, in which the protein kinases can play an essential role. These processes are especially essential for the growth of solid tumors as well as for other diseases: mainly the inhibitory molecules of such kinases are capable of limiting unwanted cell proliferations such as those observed in cancers, and can intervene in the prevention, regulation or treatment of neurodegenerative diseases such as Alzheimer's disease or also neuronal apoptosis.

The present invention has as its object new derivatives endowed with inhibitory effects on protein kinases. The products according to the present invention can be used in this way mainly for the prevention or treatment of diseases that can be modulated by the inhibition of protein kinases.

The products according to the present invention mainly have an anti-cancer activity, by modulating the activity of the kinases. Among the kinases for which modulation of activity has been investigated, MET is preferred as well as mutants of the MET protein.

The present invention also relates to the use of such derivatives for the preparation of a medicament for the treatment of humans.

Thus, one of the objects of the present invention is to propose compositions that have an anticancer activity, acting in particular against the kinases. Among the kinases for which modulation of activity has been investigated, MET is preferred.

In the pharmacological part that follows, it is shown in biochemical tests and on cell lines that the products of the present application thus inhibit mainly the autophosphorylation activity of MET and the proliferation of the cells whose growth depends on MET or its mutant forms.

The MET receptor, or Hepatocyte Growth Factor Receptor, is a receptor with tyrosine kinase activity that is expressed in particular in epithelial and endothelial cells. The HGF, Hepatocyte Growth Factor, is described as the specific ligand of MET. HGF is secreted by mesenchymal cells and activates the MET receptor that homodimerizes. As a consequence, the receptor is autophosphorylated in the tyrosines of the catalytic domain Y1230, Y1234 and Y1235.

The stimulation of MET by HGF induces proliferation, spreading (or dispersion), cell motility, resistance to apoptosis, invasion and angiogenesis.

MET in the same way as HGF, is overexpressed in numerous human tumors and in a great variety of cancers. MET is also amplified in gastric tumors and glioblastomas. Numerous point mutations of the MET gene have also been described in tumors, in particular in the kinase domain but also in the juxtamembrane domain and the SEMA domain. Overexpression, amplification or mutations cause the constitutive activation of the receptor and deregulation of its functions.

The present invention thus relates mainly to new inhibitors of the protein kinase MET and its mutants, which can be used for an antiproliferative and ntimetastatic treatment, mainly in oncology.

The present invention also relates to new inhibitors of the MET protein kinase and its mutants, which can be used for an antiangiogenic treatment mainly in oncology.

The subject of the present invention is the products of formula (I): where represents a single or double bond; Rb represents a hydrogen atom or a fluorine atom; Ra represents a radical -O-Z-Rc wherein: Z represents a single bond or a linear or branched alkylene radical having 1 to 6 carbon atoms and which is optionally substituted with an alkyl group or a halogen atom; Re represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical; X represents S, SO or S02; A represents NH or S; W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, -0-CO-R5, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, being themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n represents an integer from 1 to 4; or the radical NR1R2 wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals selected from the hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 radicals, optionally substituted phenyl; or R1 and R2 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or several different heteroatoms selected from O, S, N and NH, being able to be S optionally in the form of SO or S02; what even the radicals containing NH optionally is, optionally substituted; with R3 and R4, identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals selected from the radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIq, N (Alq) 2 and phenyl itself optionally substituted; or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, S optionally being optionally in the form of SO or S02; what even the radicals containing NH optionally is, optionally substituted; all the radicals defined above being alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, substituted optionally with one or more radicals selected from the halogen atoms, the hydroxyl, oxo, alkoxy, -0-CO-R5, -OR5 -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH- radicals CO-R5, -NHCOOR5 and the alkyl, heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl radicals, CO-phenyl, heteroaryl and S-heteroaryl, as in the latter radicals, the alkyl, alkoxy, heterocycloalkyl, phenyl and heteroaryl radicals themselves are optionally substituted with one or more radicals selected from the halogen atoms and the hydroxyl, oxo radicals, alkyl and alkoxy having from 1 to 4 carbon atoms, NH2, NHalq and N (alk) 2; all the radicals defined above being also, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl, optionally substituted with a radical Si (alk) 3; R5 and R5 ', identical or different, represent an alkyl or cycloalkyl radical having at most 6 carbon atoms; alk represents an alkyl radical having at most 4 carbon atoms; it being understood that: i) when Rb represents hydrogen and Z represents a single bond, then Re does not represent a cycloalkyl radical; and ii) when Rb represents hydrogen and Z represents an alkylene radical, then Re does not represent a heterocycloalkyl radical; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

The present invention relates to the products of formula (I) such as those defined above or defined below, wherein represents a single or double bond; Ra represents a radical -O-Z-Rc wherein Z represents a single bond and Re represents an aryl optionally substituted; Rb represents a hydrogen or fluorine atom; X represents S, SO or S02; A represents NH or S; W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, -0-CO-R5, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n represents an integer from 1 to 4; or the radical NR1R2 wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals selected from the hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 form with the nitrogen atom to which they are attached, a cyclic radical having 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, S optionally being optionally in the form of SO or S02; what even the radicals containing NH optionally is, optionally substituted; with R3 and R4, identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals selected from the radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIq, N (Alk) 2 or optionally substituted phenyl; or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, S optionally being optionally in the form of SO or S02, which even the radicals containing NH optionally is, optionally substituted; all the radicals defined above being alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as the cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, optionally substituted with one or more radicals selected from the halogen atoms, the hydroxyl, oxo, alkoxy, -0-CO-R5, -OR5, NH2 radicals , NHalk, N (alk) 2 and the alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl radicals, such that in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or more radicals selected from the halogen atoms and the hydroxyl, oxo, alkyl and alkoxy radicals having from 1 to 4 carbon atoms, NH2, NHalq and N (alk) 2; R5 represents an alkyl or cycloalkyl radical having at most 6 carbon atoms; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

The present invention relates to the products of formula (I) such as those defined above or defined below where ZIZ .. Ra, Rb and X have the values defined in any of the other claims and: A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, 5 - . 5 -0-CO-R5, hydroxy, phenyl or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n IÜ represents an integer from 1 to 4; or the radical NR1R2, wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an optionally substituted alkyl radical I5 with an alkoxy, heterocycloalkyl, or NR3R4 radical; or R1 and R2 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, which even the radicals containing NH optionally is, 0 optionally substituted; with NR3R4 such that R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical or a heterocycloalkyl radical optionally substituted with one or more identical or different radicals selected from the group consisting of alkoxy, heteroaryl, heterocycloalkyl or NH2 radicals, NHAIq , N (Alk) 2, or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, what even the radicals containing NH optionally is, optionally substituted; all the alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, defined above, optionally substituted with one or several radicals selected from the halogen atoms, the hydroxyl, alkoxy, O-cycloalkyl, NH2, NHalq, N (alk) 2 radicals and the alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals themselves are optionally substituted with one or more radicals selected from the halogen atoms and the hydroxyl, alkyl and alkoxy radicals having from 1 to 4 carbon atoms, NH2, NHalq and N (alq) 2, such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

Where it refers to cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, these radicals optionally have one or more different heteroatoms selected from O, S, N and NH, and can be optional S optionally in the form of SO or SO 2; what even the NH-containing radicals optionally are, optionally substituted especially with a radical selected from alkyl, alkoxy, cycloalkyl or heterocycloalkyl, themselves optionally substituted with one or more radicals selected from the halogen atoms and the alkyl, alkoxy radicals , NH2, NHAIq or N (Alq) 2; The subject of the present invention is the products of formula (I): where represents a single or double bond; Rb represents a hydrogen atom or a fluorine atom; Ra represents a radical -O-Z-Rc wherein: Z represents a single bond or a linear or branched alkylene radical having 1 to 6 carbon atoms and which is optionally substituted with an alkyl group or a halogen atom; Re represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical, X represents S, SO or S02; A represents NH or S; W represents a hydrogen atom; an alkyl or cycloa radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, hydroxy, phenylene, heteroaryl, or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n represents an integer from 1 to 4; or the radical NR1R2 wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals selected from the hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 form, with the nitrogen atom to which they are attached, a cyclic radical having 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; with R3 and R4, identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted or R3 and R4 form with the nitrogen atom to which they are attached, a cyclic radical containing from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; all the radicals defined above being alkyl, cycloalkyl, heterocycle Iq ui I, heteroaryl, aryl and phenyl as well as the cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, optionally substituted with one or several radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, -0-CO-R5, -OR5, -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO- R5 and the alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and .S-heteroaryl radicals, such that in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or more radicals selected from the halogen atoms and the hydroxyl, oxo, alkyl and alkoxy radicals having from 1 to 4 carbon atoms, NH2, NHalq and N (alk) 2, all the radicals defined above being also cycloalkyl, heterocycloalkyl, heteroaryl and phenyl, optionally substituted with a radical S i (a I q) 3; R5 and R5 ', identical or different, represent an alkyl or cycloalkyl radical having at most 6 carbon atoms; alk represents an alkyl radical having at most 4 carbon atoms; it being understood that: i) when Rb represents hydrogen and Z represents a single bond, then Re does not represent a cycloalkyl radical, and ii) when Rb represents hydrogen and Z represents an alkylene radical, then Re does not represent a heterocycloalkyl radical; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

The present invention relates to the products of formula (I) such as those defined above or defined below, wherein represents a single or double bond; Ra represents a radical -O-Z-Rc wherein Z represents a single bond and Re represents an aryl optionally substituted; Rb represents a hydrogen or fluorine atom; X represents S, SO or S02; A represents NH or S; W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n represents an integer from 1 to 4; or the radical NR1R2 wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals selected from the hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 form with the nitrogen atom to which they are attached, a cyclic radical having 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; with R3 and R4, identical or different, representing one atom 5 of hydrogen, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or an optionally substituted phenyl radical or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical containing from 3 to 10 members and optionally one or several different heteroatoms selected from O, S, N IÜ and NH, which even the radicals containing NH optionally is, optionally substituted; all the radicals defined above being cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, optionally substituted with one or more selected radicals between the halogen atoms, the hydroxyl, oxo, alkoxy, -0-CO-R5, -OR5, NH2, NHalq, N (alk) 2 radicals and the alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, or CH2 radicals -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such that in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals themselves are optionally substituted with one or more radicals selected from halogen atoms and radicals 25 hydroxyl, oxo, alkyl and alkoxy having from 1 to 4 carbon atoms carbon, NH2, NHalq and N (alk) 2; R5 represents an alkyl or cycloalkyl radical having at most 6 carbon atoms; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein z. < Rg > And X have the values defined in any of the other claims and: A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, alkoxy, hydroxy, phenyl or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n represents an integer from 1 to 4; or the radical NR1R2, wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with an alkoxy, heterocycloalkyl, or NR3R4 radical; or R1 and R2 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; with NR3R4 such that R3 and R4, identical or different, represent a hydrogen atom or an alkyl radical or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical containing from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; all the cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, defined above, optionally substituted with one or more radicals selected from the halogen atoms , the hydroxyl, alkoxy, O-cycloalkyl, NH2, NHalk, N (alk) 2 radicals and the alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals, the alkyl radicals, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or more radicals selected from the halogen atoms and the hydroxyl, alkyl and alkoxy radicals having from 1 to 4 carbon atoms, NH2, NHalq and N (alk) 2; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein II ^, Ra. and X have the values defined in any of the other indications and: A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with a heterocycloalkyl radical or NR3R4; or the radical COR where R represents: a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, or alkoxy; an O-phenyl radical or 0- (CH2) n-phenyl, with the phenyl optionally substituted and n represents an integer from 1 to 2; or the radical NR1R2, wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, an alkyl radical optionally substituted with a heterocyclic radical or NR3R4, or R1 and R2 form with the nitrogen atom to which they are attached, a cyclic radical optionally having one or more different heteroatoms selected from O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; with NR3R4 such that R3 and R4, identical or different, represent a hydrogen atom or an alkyl radical or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical optionally containing one or more different heteroatoms selected between O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; all the cycloalkyl, heterocyclic and phenyl radicals as well as the cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, defined above, optionally substituted with one or more radicals selected from the halogen atoms , the hydroxyl, alkoxy, O-cycloalkyl, NH2, NHalk, N (alk) 2 radicals and the alkyl and phenyl radicals, the latter themselves being optionally substituted with one or more radicals selected from halogen atoms and hydroxyl radicals, alkyl and alkoxy having from 1 to 4 carbon atoms, NH2, NHalq and N (alk) 2; such products of formula (I) being in all possible forms of isomers, racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein A represents NH, the substituents z ^, Ra, Rb, X and W being selected from all the defined values. for these radicals in any of the other claims, such products of formula (I) being in all possible forms of isomers, racemates, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with mineral bases and organic compounds of such products of formula (I).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein A represents S, the substituents zn, Ra, R °, X and W being selected among all the defined values for these radicals in any of the other claims, such products of formula (I) being in all possible forms of isomers, racemates, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with mineral bases and organic compounds of such products of formula (I).

The present invention relates to the products of formula (I) such as those defined above or defined below, which correspond to formula (la) or (Ib): where ?? · Ra. Rb, and W are selected from the meanings indicated in any of the other claims, such products of formula (la) and (Ib) being in all possible forms of isomers, racemates, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the mineral and organic bases of such products of formula (la) and (Ib).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein it represents a single bond, which correspond to the products of formula (): wherein the substituents Ra, Rb, X, A and W have any of the meanings indicated above or indicated below, such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein it represents a double bond, which correspond to the products of formula (! "): wherein the substituents Ra, Rb, X, A and W have any of the meanings indicated above or indicated below, such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts, with the mineral and organic acids or with the mineral and organic bases, of such products of formula (I) ).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein it represents a simple bond, which correspond to the products of formula (la '): wherein Ra, Rb, and W are selected from any of the meanings indicated above or indicated below, such products of formula (I) being in all possible forms of isomers, racemics, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I). 'to).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein represents a double bond that respond to the products of formula (I "a): wherein Ra, Rb, and W are selected from any of the meanings indicated above or indicated below, such products of the formula (I "a) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of the formula (I). "to).

The subject of the present invention is the products of formula (I) such as those defined above or defined below, wherein it represents a simple bond corresponding to the products of formula (I b): w R a (l'b) wherein Ra, Rb and W are selected from any of the meanings indicated above or indicated below, such products of formula (I b) being present in all possible forms of enantiomeric and diastereomeric racemic isomers, as well as addition salts with mineral and organic acids or with the mineral and organic bases of such products of formula (I) b) The present invention relates to the products of formula (I) such as those defined above or defined below, wherein represents a double bond that respond to the products of formula (1b): wherein Ra, Rb and W are selected from any of the meanings indicated above or indicated below, such products of formula (1b) being present in all possible forms of isomers, racemates, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I). "b).

In the products of formula (I) and after the following: the term alkyl radical (or Alk) designates the radicals, linear and, according to the case, branched, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, urea-butyl, pentyl, isopentyl, hexyl, isohexyl and likewise heptyl, octyl, nonyl and decyl, as well as their linear or branched positional isomers: alkyl radicals containing from 1 to 6 carbon atoms and more especially are preferred alkyl radicals containing 1 to 4 carbon atoms from the above list; the term "alkoxy radical" denotes the linear and, as the case may be, branched, methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy radicals, as well as their linear or branched positional isomers: radicals are preferred alkoxy containing 1 to 4 carbon atoms from the above list; the term "halogen atom" designates the chlorine, bromine, iodine or fluorine atoms and preferably the chlorine atom, 5 bromine or fluorine. the term "cycloalkyl radical" refers to a saturated carbocyclic radical containing from 3 to 10 carbon atoms and thus denotes, in particular, the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals and very particularly the cyclopropyl, cyclopentyl and cyclohexyl radicals; The term heterocycloalkyl radical thus denotes a monocyclic or bicyclic carbocyclic radical, containing from 3 to 10 members, interrupted by one or more heteroatoms, identical or different, selected from the oxygen, nitrogen or sulfur atoms: for example, , morpholinyl, thiomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyran, tetrahydrothiopyran, oxydihydropyridazinyl, or also oxetanyl or thietanyl, all of these radicals being optionally substituted; it can be seen that these heterocycloalkyl radicals can be bridged from two members to form, for example, an oxa-5-azabicyclo [2.2.1 jheptane or also azaspiro [3.3] heptane or other 5 azabicyclo-alkane or azaspiro- alkanes. the terms "aryl" and "heteroaryl" designate unsaturated or partially unsaturated, respectively carbocyclic and heterocyclic, monocyclic or bicyclic radicals containing at most 12 members, which may optionally contain a -C (O) member, the heterocyclic radicals containing one or more identical heteroatoms or different selected among O, N, or S with N, according to the case, optionally substituted; the term aryl radical thus designates monocyclic or bicyclic radicals containing 6 to 12 members such as, for example, the phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly the phenyl and naphthyl radicals and even more particularly the phenyl radical . It can be seen that a carbocyclic radical containing a -C (O) member is, for example, the tetralone radical; it can also be observed that the aryl radical such as phenyl can optionally be substituted for example with two alkoxy radicals to form a benzodioxole radical which is itself optionally substituted as indicated for the aryl radical the term heteroaryl radical thus designates monocyclic or bicyclic radicals containing 5 to 12 members: monocyclic heteroaryl radicals such as, for example, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, 3- furyl, pyranyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl such as 3 or 4-isoxazolyl, furazanyl, free or salted tetrazolyl, all of these radicals being optionally substituted among which more particularly thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl , pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, these radicals being optionally substituted; bicyclic heteroaryl radicals such as, for example, benzothienyl radicals such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolone, tetralone, adamentyl, benzofuryl, isobenzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thiantrenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl. indolyl, azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl or oxodihydropyridinopyridylol, all of these radicals being optionally substituted; As examples of heteroaryl or bicyclic radicals, mention may be made more particularly of pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl radicals, optionally substituted with one or more identical or different substituents as indicated above.

It can be seen that two substituents on the cycloalkyl, heterocycle Iq, halo, heteroaryl, aryl and phenyl radicals as well as on the cyclic radicals which can form R1 and R2 or R3 and R4 respectively with the nitrogen atom to which they are attached, can optionally forming a cycloalkyl or heterocycloalkyl type cycle according to the case and the usual methods known to those skilled in the art.

The carboxyl radical (s) of the products of formula (I) can be salified or esterified with various groups known to the person skilled in the art, among which may be mentioned, for example: among the salification compounds, mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine,?,? -dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, Usina, arginine, histidine and N-meti Ig I mine, among the esterification compounds, the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, ferc-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals may be substituted with selected radicals, for example, between the halogen atoms, the radicals hydroxyl, alkoxy, acyl, acyloxy, alkyl, amino or aryl as, for example, in the groups chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl.

The addition salts with mineral or organic acids of the products of formula (I) can be, for example, the salts formed with the hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic acids , maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, the alkoxymonosulfonic acids such as, for example, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, the alkyldisulfonic acids such as, for example, methanedisulfonic acid, alpha acid , beta-ethanedisulfonic, arylmonosulfonic acids, such as benzenesulfonic acid and aryldisulfonic acids.

It can be recalled that stereoisomeria can be defined in its broad sense as the salience of compounds that have the same developed formulas but where different groups occupy different positions in space, such as occurs mainly in monosurfaced cyclohexanes, where the substituent may be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives. However, there is another type of stereoisomeria, due to the different spatial dispositions of the fixed substituents, either on the double bonds, or on cycles, which is usually called geometric isomerism or cis-trans isomerism. The term "stereoisomers" is used in the present application in its broadest sense and refers, therefore, to the set of compounds indicated above.

The cyclic radicals which can on the one hand form R1 and R2 with the nitrogen atom to which they are attached and on the other hand R3 and R4 with the nitrogen atom to which they are attached, are optionally substituted with one or more radicals selected from those indicated above for the optional substituents of the heterocycloalkyl radicals, i.e., one or more radicals selected from the halogen atoms, the hydroxyl, oxo, alkoxy, NH2 radicals; NHalk, N (alk) 2 and the alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl and CO-phenyl radicals, such that in the latter radicals, the alkyl, heterocycloalkyl and phenyl radicals are themselves optionally substituted with one or more radicals selected from the halogen atoms and the hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2; NHalq and N (alq) 2, The cyclic radicals which can on the one hand form R1 and R2 with the nitrogen atom to which they are attached and on the other hand R3 and R4 with the nitrogen atom to which they are attached, are preferably optionally substituted with one or more identical or different radicals selected from the halogen atoms and the alkyl, hydroxyl, alkoxy, CH2-pyrrolidinyl, CH2-phenyl, heteroaryl and phenyl radicals, wherein the alkyl, pyrrolidinyl and phenyl radicals are themselves optionally substituted with one or more identical or different radicals selected between the halogen atoms and the alkyl, hydroxyl, oxo and alkoxy radicals.

The heterocycloalkyl radicals as defined above represent mainly the azepanyl, morpholinyl and pyrrolidinyl, piperidyl and piperazinyl radicals, themselves optionally substituted, such as those defined above or defined below.

When NR1R2 or NR3R4 forms a ring as defined above, such a ring can be selected mainly from the pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholino or piperazinyl radicals, these radicals themselves being optionally substituted as indicated above or indicates below: for example with one or more identical or different radicals selected from the halogen atoms and the alkyl, hydroxyl, alkoxy, phenyl and CH2-phenyl radicals, the alkyl or phenyl radicals themselves being optionally substituted with one or more radicals identical or different selected from the halogen atoms and the alkyl, hydroxyl and alkoxy radicals.

The NR1R2 or NR3R4 cycle can be selected more particularly between the pyrrolidinyl, morpholino radicals optionally substituted with one or two alkyl or piperazinyl optionally substituted on the second nitrogen atom with an alkyl, phenyl or CH 2 -phenyl radical, themselves optionally substituted with one or more identical or different radicals selected from the halogen atoms and the alkyl, hydroxyl and alkoxy radicals.

The subject of the present invention is especially the products of formula (I) such as those defined above or defined below, wherein Rb represents a fluorine atom, the other substituents of such products of formula (I) having any of the definitions indicated above or indicated below.

The subject of the present invention is especially the products of formula (I) such as those defined above or defined below, wherein Ra represents an -O-phenyl radical optionally substituted with one or more radicals selected from halogen atoms and the hydroxyl, alkoxy, O-cycloalkyl, alkyl and CF3 radicals, the other substituents of such products of formula (I) having any of the definitions indicated above or indicated below.

The present invention relates to the products of formula (I) such as those defined above or defined below, wherein represents a single or double bond Ra represents an -O-phenyl radical optionally substituted with one or more halogen atoms; Rb represents a hydrogen atom; X represents S; A represents S; W represents a hydrogen atom; or the radical COR where R represents: a cycloalkyl radical, or an alkyl radical; or the radical NR1R2 wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, and the other of R1 and R2 represents an alkyl radical optionally substituted with a heterocycloalkyl radical; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

The subject of the present invention is therefore the products of formula (I) such as those defined above or defined below, which correspond to the following formulas: 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine; N-. { 6 - [(6-phenoxy [1,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} Cyclopropanecarboxamide; N-. { 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide; 1- [2- (morpholin-4-yl) ethyl] -3-. { 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole-2-yl} urea; 1- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1, 3-benzothiazole-2- il) -3- [2- (morpholin-4-yl) etl] urea; 6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; N- (6- { [6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1, 3- benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide; N2, N2-diethyl-N- (6- { [6- (3-fluorophenoxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfan l.,., -1, 3-benzothiazol-2-yl) glycinamide; N2-Cyclopropyl-N- (6- { [6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1. 3-benzothiazol-2-yl) glycinamide; N- [6- (. {6- [3- (Morpholin-4-ylmethyl) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl}. Sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1, 2, 4] triazolo [4, 3-b] pyrid azin-3-yl] sulfanyl] -1, 3-benzothiazol-2-yl) acetamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazole -2-i) cyclopropanecarboxamide; 1- (6- { [6- (4-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole- 2-l) -3- [2- (morpholin-4-yl) etl] urea; 1 - . 1 - . 1 - . 1 - . 1 - (6- { [6- (3-fluoro-4-methylphenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1,3- benzothiazol-2-yl) -3- [2- (morpholin-4- i i) e t i i a re; 6- { [6- (tetrahydro-2H-pyran-4-yloxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; 6- { [6- (4-fluorophenoxy) [1, 2, 4] triazolo [4, 3-b] pyrid azi n-3-yl] sulfanyl} -1,3-benzothiazol-2-amine; 1- [2- (morpholin-4-yl) ethyl] -3- (6- { [6- (tetrahydro-2 H -pyran-4-yloxy) [1, 2,4] triazolo [4.3- b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazol-2-yl) urea; 1 - [6- ( {6 - [(1-ethylpiperidin-4-yl) oxy] [1, 2, 4] t riazolo [4, 3-b] pyridazin-3-yl.}. Sulfanyl) - 1,3-benzothiazol-2-yl] -3- [2- (morpholin-4-yl) ethyl] urea; N- (6- { [6- (tetrahydro-2H-pyran-4-yloxy) [1, 2, 4] triazolo [4, 3 b] pindazin-3-yl] sulfanyl.} -1,3 -benzothiazol-2-yl) cyclopropanecarboxamide; N- (6- { [6- (4-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) cyclopropanecarboxamide; N- (6- { [6- (3-fluoro-4-methylphenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1.3- benzothiazol-2-yl) cyclopropanecarboxamide; N- [6- ( {6 - [(1-ethylpiperidin-4-yl) oxy] [1, 2,4] tfiazolo [4,3-b] pyridazin-3-yl.}. SulfanM) -1 , 3-benzothiazol-2-yl] cyclopropanecarboxamide; 1 - [2- (Morpholin-4-yl) ethyl] -3- (6- { [6- (tetrahydrofuran-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin- 3-yl] sulfanyl.] -1,3-benzothiazole-2 M) urea; 1 - . 1 - (6- { [6- (1, 3-benzodioxol-5-yloxy) [1, 2, 4] t riazo [4, 3-b] pyridazin-3-yl] sulfanyl. -1, 3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) et I] rea; 1 - (6- { [6- (3,4-dichlorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole- 2-yl) -3- [2- (morpholin-4-yl) ethyl] urea; 6- { t6- (3,4-dichlorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-M] sulfanM} -1, 3-benzothiazol-2-amine; 6- { [6- (tetrahydrofuran-3-yloxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfanil} -1, 3-benzothiazol-2-amine; 1- (6- { [6- (1 H -indole-6-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1, 3 -benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea; N- (6- { [6- (tetrahydrofuran-3-yloxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole- 2-yl) cyclopropanecarboxamide; N- (6- { [6- (1, 3-benzodioxol-5-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1, 3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6- { [6- (3,4-dichlorophenoxy) [1, 2, 4] t riazo [4, 3-b] pyridazin-3-yl] sulphanyl. , 3-benzothiazol-2-yl) cyclopropanecarboxamide; N- (6- { [6- (1 H -indole-6-yloxy) [1, 2, 4] trio azo [4, 3-b] p-rid azi n-3-yl] sulfanil ., -1, 3-benzothiazol-2-yl) cyclopropanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2 -yl) cyclobutanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazole -2-il) -N2, N2-d-methylglucinamide; 2-ethoxy-N- (6- { [6- (3-fluorophenoxy) [1, 2, 4] tr azoo [4, 3-b] pyridazin-3-yl] sulphanil .}. -1, 3-benzothiazol-2-yl) acetamida, 2- (cyclohexyloxy) -N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide; 6- { [6- (pyridin-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; - 6- ( { 6- [3- (trifluoromethoxy) phenoxy] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl.] Sulfanyl) - 1,3-benzothiazol-2-amine; [3- ( { 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin -6-yl.}. Oxi) phenyl] carbamate 2- methylpropan-2-yl; - N- (6- { [6- (pyridin-3-xloxy) [1, 2,4] triazolo [4,3-b] p¡r¡daz¡n-3- il] sulfanyl.] -1,3-benzothiazol-2-yl) -cyclobutanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazoto [4,3-b] pyridazin-3-l] sulfanyl.} -1,3 -benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide; N2-cyclohexyl-N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl}. -1,3-benzothiazol-2-yl) glycinamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazole -2-l) -N2-methyl-N2- [2- (morpholin-4-yl) et1] glycanamide; 2- (4-ethylpiperazin-1-yl) -N- (6- { [6- (3- fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-yl) acetamide; 6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; - 6- { [6- (3-aminophenoxy) [1, 2, 4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) -N ~ 2 ~ - (tetrahydro-2H-pyran-4-yl) glycinamide; - N- [6- (. {6- [4- (trifluoromethyl) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl}. Sulfanyl) -1, 3- benzothiazol-2-yl] cyclopropanecarboxamide; N- [6- (. {6- [3- (trifluoromethoxy) phenoxy] [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl}. Sulfanyl) -1,3-benzothiazole -2-ylcyclopropanecarboxamide; N- [6- ( {6 - [(2-methylpyridin-3-M) oxy] [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl.} Sulfanil) -1 , 3-benzothiazol-2-yl] cyclopropanecarboxamide; N- (6- { [6- (3,5-difluorophenoxy) [1, 2, 4] t ri azolo [, 3-b] pyridazin-3-yl] sulfanyl.] -1, 3-benzothiazole -2-yl) cyclopropanecarboxamide; 2 - [(6- {[6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole acetate -2-yl) amino] -2-oxoetite; N- [6- (. {6 - [(6-Methylpyridin-3-yl) oxy] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanil) -1 , 3-benzothiazole-2- L] cyclopropanecarboxamide; N- [6- (. {6- [4- (Morpholin-4-ylmethyl) phenoxy] [1,4] triazolo [4,3- b] pyridazin-3-yl}. Sulfanil) -1,3-benzothiazol-2-yl] -cyclopropanecarboxamide; 5 - . 5 - (3- { [3- ( { 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl}. Sulfanyl) [1,2,4] triazolo [4.3 -b] pyridazin-6-yl] oxy}. phenyl) carbamate of 2-methylpropan-2-yl; N- (6- { [6- (pyridin-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole- 2-yl) cyclopropanecarboxamide; K) - N-. { 6 - [(6- { 3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy]. [1, 2,4] triazolo [4 , 3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole-2-M} Cyclopropanecarboxamide; N-. { 6 - [(6- { 3- [(diethylamino) methyl] phenoxy]. [1, 2,4] triazolo [4,3-b] pyridazin-3-I5 i) its If ani I] - 1,3-benzothiazol-2-yl} Cyclopropanecarboxamide; N- (6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole- 2-yl) -N2, N2-diethylglycine amide; N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2 -yl) -2-hydroxyacetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pindazin-3-yl] sulfanil .}. -1,3-benzothiazol-2-yl) acetamide; N- (6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4,3-25 b] pyridazin-3-yl] sulfanyl.} -1,3-benzothiazole -2-il) -2- (4-ethylpiperazin-1-yl) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; N-. { 6 - [(6- { 3- [(diethylamino) methyl] phenoxy]. [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-il} acetamide; N-. { 6 - [(6- { 3- [(diethylamino) methyl] phenoxy]. [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-il} -2-methoxyacetamide; 2-methoxy-N-. { 6 - [(6- { 3 - [(1 S, 4 S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy]. [1, 2,4] triazolo [ 4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide; 6- { [6- (oxetan-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; 2- (morpholin-4-yl) -N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] tri zolo [4,3-b] pyridazin-3-yl] Sulfanyl.) -1,3-benzothiazol-2-yl) acetamide; N- (6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole- 2-yl) -2- (morpholin-4-yl) acetamide; N2, N2-diethyl-N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl}. 1,3-benzothiazol-2-yl) glycinamide; 2- (4-ethylpiperazin-1-yl) -N- (6- { [6- (tetrahydrofuran-3- iloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-yl) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl.] -1, 3-benzothiazol-2-yl) acetamide; N- (6- { [6- (oxetan-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanM.} -1,3-benzothiazole- 2-yl) cyclopropanecarboxamide; 2- (4-ethylpiperazin-1-yl) -N- (6- { [6- (oxetan-3-yloxy) [1,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl] -1,3-benzothiazole-2-M) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (oxetan-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; as well as the addition salts with the mineral and organic acids or with the mineral and organic bases, of such products of formula (I).

The subject of the present invention is also any process for preparing the products of formula (I) as defined above.

The subject of the present invention is therefore any process for the preparation of the products of formula (I), as defined above, wherein A represents NH.

The subject of the present invention is therefore any process for preparing the products of formula (I) such as defined above where A represents S.

The products according to the invention can be prepared from conventional methods of organic chemistry. The following Reaction Schemes 1, 2, 2bis, 3, 4, 5 and 6 are illustrative of the methods used for the preparation of the products of formula (I). In this regard, they are not intended to limit the scope of the invention as far as the methods of preparation of the claimed compounds are concerned.

The products of formula (I) such as those defined above according to the present invention can thus be prepared especially according to the procedures described in Reaction Schemes 1, 2, 2bis, 3, 4, 5 and 6 below.

The subject of the present invention is also the process for preparing the products of formula (I) according to Reaction Scheme 1 as defined below.

The subject of the present invention is also the process for preparing the products of formula (I) according to Reaction Scheme 2 as defined below.

The subject of the present invention is also the process for preparing the products of formula (I) according to Reaction Scheme 2bis as defined below.

The subject of the present invention is also the process for preparing the products of formula (I) according to Reaction Scheme 3 as defined below.

The present invention thus also has as an object the process for the preparation of the products of formula (I) according to Reaction Scheme 4 as defined below.

The subject of the present invention is also the process for the preparation of the products of formula (I) according to Reaction Scheme 5 as defined below.

The present invention thus also has as an object the process for the preparation of the products of formula (I) according to Reaction Scheme 6 as defined below.

The same as between the products of formula (I) as defined above where represents a single or double bond, define the products of formula (G) representing the products of formula (I) where represents a simple link and the products of formula (I ") which represent the products of formula (I) wherein represents a double bond, likewise for the synthesis intermediates as defined below of formulas (a), (b), (c), (d), (e) and (f) where it represents a single or double bond, the compounds of formulas (a '), (b'), (c '), (d'), (e ') and (f) where represents a single bond and the compounds of formulas (a "), (b"), (c "), (d"), (e ") and (f") where it represents a double bond.

Reaction Scheme 1: synthesis of benzimidazole derivatives of formulas (1a "), (1b"), (1"c), (1d"), (1e "), (1a '), (1b'), (1c ') ), (1d ') and (1e'); I0 NC-S NH Reduction HS K + R NO, when R when Rb = H Rb = F commercial N- A V- Cl Ra-H according to scheme Cl Reaction 3 Ra trade Reduction fifteen (R) (J) V // R a H7 H " R a 1a71a " BrCN N 0 5 In Reaction Scheme 1 above, the substituents, Ra and Rb, have the meanings indicated above for the products of formula (G) and (I ") The substituent R5, in the compounds of formulas (J), (1a ') ) and (1a "), represents an alkyl radical.

In Reaction Scheme 1 above, the groups CONR1R2, C02R6 and COR7, which constitute W, can take the values of W such as those defined above for the products of formula (G) and (I "), when W? H.

In Reaction Scheme 1 above, the benzimidazoles of general formula (1a "), (1b"), (1c "), (1d") and (1e ") as well as their reduced analogs of general formula (1a ') , (1b '), (1c'), (1d ') and (1e') can be prepared from commercial 3,6-dichloro [1, 2,4] triazolo [4,3-b] pyridazine from formula (S).

I5 Ra The compounds (E) can be obtained, for example, by the reaction of phenols or alcohols in the presence of a base on the compound (S). The reaction is carried out, for example, at a temperature close to 20 ° C.

F Ra The compounds (G), with Rb = H, can be obtained, for example, by reaction of 3-amino-4-nitro-benzenethiol of formula (F) on the compounds of formula (E), in the presence of a base such as the sodium hydride in a solvent such as N, N-dimethylformamide at a temperature close to 20 ° C. The compounds of formula (F) are obtained by in situ reduction of thiocyanate of 3-amino-4-nitrophenyl (Q) (commercial compound), for example, in the presence of sodium borohydride in a solvent such as N, N-dimethylformamide. , at a temperature close to 20 ° C.

Compounds (G), with Rb = F, can be obtained, for example, by reaction of the 2-fluoro-5-amino-4-nitro-benzenethiol of formula (F) on the compounds of formula (E) in the presence of a base such as sodium hydride in a solvent such as N, N-dimethylformamide at a temperature close to 20 ° C. The compounds of formula (F), with Rb = F, are obtained by reaction of 2-nitro-4,5-difluoroaniline (Q ') (commercial compound), for example, in the presence of potassium thioacetate (C) in a solvent such as N, -dimethylformamide, at a temperature close to 20 ° C.

H7H " Ra The compounds (H ") where represents a double bond, can be obtained, for example, by reduction with iron (0) of the compounds of formula (G), in a solvent such as methanol, in the presence of acetic acid, a a temperature close to 70 ° C.

Compounds (H), where represents a single bond, can be obtained, for example, by reduction with zinc (0) on the compounds of formula (G), in the presence of acetic acid, at a temperature close to 20 ° C.

More particularly, the carbamates of general formula (1a ') and (1a ") can be prepared mainly as described in WO03028721 A2, but from, respectively, a 3,4-diamino phenyl sulfide of formula (H) and (H ") and a pseudo thio-urea of formula (J), in the presence of acetic acid and in a protic solvent such as methanol, at a temperature close to 80 ° C.

More particularly, the benzimidazoles of general formula (1b ') and (1b ") can be prepared respectively by reaction of an amine NHR1R2 of formula (R) (with R1 and R2 as defined above) on a carbamate of formula ( 1a ') and (1a "), for example, in the presence of an aprotic solvent such as 1-methyl-2-pyrrolidinone. The reaction is carried out, for example, at a temperature close to 120 ° C, in a sealed tube under microwave.

More particularly, the 2-amino-benzimidazoles of general formula (1c ') and (1c ") can be prepared, for example, by reaction of cyanogen bromide on a compound of formula (' ') and (H") respectively, in the presence of a protic solvent such as ethanol. The reaction is carried out at a temperature close to 80 ° C.

More particularly, the carbamates of general formula (1d ') and (1d ") can be obtained by reaction with a chlorocarbonate of formula (O) (X = CI) on a compound of general formula (1c') and (1c") respectively, for example, in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature close to 20 ° C.

More particularly, the carboxamides (1e ') and (1e ") can be obtained respectively from the amines of general formula (1c') and (1c") by reacting the amines (1c ') and (1c ") with an acid chloride of the formula (P) (X = Cl), in the presence, for example, of a solvent such as pyridine, at a temperature close to 20 °. C. by reaction of the amines (1c ') and (1c ") with an acid anhydride of formula (P) (X = OCOR7), in the presence, for example, of pyridine, at a temperature close to 20 ° C. by coupling the amines (1c ') and (1c ") with an acid of the formula (P) (X = OH) under the conditions described, for example, by DD DesMarteau; V. Montanari (Chem Lett, 2000 (9) , 1052), in the presence of 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as triethylamine, at a temperature close to 40 ° C.

Reaction Scheme 2: Synthesis of benzothiazole derivatives of formulas (2a '), (2b'), (2c '), (2d'), (2a) ', (2b'), (2C), (2d ').

N-N ~ CI T ^ Rb ^^ N \\ / O-N R2 NC'XIS /) "'" ^ "IO" SYY N *, * A Ra 2bV 2b " L2 ° R2 M2 OR R2 NHR, Rj N l-N > -ci (R) N ^ N j b NC Y ** _¡¡ Ra E reduction? ^? -. OR Rs Rb ?? ^ > ? > - - Rb ^^ N -o. 2a72a " OR R6 OR R " M1 R6OCOX (O) N-N N S reduction N Rn E NH, frX 2d72d " Ra R, COX N-N (P) N N HS Ra E reduction T ^ Rb ^^ N -R; Rb ^ < ^ ~ «Í-«, L3 M3 2cV2c "Ra In Reaction Scheme 2 above, the substituents, Ra and, Rb have the meanings indicated above for the products of formula () and (I "). Also, the groups CONR1R2, C02R6 and COR7, which constitute W, can take the values of W such as those defined above for the products of formula (G) and (I "), when W? H.

In Reaction Scheme 2 above, the benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogs of general formula (2a '), (2b'), (2c ') and (2d') with Rb = H can be prepared from the thiocyanate of 2-amino-1,3-benzothiazol-6-yl (K) (commercial compound).

K R6 The carbamates of the general formula (L1) can be obtained, for example, by reaction with a chlorocarbonate of formula (O) (X = Cl) on the thiocyanate of 2-amino-1,3-benzothiazol-6-yl (K) , in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature close to 20 ° C.

CN KSCN C H.H NH ^ "N NH > AcOH F co ni ere?;? I K In Reaction Scheme 2 above, the benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogs of general formula (2a '), (2b'), (2c ') and (2d') with Rb = F can be prepared from the thiocyanate of 2-amino-5-fluoro-1,3-benzothiazol-6-yl. The thiocyanate of 2-amino-5-fluoro-1,3-benzothiazol-6-yl (K) can be prepared from 3-fluoroaniline in the manner described by K, Papke and R, Pohloudek-Fabini in Pharmazie; GE; 22, 5 1967, P229-233, by reaction of potassium thiocyanate and 3-fluoroaniline in the presence of bromine in acetic acid.

The compounds of general formula (L2) can be obtained, for example, by reaction of the carbamates of formula (L1) wherein R6 = phenyl, with NHR1R2 amines of formula (R) (with Rb, R1 and R2 such as defined above), in the presence of an aprotic solvent such as tetrahydrofuran, at a temperature close to 20 ° C.

The ureas (2b ') and (2b ") can be obtained, for example, respectively from the carbamates (2a') and (2a") wherein R6 = phenyl, in the same manner as the ureas (L2) are obtained by reaction of the amines on the carbamates of type (L1).

L3 The compounds of general formula. (L3) can be obtained, for example: by reaction of an acid chloride of formula (P) (X = Cl) on the thiocyanate of 2-amino-1,3-benzothiazol-6-yl (K), in the presence, for example, of a solvent such as pyridine , at a temperature close to 20 ° C. by reaction of an acid anhydride of formula (P) (X = OCOR7) on the thiocyanate of 2-amino-1,3-benzothiazol-6-yl (K), in the presence, for example, of a solvent such as pyridine at a temperature close to 20 ° C. by coupling the 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) with an acid of formula (P) (X = OH) under the conditions described, for example, by D.D. DesMarteau; V. Montanari (Chem Lett, 2000 (9), 1052), in the presence of 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as triethylamine, at a temperature close to 40 ° C.

In the same way that the carboxamides (L3) can be obtained by acylation of the amine (K), the carboxamides (2c ') and (2c ") can be obtained respectively from the amines (2d') and (2d"). ) by coupling with an acid of formula (P) (X = OH) under the conditions, for example, described by N. Xi et al / Bioorg. Med. Chem. Lett. 15 (2005) 5211 -5217, in the presence of 0- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU), in a solvent such as N, Nd i meti If orma m ida, in the presence of a base such as di-isopropyl-ethylamine, at a temperature close to 20 ° C.

Reaction Scheme 2bis Synthetic routes of the glycinamide derivatives (2c ') and (2c ").

.N ^ HO s yr O «H. O NR3R4 (? ') 2d '/ 2d "2c72c" " Ra R7 = CH2-NR3R4 HNR3R4 2e72e " Ra In Reaction Scheme 2bis above the substituent R7 can have the meaning of an aminomethyl group. These glycinamide (2c72c ") can be obtained by coupling the amines (2d ') and (2d") with an acid. glycidic (? ') using the methods described above for the acids (P) (X = OH).

The glycidic acids (? ') Can be prepared from the bromoacetic acid and the amines HNR3R4 under conditions similar to those described by D. T. Witiak et al .; J. Med. Chem. 1985, 28, 1228.

Alternatively, the amines (2d ') and (2d ") can be treated with the chloroacetyl chloride in the presence of a base such as pyridine, triethylamine or N-methylmorpholine, in a solvent such as dichloromethane at a temperature close to 0 °. C up to 20 ° C. The alpha-chloroacetamides (2e72e ") thus formed can reacting with the amines of the HNR3R4 type, such as defined above, in a solvent such as pyridine at a temperature close to 20 ° C, to give the derivatives (2c72c ") such as those defined in Reaction Scheme 2bis above.

The compounds of general formula (M1), (M2) and (M3) can be obtained, for example, by reduction of the compounds of general formula (L1), (L2), (L3) with DL-dithiothreitol, in the presence of sodium dihydrogencarbonate, in a solvent such as ethanol and at a temperature close to 80 ° C.

The compound of general formula (N) can be prepared in situ by reduction of the compound of formula (K), for example with sodium borohydride in a solvent such as N, N-dimethylformamide, in the presence of a base such as triethylamine and at a temperature close to 95 ° C or between 20 ° C and 95 ° C.

The above aryl thiol intermediates may exist in the form of free thiols or in the form of disulfides or a mixture of the two forms which may be involved indifferently in the sequence of the reactions.

More particularly, benzothiazoles of general formula (2d ') and (2d ") can also be prepared from respectively of the carbamates of formula (2a ') and (2a') wherein R6 = t-butyl by reaction, for example, with trifluoroacetic acid in a solvent such as dichloromethane, at a temperature close to 20 ° C.

Reciprocally, the benzothiazoles of the general formula (2a ') and (2a ") can also be prepared from the benzothiazoles of the formula (2d') and (2d") respectively, for example, by reaction with a chlorocarbonate of the formula (O ) (X = Cl), in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature close to 20 ° C.

More particularly, the benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogs of general formula (2a '), (2b'), (2c ') and (2d ') can be prepared, for example: 1) or by coupling a compound of formula (E) with the derivatives (M1), (2) and (M3) and (N) generated in situ by reduction of the derivatives (L1), (L2), (L3) and (K) with sodium borohydride, in a solvent such as N, N-dimethylformamide and in the presence of a base such as triethylamine, at a temperature close to 95 ° C or between 50 ° C and 95 ° C. 2) or by coupling the isolated derivatives (M1), (M2) and (M3) and a compound of formula (E), in the presence of sodium borohydride in a solvent such as N, N- dimethylformamide and in the presence of a base such as triethylamine, at a temperature close to 95 ° C. 3) or by coupling a compound of formula (E) with the derivatives (M1), (M2) and (M3) and (N) generated in situ by reduction of the derivatives (L1), (L2), (L3) and (K) in the presence of DL-dithiothreitol and sodium dihydrogencarbonate, in a solvent such as ethanol and at a temperature close to 80 ° C.

The reducing conditions 1) and 2) can provide products of formula (2a), (2b), (2c) and (2d) where represents a single or double bond while conditions 3) and 4) provide products of formula ( 2a), (2b), (2c) and (2d) where it represents a double bond ..

Reaction Scheme 3: Synthetic routes of the triazolopyridazine derivatives of formula (E).

N-N N-N x ~ a rc-z- ° or J? 0 I Ra = E O-Z-Rc Cl s Ra In Reaction Scheme 3 above, the substituents Ra, Z and Re have the meanings indicated above for the products of formula (G) and (I ").

The compounds of formula (E) can be obtained, for example, as indicated in Reaction Scheme 3 above, from 3,6-dichloro [1, 2,4] triazolo [4,3-b] pyridazine commercial of formula (S).

More particularly, the compounds of formula (E) wherein Ra represents an OZ-Rc radical can be obtained by the treatment of 3,6-dichloro [1, 2,4] triazolo [4,3-b] pyridazine (S ) at a temperature close to 20 ° C in a solvent such as tetrahydrofuran with an alcoholate of formula (U), itself obtained by treatment of the corresponding alcohol with a base such as sodium hydride at a temperature close to 0 ° C. 20 ° C.

Reaction Scheme 4: Synthesis of the benzothiazole derivatives of formula (2e ') and (2e ").

According to Reaction Scheme 4 above, benzothiazoles of general formula (2e ') and (2e ") can be prepared respectively from the compounds of formula (2a') and (2a").

In Reaction Scheme 4 above, substituent OR6 preferably represents O-t-butyl. The R9 substituent represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical (R3 and R4 as defined above).

Ra TV T " The carbamates of the general formula (? ') And (T ") can be obtained respectively by reaction of the carbamates of the general formula (2a') and (2a") with R6 = tBu, preferably, for example, with alkyl halides of the formula (W), in a solvent such as N, N -di-methyl-I-form, in the presence of sodium hydride, at a temperature comprised between 20 and 90 ° C.

The benzothiazoles of the general formula (2e ') and (2e ") can also be prepared from the compounds of the formula (L1), preferably with R6 = tBu, through the compounds of the formula (' ') and (T"). ).

More particularly, the compounds of general formula (2e ') and (2e ") can be obtained respectively by treating the compounds (?') And (T") isolated, for example, with trifluoroacetic acid, in a solvent such as dichloromethane , at a temperature close to 20 ° C, Alternatively, compounds of general formula (2e ") can be obtained directly by reaction of the compounds of formula (L4) and (E), through the compound (T") formed in situ, for example, in the presence of D Ld itiotreitol and of sodium dihydrogencarbonate, in a solvent such as ethanol and at a temperature close to 80 ° C, optionally followed by an in situ treatment with trifluoroacetic acid at 20 ° C if necessary.

The carbamates of the general formula (L4) can be obtained by reacting the carbamates of the general formula (L1), for example, with the alkyl halides of the formula (W), in a solvent such as N -dimethylformamide. gone, in the presence of sodium hydride, at a temperature between 20 and 90 ° C.

Reaction Scheme 5: Synthesis of the benzothiazole derivatives of formula (2e) and (2e ").

Alternatively, according to Reaction Scheme 5 above, benzothiazoles of general formula (2e ") can be prepare from the compounds of formulas (L6) and (E), for example, in the presence of DL-dithiothreitol and sodium dihydrogencarbonate, in a solvent such as ethanol and at a temperature close to 80 ° C.

The benzothiazoles of the general formula (2e ') can be prepared from the compounds of the formula (2e "), according to the methods described above for the preparation of the compounds (G) from the compounds (I").

The compounds of formulas (L6) can be prepared from the 2-bromo-benzothiazole derivative (L5) by treatment with an NH2R9 derivative, for example, in a solvent such as tetrahydrofuran, at a temperature close to 20 ° C.

The R9 substituent represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical (R3 and R4 as defined above).

Compounds of formulas (L5) can be prepared from 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) (commercial compound), for example, by treatment with an alkyl nitrite and cuprous bromide in a solvent such as acetonitrile, at a temperature close to 0-20 ° C, according to the method described by Jagabandhu Das et al. in J. Med. Chem. 2006, 49, 6819-6832.

Reaction Scheme 6: Other synthetic routes of reduced derivatives of formulas (? ').

Ra (> reduction According to Reaction Scheme 6 above, benzothiazoles of general formula () can also be prepared from the compounds of formula (I "), by reduction, for example, with sodium borohydride, in a solvent such as ethanol, at a temperature close to 80 ° C or by reduction with zinc (0) in the presence of acetic acid, at a temperature close to 20 ° C.

Alternatively, the compounds () can also be prepared, starting from the compounds of formula (A ') by coupling with the compounds of type M1, M2, M3 or N, obtained as intermediates by reduction of the compounds L1, L2, L3 or K on site, as described above in Reaction Scheme 2. Compounds of type M1, M2 or M3 can also be isolated and used for coupling with (''). The compounds (? ') Can be obtained from the compounds of formula (E) by reduction, for example, by reduction with zinc (0) in the presence of acetic acid, at a temperature close to 20 ° C.

Alternatively the compounds (G) can also be prepared from other compounds () by transformation of the group W into group W of the same nature defined above for W and according to the type of reactions defined in Reaction Scheme 2: the transformations of 2d72d "in 2a '/ 2a" and in 2c' / 2c ", the transformations of 2a72a" in 2d '/ 2d "and in 2b72b".

In the compounds of general formula (I) as defined above, the sulfur S in sulfoxide SO or sulphone S02 can be oxidized according to the methods known to the person skilled in the art and protecting, if necessary, the groups optionally reagents with appropriate protecting groups.

Among the formula starting products J, K, O, P, P ', Q, Q', R, S, U, V, W some are known and can be obtained either commercially or according to the usual known methods by the person skilled in the art, for example, from commercial products.

The person skilled in the art will understand that, in order to implement the methods according to the invention described above, it may be necessary to introduce protective groups of the amino, carboxyl and alcohol functions in order to avoid secondary reactions.

In the following list, not exhaustive, examples of protection of reactive functions can be cited: the hydroxyl groups can be protected, for example, with alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl, the amino groups can be protected, for example, with acetyl, trityl, benzyl, re-butoxycarbonyl, BOC, benzyloxycarbonyl, phthalimido or other radicals known in peptide chemistry.

The acid functions can be protected, for example, in the form of esters formed with readily cleavable esters, such as the benzylic or re-butyl esters or esters known in peptide chemistry.

A list of different protective groups which can be used in the manuals known by the person skilled in the art will be found and, for example, in patent BF 2 499 995.

It can be seen that it can be subjected, if desired and if necessary, to the intermediates or to the products of formula (I) thus obtained by the procedures indicated above, to obtain other intermediates or other products of formula (I), one or more transformation reactions known to the person skilled in the art such as, for example: a) an acid function esterification reaction, b) an ester function saponification reaction in acid function, c) a free carboxy function reduction reaction or esterified alcohol function, d) a reaction of alkoxy function transformation in hydroxyl function, or also of hydroxyl function in alkoxy function, e) a removal reaction of the protective groups that can carry the reactive protected functions, f) a salification reaction with a mineral or organic acid or with a base to obtain the corresponding salt, g) a splitting reaction of the racemic forms in split products, such products of formula (I) being thus obtained in all possible forms of isomers, racemates, enantiomers and d and isomeric isomers.

Reactions a) to g) can be carried out under the usual conditions known to the person skilled in the art, such as, for example, those indicated below. a) The products described above, if desired, can be subject to esterification reactions on the optional carboxy functions, which can be carried out according to the usual methods known to the person skilled in the art. b) The optional transformations of ester functions in acid function of the products described above can be carried out if desired, under the usual conditions known to the person skilled in the art, mainly by acid or alkaline hydrolysis, for example with soda or potash in medium alcohol, such as, for example, in methanol or also with hydrochloric or sulfuric acid.

The saponification reaction can be carried out according to the usual methods known to the person skilled in the art, such as for example in a solvent, such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of soda or potash. c) The optional free or esterified carboxy functions of the products described above can be reduced, if desired, to alcohol function by methods known to the person skilled in the art: the optional functions of esterified carboxy can be reduced, if desired , to alcohol function by the methods known to the person skilled in the art and mainly with lithium aluminum hydride in a solvent such as, for example, tetrahydrofuran or also dioxane or ethyl ether.

The optional free carboxy functions of the products described above can be reduced, if desired, to alcohol function mainly with boron hydride. d) The optional alkoxy functions, such as mainly methoxy, of the products described above can be converted, if desired, into hydroxyl function under the usual conditions known to the person skilled in the art for example with boron tribromide in a solvent, such such as for example methylene chloride, with hydrobromide or pyridine hydrochloride or also with hydrobromic or hydrochloric acid in water or trifluoroacetic acid at reflux. e) The removal of the protective groups such as those indicated above can be carried out under the usual conditions known to the person skilled in the art mainly by acid hydrolysis carried out with an acid such as hydrochloric, benzenesulfonic or para-toluenesulfonic acid, formic acid or trifluoroacetic or also by catalytic hydrogenation.

The phthalimido group can be removed with hydrazine. f) The products described above, if desired, may be subject to salification reactions, for example, with a mineral or organic acid or with a mineral or organic base, according to the usual methods known to the person skilled in the art: such a salification reaction can be carried out, for example, in the presence of hydrochloric acid, for example, or else tartaric, citric or methanesulfonic acid, in an alcohol such as, for example, ethanol or methanol. g) Optional optically active forms of the products described above can be prepared by splitting the racemates according to the usual methods known to the person skilled in the art.

The products of formula (I) as defined above as well as their addition salts with acids exhibit interesting pharmacological properties due mainly to their kinase inhibitory properties as indicated above.

The products of the present invention are useful primarily for the therapy of tumors.

The products of the invention can thus also increase the therapeutic effects of the currently used anti-tumor agents.

These properties justify their application in therapy and the invention has as its object in particular as medicaments, the products of formula (I) such as those defined above, such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the pharmaceutically acceptable mineral and organic bases of such products of formula (I).

The invention has particularly as its object, as medicaments, the products that respond to the following formulas: 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine; N-. { 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} Cyclopropanecarboxamide; N-. { 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide; 1 - . 1 - . 1 - . 1 - . 1 - . 1 - . 1 - . 1 - [2- (Morpholin-4-yl) ethyl] -3-. { 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea; 1 - (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1, 3-nzole a zo I-2 - i I) - 3- [2 - (mo rf o I in -4- il;) eti I] u re a; 6- { [6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole- 2-yl) -2- (2-methoxyethoxy) acetamide; N2, N2-diethyl-N- (6- { [6- (3-fluorophenoxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfanyl.} -1 , 3-benzothiazol-2-yl) glycinamide; N2-cyclopropyl-N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulphanil.} -1.3- benzothiazol-2-yl) glycinamide; N- [6- (. {6- [3- (morpholin-4-ylmethyl) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl}. Sulfanil) -1, 3-benzothiazole-2-ylcyclopappa ncaca rboxa m id a; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- L) acetamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1, 3-benzothiazole- 2-yl) cyclopropanecarboxamide; 1 - (6- { [6- (4-fluorophen i) [1, 2, 4] triazolo [4, 3-b] pyrid azin-3-yl] its Ifa or I.} - 1, 3 -benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea; - 1 - (6- { [6- (3-fluoro-4-methylphenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} - 1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea; 6- { [6- (tetrahydro-2 H -pyran-4-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; - 6- { [6- (4-fluorophenoxy) [1, 2, 4] triazo lo [4, 3-b] p, rid azi n-3 L] sulfanl} -1,3-benzothiazol-2-amine; 1 - [2- (Morpholin-4-yl) ethyl] -3- (6- { [6- (tetrahydro-2 H -pyran-4-yloxy) [1,2,4] triazole [4 , 3-b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazol-2-yl) urea; 1 - [6- ( {6 - [(1-ethylpperidin-4-yl) oxy] [1,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] -3- [2- (morpholin-4-yl) ethyl] urea; N- (6- { [6- (tetrahydro-2H-pyran-4-yloxy) [1, 2, 4] triazolo [4, 3 b] pyridazin-3-yl] sulfanyl. -1, 3-benzothiazol-2-yl) -cyclopropanecarboxamide; N- (6- { [6- (4-fluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulphanil.} -1.3- benzothiazol-2-yl) c-chloroppanecarboxamide; N- (6- { [6- (3-fluoro-4-methylphenoxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfanyl}. 1,3-benzothiazol-2-yl) cyclopropanecarboxamide; N- [6- ( {6 - [(1-ethyl-pyridin-4-yl) oxy] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl ., sulfanyl) -1,3-benzothiazol-2-yl-cyclopropanecarboxamide; 1 - [2- (Morpholin-4-yl) ethyl] -3- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] p rdazin-3-yl] sulfanyl] -1,3-benzothiazol-2-yl) urea; 1- (6- { [6- (1, 3-benzodolox-5 -loxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfan 1., -1, 3-benzothiazo! -2-yl) -3- [2- (morpholin-4-yl) eti I] rea; 1 - (6- { [6- (3, 4-d-chloro-noxy) [1, 2, 4] t riazo [4, 3-b] pyridazin-3-yl] sulfanyl} -1, 3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) etl] urea; 6- { [6- (3,4-dichlorophenoxy) [1, 2, 4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine; 5 - . 5-6. { [6- (tetrahydrofuran-3-yloxy) [1, 2, 4] triazolo [4,3- b] pyridazin-3-yl] sulfanyl} -1, 3-benzothiazol-2-amine; 1- (6- { [6- (1 H -indole-6-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulphanil. -1, 3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl,) ethyl] urea; N- (6- { [6- (tetrahydrofuran-3-yloxy) [1, 2,4] triazolo [4,3-K) b] pyridazin-3-yl] sulfanil} -1, 3-benzothiazol-2-yl) cyclopropanecarboxamide; N- (6- { [6- (1,3-benzodioxol-5-yloxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfan 1.) -1, 3-benzothiazol-2-yl) c-chloroppanecarboxamide; I5-N- (6- { [6- (3,4-dichlorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1, 3-benzothiazol-2-yl) cyclopropanecarboxamide; N- (6- { [6- (1 H -indole-6-yloxy) [1, 2, 4] t riazolo [4, 3-b] pi ridazi n-3-yl] sulphanil. -1,3-benzothiazol-2-yl) cyclopropanecarboxamide; twenty - . 20-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1,3-benzot Azole-2-yl) cyclobutanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.] -1, 3-benzothiazol-2-yl) -N2, N2-dimethylglycinamide; 2- ethoxy-N- (6- { [6- (3-fluorophenoxy) [1, 2, 4] triazolo [4, 3-25 b] pyridazin-3-yl] sulfanyl. , 3-benzothiazol-2-yl) acetamide; 2- (cyclohexyloxy) -N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-M] sulfanM.} -1, 3-benzothiazol-2-yl) acetamide; 6- { [6- (pyridin-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazole-2-amino; 6- (. {6- [3- (trifluoromethoxy) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl}. Sulfanyl) -1, 3- benzothiazole-2-amino; [3- ( { 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6 il.) oxy) phenyl] carbamate of 2-methyl I p ro pan-2-i I o; N- (6- { [6- (pyridn-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfan 1.) -1,3-benzothiazol-2-yl) c-cyclobutanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1, 3 -benzothiazol-2-yl) -2- (mo rfol ¡? -4-i I) to m arta; N2-cyclohexyl-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1.3- benzothiazol-2-yl) glycinamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] su I fani I. -., 1,3-benzothiazole -2-yl) -N2-methyl-N2- [2- (morpholin-4-y1) eti I] g I icinamide; 2- (4-ethylpiperazin-1-i I) - N - (6 - { [6 - (3-Fluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] Sulfanyl.) -1,3-benzothiazol-2-yl) acetamide; 6- { [6- (3,5-difluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine; 6- { [6- (3-aminophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazole-2-amine; N- (6- { [6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1 .3 -benzothiazol-2-yl) -N ~ 2 ~ - (tetrahydro-2H-pyran-4-yl) glycinamide; N- [6- (. {6- [4- (Trifluoromethyl) phenoxy] [1, 2, 4] tr, azolo [4, 3-b] pyridazin-3-yl}. Sulfanyl) -1 , 3-benzothiazol-2-yl] -cyclopropanecarboxamide; N- [6- (. {6- [3- (trifluoromethoxy) phenoxy] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl.] Sulfanil) - 1,3-benzothiazol-2-yl] -cyclopropanecarboxamide; N- [6- ( {6 - [(2-methylpyridin-3-yl) oxy] [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl.} Sulfanil) -1 , 3-benzothiazol-2-yl] -cyclopropanecarboxamide; - N- (6- { [6- (3,5-difluorophenoxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfanyl. , 3-benzothiazol-2-yl) -cyclopropanecarboxamide; 2 - [(6- {[6- (3-fluorophenoxy)] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl acetate. 1,3-benzothiazol-2-yl) amino] -2-oxoetyl; - N- [6- ( {6 - [(6-methylpyridin-3-yl) oxy] [1, 2, 4] triazolo [4, 3-b] pyridazin-3 L.) Sulfanyl) -1,3-benzothiazol-2-yl] -cyclopropanecarboxamide; N- [6- ( { 6- [4- (morpholin-4-ylmethyl) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl. sulfonyl) -1,3-benzothiazole-2-ylcyclohexpa noca rboxa in id a; (3- { [3- ( { 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl.} Sulfanyl) [1,2,4] triazolo [4,3- b] pyridzin-6-yl] oxy] phenyl) carbamate of 2-methylpropan-2-yl; N- (6- { [6- (pyridin-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl. -1,3-benzothiazol-2-yl) cyclopropanecarboxamide; N-. { 6 - [(6- { 3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-methylmethyl] phenoxy]. [1, 2.4 triazole [4,3-b] pyridzin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} Cyclopropanecarboxamide; N-. { 6 - [(6- { 3- [(detholamine) methyl] phenoxy]. [1,2,4] triazolo [4,3-b] pyridazin-3 il) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide, N- (6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.] -1, 3-benzot azol-2-yl) -N2, Nz-diethylglycinamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulphanil.] -1, 3 -benzothiazol-2-yl) -2-hydroxyacetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pyridaz n-3-yl] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; N- (6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4, 3-b] pyridazin-3-yl] sulfanyl.} -1,3- benzothiazol-2-yl) -2- (4-ethylpiperazin-1-yl) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (3,5-difluorophenoxy) [1,4] triazolo [4,3-b] pyridazine -3-yl] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; N-. { 6 - [(6- { 3- [(diethylamino) methy1] phenoxy]. [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 -benzothiazol-2-yl} acetamide; N-. { 6 - [(6- { 3- [(diethylamino) methyl] phenoxy]. [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-il} -2-methoxyacetamide; 2-methoxy-N-. { 6 - [(6- { 3 - [(1 S, 4 S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy]. [1, 2,4] triazolo [ 4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide; 6- { [6- (oxetan-3-yloxy) [1, 2,4] tnazolo [4,3-b] pindazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; 2- (morpholin-4-yl) -N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil .}. -1,3-benzothiazol-2-yl) acetamide; N- (6- { [6- (3,5-difluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazole- 2-yl) -2- (morpholin-4-yl) acetamide; N2, N2-diethyl-N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl}. 1,3-benzothiazol-2-yl) glycinamide; 2- (4-ethylpiperazin-1-yl) -N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanM.} -1, i3-benzothiazole-2-i I) acetamide; N- (6- { [6- (oxetan-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 -benzothiazol-2-yl) cyclopropanecarboxamide; 2- (4-ethylpiperazin-1-yl) -N- (6- { [6- (oxetan-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3 -yl] sulfanyl.] -1,3-benzothiazol-2-yl) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (oxetan-3-Moxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.] -1,3-benzothiazol-2-yl) acetamide; as well as the addition salts with the mineral and organic acids or with the pharmaceutically acceptable mineral and organic bases of such products of formula (I).

The invention also relates to; pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, as the case may be, a pharmaceutically acceptable carrier.

The invention thus extends to pharmaceutical compositions containing as active ingredient at least one of the medicaments as defined above.

Such pharmaceutical compositions of the present invention can also comprise, according to the case, the active principles of other antimitotic drugs such as mainly those based on taxol, c / s-platinum, intercalating DNA agents and others.

These pharmaceutical compositions can be administered orally, parenterally or locally via topical application on the skin and mucous membranes or by injection intravenously or intramuscularly.

These compositions may be solid or liquid and may be present in all pharmaceutical forms commonly used in human medicine such as, for example, plain tablets or pills, pills, tablets, capsules, drops, granules, injectable preparations, ointments, creams or gels; such compositions are prepared according to the usual methods. The active ingredient can be incorporated into the excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, paraffin derivatives , glycols, various wetting agents, dispersants or emulsifiers, and preservatives.

The usual dosage, variable according to the product used, the subject treated and the condition being treated, can be, for example, 0.05 to 5 g per day in adults or preferably 0.1 to 2 g per day.

The subject of the present invention is also the use of products of formula (I) as defined above or of the pharmaceutically acceptable salts of these products for the preparation of a medicament for the inhibition of the activity of a protein kinase.

The subject of the present invention is also the use of products of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease characterized by the malfunction of the activity of a protein kinase.

Such a medicament may be primarily intended for the treatment or prevention of a disease in a mammal.

The subject of the present invention is also the use defined above wherein the protein kinase is a protein tyrosine kinase.

The subject of the present invention is also the use defined above in which the protein tyrosine kinase is MET or its mutant forms.

The subject of the present invention is also the use defined above in which the protein kinase is in a cell culture.

The subject of the present invention is also the use defined above wherein the protein kinase is in a mammal.

The main subject of the present invention is the use of a product of formula (I) as defined above for the preparation of a medicament for the prevention or treatment of diseases associated with uncontrolled proliferation.

The subject of the present invention is particularly the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders of vessel proliferation blood disorders, fibrotic disorders, disorders of mesangial cell proliferation, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.

The present invention thus has very particularly the object of the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of diseases in oncology and mainly intended for the treatment of cancers.

Among these cancers, the treatment of solid or liquid tumors is of interest in the treatment of cancers resistant to cytotoxic agents The products of the present invention cited can be used mainly for the treatment of primary tumors and / or metastases in particular in gastric cancers, hepatic, renal, ovarian, colon, prostate, lung (NSCLC and SCLC), glioblastomas, thyroid, gallbladder, breast cancers, in melanomas, in lymphoid or myeloid hematopoietic tumors, in sarcomas , in cancers of the brain, larynx, lymphatic system, cancers of bones and pancreas.

The subject of the present invention is also the use of the products of formula (I) as defined above for the preparation of medicaments for the chemotherapy of cancers.

Such drugs intended for the chemotherapy of cancers can be used alone or in association.

The products of the present application can be administered mainly alone or in association with chemotherapy or radiotherapy or also in association, for example, with other therapeutic agents.

Such therapeutic agents may be the antitumor agents commonly used.

As inhibitors of the kinases, there may be mentioned butyrolactone, flavopiridol and 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomoucine.

The present invention also has as its object, as new industrial products, the synthesis intermediates of formulas M1, M2, M3 and N wherein Rb represents a fluorine atom F, such as those defined above and which remember below: wherein the groups CONR1R2, C02R6 and COR7, which constitute W, can take the values of W such as those defined above for the products of formulas () and (I "), when W? H.

The following examples which are of the products of formula (I) illustrate the invention without limiting it in any way.

Experimental part The nomenclature of the compounds of this invention has been made with the computer program ACDLABS version 11.0.

Microwave oven used: Biotage, Initiator EXP-EU, 300W max, 2450MHz The 1 H NMR spectra at 400 MHz and 1 H at 300 MHz were performed on the BRUKER AVANCE DRX-400 or BRUKER AVANCE DPX-300 spectrometer with the chemical shifts (d in ppm) in the solvent dimethylsulfoxide-d6 (DMSO-d6) with reference at 2.5 ppm at the temperature of 303K.

The mass spectra have been made by one of these analyzes: - LC-EM-DAD-ELSD (EM = Waters ZQ) - LC-EM-DAD-ELSD (EM = Platform II Waters Micromass) 5 - UPLC-EM-DAD-ELSD (EM = Quattro Premier XE Waters) - DAD considered wavelength? = 210 - 400 nm - ELSD: Sedere SEDEX 85; misting temperature = 35 ° C; Misting pressure = 3.7 bar Example 1 : IÜ 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine; a) 6 - [(6-Phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine can be prepared as follows : i5 Through a solution of 622 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate in 30 cm 3 of ethanol, a stream of argon is bubbled for 5 minutes. 14 mg of potassium dihydrogen phosphate in 0.3 cm3 of water, 1.39 g of DL-dithiothreitol and 740 mg of 3-chloro-6-phenoxy [1, 2,4] triazolo [4.3-] are then added. b] pyridazine. The reaction mixture is heated at 80 ° C for 24 h, and then concentrated to dryness under reduced pressure. The residue is purified on silica by solid deposit eluting with a gradient of dichloromethane / (dichloromethane 38 / methanol 17 / ammonia 2) 25 95/05 to 80/20. 717 mg of 6 - [(6- phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine in the form of a white powder whose characteristics are the following: NMR SPECTRO 1 H NMR (400 MHz, DEMO-c / 6) d ppm 7.13 (dd, J = 8.3, 2.0 Hz, 1 H) 7.21 (d, J = 8.3 Hz, 1 H) 7.25 - 7.32 (m, 2 H ) 7.32 - 7.39 (m, 2 H) 7.50 (t, J = 7.8 Hz, 2 H) 7.61 (d, J = 1.5 Hz, 1 H) 7.64 (s, 2 H) 8.43 (d, J = 9.8 Hz, 1 HOUR).

SPECTRUM OF MASSES: Waters UPLC-SQD: MH + m / z = 393 +; MH- = 391-. b) 3-Chloro-6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazine can be prepared in the following manner. to a solution of 996 mg of phenol in 20 cm 3 of tetrahydrofuran, at 0 ° C under argon, 254 mg of 60% sodium hydride in oil are added. After 15 min of stirring, 1 g of 3,6-dichloro [1, 2,4] triazolo [4,3-b] pyridazine (commercial) is added. The reaction medium is stirred, allowing it to progressively return at 20 ° C for 23 h. The reaction mixture is poured into water and the mixture obtained is extracted with ethyl acetate. The organic phase is concentrated to dryness under vacuum. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A; 32-63 μ?) Eluting with a gradient of cyclohexa no / ethyl acetate from 95: 5 to 50:50. Thus 1.07 g of 3-chloro-6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazine are obtained in the form of a white powder whose characteristics are the following: SPECTRUM OF MASSES: Waters UPLC-SQD: MH + m / z = 247+.

Example 2: N-. { 6 - [(6-phenoxy] [1 l2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} Cyclopropanecarboxamide; a) The N-. { 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} ciclop ropa nocarboxam ida can be prepared as follows: to a mixture of 250 mg of 6 - [(6-phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine (1a) in 5 cm3 of pyridine at 20 ° C, 0.120 cm3 of cyclopropane-carboxylic acid chloride are added. After 2.5 h, the reaction mixture is concentrated to dryness and the solid residue is chromatographed by solid deposit on Biotage Quad 12/25 (KP-SIL, 60A; 32-63 μ?) Eluting with a gradient from 100% dichloromethane. to dichloromethane / methanol 96/4. 221 mg of N- are thus obtained. { 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} Cyclopropanecarboxamide in the form of a white powder whose characteristics are the following: H NMR NMR SPECTRUM (400 MHz, DEMO-d6) d ppm 0.93 -0.98 (m, 4 H) 1.99 (who, J = 6.2 Hz, 1 H) 7.20 - 7.45 (m, 7 H) 7.60 (d, J = 8.3 Hz, 1 H) 7.86 (d, J = 1.7 Hz, 1 H) 8.46 (d, J = 10.0 Hz, 1 H) 12.67 (broad s, 1 H) SPECTRUM OF MASSES: Waters UPLC-SQD: MH + m / z = 461 +; MH- = 459-.

Example 3: N-. { 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide; The N-. { 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-M) sulfanyl] -1,3-benzothiazol-2-yl} acetamida can be prepared in a manner similar to example 2a but from 302 mg of 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanil] -1, 3-benzothiazol-2-amine (1a) in 10 cm3 of pyridine with 0.220 cm3 of acetyl chloride after 24 h of reaction at 20 ° C. Thus 280 mg of N- are obtained. { 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide in the form of a white powder whose characteristics are the following: 1 H NMR spectrum NMR (400 MHz, DEMO-c / e) d ppm 2.20 (s, 3 H) 7.23 (d, J = 7.6 Hz, 2 H) 7.26 - 7.33 (m, 2 H) 7.34 - 7.44 (m, 3 H) 7.61 (d, J = 8.6 Hz, 1 H) 7.87 (d, J = 1.7 Hz, 1 H) 8.46 (d, J = 9.8 Hz, 1 H) 12.39 (extended s, 1 H).

SPECTRUM OF MASSES: Waters UPLC-SQD: MH + m / z = 435 +; MH- = 433-.

Example 4: 1 - . 1 - [2- (morpholin-4-yl) etl] -3-. { 6 - [(6-phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea; a) 1 - [2- (Morpholin-4-yl) ethyl] -3-. { 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} Urea can be prepared in a manner similar to that of Example 1a but from 533 mg of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazole-2-) il) urea, 10 cm3 of degassed ethanol, 6 mg of potassium dihydrogen phosphate in 0.1 cm3 of water, 606 mg of DL-dithiothreitol and 324 mg of 3-chloro-6-phenoxy [1, 2,4] triazolo [4 , 3-b] pyridazine (1b), after 32 h at 80 ° C. 320 mg of 1 - [2- (morpholin-4-yl) ethyl] -3- are thus obtained. { 6 - [(6-phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea in the form of a white powder whose characteristics are the following: NMR SPECTRO 1 H NMR (400 MHz, DEMO-d6) d ppm 2.36 -2.46 (m, 6 H) 3.24 - 3.29 (m, 2 H) 3.59 (t, J = 4.4 Hz, 4 H) 6.80 (t, J = 5.7 Hz, 1 H) 7.20 - 7.28 (m, 3 H) 7.29 - 7.34 (m, 1 H) 7.36 (d, J = 9.8 Hz, 1 H) 7.44 (t, J = 7.8 Hz, 2 H) 7.49 ( d, J = 8.6 Hz, 1 H) 7.80 (d, J = 1.7 Hz, 1 H) 8.45 (d, J = 9.8 Hz, 1 H) 10.93 (broad s, 1 H).

SPECTRUM OF MASSES: Waters UPLC-SQD: MH + m / z = 549 +; MH- = 547-. b) 1- (2-morpholin-4-ylethyl) -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea can be prepared as follows: in a mixture of 900 mg of thiocyanate 2-. { [(2-morpholin-4-ylethyl) carbamoyl] amino} -1, 3-benzothiazol-6-yl and 40 cm3 of ethanol at 20 ° C, a stream of argon is bubbled in for 5 min. 11 mg of potassium dihydrogen phosphate in 0.4 cm 3 of water and 1.1 g of DL-dithiothreitol are then added. The mixture is heated at 80 ° C for 3.5 h. The reaction mixture is cooled to 20 ° C and then poured into water. The suspension is stirred for 45 min maintaining a slight bubbling of argon. The formed precipitate is drained and washed with 3 x 10 cm3 of water, and then Dry in vacuo at 20 ° C. 633 mg of 1- (2-morpholin-4-ylethyl) -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea are thus obtained in the form of a white solid whose characteristics are the following: SPECTRUM OF MASSES: LC-EM-DAD-ELSD: MH + m / z = 339 +; (M-H) - = 337-. c) Thiocyanate 2-. { [(2-morpholin-4-ethyl) carbamoyl] amino} -1, 3-benzothiazol-6-yl can be prepared as follows: To a solution of 1 g of phenyl ester (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate in 30 cm 3 of tetrahydrofuran, 0.44 cm 3 of 2-morpholin-4-ylethanamine are added at 20 ° C. After 24 h, the reaction mixture is evaporated to dryness and the residue obtained is chromatographed on a Merck 70 g cartridge (solid deposition, elution with a gradient of dichloromethane and then dichloromethane / methanol 90/10). Thus, 902 mg of thiocyanate of 2- is recovered. { [(2-morpholin-4-ylethyl) carbamoyl] amino} -1, 3-benzothiazol-6-yl in the form of a colorless foam whose characteristics are the following: SPECTRUM OF MASSES: UPLC-EM-DAD-ELSD: MH + m / z = 364 +. d) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate has been prepared in the following manner: To a solution of 2.5 g of commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm 3 of tetrahydrofuran, 7.5 g of phenyl chlorocarbonate, 4.05 g of sodium hydrogen carbonate are added at 20 ° C. and 9.4 cm3 of water. The resulting mixture is then stirred at 20 ° C for 20 h and then extracted with 2 x 150 cm 3 of ethyl acetate. The organic phases are combined and then washed with 3 X 50 cm.sup.3 of a saturated aqueous solution of sodium hydrogencarbonate. The organic phase obtained is dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm 3 of water, filtered with suction and dried under vacuum at 20 ° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate are obtained in the form of a light yellow solid whose characteristics are the following: SPECTRUM OF MASSES: LC-EM-DAD-ELSD: MH + m / z = 328 +; (M-H) - = 326-.

Example 5: 1 - . 1 - (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1,3-benzot Azol-2-yl) -3- [2- (morpholin-4-yl) etl] urea; a) 1 - (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-il) -3- [2- (morpholin-4-i I) eti I] u rea can be prepared in a manner similar to example 1a but from 305 mg of 1- [2- (morpholin-4 -yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (4b), 5 cm3 of degassed ethanol, 4 mg of potassium dihydrogen phosphate in 0.1 cm3 of water, 347 mg of DL -dithiothreitol and 202 mg of 3-chloro-6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazine. 253 mg of 1 - (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3i] are thus obtained. -, 3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea in the form of a white powder whose characteristics are the following: SPECTRO NMR 1H NMR (400 MHz, DEMO-d6) d ppm 2.36 -2.45 (m, 6 H) 3.25 - 3.28 (m, 2 H) 3.59 (t, J = 4.3 Hz, 4 H) 6.78 (broad s, 1 H) 7.14 (dd, J = 8.3, 1.7 Hz, 1 H) 7.18 (td, J = 8.5, 2.3 Hz, 1 H) 7.23 - 7.31 (m, 2 H) 7.38 (d, J = 9.8 Hz, 1 H) 7.42 -7.51 (m, 2 H) 7.84 (d, J = 1.7 Hz, 1 H) 8.47 (d, J - 9.8 Hz, 1 H) 10.89 (broad s, 1 H).

SPECTRUM OF MASSES: Waters UPLC-SQD: MH + m / z = 567 +; MH- = 565-. b) 3-Chloro-6- (3-fluorophenoxy) [, 2,4] triazolo [4,3-b] pyridazine can be prepared in a manner similar to Example 1b but from 1.19 g of 3-fluorophenol in 15 cm 3 of tetrahydrofuran, 254 mg of 60% sodium hydride in oil and 1 g of 3,6-dichloro [1, 2, 4] triazolo [4, 3-b] iridazine (commercial). Thus, 837 mg of 3-chloro-6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pyridazine are obtained in the form of a white powder whose characteristics are the following: SPECTRUM OF MASSES: Waters UPLC-SQD: MH + m / z = 265 + Example 6: 6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; The 6-. { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3 i I s i I f a n I. I. 1, 3-benzothiazol-2-amine can be prepared in a manner similar to that of Example 1a but from 529 mg of 3-chloro-6- (3-fluorophenoxy) [1, 2,4] triazolo [4.3 -b] pyridazine (5b), 10 mg of potassium dihydrogen phosphate in 0.1 cm3 of water, 926 mg of DL-dithiothreitol and 414 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial), in 10 cm3 of ethanol. Thus, 587 mg of 6- are obtained. { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine in the form of a white powder whose characteristics are the following: H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 7.11 to 7.25 (m, 4 H); 7.32 (td, J = 2.3 and 10.0 Hz, 1H); 7.37 (d, J = 9.8 Hz, 1H); 7.53 (dt, J = 6.8 and 8.3 Hz, 1 H); 7.63 (broad s, 2 H); 7.65 (d, J = 2.0 Hz, 1 H); 8.45 (d, J = 9.8 Hz, 1 H).

SPECTRUM OF MASSES: Waters UPLC-SQD: [M + H] +: m / z 411; [M-H] -: m / z 409.

Example 7: N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1,3- benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide; a) N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-l) -2- (2-methoxyethoxy) acetamide can be prepared as follows: a mixture of 131 mg of (2-methoxyethoxy) acetic acid (commercial), 0.17 cm3 of diisopropyl-ethylamine and 371 mg of 0- (7-aza be nzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) in 3 cm3 of N, N-dimethylformamide at 20 ° C, is stirred for 1 h. ° C. 200 mg of 6- are added to the reaction medium. { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1, 3-benzothiazol-2-amine (6). After 18 h the brown solution is poured into ice water and the precipitate is filtered. After drying the precipitate, 219 mg of N- (6-. {[6- (3-fluorophenoxy) [1,2,4] triazolo [, 3-bjpi ridazin-3-yl] sulfanyl] are obtained. 1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide in the form of a white powder whose characteristics are the following: H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 3.29 (s partially masked, 3 H); 3.48 to 3.54 (m, 2 H); 3.66 to 3.71 (m, 2 H); 4.29 (s, 2 H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.2 and 8.3 Hz, 1 H); 7.24 (td, J = 2.2 and 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1H); 7.42 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.63 (d, J = 8.6 Hz, 1 H); 7.93 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.20 (broad m, 1 H).

SPECTRUM OF MASSES: Waters ZQ: [M + H] +: m / z 527; [M-H] -: m / z 525.

Example 8: N2, N2-diethyl-N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1, 3-benzothiazol-2-yl) glycinamide; a) N2, N2-diethyl-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl}. -1,3- benzothiazol-2-yl) glycinamide can be prepared as follows: a mixture of 373 mg of sodium?, diethylglycinate (commercial) in 2.4 cm3 of a 2 N solution of hydrogen chloride in ether is stirred for 1 h at 20 ° C. The resulting suspension is evaporated to dryness in vacuo. To the white residue obtained, 4 cm3 of pyridine, 100 mg of 6- are added at 20 ° C. { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6) and 467 mg of N- (3-dimethylaminopropyl) N'-ethylcarbodiimide hydrochloride. After 4.5 h, the brown reaction medium is evaporated to dryness. The residue is taken up in water and then the mixture is extracted with ethyl acetate. The organic phase is evaporated to dryness. The brown oily residue is taken up in ether and the precipitate is drained. In this way, 76 mg of N 2, N 2 -dixtiNN- (6- { [6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3 are obtained. il] sulfanyl.] -1,3-benzothiazol-2-yl) glycinamide in the form of a beige powder whose characteristics are the following: 1 H NMR spectrum (400 MHz, d in ppm, D E M 0-ds): for this lot, all signals are broad with: 1.00 (t, J = 6.9 Hz, 6 H); 2.63 (q, J = 6.9 Hz, 4 H); 3.41 (s, 2 H); 7.06 to 7.20 (m, 2 H); 7.24 (d, J = 9.5 Hz, 1 H); 7.31 (d, J = 8.3 Hz, 1 H); 7.35 to 7.47 (m, 2 H); 7.61 (d, J = 8.3 Hz, 1 H); 7.92 (s, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 9.44 to 14.07 (very broad m, 1 H).

SPECTRUM OF MASSES: Waters UPLC-SQD: [M + H] +: m / z 524; [M-H] -: m / z 522.

Example 9: N 2 -cyclopropyl-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1,3- benzothiazol-2-jl) glycinamide; a) N2-cyclopropyl-N - ('6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl}. 1,3-benzothiazol-2-yl) glycinamide can be prepared as follows: to 137 mg of 2-chloro-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl}. 1,3-benzothiazol-2-yl) acetamide (9b) in 1.5 cm 3 of pyridine at 20 ° C is added 0.13 cm 3 of cyclopropylamine. After 5 h of stirring the reaction medium is evaporated to dryness at 20 ° C. The residue is purified by chromatography on a Merck silica cartridge by solid deposit eluting with a gradient of 100% dichloromethane to 97: 3 dichloromethane / methanol. This gives 52 mg of N2-cyclopropyl-N- (6- { [6- (3-fluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl .) -1,3-benzothiazol-2-yl) glycinamide in the form of a white solid whose characteristics are the following: 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d 6): 0.19 to 0.42 (m, 4 H); 2.18 (m, 1 H); 3.52 (s, 2 H); 7.11 (dd, J = 2.3 and 8.3 Hz. 1 H); 7.16 (ddt, J = 1.0 and 2.3 and 8.3 Hz, 1 H); 7.25 (td, J = 2.3 and 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.45 (dt, J = 6.9 and 8.3 Hz, 1H); 7.45 (broad m, 1 H); 7.60 (d, J = 8.3 Hz, 1 H); 7.91 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H).

SPECTRUM OF MASSES: Waters ZQ: [M + H] +: m / z 508; [M-H] -: m / z 506. 5 b) 2-Chloro-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl}. 1,3-benzothiazol-2-yl) acetamide can be prepared as follows: to 205 mg of 6-. { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanil} -1, 3-benzothiazol-2-amine (6) in 2 cm3 of IU dichloromethane and 0.5 cm3 of pyridine at 0-5 ° C, 0.06 cm3 of chloroacetyl chloride are added dropwise. The resulting white suspension is stirred 30 min at 20 ° C. Add 0.03 cm3 of chloroacetyl chloride again and allow 30 min more stirring. A little methanol is added to the mixture, and then the medium i5 is evaporated to dryness under argon at 20 ° C. The residue is purified by chromatography on Merck silica cartridge by solid deposit eluting with a gradient of 100% dichloromethane to 92: 8 dichloromethane / (dichloromethane: 38 / methanol: 17 / ammonia: 2). 137 mg of 2-chloro-N- (6- {[6- (3-2-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulphanil are thus obtained} -1, 3- benzothiazol-2-yl) acetamide in the form of a white solid whose characteristics are the following: SPECTRUM OF MASSES: Waters ZQ: [M + HJ +: m / z 487; [M-H] -: m / z 485. 25 Example 10: N- [6- ( { 6- [3- (morpholin-4-ylmethyl) phenoxy] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl.] Sulfanil) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide; a) N- [6- (. {6- [3- (Morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide can be prepared in a similar manner to example 2a but from 85 mg of 6- (. {6- [3- (morpholin-4 -ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-i.}. its I fani I) -1,3-benzothiazol-2-amine (10b) in 5 cfn3 of pyridine with 0.124 cm3 of cyclopropanecarbonyl chloride after 3.5 h of reaction at 50 ° C. Thus, 57.3 mg of N- [6- (. {6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-i are obtained. .). Its I fani I) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide in the form of a white powder whose characteristics are the following: 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 0.88 a 1. 00 (m, 4 H); 1.92 to 2.04 (m, 1 H); 2.30 to 2.35 (m, 4 H); 3.39 (s, 2 H); 3.51 to 3.57 (m, 4 H); 7.09 to 7.14 (m, 1 H); 7.20 to 7.25 (m, 2 H); 7.28 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.31 to 7.39 (m, 2 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.83 (d, J = 2.0 Hz, 1 H); 8.47 (d, J = 9.8 Hz, 1H); 12.68 (broad m, 1 H).

SPECTRUM OF MASSES: Waters UPLC-SQD: [M + H] +: m / z 560; [M-H] -: m / z 558 b) 6- (. {6- [3- (Morpholin-4-ylmethyl) phenoxy] [1, 2, 4] triazolo [4,3-b] pyridazin-3-yl.}. sulfanyl) -1 , 3-benzothiazol-2-amine (10b) can be prepared in a manner similar to example 1a but from 133 mg of 3-chloro-6- [3- (morpholin-4-ylmethyl) phenoxy] [1, 2,4] triazolo [4,3-bjpyridazine (10c), 3 mg of potassium dihydrogen phosphate in 0.1 cm3 of water, 176 mg of DL-dithiothreitol and 79 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial) in 5 cm 3 of ethanol. 111 mg of 6- (. {6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl. sulfanyl) -1,3-benzothiazol-2-amine in the form of a colorless oil whose characteristics are the following: SPECTRUM OF MASSES: Waters UPLC-SQD: [M + H] +: m / z 492; [M + 2H] 2 +: m / z 246.5 (base peak): [M-H] -: m / z 490. c) 3-Chloro-6- [3- (morpholin-4-ylmethyl) phenoxy] [1,4] triazolo [4,3-b] pyridazine (10c) is it may be prepared in a manner similar to Example 1b but from 310 mg of 3- (morpholin-4-ylmethyl) phenol (10d) in 5 cm 3 of tetrahydrofuran, 76 mg of 60% sodium hydride in oil and 275 mg of 3, 6-d icloro [1, 2, 4] triazolo [4, 3-b] pi rid azi na (commercial). 138 mg of 3-chloro-6- [3- (morpholin-4-ylmethyl) phenoxy] [1,4] triazolo [4,3-b] pyridazine are thus obtained in the form of a brown oil whose characteristics are the following: SPECTRUM OF MASSES: Waters ZQ: [M + H] +: m / z 346. d) The 3- (morpholin-4-ylmethyl) phenol (10d) can be prepared as follows: to a solution of 188 mg of 3- (bromomethyl) phenol (10e) in 5 cm3 of THF at 20 ° C is added 438 mg of morpholine. After 24 h the white suspension is concentrated to dryness under pressure reduced. The residue is taken up in water and then extracted with dichloromethane. The organic phase is evaporated to dryness to give a colorless oil that crystallizes progressively. Thus 182 mg of 3- (morpholin-4-ylmethyl) phenol are obtained whose characteristics are the following: SPECTRUM OF MASSES: Waters UPLC-SQD: [M + H] +: m / z 194. e) 3- (Bromomethyl) phenol (10e) can be prepared as follows: To a solution of 500 mg of 1- (chloromethyl) -3-methoxybenzene (commercial) in 5 cm 3 of dichloromethane at 20 ° C is added 3.19 cm 3 of a 1 M solution of boron tribromide in dichloromethane. After 19 h the red solution is poured into ice water and then extracted with dichloromethane. The organic phase is evaporated to dryness in vacuo to give a violet oil which crystallizes. This residue is purified by chromatography on an SPOT II apparatus, provided with a SVF D26 silica cartridge of 15-40 μ ?, after solid deposition eluting with a gradient of 100% dichloromethane to 100% methanol. 328 mg of 3- (bromomethyl) phenol are thus obtained in the form of pink crystals whose characteristics are the following: SPECTRUM OF MASSES: Waters ZQ: [M-H] -: m / z 185.

Other examples as well as their intermediates prepared by analogy with the previous examples are described in the table below: Quantity Eg Name from: isolated N- (6- { [6- (3- 212 mg of 6- { [6- (3-fluorophenoxy) [1, 2,4] t fluorophenoxy) [1, 2, riazolo [4,3- 4] triazolo [4,3- b] pyridazine-3- 11 b] p i r i d a z i n - 3 - 3 201 mg i l] s Ifan i I.}. - 1, 3-yl] sulfanil} -1, 3- benzothiazol-2-amine benzothiazole-2- preparation (6) and 41 mg of iill smar a il) acetamide jl eempo: acetyl chloride 205 mg of 6-. { [6- (3- N- (6- { [6- (3-fluorophenoxy)] [1, 2,4] t fluorophenoxy) [1, 2, riazole [4,3- 4] triazolo [4,3- b] pyridazin-3-b] pi ridazi-3-l] sulfanil} -1, '3-12 3 194 mg il] sulfanil} -1, 3- benzothiazol-2-amine benzothiazole-2- (6) and 104 mg of chloride il) ciclopropanocar cyclopropanecarboni b or x a m i d a the 200 mg of 3-chloro- 1- (6- { [6- (4-6- (4- f Iorophenoxy) [1, 2, fluorophenoxy] [1, 2,4] t 4] triazolo [4,3-riazolo [4, 3-b] pyridazin-3-b] pyridazine (13b) and 13 5a 133 mg il] sulfanil} -1, 3- of 358 mg of 1- [2-benzothiazol-2-yl) - (morphin-4-yl) ethyl] -3- (6-sulfanyl-1, 3- 3- [2- (morpholine) -4- benzothiazole-2- i I) eti I] u rea L) urea (4b) Quantity Eg Name after part of: isolated 1 g of 3,6- 3-chloro-6- (4- d i c I o ro [1, 2,4] triazole fluorophenoxy) [1, 2 or [4,3-b] pyridazine 3b 1b 1.11 g , 4] triazolo [4.3- (commercial) and bjpiridazine ói pcnre for 1.46 g of 4- iill sr ama Ij or e em p: fluorophenol 200 mg of 3-chloro-1- (6- { [6- (3- 6- (3-fluoro-4-fluoro-4-methylphenoxy) [1, 2,4] tri methylfox) [1, 2, azolo [4,3- 4] triazolo [4,3-bjpyridazine (14b) and 14 b] pyridazin-3a-5a 202 mg of 340 mg of 1 - [2-it] sulfanil} -1, 3- (morpholin-4-yl) ethyl] -3- benzothiazol-2-yl) - (6-sulfanyl-1, 3- 3- [2- (morpholin-4-benzothiazole-2-yl) ) ethyl] urea il) urea (4b) 1 g of 3,6- 3-chloro-6- (3-dichloro [1, 2,4] triazole fluoro-4- or [4,3-b] pyridazine 4b methylphenoxy) [1, 2, 1 b 1.15 g (commercial) and of 4] triazolo [4.3- 1.64 g of 3-fluoro-b] pyridazine 4-methylphenol m OI s > s heard coi Cü CT CT CT T3 00 CT or NO co i in 3 a > C D i C C? C D cu O n o 13 3: _3 X C o Z3? O) O 13 N 00 Cü O CU O 00 ) O. co 0 CL or 01 z .3 co? a > a 3 O) u o > ? or 3 CD cu N 13 CD "- 3 ? ? _ o O N -i o_ .3 CO s? X? J 00 IV) 00 00 CU N OR (repair similar to the peep example: CT 0) Q. T O) 00 Q. CT Cü Q_ co in 3 or CD T3 to O CD ~ o O O 13 3 CD or ?? O | o N O o 3 N C0 O o; in 3 oo O N .3 CT i o C CD C - or T D O or N > to. azin CD CQ O O or O -% O "O 3 O T3 ~ ^ 1 0) CD c CO (Q or CD | a O) or No Cü "D 0) N 00 or to NOT your or Q.? N - 1 00 -3 00 13 O. D- Q_ Q. > OR to X CD N3 CQ 2 t oazox Q. O r F ,, i4 The Cü CD Cú - l CD N O co co 0 i 3 .. 00 H 00 ro CO O Cü a OJ O Q_ O -3 C0 ^ 1 N o (D O s d¡ r- N 00 CD O Cü C0o 2H Q. -3 CL ° "co 3 CD 1 CD (O CO to O su -you. N > C0 < ñ 3 co CD 7 3 3 a.

CQ CQ CQ its cu Quantity Ej- Name from: isolated 1- [2- (morpholin-4- 200 mg of 3-chloro-yl) ethyl] -3- (6- { [6-6 (tetrahydro-2H- (tetrahydro-2H-pyrn-4) - piran-4- lox) [1, 2,4] triazolo [ I or x i) [1, 2, 4] triazo 4,3-b] pyridazine 17 pre-179a óiparacn 179 mg lo [4,3-ililmar a s (15b) and 372 mg j l em po: e b] pyridazin-3- of 1 - [2- (morpholin-4-yl) sulfanyl] -1, 3-l) ethyl] -3- (6-sulfanyl-benzothiazole-2-1, 3 -benzothiazol-2- l) urea il) urea (4b) 1- [6- ( { 6 - [(1- 200 mg of 3-chloro-ethylpiperidin-4-6 - [(1-ethylpiperidin-4-yl) oxy] [1, 2,4] triaz il) oxy] [1, 2,4] triazolo [ [4,3- 4,3-b] pyridazine 18 b) pyridazin-3a-5a (18b) and 336 mg of 153 mg} sulfanyl) -1, 3-1 - [2- (morpholin-4-benzothiazol-2-yl] -yl) ethyl] -3- (6-sulfanyl-3- [2- (morpholin-4-1, 3- benzothiazol-2-yl) etl] urea il) urea (4b) 1 g of 3,6- 3-chloro-6 - [(1-d-chloro [1, 2,4] triazole ethylpiperidin-4- or [4,3-b] pyridazine 8b i I) or x i] [, 2,4] triaz 1b 758 mg (commercial) and of olo [4.3- 168 g of 1-b] pyridazine ethylpiperidin-4-ol Quantity Ej- Name from: isolated 354 mg of 6-. { [6- N- (6- { [6- (tetrahydro-2H- (tetrahydro-2H-pyran-4-pyran-4-yi-oxy) [1, 2,4] triazolo [ iloxi) [1, 2,4] triazo 4,3-b] pyridazin-3-lo [4,3- 19 3-yl] sulfanil} -1, 3- 198 mg b] pyridazin-3-benzothiazole-2-amine il] sulfanil} -1, 3- й preparation iill smar a (15) and 0.162 cm3 benzothiazole-2- ij eem po: chloride il) ciclopropanoca cyclopropanecarboni rboxamide the 210 mg of 6-. { [6- (4- N- (6- { [6- (4- fluorophenoxy)] [1, 2,4] t fluorophenoxy) [1, 2 riazolo [4,3-, 4] triazolo [4,3- b] pyridazin-3-b] pyridazin-3-yl] sulfanil} -1, 3- 20 3 149 mg ¡l] its Ifa n i I.}. -, 3-benzothiazole-2-amine benzothiazole-2- (16) and 0.094 cm3 of il) cyclopropanoca chloride rboxamide cyclopropanecarboni the 560 mg of 6-. { [6- (3- N- (6- { [6- (3-fluoro-4-fluoro-4-methylphenoxy) [1, 2,4] tr! methylphenoxy) [1, 2, azolo [4,3- 4] triazolo [4,3- b] pyridazin-3-21 b] pyridazin-3 -3] l] its Ifan i I.}. - 1, 3-326 mg il] sulfanil} -1, 3- benzothiazol-2-amine benzothiazole-2- (21b) and 0.241 il) cyclopropanoca cm3 of chloride rboxamide cyclopropanecarboni the Quantity Ej- Name from: isolated 500 mg of 3-chloro-6- (3-fluoro-4-6 { [6- (3-fluoro-4- methylphenoxy) [1, 2,4] tri methylphenoxy) [1, 2, azolo [4,3- 4] triazolo [4,3- b] pyridazine (14b) and 1 b b] pyridazin-3-1a 360 mg of 372 mg of il] sulfanil} -1, 3- io-2-benzothiazole-2-iyl siazole thiocyanate preparation eem po: amino-1, 3- amine j benzothiazol-6-yl (commercial) 235 mg of 6- ( { 6 - [(1- N- [6- (. {6 - [(1-ethylpiperidin-4-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [ il) oxy] [1, 2,4] triaz 4,3-b] pyridazin-3-yolo [4,3-il} sulfanyl) -1, 3- 22 b] pyridazin-3-3 155 mg benzothiazol-2-amine il} sulfanil) -1, 3- (22b) and 0.101 benzothiazole-2 cm3 of chloride il] ciclopropanoca cyclopropanecarboni rboxamide the 500 mg of 3-chloro-6- (. {6 - [(1-6 - (3-fl uo or o-4-ethylpiperidin-4-methylphenoxy) [1, 2, 4] tr il) oxy] [1, 2,4] triaz azolo [4,3-olo [4,3-b] pyridazine (14b) and 2b 1a 286 mg b] pyridazin-3- of 368 mg of il} Sulfanyl) -1, 3-benzothiazol-2-amino-1, 3-benzothiazol-6-yl-3-thiocyanate (commercial) Quantity Eg Name from: isolated rac-1 - [2- 200 mg of rac-3- (morpholin-4-chloro-6-yl) ethyl] -3- (6- { [6- (tetrahydrofuran-3- (tetrahydrofuran-lox) ) [1, 2,4] tr¡azolo [ or 4.3-b] pyridazine 23 iloxi) [1, 2,4] triazo óicn prepares 5a 173 mg (23b) and 394 mg it [4,3- liilr a sma Ye eem p: from 1 - [2- (morpholin-4-b] pyridazin-3-yl) ethyl] -3- (6-sulfanyl-yl] sulfanyl} -1, 3-1, 3-benzothiazole- 2- benzothiazol-2-yl) urea (4b) il) urea rac-3-chloro-6- 1 g of 3,6- (tetrahydrofuran-dichloro [1, 2,4] triazole 3- or [4,3-b] pyridazine 23b 1 b 410 mg iloxy) [1, 2, 4] triazo (commercial) and it [4.3-954 mg of rac-b] pyridazine tetrahydrofuran-3-ol 200 mg of 6- (1,3-1- (6- { [6- (1,3-benzodioxol-5-benzodioxol-5-yloxy) -3-yloxy) [1,2,4] triazo chloro [1, 2,4] triazolo [ it [4,3- 4,3-b] pyridazine 24 b] pyridazin-3- 5a 174 mg (24b) and 327 mg il] sulfanil} -1, 3- of 1 - [2- (morpholin-4-benzothiazol-2-yl) -yl) ethyl] -3- (6-sulfanyl-3- [2- (morpholin-4-1,3-benzothiazole -2- il) ethyl] urea L) urea (4b) Quantity Eg Name from: isolated 6- (1, 3-1 g of 3,6-benzodioxol-5-dichloro [1, 2, 4] triazole iloxy) -3- or [4, 3-b] pyridazine 4b 1b 1.07 g chloro [1, 2,4] triazo (commercial) and 1.8 what [4.3- iorepac parn g of 1,3- iill samr a bjpiridazine jí p eemo: benzod¡oxol-5-ol 200 mg of 3-chloro-1- (6- { [6- (3,4- 6- (3,4-dichlorophenoxy) [1, dichlorophenoxy] [1, 2,4] 2,4] triazolo [4,3-triazolo [4,3- b] pyridazin-3-b] pyridazine (25b) and 25 5a 90 mg il] sulfanil} -1, 3- of 300 mg of 1- [2-benzothiazol-2-yl) - (morpholin-4-yl) ethyl] -3- 3- [2- (morpholin-4- (6-su Ifan il- 1, 3-yl) ethyl] urea benzothiazole-2-l) urea (4b) 1 g of 3,6- 3-chloro-6- (3,4-dichloro [1, 2,4] triazole dichlorophenoxy) [1, or [4,3-b] pyridazine 5b 1b 680 mg 2,4] triazolo [4.3- (commercial) and b] pyridazine 2.12 g of 3,4-dichlorophenol r ro ro 00 in co CT CD s u ro in or 3 o F o o U F o 3 3 or 3 F 3 o O) ? 3 N 3 N or O) CD CD O _ U O 0) Q.? OR CD Q u o. or -3, CD 3 CU u u CO CU CU CU CU 3 N CD ? N N o_ 3 3 O 3 O 3 O 3 CT OR CO CO O ro CO co co what cu CO N N or O prepa ration 0) s i m i la r a l ej em pl o: CD ro CT cu Q. o en cr cu CL CT CL CD en to O on CD CD to o o t o co oo co co F o 1 or 3 3 co 3 or 3 or F or CU O CO or CD CT CT T N 3 CT N 3 N O ^ C < -T > _ cu O Cü O -i cu U (D 1 O or O O O ^ 3 3 C) 3 co or 3 .3 __ 3 CQ O | s 3 CU ro u O o "O N ro cu "ro CL CQ CD co CU CT O CO N Q. CO Q. CL CO or CL or CL O 3 O 1 in 0) Cü CU CU CD Q. F U in N t ? c F N CO CT -P. "- 1 co 1 co or 3 u 3 u 3. .

CO CQ ro 1 U CD 1 N O Q_ CU = 5 CQ CU F o ro 3 O O _ CO O s ro -i CL o ro 3 C0 ro CL 1 F · < ro ro U o cu D o in CO 3 in ^ 1 in cu 3 3 3 a co azoi enCQ 0) its to from to zin [, 43- enox I Quantity Eg Name from: isolated 1 g of 3,6- 3-chloro-6- (1 H- dichloro [1, 2, 4] triazole Indole-6- or [4,3-b] pyridazine 28b iloxy) [1, 2,4] triazo 1 b 1.01 g (commercial) and of it [4.3- 1.73 g of 1H-indol-b] pyridazine oireracn ppa 6-ol illi smar a jim ee po: 228 mg of rac-6- rac-N- (6- { [6- { [6- (tetrahydrofuran- (tetrahydrofuran-3-3-yloxy) [1, 2,4] triazolo [ iloxi) [1, 2,4] triazo 4.3-b] pyridazin-3- lo [4.3- 29 3 iljsulfa ni I.}. - 1, 3- 164 mg b] pyridazin-3-benzothiazole-2-amine il] sulfanil} -1, 3- (27) and 0.108 cm3 benzothiazole-2- chloride i l) ccloclopa noca cyclopropanecarboni rboxamide the 300 mg of 6-. { [6- N- (6- { [6- (1, 3- (1, 3-benzodioxol-5-benzodioxol-5- i loxi) [1, 2,4] triazolo [ iloxi) [1, 2,4] triazo 4,3-b] pyridazin-3-lo [4,3-yl] sulfanil} -1, 3- Quantity Ej- Name from: isolated 360 mg of 6- (1, 3-6 { [6- (1, 3-benzodioxol-5-benzodioxol-5-loxi) -3-yloxy) [1, 2,4] triazo-chloro [ 1, 2, 4] triazolo [ [4,3- 4,3-b] pyridazine 0b 1 to 679 mg b] pyridazin-3- (24b) and 357 mg of i l] s or Ifan i I.}. - 1, 3-io-benzothiazole-2-yl siamino-1-3-amine-2-benzothiazole-2-benzothiazole (commercial) 115 mg of 6-. { [6- (3,4- N- (6- { [6- (3,4-dichlorophenoxy) [1, 2,4] dichlorophenoxy) [1, triazolo [4,3- 2,4] triazolo [4,3- b] pyridazin-3-b] pyridazin-3-yl 3-yl] sulfanyl} -1, 3-75 mg il] sulfanil} -1, 3- benzothiazol-2-amine Benzothiazole-2- (26) and 0.046 cm3 il) ciclopropanoca of chloride rboxamide cyclopropanecarboni the 345 mg of 6-. { [6- N- (6- { [6- (1 H- (1 H-indol-6-nol-6-loxi) [1, 2,4] triazolo [ ilox¡) [1, 2,4] triazo 4,3-b] pyridazin-3-lo [4,3-yl] sulfanil} -1, 3- 32 b] pyridazin-3-3 396 mg benzothiazole-2-amine i I s s Ifa n i I.}. - 1, 3- (32b) and 0.147 benzothiazole-2 cm3 of chloride il) ciclopropanoca cyclopropanecarboni rboxamide the OJ C0 ro m CO cr cu cr cr -| c crr =; cr - z2 CJ O "cr ~ CD CD OR (D or CD> 3 * in .3 X or 3 3 F 3 c - · -| F N u or N C 3 N - ^ s - CO ro , N O - Cü 3 O. CO CO O CO z Cü N or Q Q.

N 0) or cu 3 O O) Q. cr 3 CU 3 C0 in CJ 3 c N O N N 0) N 3 o - N ro O O # - t o 3 00 O D "J> -| cr O J X CJ O 3 O o i 3 i co J - - 3 0) by dr CO M co o CO CO CO C0 or of CO NO N G? OR eoaan z l2 my n-- daz • repair or CO da cu cu similar to the example: az Q. Q. O rr cr ~ · cr - > - NO or Q. cr cr co Q. co in CD) [¡c O F 3 F 1 O 3 (? 3 or F O) CD CJ c O 00 CO or c or O 3 N or O _. or c: O CD c o o N or N O N * o O o O o cr O Q. O I Q. CU or * 3 or 3 3 CD CQ Q. cu or CD 3 20 (0 CQ "O 3 CQ Cü 3 3 (Q J 3 CJ CD Ü N 3 Cü J 0) CD ü N Q.

£ Z CO - 3"co O Q. 3 N 3 co O Q. 3 Q. Q. OR Q. 00 X F O O O i X F O J F U F OR 3 OR CO or CO? | N in CO '- > · O CO CJ ro in CO co CO CO CO O. in J 3 CU (D Q.

G? z CQ s5 I co N O F O O a 3 n O CD z C 3 CJ NJ 3 O O 3 (Q CO CU O cu ro CD « DOC ? ) [i 3 3 a.

CQ (Q (Q cu u a tria dol c :2" or o Amount Eg Name from: isolated 200 mg of 6-. { [6- (3- 2-ethoxy-N- (6- { [6- fluorophenoxy) [1, 2,4] t (3- riazolo [4,3-fluorophenoxy] [1, 2 b] pyridazin-3-, 4] triazolo [4.3-35 7-yl] sulfanyl} -1, 3-223 mg b] pyridazin-3-benzothiazole-2-amine il] sulfanil} -1, 3- ea prpar (6) and 101 mg of benzothiazol-2-iil smar ethoxyacetic acid and il) acetamide jl eem p of 371 mg of HATU 200 mg of 6-. { [6- (3-fluorophenoxy) [1, 2,4] t 2- (cyclohexyloxy) -riazolo [4,3- N- (6- { [6- (3-b] pyridazin-3-fluorophenoxy) [1, 2 il] sulfanil} -1, 3-, 4] triazolo [4.3-36 7 benzothiazol-2-amine 130 mg b] pyridazin-3- (6) and 154 mg of il] sulfanil} -1, 3- acid benzothiazole-2- (cyclohexyloxy) acetic il) acetamide o and 371 mg of HEY YOU 460 mg of 3-chloro-6-. { [6- (pyridin-3-6- (pyridin-3-yloxy) [1, 2,4] triazo-yloxy) [1, 2,4] triazolo [ [4,3- 4,3-b] pyridazine 37 b] pyridazin-3-1a (37b) and 347 mg 400 mg il] sulfanil} -1, 3- 2-benzothiazol-2-amino-1, 3-amine benzothiazol-6-yl thiocyanate (commercial) Quantity Eg Name from: isolated 1 g of 3,6- 3-chloro-6-dichloro [1, 2,4] triazole (pyridin-3- or [4,3-b] pyridazine 7b i loxi) [1, 2,4] triazo 1b 408 mg (commercial) and of what [4.3-io pparacnre 1.01 g of pyridine-3-bjpiridazine iill smar a ol jé eem po: 200 mg of 3-chloro-6- (. {6- [3- 6- [3- (trifluoromethoxy) f (trifluoromethoxy) pheno enoxi] [1, 2,4] triaz xi] [1, 2,4] triazolo [4,3] olo [4,3- -b] pyridazine (38b) and 38 1a 111 mg b] pyridazin-3- of 126 mg of il} Sulfanyl) -1, 3-benzothiazol-2-amino-1, 3-benzothiazol-6-yl-3-thiocyanate (commercial) 500 mg of 3,6- 3-chloro-6- [3- dichloro [1, 2,4] triazole (trifluoromethoxy) f or [4,3-b] pyridazine 8b enoxi] [1, 2, 4] triaz 1b (commercial) and 216 mg olo [4.3-950 mg of 3-b] pyridazine (trifluoromethoxy) pheno I or co m O cr cr cr cr 3 3 T o o 3 3 cr co or CD CD cu x O 3"? CD co X O 3 -JL, r-t- O -C¡ CÜ n O co O N o X 1 ? a b CO or co or X - i N cr CO CO 3 O O 1 CL e d colr Cú Q. O CD z Q. CT 3 Cü - s D cu - 3 o N or C 3 N Ni Cú c N rv) 3 from - CL your O 3 u CD CO CO s -i 3 3 eaanm n - CO CO CO 1 i Cú 3 CD O IV) co 1 IV) IV) 1 IV) N or 3 cr co N 3 M? N IV) ü O O 1 O 1 O ] tria ireparacion co or txri cu similar to the pio example: idiri o O. --| CT 3_ co O Q. cr rv) "O 3 IV) Or in o CD co co CD -4 CO CO - t or -fc- o_ co CQ in Q. 3 CL o o or N cr. - CL CD O or O N 3 Q. o CD o O "CU > < or r- i t -i O CD c CO 3 3 cr O CQ 3 1 3 CD 3 CD Cü Cú '3 - i rv) O CQ of CQ - T3 Cú co IV) CQ 3 CU N __ 3) NO IV) s 3 Q.

Or to back O - O CD O c o Cú Q. c O Cú CL ^ t N CL 1 co CD O CL CD t CÜ > < O N CD o o IV) co Cú co CDd ri -i -i CD 3 or 3 a. cr i Cu co N a O cr o O o 1 CO N CO 1 O "O CU O N co o 3 3 O £ D co O 3 - 3 or CD 3 O 0 O) Cú] otarir ° "c Q. 3 o o 0 CD in IV) U o CU co CO W 3 IV) CO CU 3 poan- "3 CQ CQ CQ your cu o. or in-] c elarni at n azri e d [, o4 nzo m co 's cr cr O " CD c < J > CD CD 3 CQ c / > T3 Cú Cfl or z ° s5 c 3 c - CD o cu o o o O CO Q. CU CQ N .3 CD on CD with U N O cu O -3 Cú CÚ 13 co o ú - 3 Z N O 3 or O CD ^ o ~ co cr .3 - i X O X .3 O X CL C i ? ú i ZO co co. 73 co co Q) coconut coconut to lz sugar preparation U3 CO similar to ox example: CT cr - h cr CT cr CD c -tiCD CD CU M 13 3 3 T3 in cu 13 in or o CU CJ «O) ú CD or > or N C N O or CD -h -| or CD Cu OR - > |) Or ^ 3 O CU O? 3 or ¾ 3 What n? i i CD CJ5 CQ £ U - .3 U 3 3 Cu 3 or .3? or 3 O- o o co co 13 or 3 CD CL O i o. o_ 13 i Cü cu CQ CU n fi i - he has Or co 1 'co Q Q. daz o O o CD 13 CT s CT azole CL CD · < CU o u oí V) 3 O 3 ? CQ CQ CQ 0) 0) Q. c or _ Quantity Ej Name from: isolated 200 mg of.6-. { [6- (3-fluorophenoxy) [1, 2,4] t 2- (4- riazolo [4, 3-etllperazin-1-b] pyridazin-3-yl) -N- (6- { [6- (3-yl] its Ifan i.] - 1, 3-fluorophenoxy) [1, 2 benzothiazole-2-amine 44, 4] triazolo [4.3- preparai 7 154 mg (6) and 247 mg of the b] p i r i d a z i n - 3 - iilmar s jlemp and hydrobromide il] sulfanil} -1, 3- (4-benzothiazole-2-ethylpiperazin-1-yl) acetamide acid il) acetic and 371 HATU mg 350 mg of 3-chloro-6- (3,5-6 { [6- (3,5-d-fluorophenoxy) [1, 2,4 difluorophenoxy) [1, ] triazolo [4,3- 2,4] triazolo [4,3-bjpyridazine (45b) and 45 b] pyridazine-3-1a 85 mg of 257 mg of L] sulfanl} -1, 3- 2-benzothiazole-2-amino-1, 3-amine thiocyanate benzothiazol-6-yl (commercial) 1 g of 3,6- 3-chloro-6- (3,5-dichloro [1, 2,4] triazole difluorophenoxy) [1, or [4,3-b] pyridazine 5b 1 b 363 mg 2,4] triazolo [4.3- (commercial) and of b] pyridazine 1.38 g of 3,5-difluorophenol m ? 3 7? cr 0) CD CQ 0)) 3 3 - ^ ?? 13 ? ? - 2. s > | 3? "3 CD ? ? co _t OR Q. co 0) O O z 3 ? 0) Q. ? or C0 CU 3 ? or CD C .3 C0 .3 ? O 3 3 ? O? ? .3 O s X O o 00? co ?? ?? ?? 0) similar to the pío example: -: c z. =: o O CD 3 O CT O CL iso o en C0 3 O in CO O in co C0 13 N OJ or O .3 3 Q. o o ? O N «CD O cr 3 zr CD of N £ 0 co o OR 3 O CL O C0 or 3 O OR NJ < 0 3 co O CQ 3 CQ or CO -3 s > N O- o o o o C0 O or 3 N 3? N Q. O OJ or CO o oo |3 CT 3 X OJ dcesi n O co CL or co C0 J CD or N 3 OJ -3 i d ¡n CL o 00 «O cr C0. * to O O N < D CD OJ s co OI o l 3 O co O Cf ? 3 O. Q. CU C > > CD M 13 o fD Cfl CQ, OJ or 00 OJ 0) w 3 3 ? CQ 3 O.

CQ or 0) CL Quantity Ej- Name from: isolated 85 mg of 6- (. {6- [4- N- [6- (. {6- [4- (trifluoromethyl) phenoxy] (tnfluoromethyl) faith ] [1, 2,4] triazolo [4,3-noxy] [1, 2, 4] triazo b] pyridazin-3-lo [4,3-il} sulfanyl) -1, 3-48 b] p r i d a z i n - 3 - 3 58 mg pre-benzothiazole-2-amine ion il} sulfanil) -1, 3- iill a smar jío: eem p (48b) and 0.034 benzothiazole-2 cm3 of chloride il] ciclopropanoca cyclopropanecarboni rboxamide the 350 mg of 3-chloro-6- (. {6- [4- 6- [4- (trifluoromethyl) fe (trifluoromethyl) phenoxy] noxi] [1, 2, 4] triazo] [1, 2,4] triazolo [4,3- lo [4,3- b] pyridazine (45b) and 8b 1a 109 mg b] pyridazin-3- of 231 mg of il} Sulfanyl) -1, 3-benzothiazol-2-amino-1, 3-benzothiazol-6-yl-3-thiocyanate (commercial) 1 g of 3,6- 3-chloro-6- [4- dichloro [1, 2, 4] triazole (trifluoromethyl) fe or [4,3-b] pyridazine 8c noxi] [1, 2,4] trtazo 1b 356 mg (commercial) and of it [4.3- 1.29 g of 4-b] pyridazine (trifluoromethyl) phenol Quantity Eg Name, part of: isolated 144 mg of 6- ( { 6- [3- N- [6- ( { 6- [3- (trifluoromethoxy) pheno) (trifluoromethoxy) f xi] [1, 2,4] triazolo [4.3 enoxi] [1, 2,4] triaz -b] pyridazin-3- olo [4,3-il} sulfanil) -1, 3-49 b] p i r a d i i n - 3 - 3 61 mg benzothiazol-2-amine il} sulfanil) -1, 3- oi prearacnp iill a smar (38) and of 0.055 cm3 benzothiazole-2- jlm ee p o: of chloride L] ciclopropa noca cyclopropanecarboni rboxamide the 84 mg of 6- ( {6 - [(2- N- [6- (. {6 - [(2-methylpyridin-3-methylpyridin-3-yl) oxy] [1, 2,4] triazolo [ i I) or x i] [1, 2,4] triaz 4,3-b] pyridazin-3-yolo [4,3-il} sulfanyl) -1, 3- 50 b] pyridazin-3-3 71 mg benzothiazole-2-amine il} sulfanil) - 1, 3- (50b) and 0.040 benzothiazole-2 cm3 of chloride il] ciclopropanoca cyclopropanecarboni rboxamide the 550 mg of 3-chloro-6- (. {6 - [(2-6 - [(2-methylpyridin-3-methylpyridin-3-yl) oxy] [1, 2,4] triazolo [ il) oxy] [1, 2,4] triaz 4.3-b] pyridazine olo [4.3- 0b 1a (50c) and 436 mg 84 mg b] pyridazin-3-thiocyanate of 2-yl} sulfanyl) -1, 3-amino-1, 3-benzothiazol-2-benzothiazol-6-yl amine (commercial) in < J1 n o m r o or 1 cr u cr O X - 3 co F or cr F or U in F or O 3 o o F o_ F 3 x O N N C X i o O £ 0 CO U cu O o -i .3 cu CL N O cu Q. i-; -OR o O F O co U u 3 C u u o CU N O U 3 3 N N N N CL CL N O F ro Q. CD M 3 O or 3 3 cr O F CU o 3 CO X? O i or U 3 co ro CU CO O in i ro co ro CD co co 3 ro x co O u ro in o a preparation or similar to the example: o Q. cr n cr or - or Q. or CD F F | P- F in 3 -1 · 3 co CU cn F O O c N o ro 3 co c or N or CU N N 3 co 3 CO O CU O 3 O O co 3 F 03 o cu CL CQ o 3 u CL o_ · . u cr O Q.

U 3 O CL or '1 | a CD 3 u or O Q o or F CU N X U N - a F N F CQ cu 3 CO u O P- (0 3 ro o o_ O 3 - 3 i c O in CL CD or O Q.

O i O C0 O F ro X co O O O o b ro CO Q. U cu CO O) co cu O · < CD ro 3 c O 3 cr u ONE CO 3 - . 3 -P > o o ro co ro 3 co 3 Q. 3 3 in ro CL o "in CU F CU F - ^ 1 Or O in CO su CO ro W -P- 3 3 3? CQ CQ o. to 0)? to. din from p airizi Quantity Ej- Name from: isolated 69 mg of 6- (. {6 - [(6- N- [6- (. {6 - [(6-methylpyridin-3-methylpyridin-3-yl)]] [1,2,4] triazolo [ il) oxy] [1, 2,4] triaz 4,3-b] pyridazyl-3-olo [4,3-il} sulfanil) -1, 3- 53 b] pyridazin-3- io paacnrepr 3 45 mg Liilar to sm benzothiazol-2-amine il} sulfanil) -1, 3- ljmpo: ee (53b) and 0.031 benzothiazole-2 cm3 of chloride il] ciclopropanoca cyclopropanecarboni rboxamide the 255 mg of 3-chloro-6- (. {6 - [(6-6 - [(6-methylpyridin-3-methylpyridin-3-yl) oxy] [1, 2,4] triazolo [ il) oxy] [1, 2,4] triaz 4.3-b] pyridazine olo [4.3- 3b 1 a (53c) and 202 mg 69 mg b] pyridazin-3-thiocyanate of 2-yl} Sulfanyl) -1,3-amino-1, 3-benzothiazol-2-benzothiazol-6-yl amine (commercial) 1 g of 3,6- 3-chloro-6 - [(6- dichloro [1, 2, 4] triazole methylpyridin-3- or [4,3-b] pyridazine 3c il) oxy] [1, 2,4] triaz 1 b 260 mg (commercial) and of olo [4.3- 1.16 g of 6- b] pyridazine methylpyridin-3-ol or OI OI OI -P- m G) cr ) () eteo ilmilfnl54d (] pmorfol b i d a z n n ain4 r-- g] [,, oo3207 m of 24 triazl44-- (yg)] [), coeca58metifenomril of 1 m illxi1 [(] p, o3oo4birdazamrflin4iin --- [[] ,, c 3coo6 d¡loro12taolr44r¡zl ---- g, 89 of 36 1 m- preparation () comercail s ta similar to benzotazo6o aminailyl-- example: , beotao amio3nzizl2n1 ---- tociianato of 2-] pg bda3 of 93 deir¡zin m-- g 91 m ] p y] [(), tao bdaa524rizlo43irizin4c- [)] [,, ethe thiazoo 3-ylmilfnxi1rl4- ()] [], emoron ilmtilfenox2fli4i14--. { [([(666oo44mrflin4 ------- g 155 m 3cloro-- or l ppboad cco rxmiailroanocarboni ] pp ilccooaoca cm de couoilrnlrr de3 () and benzothiazol254b of 00.24-- beotaonzizl2amnai i lc I f a n i U 1 ---} ] p) g, bdsu 8yriazin3 illfanil136 m ----]] p [,, 2taoo bd4rizl43iriazin3 ---)] [[,, imeteo taoo3lilfnxi1rizl4- ()] [] ,, morfoi ieteoln4lmilfnxi214-- [( { [ (6 N6oo4mrflin4 ------ g ( { [87 of 6 m64 --- asadail p Nobemr aarti de r: Ci OI m? n the boada rxmi pp ciclooaocrnarboni ppccooaoca ililrn of coulrro bezotazo2nil-- and () of 000 c37.7m3 ] } , 3 isuanil1llf-- ezotazoaa bnil2min--] gp 143 brdaz3 miiin--} ], i i i i n i i 13-- [, o3 l4-] p, 3bdaz34iriin ---) [], aoo124rix lxi ) [] [,, oo í I x i 124triazol preparation 3- similar to (pyridin3-- example: . { ([(p N66iridin ---- g { [50 of 66 1 m-- or l ppppetoa2io cicloroaocabon milrnlnri- mato of 2 c de couo demlrr-3 ] } y) () oeaba 2o39 of 003 ilxifn ilcril.1-] ppp or bdaz6 of 2metioairiinlrn ----} [)], or 3oec triazol4 ilxifnilarbamat- g 59 m } ) [], 6-ilsulfanyl124- [] p, benzothiazole6 zolo43biridazin ----)])] [], ,, oao3suatanilmin1 illfnil124ri-- [(ppccoocab beotao6ilrilrnzizl-- . { ([( {, 332 amino13 ----- g [( { [(8 de3324 m --- ooa mrflin g of 364 m ilmeteoilfnl () yg 5dcooe4 10dlrmtilfenlo 20 mi7 (oo 4mrflin4 ---. de4- g85 of aceao 1 mtt asadail po Nmbre aarti r de: Quantity n in m cr coi co cr in ^ CD u in ^ cr z in 3 CD 3 3 N C / > CD? what o cr? 3 co 3 N O) CD or N C cu my O CU Q. in CU Q. in cu u CO 3 CU U cu 3 N N CD N N CD N O or O 3 o o O - cu o 3 O O co cr X M O u X O CO X 3 M CO ] pdaair ¡n cu O - ^ O - - u '- 1 olo ZB | • repair he met nox 0) similar to c az icil example: c 05 cr -. on CD __ O O cr - cr or and iil2 - s u Or CD in [pcc N or tn O 3 N Or, u CO? c / > 3 co u 3 n CU 3 N 3 cr O s N c N CD 1 cr CO CU) S 4- or 3 O U O 3 Q. o cu Q.

CO CQ or - CU OR CO u - > · CU O N. { 3 xa c / - CD > ^ < U 3 N '1 CD o_ "O u cu N co 1| CD cu N O 3 or Q. r O F * or g of m 3 or 1- 1 CO O J o. NJ CO X o CD N > co O x CO Q. 3 ^ in O CD CQ or Q. CD n c t CO N > or Or cu CD ad < my O O cr o O 3 on CD ) or Q. or do 3po lr Q. o 3 O CD CD in u 3 C bae oti; or in co 0) saw ? in co " Q Q a a CU cu. ab icci ) Sa 4 x G? 6 - Norr G c 1 * n ai in -vi m 8 a o cr zr? O O 00 3"u CO cr CD N X 1 CD N i 3 CD o o 13 CO N? cu CO O X O CD or N c CD 3 # -t- cu 3 CD t cr 1 CT oo in o- o O Q. O O ai 3 or 1 00 O z or 3 co X o CU a CD or N O CL in 3? O N 00 3 o 00 3 O ? O oo i 3 O o s X oo cu 00 O O CD -3 or M X O 3 O 00 or CD cu preparation Or similar to a ethyl example pio: o o - o cr CD O U n 3 d C mO o 3 e CD N CO in o o CL 00 C N o in _ 03 co CL ge 00 O U or C CU o or s 3 00 N 1 X O "< D O O CL CT 3 00 or -c¡ O CT 1 CL cu o 3 00 or o CD CT or or CD your CD cu 3 3 __ 00 3 o o_ 3 o 1 CQ |o T3 3 - N 3 CU or o_ o o CL CD? r ca? or. or CL 3 - . 3 - 3 o_ or CD O O i CD O 73 or CD X or CL CL or M N__ in 3 X £ U 1 ? CL CL F C oo | a 3 3 c CD F O O N - i O or CU 1 SO CD in 3 CD D CD or 0 3 Or in cu o 3 OO N CO 1 1 3"U N 00 Or, - « CL 3 CD F oo CL 3 00 00 CL O en CD 00 U O 1? 3 F o oo o cu o V) 00 -. 00 -h 3 ea a (CQ how in OI m 00 00 or s da deietlamini - "w ^ g) and (d30ee 7 m11 o. ' S g8 18 m0d or · 1 P -89 ·) (eebomomtfnolril or 3 D g5 of 3 37 m- O 3) (d eol58n CD eana etltanmii } )] oxbencN iliil-- preparation g 3 m cu s similar to] p6 brdaziiin-- example: g y () 96a6 13 mcomerci 1l [, lo43- [] p, o43bidaziarin-] [,, ao chloro12triz4 ] [,, co2tiaol dilro14rz . { [(33 N --- g, 8 of 36 m 14- () comcaeril zaz6io benotioll amina--, eaz2 ano3 bnzotiolmi1 ----)], or from ilsua3 tociaat 2lfnil1in --- g and] p d from birdaz3e 120 miin-- g5 1 m7 () [, azo3 eteaama58c ilo4iltnin-} ] [] } ]) ,, ecfeo2oxibnilN ilnxi4tr il--)] p [(, 3bridazn6detamomet 4iiiilin ---] [[( { [,, oo2triazolo 663 clr14 --- g { [(0 d336e N 1 m --- to aisadl part deombe air: Nr a Cantidd Quantity Ej- Name from: isolated 200 mg of 6-. { [6- N- (6- { [6- (3,5- (3,5-difluorophenoxy) [1, difluorophenoxy] [1, 2,4 2,4] triazolo [4,3-] triazolo [4,3- b] pyridazin-3-b] pyridazin-3- 59 8 127 mg il] sulfanil} -1, 3 -profile] sulfanil} -1, 3- benzothiazol-2-yl) - liilmar to s benzothiazol-2-amine lj eempo: N2, N2- (45) and 715 mg of diethylglycinamide the sodium salt of the ?,? - diethylglycine 510 mg of acetate of 2 - [(6- { [6- (3-fluorophenoxy)] [1, 2,4] t riazolo [4, 3-b] pyridazin-3-N- (6- { [6- (3-yl) sulfanyl} -1, 3-fluorophenoxy) [1, 2 benzothiazol-2-, 4] triazolo [4,3-yl) amino] -2-oxoethyl b) pyridazin-3-60 (52) and 42 mg of 262 mg il] sulfanil} -1, 3- lithium hydrate in benzothiazol-2-yl) - conditions 2- similar to hydroxyacetamide described by T. G.

Murali Dhar and collaborators in J.

Med. Chem. 2002, 45, 2127-2130 s > s? m? () ccomerial ); iacétcoli ) ilmi pp eteailirzin1- - pp eteaz1ilirin- - (coid4- (24-- and g () of 9 of 451.1 bezotazo2ilnil --- bezotiazo2aanlmin-- g]} , 3 144 msuanil1 illf--} ], ilsu Ifani l13--] p3 biridazin--] p bda3irizin-- preparation 8] [,, 3 2tiazoo44rl- or similar to ] [taoo 3rizl4- example: ) [, eo difluorofnxi1 ) [,, duooeno124iflrfxi ( { [(, 6635 N ---- (, 35- g { [200 of 66 m-- dimethylformamide , etaa e triilminn N N- () commercial with ilactmide ppeaairzin benzotazol2i-- pp ccooilril-]} , su3 illfanil1-- docouo de hirlrr 1-] p b3¡ridazin-- g 200 m ] [,, 4triazolo43-) () ygc ilaetamida9b 242 m ) [, uooeo flrfnxi12 boaoenztizl2--. { [(63--.].], Lsulfanil31--) (zin1ilN6- ----] p bda3irizin-- pppp cicoroeralili [, razolo3i4- (24--) [] ,, uooeot flrfnx¡124 . { ([(N663 ---- g 243 of 2coo mlr-- asladai p Nobe aarti demrr: Candad Quantity Eg Name after part of: isolated 142 mg of 6-. { [6- (3,5-2- (4-difluorophenoxy) [1, 2.4 cyclopropylpipe ] triazolo [4,3- zin-1 -yl) -N- (6- b] pyridazin-3 { [6- (3,5-oiaacn prepr illi smar to il] sulfanil} -1, 3- difluorophenoxy) [1, l eempo: 63 8 benzothiazol-2-amine 65 mg 2,4] triazolo [4.3- (45) and 683 mg of b] pyridazin-3- the potassium salt of il] sulfanil} -1, 3- acid (4-benzothiazole-2-cyclopropylpiperazine- I) a c e t a m a d 1-yl) acetic (63b) (or commercial) 2. 1 g of acid bromoacetic and 3 g of hydrochloride 4- potassium salt cyclopropylpiperazine of acid (4- a in conditions 3b § 2.66 g cyclopropylpipe similar to those zin-1-yl) acetic described by D. T.

Witiak and collaborators; J.

Med. Chem. 1985,28, 1228 s > s > m I heard meto icet cloru cr 03 ro 3 cr l cr * cr 03 03 ? T3 - N 3 g (5 deb7 m 3 03 3 or in O O "F -% 3 N CD 03 «- t- O o - h or O O O 0) be azoz n o 03 ÓT e- Cú X 03 3 03 03 Oí 03 o 3 CU 3 N i N 3 N s i 11 co? O 3) u co 1 co O 3 cr o o i 3 03 03 co] p bir da zin- X o C0 O CD CO 3 co CD 3? CO co 3 * [, ta oo3rizl4i- o. i ' F 03 - ilmet eno (repair 5 t-- similar to the azab example: ) S2 4-- or cr! - > | co CTI - n Q_ G? '-' 3 N3 o 00 oo I heard 3 co o O 3 c s N c 1 X F s c - - h 0) X -i or - h |-| < - t O cr O - * cr OR eto c o 3 03 > < - _J 1 - h et 3 03 (O? 0) CL o Q_ ro F F F or 1 - 3 - X M or CO 1 or 03 Q. or G? 03 or o CO enz de de ro X F ozenO I in or O < J > -| l 1 F - · o. 1 03 _ ~ 3 3 '1' 3 be tao 0aiz n3 CD 1 0) 3 03 CO i-? 0 3 · 1 i 3 - zn anil 3 M c 3 03 O G? o - h co F 03 o - h oo od to zl iriz - i e zon 03 O 0) or O) W 3 min min me < - + | 3 07 a of 0) 0) a taiz am indigo ] piir az to lmi Quantity Eg Name after part of: isolated 1. 02 g of 3-chloro-6- 6-. { [6- (oxetan-3- (oxetan-3-yloxy) [1, 2,4] triazo i loxi) [1, 2,4] triazolo [ it [4,3- 4,3-b] pyridazine 67 b] pyridazin-3-1a (67b) and of 1.12 g of 383 mg io peracnrpa il] suifanil} -1, 3- liil sar am thiocianato de 2- íj eem po: benzothiazol-2-amino-1, 3-amine benzothiazol-6-yl (commercial) 2 g of 3,6- 3-chloro-6-dichloro [1, 2, 4] triazole (oxeta n-3- or [4,3-b] pyridazine 7b i I oxy) [1, 2,4] triazo 1b 1.01 g (commercial) and of [4.3- 1.96 g of oxetane-3-b] pyridazine ol rac-2- (morpholin-250 mg of rac-6- 4-yl) -N- (6- { [6- { [6- (tetrahydrofuran- (tetra idrofuran- 3- 3- i loxi) [, 2,4] triazolo [ i lox!) [1, 2,4] triazo 4,3-b] pyridazin-3-68 8 86 mg lo [4,3-yl] sulfanil} -1, 3-b] pyridazin-3-benzothiazole-2-amine il] sulfanil} -1, 3- (27) and 939 mg of benzothiazole-2-acid. morpholin-4-yl) acetylamide ilacetic (commercial) Quantity Ej- Name from: isolated 150 mg of 6-. { [6- N- (6- { [6- (3,5- (3,5-difluorophenoxy)] [1, difluorophenoxy] [1, 2,4 2,4] triazolo [4,3-] triazolo [4,3- oireparacn p b) pyridazin-3- l l i i s ma r a b] pyridazin-3- 69 8 jl eempo: 111 mg M] sulphanil} -1, 3-yl] sulfanil} -1, 3- benzothiazol-2-yl) -benzothiazole-2-amine 2- (morpholin-4- (45) and 508 mg of il) acetamide morpholin-4-ylacetic acid (commercial) 250 mg of rac-6- rac-N2, N2-diethyl-. { [6- (tetrahydrofuran- N- (6- { [6-3- (tetrahydrofuran- i Io i) [1, 2,4] triazolo [ 3-4,3-b] pyridazin-3-yloxy) [1, 2,4] triazo 70 8] sulfanil} -1, 3- 48 mg [4.3- benzothiazole-2-amine] b) pyridazin-3- (27) and 991 mg of il] sulfanil} -1, 3- the sodium salt of the benzothiazole-2-N, N-diethylglycine il) glycinamide (commercial) Quantity Eg Name from: isolated 250 mg of rac-6- rac-2- (4-. {[[6- (te trah id break n-etilp¡peraz¡n-1-3-il) -N- (6- { [6 - i loxi) [1, 2,4] triazolo [ (tetrahydrofuran-4,3-b] pyridazin-3- 3 -acetic acid iill sr ama i l] s u Ifa n i I.}. - 1, 3- 71! Oxy) [1, 2,4] triazo 8 ji ee pom: 50 mg benzothiazol-2-amine it [4.3- (27) and of 655 mg b] pyridazin-3- (4-yl) sulfanyl} -1-, 3-ethylpiperazin-1-benzothiazole-2-yl) acetic acid il) acetamide (commercial) 198 mg of rac-6- rac-2- (4- { [6- (tetrahydrofuran-cyclopropylpipera) 3- zin-1 -yl) -N- (6- i loxi) [1, 2,4] triazolo [ . { [6-4,3-b] pyridazole-3- (tetrahydrofloxane) sulphanil.] -1, 3-3-72 8 benzothiazol-2-amine 83 mg iloxy ) [, 2,4] triazo (27) and 619 mg of [4.3 - the potassium salt of the b] pyridazin-3- (4-yl) sulfanyl} -1, 3-cyclopropylpiperazin-benzothiazol-2-yl) acetic acid (63b) (or il) acetamide commercial) c Quantity Eg Name from: isolated 60 mg of 6-. { [6- N- (6- { [6- (oxetane- (oxetan-3- i I oxy) [1, 2,4] triazolo [ iloxi) [1, 2,4] triazo 4,3-b] pyridazin-3-lo [4,3-yl] sulfanil} -1, 3- 73 b] p i r i d a z i n - 3 - 3 42 mg benzothiazole-2-amine il] sulfanil} -1, 3- (67) and 0.022 cm3 benzothiazole-2-paa prer < ilima sr chloride il) ciclopropanoca jlem p e ciclopropanocarboni rboxamide the 150 mg of 6-. { [6- 2- (4- (oxetane-3-ethylpiperazin-1-yloxy) [1, 2,4] triazolo [ il) -N- (6- { [6-4,3-b] pyridazin-3- (oxetane-3-yl] sulfanyl} -1, 3-yloxy) [1, 2,4] triazo 74 8 benzothiazol-2-amine 123 mg lo [4.3- (67) and 357 mg b] pyridazin-3- (4-yl) sulfanyl) -1-, 3-ethylpiperazin-1-benzothiazol-2-yl) acetic acid il) acetamide (commercial) 143 mg of 6-. { [6- 2- (4- (oxeta n-3-cyclopropylpiper i i or x i) [1, 2,4] triazolo [ zin-1 -yl) -N- (6- 4, 3-b] pyridazin-3 - { [6- (oxetan-3-yl] sulfanyl} -1, 3-yloxy) [1, 2 , 4] triazo benzothiazol-2-amine 75 8 90 mg lo [4.3- (67) and 427 mg b] pyridazin-3- the potassium salt of il] sulfanil} -1, 3- (4- benzothiazole-2-cyclopropylpiperazine-1) to c a t a m i d a 1-yl) acetic acid (63b) (or commercial) The characteristics of the products of the previous table are the following: Ex-EM NMR NMR spectrum nH (400 MHz, d in ppm, DEMO-d6): 2.20 (s, 3 H); 7.11 (broad dd, J = 2.2 and 8.5 Hz, 1 H); 7.16 (ddt, J = 1.0 and [M + H] +: m / z 2.2 and 8.5 Hz, 1 H); 7.25 (td, J = 2.2 and 10.0 11 453; [M-H] -: Hz, 1 H); 7.30 (dd, J = 1.9 and 8.6 Hz, 1 H); m / z 451. 7.39 (d, J = 9.8 Hz, 1 H); 7.43 (dt, J = 7.1 and 8.6 Hz, 1 H); 7.60 (d, J · = 8.6 Hz, 1 H); 7. 91 (d, J = 1.9 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.39 (broad m, 1 H). 1 H NMR spectrum (400 MHz, d in PPm, DEMO- / 6): 0.92 to 1.00 (m, 4 H); 1 .94 a 2. 04 (m, 1 H); 7.12 (broad dd, J = 2.3 and 8. 3 Hz, 1 H); 7.16 (ddt, J = 1.0 and 2.3 and 8.3 [M + H] +: m / z Hz, 1 H); 7.25 (td, J = 2.3 and 10.0 Hz, 1 H); 12 479; [M -H] -: 7. 31 (dd, J = 1.9 and 8.6 Hz, 1 H); 7.39 m / z 477. (d, J = 9.8 Hz, 1 H); 7.43 (dt, J = 6.8 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.90 (d, J = 1.9 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.69 (broad m, 1 H).

E NMR H NMR spectrum (400 MHz, d in ppm, DEM0-d6): 2.36 to 2.46 (m, 6 H); 3.26 to 3.34 (partially masked m, 2 H); [M + H] +: m / z 3. 59 (m, 4 H); 6.78 (broad m, 1 H); 7.18 to 567; [-H] -: 7. 26 (m, 3 H); 7.26 to 7.32 (m, 2 H); 7.36 m / z 565. (d, J = 9.8 Hz, 1 H); 7.50 (d, J = 8.6 Hz, 1 H); 7.82 (d, J = 1.9 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 10.89 (broad m, 1 H).

Weather retention (min) 0. 78; [M + H] +: 265; H NMR spectrum (400 MHz, d in ppm, DEMO-cy6): 2.27 (s, 3 H); 2.41 (m, 6 H); 3.25 to 3.35 (partially masked m, 2 H); 3.60 (m, 4 H); 6.78 (broad m, 1 H); [M + H] +: m / z 7. 00 (broad d, J = 8.3 Hz, 1 H); 7.19 581; [M-H] -: (broad d, J = 10.3 Hz, 1 H); 7.23 to 7.31 m / z 579. (m, 2 H); 7.35 (d, J = 9.8 Hz, 1 H); 7.48 (d, J = 8.6 Hz, 1 H); 7.84 (d, J = 1.9 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 10.89 (broad m, 1 H).

Eg E R N Time of Retention Tr (min) = 14b 0. 88; [M + H] +: m / z 279; 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 1.55 (m, 2 H); 1.87 (m, 2 H); [M + H] +: m / z 3. 41 (m, 2 H); 3.72 to 3.80 (m, 2 H); 4.91 15 399; [M-H] -: (m, 1 H); 7.04 (d, J = 9.8 Hz, 1 H); 7.22 to m / z 401. 7. 30 (m, 2 H); 7.61 (s, 2 H); 7.82 (d, J = 1.0 Hz, 1 H); 8.28 (d, J = 9.8 Hz, 1 H).

Time of Retention Tr (min) = 15b 2. 74; [M + H] +: m / z 255; 1 H NMR spectrum (400 MHz, d in ppm, [M + H] +: m / z DEMO-d6): 7.12 (dd, J = 1.9 and 8.4 Hz, 1 H); 16 411; [M-H] -: 7.22 (d, J = 8.4 Hz, 1 H); 7.24 to 7.38 (m, 5 m / z 409. H); 7.62 (d, J = 1.9 Hz, 1 H); 7.64 (broad s, 2 H); 8.44 (d, J = 9.8 Hz, 1 H).

Ex. EM R N 1 H NMR spectrum (400 Hz, d in ppm, DEMO-c / 6): 1.52 (m, 2 H); 1.81 (m, 2 H); 2. 35 to 2.45 (m, 6 H); 3.23 to 3.27 (masked m, 2 H); 3.32 to 3.39 (m [M + H] +: masked m / z, 2 H); 3.59 (t, J = 4.6 Hz, 4 17,557; [M- H] -: H); 3.71 (m, 2 H); 4.86 (m, 1 H); 6.79 (s m / z 555. broad, 1 H); 7.05 (d, J = 9.8 Hz, 1 H); 7. 33 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.55 (d, J = 8.6 Hz, 1 H); 8.01 (d, J = 2.0 Hz, 1 H); 8. 30 (d, J = 9.8 Hz, 1 H); 10.91 (s broad, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 0.96 (t, J = 7.2 Hz, 3 H); 1.49 (m, 2 H); 1.76 (m, 2 H); 1.93 (t, J = 9.5 Hz, 2 H); 2.28 (q, J = 7.1 Hz, 2 H); 2.41 (m, 6 H); 2.51 to 2.59 (m, 2 H); 3.24 to 3.28 (m [M + H] +: m / z 18 masked, 2 H); 3.59 (t, J = 4.6 Hz, 4 584 H); 4.61 (m, 1 H); 6.77 (broad s, 1 H); 7. 03 (d, J = 9.8 Hz, 1 H); 7.28 (dd, J = 2.1 and 8.4 Hz, 1 H); 7.53 (d, J = 8.6 Hz, 1 H); 8. 02 (d, J = 2.0 Hz, 1 H); 8.28 (d, J = 9.8 Hz, 1 H); 10.89 (broad s, 1 H).

Ex. EM NMR NMR spectrum? (400 MHz, d in ppm, DEMO- / g): 1.01 (t, J = 7.2 Hz, 3 H); 1.67 a 1. 86 (m, 2 H); 2.03 to 2.12 (m, 2 H); 2.21 to 8b 2.28 (m, 2 H); 2.35 (q, J = 7.2 Hz, 2 H); 2. 61 to 2.75 (m, 2 H); 5.01 (tt, J = 4.1 and 8.2 Hz, 1 H); 7.10 (d, J = 10.0 Hz, 1 H); 8.27 (d, J = 10.0 Hz, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, DEM0-d6): 0.90 to 0.98 (m, 4 H); 1.51 (m, 2 H); 1.78 (m, 2 H); 1.97 (m, 1 H); 3.31 a [M + H] +: m / z 3.36 (masked m, 2 H); 3.70 (m, 2 H); 19 469; [M-H] -: 4.84 (m, 1 H); 7.05 (d, J = 9.8 Hz, 1 H); m / z 467. 7.38 (dd, J = 2.0 and 8.8 Hz, 1 H); 7.66 (d, J = 8.6 Hz, 1 H); 8.06 (d, J = 1.2 Hz, 1 H); 8. 31 (d, J = 9.8 Hz, 1 H); 12.68 (s broad, 1 H).

NMR spectrum? (400 MHz, d in ppm, DEMO-c / e): 0.92 to 1.00 (m, 4 H); 1.96 a [M + H] +: m / z 2.04 (m, 1 H); 7.18 (t, J = 8.3 Hz, 2 H); 20 479; [M-H] -: 7.22 to 7.32 (m, 3 H); 7.37 (d, J = 10.0 Hz, m / z 477. 1 H); 7.62 (d, J = 8.6 Hz, 1 H); 7.87 (d, J = 1. 9 Hz, 1 H); 8.47 (d, J = 10.0 Hz, 1 H); 12. 70 (broad m, 1 H).

Ex. EM R N 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d 6): 0.92 to 1.00 (m, 4 H); 1.96 to 2.03 (m, 1 H); 2.25 (d, J = 1.5 Hz, 3 H); 6.97 (dd, J = 2.3 and 8.6 Hz, 1 H); 7.16 (dd, J [M + H] +: m / z 21 = 2.3 and 10.6 Hz, 1 H); 7.24 (broad t, J = 493; [M-H] -: 8. 6 Hz, 1 H); 7.30 (dd, J = 1.9 and 8.6 Hz, 1 m / z 491.

H); 7.36 (d, J = 9.8 Hz, 1 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.89 (d, J = 1.9 Hz, 1 H); 8.47 (d, J = 9.8 Hz, 1 H); 12.69 (broad m, 1 H).

Time of Retention Tr (m i n) = 1 B 0. 82; [M + H] +: m / z 425; [M-H] -: m / z 423. 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d 6): 0.89 (d, J = 6.1 Hz, 4 H); 0.94 (t, J = 7.1 Hz, 3 H); 1.48 (m, 2 H); 1.75 (m, [M + H] +: m / z 2 H); 1.84 to 1.95 (m, 3 H); 2.26 (q, J = 7.1 22 496; [M-H] -: Hz, 2 H); 2.52 to 2.57 (masked m, 2 m / z 494. H); 4.58 (m, 1 H); 7.02 (d, J = 9.8 Hz, 1 H); 7. 29 (dd, J = 1.8 and 8.4 Hz, 1 H); 7.58 (d, J = 8.3 Hz, 1 H); 8.03 (d, J = 1.2 Hz, 1 H); 8.28 (d, J = 9.8 Hz, 1 H); 12.62 (s, 1 H).

RM NMR Time of Retention Tr (min) = 0. 36; [M + H] +: m / z b 428; M + 2H] 2+: m / z 214.5 (base peak); [M-H] -: m / z 426.

H NMR spectrum (400 MHz, d in ppm, DEMO-de): 1 98 (m, 1 H); 2.17 (m, 1 H); 2.35 to 2.45 (m, 6 H); 3.22 to 3.28 (masked m, 2 H); 3.59 (t, J = 4.6 Hz, 4 [M + H] +: m / z H); 3.66 to 3.85 (m, 4 H); 5.32 (m, 1 H); 543; [M-H] -: 6. 78 (t, J = 5.9 Hz, 1 H); 7.07 (d, J = 9.8 m / z 541.

Hz, 1 H); 7.42 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.57 (d, J = 8.6 Hz, 1 H); 8.06 (d, J = 2.0 Hz, 1 H); 8.30 (d, J = 9.8 Hz, 1 H); 10.88 (s broad, 1 H).

Time of 1 H NMR spectrum (400 MHz, d in ppm, Tr retention) DEMO-d6): 2.05 to 2.18 (m, 1 H); 2.25 a (min) = b 2.39 (m, 1 H); 3.78 (m, 1 H); 3.88 (m, 1 H); 0. 49; 3. 94 (m, 2 H); 5.52 (m, 1 H); 7.12 (d, J = [M + H] +: m / z 9. 8 Hz, 1 H); 8.29 (d, J = 9.8 Hz, 1 H). 241.

Ex. EM R N H NMR spectrum (400 MHz, d in ppm, DEMO-tf6): 2.36 to 2.45 (m, 6 H); 3.25 to 3.32 (partially masked m, 2 H); 3.59 (m, 4 H); 6.12 (s, 2 H); 6.72 (dd, J = [M + H] +: m / z 2. 4 and 8.6 Hz, 1 H); 6.79 (broad m, 1 H); 24,593; [M-H] -: 6. 93 (d, J = 8.6 Hz, 1 H); 6.95 (d, J = 2.4 m / z 591.

Hz, 1 H); 7.27 to 7.33 (m, 2 H); 7.50 (d, J = 8.6 Hz, 1 H); 7.87 (d, J = 1.9 Hz, 1 H); 8.42 (d, J = 9.8 Hz, '1 H); 10.90 (broad m, 1 H).

Time of Retention Tr (min) = 4b 0. 73; [M + H] +: m / z 291. 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 2.37 to 2.45 (m, 6 H); 3.24 to 3.33 (partially masked m, 2 H); 3.59 (m, 4 H); 6.78 (broad m, 1 H); 7.24 [M + H] +: m / z (dd, J = 2.0 and 8.3 Hz, 1 H); 7.30 (dd, J = 617; [M-H] -: 2. 7 and 8.8 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 m / z 615.

H); 7.48 (d, J = 8.3 Hz, 1 H); 7.62 (d, J = 8. 8 Hz, 1 H); 7.74 (d, J = 2.7 Hz, 1 H); 7.84 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 10.92 (broad m, 1 H).

Ex. EM R N Time of Retention Tr (min) = 5b 0. 98; [M + H] +: m / z 315.

NMR 'H spectrum (400 MHz, d in ppm, DEMO-d6): 7.13 (dd, J - 2.0 and 8.4 Hz, 1 H); [M + H] +: m / z 7.20 (d, J = 8.4 Hz, 1 H); 7.34 (dd, J = 2.7 26 461; [M- H] -: and 8.8 Hz, 1 H); 7.38 (d, J = 9.8 Hz, 1 H); m / z 459. 7.64 (s, 2 H); 7.66 (d, J = 2.0 Hz, 1 H); 7. 71 (d, J = 8.8 Hz, 1 H); 7.79 (d, J = 2.7 Hz, 1 H); 8.47 (d, J = 9.8 Hz, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 2.02 (m, 1 H); 2.22 (m, 1 H); [M + H] +: m / z 3.69 to 3.86 (m, 4 H); 5.35 (m, 1 H); 7.06 27 387; [M- H] -: (d, J = 10.0 Hz, 1 H); 7.29 (d, J = 8.6 Hz, 1 m / z 385. H); 7.34 (dd, J = 2.0 and 6.6 Hz, 1 H); 7.62 (s, 2 H); 7.88 (d, J = 2.0 Hz, 1 H); 8.28 (d, J = 9.8 Hz, 1 H).

EM RN1N 1 H NMR spectrum (400 MHz, d in ppm, DEMO- / 6): 2., 38 to 2.45 (m, 6 H); 3.22 to 3.35 (partially masked m, 2 H); 3.60 (m, 4 H); 6.51 (m, 1 H); 6.77 (m [M + H] +: broad m / z, 1 H); 6.91 (dd, J = 2.3 and 8.6 Hz, 1588; [M-H] -: H); 7.21 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.33 m / z 586. (d, J = 10.0 Hz, 1 H); 7.34 to 7.37 (m, 2 H); 7. 42 (dd, J = 2.3 and 3.0 Hz, 1 H); 7.58 (d, J = 8.6 Hz, 1 H); 7.88 (d, J = 2.0 Hz, 1 H); 841 (d, J = 10.0 Hz, 1 H); 10.89 (broad m, 1 H); 11.25 (broad m, 1 H).

Time of Retention Tr (min) = 0. 76; [M + H] +: m / z 286; [M-H] -: m / z 284. 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d 6): 0.95 (m, 4 H); 1.97 (m, 2 H); 2.15 (m, 1 H); 3.63 to 3.73 (m, 3 H); 3.78 [M + H] +: m / z (q, J = 7.7 Hz, 1 H); 5.33 (m, 1 H); 7.08 (d, 455; [M-H] -: J = 10.0 Hz, 1 H); 7.46 (dd, J = 2.1 and 8.4 m / z 453.

Hz, 1 H); 7.69 (d, J = 8.3 Hz, 1 H); 8.11 (d, J = 2.0 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 12.67 (broad s, 1 H).

Ex. EM NMR 1 H NMR spectrum (400 MHz, d in ppm, DEMO- / 6): 0.90 to 1.00 (m, 4 H); 1.92 a 2. 05 (m, 1 H); 6.09 (s, 2 H); 6.70 (dd, J = [M + H] +: m / z 2.3 and 8.4 Hz, 1 H); 6.89 (d, J = 8.4 Hz, 1 30 505; [M- MiH); 6.92 (d, J = 2.3 Hz, 1 H); 7.32 (d, J = m / z 503. 9.8 Hz, 1 H); 7.35 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.62 (d, J = 8.6 Hz, 1 H); 7.92 (d, J = 2. 0 Hz, 1 H); 8.43 (d, J = 9.8 Hz, 1 H); 12. 68 (broad m, 1 H).

Time of Retention Tr (min) - 0b 0.70; [M + H] +: m / z 437; [M- H] -: m / z 435.

NM 1 H spectrum (400 MHz, d in ppm, DEMO-d6): 0.90 to 0.99 (m, 4 H); 1.94 a [M + H] +: m / z 2.05 (m, 1 H); 7.24 to 7.30 (m, 2 H); 7.40 31 529; [M- H] -: (d, J = 9.8 Hz, 1 H); 7.55 to 7.61 (m, 2 H); m / z 527. 7.71 (d, J = 2.7 Hz, 1 H); 7.89 (d, J = 2.0 Hz, 1 H); 8.50 (d, J = 9.8 Hz, 1 H); 12.70 (broad m, 1 H).

Ex. EM NMR 1 H NMR spectrum (400 MHz, d in ppm, DEMO-de): 0.86 to 1.03 (m, 4 H); 1.94 to 2.06 (m, 1 H); 6.50 (t, J = 2.2 Hz, 1 H); [M + H] +: m / z 6.90 (dd, J = 2.2 and 8.6 Hz, 1 H); 7.25 (dd, J 32,500; [M-H] -: = 1.9 and 8.6 Hz, 1 H); 7.30 to 7.36 (m, 2 H); m / z 499. 7.40 to 7.46 (m, 2 H); 7.55 (d, J = 8.6 Hz, 1 H); 7.94 (d, J = 1.9 Hz, 1 H); 8.41 (d, J = 9.8 Hz, 1 H); 11.24 (broad s, 1 H); 12.69 (broad m, 1 H).

Time of Retention Tr (min) = 3. 32; [M + H] +: m / z 432; [M-H] -: m / z 430.

H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 1.76 to 1.89 (m, 1 H); 1.89 to 2.04 (m, 1 H); 2.07 to 2.33 (m, 4 H); 3.34 to 3.45 (m, 1 H); 7.12 (dd, J = 2.3 and 8.4 Hz, 1 [M + H] +: m / z H); 7.17 (broad dt, J = 2.3 and 8.4 Hz, 1 H); 493; [M-H] -: 7.25 (td, J = 2.3 and 10.0 Hz, 1 H); 7.31 (dd, m / z 491 = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 HOUR); 7.43 (dt, J = 6.9 and 8.4 Hz, 1 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.91 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.25 (broad m, 1 H).

Ex-EM NMR H NMR spectrum (400 Hz, d in ppm, DEM0-d6): 2.30 (s, 6 H); 3.22 to 3.42 (m partially masked, 2 H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.3 and [+ H] +: m / z 8. 3 Hz, 1 H); 7.24 (td, J = 2.3 and 9.9 Hz, 1 34,496; [M-H] -: H); 7.31 (dd, J = 1.9 and 8.6 Hz, 1 H); 7.39 m / z 494. (d, J = 10.0 Hz, 1 H); 7.42 (dt, J = 6.9 and 8. 3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7. 91 (d, J = 1.9 Hz, 1 H); 8.49 (d, J = 10.0 Hz, 1 H); 11.93 (very broad m, 1H).

H NMR spectrum (400 Hz, d in ppm, DEMO-tf6): 1.17 (t, J = 7.1 Hz, 3 H); 3.56 (q, J = 7.1 Hz, 2 H); 4.24 (s, 2 H); 7.11 [M + H] +: m / z (dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 35,497; [M-H] -: 2.2 and 8.3 Hz, 1 H); 7.24 (td, J = 2.2 and 10.0 m / z 495. Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7. 36 to 7.46 (m, 2 H); 7.62 (d, J = 8.6 Hz, 1 H); 7.93 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9. 8 Hz, 1 H); 12.29 (broad m, 1 H).

Ex-EM WIN 1 H NMR spectrum (400 MHz, d in ppm, DEMO-cy6): 1.11 to 1.36 (m, 5 H); 1.42 a 1. 53 (m, 1 H); 1.68 (m, 2 H); 1.88 (m, 2 H); 3. 36 to 3.44 (m, 1 H); 4.26 (s, 2 H); 7.11 [M + H] +: m / z (dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 36 551; [- H] -: 2. 2 and 8 3 Hz, 1 H); 7.24 (td, J = 2.2 and 10.0 m / z 549.

Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7. 37 to 7.46 (m, 2 H); 7.62 (d, J = 8.6 Hz, 1 H); 7.93 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.19 (broad m, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 7.10 (dd, J = 1.8 and 8.4 Hz, 1 H); 7. 21 (d, J = 8.3 Hz, 1 H); 7.42 (d, J = 9.8 [M + H] +: m / z Hz, 1 H); 7.53 (dd, J = 4.8 and 8.4 Hz, 1 H); 37 394; [M- H] -: 7. 61 (d, J = 2.0 Hz, 1 H); 7.64 (s, 2 H); m / z 392. 7. 76 to 7.81 (m, 1 H); 8.47 (d, J = 9.8 Hz, 1 H); 8.59 (dd, J = 1.2 and 4.6 Hz, 1 H); 8.63 (d, J = 2.9 Hz, 1 H).

H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 7.46 (d, J = 10.0 Hz, 1 H); 7.58 (ddd, J = 0.5 and 4.7 and 8.3 Hz, 1 H); 7.90 7b (ddd, J = 1.2 and 2.7 and 8.3 Hz, 1 H); 8.49 (d, J = 10.0 Hz, 1 H); 8.56 (dd, J = 1.2 and 4.7 Hz, 1 H); 8.68 (broad d, J = 2.7 Hz, 1 H).

Ex. EM NMR 1 H NMR spectrum (400 MHz, d in ppm, [M + H] +: m / z DEMO-): 7.19 (dd, J = 1.9 and 8.5 Hz, 1 H); 38 477; [M- Mi7.24 (d, J = 8.5 Hz, 1 H); 7.37 to 7.46 (m, 3 m / z 475. H); 7.58 (broad s, 1 H); 7.63 to 7.75 (m, 4 H); 8.52 (d, J = 9.8 Hz, 1 H).

Time of Retention Tr (min) - 8b 4. 12; [M + H] +: m / z 331. 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 1.48 (s, 9 H); 6.86 (broad d, J = 7.8 Hz, 1 H); 7.17 (dd, J = 1.8 and 8.5 Hz, [M + H] +. m / z 1 HOUR); 7.22 (d, J = 8.5 Hz, 1 H); 7.28 to 7.40 39 508; [M- H] -: (m, 3 H); 7.51 (broad s, 1 H); 7.62 (s m / z 506. broad, 2 H); 7.71 (d, J = 1.8 Hz, 1 H); 8. 42 (d, J = 9.8 Hz, 1 H); 9.59 (s broad, 1 H).

[M + H] +: m / z 9b 362; [M- H] -: m / z 360.

Ex-EM R N 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 1.78 to 2.04 (m, 2 H); 2.11 a 2. 34 (m, 4 H); 3.41 (m, 1 H); 7.27 (dd, J = [M + H] +: m / z 2. 0 and 8.3 Hz, 1 H); 7.38 to 7.46 (m, 2 H); 40,476; [M- H] -: 7. 60 (d, J = 8.3 Hz, 1 H); 7.72 (dd, J = 3.9 m / z 474. and 8.3 Hz, 1 H); 7.89 (d, J = 2.0 Hz, 1 H); 8.47 to 8.55 (m, 2 H); 8.58 (d, J = 2.9 Hz, 1 H); 12.27 (broad s, 1 H).

H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 2.54 (m, 4 H); 3.34 (s, 2 H); 3. 62 (m, 4 H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1 H); 7.16 (ddt, J = 0.9 and 2.3 and 8.3 Hz, 1 H); [M + H] +: m / z 7. 25 (td, J = 2.3 and 10.0 Hz, 1 H); 7.31 (dd, 41 538; [M-|?] -: J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, m / z 536. 1 HOUR); 7.43 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.91 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.21 (broad m, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 1.00 to 1.29 (m, 5 H); 1.50 a 1. 57 (m, 1 H); 1.61 to 1.72 (m, 2 H); 1.83 [M + H] +: m / z (m, 2 H); 2.46 (m partially 42 550; [M -H] -: masked, 1H); 3.52 (s, 2 H); 7.09 to m / z 548 7.20 (m, 2 H); 7.23 to 7.30 (m, 2 H); 7.38 (d, J - 9.8 Hz, 1 H); 7.44 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.57 (d, J = 8.3 Hz, 1 H); 7.88 (d, J = 2.0 Hz, 1 H); 8.48 (d, J - 9.8 Hz, 1 H).

E R N 1 H NMR spectrum (400 MHz, d in ppm, DEMO-dg): 2.35 to 2.46 (m, 9 H); 2.65 (t, J = 6.1 Hz, 2 H); 3.39 (s, 2 H); 3.64 (m, 4 H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J [M + H] +: m / z = 2.2 and 8.3 Hz, 1 H); 7.25 (td, J = 2.2 and 595; [M-H] -: 10. 0 Hz, 1 H); 7.31 (dd, J = 1.7 and 8.6 Hz, 1 m / z 593.

H); 7.39 (d, J = 9.8 Hz, 1 H); 7.42 (m, 1 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.91 (d, J = 1.7 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.01 (broad m, 1 H).

NMR spectrum 1H (400 Hz, d in ppm, DEMO-d6): 1.00 (broad t, J = 6.8 Hz, 3 H); [M + H] +: m / z 2. 30 to 2.62 (partially masked m, 565; 10 H); 3.34 (s, 2 H); 7.11 (dd, J = 2.3 and 8.3 [M + 2H] 2 +: Hz, 1 H); 7.16 (dt, J = 2.3 and 8.3 Hz, 1 H); m / z 283 7. 24 (td, J = 2.3 and 10.0 Hz, 1 H); 7.32 (dd, (base peak): J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, [M-H] -: m / z 1 HOUR); 7.43 (m, 1 H); 7.62 (d, J = 8.6 Hz, 1 563.

H); 7.92 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.11 (broad m, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, [M + H] +: m / z DEMO-c / g): 7.19 (broad s, 2 H); 7.21 to 429; [M-H] -: 7.33 (m, 3 H); 7.39 (d, J = 9.8 Hz, 1 H); m / z 427. 7.64 (broad s, 2 H); 7.69 (broad s, 1 H); 8. 48 (d, J = 9.8 Hz, 1 H).

Ex. EM R N Time of Retention Tr (min) 5b 0. 83; [M + H] +: miz 283.

NMR spectrum? (400 MHz, d in ppm, DEMO-cí6): 5.36 (s broad, 2 H); 6.36 (dd, J [M + H] +: miz = 2.0 and 8.1 Hz, 1 H); 6.45 (t, J = 2.0 Hz, 1 46 408; [M- H] -: H); 6.54 (dd, J = 2.0 and 8.1 Hz, 1 H); 7.11 m / z 406. (t, J = 8.1 Hz, 1 H); 7.20 to 7.33 (m, 3 H); 7. 63 (broad s, 2 H); 7.74 (d, J = 1.8 Hz, 1 H), 8.39 (d, J = 9.8 Hz, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, DEMO-cf6): 1.22 to 1.34 (m, 2 H); 1 .76 (m, 2 H); 2.68 (m, 1 H); 3.30 (m, 2 H); 3.52 (s, 2 H); 3.81 (m, 2 H); 7.12 (dd, J = 2.0 and 8.3 [M + H] +: m / z Hz, 1 H); 7.16 (dt, J = 2.0 and 8.3 Hz, 1 H); 47,552; [M- H] -: 7. 25 (td, J = 2.0 and 10.0 Hz, 1 H); 7.30 (dd, m / z 550.

J = 2.0 and 8.3 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 HOUR); 7.44 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.59 (d, J = 8.3 Hz, 1 H); 7.90 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H).

Ex. EM NMR 1 H NMR spectrum (400 MHz, d in ppm, DEMO-dg): 0.89 to 1.01 (m, 4 H); 2.01 (m, 1 [M + H] +: m / z H); 7.25 (dd, J = 1.8 and 8.7 Hz, 1 H); 7.37 a 48 529; [M-H] -: 7.47 (m, 3 H); 7.58 (d, J = 8.7 Hz, 1 H); m / z 527. 7.66 (d, J = 8.6 Hz, 2 H); 7.83 (d, J = 1.8 Hz, 1 H); 8.53 (d, J = 9.8 Hz, 1 H); 12.69 (s broad, 1 H).

[M + H] +: m / z 8b 461; [M- H] -: m / z 459.

Time of Retention Tr (m i n) = 8c 0. 93; [M + H] +; m / z 315. 1 H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 0.86 to 1.01 (m, 4 H); 1.99 (m, 1 [M + H] +: m / z H); 7.24 to 7.35 (m, 3 H); 7.40 (d, J = 9.8 49 545; [M -H] -: Hz, 1 H); 7.46 (broad s, 1 H); 7.52 (t, J = m / z 543 8.3 Hz, 1 H); 7.59 (d, J = 8.3 Hz, 1 H); 7. 89 (broad s, 1 H); 8.49 (d, J - 9.8 Hz, 1 H); 12.67 (broad m, 1 H).

RM NMR 1 H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 0.96 (m, 4 H); 1.98 (m, 1 H); 2.23 (s, 3 H); 7.17 (dd, J = 2.0 and 8.6 Hz, 1 [+ HJ +: m / z H); 7.25 (dd, J = 5.1 and 8.1 Hz, 1 H); 7.45 476; [M-H] -: (d, J = 9.8 Hz, 1 H); 7.57 (d, J = 8.6 Hz, 1 m / z 474. H); 7.61 (dd, J = 1.6 and 8.2 Hz, 1 H); 7.79 (d, J = 2.0 Hz, 1 H); 8.42 (dd, J = 1.7 and 4.6 Hz, 1 H); 8.50 (d, J = 9.8 Hz, 1 H); 12.67 (broad s, 1 H).

Time of Retention Tr (min) -0.48; [M + H] +: m / z 408; [M-H] -: m / z 406.

Time of Retention Tr (min) = 0. 37; [M + H] +: m / z 262.

Ex. EM NMR H NMR spectrum (400 MHz, d in ppm, DEM0-cf6): 0.91 to 1.00 (m, 4 H); 1.94 a [M + H] +: m / z 2.03 (m, 1 H); 7.11 to 7.25 (m, 3 H); 7.33 51,497; [M-H] -: (dd, J = 2.0 and 8.6 Hz, 1 H); 7.40 (d, J = m / z 495 10.0 Hz, 1 H); 7.59 (d, J = 8.6 Hz, 1 H); 7. 91 (d, J = 2.0 Hz, 1 H); 8.51 (d, J = 10.0 Hz, 1 H); 12.67 (broad m, 1 H). 1 H-NMR spectrum (400 MHz, d in ppm, D E M 0-cf6): 2.14 (s, 3 H); 4.83 (s, 2 H); 7.11 (dd, J = 2.1 and 8.5 Hz, 1 H); 7.15 (dt, J [M + H] +: m / z = 2.1 and 8.5 Hz, 1 H); 7.24 (td, J = 2.1 and 52 511; [M-H] -: 10. 0 Hz, 1 H); 7.32 (dd, J = 2.0 and 8.6 Hz, 1 m / z 509.

H); 7.36 to 7.46 (m, 2 H); 7.64 (d, J = 8.6 Hz, 1 H); 7.93 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.64 (broad m, 1 H). 1 H-NMR spectrum (400 MHz, d in ppm, DEMO-d 6): 0.96 (m, 4 H); 1.99 (m, 1 H); 2.51 (masked, 3H); 7.20 (d, J = 8.6 [M + H] +: m / z Hz, 1 H); 7.26 (dd, J = 2.0 and 8.3 Hz, 1 H); 53 476; [M-H] -: 7.41 (d, J-10.0 Hz, 1 H); 7.55 (dd, J = m / z 474. 2.8 and 8.4 Hz, 1 H); 7.60 (d, J = 8.6 Hz, 1 H); 7.86 (d, J = 2.0 Hz, 1 H); 8.40 (d, J = 2. 9 Hz, 1 H); 8.48 (d, J = 9.8 Hz, 1 H); 12.68 (broad s, 1 H).

RM NMR Time of Retention Tr (min) = 0. 51; [+ H] +: m / z 408; [M-H] -: m / z 406.

Time of Retention Tr (min) -0.40; [M + H] +: m / z 262.

NMR 'H spectrum (400 MHz, d in ppm, DEMO-d6): 0.89 to 1.00 (m, 4 H); 1.93 to 2.06 (m, 1 H); 2.33 (m, 4 H); 3.45 (s, 2 H); [M + H] +: m / z 3. 52 to 3.59 (m, 4 H); 7.11 (d, J = 8.6 Hz, 2 560; [M-H] -: H); 7.17 to 7.26 (m, 3 H); 7.36 (d, J = 9.8 m / z 558.

Hz, 1 H); 7.60 (d, J = 8.6 Hz, 1 H); 7.83 (d, J = 2.0 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 2.70 (broad m, 1 H).

Ex. EM NMR Time of Retention Tr (min) = 4b 0.42; [M + H] +: m / z 492; [M-H] -: m / z 490.

Time of Retention Tr (min) = 4c 0. 32; [+ H] +: m / z 346.

Time of Retention Tr (min) = 0.3; 4d [+ H] +: m / z 194; [M-H] -: m / z 192. 1 H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 0.95 (m, 4 H); 1.44 (s, 9 H); [M + H] +. m / z 1.99 (m, 1 H); 6.81 (d, J = 8.3 Hz, 1 H); 55,576; [M-H] -: 7.23 (t, J = 8.3 Hz, 1 H); 7.33 (d, J = 9.8 m / z 574. Hz, 3 H); 7.49 (s, 1 H); 7.61 (d, J = 8.3 Hz, 1 HOUR); 7.95 (s, 1 H); 8.44 (d, J = 9.8 Hz, 1 H); 9.56 (s, 1 H); 12.52 (broad m, 1 H).

E NMR Spectrum R N 1 H (400 MHz, d in ppm, DEMO-de): 0.96 (m, 4 H); 2.00 (m, 1 H); 7.27 (dd, J = 1.7 and 8.6 Hz, 1 H); 7.39 a [M + H] +: m / z 7. 47 (m, 2 H); 7.62 (d, J = 8.3 Hz, 1 H); 462; [M-H] -: 7. 72 (dt, J = 2.0 and 8.3 Hz, 1 H); 7.87 (d, J m / z 460. = 2.0 Hz, 1 H); 8.50 (d, J = 9.8 Hz, 1 H); 8.53 (d, J = 4.9 Hz, 1 H); 8.58 (d, J = 2.9 Hz, 1 H); 12.69 (, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d 6): 0.90 to 0.99 (m, 4 H); 1.55 (broad d, J = 9.8 Hz, 1 H); 1.73 (broad d, J = 9.8 Hz, 1 H); 1.94 to 2.05 (m, 1 H); 2.39 (broad d, J = 9.8 Hz, 1 H); 2.70 (broad d, = 9.8 Hz, 1 H); 3.41 (broad s, 1 H); 3.49 [M + H] +: m / z (dd, J = 1.5 and 7.6 Hz, 1 H); 3.61 (d, J = 572; [M-H] -: 14. 0 Hz, 1 H); 3.67 (d, J = 14.0 Hz, 1 H); m / z 570. 3. 87 (d, J = 7.6 Hz, 1 H); 4.29 (s, 1 H); 7.10 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.21 to 7.30 (m, 3 H); 7.31 to 7.39 (m, 2 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.84 (d, J = 2.0 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 12.68 (broad m, 1 H).

RM NMR Time of Retention Tr (min) = 0. 43; [M + H] +: m / z 504; [M-H] -: m / z 502.

Time of Retention Tr (min) = c 0. 3. 4; [M + H] +: m / z 358.

Time of Retention Tr (min) = d 0. 16; [M + H] +: m / z 206. 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 0.93 (t, J = 7.2 Hz, 6 H); 0.95 (m, 4 H); 1.97 to 2.04 (m, 1 H); 2.42 (q, J = 7.2 Hz, 4 H); 3.45 (s, 2 H); 7.08 (dd [M + H] +: m / z broad, J = 2.0 and 8.2 Hz, i H); 7.19 to 7.26 546; [M-H] -: (m, 2 H); 7.28 (dd, J = 2.0 and, 6 Hz, 1 H); m / z 544. 7. 33 (t, J = 8.2 Hz, 1 H); 7.36 (d, J = 9.8 Hz, 1 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.84 (d, J = 2.0 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 12.68 (broad m, 1 H).

RM NMR Time of Retention Tr (min) = 0. 46; [M + H] +: m / z b 478; [M + 2H] 2 +: m / z 239.5 (base peak): [M-H] -: m / z 476.

Time of Retention Tr (min) = c 0. 40; [M + H] +: m / z 332.

Time of Retention Tr (min) = d 0. 22; [M + H] +: m / z 180.

H NMR spectrum (400 MHz, d in ppm, DEMO-de): 1.00 (t, J = 7.2 Hz, 6 H); 2.62 (q, J = 7.2 Hz, 4 H); 3.40 (s, 2 H); 7.09 a [M + H] +: m / z 7. 25 (m, 3 H); 7.33 (dd, J = 2.0 and 8.6 Hz, 1542; [M-H] -: H); 7.41 (d, J = 9.8 Hz, 1 H); 7.60 (d, J = m / z 540. 8. 6 Hz, 1 H); 7.93 (d, J = 2.0 Hz, 1 H); 8.52 (d, J = 9.8 Hz, 1 H); 11.79 (broad m, 1 H).

Ex. EM NMR NMR spectrum 'H (400 MHz, d in ppm, DEMO-c6): 4.19 (broad s, 2 H); 5.49 (broad s, 1 H); 7.11 (broad dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (, J = 1.0 and 2.2 and 8.3 Hz, 1 [M + H] +: m / z H); 7.25 (td, J = 2.2 and 10.0 Hz, 1 H); 7.31 60 469; [M-H] -: (dd, J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 m / z 467.

Hz, 1 H); 7.42 (dt, J-6.9 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.09 (broad m, 1 H).

N H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 0.26 (m, 2 H); 0.39 (m, 2 H); 1.61 (m, 1 H); 2.43 to 2.60 (partially masked m, 8 H); 3.31 (broad s, 2 H); [M + H] +: m / z 7.11 (dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J 61 577; [M-H] -: = 2.2 and 8.3 Hz, 1 H); 7.25 (td, J = 2.2 and m / z 575. 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.43 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.07 (broad m, 1 H).

Ex-EM NMR 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 1.00 (t, J = 6.8 Hz, 3 H); 2.28 a 2. 62 (partially masked m, 10 H); [M + H] +: m / z 3. 34 (s, 2 H); 7.10 to 7.26 (m, 3 H); 7.34 62 583; [M-H] -: (dd, J = 2.0 and 8.6 Hz, 1 H); 7.41 (d, J = 9.8 m / z 581.

Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.94 (d, J = 2.0 Hz, 1 H); 8.52 (d, J = 9.8 Hz, 1 H); 11.88 (broad m, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, [M + H] +: m / z DEMO-d6): 0.23 to 0.30 (m, 2 H); 0.35 a 595; 0.44 (m, 2 H); 1.61 (m, 1 H); 2.40 to 2.60 [M + 2H] 2 +: (partially masked m, 8 H); 3.31 63 m / z 298 (s, 2 H); 7.08 to 7.24 (m, 3 H); 7.33 (dd, J = (base peak): 1.7 and 8.6 Hz, 1 H); 7.41 (d, J = 9.8 Hz, 1 [M-H] -: m / z H); 7.61 (d, J = 8.6 Hz, 1 H); 7.94 (d, J = 593. 1.7 Hz, 1 H); 8.52 (d, J = 9.8 Hz, 1 H); 12. 10 (broad m, 1 H).

Time of Retention Tr 3b (min) = 0.1; [M + H] +: m / z 185.

Ex. EM NMR 1 H NMR spectrum (400 MHz, d in ppm, DEMO-d6): 0.93 (t, J = 7.1 Hz, 6 H); 2.19 [M + H] +: m / z (s, 3 H); 2.43 (q, J = 7.0 Hz, 4 H); 3.46 (s, 64 520; [M-H] -: 2 H); 7.08 (dd, J = 1.7 and 8.1 Hz, 1 H); 7.21 m / z 518. to 7.38 (m, 5 H); 7.58 (d, J = 8.3 Hz, 1 H); 7. 86 (d, J = 1.7 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 12.37 (broad m, 1 H).

H NMR spectrum (400 MHz, d in ppm, DEMO-de): 0.93 (t, J = 7.1 Hz, 6 H); 2.43 (q, J = 7.1 Hz, 4 H); 3.37 (s, 3 H); 3.46 (s, [M + H] +: m / z 2 H); 4.19 (s, 2 H); 7.03 to 7.10 (m, 1 H); 65 550; [M- H] -: 7. 21 to 7.34 (m, 4 H); 7.36 (d, J = 9.8 Hz, 1 m / z 548 H); 7.60 (d, J = 8.6 Hz, 1 H); 7.87 (d, J = 1.7 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 12.34 (broad m, 1 H). 1 H NMR spectrum (400 MHz, d in ppm, DEMO-dg): 1.55 (broad d, J = 9.3 Hz, 1 H); 1.73 (dd, J = 2.0 and 9.3 Hz, 1 H); 2.39 (d, J = 9.9 Hz, 1 H); 2.70 (dd, J = 1.7 and 9.9 Hz, 1 H); 3.37 (s, 3 H); 3.41 (s broad, 1 [M + H] +: m / z H); 3.49 (dd, J = 1.7 and 7.6 Hz, 1 H); 3.61 66,576; [M- H] -: (d, J = 14.0 Hz, 1 H); 3.67 (d, J = 14.0 Hz, m / z 574. 1 H); 3.87 (d, J = 7.6 Hz, 1 H); 4.20 (s, 2 H); 4.29 (broad s, 1 H); 7.03 to 7.13 (m, 1 H); 7.22 to 7.34 (m, 4 H); 7.36 (d, J = 9.8 Hz, 1 H); 7.61 (d, J = 8.3 Hz, 1 H); 7.87 (d, J = 1.7 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 12.38 (broad m, 1 H).

RM NMR 1 H-NMR spectrum (400 MHz, d in ppm, DEMO-d 6): 4.53 (m, 2 H); 4.81 (m, 2 H); [M + H] +: m / z 5. 40 to 5.55 (m, 1 H); 7.17 (d, J = 10.3 Hz, 373; [M-H] -: 1 HOUR); 7.22 to 7.36 (m, 2 H); 7.61 (s broad, m / z 371. 2 H); 7.82 (broad s, 1 H); 8.34 (d, J = 9.8 Hz, 1 H) Time of Retention Tr (min) = 0. 41; [+ H] +: m / z 227. 1 H NMR spectrum (400 M Hz, d in ppm, DEMO-dfi): 1.91 to 2.05 (m, 1 H); 2.08 to 2.20 (m, 1 H); 2.53 (m, 4 H); 3.34 (s, 2 H); [+ H] +: m / z 3.58 to 3.63 (m, 4 H); 3.65 to 3.82 (m, 4 H); 514; [M-H] -: 5.30 (m, 1 H); 7.08 (d, J = 9.8 Hz, 1 H); m / z 512. 7.47 (dd, J = 2.1 and 8.6 Hz, 1 H); 7.70 (d, J = 8.6 Hz, 1 H); 8.12 (d, J = 2.1 Hz, 1 H); 8. 31 (d, J = 9.8 Hz, 1 H); 12.16 (broad m, 1 H).

Ex. EM NMR H NMR spectrum (400 MHz, d in ppm, DEMO-de): 2.53 (m, 4 H) 3.32 (s, 2 H); 3. 56 to 3.63 (m, 4 H); 7.12 to 7.24 (m, 3 H); [M + H] +: m / z 7. 32 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.41 (d, J 69 556; [M- H] -: = 9.8 Hz, 1 H); 7.58 (d, J = 8.6 Hz, 1 H); m / z 554. 7. 92 (d, J = 2.0 Hz, 1 H); 8.51 (d, J = 9.8 Hz, 1 H); 10.47 to 13.46 (very broad m, 1 H).

H NMR spectrum (400 MHz, d in ppm, DEMO-c / 6): 1.00 (t, J = 7.1 Hz, 6 H); 1.90 to 2.03 (m, 1 H); 2.07 to 2.22 (m, 1 H); 2.62 (q, J = 7.1 Hz, 4 H); 3.40 (s, 2 H); 3.63 a [M + H] +: m / z 70 3.84 (m, 4 H); 5.29 (m, 1 H); 7.08 (d, J = 500. 9. 8 Hz, 1 H); 7.47 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.69 (d, J = 8.3 Hz, 1 H); 8.12 (el, J = 2. 0 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 12.11 (broad m, 1 H).

H NMR spectrum (400 MHz, d in ppm, DEMO-de): 0.98 (t, J = 7.1 Hz, 3 H); 1.92 a [M + H] +: m / z 2.03 (m, 1 H); 2.10 to 2.22 (m, 1 H); 2.31 541; (q, J = 7.1 Hz, 2 H); 2.22 to 2.48 (broad m [M + 2H] 2 +: partially masked, 8 H); 3.30 (s) 71 m / z 271 partially masked, 2 H); 3.64 a (base peak): 3.84 (m, 4 H); 5.30 (m, 1 H); 7.08 (d, J = [M-H] -: m / z 9.8 Hz, 1 H); 7.47 (dd, J = 2.0 and 8.6 Hz, 1 539. H); 7.69 (d, J = 8.6 Hz, 1 H); 8.12 (d, J = 2. 0 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 11. 96 (broad m, 1 H).

RM NMR 1 H NMR spectrum (400 MHz, d in ppm, DEMO-de): 0.22 to 0.30 (m, 2 H); 0.36 to 0.43 (m, 2 H); 1.54 to 1.64 (m, 1 H); 1.90 a [M + H] +: m / z 2. 03 (m, 1 H); 2.06 to 2.19 (m, 1 H); 2.40 to 553; 2. 60 (m broad partly masked, [M + 2HJ2 +: 8 H); 3.36 (m partially masked, m / z 277 2H), 3.64 to 3.83 (m, 4 H); 5.30 (m, 1 H) (base peak): 7. 08 (d, J = 9.8 Hz, 1 H); 7.47 (dd, J = 2.0 [M-H] -: m / z and 8.6 Hz, 1 H); 7.69 (d, J = 8.6 Hz, 1 H); 551 8. 12 (d, J = 2.0 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 10.51 to 13.65 (very broad m, 1 H).

NMR spectrum? (400 MHz, d in ppm, DEMO-d6): 0.90 to 0.98 (m, 4 H); 1.94 to 2.04 (m, 1 H); 4.47 (m, 2 H); 4.71 (m, 2 H); [M + H] +: m / z 5'.39 to 5.48 (m, 1 H); 7.19 (d, J = 9.8 Hz, 1441; [M-H] -: H); 7.44 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.69 m / z 439 (d, J = 8.6 Hz, 1 H); 8.05 (d, J = 2.0 Hz, 1 H); 8.37 (d, J = 9.8 Hz, 1 H); 12.68 (broad m, 1 H).

RM NMR 1 H NMR spectrum (400 MHz, d in ppm, [M + H] +: m / z DEMO-rJ6): 0.97 (t, J = 7.1 Hz, 3 H); 2.30 527; (q, J = 7.1 Hz, 2 H); 2.32 to 2.57 (broad m [M + 2H] 2 +: partially masked, 8 H); 3.31 (s, 2 74 m / z 264 H); 4.46 (m, 2 H); 4.70 (m, 2 H); 5.42 (m, 1 (base peak): H); 7.20 (d, J = 9.8 Hz, 1 H); 7.44 (dd, J = [M-H] -: m / z 2.0 and 8.6 Hz, 1 H); 7.70 (d, J = 8.6 Hz, 1525. H); 8.06 (d, J = 2.0 Hz, 1 H); 8.38 (d, J = 9. 8 Hz, 1 H); 12.03 (broad m, 1 H).

H NMR spectrum (400 MHz, d in ppm, DEMO-de): 0.23 to 0.29 (m, 2 H); 0.35 a [M + HJ +: m / z 0. 42 (m, 2 H); 1.60 (m, 1 H); 2.40 to 2.60 539; (m broad partly masked, 8 [M + 2H] 2 +: H); 3.31 (s, 2 H); 4.46 (m, 2 H); 4.70 (m, 2 75 m / z 270 H); 5.42 (m, 1 H); 7.20 (d, J = 9.8 Hz, 1 H); (base peak): 7. 44 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.70 (d, J [M-H] -: m / z = 8.6 Hz, 1 H); 8.06 (d, J = 2.0 Hz, 1 H); 537 8. 38 (d, J = 9.8 Hz, 1 H); 12.09 (broad m, 1 H).

Example 76: Pharmaceutical composition Tablets have been prepared that respond to the following formula: Product of example 2 0.2 g Excipient for one tablet c. s. p 1 g (detail of the excipient: lactose, talc, starch, magnesium stearate).

Example 77: Pharmaceutical composition Tablets have been prepared that respond to the following formula: Product of example 5 0.2 g Excipient for one tablet c. s. p 1 g (detail of the excipient: lactose, talc, starch, magnesium stearate).

Examples 2 and 5 are taken as examples of pharmaceutical preparation, this preparation may be carried out, if desired, with other products of the examples of the present application.

Pharmacological part: Experimental protocols I) Expression and Purification of MET, cytoplasmic domain Expression in Baculovirus: The recombinant DNA H is-Tev-M ET (956-1390) in pFastBac (invitrogen) is transfected into insect cells and after several stages of viral amplification, the final set of baculoviruses is assayed for the expression of the protein of interest.

After infecting for 72 h at 27 ° C with the recombinant virus, the cultures of the SF21 cells are collected by centrifugation and the cell pellets are stored at -80 ° C.

Purification: Cell pellets are suspended in the lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, 10% Glycerol, 1 mM TECP] + Roche Diagnostics protease inhibitor mixture without EDTA, ref 1873580 ), are stirred at 4 ° C until homogeneity and then mechanically used using a "Dounce" type apparatus.

After centrifugation, the lysis supernatant is incubated 2 h at 4 ° C with the Nickel Chelate resin (His-Trap 6 Fast Flow ™, GE HealthCare). After washing with 20 volumes of Tp A, the suspension is packaged in a column and the proteins are eluted with a gradient of buffer B (TpA + imidazole 290 mM).

The fractions containing the protein of interest in view of the electrophoretic analysis (SDS PAGE) are pooled, concentrated by Ultrafiltration (10 kDa cut-off point) and injected onto an exclusion chromatography column (Superdex ™ 200, GE HealthCare) balanced with cushion A.

After the enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new Nickel Chelate IMAC chromatography column (His-Trap 6 Fast Flow ™, GE HealthCare) equilibrated with Shock Absorber A. The fractions eluted with a B buffer gradient. and which contain the protein of interest after electrophoresis (SDS PAGE), are finally pooled and stored at -80 ° C.

For the production of the autophosphorylated protein, the above fractions are incubated 1 h at room temperature after adding 2 mM ATP, 2 mM MgCl 2 and 4 mM Na 3 V0 4. After stopping the reaction with 5 mM EDTA, the reaction mixture is injected over a HiPrep desalting column (GE HealthCare) previously equilibrated in 4 mM A + Na3V04 buffer, the fractions containing the protein of interest (SDS PAGE analysis) are brought together and stored at -80 ° C. The phosphorylation rate is verified by mass spectrometry (LC-MS) and by peptide mapping.

II) Tests A and B and C A) Assay A: HTRF MET assay in 96-well format In a final volume of 50 μ? of enzymatic reaction, final 5 nM MET is incubated in the presence of the molecule to be tested (for a range of final concentrations of 0.17 nM to 10 μ, final 3% DEMO) in 10 mM MOPS buffer pH 7.4, 1 mM DTT, Tween 20 at 0.01%. The reaction is initiated by the solution of the substrates to obtain the final concentrations of p or I i - (GAT) 1 pg / ml, ATP 10 μ? and 5 mM MgCl 2. After a 10 min incubation at room temperature, the reaction is stopped by a mixture of 30 μ? to obtain a final solution of 50 mM Hepes pH 7.5, 500 mM potassium fluoride, 0.1% BSA and 133 mM EDTA in the presence of 80 ng of Streptavidin 61 SAXLB Cis-Bio Int. and 18 ng of anti-Phosphotyrosine Mab PT66- Euripium cryptate per well. After 2 hours of incubation at room temperature, the reading is performed at 2 wavelengths 620 nm and 665 nm in a reader for the TRACE / HTRF technique and the% inhibition is calculated according to the 665/620 ratios.

The results obtained with this test A for the products of formula (I) of the examples of the experimental part are such that CI5o is less than 500 nM and especially 100 nM. B) Test B: Inhibition of MET autophosphorylation; ELISA technique (pppY1230, 1234, 1235). a) Cell lysates: Seed KN45 cells in 96-well plates (coated with polylysine BD) at 20,000 cells / well in 200 μ? in RPMI medium + 10% SVF + 1% L-glutamine. Leave to adhere 24 hours in the incubator.

The cells are treated the day after sowing with the products at 6 concentrations in duplicate for 1 h. At least 3 control wells are treated with the same amount of final DEMO.

Dilution of the products: Mother dissolution at 10 mM in pure DEMO - Interval from 10 mM to 30 μ? with a step of 3 in pure DEMO - Intermediate dilutions to 1/50 in culture medium and 10 μ intake? that are added directly to the cells (200 μ?): final interval of 10000 to 30 nM.

At the end of the incubation, gently remove the supernatant and wash with 200 μ? of PBS. Then enter 100 μ? of lysis buffer directly in ice wells and incubate at 4 ° C for 30 minutes. Lysis buffer: 10 mM Tris, HCl pH 7.4, 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 20 mM NaF , 2 mM Na3V04, 1 mM PEMF and antiprotease mixture.

The 100 μ? Used are transferred to a V-bottom polypropylene plate and ELISA is performed immediately or the plate is frozen at -80 ° C. b) ELISA Phospho ET BioSource Kit KHO0281 In each well of the kit plate, add 70 μ? of dilution buffer of the kit + 30 pL of cell lysate or 30 μ? of lysis buffer for whites. Incubate for 2 h with gentle shaking at room temperature.

Wash the wells 4 times with 400 μ? of the wash buffer of the kit. Incubate with 100 μ? of anti-phospho TEM antibodies for 1 h at room temperature.

Wash the wells 4 times with 400 μ? of the wash buffer of the kit. Incubate with 100 μ? of rabbit anti-HRP antibodies for 30 minutes at room temperature (except for the wells only with chromogen).

Wash the wells 4 times with 400 μ? of the wash buffer of the kit. Put 100 pL of chromogen and incubate for 30 minutes in the dark at room temperature.

Stop the reaction with 100 μ? of stop dissolution. Read immediately at 450 nM 0.1 seconds in Wallac Víctor plate reader.

C) Test C: Measurement of cell proliferation by pulses with 14C-thymidine.

The cells are seeded in 96-well Cytostar plates in 180 μ? for 4 hours at 37 ° C and 5% C02: HCT116 cells at a rate of 2500 cells per well in DMEM medium + 10% fetal calf serum + 1% L-Glutamine and MKN45 cells at a rate of 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine. After these 4 hours of incubation, the products are added in 10 μ? in solution 20 times concentrated according to the aforementioned dilution method for ELISA. The products are tested at 10 concentrations in duplicate from 10000 nM to 0.3 nM with a step of 3.

After 72 h of treatment, add 10 μ? of 14 C-thymidine at 10 pCi / ml to obtain 0.1 pCi per well. The incorporation of 14C-thymidine is determined with a Micro-Beta (Perkin-Elmer) after 24 hours of pulses and 96 hours of treatment.

All stages of the test are automated at the BIOMEK 2000 or TECAN stations.

The results obtained with this test B for the products of formula (I) of the examples of the experimental part are such that they have a Cl50 of less than 10 microM and especially of 1 microM.

The results obtained for the products in the examples in the experimental part are given in the pharmacological results table below, as follows: for test A, the + sign corresponds to less than 500 nM and the sign ++ corresponds to less than 100 nM. for test B the + sign corresponds to less than 500 nM and the sign ++ corresponds to less than 100 nM. for the C test the + sign corresponds to lower microM and the sign ++ corresponds to less than 1 microM.

Table of pharmacological results: number of ej. test A test B test C 1 + + + + + + 2 + + + + + + 3 + + + + + + 4 + + + + + + 5 + + + + + + 6 + + + + + + 7 + + + +. + + 8 + + + + 9 + + + + + + 10 + + + + + + 11 + + + + + + 12 + + + + + + number of ej. test A test B test C 13 + + + + + + 14 + + + + + + 15 + + + 16 + + + + + 17 + + + + + + 18 + + + 19 + + + + + + 20 + + + + + + 21 + + + + + + 22 + + + + + + 23 + + + + + + 24 + + + + + + 25 + + + + + + 26 + + + + + 27 + + + 28 + + + + + 29 + + + + + + 30 + + + + + + 31 + + + + + + 32 + + + + + + 33 + + + + + + 34 + + + + + + number of ej. test A test B test C 35 + + + + + + 36 + + + + 37 + + + + 38 + + + + + 39 + + 40 + + + + + 41 + + + + + + 42 + + + + + + 43 + + + + + + 44 + + + + + + 45 + + + + + + 46 + + + + + 47 + + + + + + 48 + + + 49 + + + + + + 50 + + + + + + 51 + + + + + + 52 + + + + + 53 + + + + + 54 + + + + + 55 + + + + + 56 + + + + + + number of ej. test A test B test C 57 + + + + + + 58 + + + + + + 59 + + + + + 60 + + + + + + 61 + + + + + + 62 + + + + + + 63 + + + + + + 64 + + + + + + 65 + + + + 66 + + + + + 67 + + + 68 + + + + + 69 + + + + + + 70 + + + + 71 + + + + + 72 + + + + + + 73 + + + + + + 74 + + + 75 + + +

Claims

CLAIMS Products of formula Ra where represents a single or double bond; Rb represents a hydrogen atom or a fluorine atom; Ra represents a radical -O-Z-Rc wherein: Z represents a single bond or a linear or branched alkylene radical having 1 to 6 carbon atoms and which is optionally substituted with an alkyl group or a halogen atom; Re represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical; X represents S, SO or S02, A represents NH or S; W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, -0-CO-R5, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n represents an integer from 1 to 4; or the radical NR1R2 wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals selected from the hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 radicals, optionally substituted phenyl; or R1 and R2 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, optionally S being optionally in the form of SO or S02; what even the radicals containing NH optionally is, optionally substituted; - with R3 and R4, identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals selected from the group consisting of hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIq, N (Alq) 2 radicals, optionally substituted phenyl; or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, optionally S being optionally in the form of SO or S02; what even the radicals containing NH optionally is, optionally substituted; all the radicals defined above being alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, substituted optionally with one or more radicals selected from the halogen atoms, the hydroxyl, oxo, alkoxy, -0-CO-R5, -OR5 -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH- radicals CO-R5, -NHCOOR5 and the alkyl, heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl radicals, in the latter radicals, the alkyl, alkoxy, heterocycloalkyl radicals, phenyl and heteroaryl are themselves optionally substituted with one or more radicals selected from the halogen atoms and the hydroxyl, oxo, alkyl and alkoxy radicals having from 1 to 4 carbon atoms, NH2, NHalq and N (alk) 2; all the radicals defined above being also, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl, optionally substituted with a radical Si (alk) 3; R5 and R5 ', identical or different, represent an alkyl or cycloalkyl radical having at most 6 carbon atoms; alk represents an alkyl radical having at most 4 carbon atoms; it being understood that:

1) when Rb represents hydrogen and Z represents a single bond, then Re does not represent a cycloalkyl radical; and ii) when Rb represents hydrogen and Z represents an alkylene radical, then Re does not represent a heterocycloalkyl radical, such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

2) The products of formula (I) as defined in claim 1, wherein represents a single or double bond; Ra represents a radical -O-Z-Rc wherein Z represents a single bond and Re represents an optionally substituted aryl; Rb represents a hydrogen or fluorine atom; X represents S, SO or S02; A represents NH or S; W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, -0-CO-R5, hydroxy, phenyl, heteroalkyl, or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n represents an integer from 1 to 4; or the radical NR1R2 wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals selected from the hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 form with the nitrogen atom to which they are attached, a cyclic radical having 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, optionally S being optionally in the form of SO or S02; what even the radicals containing NH optionally is, optionally substituted; with R3 and R4, identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals selected from the radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIq, N (Alq.) 2 or phenyl optionally substituted; or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, optionally S being optionally in the form of SO or S02; what even the radicals containing NH optionally is, optionally substituted; all the radicals defined above being alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, substituted optionally with one or several radicals selected from the halogen atoms, the hydroxyl, oxo, alkoxy, -0-CO-R5, -OR5, NH2, NHalq, N (alk) 2 radicals and the alkyl, cycloalkyl, heterocycloalkyl, CH2 radicals -heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such that in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals selected from the group consisting of halogen atoms and the hydroxyl, oxo, alkyl and alkoxy radicals having from 1 to 4 carbon atoms, NH2, NHalq and N (alk) 2; R5 represents an alkyl or cycloalkyl radical having at most 6 carbon atoms; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

3) The products of formula (I) as defined in any of the claims, wherein zz > Ra > And X have the values defined in any of the other claims and: A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR where R represents: a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, '-0-CO-R5, hydroxy, phenyl or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or with heterocycloalkyl; an O-phenyl radical or a 0- (CH2) n-phenyl radical, with the phenyl optionally substituted and n represents an integer from 1 to 4; or the radical NR1R2, wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with an alkoxy, heterocycloalkyl, or NR3R4 radical; or R1 and R2 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more heteroatoms, selected from O, S, N and NH, including the radicals it contains. NH optionally is, optionally substituted; with NR3R4 such that R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical or a heterocycloalkyl radical optionally substituted with one or more identical or different radicals selected from alkoxy, heteroaryl, heterocycloalkyl or NH2 radicals, NHAIq, N (Alk) 2, or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical having from 3 to 10 members and optionally one or more different heteroatoms selected from O, S, N and NH, that even the radicals containing NH optionally are, optionally substituted; all the alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, defined above, are optionally substituted with one or several radicals selected from the halogen atoms, the hydroxyl, alkoxy, O-cycloalkyl, NH2, NHalq, N (alk) 2 radicals and the alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter In the case of radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals themselves are optionally substituted with one or more radicals selected from the halogen atoms and the hydroxyl, alkyl and alkoxy radicals having from 1 to 4 carbon atoms, NH2, NHalk and N (alk) 2; IÜ such products of the formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of the formula (I) . i5

4) The products of formula (I) such as those defined in any of the claims, wherein z i. < ^ a > V * have the values defined in any of the other claims and: A represents NH or S; 0 W represents a hydrogen atom; an alkyl radical optionally substituted with a heterocycloalkyl radical or NR3R4; or the radical COR where R represents: a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, or alkoxy; 25 -. 25 - an O-phenyl radical or 0- (CH2) n-phenyl, with the phenyl optionally substituted and n represents an integer from 1 to 2; or the radical NR1R2, wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, an alkyl radical optionally substituted with a heterocyclic radical or NR3R4, or R1 and R2 form with the nitrogen atom to which they are attached, a cyclic radical optionally having one or more different heteroatoms selected from O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; with NR3R4 such that R3 and R4, identical or different, represent a hydrogen atom or an alkyl radical or R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical optionally containing one or more different heteroatoms selected between O, S, N and NH, which even the radicals containing NH optionally is, optionally substituted; all the cycloalkyl, heterocyclic and phenyl radicals as well as the cyclic radicals which can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, defined above, optionally substituted with one or more radicals selected from the halogen atoms , the hydroxyl, alkoxy, O-cycloalkyl, NH2, NHalk, N (alk) 2 radicals and the alkyl and phenyl radicals, the latter themselves being optionally substituted with one or more radicals selected from halogen atoms and hydroxyl radicals, alkyl and alkoxy having from 1 to 4 carbon atoms, NH2, NHalq and N (alk) 2; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

5) The products of formula (I) as defined in any of the claims, wherein A represents NH, the substituents Ra, Rb, X and W being selected from all values defined for these radicals in any of the other claims , such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I) .

6) The products of formula (I) as defined in any of the claims, wherein A represents NH, substituents Ra, Rb, X and W being selected from all values defined for these radicals in any of the other claims , such products of formula (I) being in all possible forms of isomers, racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

7) The products of formula (I) such as those defined in any of the other claims, which correspond to formula (la) or (Ib): R a wherein z, Ra, Rb, and W are selected from the meanings indicated in any of the other claims, such products of formula (la) and (Ib) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (la) and (Ib).

8) The products of formula (I) as defined in any of the claims, wherein represents a double bond that respond to the products of formula (I "): A H \ / - /? N W (i ") wherein the substituents Ra, Rb, X, A and W have any of the meanings indicated above or indicated below, such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

9) The products of formula (I) as defined in any of the claims, wherein represents a double bond that respond to the products of formula (I "a): wherein Ra, Rb, and W are selected from any of the meanings indicated above or indicated below, such products of the formula (I "a) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of the formula (I). "to).

10) The products of formula (I) as defined in any of the claims, wherein represents a double bond that respond to the products of formula (I "b): Ra wherein Ra, Rb and W are selected from any of the meanings indicated above or indicated below, such products of formula (1b) being present in all possible forms of isomers, racemates, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I). "b).

11) Products of formula (I) as defined in any of the claims, wherein: represents a single or double bond Ra represents an -O-phenyl radical optionally substituted with one or more halogen atoms; Rb represents a hydrogen atom; X represents S; A represents S; W represents a hydrogen atom; or the radical COR where R represents: a cycloalkyl radical, or an alkyl radical; or the radical NR1R2 wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, and the other of R1 and R2 represents an alkyl radical optionally substituted with a heterocycloalkyl radical; such products of formula (I) being present in all possible forms of isomers, racemates, enantiomers and diastereomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of such products of formula (I).

12) The subject of the present invention is therefore the products of formula (I) such as those defined above or defined below, which correspond to the following formulas: 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine; N-. { 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide; N-. { 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acet amide; 1- [2- (morpholin-4-yl) ethyl] -3-. { 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea; 1- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2 -yl) -3- [2- (morpholin-4-yl) ethyl] urea; 6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; - N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2 -yl) -2- (2-methoxyethoxy) acetamide; N2, N2-diethyl-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1, 3-benzothiazol-2-yl) glycinamide; N 2 -cyclopropyl-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1,3- benzothiazol-2-yl) glycinamide; N- [6- ( { 6- [3- (morpholin-4-ylmethyl) phenoxy] [1, 2,4] triazolo [4,3-b] pindazin-3-M.}. Sulfanil) -1 , 3-benzothiazol-2-yl-cyclopropan oca rboxa mide; - N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2 -yl) acetamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) cyclopropanecarboxamide; 1- (6- { [6- (4-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) -3- [2- (morpholin-4-yl) ethyl] urea; 1- (6- { [6- (3-fluoro-4-methylphenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1,3- benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea; 6- { [6- (tetrahydro-2 H -pyran-4-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1, 3-benzothiazol-2-amine; 6- { [6- (4-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; 1- [2- (morpholin-4-yl) ethyl] -3- (6- { [6- (tetrahydro-2 H -pyran-4-yloxy) [1,2,4] triazolo [4.3- b] pyridazin-3-yl] sulfanyl.] -1,3-benzothiazol-2-yl) urea; 1 - . 1 - . 1 - . 1 - [6- ( {6 - [(1-ethylpiperidin-4-yl) oxy] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl}. Sulfanil) -1 , 3-benzothiazol-2-yl] -3- [2- (morpholin-4-yl) ethyl] urea; N- (6- { [6- (tetrahydro-2 H -pyran-4-yloxy) [1, 2,4] triazolo [4,3 b] pyridazin-3-yl] sulfanyl.} -1, 3 -benzothiazol-2-yl) cyclopropanecarboxamide; N- (6- { [6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) cyclopropanecarboxamide; N- (6- { [6- (3-fluoro-4-methylphenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1.3- benzothiazol-2-yl) cyclopropanecarboxamide; N- [6- ( {6 - [(1-ethylpiperidin-4-yl) oxy] [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl.}. Sulfanyl) -1 , 3-benzothiazol-2-yl] cyclopropanecarboxamide; 1- [2- (morpholin-4-yl) ethyl] -3- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin- 3-yl] sulfanyl.] -1,3-benzothiazol-2-yl) urea; 1 - (6- { [6- (1, 3-benzodioxol-5-yloxy) [1, 2, 4] triazolo [4, 3-b] pyridazin-3-yl] sulfanyl.} -1, 3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea; 1 - . 1 - (6- { [6- (3,4-dichlorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1, 3 -benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea; 6- { [6- (3,4-dichlorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; 6- { [6- (tetrahydrofuran-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; 1 - (6- { [6- (1 H -indole-6-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulphanil.} -1,3 -benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea; - N- (6- { [6- (tetrahydrofuran-3-yloxy) [1, 2, 4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) cyclopropanecarboxamide; N- (6- { [6- (1, 3-benzodioxol-5-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1, 3-benzothiazol-2-yl) cyclopropanecarboxamide; N- (6- { [6- (3,4-dichlorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazole- 2-yl) cyclopropanecarboxamide; N- (6- { [6- (1 H -indole-6-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1, 3-benzothiazol-2-yl) cyclopropanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) cyclobutanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) -N, N2-dimethylglycinamide; - 2-ethoxy-N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanil} -1, 3-benzothiazol-2-yl) acetamide; 2- (cyclohexyloxy) -N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1, 3-benzothiazol-2-yl) acetamide; - 6- { [6- (pyridin-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-I] s or I f a n i I} - 1, 3 - b e n z o t i a z o I - 2 - a m i n a; 6- ( { 6- [3- (trifluoromethoxy) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-M.}. Sulfanyl) -1,3-benzothiazole- 2-amine; [3- ( { 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl}. oxy) phenyl] carbamate of 2-methylpropan-2-yl; N- (6- { [6- (pyridin-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazole- 2-yl) cyclobutanecarboxamide; N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) -2- (morpholin-4-yl) acetamide; N 2 -cyclohexyl-N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1,3- benzothiazol-2-yl) glycinamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-M] sulfanyl.] -1, 3-benzothiazole-2- il) -N2-methyl-N2- [2- (morpholin-4-yl) ethyl] glycinamide; 2- (4-ethylpiperazin-1-yl) -N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pindazin-3-M] sulfani !.) -1,3-benzothiazol-2-yl) acetamide; - 6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1, 3-benzothiazol-2-amine; 6- { [6- (3-aminophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazol-2-amine; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole-2- il) -N ~ 2 ~ - (tetrahydro-2H-pyran-4-yl) glycinamide; N- [6- ( { 6- [4- (trifluoromethyl) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl}. Sulfanyl) -1,3-benzothiazole -2-yl] cyclopropanecarboxamide; - N- [6- (. {6- [3- (trifluoromethoxy) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl.} Sulfanil) -1,3- benzothiazol-2-yl] cyclopropanecarboxamide; N- [6- ( {6 - [(2-methylpyridin-3-yl) oxy] [1, 2, 4] triazolo [4,3-b] pyridazin-3-yl}. Sulfanil) -1 , 3-benzothiazol-2-yl] cyclopropanecarboxamide; N- (6- { [6- (3,5-difluorophenoxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl] -1,3-benzothiazole- 2-yl) cyclopropanecarboxamide; 2 - [(6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole acetate -2-yl) amino] -2-oxoethyl; N- [6- (. {6 - [(6-Methylpyridin-3-yl) oxy] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanil) -1 , 3-benzothiazole-2-I-cyclop clothing noca rboxam da; N- [6- (. {6- [4- (Morpholin-4-ylmethyl) phenoxy] [1,4] triazolo [4,3-b] pyridazin-3-yl}. Sulfanyl) -1 , 3-benzothiazole-2- il] cyclopropanecarboxamide; (3- { [3- ( { 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl.] Sulfanyl] [1,2,4] triazolo [4, 3-b] pyridazin-6-yl] oxy] phenyl) carbamate of 2-methylpropan-2-yl; N- (6- { [6- (pyridin-3-yloxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulphanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide; N-. { 6 - [(6- { 3 - [(1 S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy]. [1,2, 4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide; N-. { 6 - [(6- { 3- [(diethylamino) met.l] phenoxy]. [1,2,4] triazolo [4,3-b] p¡r¡daz¡n-3- il) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide; N- (6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl. 1,3-benzothiazol-2-yl) -N2, N2-diethylglycinamide; N- (6- { [6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanii.] -1,3-benzothiazole -2-l) -2-hydroxyacetamide; 2- (4-Cyclopropyl-piperazin-1-yl) -N- (6- { [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyra dazin-3-yl] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; N- (6- { [6- (3,5-d.fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.} -1,3 -benzothiazol-2-yl) -2- (4-ethylpiperazin-1-yl) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin -3-yl] sulfanyl] -1,3- benzothiazol-2-yl) acetamide; N-. { 6 - [(6- { 3- [(diethylamino) methyl] phenoxy]. [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulphanyl] -1, 3-benzothiazol-2-yl} acet amide; N-. { 6 - [(6- { 3- [(diethylamino) methyl] phenoxy]. [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] - 1,3-benzothiazol-2-yl} -2-methoxyacetamide; 2-methoxy-N-. { 6 - [(6- { 3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy]. [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamida; 6- { [6- (oxetan-3-yloxy) [1,4] triazolo [4,3-b] pyridazin-3-yl] sulfanil} -1,3-benzothiazole-2-amino; 2- (morpholin-4-yl) -N- (6- { [6- (tetrahydrofuran-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazine- 3-yl] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; N- (6- { [6- (3,5-difluorophenoxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl.] -1, 3-benzot Azol-2-yl) -2- (morpholin-4-yl) acetamide; N2, N2-diethyl-N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] p¡r¡dazin-3-l ] sulfanyl] -1,3-benzothiazol-2-yl) gluccinamide; 2- (4-ethylpiperazin-1-U) -N- (6- { [6- (tetrahydrofuran-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin -3-yl] sulfanyl.] -1,3-benzothiazole-2-yl) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3- il] sulfanyl.] -1, 3-benzothiazol-2-yl) acetamide; N- (6- { [6- (oxetan-3-yloxy) [1, 2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanM.] -1, 3-benzothiazole- 2-yl) cyclopropanecarboxamide; 2- (4-ethylpiperazin-1-yl) -N- (6- { [6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; 2- (4-cyclopropylpiperazin-1-yl) -N- (6- { [6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl] -1,3-benzothiazol-2-yl) acetamide; as well as the addition salts with the mineral and organic acids or with the mineral and organic bases, of such products of formula (I).

13) A process for preparing the products of formula (I) as defined in any of the other claims.

14) A process for preparing the products of formula (I) as defined in any of the other rei indications, wherein A represents NH.

15) A process for preparing the products of formula (I) as defined in any of the other claims, wherein A represents S.

16) As medicaments, the products of formula (I) as defined in any of claims 1 to 12, as well as the addition salts with the mineral acids and organic or with the pharmaceutically acceptable organic and mineral bases of such products of formula (I).

17) As medicaments, the products of formula (I) as defined in claim 12, as well as the addition salts with the mineral and organic acids or with the pharmaceutically acceptable mineral and organic bases of such products of formula (I) ).

18) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in any of claims 1 to 12, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable support.

19) The use of the products of formula (I) as defined in any of claims 1 to 12, or of pharmaceutically acceptable salts of these products for the preparation of a medicament intended for the inhibition of the activity of the protein MET kinase and its mutant forms.

20) The use as defined in claim 19, wherein the protein kinase is in a cell culture.

21) The use as defined in any of claims 19 or 20, wherein the protein kinase is in a mammal.

22) The use of a product of formula (I) as defined in any of claims 1 to 12, for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders of proliferation of blood vessels, fibrotic disorders, disorders of the proliferation of 'mesangial' cells, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.

23) The use of a product of formula (I) as defined in any of claims 1 to 12, for the preparation of a medicament for the treatment of cancers.

24) The use according to claim 23, for the treatment of solid or liquid tumors.

25) The use according to claim 23 or 24, for the treatment of cancers resistant to cytotoxic agents.

26) The use according to one or more of claims 23 to 24, intended for the treatment of primary tumors and / or metastases in particular in gastric, hepatic, renal, ovarian, colon, prostate, lung (NSCLC and SCLC), glioblastomas, thyroid, gallbladder, breast cancers, in melanomas, in lymphoid or myeloid hematopoietic tumors, in sarcomas, in cancers of the brain, larynx, lymphatic system, cancers of bones and pancreas.

27) The use of the products of formula (I) as defined in claims 1 to 12, for the preparation of drugs intended for the chemotherapy of cancers.

28) The use of the products of formula (I) as defined in claims 1 to 12, for the preparation of drugs intended for the chemotherapy of cancers alone or in association.

29) The products of formula (I) as defined in any of claims 1 to 12, as inhibitors of kinases.

30) The products of formula (I) as defined in any of claims 1 to 12, as MET inhibitors.

31) As new industrial products, the synthesis intermediates of formulas 1, M2, M3 and N where Rb represents a fluorine atom F, such as defined below: wherein the groups CONR1R2, C02R6 and COR7, which constitute W, can take the values of W such as defined in any of claims 1 to 11, for the products of formulas (G) and (I "), when W? H.