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EP1441725A1 - Benzimidazoles and analogues and their use as protein kinases inhibitors - Google Patents

Benzimidazoles and analogues and their use as protein kinases inhibitors

Info

Publication number
EP1441725A1
EP1441725A1 EP02801954A EP02801954A EP1441725A1 EP 1441725 A1 EP1441725 A1 EP 1441725A1 EP 02801954 A EP02801954 A EP 02801954A EP 02801954 A EP02801954 A EP 02801954A EP 1441725 A1 EP1441725 A1 EP 1441725A1
Authority
EP
European Patent Office
Prior art keywords
benzoimidazol
pyrazol
carboxylic acid
dimethyl
amide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02801954A
Other languages
German (de)
English (en)
French (fr)
Inventor
Michael Louis Edwards
Paul Joseph Cox
Shelley Amendola
Stephanie Daniele Deprets
Timothy Alan Gillespy
Christopher David Edlin
Andrew David Morley
Charles J. Gardner
Brian Pedgrift
Hervé Bouchard
Didier Babin
Laurence Gauzy
Alain Le Brun
Tahir Nedeem Majid
John C. Reader
Lloyd J. Payne
Nawaz M. Khan
Michael Cherry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
Original Assignee
Aventis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR0113868A external-priority patent/FR2831537B1/fr
Priority claimed from GB0206893A external-priority patent/GB0206893D0/en
Priority claimed from GB0206895A external-priority patent/GB0206895D0/en
Application filed by Aventis Pharmaceuticals Inc filed Critical Aventis Pharmaceuticals Inc
Publication of EP1441725A1 publication Critical patent/EP1441725A1/en
Withdrawn legal-status Critical Current

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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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Definitions

  • This invention is directed to benzimidazoles of formula (Ix), their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of the protein kinases.
  • protein kinases belong especially to the following group: EGFR, Fak, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PDGFR, tie2, VEGFR, ITK and SYK.
  • Protein kinases are a family of enzymes that participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in ' the environment. In general, these kinases fall into several groups; those which preferentially catalyse the phosphorylation of hydroxy groups of serine and/or threonine residues and those which preferentially catalyse the phosphorylation of hydroxy groups of tyrosine residues [S.K.Hanks and T.Hunter, FASEB. J., 1995, 9, pages 576-596]. Such phosphorylations may greatly modify the function of the proteins; thus, protein kinases play an important role in regulating a wide variety of cell processes including, especially, metabolism, cell proliferation, cell differentiation or cell survival.
  • Angiogenesis or the formation of new blood vessels by sprouting from the preexisting vasculature is of central importance for embryonic development and organogenesis. Should the need arise, the vascular system has the potential to generate a network of new vessels so as to maintain the correct functioning of the tissues and organs.
  • Angiogenesis is a complex multistage process which includes activation, migration, proliferation and survival of endothelial cells. In adults, angiogenesis is fairly limited, appearing mainly only in the processes of repair after an injury or of vascularization of the endometrium. (Merenmies et al., Cell Growth & Differentiation, 8, 3-10, 1997).
  • VEGF-R2 vascular endothelial growth factor receptor 2, also known as KDR, kinase insert domain receptor, or FLK-1
  • FGF-R fibroblast growth factor receptor
  • Tie-2 vascular endothelial growth factor receptor 2
  • VEGFRs Vascular Endothelial Growth Factor receptors
  • the family VEGFR includes VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR3 (Flt4).
  • the receptor VEGF-R2 which is expressed only in the endothelial cells, binds to the angiogenic growth factor VEGF, and thus serves as a transduction signal mediator via the activation of its intracellular kinase domain.
  • VEGF-R2 direct inhibition of the kinase activity of VEGF-R2 makes it possible to reduce the phenomenon of angiogenesis in the presence of exogenous VEGF (Strawn et al., Cancer Research, 56, 3540-3545, 1996), this process being demonstrated especially with the aid of VEGF-R2 mutants (Millauer et al., Cancer Research, 56, 1615-1620, 1996).
  • the VEGF-R2 receptor appears to have no other function in adults than that associated with the angiogenic activity of VEGF.
  • a selective inhibitor of the kinase activity of VEGF-R2 should show only little toxicity.
  • KDR inhibitors thus especially constitute anti-angiogenic agents and such agents might be used as a first line treatment against the emergence or regrowth of malignant tumours.
  • the inhibition or regulation of VEGFR-2 (KDR) thus provides a powerful new mechanism of action for the treatment of a large number of solid tumours.
  • the present patent application thus relates particularly to novel inhibitors of the VEGFR-2 (KDR) receptor that may be used especially for anti-angiogenic treatment in oncology.
  • KDR VEGFR-2
  • the protein kinases which preferentially catalyse the phosphorylation of hydroxy groups of serine and/or threonine residues include for example, protein kinase C isoforms [A.C.Newton, J. Biol. Chem., 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases such as cdk2 [J.Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-197].
  • the protein kinases which preferentially catalyse the phosphorylation of hydroxy groups of serine and/or threonine residues include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [S.Iwashita and M.Kobayashi, Cellular Signalling, 1992, 4, pages 123-132], and cytosolic non-receptor kinases such as p561ck, p59fYn, ZAP-70 and csk kinases [C.Chan et. al., Ann. Rev. Immunol, 1994, 12, pages 555-592].
  • membrane-spanning growth factor receptors such as the epidermal growth factor receptor [S.Iwashita and M.Kobayashi, Cellular Signalling, 1992, 4, pages 123-132]
  • cytosolic non-receptor kinases such as p561ck, p59fYn, ZAP-70 and csk kinases [C.Chan et. al
  • SYK Single Tyrosine Kinase
  • Fc ⁇ Rl the high affinity IgE receptor
  • Fc ⁇ Rl the high affinity IgE receptor
  • T and B lymphocytes The signal transduction pathways present in mast, T and B cells have common features.
  • the ligand binding domain of the receptor lacks intrinsic tyrosine kinase activity.
  • ITAMs immunoreceptor tyrosine based activation motifs
  • TCR T cell receptor
  • BCR B cell receptor
  • SYK belongs to a unique class of tyrosine kinases that have two tandem Src homology 2 (SH2) domains and a C terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs and this SH2 -mediated association of SYK with an activated receptor stimulates SYK kinase activity and localises SYK to the plasma membrane.
  • SH2 domains bind with high affinity to ITAMs and this SH2 -mediated association of SYK with an activated receptor stimulates SYK kinase activity and localises SYK to the plasma membrane.
  • SYK is further involved in the activation of platelets stimulated via the low-affinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen [F.Yanaga et al., Biochem. J., 1995, 311, (PL 2) pages 471- 478].
  • Fc gamma-RIIA low-affinity IgG receptor
  • ITK is a T cell specific tyrosine kinase of the Tec family that is required for normal Th2 function. Asthma is a disease characterised by increased Th2 cytokine production including IL-4. An inhibitor of ITK should therefore have an impact on disease progression in asthma through inhibition of Th2 cytokine production.
  • the present invention is directed to pharmaceutical compositions comprising compounds of general formula (Ix):-
  • X represents C-R ⁇ and W, Y and Z, which may be identical or different, represent CH or CR ⁇ ; or
  • W represents CH, X represents N, Y represents CH or CR ⁇ , and Z represents CH or CR ⁇ ; or
  • W represents N
  • X represents CH or CR ⁇
  • Y represents CH and CR ⁇
  • Z represents CH or CR ⁇
  • W represents N
  • X represents CH or CR ⁇
  • Y represents N
  • Z is CH or CR ⁇
  • W represents N
  • X represents CH or CR ⁇
  • Y represents CH or CR ⁇
  • Z represents N
  • W represents N
  • X represents N
  • Y represents CH or CR ⁇
  • Z represents CH or CR ⁇
  • A5 represents H or alkyl
  • R 2 and R 3 are such that:
  • R 5 is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
  • the invention concerns the compounds of formula (Ix) as defined above wherein R 1
  • R ' is hydrogen or alkyl
  • Patient includes both human and other mammals.
  • Acid bioisostere means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,2 l,p283 "Bioisosterism In Drug Design”; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application Of Bioisosterism To New Drug Design”; Zhao, Huaxue Tongbao, 1995, pages 34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design”; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Desig ab initio Electronic Distributions In Bioisosteres”).
  • Alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain and containing one or more double bonds. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain, which may be straight or branched.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, decenyl, and 3,7-dimethyl-octa-2,6-dienyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as described herein.
  • exemplary alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear or branched positional isomers thereof.
  • Alkoxycarbonyl means an alkyl-O-CO- group in which the alkyl group is as described herein.
  • exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • Alkyl means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain having about 1 to about 15 carbon atoms in the chain, optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms.
  • “Lower alkyl” as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be a straight or branched chain having 1 to about 4 carbon atoms in the chain.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl and dodecyl, and also the linear or branched positional isomers thereof.
  • Exemplary alkyl groups substituted by one or more halogen atoms include trifluoromethyl, difluoromethyl, trifluoroethyl and difluoroethyl.
  • Alkylene means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein.
  • Exemplary alkylene radicals include methylene, ethylene and trimethylene.
  • Alkylenedioxy means an -O-alkylene-O- group in which alkylene is as defined above.
  • exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
  • Alkylsulfmyl means an alkyl-SO- group in which the alkyl group is as previously described.
  • Preferred alkylsulfmyl groups are those in which the alkyl group is C
  • Alkylsulfonyl means an alkyl-S0 2 - group in which the alkyl group is as previously described.
  • Preferred alkylsulfonyl groups are those in which the alkyl group is Ci ⁇ alkyl.
  • Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C ⁇ alkyl.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • exemplary alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio, isohexylthio and heptylthio, and also the linear or branched positional isomers thereof.
  • Preferred alkylthio groups have not more than 4 carbon atoms.
  • Alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which group may be a straight or branched chain having about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain.
  • Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
  • Aroyl means an aryl-CO- group in which the aryl group is as described herein.
  • Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
  • Aroylamino is an aroyl-NH- group wherein aroyl is as previously defined.
  • Aryl as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which a monocyclic aromatic carbocyclic moiety and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring.
  • aryl groups may be substituted with one or more aryl group substituents, which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfmyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfmyl, arylsulfonyl, arylthio, carboxy (or an acid bioisostere), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Ci _4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
  • Arylalkyloxy means an arylalkyl-O- group in which the arylalkyl group is as previously described.
  • exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • Arylalkyloxycarbonyl means an arylalkyl-O-CO- group in which the arylalkyl group is as previously described.
  • An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
  • Arylalkylthio means an arylalkyl-S- group in which the arylalkyl group is as previously described.
  • An exemplary arylalkylthio group is benzylthio.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • exemplary aryloxy groups include phenoxy and naphthoxy, each optionally substituted.
  • exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • Arylsulfmyl means an aryl-SO- group in which the aryl group is as previously described.
  • Arylsulfonyl means an aryl-S0 2 - group in which the aryl group is as previously described.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • exemplary arylthio groups include phenylthio and naphthylthio.
  • Carbocyclic means a saturated ring system comprising carbon atoms.
  • cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline and the like groups.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Cycloalkyl means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted by oxo.
  • Exemplary monocyclic cycloalkyl rings include C3_gcycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Halo or "halogen” means fluoro, chloro, bromo, or iodo. Preferred are fluoro, bromo and chloro.
  • Haloallcyl means an alkyl group having about 1 to about 6 carbon atoms in the chain and substituted by one or more halo atoms.
  • exemplary haloalkyl groups include trifluoromethyl.
  • exemplary heteroaryl groups include pyridylcarbonyl.
  • Heteroaroylamino means a heteroaroyl-NH- group in which the heteroaryl moiety is as previously described.
  • Heteroaryl as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of such groups include benzoimidazolyl, benzothiazolyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group
  • Optional substituents include one or more "aryl group substituents" as defined above, except where otherwise defined.
  • R 1 is heteroaryl this may particularly represent pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, phenyl, pyridinyl, oxodihydropyridinyl, pyrimidinyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, te
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C ⁇ alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • Heteroarylalkyloxy means an heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described.
  • exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
  • Heteroaryloxy means an heteroaryl-O- group in which the heteroaryl group is as previously described.
  • exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
  • Heterocycloalkyl means: (i) a cycloalkyl group of about 3 to 10 ring members which contains one or more heteroatoms or heteroatom-containing groups selected from O, S and NY" and may be optionally substituted by oxo (examples of such groups include hexahydropyran, pyrrolidinyl, piperidinyl, tetrahydropyranyl and octahydro-pyrido[l,2-c]pyrimidin-l-one); (ii) a partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl) ring, each optionally substituted by one or more "aryl group substituents," and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • Hydroalkyl means an alkyl group substituted by one or hydroxy groups.
  • NH(alk) and “N(alk)(alk)” denote an amino radical substituted, respectively, with one or two alkyl radicals, such alkyl radicals being linear or branched and chosen from alkyl radicals as defined above, preferably containing not more than 4 carbon atoms.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (Ix), including N-oxides thereof.
  • an ester of a compound of formula (Ix) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • an ester of a compound of formula (Ix) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (Ix) containing a hydroxy group are, for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
  • Suitable esters of compounds of formula (Ix) containing a carboxy group are, for example, those described by FJ.Leinweber, Drug Metab. Res., 1987, 18, page 379.
  • esters of compounds of formula (Ix) containing a hydroxy group may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , pages 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an allcylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-l-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-l-yl)benzoates.
  • substituted (aminomethyl)-benzoates for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or
  • base addition salts may be formed and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations.
  • Pharmaceutically acceptable salts including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
  • acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions.
  • compositions are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
  • Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g.
  • salts of compounds of the invention of compounds of formula (Ix) are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • compounds of the present invention of formula (Ix) may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (Ix) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates. Additionally, tautomers of the compounds of formula (Ix) are possible, and the present invention is intended to include all tautomeric forms of the compounds.
  • One subject of the present invention is thus the compounds of formula (I):
  • X represents C-R 2 and W, Y and Z, which may be identical or different, represent CH or CR 3 ;
  • R 1 represents aryl or heteroaryl chosen from pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thieno- pyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydropyridinopyrazolyl radicals, all these radicals being optionally substituted with one or more radicals X 1 , X 2 or X 3 chosen from H, halogen, hal
  • R 2 and R 3 together form a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from O, N and S,
  • R 5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl.
  • Y 1 and Y 2 are such that: either Y 1 and Y 2 , which may be identical or different, represent H and optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or Y 1 and Y 2 form, together with the nitrogen atom to which they are attached, a cyclic amino radical,
  • Y 3 and Y 4 are such that: either Y 3 and Y 4 , which may be identical or different, represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y 3 and Y 4 form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical,
  • a 5 represents H or alkyl
  • radicals containing allcyl, aryl and heteroaryl being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH-C(0)R 5 ,
  • the phenyl radicals furthermore being optionally substituted with a dioxole radical
  • n an integer from 0 to 2
  • W necessarily represents H or unsubstituted alkyl
  • Xa represents C-R 2 a and Wa, Ya and Za, which may be identical or different, represent CH or CR 3 a;
  • R 5 a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, all these radicals being optionally substituted
  • Y [ a and Y 2 a are such that: either Y'a and Y 2 a, which may be identical or different, represent H, alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkyl, aryl and heteroaryl, all these radicals being optionally substituted, or Y'a and Y 2 a form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical, Y 3 a and Y 4 a are such that: either Y 3 a and Y 4 a, which may be identical
  • Y 3 a and Y 4 a form, together with the nitrogen atom to which they are attached, a cyclic amino radical
  • a 5 represents H or alkyl
  • radicals containing allcyl, aryl and heteroaryl themselves being optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, alkoxy radicals, free, salif ⁇ ed or esterified carboxyl radicals and acylamino radicals NH-C(0)R 6 a,
  • the phenyl radicals furthermore being optionally substituted with a dioxole radical
  • R 6 a is chosen from the values of R 5 a,
  • n an integer from 0 to 2
  • X represents C-R 2 and W, Y and Z, which may be identical or different, represent CH or CR 3 ;
  • R 1 represents aryl or heteroaryl chosen from pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thieno- pyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydro-pyridinopyrazolyl radicals, all these radicals optionally being substituted with one or more radicals X 1 , X 2 or X 3 chosen from H, halogen,
  • R 6 represents H and C1-C4 alkyl
  • n represents an integer from 0 to 2
  • W necessarily represents H or unsubstituted alkyl, the said compounds of formula (F) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral bases.
  • R 1 can comprise one, two or three substituents represented by X 1 , X 2 and X 3 .
  • Xa represents C-R 2 a and Wa, Ya and Za, which may be identical or different, represent CH or CR 3 a;
  • R 4 a represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from aryl, OH, OR 5 a,
  • R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl,
  • R 6 a represents H and C1-C4 alkyl, n represents an integer from 0 to 2,
  • Y 3 a and Y 4 a form, together with the nitrogen atom to which they are attached, a cyclic amino radical
  • Y 3 a and Y 4 a are such that: either Y 3 a and Y 4 a, which may be identical or different, represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y 3 a and Y 4 a form, together with the nitrogen atom to which they are attached, a cyclic amino radical,
  • a 5 represents H or alkyl, the said compounds of formula (la) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral bases.
  • A represents a saturated heterocyclic radical which is either a 5- or 6-membered monocyclic radical or a bicyclic radical that is not more than 10-membered, these members being such that at least two of them represent a nitrogen atom and the others, which may be identical or different, represent a carbon member or a hetero atom member chosen from O, N and S, this heterocycle A being optionally substituted with one or more radicals XA 1 , XA 2 or XA 3 chosen from the values indicated hereinabove for the radicals X 1 , X 2 or X 3 ,
  • Ai, A 2 , A 3 and A 4 which may be identical or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy radicals, a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 A 7 such that either A 6 and A 7 , which may be identical or different, are chosen from a hydrogen atom and optionally substituted alkyl, alkoxyalkyl, phenoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl radicals, or A 6 and A 7 form, together with the nitrogen atom to which they are attached, an optionally substituted 5- or 6-membered cyclic radical, it being understood that two consecutive radicals among Ai, A 2 ,
  • R 6 b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl,
  • n an integer from 0 to 2
  • Aa represents a pyrazolyl, triazolyl or indazolyl radical, this heterocycle Aa being optionally substituted with one or more radicals XA 1 , XA 2 or XA 3 chosen from the values indicated hereinabove for the radicals X 1 , X 2 or X 3 ,
  • Aia, A 2 a, A 3 a and A 4 a which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA aA 7 a such that either A ⁇ a and A 7 a, which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl radicals, or A6a and A7a form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, morph
  • a 5 a represents a hydrogen atom or an alkyl radical
  • the phenyl and phenoxy radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl, and dioxole radicals, all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 6 carbon atoms,
  • the said compounds of formula (IAa) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAa).
  • R 4 a, Y'a, Y 2 a and R 6 b having the values defined above and alk representing a linear or branched alkyl radical including not more than 6 carbon atoms and optionally substituted as indicated above.
  • alkylthio radicals are such that the sulfur atom is optionally oxidized to sulfone or sulfoxide with one or two oxygen atoms.
  • Tables I, II and III described below give examples of compounds illustrating the present invention, with in particular substituents chosen from the values of X 1 , X 2 and X 3 as defined above.
  • X represents hydrogen, alkynyl or NHCOCH 2 Ph which is optionally substituted.
  • the subject of the present invention is thus the compounds of formula (I) as defined above in which the substituents of the said compounds of formula (I) have the any of the values indicated as defined hereinabove and in which the aryl radicals represent the phenyl and naphthyl radicals; the heteroaryl radicals represent the furyl, thienyl, benzothienyl, thianthrenyl, pyridyl, pyrazolyl, benzimidazolyl, benzofuran, isobenzofuran and dihydrobenzofuran radicals; the cycloalkyl radicals represent a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical; the heterocycloalkyl radicals represent the hexahydropyran, piperidyl or morpholino radicals; the heterocycloalkylalkyl radicals represent the hexahydropyranylalkyl, piperidylalkyl and
  • One subject of the present invention is, more particularly, the compounds of formula (I) as defined above corresponding to the formula (IA):
  • A represents a saturated heterocyclic radical which is either a 5- or 6-membered monocyclic radical or a bicyclic radical that is not more than 10-membered, these members being such that at least two of them represent a nitrogen atom and the others, which may be identical or different, represent a carbon member or a hetero atom member chosen from O, N and S, this heterocycle A optionally being substituted with one or more radicals XA 1 , XA 2 or XA 3 chosen from halogen atoms, alkyl, alkoxy or alkylthio radicals or thienyl radicals optionally substituted with an allcyl radical,
  • Ai, A 2 , A 3 and A which may be identical or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 A 7 such that either A 6 and A 7 , which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and heteroarylalkyl radicals, or A 6 and A 7 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered cyclic radical, it being understood that two consecutive radicals among A A 2 , A 3 and A can form, with the benzimidazole radical to which they are attached, a 5- to 6-membered carbon-based ring containing one or more
  • a subject of the present invention is also, more particularly, the compounds of formula (I) as defined above, corresponding to the formula (IAb):
  • Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or two radicals chosen from halogen atoms and OH, alkyl, alkynyl, -OR ⁇ b (including alkoxy), -COR 6 b, -0-COR 6 b, -OS(0) n R 6 b, -0(CH 2 ) n -CO-R 6 b, phenyl, phenylalkyl, CF 3 , OCF 3 , N0 2 , CN, NYWb,
  • Y'b and Y 2 b which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y'b and Y 2 b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical,
  • Aib, A 2 b, A 3 b and A t b which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, -OR 6 b (including alkoxy), -CO-R 6 b, -0-COR 6 b, -OS(0) n R 6 b, -0(CH 2 ) n -CO-R 6 b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 bA 7 b such that either A 6 b and A 7 b, which may be identical or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl
  • a 5 b represents a hydrogen atom
  • n an integer from 0 to 2
  • R 6 b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinolone, -NH-phenyl, phenylalkyl and cycloalkylalkyl, all these radicals being optionally substituted with a morpholino, piperidyl or phenyl radical itself optionally substituted with one or more radicals chosen from halogen atoms and the cyano, CF 3 , OCF 3 , alkyl, phenyl-S(0)n-alk-phenyl, alkoxy, NH 2 , NHalk, N(alk) 2 , S0 2 NH 2 , S0 2 Nalk or S0 2 N(alk) 2 radical,
  • the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).
  • Y'b and Y 2 b which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y L b and Y 2 b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical,
  • Ajb, A 2 b, A 3 b and AJ which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 bA 7 b such that either
  • a 6 b and A 7 b which may be identical or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl radicals, all these radicals being optionally substituted, or A 6 b and A 7 b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom
  • a 5 b represents a hydrogen atom
  • Y ! b and Y 2 b which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y'b and Y 2 b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical,
  • Aib, A 2 b, A 3 b and A 4 b which may be identical or different, are such that two of them represent hydrogen and the other two, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, -OR 6 b (including alkoxy), -CO-R 6 b, -0-COR 6 b, -OS(0) n R 6 b, -0(CH 2 ) n -CO-R ⁇ b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA ⁇ bA 7 b such that either A ⁇ b and
  • a 7 b which may be identical or different, are chosen from hydrogen and allcyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benz- imidazolylalkyl radicals, all these radicals being optionally substituted, or A 6 b and A 7 b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an al
  • R ⁇ b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinolone, -NH-phenyl, phenylalkyl and cycloalkylalkyl, all these radicals being optionally substituted with a morpholino, piperidyl or phenyl radical itself optionally substituted with one or more radicals chosen from halogen atoms and the cyano, CF 3 , OCF 3 , alkyl, phenyl-S(0)n-alk-phenyl, alkoxy, NH 2 , NHalk, N(alk) 2 , S0 2 NH 2 , S0 2 Nalk or S0 2 N(alk) 2 radical,
  • the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).
  • a subject of the present invention is thus in particular the compounds of formula (I) as defined above corresponding to the formula (IAb) in which Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy and thienyl radicals,
  • Aib, A 2 b, A 3 b and AJa which may be identical or different, are chosen from a hydrogen atom; halogen atoms; radicals of the following types: hydroxyl, alkyl, alkenyl optionally substituted with phenyl itself optionally substituted with one or more halogen atoms, alkoxy, nitro, cyano, furyl, thienyl optionally substituted with acyl COalk, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy which are optionally substituted; and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 bA 7 b such that either A 6 b and A 7 b, which may be identical or different, are chosen from hydrogen and radicals of the following types : alkyl, alkoxyalkyl containing not more than 6 carbon atoms, phenoxyalkyl optionally substituted with
  • a 6 b and A 7 b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals among A[b, A 2 b, A 3 b and A 4 b can form, with the benzimidazole radical to which they are attached, an optionally substituted
  • a 5 a represents a hydrogen atom
  • the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).
  • a subject of the present invention is thus in particular the compounds of formula (I) as defined above corresponding to the formula (IAb) in which Ab, A]b, A 2 b, A 3 b, A 4 b and A 5 b have any of the meanings indicated hereinabove,
  • NA ⁇ bA 7 b either one of A 6 b and A 7 b represents a hydrogen atom or an alkyl radical and the other of A ⁇ b and A 7 b is chosen from the values defined for A ⁇ b and A 7 b, or A ⁇ b and A 7 b form, together with the nitrogen atom to which they are attached, a 5- or 6-membered cyclic radical,
  • the said compounds of formula (IAb) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IAb).
  • a subject of the present invention is thus in particular the compounds of formula (I) as defined above in which X, W, Y and Z are such that two or three of them represent CH and the others are chosen from the values of CR 2 or CR 3 and, if appropriate, i.e., when two of them represent CH and CR 2 and CR 3 are adjacent to each other, can form a dioxole radical,
  • the present invention thus relates in particular to the compounds of formula (IA) as defined above in which Ai, A 2 , A 3 and A 4 are such that two or three of them represent a hydrogen atom and the others are chosen from the values of Ai, A 2 , A 3 and A 4 and, if appropriate, i.e., when two of them represent a hydrogen atom and the other two are on adjacent carbons, can form a dioxole radical,
  • the said compounds of formula (IA) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said compounds of formula (IA).
  • a subject of the present invention is also, more particularly, the compounds of formula (I) as defined above, corresponding to the formula (IAa):
  • Aa represents a pyrazolyl, triazolyl or indazolyl radical, this heterocycle Aa being optionally substituted with one or more radicals XA 1 , XA 2 or XA 3 chosen from halogen atoms, alkyl, alkoxy or alkylthio radicals and thienyl radicals optionally substituted with an alkyl radical, Aia, A 2 a, A 3 a and A 4 a, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA ⁇ aA 7 a such that either A 6 a and A 7 a, which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl
  • One subject of the present invention is, more particularly, the compounds of formula (I) as defined above in which R represents a pyrazolyl or indazolyl radical, the other substituents having the values indicated above or below.
  • Aia represents hydrogen or carboxyl or forms a ring with the adjacent member A 2 a
  • - t a represents hydrogen or carboxyl or forms a ring with the adjacent member A 3 a
  • a 2 a represents a carboxyl radical that is free, salified, esterified with an optionally substituted alkyl radical or an amidated carboxyl as indicated above or below,
  • a 5 represents hydrogen
  • Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy and thienyl radicals,
  • Aib, A 2 b, A 3 b and A b which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl and alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidated with a radical NA 6 bA 7 b such that either A ⁇ b and A 7 b, which may be identical or different, are chosen from alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and furylalkyl radicals, or A 6 b and A 7 b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals from among Ajb, A 2 b
  • a 5 b represents a hydrogen atom, the phenyl and phenoxy radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and free, salified or esterified carboxyl radicals, all the allcyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than
  • R 1 may particularly represent optionally substituted heteroaryl.
  • exemplary optionally substituted heteroaryls include dihydrofuropyrazolyl, imidazolyl, indazolyl, indolyl, isoxazolyl, oxodihydropyridazinyl, oxodihydropyridinopyrazolyl, oxodihydropyridinyl, oxotetrahydropyrrolopyrazolyl, pyrazolyl, thiazolyl, thienopyrazolyl, tetrahydrocyclopentapyrazolyl, tetrahydroindazolyl, tetrahydropyranopyrazolyl, tetahydropyridinopyrazolyl, tetrahydropyrrolopyrazolyl or triazolyl.
  • heteroaryl moiety and R ' is hydrogen can exist in the tautomeric forms
  • W may particularly represent CH when X is CR 2 , Y is CH or CR ⁇ and Z are CH or CRA
  • W may also particularly represent CH when X is N, Y is CH or CR ⁇ and Z is CH or CR?.
  • W may also particularly represent N when X is CH or CR 2 , Y is CH or CR ⁇ and Z is CH or CR ⁇ .
  • W may also particularly represent N when X is CH or CR 2 , Y is CH or CR ⁇ and Z is N.
  • W, X, Y, Z and R ' are as hereinbefore defined for compounds of formula (Ix), and R° and R" are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4 ,
  • R° represents: (i) hydrogen; (ii) C 1 . 4 alkyl [e.g. CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 ];
  • R ⁇ represents: (i) hydrogen; (ii) Ci.yalkyl [e.g. -CH3, -CH 2 CH 2 CH 3 , -CH(CH ) 2 or -CH 2 -CH?-CH(CH 3 ) 2 ];
  • aryl e.g. phenyl
  • R 4 is aryl [e.g.,
  • R 4 is heteroaryl [e.g.
  • a preferred group of compounds of the invention are compounds of formula (Ixa) in which:- W represents CH; X represents CH; Y represents CH; Z represents CH or C-CH3; R? represents hydrogen; R° > represents (i) hydrogen, (ii) C ⁇ alkyl [e.g. CH3, CH 2 CH_3, CH(CH3) 2 or
  • R 9 represents (i) hydrogen; (ii) C yalkyl [e.g. -CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 or -CH 2 -CH 2 -CH(CH 3 ) 2 ]; (iii) aryl [e.g.
  • R 4 is aryl [e.g.
  • a further preferred group of compounds of the invention are compounds of formula (Ixa) in which:- W represents CH; X represents CH; Z represents CH; Y represents (i) C-C j ⁇ alkyl [e.g. C-CH3,
  • C-Br C-Cl or C-F
  • C-haloalkyl e.g. C-CF3
  • C-heteroaryl e.g. C V N or
  • C-OR 4 e.g. C-OCH 3 , C-OCH 2 CFL , C-OCHF 2 , C-OCF 3
  • R° represents hydrogen
  • R° represents (i) hydrogen
  • R 9 represents (i) hydrogen; (ii) C ⁇ yalkyl [e.g. -CH3, -CH 2 CH 2 CH , -CH(CH 3 ) 2 or -CH 2 -CH 2 -CH(CH ) 2 ]; (iii) aryl [e.g. phenyl]; (iv) -C ⁇ NY ⁇ 2 [e.g.
  • R 4 is alkyl optionally substituted by aryl, cycloalkyl, heteroaryl, heterocycloalkyl, NY ⁇ 2 or -OR 5 [e.g.
  • R 4 is aryl [e.g.
  • a further preferred group of compounds of the invention are compounds of formula (Ixa) in which:- W represents CH; X represents C-CH3, C-CH 2 CH 3 , C-CH(CH 3 ) 2 , C-OCH3, C-OCH 2 CH 3 , C-Br or
  • Y represents C-CH3, C-CH 2 CH , C-OCH3, C-Br, C-Cl, C-F, C ⁇ or
  • R 7 represents hydrogen
  • R& represents (i) hydrogen, (ii) C ⁇ alkyl [e.g. CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 or CH(CH )CH 2 CH 3 ], (iii) -SR 4 [e.g.
  • R 4 is aryl [e.g,
  • R 4 is cycloalkyl [e.g. — NH-C(O) or ], (d) R 4 is
  • a further preferred group of compounds of the invention are compounds of formula (Ixa) in which: -W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R 7 represents hydrogen;
  • R s represents (i) hydrogen, (ii) Chalky! [e.g. CH3, CH 2 CH 3 , CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH ], (iii)
  • -SR 4 [e.g. -S— CH, , -S— CH,CH, or — S— CH
  • R 4 is aryl [e.g.
  • a further preferred group of compounds of the invention are compounds of formula (Ixa) in which:-W represents CH; X represents CR 2 and Y represents CR ⁇ where R 2 and R ⁇ form the group -CH 2 -0-CH 2 -; Z represents CH; R? represents hydrogen; R° > represents (i) hydrogen, (ii) Ci _4alkyl [e.g. CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 ], (iii) -SR 4 [e.g. — S— CH 3 , -S— CH 2 CH 3
  • R 9 represents (i) hydrogen; (ii) C ⁇ alkyl [e.g. -CH ,
  • R 4 is aryl [e.g.
  • a further preferred group of compounds of the invention are compounds of formula (Ixa) in which:-W represents CH; X represents CR 2 and Y represents CR where R 2 and R3 form the group -CH 2 -CH 2 -CH 2 - ; Z represents CH; R 7 represents hydrogen; R ⁇ represents (i) hydrogen, (ii) C ⁇ alkyl
  • R 9 represents (i) hydrogen; (ii) C yalkyl [e.g. -CH3,
  • R 4 is aryl [e.g.
  • N-oxides, and their prodrugs, and their acid bioisosteres and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • Another particular group of compounds of the invention are compounds of formula (Ix) wherein R 1 is a
  • p is zero, or an integer 1 ; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • C-heteroaryl e.g. C ( N or ]
  • C-OR 4 e.g. C-OCH 3 , C-OCH,CH 3 , C-OCHF 2 , C ⁇ OCF 3 , C— O- // ⁇
  • halo e.g. chloro, fluoro
  • C ⁇ alkyl e.g. methyl
  • -OR 4 e.g. -OCH , -OCH 2 CH 3 ]
  • a preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CH; Y represents CH; Z represents CH or C-CH3; R' represents hydrogen; R ⁇ represents (i) cyano, (ii) halo [e.g. chloro, fluoro], (iii) C ⁇ alkyl [e.g. methyl], (iv)
  • a further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CH; Z represents CH; Y represents (i) C-C ⁇ allcyl [e.g. C-CH3,
  • C-Br C-Cl or C-F
  • C-haloalkyl e.g. C-CF3
  • C-heteroaryl e.g. C N or
  • R u represents (i) cyano, (ii) halo [e.g. chloro, fluoro], (iii)
  • a further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents C-CH3, C-CH9CH3, C-CH(CH ) 2 , C-OCH3, C-OCH 2 CH 3 , C-Br or
  • Y represents C-CH3, C-CH 2 CH 3 , C-OCH3, C-Br, C-Cl, C-F, C or
  • a further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; J represents hydrogen; p is zero or one; R iU represents (i) cyano, (ii) halo [e.g. chloro, fluoro], (iii) Cl-4alkyl [e.g. methyl], (iv)
  • a further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CR 2 and Y represents CR? where R 2 and R? form the group -CH 2 -0-CH 2 -; Z represents CH; J represents hydrogen; p is zero or one; R 1 ⁇ represents (i) cyano, (ii) halo [e.g. chloro, fluoro], (iii) Cl-4alkyl [e.g. methyl], (iv) -OR 4 [e.g. -OCH3 or -OCH 2 CH 3 ] or
  • a further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CR 2 and Y represents CR ⁇ where R 2 and R ⁇ form the group -CH 2 -CH 2 -CH 2 - ; Z represents CH; R7 represents hydrogen; p is zero or one; R iU represents (i) cyano, (ii) halo [e.g. chloro, fluoro], (iii) Cl-4alkyl [e.g. methyl], (iv) -OR 4 [e.g. -OCH3 or
  • Another particular group of compounds of the invention are compounds of formula (Ix) wherein R 1 is a
  • pharmaceutically acceptable salts and solvates e.g. hydrates
  • C-OR 4 [e.g. C-OCH 3 , C-OCH,CH 3 , C-OCHF, , C ⁇ OCF 3 , C— 0— P ,
  • a preferred group of compounds of the invention are compounds of formula (Ixc) in which:- W represents CH; X represents CH; Y represents CH; Z represents CH or C-CH3; R 7 represents
  • a further preferred group of compounds of the invention are compounds of formula (Ixc) in which:- W represents CH; X represents CH; Z represents CH; Y represents (i) C-Cj ⁇ alkyl [e.g. C-CH3,
  • C 7 — Cl C ([ 7 or ], (iii) C-CN, (iv) C-N0 2 , (v) C-halo [e.g. C-Br, C-Cl or C-F], (vi) C-haloalkyl [e.g. C-CF3], (vii) C-heteroaryl [e.g. or
  • C-OR 4 [e.g. C-OCH 3 , C ⁇ OCH,CH 3 , C-OCHF, , C-OCF, .
  • a further preferred group of compounds of the invention are compounds of formula (Ixc) in which:- W represents CH; X represents C-CH3, C-CH 2 CH 3 , C-CH(CH 3 ) 2 , C-OCH3, C-OCH 2 CH 3 , C-Br or
  • Y represents C-CH3, C-CH 2 CH 3 , C-OCH3, C-Br, C-Cl, C-F, C (' 7 or
  • Z represents CH
  • J represents hydrogen
  • q is zero
  • pharmaceutically acceptable salts and solvates e.g. hydrates of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • a further preferred group of compounds of the invention are compounds of formula (Ixc) in which:-W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R' represents hydrogen;
  • a further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CR 2 and Y represents CR ⁇ where R 2 and R ⁇ form the group
  • Z represents CH; represents hydrogen; represents a cyclopentyl cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • pharmaceutically acceptable salts and solvates e.g. hydrates
  • a further preferred group of compounds of the invention are compounds of formula (Ixb) in which:- W represents CH; X represents CR 2 and Y represents CR ⁇ where R 2 and R? form the group
  • Z represents CH;
  • R' represents hydrogen; represents a cyclopentyl cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • Another particular group of compounds of the invention are compounds of formula (Ix) wherein R 1 is a
  • W, X, Y, Z and X are as hereinbefore defined for compounds of formula (Ix),
  • r is zero or an integer one or two and R 1 ⁇ is alkyl or two R 1 ⁇ groups attached to the same carbon atom form an oxo group; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • pharmaceutically acceptable salts and solvates e.g. hydrates
  • C-haloalkyl e.g. C-CF3
  • C-heteroaryl e.g. C V N or C V ]
  • N-S0 R 4 e.g. N-S0 2 CH 3 or N-S0 2 CH(CH 3 ) 2 ]; are preferred.
  • N-C( 0)OCH 2 CH ]; or (v) N-S0 R 4 [e.g. N-S0 2 CH or N-S0 2 CH(CH 3 ) 2 ] and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • N-S0 R 4 e.g. N-S0 2 CH or N-S0 2 CH(CH 3 ) 2
  • r is zero
  • pharmaceutically acceptable salts and solvates e.g. hydrates
  • a further preferred group of compounds of the invention are compounds of formula (Ixd) in which:- W represents CH; X represents CH; Z represents CH; Y represents (i) C-C ⁇ alkyl [e.g. C-CH3,
  • C-Br C-Cl or C-F
  • C-haloalkyl e.g. C-CF3
  • C-heteroaryl e.g. C ⁇ N or
  • N-C( 0)OCH CH 3 ]; or (v) N-S0 R 4 [e.g. N-S0 2 CH 3 or N-S0 2 CH(CH 3 ) 2 ] and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • pharmaceutically acceptable salts and solvates e.g. hydrates
  • a further preferred group of compounds of the invention are compounds of formula (Ixd) in which:- W represents CH; X represents C-CH3, C-CH 2 CH 3 , C-CH(CH 3 ) , C-OCH3, C-OCH 2 CH 3 , C-Br or
  • Y represents C-CH3, C-CH 2 CH 3 , C-OCH3, C-Br, C-Cl, C-F, or
  • X 1 is (i) O; (ii)
  • N-S0 2 CH(CH3) 2 ] and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • a further preferred group of compounds of the invention are compounds of formula (Ixd) in which: -W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R' represents hydrogen;
  • N-S0 2 R 4 [e.g. N-S0 2 CH3 or N-S0 2 CH(CH3) 2 ] and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • N-S0 2 CH(CH3) 2 ] and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • N-S0 2 CH(CH3) 2 ] and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisosteres; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisosteres.
  • Particular compounds of the invention of formula (Ix) are selected from the compounds formed by joining the carbon atom (C*) of one of the benzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine or imidazo[4,5-b]pyrazine fragments (Al to A110) shown in Table 1 to the carbon atom (*C) in the heteroaryl moiety of one of the fragments (Bl to B168) shown in Table 2.
  • Particular compounds of the invention of formula (Ixa) are selected from the compounds formed by joining the carbon atom (C*) of one of the benzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine or imidazo[4,5-b]pyrazine fragments (Al to A110) shown in Table 1 to the carbon atom (*C) in the pyrazole ring of one of the fragments (Bl to B48, B74 to B107, B124 to B127, 130 to 142 or 144 to 150) shown in Table 2.
  • Particular compounds of the invention of formula (Ixb) are also selected from the compounds formed by joining the carbon atom (C*) of one of the benzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine or imidazo[4,5-b]pyrazine fragments (Al to Al 10) shown in Table 1 to the carbon atom (*C) in the five membered ring of one of the fragments (B63 to B73, B108 to Bl 14, B128 or B151) shown in Table 2.
  • Particular compounds of the invention of formula (Ixc) are selected from the compounds formed by joining the carbon atom (C*) of one of the benzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine or imidazo[4,5-b]pyrazine fragments (Al to Al 10) shown in Table 1 to the carbon atom (*C) in the five membered ring of one of the fragments (B56, B59 or B129) shown in Table 2.
  • Particular compounds of the invention of formula (Ixd) are selected from the compounds formed by joining the carbon atom (C*) of one of the benzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine or imidazo[4,5-b]pyrazine fragments (Al to Al 10) shown in Table 1 to the carbon atom (*C) in the five membered ring of one of the fragments (B115 to B 123 or B 157) shown in Table 2.
  • the compound denoted as A9-B9 is the product of the combination of group A9 in Table 1 and B9 in Table 2, namely
  • Preferred compounds of formula (Ixa) of the invention for the inhibition of SYK are:-

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FR0113868A FR2831537B1 (fr) 2001-10-26 2001-10-26 Nouveaux derives de benzimidazoles, leur procede de preparation, leur application a titre de medicament, compositions pharmaceutiques et nouvelle utilisation
FR0113868 2001-10-26
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GB0206895A GB0206895D0 (en) 2002-03-22 2002-03-22 Chemical compounds
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MXPA04003954A (es) 2004-11-29
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