WO2009093009A1 - Fused tricyclic thiophene derivatives as mek inhibitors - Google Patents

Abstract

A series of fused tricyclic thiophene derivatives, which are substituted in the 2-position by a substituted anilino moiety, being selective inhibitors of human MEK (MAPKK) enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive conditions.

Description

FUSED TRICYCLIC THIOPHENE DERIVATIVES AS MEK

INHIBITORS

The present invention relates to a class of fused tricyclic thiophene derivatives and to their use in therapy. More particularly, the invention provides a family of fused tricyclic thiophene derivatives which are substituted in the 2-position by a substituted anilino moiety. These compounds are selective inhibitors of MEK (MAPKK) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive conditions.

MEK enzymes are implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases. These functions are summarised in paragraphs [0004] and [0005] of US 2005/0049276 Al.

The compounds of use in the present invention, being potent and selective MEK inhibitors, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g. during heart failure); proliferative disorders such as restenosis, and oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; and pain and nociceptive disorders, including chronic pain and neuropathic pain.

In addition, the compounds of use in the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of use in this invention may be useful as radioligands in assays for detecting compounds capable of binding to human MEK enzymes.

MEK inhibitors based on a fused bicyclic aromatic ring system attached to a substituted aniline moiety are known from the art, such as from WO 2007/088345. Also relevant is copending international patent application no. PCT/GB2007/003114, published on 21 February 2008 as WO 2008/020206. Nowhere in the prior art, however, is there any disclosure of a class of fused tricylic thiophene derivatives attached at the 2-position of the thiophene ring to a substituted anilino moiety. It has now been found that such compounds are particularly valuable as selective inhibitors of MEK enzymes. The compounds of the present invention are potent and selective MEK inhibitors having a binding affinity (IC₅₀) for the human MEKl and/or MEK2 enzyme of 50 μM or less, generally of 20 μM or less, usually of 5 μM or less, typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC_5O figure denotes a more active compound). The compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for the human MEKl and/or MEK2 enzyme relative to other human kinases.

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein W represents a covalent bond or a methylene linkage; the moiety X-Y-Q represents an optionally substituted five-membered heteroaliphatic or heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolinyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl; R¹ and R² independently represent hydrogen; or Cj_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (C_1-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups maybe optionally substituted by one or more substituents; or R¹ and R², when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C_3-7 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or

R¹ and R², when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C_5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents;

R³ represents hydrogen, Ci_-6 alkyl, C_3-7 heterocycloalkenyl (optionally substituted by one or two methyl groups), cyano, -CO₂R³, -COR^b, -CONR^bR^c, -SO₂NR^bR^c, -CON(OR^b)R°, -CON(R^c)COR^b, -CON(R^c)SO₂R^b, -SO₂N(R^c)COR^b, -CON(R^d)NR^bR°, -C(=NR^e)NR^bR^c or -CON(R^d)C(=NR^e)NR^bR^c; or

R³ represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or R³ represents an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl;

R^4a and R^4b independently represent hydrogen, halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, Ci_-6 alkoxy, trifiuoromethoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphinyl or C_1-6 alkylsulphonyl; R⁵ represents halogen, nitro, cyano, Cj_-6 alkyl, C_2-6 alkynyl, hydroxy(Ci.₆)alkyl or formyl;

R^a represents hydrogen, C_1-6 alkyl or C_3-7 heterocycloalkyl(C_1-6)alkyl;

R^b represents hydrogen or trifluoromethyl; or C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(C_1-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (Ci_-6)alkyl, C_4-9 heterobicycloalkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and

R^c represents hydrogen or Ci_-6 alkyl (optionally substituted by hydroxy); or - A -

R^b and R^c, when taken together with the nitrogen atom to which they are both attached, represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, homomorpholinyl or homopiperazinyl, any of which groups may be optionally substituted by one or more substituents; or the moiety -N(OR^b)R^c represents an optionally substituted heterocyclic ring wherein R^b and R^c are taken together and represent a C_2-5 alkylene linkage; and R^d and R^e independently represent hydrogen or C_1-6 alkyl. Where a group in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such a group will be unsubstituted, or substituted by one or two substituents. Suitably, such a group will be unsubstituted or monosubstiruted.

For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) maybe formed with water, in which case they will be hydrates.

Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched C_1-6 alkyl groups, for example Ci_-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, rc-butyl, sec-butyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as "C_1-6 alkoxy", "C_1-6 alkylthio", "C_1-6 alkylsulphonyl" and "C_1-6 alkylamino" are to be construed accordingly. Specific C_3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

Suitable aryl(C_1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl. Suitable heterocycloalkyl groups, which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, l,2,3,4-tetrahydroquinoxalinyl, morpholinyl, thiomorpholinyl, homopiperidinyl and homopiperazinyl. A typical C_3-7 heterocycloalkenyl group is dihydroimidazolyl (e.g. 4,5-dihydro- lH-imidazol-2-yl).

A typical C_4-9 heterobicycloalkyl group is azabicyclo[2.2.2]octyl (e.g. quinuclidin-

3-yi).

Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-έ>]pyridinyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazo[l,2-α]pyridinyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups.

The term "halogen" as used herein is intended to include fluorine, chlorine, bromine and iodine atoms.

Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise, hi addition, compounds of formula (I) may exist as tautomers, for example keto (CΗ₂C=0)^→-enol (CH=CHOH) tautomers or amide (NHC=O)<→hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.

In one embodiment, the moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted fϊve-membered heteroaliphatic or heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolinyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl. In another embodiment, the moiety X-Y-Q in the compounds of formula (I) above represents an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

Suitably, the moiety X-Y-Q represents an imidazolinyl, imidazolyl or triazolyl ring, any of which may be optionally substituted by one or more substituents.

The five-membered or six-membered heteroaliphatic or heteroaromatic ring represented by the moiety X-Y-Q in the compounds of formula (I) above may be unsubstituted, or may suitably be substituted, where possible, by one or more, typically by one or two, substituents. In one embodiment, this ring is unsubstituted. In another embodiment, this ring is monosubstiruted. In a further embodiment, this ring is disubstituted. Examples of typical substituents on the five-membered or six-membered heteroaliphatic or heteroaromatic ring as specified for the moiety X-Y-Q include C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(C_1-6)alkyl, heteroaryl, heteroaryl(Ci_-6)alkyl, hydroxy, C_1-6 alkoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphinyl, Cu₆ alkylsulphonyl, C_2-6 alkylcarbonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, halogen, cyano and trifluoromethyl. Examples of suitable substituents include Ci_-6 alkyl, C_3-7 cycloalkyl, aryl and trifluoromethyl.

Specific sub-classes of compounds in accordance with the present invention are represented by the compounds of formula (IA), (IB) and (IC):

wherein W, R¹, R², R³, R^4a, R^4b and R⁵ are as defined above; and

R^y and R^z independently represent hydrogen, Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(C_1-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (C_1-6)alkyl, heteroaryl, heteroaryl(C_1-6)alkyl, C_1-6 alkoxy, Cj_-6 alkylthio, Ci_-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl, amino, Ci_-6 alkylamino, di(C]_-6)alkylamino, halogen, cyano or trifluoromethyl.

Suitable values of R^y and/or R^z include hydrogen, Ci_-6 alkyl, C_3-7 cycloalkyl, aryl and trifluoromethyl.

In one embodiment, R^y represents hydrogen. In another embodiment, R^y represents Ci_-6 alkyl, especially methyl. In another embodiment, R^y represents C_3-7 cycloalkyl, especially cyclopropyl or cyclobutyl. In another embodiment, R^y represents aryl, especially phenyl. In a further embodiment, R^y represents trifluoromethyl.

In a particular embodiment, R^z represents hydrogen.

In one embodiment, W represents a covalent bond. In another embodiment, W represents a methylene linkage.

Suitably, R¹ represents hydrogen; or C_1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

Suitably, R represents hydrogen or optionally substituted C_1-6 alkyl.

Examples of typical substituents on R and/or R include halogen, cyano, nitro, C_1-6 alkyl, trifluoromethyl, hydroxy, C_1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, C_1-6 alkylthio, C_1-6 alkylsulphonyl, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulphonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylamino- carbonyl, di(C_1-6)alkylaminocarbonyl, aminosulphonyl, Ci_-6 alkylaminosulphonyl and di(Ci_-6)alkylaminosulphonyl; especially halogen, C_1-6 alkoxy or C_1-6 alkylthio.

Examples of particular substituents on R¹ and/or R² include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.

Typical values of R¹ include hydrogen, methyl, n-propyl, isopropyl, phenyl, chlorophenyl, methoxyphenyl, methylthiophenyl and furyl. In one embodiment, R¹ is hydrogen. In another embodiment, R¹ is C_1-6 alkyl, especially methyl.

Typical values of R include hydrogen and methyl. In one embodiment, R is hydrogen. In another embodiment, R² is C_1-6 alkyl, especially methyl.

Alternatively, R and R², when both are attached to the same carbon atom, may together form an optionally substituted spiro linkage. Thus, R¹ and R², when both are attached to the same carbon atom, may represent, when taken together with the carbon atom to which they are both attached, C_3-7 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, R¹ and R², when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl.

Alternatively, R¹ and R², when attached to adjacent carbon atoms, may together form an optionally benzo-fused and/or substituted cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl) ring fused to the ring containing the variable W. Thus, R¹ and R², when attached to adjacent carbon atoms, may represent, when taken together with the carbon atoms to which they are attached, C_5-7 cycloalkyl, phenyl or heteroaryl (e.g. pyridinyl), any of which groups may be benzo-fused and/or unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, in one embodiment, R¹ and R², when taken together with the adjacent carbon atoms to which they are attached, suitably represent a phenyl ring fused to the ring containing the variable W. Also in this context, in another embodiment, R and R , when taken together with the adjacent carbon atoms to which they are attached, suitably represent a benzo-fused cyclopentyl ring, i.e. an indanyl moiety fused to the ring containing the variable W.

Typically, R^a represents hydrogen or Ci_-6 alkyl. Suitably, R^a represents hydrogen, methyl or ethyl, especially hydrogen or ethyl. In one embodiment, R^a represents hydrogen. In another embodiment, R^a represents Ci_-6 alkyl. In one aspect of that embodiment, R^a represents methyl. In another aspect of that embodiment, R^a represents ethyl. In a further embodiment, R^a represents C_3-7 heterocycloalkyl(Ci_-6)alkyl, especially piperidinylmethyl.

Suitably, R^b represents hydrogen; or Ci_-6 alkyl, C_3-7 cycloalkyl(Ci_₆)alkyl, aryl- (Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(Ci_-6)alkyl, C_4-9 heterobicyclo- alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Typical values of R^b include Ci_-6 alkyl, C_3-7 heterocycloalkyl and C_3-7 heterocycloalkyl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents.

Illustratively, R^b represents hydrogen; or methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexylmethyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, quinuclidinyl, azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylethyl, morpholinylpropyl, pyridinyl, indolylethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents. Typically, R^b represents propyl, butyl, pyrrolidinyl, piperidinyl or pyrrolidinylmethyl, any of which groups may be optionally substituted by one or more substituents.

Typical examples of suitable substituents on R^b, or on the heterocyclic moiety -NR^bR^c or -N(OR^b)R°, include C_1-6 alkyl, C_1-6 alkoxy, Ci_-6 alkylamino(Ci_-6)alkoxy, Ci_-6 alkoxy(C_1-6)alkyl, C_1-6 alkylthio, C_1-6 alkylsulphonyl, hydroxy, hydroxy(C_1-6)alkyl, amino(C_1-6)alkyl, nitro(Ci_-6)alkyl, cyano, trifluoromethyl, oxo, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, amino, Ci_-6 alkylamino, di(C_1-6)alkylamino, bis[hydroxy(Ci_-6)alkyl]amino, Ci_-6 alkylamino(Ci_-6)alkylamino, phenylamino, pyridinylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, [(C_2-6)alkoxy- carbonyl][(C_!.₆)alkyl]amino, bis[(C_2-6)alkoxycarbonyl(Ci_-6)alkyl]amino, C_2-6 alkoxycarbonylamino(C_1-6)alkyl, aminocarbonyl and guanidinyl.

Examples of typical substituents on R , or on the heterocyclic moiety -NR R^c or -N(OR^b)R^c, include C_1-6 alkyl, hydroxy, amino(C_1-6)alkyl, C_2-6 alkylcarbonyl, amino and C_2-6 alkoxycarbonylamino(C_1-6)alkyl. Typical examples of specific substituents on R^b, or on the heterocyclic moiety

-NR^bR^c or -N(OR^b)R^c, include methyl, ethyl, isopropyl, methoxy, isopropoxy, methylaminoethoxy, methoxymethyl, methylthio, ethylthio, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, nitromethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tørt-butoxycarbonyl, amino, methylamino, ethylamino, dimethylamino, bis(hydroxyethyl)amino, ethylaminoethylamino, phenylamino, pyridinylamino, acetylamino, tert- butoxycarbonylamino, (/ert-butoxycarbonyl)(methyl)amino, bis(ethoxycarbonylmethyl)- amino, ter^-butoxycarbonylaminomethyl, aminocarbonyl and guanidinyl.

Examples of particular substituents on R^b, or on the heterocyclic moiety -NR^bR^c or -N(OR^b)R^c, include methyl, hydroxy, aminomethyl, fe?t-butoxycarbonyl, amino and tert-butoxycarbonylaminomethyl.

Typically, R^b represents Ci_-6 alkyl, optionally substituted by one or more, preferably one or two, hydroxy groups. Specific values of R^b include hydrogen, methyl, carboxymethyl, aminocarbonyl- methyl, methoxyethyl (especially 2-methoxyethyl), methylaminoethoxyethyl (especially 2-[2-(methylamino)ethoxy]ethyl), ethylthioethyl (especially 2-(ethylthio)ethyl), methylsulphonylethyl (especially 2-(methylsulphonyl)ethyl), hydroxyethyl (especially 2- hydroxyethyl), cyanoethyl (especially 2-cyanoethyl), (hydroxy)(trifluoromethyl)ethyl (especially 2-hydroxy-3,3,3-trifluoropropyl), carboxyethyl (especially 2-carboxyethyl), ethoxycarbonylethyl (especially 2-(ethoxycarbonyl)ethyl), aminoethyl (especially 2- aminoethyl), (amino)(carboxy)ethyl (especially 2-amino-2-carboxyethyl), methylamino- ethyl (especially 2-(methylamino)ethyl), dimethylaminoethyl (especially 2-(dimethyl- amino)ethyl), bis(hydroxyethyl)aminoethyl (especially 2-[bis(2-hydroxyethyl)amino]- ethyl), ethylaminoethylaminoethyl (especially 2-[2-(ethylamino)ethylamino]ethyl), phenylaminoethyl (especially 2-(phenylamino)ethyl), pyridinylaminoethyl (especially 2- (pyridin-2-ylamino)ethyl), acetylaminoethyl (especially 2-(acetylamino)ethyl), (tert- butoxycarbonylamino)(carboxy)ethyl (especially 2-(tert-butoxycarbonylamino)-2- carboxyethyl), (tert-butoxycarbonyl)(methyl)aminoethyl (especially 2-[N-(tert- butoxycarbonyl)-iV-methylamino] ethyl), aminocarbonylethyl (especially l-(amino- carbonyl)ethyl), propyl, methoxypropyl (especially 2-methoxy-l-methylethyl), isopropoxypropyl (especially 3-isopropoxypropyl), hydroxypropyl (especially 2- hydroxypropyl or 3 -hydroxypropyl), dihydroxypropyl (especially 2,3-dihydroxypropyl), (carboxy)(methylthio)propyl (especially l-carboxy-3-(methylthio)propyl), ethoxy- carbonylpropyl (especially 2-ethoxycarbonyl-l-methylethyl), aminopropyl (especially 3- aminopropyl), (amino)(hydroxy)propyl (especially 3-amino-2-hydroxypropyl), methylaminopropyl (especially 3-(methylamino)propyl), ethylaminopropyl (especially 3- (ethylamino)propyl), dimethylaminopropyl (especially 3-(dimethylamino)propyl), tert- butyl, hydroxybutyl (especially 1,1 -dimethyl -2-hydroxyethyl or 2-hydroxy-2- methylpropyl), dihydroxybutyl (especially 3,4-dihydroxybutyl), aminobutyl (especially 2- amino-2-methylpropyl or 4-aminobutyl), (carboxy)(guanidinyl)butyl (especially 1- carboxy-4-(guanidinyl)butyl), aminopentyl (especially 3-amino-2,2-dimethylpropyl), dimethylaminopentyl (especially 3-(dimethylamino)-2,2-dimethylpropyl), hydroxyhexyl (especially l-(tert-butyl)-2-hydroxyethyl), hydroxycyclohexylmethyl, (aminomethyl)- cyclohexylmethyl, methoxybenzyl, (hydroxy)(phenyl)ethyl, (oxo)(phenyl)ethyl, (carboxy)(hydroxyphenyl)ethyl, azetidinyl, (oxo)tetrahydrofuryl, (dioxo)tetrahydro- thienyl, pyrrolidinyl, methylpyrrolidinyl, fert-butoxycarbonylpyrrolidinyl, piperidinyl, methylpiperidinyl, tørt-butoxycarbonylpiperidinyl, (oxo)homopiperidinyl, quinuclidinyl, azetidinylmethyl, hydroxyazetidinylmethyl, ter^-butoxycarbonylazetidinylmethyl, {tert- butoxycarbonyl)(hydroxy)azetidinylmethyl, tetrahydroforylmethyl, pyrrolidmylmethyl, ethylpyrrolidinylmethyl, tert-butoxycarbonylpyrrolidinylmethyl, pyrrolidinylethyl, methylpyrrolidinylethyl, (carboxy)(isoproρyl)(oxo)pyrrolidinylethyl,

(oxo)pyrrolidinylpropyl, thiazolidinylmethyl, (oxo)imidazolidinylethyl, piperidinyl- methyl, methylpiperidinylmethyl, tert-butoxycarbonylpiperidinylmethyl, piperidinyl- ethyl, tetrahydroquinolinylmethyl, methylpiperazinylpropyl, morpholinylethyl, morpholinylpropyl, pyridinyl, aminopyridinyl, (carboxy)indolylethyl, dimethyl- pyrazolylethyl, methylimidazolyhnethyl, imidazolylethyl, benziniidazolylmethyl, triazolylethyl, pyridinylmethyl and pyridinylethyl.

Typical values of R^b include dihydroxypropyl (especially 2,3-dihydroxypropyl), aminobutyl (especially 2-amino-2-methylpropyl), pyrrolidinyl, tert-butoxycarbonyl- pyrrolidinyl, piperidinyl, ferϊ-butoxycarbonylpiperidinyl, pyrrolidinylmethyl and tert- butoxycarbonylpyrrolidinylmethyl.

Suitably, R^c represents hydrogen or Ci_-6 alkyl. In one embodiment, R° is hydrogen. In another embodiment, R^c represents Cj_-6 alkyl, especially methyl or ethyl, particularly methyl. In a further embodiment, R^c represents hydroxy-substituted C_1-6 alkyl, e.g. hydroxyethyl (especially 2-hydroxyethyl). Alternatively, the moiety -NR^bR° may suitably represent azetidin-1-yl, pyrrolidin-

1-yl, ρiperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin- 1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substiruents. Favourably, the moiety -NR^bR° may suitably represent azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morρholin-4-yl, piρerazin-1-yl or homopiperazin- 1 -yl, any of which groups may be optionally substituted by one or more substiruents. Typically, the moiety -NR^bR^c may suitably represent azetidin-1-yl or piperazin-1-yl, any of which groups may be optionally substituted by one or more substiruents.

Typical substituents on the heterocyclic moiety -NR^bR^c include Ci_-6 alkyl, C_1-6 alkoxy(C_1-6)alkyl, hydroxy, hydroxy(Ci_-6)alkyl, amino(Ci_-6)alkyl, nitro(Ci_-6)alkyl, oxo, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, amino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, bis[(C2-₆)alkoxycarbonyl(Ci.₆)alkyl]amino, C_2-6 alkoxycarbonyl- amino(Ci_₆)alkyl and aminocarbonyl; especially amino(Ci_-6)alkyl or C_2-6 alkoxycarbonyl- amino(Ci_-6)alkyl. Specific substituents include methyl, ethyl, methoxymethyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, nitromethyl, oxo, acetyl, carboxy, methoxycarbonyl, tert-butoxycarbonyl, amino, acetylamino, tert-butoxycarbonylamino, bis(ethoxycarbonylmethyl)amino, tert-butoxycarbonylaminomethyl and aminocarbonyl; especially aminomethyl or tert-butoxycarbonylaminomethyl.

Particular values of the heterocyclic moiety -NR^bR^c include (aminomethyl)- azetidin-1-yl, (tert-butoxycarbonylaminomethyl)azetidin-l-yl and piperazin-1-yl.

Where the moiety -N(OR^b)R^c represents an optionally substituted heterocyclic ring wherein R^b and R^c are taken together and represent a C_2-5 alkylene linkage, this is suitably a C₃ alkylene linkage whereby the moiety -N(OR^b)R^c represents an optionally substituted isoxazolidin-2-yl ring. Typical examples of suitable substituents on this heterocylic ring are as described above. A particular substituent is hydroxy.

In one embodiment, R^d is hydrogen. In another embodiment, R^d represents C_1-6 alkyl, especially methyl. In one embodiment, R^e is hydrogen. In another embodiment, R^e represents Ci_-6 alkyl, especially methyl.

Where R³ represents a five-membered heteroaromatic ring, this ring may be optionally substituted by one or, where possible, two substituents. As will be appreciated, where R³ represents an oxadiazolyl, thiadiazolyl or tetrazolyl ring, only one substituent will be possible; otherwise, one or two optional substituents may be accommodated around the five-membered heteroaromatic ring R³. Where R³ represents a six-membered heteroaromatic ring, this ring may be optionally substituted by one or more substituents, typically by one or two substituents. Examples of suitable substituents on the five- membered or six-membered heteroaromatic ring as specified for R³ include C_1-6 alkyl, C_3-7 cycloalkyl, aryl, aryl(C_1-6)alkyl, C_3-7 heterocycloalkyl, heteroaryl, heteroaryl(C_1-6)- alkyl, Ci_-6 alkoxy, Ci_-6 alkylthio, amino, C_1-6 alkylamino, di(Ci_-6)alkylamino, halogen, cyano and trifluoromethyl.

Favourably, R³ represents hydrogen, Ci_-6 alkyl, C_3-7 heterocycloalkenyl (optionally substituted by one or two methyl groups), cyano, -CO₂R^a, -CONR^bR^c, -CON(OR^b)R^c, -CON(R^d)NR^bR^c, -C(=NR^e)NR^bR^c or -CON(R^d)C(=NR^e)NR^bR^c, in which R^a, R^b, R^c, R^d and R^e are as defined above.

Typically, R³ represents hydrogen, -CO₂R³, -CONR^bR^c, -CON(OR^b)R^c or -CONHNR^bR^c, in which R^a, R^b and R^c are as defined above. Suitably, R³ represents hydrogen, -CO₂R³ or -CONR^bR^c, in which R^a, R^b and R^c are as defined above.

In one embodiment, R³ represents hydrogen. In another embodiment, R³ represents Cj_-6 alkyl, especially methyl. In another embodiment, R³ represents C_3-7 heterocycloalkenyl (optionally substituted by one or two methyl groups), e.g. 4,4- dimethyl-4,5-dihydro-lH-imidazol-2-yl. In another embodiment, R³ represents cyano. In another embodiment, R³ represents -CO₂R^a, in which R^a is as defined above. In a further embodiment, R³ represents -CONR^bR^c, in which R^b and R^c are as defined above. In a still further embodiment, R³ represents -CON(OR^b)R^c, in which R^b and R^c are as defined above. In an additional embodiment, R³ represents -CONΗNR^bR^c, in which R^b and R^c are as defined above. In another additional embodiment, R³ represents -C(=NH)NR R^c, in which R^b and R^c are as defined above. In a further additional embodiment, R³ represents -CONHC(=NH)NR^bR^c, in which R^b and R^c are as defined above.

Suitable values of R^4a and/or R^4b include hydrogen, halogen (especially fluoro or chloro) and C_1-6 alkyl (especially methyl).

Preferably, R^4a is attached at the 2-position relative to the anilino nitrogen atom.

Suitably, R^4a represents halogen. In one embodiment, R^4a is fluoro. In another embodiment, R^4a is chloro.

Typically, R^4b may be attached at the 6-position relative to the anilino nitrogen atom.

Suitably, R^4b is hydrogen.

Suitably, R⁵ represents halogen, nitro, cyano, C_2-6 alkynyl, hydroxy(Ci_-6)alkyl or formyl. Typically, R⁵ represents halogen, nitro, hydroxy(Ci_-6)alkyl or formyl.

In one embodiment, R⁵ represents halogen, especially bromo or iodo, particularly iodo. In another embodiment, R⁵ represents nitro. In another embodiment, R represents cyano. In another embodiment, R⁵ represents C_1-6 alkyl, especially methyl. In another embodiment, R⁵ represents C_2-6 alkynyl, especially ethynyl. In a further embodiment, R⁵ represents hydroxy(Ci,g)alkyl, especially hydroxymethyl. In an additional embodiment, R⁵ represents formyl. One sub-class of compounds according to the invention is represented by the compounds of formula (IIA), and pharmaceutically acceptable salts and solvates thereof:

wherein

W, the moiety X-Y-Q, R³, R^4a, R^4b and R⁵ are as defined above; R¹¹ represents hydrogen or optionally substituted C_1-6 alkyl; and

R¹² represents hydrogen; or C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(C_1-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(C_1-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or R^u and R¹², when taken together with the carbon atom to which they are both attached, represent C_3-7 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.

Where R¹¹ and/or R¹² in the compounds of formula (IIA) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, R¹¹ and/or R¹² will be unsubstituted, or substituted by one or two substituents. Suitably, R¹¹ and/or R¹² will be unsubstituted or monosubstituted.

Suitably, R ^l represents hydrogen or unsubstituted Ci_-6 alkyl.

Suitably, R¹² represents hydrogen; or Cj_-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents. Particular values of R¹² include hydrogen and unsubstituted C_1-6 alkyl.

Examples of typical substituents on R¹¹ and/or R¹² include halogen, cyano, nitro, C_1-6 alkyl, trifluoromethyl, hydroxy, C_1-6 alkoxy, difluoromethoxy, trifiuoromethoxy, aryloxy, Ci_-6 alkylthio, Ci_-6 alkylsulphonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, Ci_-6 alkylsulphonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, Ci_-6 alkylamino- carbonyl, di(Ci_-6)alkylaminocarbonyl, aminosulphonyl, Ci_-6 alkylaminosulphonyl and di(Ci_-6)alkylaminosulphonyl; especially halogen, Ci_-6 alkoxy or Ci_-6 alkylthio. Exatnples of particular substituents on R¹¹ and/or R¹² include fluoro, chloro, bromo, cyano, nitro, methyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, phenoxy, methylthio, methylsulphonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, amino sulphonyl, methylaminosulphonyl and dimethylaminosulphonyl; especially chloro, methoxy or methylthio.

Typical values of R¹¹ include hydrogen and methyl. In one embodiment, R¹¹ is hydrogen. In another embodiment, R¹¹ is Ci_-6 alkyl, especially methyl.

Typical values of R¹ include hydrogen, methyl, n-propyl, isopropyl, phenyl, chlorophenyl, methoxyphenyl, methylthiophenyl and furyl, especially hydrogen or methyl. In one embodiment, R¹² is hydrogen. In another embodiment, R¹² is C_1-6 alkyl, especially methyl.

Alternatively, R¹¹ and R¹² may together form an optionally substituted spiro linkage. Thus, R¹¹ and R¹², when taken together with the carbon atom to which they are both attached, may represent C_3-7 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more, typically by one or two, substituents. In this context, R¹ ' and R¹², when taken together with the carbon atom to which they are both attached, may suitably represent an optionally substituted cyclopentyl, cyclohexyl, pyrrolidine or piperidine ring, especially cyclopentyl or cyclohexyl.

One particular sub-group of the compounds of formula (HA) is represented by the compounds of formula (HB), and pharmaceutically acceptable salts and solvates thereof:

(IIB) wherein

R³, R^y, R^z, R¹ ' and R¹² are as defined above;

R¹⁴ represents halogen; and

R¹⁵ represents halogen, nitro, cyano, C_2-6 alkynyl, hydroxy(C_1-6)alkyl or formyl. In one specific embodiment, R¹⁴ is fluoro. In another specific embodiment, R¹⁴ is chloro.

Typically, R¹⁵ represents halogen, nitro, hydroxy(C].₆)alkyl or formyl.

In one embodiment, R¹⁵ represents halogen, especially iodo. In another embodiment, R¹⁵ represents nitro. In another embodiment, R¹⁵ represents cyano. In another embodiment, R¹⁵ represents C_2-6 alkynyl, especially ethynyl. In a further embodiment, R¹⁵ represents hydroxy(C_1-6)alkyl, especially hydroxymethyl. In an additional embodiment, R¹⁵ represents formyl.

Another sub-group of the compounds of formula (IIA) is represented by the compounds of formula (HC), and pharmaceutically acceptable salts and solvates thereof:

(IIC)

wherein

R³, R^y, R^z,

R¹², R¹⁴ and R¹⁵ are as defined above. A further sub-group of the compounds of formula (IIA) is represented by the compounds of formula (HD), and pharmaceutically acceptable salts and solvates thereof:

(ΠD)

wherein

R³, R^y, R", R¹², R¹⁴ and R¹⁵ are as defined above. Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.

The present invention also provides a pharmaceutical composition which comprises a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. In addition to the formulations described above, the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.

For nasal administration or administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoro ethane, carbon dioxide or other suitable gas or mixture of gases.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.

For topical administration the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.

For ophthalmic administration the compounds according to the present invention may be conveniently formulated as microionized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum.

For rectal administration the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.

The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.

The compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):

wherein W, the moiety X-Y-Q, R¹, R², R³, R^4a, R^4b and R⁵ are as defined above, and L¹ represents a suitable leaving group. The leaving group L¹ is typically a halogen atom, e.g. bromo.

The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. Λζ^V-dimethylformamide, typically under basic conditions, e.g. in the presence of a base such as cesium carbonate.

By way of example, the intermediates of formula (IV) above wherein R³ is ethoxycarbonyl may be prepared by a process which comprises reacting the product formed by reacting ethyl acetoacetate and sodium ethoxide with a compound of formula (V):

(V)

wherein R ^a, R and R are as defined above.

The reaction is conveniently effected by stirring the reactants in a suitable solvent, e.g. a lower alkanol such as ethanol.

Similarly, the intermediates of formula (IV) above wherein R³ is cyano may be prepared by a process which comprises reacting compound (V) with acetonitrile, typically in the presence of a strong base such as sodium hexamethyldisilazide.

The intermediates of formula (V) above may be prepared by reacting a compound of formula (VI):

(VI)

wherein R ₁4a , τ R)4b and R are as defined above; with thiophosgene. The reaction is conveniently effected in a suitable solvent, typically a mixture of chloroform and water.

In an alternative procedure, the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (VII) with a compound of formula (VIII):

wherein W, the moiety X-Y-Q, R¹, R², R³, R^4a, R^4b and R⁵ are as defined above. The reaction is conveniently effected, at an elevated temperature if required, in a suitable solvent, e.g. Λζ,N-dimethylformamide, typically under basic conditions, e.g. in the presence of a base such as cesium carbonate.

By way of example, the intermediates of formula (VII) above wherein R³ represents -CO₂R³ may be prepared by reacting a compound of formula N≡C-CH₂-CO₂R^a with the appropriate compound of formula (IX):

wherein W, the moiety X-Y-Q, R¹, R² and R^a are as defined above; in the presence of sulphur. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of morpholine.

In another procedure, the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (VI) as defined above with a compound of formula (X):

wherein W, the moiety X-Y-Q, R¹, R² and R³ are as defined above.

The reaction is conveniently effected in the presence of a strong base such as sodium hexamethyldisilazide.

The intermediates of formula (X) above may be prepared from the precursors of formula (VII) as defined above by a multi-stage procedure which comprises the following steps: (i) diazotisation/bromination by treatment with tert-butyl nitrite and copper(II) bromide; (ii) treatment of the bromo derivative thereby obtained with dimethyl disulphide, typically in the presence of a strong base such as fert-butyllithium; and subsequently (iii) oxidation of the methylthio derivative thereby obtained, typically with an oxidising agent such as 3-chloroperoxybenzoic acid, to afford the desired compound of formula (X).

The compounds of formula (IA) above may be prepared by a process which comprises reacting a compound of formula (XI) with an ethanolamine derivative of formula (XII):

wherein W, R¹, R², R³, R^4a, R^4b, R⁵, R^y and R^z are as defined above; followed by cyclisation of the product thereby obtained. The reaction between compounds (XI) and (XII) is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, typically in the presence of an organic acid such as acetic acid.

The subsequent cyclisation reaction is conveniently accomplished by treatment with thionyl chloride. The intermediates of formula (XI) above may be prepared by reacting a compound of formula (XIII):

(XIII)

wherein W, R¹, R², R³, R^4a, R^4b and R⁵ are as defined above; with Lawesson's Reagent (i.e. 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulphide); followed by treatment of the thiolactam derivative thereby obtained with a methyl halide, e.g. iodomethane.

Reaction of compound (XIII) with Lawesson's Reagent is conveniently carried out at an elevated temperature in a hydrocarbon solvent such as toluene. Treatment of the resulting thiolactam with iodomethane is conveniently effected in a suitable solvent, e.g. acetonitrile.

The compounds of formula (IB) above maybe prepared by a process which comprises reacting a compound of formula (XIII) as defined above with phosphorus oxychloride; followed by reaction of the product thereby obtained with a compound of formula (XIV):

wherein R^y and R^z are as defined above; or a suitable carbonyl-protected form thereof, e.g. the dimethyl acetal or ketal derivative; followed in turn by cyclisation of the product thereby obtained.

Reaction of compound (XIII) with phosphorus oxychloride is conveniently carried out at an elevated temperature. Reaction of the resulting product with compound (XIV) is also conveniently effected at an elevated temperature. The subsequent cyclisation reaction is conveniently accomplished by treatment with a reagent such as p-tohxene- sulphonic acid, in which case the reaction is conveniently accomplished at an elevated temperature in a hydrocarbon solvent such as toluene.

The compounds of formula (IC) above may be prepared by a process which comprises reacting a compound of formula (XI) as defined above with a hydrazide derivative of formula (XV):

(XV)

wherein R^y is as defined above. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, typically in the presence of an organic acid such as acetic acid.

In another procedure, the compounds of formula (IC) above wherein R^y is hydrogen may be prepared by a process which comprises reacting a compound of formula (XVI):

(XVI)

wherein W, R¹, R², R³, R^4a, R^4b and R⁵ are as defined above; with a tri(Ci_-6)alkyl orthoformate, e.g. triethyl orthoformate.

The reaction is conveniently effected at an elevated temperature. In a further procedure, the compounds of formula (IC) above may be prepared by a process which comprises reacting a compound of formula (XVI) as defined above with a compound of formula R^yC(O)L², wherein L² represents a suitable leaving group; followed by cyclisation of the product thereby obtained.

The leaving group L is typically a halogen atom, e.g. chloro. The reaction between compound (XVI) and the compound of formula R^yC(O)L² is conveniently effected in a suitable solvent, e.g. a halogenated solvent such as dichloromethane, typically in the presence of an organic base such as triethylamine. The subsequent cyclisation reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile, typically in the presence of an organic acid such as acetic acid.

The intermediates of formula (XVI) may be prepared by reacting a compound of formula (XI) as defined above with hydrazine or a salt thereof, e.g. hydrazine acetate. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. acetonitrile. The intermediates of formula (XIII) above may be prepared by reacting a compound of formula (IV) as defined above with a compound of formula (XVII):

wherein W, R¹, R² and L¹ are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (IV).

Where they are not commercially available, the starting materials of formula (III), (VI), (VIII), (IX), (XII), (XIV), (XV) and (XVII) maybe prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.

It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. A compound of formula (I) wherein R³ represents -CO₂R⁸ in which R^a is other than hydrogen may be saponified to give the corresponding compound in which R³ represents -CO₂H by treatment with a base such as lithium hydroxide; more prolonged treatment with lithium hydroxide gives rise to the decarboxylated product in which R³ represents hydrogen. A compound of formula (I) wherein R³ represents -CO₂R^a may be converted into the corresponding compound wherein R³ represents -CONH₂ by treatment with ammonia, typically at elevated temperature and optionally also at elevated pressure. A compound of formula (I) wherein R represents -CO₂H may be converted into the corresponding compound wherein R³ represents -CONR^bR^Q, -CON(OR^b)R^c or -CON(R^d)C(=NR^e)NR^bR^c by treatment with the appropriate amine of formula H-NR^bR^c, H-N(OR^b)R° or H-N(R^d)C(=NR^e)NR^bR^c respectively and a condensing agent such as 1 , 1 '- carbonyldiimidazole (CDI) or l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC), typically in the presence of 4-methylmorpholine (NMM) and 1-hydroxybenzotriazole (HOBT). Alternatively, a compound of formula (I) wherein R³ represents -CO₂H maybe converted into the corresponding compound wherein R³ represents -CONR^bR°, -CON(OR^b)R^c or -CON(R^d)NR^bR° by a two-stage procedure which comprises (i) treatment with pentafluorophenol and a condensing agent such as EDC, typically in the presence of NMM and HOBT; and (ii) reaction of the pentafluorophenyl ester thereby obtained with the appropriate amine of formula H-NR^bR^c, H-N(OR^b)R° or H-N(R^d)NR^bR^c respectively, typically in the presence of an organic base such as triethylamine.

A compound of formula (I) wherein R³ represents -CO₂H may be converted into the corresponding compound wherein R³ represents -CO₂R⁸ by a two-stage procedure which comprises (i) treatment with pentafluorophenol and a condensing agent such as EDC, typically in the presence of NMM and HOBT; and (ii) reaction of the pentafluorophenyl ester thereby obtained with the appropriate alcohol of formula R^aOH, typically in the presence of an organic base such as triethylamine.

A compound of formula (I) wherein R³ represents -CO₂H may be converted into the corresponding compound wherein R^J represents -CONR R^c by a two-stage procedure which comprises (i) treatment with tetrafluorophenol resin and a condensing agent such as 1,3-diisopropylcarbodiimide, typically in the presence of 4-(dimethylamino)pyridine; and (ii) reaction of the tetrafluorophenyl ester functionalised resin thereby obtained with the appropriate amine of formula H-NR^bR^c.

A compound of formula (I) wherein R³ represents -CO₂R^a (e.g. ethoxycarbonyl) may be converted into the corresponding compound wherein R³ represents methyl by treatment with a reducing agent such as diisobutylaluminium hydride.

A compound of formula (I) wherein R³ represents -CO₂R^a (e.g. ethoxycarbonyl) may be converted into the corresponding compound wherein R³ represents -CONR^bR^c by treatment with the appropriate amine of formula H-NR^bR° in the presence of trimethyl- aluminium. Similarly, a compound of formula (I) wherein R³ represents cyano may be converted into the corresponding compound wherein R³ represents -C(=NH)NR^bR^c by treatment with the appropriate amine of formula H-NR^bR^c in the presence of trimethyl- aluminium. A compound of formula (I) wherein R³ represents cyano may be converted into the corresponding compound wherein R³ represents 4,4-dimethyl-4,5-dihydro-lϋf- imidazol-2-yl in a single step by treatment with l,2-diamino-2-methylpropane in the presence of trimethylaluminium. A compound of formula (I) wherein R³ represents cyano maybe converted into the corresponding compound wherein R³ represents -CONH₂ by treatment with hydroxylamine.

A compound of formula (I) wherein R³ contains a NH functionality may be converted into the corresponding compound wherein R³ contains a N-methyl functionality by treatment with formaldehyde in the presence of a suitable reducing agent, e.g. sodium cyanoborohydride.

A compound of formula (I) wherein R³ contains an amino moiety protected by a fert-butoxycarbonyl (BOC) group may be deprotected by treatment with an acid, e.g. an organic acid such as trifluoroacetic acid, or a mineral acid such as hydrochloric acid.

A compound of formula (I) wherein R⁵ represents formyl may be converted into the corresponding compound wherein R⁵ represents hydroxymethyl by treatment with a suitable reducing agent, e.g. sodium borohydride.

A compound of formula (I) wherein R⁵ represents iodo may be converted into the corresponding compound wherein R⁵ represents ethynyl by treatment at an elevated temperature with (trimethylsilyl)acetylene and a transition metal catalyst, e.g. bis(triphenylphosphine)palladium(II) dichloride, typically in the presence of copper(I) iodide and a base such as diisopropylamine.

Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3^rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds according to the invention.

The compounds in accordance with this invention potently inhibit the activity of human MEK enzyme.

In vitro MEK assay

MEKl activity was measured in a cascade assay initiated by active Raf, via activation of MEK, Erk2 and subsequent phosphorylation of fluorescein-labelled Erk-tide substrate in an assay based on fluorescence polarisation (IMAP). The assay was carried out in 20mMTris + 5mMMgCl₂ + 2mMDL-dithiothreitol + 0.01% Tween 20 pH 7.2, containing 1.5nMunactive MEK, lOOnMunactive Erk and 20OnM Erk-tide (all concentrations are final concentrations). Compounds, or DMSO controls, were tested at a final concentration of 2% DMSO, and the assay initiated in the presence of 5μM ATP by addition of 1.25nM active Raf in assay buffer. After 20 min at r.t., stop solution was added followed by IMAP binding beads, the assay mixture was then incubated for 90 min at r.t. (with shaking) and then read on a Molecular Devices LJL HT reader. When tested in the above assay, the compounds of the accompanying Examples were all found to inhibit human MEK enzyme with IC_5O values of 10 μM or better.

EXAMPLES

Abbreviations

EtOAc - ethyl acetate DMSO - dimethylsulphoxide

THF - tetrahydrofuran DCM - dichloromethane

DMF - ΛζiV-dimethylformamide NMM - 4-methylmorpholine ether - diethyl ether HOBT - 1-hydroxybenzotriazole

MeCN - acetonitrile MeOH - methanol

CDCl₃ - deuterated chloroform

EDC - l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide h - hour(s) min - minute(s) r.t. - room temperature aq - aqueous sat. - saturated RT - retention time

All NMRs were obtained either at 300 MHz or 400 MHz.

Standard LCMS method

The LC-MS system used comprises a Waters Alliance 2795 HT quaternary HPLC, Waters 996 Photo Diode Array (PDA) detector and Waters ZQ 4000 single quadrupole mass spectrometer. The ZQ can acquire data simultaneously in positive and negative electrospray ionisation modes.

ZQ Mass Spectrometer

Capillary 3.5kV Cone 50V

Extractor 2V Source Temp 80°C

Desolvation Temp 200⁰C Cone Gas 150 1/h

Desolvation Gas 250 1/h Multiplier 650V

Data were acquired in a full scan from 100 to 1000 m/z. Scan duration 0.80 s

InterScan delay 0.20 s HPLC

The reverse phase separation was carried out on a Gemini Cl 8 from Phenomenex 50 x 4.6 mm with 5 μm silica.

Injection Volume 5 μl

UV data 240 to 400 nm

Sample Temperature 2O⁰C

Column Temperature 30°C Flow Rate 0.9 ml/min

Split to ZQ -0.40 ml/min

Solvent A: 90% 1 OmM NH₄HCO₂ in water / 0.1% formic acid / 10% CH₃CN

Solvent B: 90% CH₃CN / 0.1 % formic acid / 10% 1 OmMNH₄HCO₂ in water

Gradient Program

Time (min) A% B% Flow Curve

0.00 95.0 5.0 0.900 1

2.00 5.0 95.0 0.900 6 4.00 5.0 95.0 0.900 6

5.00 95.0 5.0 0.900 6

The aqueous solvent was approximately pH 3.2.

INTERMEDIATE 1

6, 6-Dimethylazepane-2 ,4-dione

Hydroxylamine hydrochloride (39.66 g, 0.57 mol) was added to a solution of dimedone (80 g, 0.57 mol) in MeOH (500 mL) and the reaction was heated to reflux for 4 h. The reaction was concentrated in vacuo to give an orange oil. The resulting oil was dissolved in MeCN (500 mL) and triethylamine (85.6 mL, 0.62 mol) added. The reaction was cooled to O⁰C and a solution ofp>-toluenesulphonyl chloride (112.0 g, 0.59 mol) in MeCN (600 mL) was added slowly dropwise and the reaction stirred at r.t. for 1 h. Water (32 mL) was added and the reaction heated to 6O⁰C for 18 h. The reaction was cooled, K₂CO₃ (172 g, 1.24 mol) added, and the suspension was stirred at r.t. for 2 h. The mixture was filtered and the resulting filtrate concentrated in vacuo. The residue was dissolved in DCM (800 mL) and washed with water (100 mL). The combined organic extracts were dried (MgSO₄) and filtered through silica gel (100 g). The resulting filtrate was concentrated in vacuo to give a brown solid. The solid was dissolved in 1 : 1

THF/heptane (360 mL) and heated to 5O⁰C for 1.5 h. The mixture was cooled, and the resulting precipitate filtered and dried in vacuo to give the title compound as a beige solid (32.1 g, 36%). δ_H (DMSO-d6) 7.89 (IH, br s), 3.43 (2H, s), 3.08 (2H, d, J6.3 Hz), 2.37 (2H, s), 0.90 (6H, s). LCMS (ES⁺) RT 1.87 minutes, 156 (M+H)⁺.

INTERMEDIATE 2

3-Bromo-6,6-dimethylazepane-2,4-dione iV-Bromosuccinimide (11.5 g, 64.5 mmol) was added slowly to a solution of Intermediate 1 (10.0 g, 64.5 mmol) and NaHSO₄ (1.94 g, 16.1 mmol) in THF (350 mL) at 0⁰C, and the reaction was warmed to r.t. for 1 h. Aqueous NaHCO₃ (300 mL) was added to the reaction, and the mixture extracted with DCM (3 x 100 mL). The combined organic extracts were dried (MgSO₄), and concentrated in vacuo to give a white solid. The solid was triturated with isopropyl ether and the resulting precipitate filtered and dried in vacuo to give the title compound as a white solid (11.18 g, 74%). 5H (DMSO-d6) 8.37 (IH, m), 5.74 (IH, s), 3.29 (IH, dd, J 15.1, 6.2 Hz), 2.50-2.70 (2H, m), 2.32 (IH, d, J 11.9 Hz), 0.99 (3H, s), 0.86 (3H, s). LCMS (ES⁺) RT 2.17 minutes, 236 (M+H)⁺.

INTERMEDIATE 3

2-Fluoro-4-iodo- 1 -isothiocyanatobenzene

Thiophosgene (17.8 ml, 232 mmol) was added to a rapidly stirred mixture of 2- fluoro-4-iodoaniline (50.0 g, 211 mmol) in CHCl₃ (500 ml) and water (300 ml). The mixture was stirred at room temperature for 4 hours. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried (Na₂SO₄), filtered and the volatiles removed in vacuo to give the title compound as an off-white crystalline solid (51.7 g, 88%). δ_H (DMSO-d₆) 7.87 (IH, dd, / 1.8, 9.5 Hz), 7.63 (IH, ddd, J 1.0, 1.8, 8.4 Hz), 7.25 (IH, dd, J 8.2, 8.4 Hz). INTERMEDIATE 4

(2-Fluoro-4-iodoρhenylthiocarbanioyl')acetic acid ethyl ester Sodium metal (2 g, 87 mmol) was dissolved in ethanol (250 mL), treated with ethyl acetoacetate (10.72 g, 82.5 mmol) and the reaction stirred for 15 min. Intermediate 3 (23 g, 82.5 mmol) was added portionwise and the reaction stirred at r.t. for 4 h. The reaction mixture was poured onto 2M HCl and extracted into ethyl acetate, dried (Na₂SO₄), filtered and concentrated in vacuo, yielding a red solid. 5H (DMSO-d6) 11.62 (IH, s), 7.78 (IH, dd, J 9.7, 1.8 Hz), 7.63 (IH, m), 7.40 (IH, t, J 8.1 Hz), 4.03 ( 2H, q, J 7.1 Hz), 3.89 (2H, s), 1.21 (3H, t, J 7. IHz). LCMS (ES⁺) RT 2.69 minutes, 366 (M+H)⁺.

INTERMEDIATE 5

2-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-4H-thieno[2,3- c^")azepine-3-carboxylic acid ethyl ester

Intermediate 2 (11.2 g, 47.6 mmol) was added to a mixture of Intermediate 4 (17.5 g, 47.6 mmol) and caesium carbonate (15.5 g, 47.6 mmol) in DMF (400 mL) and the mixture heated at 80⁰C for 18 h. The reaction was cooled and poured onto iced water (200 mL) and 2M HCl added (30 mL). The precipitate was filtered and washed with

MeCN to give the title compound as a yellow solid (11.53 g, 48%). δ_H (DMSO-d6) 10.32 (IH, s), 7.98 (IH, t, J4.8 Hz), 7.76 (IH, dd, 710.4, 1.6 Hz), 7.63 (IH, d, J8.6 Hz), 7.43 (IH, t, J8.6 Hz), 4.30 (2H, q, J7.1 Hz), 2.89 (2H, s), 2.84 (2H, d, J5.0 Hz), 1.32 (3H, t, J 7.1 Hz), 0.98 (6H, s). LCMS (ES⁺) RT 3.64 minutes, 503 (M+H)⁺.

INTERMEDIATE 6

2-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-8-thioxo-5,6.7.8-tetrahvdro-4i^:/- thieno[2,3-c]azepine-3-carboxylic acid ethyl ester Intermediate 5 (1O g, 20 mmol) and Lawesson's reagent (4.0 g, 10 mmol) were dissolved in toluene (200 mL) and the reaction mixture stirred at HO⁰C for 2 h. The reaction was concentrated in vacuo. The crude residue was triturated (1:1) with MeCN and isopropyl ether, and the precipitate filtered off and dried to give the title compound as a yellow solid (7.8 g, 75%). δ_H (CDCl₃) 10.72 (IH, d, J2.0 Hz)₅ 8.06 (IH, br s), 7.46- 7.36 (3H, m), 4.33 (2H, q, J7.1 Hz), 2.97 (2H, d, J5.8 Hz), 2.91 (2H, s), 1.35 (3H, t, J 7.1 Hz), 1.02 (6H, s). LCMS (ES⁺) RT 3.66 minutes, 519 (M+H)⁺.

INTERMEDIATE 7

2-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-8-methylsulfanyl-5,6-dihvdro-4Ji- thieno[2,3-glazeρine-3-carboxylic acid ethyl ester hydroiodide salt

Intermediate 6 (3.0 g, 5.8 mmol) and MeI (3.6 mL, 58 mmol) were dissolved in MeCN (100 mL) and stirred at r.t. for 18 h. The reaction was concentrated in vacuo. The crude residue was triturated in MeCN and the precipitate was filtered off and dried to give the title compound as a yellow solid (3.3 g, 87%). δ_H (DMSO-d6) 11.44 (IH, br s), 10.48 (IH, br s), 7.90 (IH, dd, J 9.9, 1.5 Hz), 7.72 (IH, d, J 8.4 Hz), 7.44 (IH, t, J 8.4 Hz), 4.38 (2H, q, J7.0 Hz), 3.25 (2H, s), 2.95 (2H, s), 2.79 (3H, s), 1.35 (3H, t, J7.1 Hz), 1.12 (6H, s). LCMS (ES⁺) RT 2.94 minutes, 533 (M+H)⁺.

INTERMEDIATE 8

2-(2-Fluoro-4-iodophenylaminoV8-hvdrazono-5,5-dimethyl-5,6,7,8-tetrahydro-4H^'- thieno|^~2,3-g1azepine-3-carboxylic acid ethyl ester

Hydrazine acetate (690 mg, 7.5 mmol) was added to a solution of Intermediate 7 (800 mg, 1.5 mmol) in MeCN (20 mL) and heated at reflux for 2 h. The reaction was cooled and poured onto 10% NaOH (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by chromatography (silica, 0-10% MeOH in DCM) to give the title compound as a yellow solid (190 mg, 24%). δ_H (DMSO-d6) 10.31 (IH, s), 7.74 (IH, dd, J 10.7, 1.9 Hz), 7.63-7.59 (IH, m), 7.41 (IH, t, J 8.7Hz), 6.04 (IH, s), 4.97 (2H, br s), 4.30 (2H, q, J 7.0 Hz), 2.83 (2H, s), 2.74 (2H, d, J 2.8 Hz), 1.32 (3 H, t, J 7.2 Hz), 0.94 (6H, s). LCMS (ES⁺) RT 3.53 minutes, 517 (M+H)⁺. INTERMEDIATE 9

8-(2-Fluoro-4-iodophenylamino)-5.5-dimethyl-5,6-dihvdro-4J^!7-9-thia-l,2,3a-triaza- cyclopenta|^"g] azulene-7-carboxylJc acid Lithium hydroxide monohydrate (35 mg, 1.5 mmol) was added to a solution of

Example 1 (385 mg, 0.7 mmol) in THF (10 mL) and water (5 mL) and heated to reflux for 18 hours. The reaction mixture was concentrated in vacuo and 5% citric acid (10 mL) added. The resulting precipitate was filtered and dried in vacuo to give the title compound as a yellow solid (307 mg, 84%). δ_H (DMSO-d6) 11.74 (IH, s), 8.29 (IH, s), 7.67 (IH, dd, J 10.4, 1.8 Hz), 7.56 (IH, d, J8.4 Hz), 7.38 (IH, t, J 8.6 Hz), 3.95 (2H, s), 3.06 (2H, s), 0.89 (6H, s). LCMS (ES⁺) RT 2.66 minutes, 499 (M+H)⁺.

INTERMEDIATE 10

8-(2-Fluoro-4-iodophenylaminoV5,5-dimethyl-5,6-dihydro-4iJ^r-9-thia-l,2,3a-triaza- cyclopenta[g^"lazulene-7-carboxylic acid pentafluorophenyl ester

EDC (236 mg, 1.2 mmol) was added to a mixture of 4-methylmorpholine (170 mg, 1.7 mmol), HOBT (166 mg, 8.44 mmol), pentafluorophenol (226 mg, 1.2 mmol) and Intermediate 9 (308 mg, 0.6 mmol) in DCM/DMF, 10:1 mixture (15 mL) and stirred at ambient temperature for 18 h. Brine (100 mL) was added to the reaction, and the mixture was extracted with DCM (3 x 100 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo. The residual DMF was azeotroped with heptane. The crude product was purified by chromatography (silica, 0-10% MeOH in EtOAc) to give the title compound as a yellow solid (162 mg, 41%). δ_H (DMSO-d6) 9.74 (IH, s), 8.41 (IH, s), 7.88 (IH, dd, J9.8, 1.7 Hz), 7.73-7.70 (IH, m), 7.46 (IH, t, J8.3 Hz), 4.07 (2H, s), 3.14 (2H, s), 0.99 (6H, s). LCMS (ES⁺) RT 3.47 minutes, 665 (M+H)⁺.

INTERMEDIATE 11

2_rr2-Fluoro-4-iodophenylamino)-8-(2-hvdroxyethyliminoV5.5-dimethyl-5.6.7.8- tetrahydro-4H-thieno(^"2.3-c1azepine-3-carboxylic acid ethyl ester

Prepared from Intermediate 7 (1.0 g, 1.5 mmol) and ethanolamine (0.9 mL, 15.0 mmol) by the method of Example 2. Title compound obtained as a yellow oil (800 mg, 97%). δ_H (DMSO-d6) 7.70 (IH, dd, J 10.5, 1.6 Hz), 7.59 (IH, d, J 8.5 Hz), 7.31 (IH, t, J 8.5 Hz), 6.62 (IH, br s), 4.28 (2H, q, J7.1 Hz), 3.52 (2H, t, J6.0 Hz), 3.17 (2H, t, J6.0 Hz), 2.74 (4H, d, J 6.0 Hz), 1.30 (3H, t, J 7.1 Hz), 0.95 (6H, s). LCMS (ES⁺) RT 2.04 minutes, 546 (M+H)⁺.

INTERMEDIATE 12

8-(2-Fluoro-4-iodophenylamino)-3,5,5-trimethyl-5,6-dihydro-4i7-9-thia-l,2,3a-triaza- cyclopenta[g] azulene-7-carboxylic acid Prepared from Example 2 (250 mg, 0.5 mmol) and lithium hydroxide monohydrate (11 mg, 0.5 mmol) by the method of Intermediate 9. Title compound obtained as a cream solid (125 mg, 53%). δ_H (DMSO-d6) 13.19 (IH, br s), 10.65 (IH, br s), 7.76 (IH, d, J 10.5 Hz), 7.65 (IH, d, J8.3 Hz), 7.47 (IH, t, J8.5 Hz), 3.83 (2H, s), 3.12 (2H, m), 2.36 (3H, s), 1.00 (6H, s). LCMS (ES⁺) RT 2.68 minutes, 513 (M+H)⁺.

INTERMEDIATE 13

8-(2-Fluoro-4-iodophenylamino)-3,5,5-trimethyl-5,6-dihydro-4H-9-thia-l,2,3a-triaza- cyclopenta[g]azulene-7-carboxylic acid pentafluorophenyl ester Prepared from Intermediate 13 (890 mg, 1.7 mmol) and pentafluorophenol (640 mg, 3.5 mmol) by the method of Intermediate 10. Title compound obtained as a cream solid (670 mg, 57%). δ_H (DMSO-d6) 9.74 (IH, s), 7.87 (IH, dd, J 9.8, 1.7 Hz), 7.70 (IH, d, J8.4 Hz), 7.46 (IH, d, J8.5 Hz), 3.87 (2H, s), 3.11 (2H, s), 2.37 (3H, s), 1.01 (6H, s). LCMS (ES⁺) RT 3.82 minutes, 679 (M+H)⁺.

INTERMEDIATE 14

8-(2-Fluoro-4-iodophenylamino^')-5,5-dimethyl-3-trifluoromethyl-5,6-dihvdro-4H^"-9-thia- 1 ,2.3a-triazacyclopenta[^glazulene-7-carboxylic acid Prepared from Example 15 (190 mg, 0.3 mmol) and lithium hydroxide monohydrate (13 mg, 0.3 mmol) by the method of Intermediate 9. Title compound obtained as a cream solid (150 mg, 85%). δ_H (DMSO-d6) 13.38 (IH, br s), 10.67 (IH, br s), 7.80 (IH, dd, J 10.4, 1.9 Hz), 7.69 (IH₃ d, J 8.5 Hz), 7.49 (IH, t, J 8.5 Hz), 4.06 (2H, s), 3.20 (2H, s), 1.04 (6H, s). LCMS (ES⁺) RT 3.35 minutes, 567 (M+H)⁺.

INTERMEDIATE 15

8-(2-Fluoro-4-iodophenylamino)-3,5,5-trimethyl-5.6-dihydro-4H-9-thia-l,2,3a-triaza- cyclopenta[^"e1azulene-7-carboxylic acid (2,2-dimethyl-Fl 31dioxolan-4-ylmethyl)amide

Prepared from Intermediate 13 (250 mg, 0.4 mmol) and 2,2-dimethyl- [1 ,3]dioxolan-4-ylmethylamine (100 mg, 0.7 mmol) by the method of Example 6. Title compound obtained as a cream solid (180 mg, 78%). δ_H (DMSO-d6) 8.75 (IH, s), 8.11- 8.02 (IH, m), 7.62 (IH, dd, J 10.7, 1.7 Hz), 7.45 (IH, d, J 8.3 Hz), 7.00 (IH, t, J 8.7 Hz), 4.07-3.97 (IH, m), 3.87-3.82 (3H, m), 3.61 (IH, dd, J 8.3, 5.7 Hz), 3.36-3.25 (IH, m), 2.90 (2H, s), 2.37 (3H, s), 1.31 (3H, s), 1.23 (3H, s), 1.00 (6H, s). LCMS (ES⁺) RT 2.74 minutes, 626 (M+H)⁺.

INTERMEDIATE 16

8-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-5,6-dihydro-4/-/-9-thia-l,3a-diaza- cyclopentafg] azulene-7-carboxylic acid To a suspension of Example 3 (730 mg, 1.4 mmol) in THF (30 mL) and water (20 mL) was added lithium hydroxide monohydrate (130 mg). The mixture was heated at 80⁰C for 48 h. The volatiles were removed in vacuo to give the title compound as the lithium salt, which was used without further purification. LCMS (ES⁺) RT 1.89 minutes, 498 (M+H)⁺.

EXAMPLE 1

8-(^"2-Fluoro-4-iodophenylaminoV5,5-dimethyl-5,6-dihydro-4H-9-thia-l,2,3a-triaza- cyclopentafβ] azulene-7-carboxylic acid ethyl ester Intermediate 8 (50 mg, 0.10 mmol) was dissolved in triethyl orthoformate (2 mL) and heated at 14O⁰C in a microwave for 10 minutes. The reaction was cooled and concentrated in vacuo. The crude product was purified by chromatography (silica, 0-50% EtOAc in DCM) to give the title compound as a cream solid (13 mg, 25%). δ_H (DMSO- dθ) 10.10 (IH, s), 8.40 (IH, s), 7.80 (IH, dd, J 10.3, 1.6 Hz), 7.67 (IH, d, J8.5 Hz), 7.46 (IH, t, J8.6 Hz), 4.31 (2H, q, J7.0 Hz), 4.04 (2H, s), 3.11 (2H, s), 1.33 (3H, t, J7.1 Hz), 0.99 (6H, s). LCMS (ES⁺) RT 3.29 minutes, 527 (M+H)⁺.

EXAMPLE 2

8-(2-Fluoro-4-iodophenylamino)-3,5,5-trimethyl-5,6-dihydro-4H-9-thia-l,2,3a-triaza- cvclopenta[^"g]azulene-7-carboxylic acid ethyl ester

Acetic acid (0.55 mL, 9.7 mmol) was added to a solution of Intermediate 7 (639 mg, 1.0 mmol) and acetic hydrazide (717 mg, 9.7 mmol) in MeCN (100 mL) and heated at reflux for 18 h. The reaction was cooled and poured onto 10% NaOH (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, 0-40% EtOAc in DCM) to give the title compound as a yellow solid (460 mg, 88%). δ_H (DMSO-d6) 10.17 (IH, d, J 1.6 Hz), 7.78 (IH, dd, J 10.4, 1.8 Hz), 7.66 (IH, d, J8.5 Hz), 7.45 (IH, t, J8.6 Hz), 4.30 (2H, q, J7.1 Hz), 3.83 (2H, s), 3.08 (2H, s), 2.36 (3H, s), 1.32 (3H, t, J 7.1 Hz), 1.01 (6H, s). LCMS (ES⁺) RT 3.32 minutes, 541 (M+H)⁺.

EXAMPLE 3

8-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-5,6-dihydro-4H^"-9-thia- 1 ,3 a-diaza- cyclopenta[e]azulene-7-carboxylic acid ethyl ester

Intermediate 5 (1.04 g, 2.0 mmol) was dissolved in POCl₃ (10 mL) and the solution heated to reflux for 1 h. The reaction was cooled, the volatiles removed in vacuo and the residue azeotroped with toluene (3 x 20 mL). The residue was suspended in aminoacetaldehyde dimethyl acetal (10 mL) and heated to 100⁰C for 1 h. The reaction was allowed to cool. The volatiles were removed in vacuo and the residue then dissolved in ethyl acetate (250 mL). The organic solution was washed with saturated NaHCO₃ solution and brine, dried (Na₂SO₄), filtered and the solvents removed in vacuo. The resultant crude residue was dissolved in toluene (50 mL) and treated withpαrø-toluene- sulphonic acid (1.5 g). The reaction mixture was heated to 100⁰C for 30 minutes before being cooled and poured into ethyl acetate (250 mL). The organic phase was washed with saturated NaHCO₃ solution and brine, dried (Na₂SO₄), filtered and the solvents removed in vacuo to give the title compound as a pale brown solid (730 mg, 70%). 6_H (CDCl₃) 10.48 (IH, d, J2.8 Hz), 7.47-7.34 (3H, m), 6.91 (IH, d, J 1.1 Hz), 6.74 (IH, d, J 1.3 Hz), 4.31 (2H, q, J7.2 Hz), 3.76 (2H, s), 3.02 (2H, s), 1.35 (3H, t, J7.2 Hz), 1.02 (6H, s). LCMS (ES⁺) RT 3.64 minutes, 526 (M+H)⁺.

EXAMPLE 4

8-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-5,6-dihydro-4i^:/^'-9-thia-l,2,3a-triaza- cyclopenta|^"g]azulene-7-carboxylic acid (2-amino-2-methylpropyl)aniide Trimethylaluminium (1.20 mL, 2.4 mmol) was added to a solution of 1,2-diamino-

2-methylpropane (210 mg, 2.4 mmol) in toluene (10 mL) at 0⁰C and stirred for 30 min. Example 1 (250 mg, 0.50 mmol) was added to the mixture and heated to 100⁰C for 18 h. Aqueous NaOH solution (10 wt %) was added and the mixture extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, 0-10% MeOH in DCM) to give the title compound as a yellow solid (20 mg, 7%). δ_H (DMSO-d6) 9.17 (IH, br s), 8.35 (IH, s), 7.54 (IH, dd, J 10.8, 1.8 Hz), 7.45 (IH, d, J8.5 Hz), 7.14 (IH, t, J 8.8 Hz), 6.80 (2H, br s), 4.01 (2H, s), 3.25 (2H, s), 3.08 (2H, s), 1.12 (6H, s), 0.97 (6H, s). LCMS (ES⁺) RT 2.47 minutes, 569 (M+H)⁺.

EXAMPLE 5

7V-(5,5-Dimethyl-5.6-dihvdro-4/-^r-9-thia-l,2,3a-triazacvclopentare]azulen-8-yl)-iV-(^"2- fluoro-4-iodophenyl)amine Prepared from Intermediate 9 (307 mg, 0.6 mmol) by the method of Intermediate

10. The title compound was obtained as a by-product from the reaction as a cream solid (15 mg, 6%). δ_H (DMSO-d6) 8.90 (IH, d, J0.9 Hz), 8.34 (IH, s), 7.59 (IH, dd, J 10.9, 1.9 Hz), 7.45 (IH, d, J 8.3 Hz)₅ 7.20 (IH, t, J 8.8 Hz), 6.42 (IH, s), 4.05 (2H, s), 2.85 (2H₅ s), 0.98 (6H, s). LCMS (ES⁺) RT 2.89 minutes, 455 (MH-H)⁺. EXAMPLE 6

(l-[8-r2-Fluoro-4-iodophenylaminoV5.5-dimethyl-5,6-dihvdro-4H-9-thia-1.23a-triaza- cyclopentare1azulene-7-carbonyl]azetidin-3-ylmethyl|carbamic acid fert-butyl ester Azetidin-3-ylmethylcarbamic acid tert-buty\ ester (90 mg, 0.5 mmol) was added to a mixture of Intermediate 10 (160 mg, 0.2 mmol) and triethylamine (70 μL, 0.5 mmol) in DCM (10 mL) and stirred at ambient temperature for 18 h. Water (50 mL) was added to the reaction, and the mixture was extracted with DCM (3 x 10 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo. The crude product was purified by chromatography (silica, 0-10% MeOH in EtOAc) to give the title compound as a cream solid (90 mg, 56%). δ_H (DMSO-d6) 8.64 (IH, s), 8.38 (IH, s), 7.62 (IH, d, J 10.2 Hz), 7.44 (IH, d, J8.1 Hz), 6.94 (2H, t, J8.6 Hz), 4.06 (2H, s), 3.91-3.85 (2H, m), 3.59-3.54 (2H, m), 3.07 (2H, t, J6.1 Hz), 2.80 (2H, s), 2.65-2.55 (IH, m), 1.35 (9H, s), 0.98 (6H, s). LCMS (ES⁺) RT 2.64 minutes, 667 (M+H)⁺.

EXAMPLE 7

[3-(Aminomemyl)azetidin-l-yl1[8-(2-fluoro-4-iodopheriylamino)-5,5-dimethyl-5,6- dihydro-4/i-9-thia-l,2,3a-triazacyclopenta[elazulen-7-yl]methanone Trifluoroacetic acid (1 mL) was added to a solution of Example 6 (84 mg, 0.1 mmol) in DCM (5 mL) and stirred at r.t. for 18 h. Aqueous saturated NaHCO₃ solution was added to the reaction and the mixture extracted with DCM (3 x 100 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo to give the title compound as a cream solid (52 mg, 71%). δ_H (DMSO-d6) 8.38 (IH, s), 7.62 (IH, dd, J 10.7, 1.7 Hz), 7.43 (IH, d, J 8.1 Hz), 6.93 (IH₅ 1, J 8.9 Hz), 4.06 (2H, s), 3.90 (2H, s), 3.58 (2H, s), 2.80 (2H, s), 2.61 (2H, d, J 6.7 Hz), 2.49-2.44 (IH, m), 0.98 (6H, s). LCMS (ES⁺) RT 2.15 minutes, 567 (M+H)⁺. EXAMPLE 8

8-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-2,4.,5,6-tetrahvdro-3//-9-thia-l,3a-diaza- cyclopenta[e1azulene-7-carboxyric acid ethyl ester A mixture of Intermediate 11 (200 mg, 0.4 mmol) and thionyl chloride (5 mL) was stirred at room temperature for 18 h. The reaction was concentrated in vacuo and the residue treated with saturated aqueous NaHCO₃ solution and extracted with DCM (3 x 100 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, 0-10% MeOH in EtOAc) to give the title compound as a cream solid (127 mg, 65%). δ_H (DMSO-d6) 10.25 (IH, br s), 7.76 (IH, dd, J 10.7, 1.5 Hz), 7.63 (IH, d, J 8.7 Hz), 7.49-7.36 (IH, m), 4.30 (2H, q, J 7.2 Hz), 3.64-3.57 (2H, m), 3.46-3.39 (2H, m), 2.94 (2H, s), 2.88 (2H, s), 1.32 (3H, t, J 7.2 Hz), 1.01 (6H, s). LCMS (ES⁺) RT 3.40 minutes, 528 (M+H)⁺.

EXAMPLE 9

{l-[8-(2-Fluoro-4-iodophenylamino)-3,5,5-trimethyl-5,6-dihydro-4H-9-thia-L2,3a-triaza-

Prepared from Inteπnediate 12 (116 mg, 0.2 mmol) and azetidin-3-ylmethyl- carbamic acid tert-butyl ester (84 mg, 0.4 mmol) by the method of Intermediate 10. Title compound obtained as a cream solid (26 mg, 16%). δ_H (DMSO-d6) 8.61 (IH, s), 7.61 (IH, dd, J 10.5, 1.9 Hz), 7.43 (IH, dd, J8.3, 0.8 Hz), 6.96-6.90 (2H, m), 3.90-3.85 (4H, m), 3.59 (2H, dd, J9.2, 5.1 Hz), 3.07 (2H, t, J6.4 Hz), 2.78 (2H, s), 2.60-2.55 (IH₅ m), 2.36 (3H, s), 1.36 (9H, s), 1.01 (6H, s). LCMS (ES⁺) RT 2.60 minutes, 681 (M+H)⁺.

EXAMPLE 10

[3-(Aminomethyl)azetidin-l-yl][8-(2-fluoro-4-iodophenylamino)-3,5,5-trimethyl-5.6- dihydro-4i^!7-9-thia- 1 ,2,3 a-triazacyclopentafgl azulen-7- yllmethanone Prepared from Example 9 (26 mg, 0.04 mmol) and trifiuoroacetic acid (1 mL) by the method of Example 7. Title compound obtained as a white solid (3 mg, 13%). δπ (DMSO-d6) 8.35 (IH, s), 7.62 (IH, dd, J 10.7, 1.7 Hz), 7.44 (IH, dd, J 8.5, 0.9 Hz), 6.94 (IH, t, J 8.7 Hz), 3.90-3.64 (6H, m), 2.78 (4H, s), 2.59-2.57 (IH, m), 2.36 (3H, s), 1.00 (6H, s). LCMS (ES⁺) RT 1.53 minutes, 581(M+H)⁺.

EXAMPLE 11

r^V3-([8-f2-Fluoro-4-iodophenylaminoV3.5.5-triiiiethyl--5.6-dihvdro-4H^'-9-thia-L2,3a- triazacvclopentare1azulene-7-carbonyl]amino|pyrrolidine-l -carboxylic acid tert-butyl ester

Prepared from Intermediate 13 (335 mg, 0.5 mmol) and (i?)-3-aminopyrrolidine-l- carboxylic acid tert-butyl ester (180 mg, 1.0 mmol) by the method of Example 6. Title compound obtained as a cream solid (280 mg, 84%). δ_H (DMSO-d6) 8.58 (IH, br s), 8.20 (IH, br s), 7.57 (IH, dd, J 10.7, 1.5 Hz), 7.43 (IH, d, J 8.5 Hz), 6.96 (IH, t, J 8.5 Hz), 4.26-4.24 (IH, m), 3.85 (2H, s), 3.40-3.35 (IH, m), 3.27-3.20 (2H, m), 3.12-3.03 (IH, m), 2.87 (2H, s), 2.37 (3H, s), 1.95-1.91 (IH, m), 1.78-1.71 (IH, m), 1.39 (9H, s), 0.99 (6H, s). LCMS (ES⁺) RT 2.89 minutes, 681 (M+H)⁺.

EXAMPLE 12

8-(2-Fluoro-4-iodophenylamino)-3,5,5-trimethyl-5,6-dihydro-4ϋr-9-thia-l,2,3a-triaza- cyclopenta[e]azulene-7-carboxylic acid (2-ammo-2-methylpropyl)amide

Prepared from Intermediate 13 (335 mg, 0.5 mmol) and l,2-diamino-2-methyl- propane (88 mg, 1.0 mmol) by the method of Example 6. Title compound obtained as a yellow solid (120 mg, 42%). δ_H (DMSO-d6) 9.67 (IH, s), 7.46 (IH, d, J 10.8 Hz), 7.38 (IH, d, J8.4 Hz), 7.14 (IH, t, J8.7 Hz), 5.88 (2H, br s), 3.77 (2H, s), 3.18 (2H, s), 3.11 (2H, s), 2.34 (3H, s), 1.06 (6H, s), 1.00 (6H, s). LCMS (ES⁺) RT 1.67 minutes, 583 (M+H)⁺.

EXAMPLE 13

r8-r2-Fluoro-4-iodophenylamino)-5,5-dimethyl-5.6-dihvdro-4iJ^r-9-thia-1.2,3a-triaza- cyclopenta[e] azulen-7-yll (piperazin- 1 - vDmethanone

Prepared from Intermediate 10 (410 mg, 0.6 mmol) and piperazine (105 mg, 1.2 mmol) by the method of Example 6. Title compound obtained as a white solid (190 mg, 55%). δ_H (DMSO-d6) 8.39 (2H, s), 7.57 (IH, d, J 10.8 Hz), 7.38 (IH, d, J 7.7 Hz), 6.86 (IH, t, J 8.7 Hz), 4.08 (2H, s), 3.38-3.15 (4H, m), 2.82-2.75 (2H, m), 2.71-2.60 (4H, m), 0.97 (6H, s). LCMS (ES⁺) RT 1.53 minutes, 567 (M+H)⁺.

EXAMPLE 14

8-(2-Fluoro-4-iodophenylaminoV3,5,5-trimethyl-5.6-dihvdro-4//-9-thia-l,2,3a-triaza- cyclopentarelazulene-7-carboxylic acid CR)-pyrrolidin-3-ylamide hydrochloride

A mixture of Example 11 (240 mg, 0.3 mmol) in DCM (5 mL) and 4M HCl in 1 ,4-dioxane (0.2 mL) was stirred at r.t. for 18 h. The resulting precipitate was filtered and dried in vacuo to give the title compound as a yellow solid (128 mg, 57%). 5_H (DMSO- d6) 9.59 (IH, br s), 9.36 (IH, br s), 9.14 (IH, s), 8.57 (IH, d, J 6.6 Hz), 7.65 (IH, dd, J 10.5, 1.7 Hz), 7.50 (IH, d, J 8.5 Hz), 7.11 (IH, t, J 8.7 Hz), 4.42-4.34 (IH, m), 3.97 (2H, s), 3.33-3.10 (4H, m), 3.03 (2H, s), 2.58 (3H, s), 2.14-2.02 (IH, m), 1.89-1.81 (IH, m), 1.05 (6H, s). LCMS (ES⁺) RT 1.39 minutes, 581 (M+H)⁺.

EXAMPLE 15

8-(2-Fluoro-4-iodophenylamino^')-5,5-dimethyl-3-trifluoromethyl-5,6-dihydro-4H^'-9-thia- l,2,3a-triazacyclopenta[e^"|azulene-7-carboxylic acid ethyl ester

Prepared from Intermediate 7 (2.0 g, 3.0 mmol) and trifluoroacetic acid hydrazide (3.9 g, 30.0 mmol) by the method of Example 2. Title compound obtained as a cream solid (54 mg, 3%). δ_H (DMSO-d6) 10.19 (IH, s), 7.83 (IH, dd, J 10.4, 1.9 Hz), 7.69 (IH, dd, J8.5, 1.1 Hz), 7.47 (IH, t, J8.5 Hz), 4.33 (2H, q, J7.0 Hz), 4.05 (2H, s), 3.16 (2H, s), 1.34 (3H, t, J 7.2 Hz), 1.05 (6H, s). LCMS (ES⁺) RT 4.10 minutes, 595 (M+H)⁺.

EXAMPLE U

3-Cyclobutyl-8-(2-fluoro-4-iodophenylaminoV5,5-dimethyl-5,6-dihydro-4H-9-thia- l,2,3a-triazacvclopenta|^"e]azulene-7-carboxylic acid ethyl ester

Cyclobutane carbonyl chloride (50 mg, 0.4 mmol) was added to a mixture of Intermediate 8 (200 mg, 0.4 mmol) and triethylamine (110 μL, 0.5 mmol) in DCM (10 mL) and stirred at r.t. for 18 h. Water (50 mL) was added to the reaction, and the mixture was extracted with DCM (3 x 10 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The crude residue was taken and dissolved in MeCN (10 mL), acetic acid (22 μL) added and the reaction was heated at reflux for 3 h. 10% aqueous NaOH solution (10 mL) was added to the reaction, and the mixture extracted with DCM (3 x 10 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, 0-40% EtOAc in DCM) to give the title compound as a yellow solid (50 mg, 22%). δ_H (DMSO-d6) 10.15 (IH, d, J 1.1 Hz), 7.80 (IH, dd, J 10.4, 1.7 Hz), 7.67 (IH, d, J8.5 Hz), 7.46 (IH, t, J8.7 Hz), 4.31 (2H, q, J7.0 Hz), 3.75 (2H, s), 3.71-3.62 (IH, m), 3.08 (2H, s), 2.38-2.30 (4H, m), 2.10-2.00 (IH, m), 1.92-1.89 (IH, m), 1.33 (3H, t, J7.0 Hz), 0.99 (6H, s). LCMS (ES⁺) RT 3.86 minutes, 581 (M+H)⁺.

EXAMPLE 17

(i?)-3-{r8-(2-Fluoro-4-iodoρhenylamino)-5,5-dimethyl-3-trifluoromethyl-5.6-dihvdro-4/J- 9-thia- 1 ,2,3 a-triazacyclopenta|^"e] azulene-7-carbonyl] amino ) pyrrolidine- 1 -carboxylic acid feft-butyl ester

Prepared from Intermediate 14 (150 mg, 0.3 mmol) and (i?)-3-aminopyrrolidine-l- carboxylic acid fert-butyl ester (100 mg, 0.5 mmol) by the method of Intermediate 10. Title compound obtained as a cream solid (130 mg, 66%). δ_H (DMSO-d6) 8.84 (IH, d, J 1.3 Hz), 8.29 (IH, d, J6.6 Hz), 7.63 (IH, dd, J 10.5, 1.7 Hz), 7.47 (IH, d, J 8.7 Hz), 7.08- 7.02 (IH, m), 4.26-4.18 (IH, m), 4.06 (2H, s), 3.44-3.32 (IH, m), 3.28-3.20 (2H, m), 3.15-3.06 (IH, m), 2.93 (2H, s), 2.05-1.90 (IH, m), 1.80-1.70 (IH, m), 1.40 (9H, s), 1.02 (6H, s). LCMS (ES⁺) RT 3.64 minutes, 735 (M+H)⁺.

EXAMPLE 18

8-(2-Fluoro-4-iodophenylamino)-3,5,5-trimethyl-5,6-dihydro-4/ir-9-thia-L2,3a-triaza- cvclopenta[g]azulene-7-carboxylic acid N-(2,3-dihvdroxypropyl)-N-methylamide Prepared from Intermediate 13 (250 mg, 0.4 mmol) and 3-(methylamino)propane-

1,2-diol (80 mg, 0.7 mmol) by the method of Example 6. Title compound obtained as a cream solid (154 mg, 70%). δ_H (DMSO-d6 at 12O⁰C) 7.79 (IH, br s), 7.51 (IH, d, J 10.6 Hz), 7.40 (IH, d, J8.5 Hz), 7.05-6.96 (IH, br m), 4.51-4.27 (IH, m), 4.09 (IH, s), 3.86 (2H, s), 3.73 (IH, s), 3.52-3.17 (4H, m), 2.95 (3H, s), 2.78-2.63 (2H, m), 2.38 (3H, s), 1.04 (6H, s). LCMS (ES⁺) RT 1.90 minutes, 600 (M+H)⁺.

EXAMPLE 19

8-(2-Fluoro-4-iodophenylaniinoV5,5-dimethyl-3-T3henyl-5.6-dihvdro-4/j^r-9-thia-l,2.3a- triazacyclopentafe^'lazulene-7-earboxylic acid ethyl ester

Prepared from Intermediate 7 (2.0 g, 3.0 mmol) and benzoic hydrazide (4.1 g, 30.0 mmol) by the method of Intermediate 8. Title compound obtained as a yellow solid (1.5 g, 83%). δ_H (CDCl₃) 10.63 (IH, d, J2.8 Hz), 7.63-7.50 (8H, m), 4.42 (2H, q, J7.2 Hz), 3.90 (2H, s), 3.20 (2H, s), 1.45 (3 H, t, J 7.2 Hz), 1.09 (6H, s). LCMS (ES⁺) RT 3.96 minutes, 603 (M+H)⁺.

EXAMPLE 20

8-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-3-trifluoromethyl-5,6-dihydro-4H-9-thia- 1 ,2,3a-triazacvclopenta[e^"lazulene-7-carboxylic acid (i?)-pyrrolidin-3-ylamide hydrochloride

Prepared from Example 17 (110 mg, 0.15 mmol) and HCl in 1,4-dioxane by the method of Example 14. Title compound obtained as a yellow solid (53 mg, 53%). 5_H (DMSO-d6) 9.40 (IH, br s), 9.18 (IH, br s), 9.06 (IH, s), 8.51 (IH, d, J6.4 Hz)₅ 7.66 (IH, dd, J 10.5, 1.1 Hz), 7.50 (IH, d, J 8.5 Hz), 7.10 (IH, t, J8.7 Hz), 4.40-4.35 (IH, m), 4.06 (2H, s), 3.41-3.21 (3H, m), 3.18-3.07 (IH, m), 3.00 (2H, s), 2.10-2.01 (IH, m), 1.85- 1.80 (IH, m), 1.03 (6H, s). LCMS (ES⁺) RT 2.18 minutes, 635 (M+H)⁺.

EXAMPLE 21

3-Cyclopropyl-8-(2-fluoro-4-iodophenylamino')-5,5-dimethyl-5,6-dihvdro-4//-9-thia- l,2,3a-triazacvclopenta[^g1azulene-7-carboxylic acid ethyl ester Prepared from Intermediate 8 (500 mg, 1.0 mmol) and cyclopropylcarbonyl chloride (100 mg, 0.1 mmol) by the method of Example 16. Title compound obtained as an orange solid (32 mg, 56%). δ_H (CDCl₃) 10.50 (IH, d, J2.4 Hz), 7.42-7.38 (3H, m), 4.33 (2H, q, J 7.2 Hz), 3.81 (2H, s), 3.07 (2H, s), 1.69-1.41 (2H, m), 1.36 (3H, t, J 7.2 Hz), 1.05 (6H, s), 1.02-0.96 (3H₅ m). LCMS (ES⁺) RT 3.63 minutes, 567 (M+H)⁺.

EXAMPLE 22

8-r2-Fluoro-4-iodophenylainino)-3,5,5-trimethyl-5,6-dihvdro-4.H-9-thia-l,2,3a-triaza- cyclopentarelazulene-7-carboxylic acid (2,3-dihydroxypropyl)amide

A mixture of Intermediate 15 (180 mg, 0.3 mmol) in MeOH (5 mL) and 2M HCl (1 mL) was stirred at room temperature for 18 h. The reaction was concentrated in vacuo to give the title compound as a cream solid (135 mg, 80%). δ_H (DMSO-d6) 9.17 (IH, s), 7.92 (IH, br s), 7.67 (IH, dd, J 10.5, 1.7 Hz), 7.52 (IH, d, J 8.4 Hz), 7.15 (IH, t, J 8.7 Hz), 3.97 (2H, s), 3.59-3.53 (IH, m), 3.38-3.32 (3H, m), 3.18-3.09 (IH, m), 3.00 (2H, s), 2.53 (3H, s), 1.04 (6H, s). LCMS (ES⁺) RT 1.89 minutes, 586 (M+H)⁺.

EXAMPLE 23

(^)-3-(r8-(2-Fluoro-4-iodophenylaminoV3,5_<5-trimethyl-5,6-dihydro-4H-9-thia-L2,3a- triazacyclopenta[e]azulene-7-carbonyl]amino}piperidine-l -carboxylic acid ferf-butyl ester Prepared from Intermediate 13 (250 mg, 0.4 mmol) and (i?)-3-aminopiperidine-l- carboxylic acid tert-butyl ester (150 mg, 0.7 mmol) by the method of Example 6. Title compound obtained as a yellow solid (190 mg, 74%). δ_H (DMSO-d6) 8.62 (IH, s), 7.87 (IH, d, J5.9 Hz), 7.60 (IH, dd, J 10.9, 1.5 Hz), 7.43 (IH, d, J8.1 Hz), 6.96 (IH, t, J8.7 Hz), 3.86 (2H₅ s), 3.65-3.58 (3H, m), 3.29 (2H₅ s), 2.88-2.72 (3H₅ m), 2.70-2.67 (IH₅ m), 2.38 (3H, s), 1.72-1.64 (2H₅ m), 1.36 (9H, s), 1.00 (6H₅ s). LCMS (ES⁺) RT 3.14 minutes, 695 (M+H)⁺.

EXAMPLE 24

8-r2-Fluoro-4-iodo^phenylamino⁾-3_t5.5-trimethyl-5.6-dihydro-4H^"-9-thia-1.2.3a-triaza- cyclopentafe^"lazulene-7-carboxylic acid fi?)-piperidin-3-ylamide hydrochloride

Prepared from Example 23 (190 mg, 0.3 mmol) and HCl in 1,4-dioxane by the method of Example 14. Title compound obtained as a yellow solid (152 mg, 80%). 5H (DMSO-d6) 9.48 (IH, br s), 9.27 (IH₅ br s), 9.09 (IH, s), 8.53 (IH, d, J 7.7 Hz), 7.64 (IH, dd, J 10.5, 1.7 Hz), 7.48 (IH, d, J 8.5 Hz), 7.08 (IH, t, J8.7 Hz), 4.10-4.02 (IH, m), 4.00 (2H, s), 3.19-3.00 (4H, m), 2.79-2.70 (2H, m), 2.62 (3H, s), 1.80-1.67 (3H, m), 1.52- 1.45 (IH, m), 1.07 (6H, d, J 3.1 Hz). LCMS (ES⁺) RT 1.60 minutes, 595 (M+H)⁺.

EXAMPLE 25

fJ?V2-r(r8-(2-Fluoro-4-iodophenylammoV3,5,5-trimethyl-5,6-dihvdro-4H^"-9-thia-l,2,3a- triazacvclopenta[elazulene-7-carbonyl]amino|methyl)pyrrolidine-l -carboxylic acid tert- butyl ester

Prepared from Intermediate 13 (250 mg, 0.4 mmol) and (i?)-2-(aminomethyl)- pyrrolidine-1 -carboxylic acid tert-hvXy\ ester (150 mg, 0.7 mmol) by the method of Example 6. Title compound obtained as a cream solid (240 mg, 94%). 5_H (DMSO-d6) 8.85-8.71 (IH, m), 7.99 (IH, br s), 7.60 (IH, dd, J 10.7, 0.9 Hz), 7.49-7.40 (IH, m), 6.99 (IH, dd, J3.6, 1.9 Hz), 3.86 (2H, s), 3.77-3.58 (IH, m), 3.50-3.45 (IH, m), 3.21-3.15 (3H, m), 3.10-2.90 (2H, m), 2.37 (3H, s), 1.82-1.70 (4H, m), 1.40 (9H, s), 1.00 (6H, d, J 5.3 Hz). LCMS (ES⁺) RT 3.26 minutes, 695 (M+H)⁺.

EXAMPLE 26

8-(2-Fluoro-4-iodophenylamino)-3,5,5-trimethyl-5,6-dihvdro-4H^r-9-thia-L2,3a-triaza- cyclopenta[e]azulene-7-carboxylic acid (ifl-(pyrrolidin-2-ylmethyl)amide hydrochloride

Prepared from Example 25 (240 mg, 0.4 mmol) and HCl in 1,4-dioxane by the method of Example 14. Title compound obtained as a yellow solid (160 mg, 73%). 5_H (DMSO-d6) 9.83 (IH, br s), 9.54 (IH, s), 9.23 (IH, br s), 8.54 (IH, t, J 5.1 Hz), 7.69 (IH, dd, J 10.5, 1.5 Hz), 7.54 (IH, d, J 8.3 Hz), 7.22 (IH, t, J 8.5 Hz), 4.01 (2H, s), 3.64-3.59 (IH, m), 3.54-3.47 (2H, m), 3.14-3.06 (4H, m), 2.62 (3H, s), 2.01-1.80 (3H, m), 1.69-1.60 (IH, m), 1.06 (6H, s). LCMS (ES⁺) RT 1.74 minutes, 595 (M+H)⁺. EXAMPLE 27

8-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-3-trifluoromethyl-5,6-dihydro-4H^'-9-thia- 1 ,2,3a-triazacyclopenta[e]azulene-7-carboxylic acid (2-ammo-2-methyrpropyl)amide Prepared from Intermediate 14 (260 mg, 0.4 mmol) and l,2-diamino-2-methyl- propane (62 mg, 0.7 mmol) by the method of Intermediate 10. Title compound obtained as a yellow solid (20 mg, 9%). δ_H (DMSO-d6) 11.04 (IH, br s), 7.45-7.38 (2H, m), 7.25- 7.19 (IH, m). 6.99 (2H, br s), 3.91 (2H, s), 3.33 (4H, d, J4.6 Hz), 1.18 (6H, s), 1.02 (6H, s). LCMS (ES⁺) RT 2.33 minutes, 637 (M+H)⁺.

EXAMPLE 28

8-(2-Fluoro-4-iodophenylamino^')-5,5-dimethyl-5,6-dihydro-4H-9-thia-l,3a-diaza- cyclopenta|^~e^'|azulene-7-carboxylic acid [(R)-I -(fert-butoxycarbonyl)pyrrolidin-3-yll- amide

From Intermediate 16 (310 mg, 0.62 mmol) and (i?)-3-aminopyrrolidine-l- carboxylic acid tert-butyl ester (190 mg) by the method of Intermediate 10 to give, after purification by column chromatography (SiO₂, 0-100% EtOAc in DCM), the title compound as an off-white solid. δ_Η (DMSO-d6) 8.38 (IH, br s), 8.14 (IH, br d, J3.7 Hz), 7.56 (IH, dd, J 10.8, 1.3 Hz), 7.40 (IH, d, J8.5 Hz), 7.13 (IH, d, J0.7 Hz), 6.91- 6.86 (IH, m), 6.84 (2H, s), 4.27-4.23 (IH, m), 3.97 (2H, s), 3.40-3.37 (IH, m), 3.34-3.26 (2H, m), 3.25-3.23 (IH, m), 2.83 (2H, br s), 1.97-1.91 (IH, m), 1.73-1.69 (IH, m), 1.39 (9H, s), 0.98 (6H, s). LCMS (ES⁺) RT 3.26 minutes, 666 (M+H)⁺.

EXAMPLE 29

8-(2-FluoiO-4-iodophenylamino)-5,5-dimethyl-5.6-dihydro-4i/-9-thia-l,3a-diaza- cyclopenta[^"g1azulene-7-carboxylic acid (i?Vpyrrolidin-3-ylamide hydrochloride

From Example 28 (150 mg) and 4M HCl in 1,4-dioxane by the method of Example 14 to give the title compound as a pale yellow solid (70 mg). δπ (DMSO-d6) 9.57 (IH, br s), 9.35 (IH, br s), 9.14 (IH, s), 8.70 (IH, d, J 6.0 Hz), 7.68 (IH, d, J 10.4 Hz), 7.59 (IH, s), 7.52-7.48 (2H, m), 7.10 (IH, t, J 8.4 Hz), 4.40 (IH, br s), 4.10 (2H, s), 3.40-3.00 (4H₅ m), 2.95 (2H₅ s), 2.08-2.04 (IH, m), 1.90-1.75 (IH, m), 1.02 (6H, s). LCMS (ES⁺) RT 2.28 minutes (pH 10), 1.54 minutes (pH 3), 566 (M+H)⁺.

EXAMPLE 30

8-(2-Fluoro-4-iodophenylamino)-5,5-dimethyl-5.6-dihvdro-4H-9-thia-l,3a-diaza- cyclopenta[g] azulene-7-carboxylic acid (2-amino-2-methylprop vDamide

From Intermediate 16 (310 mg) and 1 ,2-diamino-2-methylpropane (88 mg) by the method of Intermediate 10 to give, after column chromatography (SiO₂, 94% DCM, 5% MeOH, 1% NH₄OH), the title compound as an off-white solid. δ_H (DMSO-d6) 8.38 (IH, s), 7.55 (IH, dd, J 10.8, 1.9 Hz), 7.43-7.40 (IH, m), 7.11 (IH, s), 7.01 (IH, t, J8.8 Hz), 6.83 (IH, s), 3.96 (2H, s), 3.20 (2H, s), 2.93 (2H, s), 1.06 (6H, s), 0.98 (6H, s). LCMS (ES⁺) RT 2.61 minutes (pH 10), 1.64 minutes (pH 3), 568 (M+H)⁺.

Claims

Claims:

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein

W represents a covalent bond or a methylene linkage; the moiety X-Y-Q represents an optionally substituted five-membered heteroaliphatic or heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolinyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;

R and R independently represent hydrogen; or Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci.₆)alkyl, aryl, aryl(C_1-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (Ci_-6)alkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or

R and R , when both are attached to the same carbon atom, represent, when taken together with the carbon atom to which they are both attached, C_3-7 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; or

R¹ and R², when attached to adjacent carbon atoms, represent, when taken together with the carbon atoms to which they are attached, C_5-7 cycloalkyl, phenyl or heteroaryl, any of which groups may be optionally benzo-fused and/or substituted by one or more substituents; R³ represents hydrogen, Cj_-6 alkyl, C_3-7 heterocycloalkenyl (optionally substituted by one or two methyl groups), cyano, -CO₂R³, -COR^b, -CONR^bR^c, -SO₂NR^bR^c, -CON(OR^b)R°, -CON(R^c)COR^b, -CON(R^c)SO₂R^b, -SO₂N(R^c)COR^b, -CON(R^d)NR^bR^c, -C(=NR^e)NR^bR^c or -CON(R^d)C(=NR^e)NR^bR^c; or R³ represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl; or

R³ represents an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl; R^4a and R^4b independently represent hydrogen, halogen, cyano, nitro, C_1-6 alkyl, trifluoromethyl, Ci_-6 alkoxy, trifluoromethoxy, C_1-6 alkylthio, C_1-6 alkylsulphinyl or C_1-6 alkylsulphonyl;

R⁵ represents halogen, nitro, cyano, Ci_-6 alkyl, C_2-6 alkynyl, hydroxy(Ci_-6)alkyl or formyl; R^a represents hydrogen, C_1-6 alkyl or C_3-7 heterocycloalkyl(Cj_-6)alkyl;

R^b represents hydrogen or trifluoromethyl; or C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(Ci_-6)alkyl, aryl, aryl(Ci_₆)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (Ci_₆)alkyl, C_4-9 heterobicycloalkyl, heteroaryl or heteroaryl(Ci_-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and R^c represents hydrogen or Ci_-6 alkyl (optionally substituted by hydroxy); or

R^b and R^c, when taken together with the nitrogen atom to which they are both attached, represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, homomorpholinyl or homopiperazinyl, any of which groups may be optionally substituted by one or more substituents; or the moiety -N(OR^b)R^c represents an optionally substituted heterocyclic ring wherein R^b and R^c are taken together and represent a C_2-5 alkylene linkage; and

R^d and R^e independently represent hydrogen or C_1-6 alkyl.

2. A compound as claimed in claim 1 wherein the moiety X-Y-Q represents an imidazolinyl, imidazolyl or triazolyl ring, any of which may be optionally substituted by one or more substituents.

3. A compound as claimed in claim 1 or claim 2 wherein R³ represents hydrogen, -CO₂R^a, -CONR^bR^c, -CON(OR^b)R^c or -CONHNR^bR^c, in which R^a, R^b and R^c are as defined in claim 1.

4. A compound as claimed in claim 1 represented by formula (HA), and pharmaceutically acceptable salts and solvates thereof:

wherein

W, the moiety X-Y-Q, R , R >4a , r R>4b and R³ are as defined in claim 1;

R¹¹ represents hydrogen or optionally substituted C_1-6 alkyl; and

R¹² represents hydrogen; or C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(Ci-₆)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl(C_1-6)alkyl, heteroaryl or heteroaryl(C_1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or

R¹¹ and R¹², when taken together with the carbon atom to which they are both attached, represent C_3-7 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.

5. A compound as claimed in claim 4 represented by formula (HB), and pharmaceutically acceptable salts and solvates thereof:

(HB)

wherein

R³ is as defined in claim 1 ; R¹¹ and R¹² are as defined in claim 4;

R^y and R^z independently represent hydrogen, Ci_-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl(C_1-6)alkyl, aryl, aryl(Ci_-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (C_1-6)alkyl, heteroaryl, heteroaryl(Ci_-6)alkyl, C_1-6 alkoxy, Ci_-6 alkylthio, Ci_-6 alkylsulphinyl, Ci_-6 alkylsulphonyl, C_2-6 alkylcarbonyl, amino, Ci_-6 alkylamino, di(C_1-6)alkylamino, halogen, cyano or trifluoromethyl;

R¹⁴ represents halogen; and

R¹⁵ represents halogen, nitro, cyano, C_2-6 alkynyl, hydroxy(Ci-₆)alkyl or formyl.

6. A compound as claimed in claim 4 represented by formula (IIC), and pharmaceutically acceptable salts and solvates thereof:

(IIC) wherein

R³ is as defined in claim 1 ;

R¹¹ and R¹² are as defined in claim 4; and

R^y, R^z, R¹⁴ and R¹⁵ are as defined in claim 5.

7. A compound as claimed in claim 4 represented by formula (HD), and pharmaceutically acceptable salts and solvates thereof:

(IID)

wherein

R³ is as defined in claim 1 ;

R¹¹ and R¹² are as defined in claim 4; and

R^y, R¹⁴ and R¹⁵ are as defined in claim 5.

8. A compound as claimed in any one of claims 5 to 7 wherein R¹⁴ represents fluoro or chloro.

9. A compound as claimed in any one of claims 5 to 8 wherein R 15 . represents iodo.

10. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier.

12. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

13. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and/or prevention of disorders for which the administration of a selective MEK inhibitor is indicated.

14. The use of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of disorders for which the administration of a selective MEK inhibitor is indicated.

15. A method for the treatment and/or prevention of disorders for which the administration of a selective MEK inhibitor is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof.