MXPA01011362A - Quinoline derivatives as inhibitors of mek enzymes - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof;for use as a medicament wherein:n is 0-1;Y is selected from -NH-, -O-, -S-, or -NR7- where R7 is alkyl of 1-6 carbon atoms R5 is chloro or bromo;Y is selected from -NH-, -O-, -S-, or -NR7- where R7 is alkyl of 1-6 carbon atoms R6 is a specified cyclic group which may be substituted by various specified substituents, or R6 is a group -R8-X-R9. The compounds are particularly useful in the inhibition of MEK enzymes.

Description

QUINOLINE DERIVATIVES AS MEK ENZYME INHIBITORS DESCRIPTION OF THE INVENTION The present invention relates to some novel uinoline derivatives as well as to their use as pharmaceuticals, in particular as inhibitors of specific kinase enzymes, in particular MEK enzymes. Additional aspects of the invention include pharmaceutical compositions and methods for treatment of proliferative diseases such as cancer using the compounds. Cancer is a disease in which cells grow and divide in an uncontrolled way. This uncontrolled growth arises from abnormalities in signal transcription pathways that are used by normal cells to regulate growth and cell division in response to various signaling molecules. Normal cells do not proliferate unless stimulated to do so by specific signal molecules located outside the cell derived from nearby cells or tissues. Growth factors are bound to the cell membrane by means of specific receptors that have intrinsic enzymatic activity. These receptors retransmit the growth signal to the cell nucleus by means of a series of signaling proteins. In cancer, a number of defects in signal pathways are evident. For example, cancer cells can produce their own growth factors that bind to their cognate receptors, resulting in an autocrine loop, or the receptors can mutate or over-express leading to an increased continuous signal to proliferate. In addition, negative regulators of cell growth can be lost. Oncogenes are cancer-related genes that often encode abnormal versions of components of the signal path, such as receptor tyrosine kinases, serine-threonine kinases or signaling molecules to the 3 'end such as ras genes, which encode proteins of binding to closely related small guanine nucleotides that hydrolyze bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP). Ras proteins are active to promote cell growth and transformation when they bind to GTP and are inactivated when they bind to GDP. Transforming mutants of p21ras are defective in their GTPase activity and consequently remain in the bound state active GTP. It is known that the oncogen ras plays an integral role in some cancers and has been found to contribute to the formation of over 20% of all human cancer cases. When activated by ligand, the cell surface receptors that attach to the mitogenic response, such as the growth factor receptors, initiate a chain of reactions that leads to the activation of the guanine nucleotide exchange activity in ras . When in its state bound to active GTP, a number of proteins interact directly with ras at the plasma membrane resulting in signal transmission through several different routes. The best characterized effector protein is the product of the raf proto-oncogene. The interaction of raf and ras is a key regulatory step in the control of cell proliferation. The ras-mediated activation of the serine-threonine kinase raf in turn activates the MEK of dual specificity (MEK 1 and MEK 2), which is the activator to the immediate 5 'end of the mitogen-activated protein kinase (MAPK known as protein kinase regulated by extracellular signal or ERK1 and ERK2). To date, no other MEK substrates have been identified than MAPK, although recent reports indicate that MEK can also be activated by other signal proteins towards the 5 'end such as MEK kinase or MEKK1 and PKC. Activated MAPK is translocated and accumulated in the nucleus, where it can phosphorylate and activate transcription factors such as Elkl and Sapla, leading to increased expression of genes such as those for c-fos. The ras-dependent MEK-MAPK cascade is one of the key signaling pathways responsible for transmitting and amplifying mitogenic signals from the cell surface to the nucleus resulting in changes in gene expression and cell fate. This ubiquitous pathway seems essential for normal cell proliferation and the constitutive activation of this pathway is sufficient to induce cell transformation. Transforming mutants of p21ras are constitutively active, resulting in raf, MEK and MAPK activity and cellular transformation. Inhibition of MEK activity using antisense raf, a dominant negative MEK mutant or the PD098059 selective inhibitor has been shown to block the growth and morphological transformation of ras-transformed bifroblasts. The mechanism of activation of raf, MEK and MAPK is through phosphorylation on specific residues of serine, threonine or tyrosine. Activated raf and other kinases phosphorylate MEK1 on S218 and S222 and MEK2 on S222 and S226. This results in the activation of MEK and the subsequent activation phosphorylation of ERK1 on T190 and Y192 and ERK2 on T183 and Y185 or the dual specific MEKs. While MEK can be activated by a number of protein kinases, and active MAPKs phosphorylate and activate a number of substrate proteins including transcription factors and other protein kinases, MEKs appear to be the specific and unique activators of MAPKs and could act as a focal point for the regulation of the cross cascade. The isoforms of MEK1 and MEK2 'show unusual specificity and also contain a proline-rich insert between the catalytic subdomains IX and X that are not present in any of the other members of the known MEK family. These differences between MEK and other protein kinases, together with the known role of MEK in proliferative signaling, suggest that it may be possible to discover and employ selective MEK inhibitors as therapeutic agents for use in proliferative diseases. WO 98/43960 describes a range of 3-cyanoquinoline compound and its use in the treatment of cancer. Some of the compounds are shown to be inhibitors of the Epidermal Growth Factor Receptor Kinase, and to inhibit the growth of cancer cells. Other quinoline derivatives that inhibit the effect of growth factors such as VEGF are described in WO98 / 13350. The conformations of some diquinolinyl sulfides have been studied by NMR and have been reported by Wyszo irski et al in Phosphorus, Sulfur and Silicon, 1994, vol 95-96, pg 415-416. Methods for making specific quinoline derivatives are described by Atkins et al in Organic Process Research and Development, 1997, vol 1, pg 185-197. The use of some quinoline derivatives as inhibitors of (H + / K +) - gastric ATPase and as fungicides are described by Ife et al in J Med Chem, 1992, vol 35, pg 3413-3422 and in EP 326330 respectively. This invention provides compounds that are inhibitors of the kinase activity of MEK and as a result can produce therapeutically useful effects in the treatment of proliferative diseases and in particular cancer. According to the present invention there is provided a compound of the formula (I) (I) or a pharmaceutically acceptable salt thereof; for use as a medication where n is 0-1; Y is selected from -NH-, -0-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R5 is chloro or bromo; Y is selected from -NH-, -0-, -S-, or -NR7- where R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring can be substituted with 1, 2 or 3 groups selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2- 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; or two adjacent substituents on the phenyl, pyridyl or pyrimidinyl ring may be joined together to form a fused ring, which ring may be aromatic or non-aromatic in character and may contain additional heteroatoms; - or R6 is a group -R8-X-R9 where R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or divalent phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, carbon, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino from 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; where X is selected from CH2, -NH-, -O-, -S-, CH2 or -NR5- where R5 is alkyl of 1-6 carbon atoms, and R9 is a group (CH2) mR10 where m is 0, or an integer of 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 6 2 oxygen atoms and optionally 1 or more substituents; R1, R2, R3 and R4 are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, C? _3 alkyl, (wherein R 11 R? 2 which may be the same or different, represents each hydrogen or C? _3 alkyl), or a group R13-X1- (CH2) x wherein x is 0 to 3, X1 represents -O-, -CH2-, -OCO-, carbonyl, -S-, -SO-, -S02-, -NR14CO-, -CORN15-, -S02NR > 1J-6 ° -, -NRjli7'Sc02- or -NR > 1180- (wherein R> 114 *, R, 15a, R, 1i6a, R> 117 'and R18 each independently represent hydrogen, C? -3 alkyl or C? -3-C2_3 alkyl) and R13 is selected from one of the following 16 groups: 1) C1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino; 2) C 1 .5X2COR19 alkyl (wherein X 2 represents -0- or -N 2o (wherein R represents hydrogen, C 1-3 alkyl or C 3-3 alkoxy C 2-3 alkyl) and R 19 represents - NR21R22-OR, 23- (wherein R 21 R '22 and R which may be the same or different each represents hydrogen, C 1-3 alkyl or C 1 -C 3 alkoxy C 2-3 alkyl)) / 3 ) alkyl of C? -sX3R24 (wherein X3 represents -O-, -S-, -SO-, -SO2-, -OCO-, -NR25CO-, -CONR26-, -S02NR27-, -NR28S02- or -NR29 - (wherein R25, R26, R27, R28 and R29 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2_3 alkyl) and R24 represents hydrogen, C3_3 / cyclopentyl, cyclohexyl or a saturated 5- or 6-membered heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose C1-3 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C? _4 alkoxy and whose cyclic group can support one or two selected oxo substituents, hydroxy, halogen, C? - alkyl, C? -4 hydroxyalkyl and C? -4 alkoxy); 4) alkyl of C? _5X4-alkyl of C? -5X5R30 (wherein X4 and X5 which may be the same or different are each -0-, -S-, -SO-, -S02-, -NR31C0-, -CONR32-, S02NR33-, -NR34SO- or -NR35- (wherein R 32 R 33 R34 and R35 each independently represent hydrogen, C? -3 alkyl or C? -3-C2-3-alkoxy) and R30 represents hydrogen or C? _3 alkyl); 5) C1-5R36 alkyl (wherein R36 is a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose heterocyclic group can support one or two substituents selected from oxo, hydroxy , halogen, C? _ / hydroxyalkyl alkyl of C? _4, and C? -4 alkoxy); 6) (CH2) qX6R37 (where q is an integer from 0 to 5, X6 represents a direct bond, -0-, -S-, -SO-, -S02-, -NR38CO-, -CONR39-, - S02NR40-, -NR41S02- or -NR42- (wherein R38, R39, R40, R41 and R42 each one independently represents hydrogen, C1-3alkyl or C3-3alkyl-C2-3alkyl) and R37 is a phenyl group, a pyridone group or a 5- or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from 0, N and S, which phenyl, pyridone or aromatic heterocyclic group can carry up to 5 substituents selected from hydroxy, halogen, amino, C ?- / C alco - alkoxy, C hidro -4-hydroxyalkoxy hydroxyalkyl, C amino-aminoalkyl, C? -4 / / carboxy alkylamino, cyano, -C0NR3R44 and -NR5C0R46 (wherein R43, R44, R45 and R46, which may be the same or different, each represents hydrogen, C ?_alkyl or C?-C3-3alkyl-C2-3alkyl)); 7) C2-6R36 alkenyl (wherein R36 is as defined above); 8) C2_eR36 alkynyl (wherein R36 is as defined above); 9) X7R47 (wherein X7 is -S02-, -O- or -CONR48R49- (wherein R48 and R49, which may be the same or different each represents hydrogen, C1-3 alkyl or C3-3 alkoxy) C2-3 alkyl) and R47 represents C? _5 alkyl which may be unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro and amino) with Icon the proviso that when X7 is -S02- , X1 is -O-, when X7 is -O-, X1 is carbonyl, when X7 is -CONR48R49-, X1 is -0- or NR18 (wherein R48, R49 'and R18 are as defined above); ) C2_6R37 alkenyl (wherein R37 is as defined above); 11) C2_6R37 alkynyl (wherein R37 is as defined above); r8p37 12) C2-eX alkenyl R (wherein X represents -O-, -S-, -SO-, -S02-, -NR50CO-, -CONR51-, -S02NR52-, -NR53S02- or -NR54- ( wherein R50, R51, R52 and R54 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2-3 alkyl) and R37 is as defined above); 13) C2-eX9R37 alkynyl (wherein X9 represents -O-, -S-, -SO-, -SO2- / -NR55CO-, -CONR56-, -S02NR57-, -NR58S02- or -NR '59 wherein R, R, 56, R, 57, R, 58 and R 59, each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2-3 alkyl) and R37 is as defined above); 14) alkyl C? _3X10-alkyl C? -3R37 (wherein X10 represents -O-, -S-, -SO-, -S02-, -NR60CO-, -CONR61-, -SOJNTR62-, -NR63S02- or -NR64- (wherein R60, R61, R62, R63 and R64 each independently represents hydrogen, C3_3alkyl or C3-3alkoxy-C2-3alkyl) and R37 is as defined above); 15) R36 (wherein R36 is as defined above); and 16) C1-3X alkyl-C1-3R alkyl 36 (wherein Xio and R, 36 are as defined above). In particular the invention provides a compound of the formula (I) as shown above or a pharmaceutically acceptable salt thereof; for use as a medication where: n is 0-1; Y is selected from -NH-, -0-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R5 is chloro or bromo; Y is selected from -NH-, -0-, -S-, or -NR7- where R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 atoms of carbon, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms carbon, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino , alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; or R6 is a group -R8-X-R9 where R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or divalent phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, carbon, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano ,, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; where X is selected from -NH-, -O-, -S-, CH2 or -NRa- where Ra is alkyl of 1-6 carbon atoms, and R9 is a group (CH2) mR10 where is 0, or an integer of 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally 1 or more substituents; R1, R2, R3 and R4 are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, C? -3 alkyl, -NR11R12 (wherein R11 and R12, which may be the same or different, each represents hydrogen or C1-3 alkyl), or a group R13-Xx- (CH2) X wherein x is from 0 to 3, X1 represents -0-, -CH2-, -OCO-, carbonyl, - S-, -SO-, -S02-, -NR14C0-, -S02NRld-, -NR17S02- or -NR18- (wherein R14, R15, R16, R17 and R18 each independently represent hydrogen, C1-3 alkyl or C.sub.3 -C.sub.3 -alkyl alkoxy) and R.sub.13 is selected from one of the 16 groups defined above: Suitable pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. A preferred pharmaceutically acceptable salt is a hydrochloride salt. The alkyl portion of the alkyl, alkoxy, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsufinyl, alkylsulfonyl, alkylsulfonamido, carboalkoxy, carboalkyl, alkanoylamino aminoalkyl, alkylaminoalkyl, N, N-dicycloalkylaminoalkyl, hydroxyalkyl, and alkoxyalkyl include straight chain as well as chains of branched carbon. The cycloalkyl portions of the substituents N-cycloalkyl-N-alkylaminoalkyl and N, -dicycloalkylaminoalkyl include simple carbocycles as well as carbocycles containing alkyl substituents. The alkenyl portion of the alkenyl, alkenyloxymethyl, alkenyloxy, alkenylsulfonamido substituents include straight chain as well as branched carbon chains and one or more sites of unsaturation. The alkynyl portion of the alkynyl, alkyloxyloxymethyl, alkynylsulfonamido, alkynyloxy substituents include straight chain as well as branched carbon chains and one or more sites of unsaturation. The carboxy is defined as a -C02H radical. Carboalkoxy of 2-7 carbon atoms is defined as a -C02R radical ", where R" is an alkyl radical of 1-6 carbon atoms. The carboalkyl is defined as a -CO "radical, where R" is an alkyl radical of 1-6 carbon atoms. The alkanoyloxy is defined as a -OCOR radical ", wherein R" is an alkyl radical of 1-6 carbon atoms. The alkanoyloxymethyl is defined as a radical R "C02CH2-, wherein R" is an alkyl radical of 1-6 carbon atoms. Alkoxymethyl is defined as a radical R "OCH2-, wherein R" is an alkyl radical of 1-6 carbon atoms. Alkylsulfinyl is defined as a radical R "SO-, where R" is an alkyl radical of 1-6 carbon atoms. Alkylsulfonyl is defined as a radical R "S02-, wherein R" is an alkyl radical of 1-6 carbon atoms. The alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are defined as a radical R "S02NH-, wherein R" is an alkyl radical of 1-6 carbon atoms, an alkenyl radical of 2-6 carbon atoms, or an alkynyl radical of 2- 6 carbon atoms, respectively. N-alkylcarbayl is defined as a radical R "NHC0-, where R" is an alkyl radical of 1-6 carbon atoms. N, N-dialkylcarbamoyl is defined as a radical R "R'NCO-, wherein R" is an alkyl radical of 1-6 carbon atoms, R 'is an alkyl radical of 1-6 carbon atoms and R', and R "may be the same or different.When X is substituted, it is preferred that it be mono-, di-, or tri-substituted, with monosubstituted being the most preferred.It is preferred that of the substituents, Ri, R2, R3 and R4 at least one is hydrogen and it is more preferred that two or three are hydrogen An azacycloalkyl-N-alkyl substituent refers to a monocyclic heterocycle containing a nitrogen atom in which a straight or branched chain alkyl radical is substituted. A morpholino-N-alkyl substituent is a morpholine ring substituted at the nitrogen atom with a straight or branched chain alkenyl radical.A piperazino-N-alkyl substituent is a piperazine ring substituted at one of the nitrogen atoms with a straight or branched chain alkyl radical A substituent N-alkyl-piperidino-N-alkyl is a piperidine ring substituted on one of the nitrogen atoms with a straight or branched chain alkyl group and on the other nitrogen atom with a straight or branched chain alkyl radical. When any group contains an alkyl portion, the alkyl portion preferably contains 1-6 carbon atoms, more preferably 1-4 carbon atoms, particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl or tert-butyl. When any group contains an alkenyl or alkynyl portion, the alkenyl or alkynyl portion preferably contains 2-6 carbon atoms, more preferably 2-4 carbon atoms. The term "aryl" used herein includes aromatic carbocyclic compounds, for example from 6 to 20 atoms such as phenyl or naphthyl. The term "heterocyclic" refers to ring structures suitably of 5 to 20 atoms in size, up to 4 of which are heteroatoms such as oxygen sulfur and nitrogen. The ring structures can be monocyclic, bi or tri-cyclic and be aromatic or non-aromatic in character, including the possibility that part of a ring system has aromatic character, while the other part or parts do not. The compounds of this invention may contain an asymmetric carbon; in such cases, the compounds of this invention cover the racemate and the individual R and S enantiomers, and in the case where more than one asymmetric carbon exists, the individual diastereomers, their individual racemates and enantiomers. Preferably Y is -NH-. Preferably R5 is chlorine Suitably R6 is phenyl, pyridyl or pyrimidinyl, and preferably phenyl which is optionally substituted as defined above. Suitable substituents include halo, such as chloro or fluoro, hydroxy or benzoyl. When two adjacent substituents on the phenyl, pyridyl or pyrimidinyl ring are joined together to form a fused ring, the ring is suitably a 5- or 6-membered aromatic ring, and preferably a 5-membered ring including at least one heteroatom such as nitrogen. Particular examples of the R groups are indole, benzimidazole or indazole. In a preferred embodiment, the group Re is a group -R8-X-R9 where R8, X and R9 are as defined above. Suitably X is oxygen. Preferably n is 0. Examples of optional substituents for the R10 groups include one or more groups selected from hydroxy; halo; nitro; cyano; carboxy; C6_6 alkoxy; C? _6 alkyl; C2-e alkenyl; C2-e alkynyl; C2-e alkenyloxy; C2-6 alkynyloxy; C3-s cycloalkyl; Not me; mono- or di-alkylamino of C? _6; heterocyclyl optionally substituted with C? _6 alkyl or oxo; C (0) Ra, C (0) ORa, S (0) dRa; NRaC (0) R; C (0) NRaS (0) dRb / - C (0) NRaRb; NRaC (O) NRbRc; NRaS (0) dRb or N (S (0) dRb) S (0) dRc wherein d is 0, 1 or 2 and Ra, Rb and Rc are independently selected from hydrogen, C? -6 alkyl, aryl, cycloalkyl of C3_6 or heterocyclyl, and wherein any alkyl, alkenyl or alkynyl group or portion contained within the substituent one R10 may themselves be optionally substituted with one or more groups selected from hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbon atoms, C3-6 cycloalkyl / heterocyclyl optionally substituted with C? -5 or oxo alkyl; C (0) R, C (0) ORa NRaRe, S (0) eR, NRaC (0) Re; C (0) NRdQnRee;, NRaC (0) NReRr; NRaS (0) eRe wherein e is 0, 1 or 2 and R, Re and R1 are independently selected from hydrogen or C ?_6 alkyl optionally substituted with one or more groups selected from hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbon atoms, C3_6 cycloalkyl, heterocyclyl optionally substituted by C? -6 alkyl or oxo; C (0) Rg, C (0) 0Rg NRgRh, S (0) eRg, NRhC (0) Rg; C (0) NRgRh, NRgC (O) NRhRx, NRgS (O) eRh wherein e is as defined above and Rg, Rh and R1 are independently selected from hydrogen or C? -6 alkyl. Alternatively, two substituents on adjacent atoms can be joined to form the second ring of a bicyclic ring system wherein the second ring is optionally substituted with one or more of the groups listed above for R10 and optionally contains one or more heteroatoms. In some embodiments, the level of substitution on the R10 group is a chain substituted with a complex substituent. Thus, for example, a substituent may comprise a substituted alkyl chain which is optionally interposed with heteroatoms such as groups of sub-formula (i) -Xa-R70- (Xb-R71) q- (Xc) s-R72 ( i) where Xa, Xb and Xc are independently selected from any of the groups listed above for X1, R70 and R are independently selected from alkylene groups of C6-6, alkenylene of C2-6 or alkynylene of C2_6, any of which may be optionally substituted with hydroxy; cyano; nitro; halo; carboxy, carboalkoxy of 2-7 carbon atoms or C3-6 cycloalkyl; R 72 is hydrogen or an alkyl group of C5-5, C2_6 alkenyl or C2-6 alkynyl any of which may be optionally substituted by hydroxy; cyano; nitro; halo; carboxy or cycloalkyl of C3-6 / 'yqys are independently 0 or 1. Particular examples of the R1Q groups include phenyl or cycloalkyl of 3-8 and preferably of 6 carbon atoms which are substituted in the alpha position with an alkoxy group, in particular methoxy. When R10 is phenyl or substituted cycloalkyl, m is preferably 0. Examples of R10 heterocyclic rings include 3-7 membered rings up to two of which may be oxygen atoms. Such groups include: wherein each R, 65 is independently selected from hydrogen or C? _6 alkyl and especially methyl. In such compounds, it is conveniently 1, 2 or 3. Substituents additionally suitable for R8 include those listed above for the pyridyl, pyrimidinyl and phenyl R6 groups. Thus a preferred sub-group of the compounds of the formula (I) are compounds of the formula (II) R4 (ll) wherein R1, R, R3, R4 and R are as defined above and R, 66 is β-alkyl, in particular methyl and R1 67 is selected from hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1 -6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino. Preferably R67 is hydrogen. Examples of preferred groups for R1, R2, R3 and R4 are set forth in WO 98/13350. Preferably x is 0. Conveniently R 13 is selected from one of the following sixteen groups: 1) C 1 -C 5 alkyl which may be substituted or unsubstituted with one or more fluorine atoms, or C 2-5 alkyl which may be substituted or unsubstituted with one or more selected groups of hydroxy and amino; 2) C2-3X2C0R19 alkyl (wherein X2 is as defined above and R19 represents -NR21R22- or -OR23- (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C-alkyl? -2 or alkoxyethyl of C? 2)); 3) C2-4X3R24 alkyl (wherein X3 is as defined above and R24 represents hydrogen, C3_3 alkyl, cyclopentyl, cyclohexyl or a saturated 5- or 6-membered heterocyclic group with one or two heteroatoms, independently selected from 0 , S and N, whose C1-3 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C1-3 alkoxy, and whose cyclic group can support one or two substituents selected from oxo, hydroxy, halogen, C1-3 alkyl, C1-3 hydroxyalkyl and C1-3 alkoxy). 4) C2_3X4 alkyl-C2-3X5R30 alkyl (wherein X4 and X5 are as defined above and R30 represents hydrogen or C1-3 alkyl); 5) C1-5R70 alkyl (wherein R70 is a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose heterocyclic group is attached to C1-5alkyl via a carbon atom and whose heterocyclic group can support one or two substituents selected from oxo, hydroxy, halogen, C1-3 alkyl, C1-3 hydroxyalkyl and C1-3 alkoxy) or C2_5R71 alkyl (wherein R71 is a 5 or 6 membered saturated heterocyclic group with one or two heteroatoms of which one is N and the other is independently selected from 0, S and N, whose heterocyclic group is attached to C2-5 alkyl through a nitrogen atom and the heterocyclic group of which can support one or two substituents selected from oxo, hydroxy, halogen, C1-3alkyl, C1-3 hydroxyalkyl, and C1-3alkoxy); (CH2) aX 6 ° Rr > 37 (wherein X is as defined above, q is an integer from 0 to 4, if X is a direct bond and q is 0, 2 or 3 if X6 is different from a direct bond, and R37 is a phenyl group, a pyridone group or a 5- or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from O, N and S, of which preferably one is N, whose phenyl group, pyridone group or aromatic heterocyclic group may be substituted as defined above, advantageously substituted with up to 2 substituents as defined above, most preferably substituted with a substituent selected from the group of substituents as defined above); 7) alkenyl of C_5R72 (wherein R72 represents R70 or R71 as defined above); 8) C4-5R72 alkynyl (wherein R72 represents R70 or R > 71 as defined above); 9) X7R47 (wherein X7 is as defined above and R47 represents C? -3 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino); 10) C3-5R37 alkenyl (wherein R37 is as defined above); 11) C3-5R37 alkynyl (wherein R37 is as defined above); 12) C4-5X8R37 alkenyl (wherein X8 and R37 is as defined above); 13) C4-5X9R30 alkynyl (wherein X9 and R30 are as defined above); 14) C? _3X10 alkyl-C? -3R37 alkyl (wherein X10 and R 37 are as defined above); 15) R3e (wherein R36 is as defined above); and 16) C 1 -3R36 alkyl [wherein X 11 and R, 36 are as defined above). Advantageously R13 is selected from one of the following eleven groups: 1) C alquilo-alkyl which may be substituted or unsubstituted with one or more fluorine atoms, or C2-alkyl which may be substituted or unsubstituted with one or two selected groups of hydroxy and amino; 2) C2-3X2COR19 alkyl (wherein X2 is as defined above and R represents -NR 21pR22- or -OR, 23 (wherein R £ L, R, 2"2 and R23 which may be the same or different each one represents hydrogen, C? -2 alquiloalkyl or Ci- 2 alco alco alkoxyethyl); 3) C2-3X3R24alkyl (wherein X3 is as defined above and R24 is a group selected from C1-3alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl whose group binds to X3 through a carbon atom and whose C? -3 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C? _2 alkoxy and whose cyclopentyl group , cyclohexyl, pyrrolidinyl or piperidinyl can carry a substituent selected from oxo, hydroxy, halogen, C? _2 alkyl, C? -2 hydroxyalkyl and C? -2 alkoxy); 4) C2-3X4 alkyl C2 alkyl -3X5R30 (wherein X4 and X5 are as defined above) and R30 represents hydrogen or C? -2 alkyl); 5) C? _4R70 alkyl (wherein R70 is a selected group of pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, the group of which is attached to C? Alkyl? through a carbon atom and whose group can carry one or two substituents selected from oxo, hydroxy, halogen, C? -2 al alkoyl, C? -2 hidro hydroxyalkyl and C? -2 alco alkoxy) or C alquilo--alkyl 4R71 (wherein R71 is a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino whose group may carry one or two substituents selected from oxo, hydroxy, halogen, C? -2alkyl, hydroxyalkyl of C? -2 and C? -2 alkoxy); and 6) (CH2) qX6R37 (where X6 is as defined above, q is an integer from 1 to 3 if X6 is a direct link, and q is 2 or 3 if X6 is different from a direct link, and R37 is a phenyl group, a pyridone group or a 5- or 6-membered aromatic heterocyclic group with 1 or 2 heteroatoms selected from O, N and S, of which preferably one is N, whose phenyl group, pyridone group or aromatic heterocyclic group may be substituted as it was previously defined, preferably substituted with a substituent selected from hydroxy, halogen, C? -2alkoxy C? -2alkyl, C? -2 hydroxyalkyl, hydroxyalkoxy C? _2, carboxy, cyano, -C0NR4JR44 and -NR 4"5, COR, 4'6 ° (where R, 43, R, 44, R45 and R46, which may be the same or different, each represents hydrogen or C alquilo _2) alkyl) 7) C4-5R71 alkenyl (wherein R71 is as defined above); 8) C4-5R71 alkynyl (wherein R71 is as defined above); -3X-C1-3R alkyl 37 (where XrlO and R are as defined above); 10) R36 (wherein R36 is as defined above); and 11) C1-3X alkyl-C1-3R alkyl 36 (wherein Xrll and R, 36 are as defined above). Preferably R13 is selected from one of the following nine groups: 1) C1-3 alkyl which may be substituted or unsubstituted with one or more fluorine atoms, or C2_3 alkyl which may be substituted or unsubstituted with one or two groups selected hydroxy and arrimo; 2) 2- (3, 3-dimethylureido) ethyl, 3- (3, 3-dimethylureido) propyl, 2- (3-methylureido) ethyl, 3- (3-methylureido) propyl, 2-ureidoethyl, 3-ureidopropyl, 2- (N, N-dimethylcarbamoyloxy) ethyl, 3- (N, N-dimethylcarbamoyloxy) -propyl, 2- (N-methylcarbamoyloxy) ethyl, 3- (N-methylcarba oxyloxy) propyl, 2- (carbamoyloxy) ethyl, - (carbamoyloxy) propyl; 3) Alkyl of C2_3X3R24 (wherein X3 is as defined above and R24 is a group selected from C? _2 alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl, whose group is linked to X3 through a carbon atom and whose C? -2 alquilo alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C? -2 alco alkoxy and whose cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group can carry a substituent selected from oxo, hydroxy, halogen, alkyl of C? _2, hydroxyalkyl of C? _2 and C? -2 alkoxy); 4) C2-3X4 alkyl-C2_3X5R32 alkyl (wherein X4 and X5 are as defined above) and R30 represents hydrogen or C1-2 alkyl); 5) C? -2R70 alkyl (wherein R70 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2) -yl and 1,3-dithian-2-yl, the group of which is linked to C1-2alkyl via a carbon atom and whose group can carry a substituent selected from oxo, hydroxy, halogen, C? 2-hydroxyalkyl of C? _2 and C? -2 alkoxy) or C2-3R59 alkyl (wherein R59 is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl, the group of which may be carrying one or two substituents selected from oxo, hydroxy, halogen, C? -2 alquilo alkyl, C hidro-2 hidro hydroxyalkyl and C? _2 alkoxy); 6) (CH2) qX6R37 (where X6 is as defined above, q is an integer from 1 to 3 if X6 is a direct link, and q is 2 or 3 if X6 is different from a direct link, and R37 is a group selected from phenyl, a pyridone, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl and pyridazinyl group, preferably selected from phenyl, a pyridone, pyridyl, imidazolyl, thiazolyl and triazolyl group whose group may be substituted with a substituent selected from hydroxy, halogen, C? _2 alkyl / C? _ alkoxy, C hidro-2 hidro hydroxyalkyl, C-2-2 hidro hydroxyalkoxy, carboxy, cyano, -CONR43R44 and -NR5COR46 (wherein R43, R44, R and R, 46 are as defined above 7) C1-3X alkyl-C1-3R alkyl 37 (wherein XrlO R are as defined above) 8) R 36 (wherein R 36 is as defined above); and 9) C1-3Xn alkyl-C1-3R36 alkyl (wherein X11 and R36 are as defined above). Most preferably R13 represents 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, l-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl, 3- (4-pyridyl) propyl , 2- ((N- (1-methylimidazol-4-ylsulfonyl) -N-methyl) amino) ethyl, 2- ((N- (3-morpholinopropylsulfonyl) -N-ethyl) amino) ethyl, 2- ((N -methyl-N-4-pyridyl) amino) ethyl, 2- (4-oxido orfolino) ethyl, 3- (4-oxidomorpholino) propyl, 2- (4-oxo-1, -dihydro-l-pyridyl) ethyl, 3- (4-Oxo-l, 4-dihydro-l-pyridyl) propyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2- (N, N-dimethylsulfamoyl) ethyl, 2- (N-methylsulfamoyl) ethyl, (1,3-dioxolan-2-yl) methyl, 2- (1,3-dioxolan-2-yl) ethyl, 2- (2-methoxyethylamino) ethyl, 2- (2-hydroxyethylamino) ethyl, 3- (2-methoxyethylamino) propyl, 3- (2-hydroxyethylamino) propyl, 2- (1, 2,4-triazol-1-yl) ethyl, 2- (1, 2, 4 -triazol-4-yl) ethyl, 3- (1,2,4-triazol-1-yl) propyl, 3- (1,2,4-triazol-4-yl) propyl, 2- (4-pyridyloxy) ethyl, 3- (4-pyridyloxy) propyl, 2- (4-pyridylamino) ethyl, 3- (4-pyridylamino) propyl, 2- (2-methylimidazol-1-yl) ethyl, - (2-methylimidazol-1-yl) propyl, 2- (5-methyl-1,2,4-triazol-1-yl) ethyl, 3- (5-methyl-1,2,4-triazole-1-) il) propyl, morpholino, N-methylpiperazinyl, piperazinyl, 2- (N, -dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, 2- (pyrrolidin-1-yl) ethyl, 3- (pyrrolidin-1-yl) propyl, 2-methoxyethyl, 3-methoxypropyl, 2- (imidazol-1-yl) ethyl, 2- (1,2,3-triazol-1-yl) ethyl, 2- (1, 2, 3-triazol-2-yl) ethyl, 3- (imidazol-1-yl) propyl, 3- (1, 2,3-triazol-1-yl) propyl, 3- (1, 2, 3-triazol-2-yl) propyl, 2-thiomorpholinoethyl, 3-thiomorpholinopropyl, 2- (1,1-dioxothiomorpholino) ethyl, 3- (1,1-dioxothiomorpholino) propyl, 2- (2-methoxyethoxy) ethyl, 2- (4-methylpiperazin-1-yl) ethyl, 3- (4-methylpiperazin-1-yl) propyl, 3- (methylsulfinyl) propyl , 3- (methylsulfonyl) propyl, 2- (methylsulfinyl) ethyl, benzyl, 2-sulfamoylethyl or 2- (ethylsulfonyl) ethyl. Especially R 13 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulfonyl) ethyl, 2- (methylsulfonyl) ethyl, 2- (N, N-di-ethylsulfamoyl) ethyl, 2- (N-methylsulfamoyl) ethyl, 2-sulfamoylethyl, 2- (N, N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, 2-morpholinoethyl, -morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, 2- (pyrrolidin-1-yl) ethyl, 3- (pyrrolidin-1) -yl) propyl, (1,3-dioxolan-2-yl) methyl, 2- (1, 3-dioxolan-2-yl) ethyl, 2- (2-methoxyethylamino), 2- (2-hydroxyethylamino) ethyl, 3- (2-methoxyethylamino) propyl, 3- (2-hydroxyethylamino) propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2- (imidazol- 1-yl) ethyl, 2- (1,2,3-triazol-1-yl) ethyl, 2- (1, 2, 3-triazol-2-yl) ethyl, 2- (l, 2,4-triazole) -1-yl) ethyl, 2- (1, 2, 4-triazol-4-yl) ethyl, 4-pyridyl ethyl, 2- (4-pyridyl) ethyl, 3- (4-pyridyl) propyl, 3- (3-pyridyl) propyl, benzyl, 2- (4-pyridyloxy) ethyl, 2- (4-pyridylamino) ethyl, or 2- (4-oxo-1,4-dihydro- l-pyridyl) ethyl. More especially R 13 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, 2- (N, N-dimethylsulfamoyl) ethyl, 2- (N-methylsulfamoyl) ethyl, 2-sulfamoylethyl, 2- (N, N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, 2-morpholinoethyl, 3- morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, 2- (pyrrolidin-1-yl) ethyl, 3- (pyrrolidin-1-) il) propyl, (1,3-dioxolan-2-yl) methyl2- (1, 3-dioxolan-2-yl) ethyl, 2- (2-methoxyethylamino) ethyl, 2- (2-hydroxyethylamino) ethyl, 3- (2-methoxyethylamino) propyl, 3- (2-hydroxyethylamino) propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2- (imidazol-1-yl) ethyl, 2- (1,2,3-triazole-1-) il) ethyl, 2- (1, 2, 3-triazol-2-yl) ethyl, 2- (1,2,4-triazol-1-yl) ethyl, 2- (1, 2,4-triazole-4) ethyl), 4-pyridyl ethyl, 2- (4-pyridylamino) ethyl, 3- (4-pyridyl) propyl, benzyl, 2- (4-pyridyloxy) ethyl, 2- (4-pyridylamino) ethyl or 2- (4-Oxo-l, 4-dihydro-l-pyridyl) ethyl. In particular R1 and R4 are suitably hydrogen. Examples of the preferred groups for R2 include C?-6 alkoxy or cyano, and preferably C?-6 alkoxy such as methoxy. The group R3 is suitably selected from hydrogen or C6-6 alkoxy such as methoxy. Preferably both R 2 and R 3 are Ci-β alkoxy and are preferably methoxy. Particular examples of the compounds of the formula (I) are listed in Table 1. or Certain compounds of formula (I) are novel and these provide a further aspect of the invention. In particular, the invention provides a compound of the formula (IA), which comprises a compound of the formula (I), with the proviso that where R 5 is bromo, R 6 is different from phenyl, methyl, substituted phenyl or dinalosubstituted phenyl . Thus, the Examples of the compounds of the formula (Ia) are compounds of the formula (I) wherein R5 is chloro. Other compounds of the formula (IA) are compounds of the formula (I) wherein R 5 is bromo and R 6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with 1 or more alkyl groups of 1 to 6 carbon atoms. carbon; or is a pyridinyl, pyrimidinyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring can be substituted with one, two or three groups selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl, of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; or two adjacent substituents on the pyridyl or pyrimidinyl ring can be joined together to form a fused ring, which ring may be aromatic or non-aromatic in character and may contain additional heteroatoms, or R6 is a group -R8-X-R9 where R8 , X and R9 are as defined above. Still further compounds of the formula (IA) are compounds of the formula (I) wherein R6 is phenyl which is substituted with one, two or three groups selected from the group consisting of alkyl of 2-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; or two adjacent substituents on the phenyl ring may be joined together to form a fused ring, which ring may be aromatic or non-aromatic in character and may contain additional heteroatoms. Preferred classes of compounds of the formula (IA) include those listed above with respect to the formula (I). The compounds of the formula (I) are suitably prepared by reacting a compound of the formula (III) (IH) wherein R1 ', R2', R3 ', R4' represent R1, R2, R3 and R4 respectively as defined in relation to the formula (I) or a precursor thereof, R5 is defined in relation to the formula (I ) and Z 'is a leaving group, with a compound of the formula (IV) HY (CH2) nR6' (IV) where Y, X and n are as defined in relation to the formula (I) and R6 'is a group R6 as defined in relation to formula (I) or a precursor thereof; and subsequently if it is necessary or desired to convert the precursor groups R1 ', R2', R3 ', R4' and R6 'into groups of the formula R1, R2, R3, R4 and R6 respectively, or to convert a group R1, R2, R3 , R4 and R6 to a different group. Suitable leaving groups for Z 'include halogen such as bromine or chlorine, or a mesylate or tosylate group. In particular z 'is chlorine. The reaction is suitably carried out in an organic solvent such as an alcohol for example propanol or cyclohexanol at elevated temperatures, for example 50 to 150 ° C, for example, at about 105 ° C or 110 ° C. The conversion reactions in which the precursor groups R1 ', R2', R3 ', R4' are converted to the groups of the formula R1, R2, R3 and R4 respectively, or groups R1, R2, R3 and R4 are converted to such a different group that can be carried out using conventional chemistry as described in the literature. The particular precursor groups R1 ', R2', R3 ', R4' are groups of the formula R13'-X1- (CH2) X wherein x and X1 are as defined below, and R13 'is C1-5 alkyl which it is substituted with halo other than fluorine, and in particular chlorine or bromine. The chloro group can easily be converted into many other R13 groups as defined in relation to claim 1. Such compounds are novel and form a further aspect of the invention. They may have activity similar to those of the compounds of the formula (I) in their own right and therefore may be used in place of a compound of the formula (I). Thus the invention further provides a compound of the formula (IB) (IB) where Y, n, R5 and R6 are as defined above and at least one of R1", R2", R3", or R4" is a group R13 '-X1- (CH2) x where X1 and x are as before and R 13 'is alkyl substituted by chlorine or bromine; and the remainder are groups R1, R2, R3 and R4 respectively. Conversion reactions similarly involving R6 groups can be carried out using conventional chemistry. For example, substituent groups on a group R6 can be changed, for example by changing acids to esters or amides, etc. A further example, to produce compounds of the formula (I) wherein R6 is a group -R -X-R that to react a compound of the formula (V) (V) where R1 ', R2', R3 ', R4' are as defined in relation to formula (III) R8, X, Y and n are as defined in relation to formula (I) with a compound of formula (VI) R9'-Z "(VI) where R9 'is a group R9 as defined in relation to formula (IV) or a precursor thereof and Z" is a leaving group; and subsequently if it is necessary or desired to convert precursor groups R1 ', R2', R3 ', R4' and R9 'to groups of the formula R1, R2, R3, R4 and R9 respectively, or to convert a group R1, R2, R3, R4 and R9 to a different group. Suitable leaving groups for Z "include halogen such as bromine or chlorine or a mesylate or tosylate group The conversion reactions are as described above The reaction is suitably carried out in an organic solvent such as a DMF at elevated temperatures, for example from 40 to 120 ° C, for example at about 80 ° C. However preferably, R1, R2, R3, R4 'and R6' are groups R1, R2, R3, R4 and R6 respectively and thus no processing is required Subsequently, some compounds of formula (III) are described in WO98 / 13350 and others can be prepared from known compounds by analogous methods, for example, they are prepared suitably by reacting a compound of formula (V) where R, R, R, R and R are as defined in relation to formula (I), with a compound of formula (VI) (VI) where Z 'is as defined above and R > 20 ~ is an additional leaving group such as sulfonyl chloride. A particular example of a compound of the formula (VI) is thionyl chloride. The reaction is suitably carried out in an organic solvent such as dimethylformamide, at elevated temperatures for example from 50 to 150 ° C, and conveniently at the reflux temperature of the solvent. The compounds of the formula (V) can be prepared by chlorination or bromination of a compound of the formula (VII) R4 (vile) where R1, R2, R3 and R4 are as defined in relation to formula (I). The halogenation can be carried out using known halogenating agents such as N-halosuccinimides. The reaction is suitably carried out in an organic solvent such as carbon tetrachloride. It can be advantageously carried out in the presence of an initiator radical such as azobisisobutyronitrile. High temperatures of 40 to 76 ° C are suitably used. Where R5 is bromine, the reaction can also be carried out using bromine in aqueous solution in the presence of a base such as sodium hydroxide. A suitable temperature for such a reaction would be in the range of 20 to 25 ° C. The compounds of the formula (VII) are known compounds (see for example WO99 / 00372 and W09847873, or they can be prepared from known compounds by conventional methods The compounds of the formula (IV) are also known compounds (cf. example Rev. Chim. (Bucharest (1988), 39 (6), 477-82, DD110651: 74.01.05) or can be prepared from known compounds by conventional methods The compounds of the invention are useful in the inhibition of MEK enzyme activity and can be used in the treatment of proliferative disease, conveniently in the form of a pharmaceutical composition, in combination with a pharmaceutically acceptable carrier, such compositions form a further aspect of the invention. in a form suitable for oral use (for example as tablets, tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or dispersible granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), by administration by inhalation (for example as a finely divided powder or a liquid aerosol), by administration by insufflation (for example as a finely divided powder) or by parenteral administration (for example as a sterile aqueous or oily solution by intravenous, subcutaneous, intramuscular or intramuscular dosing). intramuscular or as a suppository by rectal dosing). The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid.; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid. The tablet formulations may be uncoated or coated either to modify their disintegration and subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and / or appearance, in any case, using conventional coating agents and well-controlled procedures. known in the art. The compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in fine powder form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example, polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or products condensation of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (such as sucrose, saccharin or aspartame). Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). Thickening agent such as beeswax, hard paraffin or cetyl alcohol Sweetening agents such as those set forth above, and flavoring agents may be added to provide an appetizing oral preparation.These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. The powders and dispersible granules suitable for the preparation of a suspension The aqueous composition by the addition of water generally contains the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents can be, for example, naturally occurring gums such as acacia gum, or tragacanth gum, natural phosphatides such as soy, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of such partial esters with ethylene oxide such as monooleate polyoxyethylene sorbitan. The emulsions may also contain sweetening, flavoring and preservative agents. The syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain an emollient, preservative, flavoring and / or coloring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally-acceptable diluent or solvent, for example, a solution in 1,3-butanediol. The suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, can generally be obtained by formulating an active ingredient with a conventional, topically acceptable vehicle or diluent, using the conventional procedure well known in the art. The compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 μ or much smaller, the powder itself comprises either the single active ingredient or diluted with one or more physiologically acceptable carriers such as lactose. The powder by insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of the active ingredient for use with a turbo-inhaler device, such as is used by insufflation of the known agent sodium cromoglycate. The compositions for administration by inhalation may be in the form of a conventional pressurized aerosol classified to deliver the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as hydrocarbons or volatile fluorinated hydrocarbons may be used and the aerosol device is conveniently classified to classify a measured amount of the active ingredient. For additional information on the Formulation, the reading refers to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990. The amount of the active ingredient that is combined with one or more excipients to produce a single dose form will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 2 g of the active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For additional information in the Administration Routes and Dosage Regimens, the reading refers to Chapter 25.3 in Volume 5 of Corwin Hansch, Chairman of the Editorial Board, Pergamon Press 1990. The size of the dose for therapeutic purposes or prophylactics of a compound of Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, in accordance with well-known medical principles. As mentioned above, the compounds of Formula I are useful in treating diseases or medical conditions that are due solely or in part to the effects of MEK enzymes. Using a compound of Formula I for therapeutic or prophylactic purposes will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg 'per kg of body weight is received, given if required in doses divided. In general lower doses will be administered when a parenteral route is used. Thus, for example, by intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg of body weight will generally be used. Similarly, by administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg of body weight will be used. However, oral administration is preferred. In a further aspect, the invention provides a method for treating proliferative disease by administering a compound of formula (I) as described above, or a pharmaceutical composition as described above. Yet a further aspect of the invention provides the use of a compound of the formula (I) as defined above, in the preparation of a medicament for use in the inhibition of MEK enzymatic activity and in particular for the treatment of proliferative disease such as cancer. The invention will now be particularly described by way of example. EXAMPLE 1 Preparation of Compound 1 in Table 1 Step 1 N-Chlorosuccinimide (1.8 g) and azobiisobutyronitrile (0. 1 g) were added to a suspension of 6,7-dimethoxy-4-quinolone (2.05 g) in tetrachloride of carbon (100 ml) the mixture was stirred and heated to reflux for 6 hours. The mixture was filtered. The solid was washed with water and then dried. Thus, 3-chloro-6,7-dimethoxy-4-quinolone (1.6 g, 66%) was obtained. Mass Spectrum m / e 240 (M ++ H). NMR spectrum (d-6-DMSO, d values) 3.85 (s, 6H), 7.0 (s, 1H), 7.4 (s, 1H), 8.2 (d, 1H). Step 2 A mixture of the product from step 1 (1.6 g), thionyl chloride (25 ml) and DMF (3 drops) was stirred and heated to reflux for 5 hours. The thionyl chloride was evaporated. The residue was treated with toluene which was then evaporated. This procedure was repeated- The residue was then triturated with diethyl ether and then filtered. This was obtained 3,4-dichloro-6,7-dimethoxyquinoline (1.65 g, 95%). NMR spectrum (CDC13, d values) 4.15 (s, 3H), 4.2 (s, 3H), 7. 5 (s, 1H), 8.2 (s, 1H), 8.8 (s, 1H). Stage 3 A mixture of 3,4-dichloro-6,7-dimethoxyquinoline (258 mg) and 4- (2-methoxyphenoxy) -aniline (243 mg) in 1-propanol (15 ml) was stirred and heated at 100 ° C for 18 hours. The mixture was cooled to room temperature and then filtered.

The crystals were washed with a small volume of 1-propanol and then dried to give 4- (2-methoxyphenoxy) -anilino-3-chloro-6,7-dimethoxy-quinoline (Compound 1 in Table 1) (243 mg, 51%). %). EXAMPLE 2 By a procedure analogous to that described in Example 1 but using an alternative aniline, the following compounds were prepared. Compound No. 3 in Table 1 - (from 2-fluoroaniline), Compound No. 4 in Table 1 - (from 4-chloro-2-fluoroaniline), Compound No. 5 in Table 1 - (from 3,4-dichloroaniline), Compound No. 6 in Table 1 - (from 4-phenoxyaniline). EXAMPLE 3 Preparation of Compound 2 in Table 1 Step 1 N-Bromosuccinimide (4.9 g) and azobisisobutyronitrile (0.2 g) were added to a suspension of 6,7-dimethoxy-4-quinolone (4.1 g) in carbon tetrachloride. (200 ml). The mixture was stirred and heated to reflux for 6 hours. The mixture was filtered. The solid was suspended in water and then filtered and then dried. Thus, 3-bromo-6,7-dimethoxy-4-quinolone (3.2 g, 56%) was obtained. Mass Spectrum m / e 284/286 (M ++ H).

NMR spectrum (d-6-DMSO, value d) 3.8 (s, 3H), 3.85 (s, 3H), 7.0 (s, 1H), 7.4 (s, 1H), 8.2 (d, 1H). Step 2 A mixture of the product obtained in Step 1 (3.2 g), thionyl chloride (50 ml) and DMF (5 drops) was stirred and refluxed for 2 hours. The thionyl chloride was evaporated. The residue was treated with toluene which was then evaporated. This procedure was repeated. Thus 3-bromo-4-chloro-6,7-dimethoxyquinoline (3.8 g) was obtained without purification. NMR spectrum (d-6-DMSO, d values) 3.9 (s, 6H), 7.4 (s, 1H), 7.45 (s, 1H), 8.8 (s, 1H). Stage 3 A mixture of 3-bromo-4-chloro-6,7-dimethoxyquinoline (302 mg) and 4- (2-methoxyphenoxy) -aniline (236 mg) in cyclohexanol (5 ml) was stirred and heated at 130 ° C for 24 hours. The mixture was cooled to room temperature and then filtered. The crystals were washed first with methanol and then with diethyl ether and then dried to give 4- (2-methoxyphenoxy) anilino-3-bromo-6,7-dimethoxyquinoline (Compound 2) (180 mg, 37%). EXAMPLE 4 By a procedure analogous to that described for Example 3 but using an alternative aniline, the following compounds were prepared Compound No. 7 in Table 1 - (from aniline), Compound No. 8 in Table 1 - (a) from 2-fluoroaniline), Compound No. 9 in Table 1 - (from 4-chloro-2-fluoroaniline), Compound No. 10 in Table 1 - (from 3,4-dichloroaniline) , Compound No. 11 in Table 1 - (from 4-phenoxyaniline). EXAMPLE 5 Preparation of Compound No. 12 in Table 1 Step 1 A solution of sodium hypochlorite (10% chlorine, 7.5 ml) was added dropwise to a suspension of 6-cyano-4-quinolone (1.7 g) in sodium chloride solution. sodium hydroxide (2 molar, 15 ml). The mixture was stirred and cooled on ice to maintain the temperature < 25 ° C. The mixture was allowed to stand for 18 hours and then an additional amount of sodium hypochlorite solution (10% chlorine, 3 ml) was added dropwise. Water (25 ml) was added to the mixture. The mixture was filtered and the filtrate was acidified with acetic acid. The solid was precipitated, collected by filtration and washed with water. This gave 3-chloro-6-cyano-4-quinoline (1.25 g), 61%). Mass Spectrum m / e 205 (M "" JH). NMR spectrum (d-6-DMSO, d values) 7.7 (d, 1H), 8.0 (, 1H), 8.5 (m, 2H). Step 2 A mixture of the product obtained in Step 1 (1.2 g), thionyl chloride (20 ml) and DMF (2 drops) was stirred and heated to reflux for 18 hours. The thionyl chloride was evaporated. The residue was treated with toluene which was then evaporated. Thus, 3,4-dichloro-6-cyanoquinoline (1.3 g) was obtained without purification. NMR spectrum (d-6-DMSO, d values) 8.15 (m, 1H), 8.25 (d, 1H), 8.75 (m, 1H), 9.15 (s, 1H). Step 3 A mixture of 3,4-dichloro-6-cyanoquinoline (230 mg) and aniline (112 mg) in 1-propanol (5 ml) was stirred and heated at 100 ° C for 24 hours. The mixture was cooled to room temperature. The product was crystallized from the solution and collected by filtration and washed with 1-propanol. Thus, 4-anilino-3-chloro-6-cyanoquinoline (102 mg, 36%) was obtained. EXAMPLE 6 By a procedure analogous to that described by Example 5 but using an alternative aniline, the following compounds were prepared: Compound No. 13 in Table 1 - (from 2-fluoroaniline), Compound No. 14 'in Table 1 - (from 4-chloro-2-fluoroaniline), Compound No. 15 in Table 1 - (from 4- (2-methoxyphenoxy) -aniline), Compound No. 16 in Table 1 - ( from 4-hydroxyaniline), Compound No. 17 in Table 1 - (from 4-benzoylaniline), Compound No. 22 in Table 1 - (from 5-aminoindole), Compound No. 23 in the Table 1 - (from 6-a inoindazole). EXAMPLE 7 Preparation of Compound No. 18 in Table 1 Step 1 A solution of bromine was prepared by dissolving bromine (16 g) in water (100 ml) containing potassium bromide. (30 g). This solution containing bromine (54 ml) was added by dripping to a suspension of 6-cyano-4-quinolone (5.1 g) in sodium hydroxide solution (2 molar, 60 ml). The mixture was stirred and cooled on ice to maintain the temperature at about 20 ° C. The mixture was allowed to stir for 4 hours and then an additional amount of the bromine solution (15 ml) was added dropwise with the temperature kept below 25 ° C. The mixture was stirred for an additional 1 hour and then filtered. Thus, 3-bromo-6-cyano-4-quinolone (5.85 g, 78%) was obtained.

Mass Spectrum m / e 249/251 (M ++ H). NMR spectrum (d-6-DMSO, d values) 7.7 (d, 1H), 7.95 (m, 1H), 8.45 (d, 1H), 8.55 (s, 1H). Step 2 A mixture of the product of Step 1 (5.8 g), thionyl chloride (100 ml) and DMF (10 drops) was stirred and heated at 90 ° C for 18 hours. The thionyl chloride was evaporated. The residue was treated with toluene which was then evaporated. Thus, 3-bromo-4-chloro-6-cyanoquinoline was obtained without purification (6.58 g). NMR spectrum (d-6-DMSO, d values) 8.2 (d, 1H), 8.25 (s, 1H), 8.75 (s, 1H), 9.2 (s, 1H). Step 3 A mixture of 3-bromo-4-chloro-6-cyanoquinoline (267 mg) and aniline (186 mg) in 1,4-dioxane (15 ml) was stirred and heated on a heater at 120 ° C for 22 hours. hours. The mixture was cooled to room temperature. The 1,4-dioxane was evaporated. The residue was treated with dichloromethane (5 ml) tetramethylguanidine (0.125 ml) and then purified by column chromatography using initially dichloromethane and then methanol / dichloromethane mixtures as eluent. The product was dissolved in ethanol. The solution was acidified to pH 1-2 by the addition of a solution of hydrogen chloride in diethyl ether (1.0 molar) and the product was isolated by filtration. Thus, 4-anilino-3-bromo-6-cyanoquinoline (104 mg, 28%) was obtained. EXAMPLE 8 By a procedure analogous to that described for Example 7 but using an alternative aniline, the following compounds were prepared. Compound No. 19 in Table 1 - (from 2-fluoroaniline), Compound No. 20 in Table 1 - (from 4-chloro-2-fluoroaniline), Compound No. 21 in Table 1 - (from 3,4-dichloroaniline). Biological Results: Test for inhibitors of the MAP kinase pathway To evaluate inhibitors of the MAPK pathway, a coupled test was carried out that measures the phosphorylation of the serine / threonine residues present in the substrate in the presence or absence of inhibitor. Glutathione S-transferase fusion protein containing human p45MEK is activated (GST-MEK) by c-raf (lysate of Sf9 insect cells from triple baculoviral infection with c-raf / ras / lck) and used for the test. GST-MEK was first used to activate a recombinant glutathione S-transferase fusion protein containing p44MAP kinase (GST.MAPK) in the presence of ATP and Mg2 + for 60 minutes at room temperature in the presence or absence of potential inhibitors. The activated GST-MAPK was then incubated with ielin basic protein (MBP) as a substrate for 10 minutes at room temperature in the presence of ATP, Mg2 and 33P-ATP. The reaction was stopped by the addition of 20% v / v phosphoric acid. The incorporation of 33P into the myelin basic protein was determined by capturing the substrate on a filter plate, washing and counting using scintillation methods. The degree of inhibition was determined by comparison with untreated controls. The final test solution contained 10 mM Tris, pH 7.5, 0.05 mM EGTA, 8.33 μM [? 33P] ATP, 8.33 mM Mg (Oac) 2, 0.5 mM sodium orthovanadate, 0.05% w / v BSA, 6.5 ng of GST-MEK, 1 μg of GST-MAPK and 16.5 μg of MBP in a reaction volume of 60 μl. The tested compounds of the present invention had IC5o results typically less than 20 μM. For example, Compound No. 5 of Example 2 gave an IC50 of 1.53 μM. MAP kinase test In vitro To determine whether the compounds inhibited GST-MEK or GST-MAPK, a direct test of MAPK activity was employed. GST-MAPK was activated by a constitutively active GST-MEK fusion protein containing two point mutations (S217E, S221E) and was used for the test in the presence and absence of potential inhibitors. The activated GST-MAPK was incubated with substrate (MBP) for 60 minutes at room temperature in the presence of ATP, Mg2 + and 33P-ATP. The reaction was stopped by the addition of 20% volume / volume phosphoric acid. The incorporation of 33P into the myelin basic protein was determined by capturing the substrate on a filter plate, washing and counting, using scintillation methods. The final test solution contained 12 mM Tris, pH 7.5, 0.06 mM EGTA, 30 μM [? 33P] ATP, 10 mM Mg (Oac) 2 0.6 mM sodium orthovanadate, 0.06% w / v BSA, 28 ng of GST-MAPK and 16.5 μg of MBP in a reaction volume of 60 μl. The compounds of the invention showed activity on this screen. Cell proliferation tests Cells were seeded in multi-well plates at 20,000-40,000 cells / ml in a culture medium containing 5% FCS and incubated overnight at 37 ° C. The compounds were prepared in a fresh medium at an appropriate concentration and added to the wells containing the cells. These were then incubated for an additional 72 hours. The cells were removed after the wells by incubating with trypsin / EDTA and counted using a Coulter counter, or treated with XTT / EMS in PBSA and the optical densities were read at 450 nM. The tested Compounds of the present invention had IC50 results typically less than 30 μM. Compound No. 1 of Example 1 gave an IC50 of 3.4 μM in HT29 human colon tumor cells.

Claims (11)

1. CLAIMS 1. A compound of the formula (I) (9 or a pharmaceutically acceptable salt thereof; for use as a medicament characterized in that: n is 0-1; Y is selected from -NH-, -0-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R5 is chloro or bromo; R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring can be substituted with 1, 2 or 3 groups selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2- 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; or two adjacent substituents on the phenyl, pyridyl or pyrimidinyl ring may be joined together to form a fused ring, which ring may be aromatic or non-aromatic in character and may contain additional heteroatoms; or R6 is a group -R8-X-R9 where R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or divalent phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, carbon, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms , hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; wherein X is selected from CH2, -NH-, -O-, -S-, CH or -NR5- where R5 is alkyl of 1-6 carbon atoms, and R9 is a group (CH2) mR10 where m is 0, or an integer of 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally 1 or more substituents; R1, R2, R3 and R4 are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, C? _3 alkyl, -NR1: LR12 (wherein R11 and R12, which may be the same or different, each represents hydrogen or alkyl of C? -3), or a group R ^ -X1- (CH2) X where x is 0 to 3, X1 represents -0-, -CH2-, -OCO-, carbonyl , -S-, -SO-, -S02-, -NR14CO-, -CORN15-, -S02NR16-, -NR17S02- or -NR18- (wherein R14, R15, R16, R17 and R18 each independently represent hydrogen, C3_3alkyl or C3_3alkyl-C2_3alkyl) and R13 is selected from one of the following 16 groups: 1) C1-5 alkyl which may be unsubstituted or may be substituted with one or more groups selected from hydroxy, fluorine and amino; 2) C? -5X2COR19 alkyl (wherein X2 represents -0- or -NR20- (wherein R20 represents hydrogen, C1-3alkyl or C? -3-alkyloxy of C2_3alkyl) and R19 represents -NR21R22- or -OR23- (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C1-3alkyl or C3-3alkyl-C2-3alkyl)); 3) C 1 -sX 3 R 24 alkyl (wherein X 3 represents -O-,
2. -S-, -SO-, -S02-, -OCO-, -NR25CO-, -CONR26- -S02NR27-, -NR28S02- or -NR29- (wherein R25, R26, R27, R28 and R29 each represent independently hydrogen, C? -3 alkyl or C? -3-C2-3 alkoxy) and R24 represents hydrogen, C1-3 alkyl, cyclopentyl, cyclohexyl or a saturated 5- or 6-membered heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose C1-3 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C4-4 alkoxy and whose cyclic group can support one or two substituents selected from oxo, hydroxy, halogen, C? _4 hydroxyalkyl alkyl of C? - and C? _ alkoxy); 4) C alquilo5X4 alkyl-C de5X5R30 alkyl (wherein X4 and X5 which may be the same or different are each -0-, -S-, -SO-, -S02-, -NR31C0-, - CONR32-, S02NR33-, -NR34S02- or -NR35- (wherein R31, R32, R33, R34 and R35 each independently represent hydrogen, C3_3alkyl or C3_3alkoxy-C2_3alkyl) and R30 represents hydrogen or O.-3 alkyl), "5) C 1-5 R36 alkyl (wherein R36 is a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose heterocyclic group can support one or two substituents selected from oxo, hydroxy, halogen, C? - alkyl, hydroxyalkyl of C? _, and C? _4 alkoxy); 6) (CH2) qX6R37 (where q is an integer of 0 to 5, X6 represents a direct bond, -O-, -S-, -SO-, -S02-, -NR38CO-, -CONR39-, -S02NR40-, -NR1S02- or -NR42- (wherein R38, R39 , R40, R41 and R42 each independently represent hydrogen, C1-3alkyl or C3-3alkyl-C2- alkyl 3) and R37 is a phenyl group, a pyridone group or a 5- or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from 0, N and S, which phenyl, pyridone or aromatic heterocyclic group can carry up to 5 substituents selected from hydroxy, halogen, amino, C? _4 alkyl / C? -4 alkoxy, C? _4 hydroxyalkoxy hydroxyalkyl, C? -4 aminoalkyl, C? -4 alkylamino, carboxy, cyano, -CONR3R44 and -NR45COR46 (where R43, R44,
3. R '45 and R, which may be the same or different, each represents hydrogen, C? -4 alquiloalkyl or C?--C-3 alquilo3alkyl)); 7) C2_6R36 alkenyl (wherein R3d is as defined above); 8) C2_6R alkynyl 36 [wherein R 36 is as defined above); 9) X7R47 (wherein X7 is -S02-, -O- or -CONR48R49- (wherein R48 and R49, which may be the same or different each represents hydrogen, C1-3alkyl or C? -3alkoxy) -alkyl of C2_3) and R47 represents C1-5 alkyl which may be unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro and amino) with the proviso that when X7 is -S02-, X1 is -O-, when X7 is -O-, X1 is carbonyl, when X7 is -CONR48R49-, X1 is -0- or
4. NR 18 (where R, R9 R 18 are as defined above); 10) C2_6R alkenyl 37 (wherein R> 37 is as defined above); 11) C2_6R37 alkynyl (wherein R is as defined above); 12) C2-6Xr8-Rn37 alkenyl (wherein X represents -O-, -S-, -SO-, -S02-, -NR50CO-, -CONR51-, -S02NR52-, -NR53S02- or
5. -NR, 5a4"- (wherein R50, R51, R52 and R54 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2_3 alkyl) and R37 is as defined above); 13) alkynyl of C2-6X9R37 (wherein X9 represents -0-, -S-, -SO-, -SO2-, -NR55C0-, -CONR56-, -S02NR57-, -NR58S02- or -NR59- (wherein R55, R56 , R57, R58 and R59, each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2_3 alkyl) and R37 is as defined above); 14) C1-3X alkyl-C1- alkyl 3R 37 (wherein XrlO represents -O-, -S-, -SO-, -S02-, -NR60CO-, -CONR61-, -S02NR62-, -NR63S02- or -NR64- (wherein R60, R61, R62 , R63 and R64 each independently represents hydrogen, C1-3alkyl or C3-3alkoxy-C2-3alkyl) and R37 is as defined above); 15) R36 (wherein R36 is as defined above); and 16) C? -3X10 alkyl-C1-3R36 alkyl (wherein X10 and R36 are as defined above), with the proviso that when n is 0, Y is -NH-, R1 to R4 are each hydrogen, R5 is bromo, R6 is different from substituted phenylmethyl. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof; for use as a medicament which is a compound of formula (I) as shown in claim 1 characterized in that: n is 0-1; Y is selected from -NH-, -0-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R5 is chloro or bromo; Y is selected from -NH-, -0-, -S-, or -NR7- where R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-di-, or tri- substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, carbon, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms , alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; or R6 is a group -R8-X-R9 where R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or divalent phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, carbon, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms , hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; wherein X is selected from -NH-, -O-, -S-, CHJ or -NRa- where Ra is alkyl of 1-6 carbon atoms, and R9 is a group (CH2) mR10 where m is 0 , or an integer of 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 6 2 oxygen atoms and optionally 1 or more substituents; R1, R2, R3 and R4 are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, C? -3 alkyl, -NR HR.12 (wherein R> 1i1"and R > 1x2, which may be the same or different, each represents hydrogen or C1-3 alkyl), or a group Ri3 _ ?? _ (CH2) X where x is 0 to 3, X1 represents -0-, -CH2 -, -OCO-, carbonyl, -S-, -SO-, ~ S02-, -NR14C0-, -S02NR16-, -NR17S02- or -NR18- (wherein R14, R15, R16, R17 and R18 each represent independently hydrogen, C 1-3 alkyl or C 1 -C 3 alkoxy) and R 13 is selected from one of the 16 groups defined in claim 1. 3. The compound of the formula (IA) characterized in that it comprises a compound of the formula (I) according to claim 1, with the proviso that: i) where R5 is bromine, R6 is different from phenyl, substituted methyl phenyl or substituted phenyl halo;; ii) where n is 0, Y is -S-, R1 to R4 are each hydrogen, R5 is chloro, R6 is different from 4-quinolyl; iii) where n is 0, Y is -O-, R1, R2 and R4 are each hydrogen, R3 is chloro, R5 is bromine, R6 is not 4-fluoro-phenyl or 2-chloro-phenyl; and iv) where n is 0, Y is -O-, R1 to R4 are each hydrogen, R5 is chloro, R6 is different from 4-fluoro-phenyl. 4. The compound of the formula (I) or a pharmaceutically acceptable salt thereof for use with a medicament according to claim 1, characterized in that Y is -NH-. 5. The compound of the formula (IA) characterized in that it comprises a compound of the formula (I) according to claim 1, characterized in that Y is -NH- and with the proviso that where R5 is bromine, R6 is different from phenyl, substituted methyl phenyl or substituted phenyl halo.
6. 6. The compound according to any of the preceding claims R6 is a group -R8-X-R9 wherein R8, X and R9 are as defined in claim 1.
7. 7. The compound according to any of claims 1 to 3, characterized in that it is a compound of the formula (II) R4 (H) where R1, R2, R3 and R4 are as defined above and R66 is C6_6 alkyl in particular methyl and R67 is selected from hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2- 7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 a. carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino.
8. 8. The compound of the formula (IB) (IB) characterized in that Y, n, R5 and R6 are as defined in claim 1 and at least one of R1", R2", R3"or R4" is a group R13'-X1- (CH2) x wherein X1 and x are as defined in claim 1 and R13 'is alkyl substituted by chlorine or bromine; and the remainder are groups R1, R2, R3 and R4 respectively, as defined in claim 1.
9. 9. The pharmaceutical composition characterized in that it comprises a compound of the formula (I) according to claim 1, in combination with a carrier or pharmaceutically acceptable excipient.
10. 10. The compound of the formula (I) according to claim 1, for use in the manufacture of a medicament for inhibiting MEK in a mammal with an MEK mediated disease. The method for preparing a compound of the formula (I) according to claim 1, with the proviso that: i) where n is 0, Y is -O-, R1, R and R are each a-one hydrogen, R3 is chlorine, R5 is bromine, R6 is not 4-fluorophenyl or 2-chlorophenyl; and ii) where n is 0, Y is -O-, R to R4 are each hydrogen, R5 is chloro, R6 is different from 4-flurophenyl whose method comprises reacting a compound of formula (III) (ffl) characterized in that R1 ', R2', R3 ', R4' represents R1, R2, R3 and R4 respectively as defined in claim 1 or a precursor thereof, R5 is as defined in 1, and Z 'is a leaving group, with a compound of the formula (IV) HY (CH2) nR6 '(IV) where Y, X and n are as defined in claim 1, and R6' is a R6 group as defined in claim 1 or a precursor thereof; and subsequently if it is necessary or desired to convert precursor groups R1 ', R2', R3 ', R4' and R6 'to groups of the formula R1, R2, R3, R4 and R6 respectively, or convert a group R1, R2, R3, R4 and R6 to a different group.