ZA200509717B - Thienopyridone derivatives as kinase inhibitors - Google Patents

Description

THIENOPYRIDONE DERIVATIVES AS KINASE INHIBITORS

This invention relates to a series of thienopyridone derivatives, to compositions containing them, to processes for their preparation and to their use in medicine. : Immune and inflammatory responses involve a variety of cell types with control and co-ordination of the various interactions occurring via both cell- cell contacts (e.g. integrin interactions with their receptors) and by way of intercellular signalling molecules. A large number of different signalling molecules are involved, including cytokines, lymphocytes, chemokines and growth factors.

Cells respond to such intercellular signalling molecules by means of intracellular signalling mechanisms that include protein kinases, phosphatases and phospholipases. There are five classes of protein kinase of which the major ones are the tyrosine kinases and the serine/threonine kinases [Hunter, T., Methods in Enzymology (Protein Kinase Classification), p. 3, Hunter, T. and Sefton, B.M. eds., vol. 200, Academic Press, San Diego, 1991].

One sub-class of serine/threonine kinases is the mitogen activating protein (MAP) kinases of which there are at least three families which differ in the sequence and size of the activation loop [Adams, J. L. et al., Progress in

Medicinal Chemistry, pp. 1-60, King, F. D. and Oxford, A. W. eds., vol. 38,

Elsevier Science, 2001]: (i) the extracellular regulated kinases (ERKSs); (ii) the c-Jun NH, terminal kinases or stress activated kinases (JNKs or SAP kinases); and (iii) the p38 kinases which have a threonine-glycine-tyrosine (TGY) activation motif. Both the JNKs and p38 MAP kinases are primarily activated by stress stimuli including, but not limited to, proinflammatory cytokines, e.g. tumour necrosis factor (TNF) and interleukin-1 (IL-1), ultraviolet light, endotoxin and chemical or osmotic shock.

Four isoforms of p38 have been described (p38a/Bly/5). The human p38a enzyme was initially identified as a target of cytokine-suppressive anti- inflammatory drugs (CSAIDs) and the two isoenzymes found were initially termed CSAID binding protein-1 (CSBP-1) and CSBP-2 [Lee, J. C. et al,

Nature (London), 1994, 372, 739-46]. CSBP-2 is now widely referred to as p38 and differs from CSBP-1 in an internal sequence of 25 amino acids as a result of differential splicing of two exons that are conserved in both mouse and human (McDonnell, P. C. et al., Genomics, 1995, 29, 301-2]. CSBP-1 and p38a are expressed ubiquitously and there is no difference between the two isoforms with respect to tissue distribution, activation profile, substrate preference or CSAID binding. A second isoform is p38p which has 70% identity with p38a.. A second form of p38p termed p38p2 is also known and of the two this is believed to be the major form. p38a and p38p2 are expressed in many different tissues. However in monocytes and macrophages p38a. is the predominant kinase activity [Lee, J. C., ibid; Jing,

Y. et al., J. Biol. Chem., 1996, 271, 10531-34; Hale, K. K. et al., J. Immun., 1999, 162, 4246-52]. p38y and p385 (also termed SAP kinase-3 and SAP kinase-4 respectively) have ~63% and ~61% homology to p38a. respectively. p38y is predominantly expressed in skeletal muscle whilst p388 is found in testes, pancreas, prostate, small intestine and in certain endocrine tissues.

All p38 homologues and splice variants contain a 12 amino acid activation loop that includes a Thr-Gly-Tyr motif. Dual phosphorylation of both Thr-180 and Tyr-182 in the TGY motif by a dual specificity upstream kinase is essential for the activation of p38 and resuits in a >1000-fold increase in specific activity of these enzymes [Doza, Y. N. et al, FEBS Lett., 1995, 364, 7095-8012]. This dual phosphorylation is effected by MKK6 and under certain conditions the related enzyme MKKS3 [Enslen, H. et al., J. Biol. Chem., 1008, 273, 1741-48]. MKK3 and MKK6 belong to a family of enzymes termed MAPKK (mitogen activating protein kinase kinase) which are in turn activated by MAPKKK (mitogen activating kinase kinase kinase) otherwise known as MAP3K.

Several MAP3Ks have been identified that are activated by a wide variety of stimuli including environmental stress, inflammatory cytokines and other factors. MEKK4/MTK1 (MAP or ERK kinase kinase/MAP three kinase-1),

ASK1 (apoptosis stimulated kinase) and TAK1 (TGF-B-activated kinase) are some of the enzymes identified as upstream activators of MAPKKs.

MEKK4/MTK1 is thought to be activated by several GADD-45-like genes that are induced in response to environmental stimuli and which eventually lead to p38 activation [Takekawa, M. and Saito, H., Cell, 1998, 95, 521-30). TAKA1 has been shown to activate MKK6 in response to transforming growth factor-

B (TGF-B). TNF-stimulated activation of p38 is believed to be mediated by the recruitment of TRAF2 [TNF receptor associated factor] and the Fas adaptor protein, Daxx, which results in the activation of ASK1 and subsequently p38.

Several substrates of p38 have been identified including other kinases [e.g.

MAPK activated protein kinase 2/3/5 (MAPKAP 2/3/65), p38 regulated/activated protein kinase (PRAK), MAP kinase-interacting kinase 1/2 (MNK1/2), mitogen- and stress-activated protein kinase 1 (MSK1/RLPK) and ribosomal S6 kinase-B (RSK-B)]; transcription factors [e.g. activating transcription factor 2/6 (ATF2/6), monocyte-enhancer factor-2A/C (MEF2A/C), C/EBP homologous protein (CHOP), Elk1 and Sap-1ail]; and other substrates [e.g. cPLA2, p47phox].

MAPKAP K2 is activated by p38 in response to environmental stress. Mice engineered to lack MAPKAP K2 do not produce TNF in response to lipopolysaccharide (LPS). Production of several other cytokines such as IL- 1, IL-6, IFN-g and IL-10 is also partially inhibited [Kotlyarov, A. et al., Nature

Cell Biol., 1999, 1, 94-7]. Further, MAPKAP K2 from embryonic stem cells from p38a. null mice was not activated in response to stress and these cells } 5 did not produce IL-6 in response to IL-1 [Allen, M. et al., J. Exp. Med., 2000, 191, 859-69]. These results indicate that MAPKAP K2 is not only essential for TNF and IL-1 production but also for signalling induced by cytokines. In addition MAPKAP K2/3 phosphorylate and thus regulate heat shock proteins

HSP 25 and HSP 27 which are involved in cytoskeletal reorganization.

Several small molecule inhibitors of p38 have been reported which inhibit iL.- 1 and TNF synthesis in human monocytes at concentrations in the low uM range [Lee, J. C. et al., Int. J. Immunopharm., 1988, 10, 835] and exhibit activity in animal models which are refractory to cyclooxygenase inhibitors |[Lee, J. C. et al., Annals N.Y. Acad. Sci., 1993, 696, 149]. In addition these small molecule inhibitors are known to decrease the synthesis of a wide variety of pro-inflammatory proteins including IL-6, IL-8, granulocyte/macrophage colony-stimulating factor (GM-CSF) and cyclooxygenase-2 (COX-2). TNF-induced phosphorylation and activation of cytosolic PLA2, TNF-induced expression of VCAM-1 on endothelial cells and -

IL-1 stimulated synthesis of collagenase and stromelysin are also inhibited by small molecule inhibitors of p38 [Cohen, P., Trends Cell Biol., 1997, 7, 353- 61].

A variety of cells including monocytes and macrophages produce TNF and

IL-1. Excessive or unregulated TNF production is implicated in a number of disease states including Crohn's disease, ulcerative colitis, pyresis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, toxic shock syndrome, endotoxic shock, sepsis, septic shock, gram negative sepsis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejection, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, cerebral malaria, scar tissue formation, keloid formation, fever and myalgias due to infection, such as influenza, cachexia secondary to acquired immune deficiency syndrome (AIDS), cachexia secondary to infection or malignancy, AIDS or AIDS related complex.

Excessive or unregulated IL-1 production has been implicated in rheumatoid arthritis, osteoarthritis, traumatic arthritis, rubella arthritis, acute synovitis, psoriatic arthritis, cachexia, Reiter's syndrome, endotoxemia, toxic shock syndrome, tuberculosis, atherosclerosis, muscle degeneration, and other acute or chronic inflammatory diseases such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease. In addition IL-1 has been linked to diabetes and pancreatic B cell destruction [Dinarello, C. A., J.

Clinical Immunology, 1985, 5, 287-97].

IL-8 is a chemotactic factor produced by various cell types including endothelial cells, mononuclear cells, fibroblasts and keratinocytes. IL-1, TNF and LPS all induce the production of IL-8 by endothelial cells. In vitro IL-8 has been shown to have a number of functions including being a chemoattractant for neutrophils, T-lymphocytes and basophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis which may contribute to increased adhesion of neutrophils to vascular endothelial cells. Many diseases are characterised by massive neutrophil infiltration. Histamine release from basophils (in both atopic and normal individuals) is induced by

IL-8 as is lysozomal enzyme release and respiratory burst from neutrophils.

The central role of IL-1 and TNF together with other leukocyte derived cytokines as important and critical inflammatory mediators is well documented. The inhibition of these cytokines has been shown or would be expected to be of benefit in controlling, alleviating or reducing many of these disease states.

The central position that p38 occupies within the cascade of signalling molecules mediating extracellular to intracellular signalling and its influence over not only IL-1, TNF and IL-8 production but also the synthesis and/or action of other pro-inflammatory proteins (e.g. IL-6, GM-CSF, COX-2, collagenase and stromelysin) make it an attractive target for inhibition by small molecule inhibitors with the expectation that such inhibition would be a highly effective mechanism for regulating the excessive and destructive activation of the immune system. Such an expectation is supported by the potent and diverse anti-inflammatory activities described for p38 kinase inhibitors [Adams, ibid; Badger et al., J. Pharm. Exp. Ther., 1996, 279, 1453- 61: Griswold et al., Pharmacol. Comm., 1996, 7, 323-29]. 16

We have now found a group of compounds which are potent and selective inhibitors of p38 kinase (p38a, B, & and y)and the isoforms and splice variants thereof, especially p38, p38 and p38p2. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described herein.

Thus according to one aspect of the invention we provide a compound of formula (1):

NHAr = 0 Y\ “

Le

Alk') Cy! (AIRCY (RY),

wherein:

Y is a linking group -C(O)- or -S(0)z-; n is zero or the integer 1; mis the integer 1,2, 3 0r4; p is the integer 1, 2,3 or 4,

RC is an -OH, -(AI®)OH (where Alk’ is a straight or branched Ci.4 alkylene chain), -OR" (where R' is a straight or branched C+.g alkyl group), (AIK®)OR', .NRZR® (where R? and R® may be the same or different and is each independently a hydrogen atom or a straight or branched C16 alkyl group),

L(AIYNRZR® or straight or branched C1.6 alkyl group;

AK is a straight or branched C1. alkylene chain;

Cy' is an optionally substituted cycloaliphatic, aromatic or heteroaromatic group; and

Ar is an optionally substituted aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof. it will be appreciated that compounds of formula (1) may have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof in any proportion, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (1) may exist as tautomers, for example keto (CH2C=0)-enol (CH=CHOH) tautomers. Formula (1) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.

The following general terms as used herein in relation to compounds of the invention and intermediates thereto have the stated meaning below unless specifically defined otherwise.

Thus as used herein the term “alkyl” whether present as a group of part of a group includes straight or branched C1.s alkyl groups, for example C44 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl groups. Similarly, the terms “alkenyl!” or “alkynyl” are intended to mean straight or branched Ca alkenyl or Cz. alkynyl groups such as Cz4 alkenyl or C4 alkynyl groups. The optional substituents which may be present on these groups include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or -OH, -CO2H, COR? [where R? is an optionally substituted straight or branched C16 alkyl group, and is in particular a straight or branched Ci4 alkyl group}, e.g. -CO,CH3; or _CO,C(CHa)s, -CONHR?, e.g. -CONHCHs, -CON(R*)., eg. -CON(CHa

COR, e.g. -COCHa, C1 alkoxy, e.g. methoxy or ethoxy, haloCi.salkoxy, e.g. trifluoromethoxy or difluoromethoxy, thiol (-SH), -S(O)R%, e.g. -S(O)CHs, -S(O)R*, e.g. -S(0)CHs, Cis alkylthio, e.g. methyithio or ethylthio, amino,

NHR?, e.g. -NHCHj, or -N(R*)z, €.9. -N(CHz)z, groups. Where two R* groups are present in any of the above substituents these may be the same or different. in addition when two R* alkyl groups are present in any of the optional substituents just described these groups may be joined, together with the N atom to which they are attached, to form a heterocyclic ring. Such heterocyclic rings may be optionally interrupted by a further heteroatom or heteroatom-containing group selected from -O-, -S-, -N(R*)-, -C(O)- or -C(S)- groups. Particular examples of such heterocyclic rings include piperidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings.

The term halogen is intended to include fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl” is intended to include those alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described.

Particular examples of such groups include -CF3, -CCly, -CHF2, -CHCl, -CH.F and -CH.Cl groups.

The term “alkoxy” as used herein is intended to include straight or branched

C1. alkoxy, e.g. C14 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy. “Haloalkoxy” as used herein includes any of these alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include -OCFs, -OCCls, -OCHF,, -OCHCI,, -OCH2F and -OCH_CI groups.

As used herein the term “alkylthio” is intended to include straight or branched

Ci alkylthio, e.g. C14 alkylthio such as methylthio or ethyithio.

As used herein the term “alkylamino® or “dialkylamino” is intended to include the groups -NHR and -N(R")(R™) where R'? and R' is each independently an optionally substituted straight or branched alkyl group or both together with the N atom to which they are attached form an optionally substituted heterocycloalkyl group which may contain a further heteroatom or heteroatom-containing group such as an -O- or -S- atom or -N(R™)- group.

Particular examples of such optionally substituted heterocycloalkyl groups include optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and N’-C1galkylpiperazinyl groups. The optional substituents which may be present on such heterocycloalkyl groups include those optional substituents as described above in relation to the term “alkyl”.

Particular examples of alkylene chains represented by Alk' and/or AIk* when each is present in compounds of the invention include -CHz-, -CH2CHz-,

-CH(CH3)CHz-, -(CH2).CHz-, -C(CHa)z-, -(CH2):CHz-, -CH,CH(CH3)CH2-, -C(CHa)2CH2- or -CH(CHg3)CH2CH2- chains.

Optionally substituted cycloaliphatic groups represented by the group Cy' in '5 compounds of the invention include optionally substituted Cs.10 cycloaliphatic groups. Particular examples include optionally substituted Cs-10 cycloalkyl, e.g.

Ca cycloalkyl, or Ca.10 cycloalkenyl, e.g. Cav cycloalkenyl, groups.

Particular cxemples of cycloaliphatic groups represented by the group cy' include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yi, 2-cyclopenten-1-yl and 3-cyclopenten-1-yl groups, especially cyclopropyl.

The optional substituents which may be present on the cycloaliphatic groups represented by the group Cy' include one, two, three or more substituents selected from halogen atoms, or C4.5 alkyl, e.g. methyl or ethyl, haloC1.salkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g. -C(OH)(CF3)2, Cis alkoxy, e.g. methoxy or ethoxy, haloC,.salkoxy, e.g. halomethoxy or haloethoxy such as diflucromethoxy or trifluoromethoxy, thiol, C16 alkylthiol, e.g. methyithiol or ethylthiol, carbonyl (=O), thiocarbonyl (=S), imino (=NR*) [where R% is an -OH group or a Ci alkyl group], or ~(AI*\R® groups in which AI is a straight or branched Cs.salkylene chain, v is zero or the integer 1 and Ris a

Cas cycloalkyl, -OH, -SH, -N(R°}R") [in which R® and R’ is each independently selected from a hydrogen atom or an optionally substituted alkyl or Cas cycloalkyl group], -OR®, -SR®, -CN, -NO2, -CO2R’, -SOR®, _SO,R?, -SO;R®, -OCO.R®, -C(O)R®, -OC(O)R®, -C(S)R®, -C(ON(R®)(R), -OC(ON(R®)(R"), -N(R®)C(O)R, -C(SN(R®)(R), N(R®C(S)R’, -SON(RE)R"), -N(R®)SOR’, NR®C(ON(R')(R®) [where R® is as defined for RY, -N(ROC(SINR")R®), -N(R®)SO,N(R")(R®) or an optionally substituted aromatic or heteroaromatic group.

Particular examples of AlK® chains include -CHz-, -CH2CHy-, -CH2CH2CH2- and -CH(CH3)CH2- chains.

When RS, R®, R” and/or R® is present as a Cas cycloalkyl group it may be for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. Optional substituents which may be present on such groups include for example one, two or three substituents which may be the same of different selected from halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxy or Cy alkoxy, e.g. methoxy, ethoxy or isopropoxy, groups.

When the groups R® and R” or R” and R® are both alkyl groups these groups may be joined, together with the N atom to which they are attached, to form a heterocyclic ring. Such heterocyclic rings may be optionally interrupted by a further heteroatom or heteroatom-containing group selected from -O-, -S-,

N(R"), -C(0)- or -C(S)- groups. Particular examples of such heterocyclic ings include piperidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings.

When R® is an optionally substituted aromatic or heteroaromatic group it may be any such group as described hereinafter in relation to Cy".

In general, optionally substituted aromatic groups represented by the group

Cy' include for example monocyclic or bicyclic fused ring Ce12 aromatic groups, such as phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indeny! groups, especially phenyl.

Heteroaromatic groups represented by the group Cy' include for example

C10 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.

Bicyclic heteroaromatic groups include for example eight- to thirteen- membered fused ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.

Particular examples of heteroaromatic groups of these types include pyrrolyl, furyl, thienyl, imidazolyl, N-Cealkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2 3-triazolyi, 1,2 4-triazolyl, 1,2,3-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyi, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2 4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl, [2,3-dihydro}benzothienyl, _ benzotriazolyl, indolyl, indolinyl, indazolinyl, benzimidazolyl, imidazo[1,2- a)pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, [3,4- dihydro]benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo[1,5- a)pyridinyl, imidazo[1,5-a]pyrazinyl, imidazo[1 5-c]pyrimidinyl, pyrido[3,4- blpyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, phthalazinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8- tetrahydroisoquinolinyl, imidyl, e.g. succinimidyl, phthalimidyl or naphthalimidyl such as 1,8-naphthalimidyf, pyrazolo[4,3-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, pyrrolo[3,2-d]pyrimidinyl, pyrazolo[3,2-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-b]pyridinyi, pyrrolo[3,2-b]pyridinyl, thiazolo[3,2-a]pyridinyl, pyrido[1,2-a]pyrimidinyl, tetrahydroimidazo[1,2-a]pyrimidinyl and dihydroimidazo[1,2-a]pyrimidinyl groups.

Optional substituents which may be present on aromatic or heteroaromatic groups represented by the group Cy' include one, two, three or more substituents, each selected from an atom or group R™ in which R'is R* or

LBAIKS(R%), where R'® is a halogen atom, or an amino (-NHy), substituted amino, nitro, cyano, hydroxyl (-OH), substituted hydroxyl, formyl, carboxy! (-CO2H), esterified carboxyl, thiol (-SH), substituted thiol, COR" [where R" is an -LSAIK3(R'™), aryl or heteroaryl group], CSR", -SOzH, -SOR",

SOR", SOR", -SONHa, -SONHR™, -SON(R™), -CONHz, -CSNH, _-CONHR". -CSNHR'", -CON(R™),, -CSN(R™)z, N(R'™2)SO,R"" [where R™ is a hydrogen atom or a straight or branched alkyl group], -N(SOR™MY,,

N(R'))SO.NH,, -N(R'})SONHR™, N(R™)SO:NR")z, N(R'?)COR",

N(R'™)CONH,, -N(R'?)CONHR", N(R™)CONR™, -N(R'*)CSNH,

N(R'Z)CSNHRY, -N(R™)CSNR"), -N(R'®)CSR", N(R"?)C(O)OR", -C=NR'}(NR'™), -SO,NHet' [where -NHet' is an optionally substituted Caz cyclicamino group optionally containing one or more other -O- or -S- atoms or

N(R), -C(O)- or -C(S)- groups], _CONHet", -CSNHet', -N(R'2)SONHet',

N(R'JCONHet!, -N(R™)CSNHet', -SON(R'?)Het [where -Het is an optionally substituted monocyclic C3.7 carbocyclic group optionally containing one or more other -O- or -S- atoms or -N(R™)-, -C(0)-, -S(O)- or -S(0)z- groups], -Het, -CON(R™)Het, .CSN(R™)Het, -N(R™)CON(R'*)Het,

NR™)CSN(R'™2)Het, -N(R'2)SO,N(R™)Het, aryl or heteroaryl groups; L%is a covalent bond or a linker atom or group; AlK® is an optionally substituted straight or branched C1.¢ alkylene, C,.¢ alkenylene or Cz. alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S(O)- [where k is an integer 1 or 2] or -N(R")-, e.g. -N(CHa)-, groups; and r is zero or the integer 1, 2, or 3. It will be appreciated that when two R' or R'? groups are present in one of the above substituents the R'! and R'? groups may be the same or different. :

When LE in the group -LSAI(R'®), is a linker atom or group it may be for example any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(0)-, -C(0)O-, -OC(0)-, -C(S)-, -8(0)-, -S(O)z, N(R?)- [where R? is a hydrogen atom or a straight or branched alkyl group], -NR)O-, -NR)N-, -CON(R’), -OC(ON(R%-, -CSN(R%-, -N(R®)CO-, -N(R})C(0)0-, -N(R®)CS-, -S(0)N(R%-, -N(R®S(0)-, N(R*)CON(R®-,

N(RY)CSN(R®)- or -N(R®)SO:N(R®)- groups. Where L® contains two R® groups these may be the same or different.

When in the group -LeAIK(R'®), r is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R'® may be present on any suitable carbon atom in -AlkS. Where more than one R'™ substituent is present these may be the same or different and may be present on the same or different atom in -AlIK®. Clearly, when ris zero and no substituent R'% is present the alkylene, alkenylene or alkynylene chain represented by Alk® becomes an alkyl, alkenyl or alkynyl group.

When R'® is a substituted amino group it may be for example a group NHR" [where R" is as defined above] or a group N(R"), wherein each R"" group is the same or different.

When R'® is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.

When R™ is a substituted hydroxyl or substituted thiol group it may be for example a group -OR™ or -SR* respectively.

Esterified carboxyl groups represented by the group R'® include groups of formula -CO,AIK® wherein AlK® is a straight or branched, optionally substituted

Cs alkyl group such as a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group; a Ce1zarylCrealkyl group such as an optionally substituted benzyl, phenylethyl, ~phenylpropyl, 1-naphthylmethyl or 2- naphthylmethyl group; a Cezaryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a Ce.12aryloxyCisalkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyi, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-galkanoyloxyCi.galkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a CgqsaroyloxyCisalkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk® group include R'® atoms and groups as described above.

When AIK® is present in or as a substituent it may be for example a -CHgx-, -CH(CHs)-, -C(CHs)-, -CHyCHo-, -CH,CH,CH2-, -CH(CH3)CH>-, -CH,CH,CHyCHp-, -CHoCH(CH3)CHz, -CH(CH3)CH:CHz-, -C(CH3)}CHz-, -CH=CH-, -CH=CHCH,-, -CH;CH=CH-, -CH=CHCH,CHg-, -CH2CH=CHCHz~, -CHoCHoCH=CH-, -C=C-, -C=CCHy-, -CH,C=C-, -CECCH,CHg-, -CH,C=CCH;- or -CH,CH,C=C- chain, optionally interrupted by one, two, or three -O- or -S- atoms or -S(O)-, -S(O)z- or -N(R'?)-, e.g. -N(CHs)-, groups. The aliphatic chains represented by Alk® may be optionally substituted by one, two or three halogen atoms in addition to any R'® groups that may be present.

Aryl or heteroaryl groups represented by the groups R'® or R"" include mono- or bicyclic optionally substituted Cs.12 aromatic or C1.¢ heteroaromatic groups as described above for the group Cy'. The aromatic and heteroaromatic groups may be attached to the group Cy' in compounds of formula (1) by any carbon atom or heteroatom, e.g. nitrogen atom, as appropriate.

It will be appreciated that when -NHet or -Het forms part of a substituent R™ the heteroatoms or heteroatom-containing groups that may be present within the ring -NHet' or -Het take the place of carbon atoms within the parent carbocyclic ring.

Thus when -NHet' or -Het forms part of a substituent R' each may be for example an optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group.

Additionally Het may represent, for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet' include those substituents described above when Cy' is a heterocycloaliphatic group.

Particularly useful atoms or groups represented by R' include fluorine, chlorine, bromine or iodine atoms, or Ci alkyl, .0. methyl, ethyl, n-propyl, isopropyl, n- butyl or tert-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrroiyl, furyl, thiazolyl, or thienyl, C15 hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1salkyl, e.g. carboxyethyl, Ci alkylthio, e.g. methyithio or ethyithio, carboxyC.salkylthio, e.g. carboxymethyithio, 2-carboxyethyithio or 3-carboxy- propylthio, Cis alkoxy, e.g. methoxy or ethoxy, hydroxyC1.ealkoxy, e.g. 2- hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenyithio or pyridyithio, Caz cycloalkyl, e.g. cyclobutyl or cyclopentyl, Cs7 cycloalkoxy, e.g. cyclopentyloxy, haloCicalkyl, e.g. trifluoromethyl, haloC4galkoxy, e.g. trifluoromethoxy, Cis alkylamino, e.g. methylamino or ethylamino, -CH(CH3)NH2 or -C(CHs)}2NHz, haloCyealkylamino, e.g. fluoroCi.salkylamino, -CH(CF3)NH2 or -C(CF3)NHz, amino (-NH), aminoCiealkyl, e.g. aminomethyl or aminoethyl, Cigdialkylamino, e.g. dimethylamino or diethylamino, CiealkylaminoCisalkyl, e.g. ethylaminoethyl,

CiedialkylaminoCyealkyl, e.g. diethylaminoethyl, aminoCi¢alkoxy, e.g. aminoethoxy, CisalkylaminoCqealkoxy, e.g. methylaminoethoxy, Cs.sdialkyl- aminoCy.galkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy or dimethylaminopropoxy, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, hydroxyl (-OH), formyl [HC(OM, carboxyl (-COzH), -COAIKE [where AlK® is as defined above], Cie alkanoyl, e.g. acetyl, optionally substituted benzoyl, thiol (-SH), thioC1.ealkyl, e.g. thiomethyl or thioethyl, sulphonyi (-SOsH), Ciealkylsulphonyl, eg. methylsulphonyl, aminosulphonyl (-SOzNH,), Ciealkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C.dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (-CONH2), Cigalkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1gdialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoCy.salkylaminocarbonyl, e.g. aminoethylamino- carbonyl, C, dialkylaminoC,.ealkylaminocarbonyi, e.g. diethylaminoethyl- : aminocarbonyl, aminocarbonylamino, C1.galkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C.¢dialkylamino- carbonylamino, e.g. dimethylaminocarbonylamino or diethylamino- carbonylamino, C..alkylaminocabonylC4.salkylamino, e.g. methylamino- carbonylimethylamino, aminothiocarbonylamino, C+.salkylaminothiocarbonyl- amino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino,

Csdialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1.salkylaminothiocarbonylC+.salkylamino, e.g. ethylaminothiocarbonyimethylamino, -CONHC(=NH)NH;, C1.salkylsulphonyl- amino, e.g. methylsulphonylamino or ethylsulphonylamino, Cedialkyl- sulphonylamino, e.g. dimethyisulphonylamino or diethylsulphonylamino, optionally substituted phenylisulphonylamino, aminosulphonylamino (-NHSO2NHz), C1.salkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosuiphonylamino, C1.sdialkylaminosulphonylamino, e.g. dimethyl- aminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonyiC4 salkylamino, optionally substituted phenylaminosulphonylamino, Cisalkanoylamino, e.g. acetylamino, aminoCy.salkanoylamino, e.g. aminoacetylamino, C..gdialkylaminoCi.galkanoyl- amino, e.g. dimethylaminoacetylamino, C.salkanoylaminoCqealkyl, e.g. acetylaminomethyl, C1¢alkanoylaminoC1.ealkylamino, e.g. acetamidoethyl- amino, Cigalkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonyi- amino or fert-butoxycarbonylamino, or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, ~~ benzyloxy- carbonylaminoC+.ealkyl, e.g. benzyloxycarbonylaminoethyl, benzothio, pyridyi- methylthio or thiazolylmethytthio groups.

A further particularly useful group of substituents represented by R'™ when present on aromatic or heteroaromatic groups includes substituents of formula _LSAIK’R'® where LS is preferably a covalent bond or an -O- or -S- atom or

NRY-, -C(O), -C(0)O-, -O-C(O)-, -N(R3CO-, -CON(R’)- or N(R®S(0)- group, AIC is an optionally substituted C4.salkyl group optionally interrupted by one of two -O- or -S- atoms or -N(R™)., -C(O), -C(S}, -CON(R™} or -N(R™2)CO- groups, and R'® is an optionally substituted Het group as herein defined or an optionally substituted heteroaromatic group as hereinbefore described in relation to Cy’.

Where desired, two R™ substituents may be linked together to form a cyclic group such as a cyclic ether, eg. a Cis alkylenedioxy group such as methylenedioxy or ethylenedioxy.

It will be appreciated that where two or more R'" substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position on the aromatic or heteroaromatic group represented by the group cy.

The substituted aromatic or heteroaromatic group represented by Ar in compounds of the invention may be any aromatic or heteroaromatic group as hereinbefore described for Cy'. Optional substituents which may be present include those R'® atoms and groups as generally or particularly described in relation to Cy' aromatic and heteroaromatic groups.

The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.

Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulfonates, e.g. methanesulfonates, ethanesulfonates, or isothionates, arylsulfonates, e.g. p-toluenesulfonates, besylates or napsylates,

phosphates, sulphates, hydrogensulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.

Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts. in one embodiment, Y is -C(O)-. In another embodiment, Y is -S(O)-.

In one class of compounds of formula (1) n is the integer 1. When in compounds of formula (1) n is the integer 1, Al! is preferably a -CH2CH.- chain or more especially is -CH-.

In one class of compounds of formula (1) n is zero.

Particularly preferred Cy’ optionally substituted cycloaliphatic groups include optionally substituted Caz cycloalkyl groups, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. Cy' is in particular a cyclopropyl group.

Each of these preferred Cy" cycloalkyl groups may be unsubstituted. When substituents are present these may in particular include halogen atoms, especially fluorine, chlorine or bromine atoms, or C1. alkyl groups, especially

Ci. alkyl groups, most especially a methyl group, or haloC.salkyl groups, especially fluoroCy.salkyl groups, most especially a -CF3 group, or C4.¢ alkoxy groups, especially a methoxy, ethoxy, propoxy Or iSOpropoxy group, or haloC4.salkoxy groups, especially fluoroC1.salkoxy groups, most especially a -OCF3 group, or a cyano (-CN), esterified carboxyl, especially -CO.CH;j or -CO2C(CHz)s, nitro (-NO,), amino (-NH2), substituted amino, especially -NHCHs or -N(CHs}2. -C(O)R®, especially -C(O)CHa, or N(RE)C(OR, especially -NHCOCHs, group.

Particularly preferred Cy' aromatic groups include optionally substituted phenyl groups. Particularly preferred heteroaromatic groups include optionally substituted monocyclic heteroaromatic groups, especially optionally substituted five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Particularly preferred optionally substituted monocyclic heteroaromatic groups include optionally substituted furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl and triazinyl groups. In a further preference, the heteroaromatic group may be an eight- to thirteen-membered bicyclic fused ring containing one or two oxygen, sulphur or nitrogen atoms.

Particularly useful groups of this type include optionally substituted indolyl groups.

Particularly preferred optional substituents which may be present on Cy" aromatic or heteroaromatic groups include one, two or three atoms or groups _R™* or -LSAI’(R'®), as hereinbefore defined. Particularly useful optional substituents include halogen atoms, especially fluorine, chlorine or bromine atoms, or Cis alkyl groups, especially Ci.3 alkyl groups, most especially a methyl group, or haloC4.¢alkyl groups, especially fluoroCi.salkyl groups, most especially a -CF3 group, or Ci.¢alkoxy groups, especially a methoxy, ethoxy, propoxy or isopropoxy group, or haloCy.galkoxy groups, especially fluoroCq.salkoxy groups, most especially a -OCF3z group, or a cyano (-CN), carboxyl (-CO-H), esterified carboxy! (-COAIK®), especially -CO2CHg, -CO,CH,CHi, or -CO,C(CHs)s, nitro (-NO2), amino (-NH), substituted amino,

especially -NHCHs or -N(CHs)}, -COR", especially -COCHs, or -N(R'?)COR", especially -NHCOCHj, group.

Further preferred optional substituents which may be present on cy' aromatic or heteroaromatic groups include groups of formula -LPAIC(R®), in which r is the integer 1 or 2, L® is a covalent bond or an -O- or -S- atom or a -N(R%-, especially -NH- or -N(CHs)-, -C(O}-, -C(S)-, -C(0)O-, -OC(O}-,

N(R®)CO-, especially -NHCO-, or -CON(R®)-, especially -CONH-, group, Ak’ is a Cig alkylene chain, especially a -CHy-, -CH2CHz-, -CH2CH2CHa- or -CH>CH.CH,CH_- chain, and R'% is a hydroxyl or substituted hydroxy! group, especially a -OCHs, -OCH.CHs; or -OCH(CHs). group, or a -NH2 or substituted amino group, especially a -N(CHj3)2 or -N(CH2CHs). group, or a -Het group, especially an optionally substituted monocyclic Cs.7 carbocyclic group containing one, two or three -O-, -S-, -N(R"®)-, especially -NH- or -N(CHzs)}-, or -C(O)- groups within the ring structure as previously described, most especially an optionally substituted pyrrolidinyl, imidazolidinyi, piperidinyl, e.g. N-methylpiperidinyl, morpholinyl, thiomorpholinyl or piperazinyl group, or R'%2 js an optionally substituted heteroaromatic group, especially a five- or six-membered monocyclic heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms, such as optionally substituted pyrrolyl, furyl, thienyi, imidazolyl, triazolyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, or pyrazinyl group. Particularly preferred optional substituents on the -Het groups just described include hydroxyl (-OH) and carboxyl (-CO,H) groups or those preferred optional substituents just described in relation to the group cy’, especially when Cy' is a cycloalkyl group.

In one particularly preferred group of compounds of formula (1) Cy' is an optionally substituted phenyl group, especially a phenyl group optionally substituted by one, two or three substituents where at least one, and preferably two, substituents are located ortho to the bond joining Cy’ to the remainder of the compound of formula (1). Particularly preferred ortho substituents include halogen atoms, especially fluorine or chlorine atoms, or

Ci.3 alkyl groups, especially methyl, C13 alkoxy groups, especially methoxy, haloCy.salkyl groups, especially -CFa, haloC4.zalkoxy groups, especially -OCF;, or cyano (-CN), groups. In this class of compounds a second or third optional substituent when present in a position other than the ortho positions of the ring Cy' may be preferably an atom or group -R"% or -LAIK3(R"?), as herein generally and particularly described. In another preference, the Cy' phenyl group may have a substituent para to the bond joining Cy’ to the remainder of the compound of formula (1). Particular para substituents include those particularly preferred ortho substituents just described. Where desired, the para substituent may be present with other ortho or meta substituents as just mentioned.

Examples of specific substituents on Cy’ include halogen (especially fluoro or chloro) and C44 alkyl (especially methyl).

Specific Cy' groups include phenyi, fluorophenyl, chlorophenyl, methylphenyl and cyclopropyl.

Particularly preferred Ar aromatic groups in compounds of formula (1) include optionally substituted phenyl groups. Particularly preferred heteroaromatic groups include optionally substituted monocyclic heteroaromatic groups, especially optionally substituted five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Particularly preferred optionally substituted monocyclic heteroaromatic groups include optionally substituted furyl, thienyi, pyrrolyi, oxazolyl, thiazolyl, pyridyl, pyrimidinyl and triazinyl groups.

Particularly preferred optional substituents which may be present on Ar aromatic or heteroaromatic groups include atoms or groups R12 or

LEAR), as hereinbefore defined. Particularly useful optional substituents include halogen atoms, especially fluorine, chlorine or bromine atoms, or Cis alkyl groups, especially C13 alkyl groups, most especially a methyl group, or haloC+.salkyl groups, especially fluoroC+.galkyl groups, most especially a -CF3 group, or C16 alkoxy groups, especially a methoxy, ethoxy, propoxy or isopropoxy group, or haloC1.salkoxy groups, especially fluoroC.salkoxy groups, most especially a -OCF3 group, or a cyano (-CN), esterified carboxyl, especially -COCH3 or -CO,C(CHa)s, nitro (-NO2), amino (-NH), substituted amino, especially -NHCH; or -N(CHa)z, -COR"", especially -COCHa, or -N(R™)COR", especially -NHCOCH;, group.

Particularly useful Ar groups in compounds of formula (1) include phenyl and mono- or disubstituted phenyl groups in which each substituent is in particular a -R™ or -L°AI’(R'®), atom or group as just defined and is especially a halogen atom or a C13 alkyl, C13 alkoxy or -CN group.

Examples of specific substituents on Ar include halogen (especially fluoro or chloro), cyano and C14 alkyl (especially methyl).

Specific Ar groups include phenyl, difluorophenyl, (chloro)(fluoro)phenyl, (fluoro)(methyl)phenyl, chlorophenyl, cyanophenyl and methyliphenyl.

Particular examples of Alk? when present in compounds of the invention include -CHy-, -CH2CH,-, -C(CHs)2- and -CH(CH3)CH2-. In one embodiment,

Ak? is -CHz-. In another embodiment, AIK is -C(CHa)z-.

Suitably, R' is methyl.

Suitably, R? is hydrogen or methyl. Suitably, R® is hydrogen or methyl. In one embodiment, RZ and R® are both hydrogen. In another embodiment, R? and R® are both methyl.

In compounds of the invention, m may be selected to vary the ring size from a ring having, in addition to the nitrogen atom, a minimum of 3 carbon atoms up to 6 carbon atoms. Particularly advantageous rings are those wherein m isthe integer 1 or 2.

In a preferred embodiment, m is the integer 2. In another embodiment, m is the integer 1. In a further embodiment, mis the integer 3.

In a particular embodiment, p is the integer 1. in another embodiment, p is the integer 2.

Each substituent R® may be present on any ring carbon atom. In one particular class of compounds of the invention one or two R? substituents are present.

Suitable values of R® include -OH, -(AI})OH, -(Alk®)OR', -NR’R® and -(AIP)NR?R®,

Detailed values of R® include -OH, -CH,OH, -C(CH3)20H, ~-CH20CHjs, -NHz, -N(CHzs)z and -CHaoNH,.

Representative values of RY include -OH, -(Alk?)OH and -(AI’)OR",

Illustrative values of RY include -OH, -CH20OH, -C(CH3)20H and -CH20CHa.

Particular RY substituents include -OH, -CH,OH, -CH(CH3;)OH and -C(CH3)20H groups.

Particularly useful compounds of the invention include each of the compounds described in the Examples hereinafter, and the salts, solvates, hydrates and N-oxides thereof.

Compounds according to the invention are potent and selective inhibitors of p38 kinases, including all isoforms and splice variants thereof. More specifically the compounds of the invention are inhibitors of p38a, p38p and p38p2. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.

The compounds of formula (1) are of use in modulating the activity of p38 kinases and in particular are of use in the prophylaxis and treatment of any p38 kinase mediated diseases or disorders in a human, or other mammal.

The invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.

Further the invention extends to the administration to a human of an effective amount of a p38 inhibitor for treating any such disease or disorder. ( 20 The invention also extends to the prophylaxis or treatment of any disease or disorder in which p38 kinase plays a role including conditions caused by excessive or unregulated pro-inflammatory cytokine production including for example excessive or unregulated TNF, IL-1, IL-6 and IL-8 production in a human, or other mammal. The invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such cytokine-mediated diseases or disorders. Further the invention extends to the administration to a human of an effective amount of a p38 inhibitor for treating any such disease or disorder.

Diseases or disorders in which p38 kinase plays a role either directly or via pro-inflammatory cytokines including the cytokines TNF, IL-1, IL-6 and IL-8 include without limitation autoimmune diseases, inflammatory diseases, destructive bone disorders, proliferative disorders, neurodegenerative disorders, viral diseases, allergies, infectious diseases, heart attacks, - angiogenic disorders, reperfusion/ischemia in stroke, vascular hyperplasia, organ hypoxia, cardiac hypertrophy, thrombin-induced platelet aggregation and conditions associated with prostaglandin endoperoxidase synthetase-2 (COX-2).

Autoimmune diseases which may be prevented or treated include but are not limited to rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis,

Crohn's disease, multiple sclerosis, diabetes, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft vs host disease and psoriasis.

The invention further extends to the particular autoimmune disease rheumatoid arthritis.

Inflammatory diseases which may be prevented or treated include but are not limited to asthma, allergies, respiratory distress syndrome and acute or chronic pancreatitis.

Destructive bone disorders which may be prevented or treated include but are not limited to osteoporosis, osteoarthritis and multiple myeloma-related bone disorder.

Proliferative diseases which may be prevented or treated include but are not limited to acute or chronic myelogenous leukemia, Kaposi's sarcoma, metastatic melanoma and multiple myeloma.

Neurodegenerative diseases which may be prevented or treated include but are not limited to Parkinson's disease, Alzheimers disease, cerebral ischemias and neurodegenerative disease caused by traumatic injury.

Viral diseases which may be prevented or treated include but are not limited to acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C),

HIV infection and CMV retinitis.

Infectious diseases which may be prevented or treated include but are not limited to septic shock, sepsis and Shigellosis.

In addition, p38 inhibitors of this invention also exhibit inhibition of expression of inducible pro-inflammatory proteins such as prostaglandin endoperoxidase synthetase-2, otherwise known as cyclooxygenase-2 (COX-2), and are therefore of use in therapy. Pro-inflammatory mediators of the cyclooxygenase pathway derived from arachidonic acid are produced by inducible COX-2 enzyme. Regulation of COX-2 would regulate these pro- inflammatory mediators such as prostaglandins, which affect a wide variety of cells and are important and critical inflammatory mediators of a wide variety of disease states and conditions. In particular these inflammatory mediators have been implicated in pain, such as in the sensitization of pain receptors, or edema. Accordingly additional p38 mediated conditions which may be prevented or treated include edema, analgesia, fever and pain such as neuromuscular pain, headache, dental pain, arthritis pain and pain caused by cancer.

As a result of their p38 inhibitory activity, compounds of the invention have utility in the prevention and treatment of diseases associated with cytokine production including but not limited to those diseases associated with TNF,

IL-1, IL-6 and IL-8 production.

Thus, TNF mediated diseases or conditions include for example rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, AIDS, ARC or malignancy, keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, viral infections such as HIV, CMV, influenza and herpes; and veterinary viral infections, such as lentivirus infections, including but not limited to equine infectious anemia virus, caprine arthritis virus, visna virus or maedi virus; or retrovirus infections, including feline immunodeficiency virus, bovine immunodeficiency virus and canine immunodeficiency virus.

Compounds of the invention may also be used in the treatment of viral infections, where such viruses elicit TNF production in vivo or are sensitive to upregulation by TNF. Such viruses include those that produce TNF as a result of infection and those that are sensitive to inhibition, for instance as a result of decreased replication, directly or indirectly by the TNF inhibiting compounds of the invention. Such viruses include, but are not limited to,

HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes group of viruses such as Herpes Zoster and Herpes Simplex.

IL-1 mediated diseases or conditions include for example rheumatoid arthritis, osteoarthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, stroke, endotoxemia and/or toxic shock syndrome, inflammatory reaction induced by endotoxin, diabetes, pancreatic p-cell disease, Alzheimers disease, tuberculosis, atherosclerosis, muscle degeneration and cachexia.

(L-8 mediated diseases and conditions include for example those characterized by massive neutrophil infiltration such as psoriasis, inflammatory bowel disease, asthma, cardiac, brain and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis. The increased IL-8 production associated with each of these diseases is responsible for the chemotaxis of neutrophils into inflammatory sites. This is due to the unique property of IL-8 (in comparison to TNF, IL-1 and IL-6) of promoting neutrophil chemotaxis and activation.

Therefore, inhibition of IL-8 production would lead to a direct reduction in neutrophil infiltration. itis also known that both IL-6 and IL-8 are produced during rhinovirus (HRV) infections and contribute to the pathogenesis of the common cold and exacerbation of asthma associated with HRV infection [Tumer et al., Clin.

Infec. Dis., 1997, 26, 840; Grunberg et al., Am. J. Crit. Care Med., 1997, 155, 1362; Zhu et al, J. Clin. Invest, 1996, 97, 421]. it has also been demonstrated in vitro that infection of pulmonary epithelial cells (which represent the primary site of infection by HRV) with HRV results in production of IL-6 and IL-8 [Sabauste et al., J. Clin. Invest., 1995, 96, 549]. Therefore, p38 inhibitors of the invention may be used for the treatment or prophylaxis of the common cold or respiratory viral infection caused by human rhinovirus infection (HRV), other enteroviruses, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus or adenovirus infection.

For the prophylaxis or treatment of a p38 or pro-inflammatory cytokine mediated disease the compounds according to the invention may be administered to a human or mammal as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.

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, polyvinylpymolidone or hydroxypropyl methylcellulose); 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 and preservatives. The preparations may also contain buffer salts, flavouring, colouring and 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 (1) 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 (1) 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 for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, 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 for use 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 for use 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 carmiers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl aicohol, 2-octyldodecanol and water.

For ophthalmic administration the compounds for use 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 for use 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 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 around 0.05 mg to around 1000 mg, e.g. around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols Ar, Cyl, AK’, n, RY, p, m and Y when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Greene, T.

W. in "Protective Groups in Organic Synthesis”, John Wiley and Sons, 1999].

In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. :

Thus, according to a further aspect of the invention a compound of formula (1) in which Y is a -C(O)- group may be prepared from a carboxylic acid of formula (2) or ester of formula (5) according to amide bond forming reactions well known to those skilled in the art. Such reactions are set forth in references such as March's Advanced Organic Chemistry (John Wiley and

Sons 1992), Larock's Comprehensive Organic Transformations (VCH

Publishers Inc., 1992) and Comprehensive Organic Functional Group

Transformations, ed. Katritzky et al., volumes 1-8, 1984, and volumes 1-11, 1094 (Pergamon). Examples of such methods that may be employed to give compounds of formula (1a) are set out, but not limited to the reactions, in

Scheme 1 and Scheme 2 below.

Scheme 1

ANAT HAT

O04 Amide coupling reagent Jor Yi 0 s om HN Jom i In

KOC! ry ® hk 57 @ (12) 7 ar ) ~ gi © Jos oP" So me pentafluorophend FNS O—PFP | Wk aC dror BOY (Ra), 2) 4) (1a)

Thus, amides of formula (1a) may be formed by reaction of a carboxylate salt of formula (2) [where M” is metal counterion such as a sodium or lithium ion or is alternatively an ammonium or trialkylammonium counterion] with an amine of formula (3) in the presence of a coupling reagent such as a carbodiimide, e.g. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or

N,N'-dicyclohexylcarbodiimide, optionally in the presence of a base such as an amine, e.g. triethylamine or N-methylmorpholine. These reactions may be performed in a solvent such as an amide solvent, e.g. N,N-dimethyl- formamide (DMF), or an ether, e.g. a cyclic ether such as tetrahydrofuran or 1,4-dioxane, or a halogenated solvent such as dichloromethane, at around ambient temperature to 60°C. In another procedure a pentafluorophenyl ester of formula (4) may be prepared by reaction of a carboxylic acid of formula (2) with pentafluorophenol in the presence of a coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in a solvent such as an amide solvent, e.g. DMF, at around ambient temperature. Amides of formula (1a) can then be prepared by reaction of the pentafluorophenyl ester with amines of formula (3) in an organic solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature, optionally in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine. The intermediate acids of formula (2) may be prepared by hydrolysis of esters of formula (5) using a base such as an alkali metal hydroxide, e.g. sodium hydroxide or lithium hydroxide, in water and a solvent such as tetrahydrofuran or an alcohol such as ethanol at a temperature from around ambient to reflux.

Amides of formula (1a) can also be prepared directly from esters of formula (5) by heating with an amine of formula (3) up to the reflux temperature of the amine optionally in the presence of a solvent such as 2-ethoxyethanol either at atmospheric pressure or under pressure in a sealed tube (Scheme 2).

Scheme 2 —Ar HN Im Ar § Ef S ’ herr Jor 5 ® (1a)

The intermediate esters of formula (5) may be prepared by the methods set out in Scheme 3 below. In the Scheme the preparation of an ethyl ester is specifically shown, but it will be appreciated that other esters may be obtained by simply varying the ester starting material and if appropriate any reaction conditions.

Scheme 3

A .

NZ Hal NaH, DMF, 0°C.t. NZ~s OE MeCN NZS OE : (12) (1) "| mCPBA

CHCl, 0o°C-r.t.

Br 1) Ac,0 reflux Br

JQ 8 2 2) THF, K,CO, aq, rt SNA 0

J 2 s or trifiuroacstic anhydride, N Ss QEt 0 N OEt puE 5 _ ® ® . HN

Cu(OAc),. pyridine, CH.Cl, Jor Yi Pd,(dba);, BINAP IL

Cy'B(OH), Cy* = aryl or hetercary| | ANH, Gs,C0,

CY ° oP~NT SS og toluene reflux om s oH &y' Cy r 8) (5a)

Jor 3 fo) N S OEt 8 ® nA

Br 7 0

PS-BEMP, DMF, 80°C Joni _Pdy(doa)y, BINAP Jos

CyNAKZ § om ANH. CaCO 07NT TS OF o N - toluene reflux din, (5b) (Akt), I

Cy!

Cy!

Thus, in Scheme 3 a compound of formula (5a) or (5b) may be prepared by reaction of a compound of formula (6) or (7) with an amine ArNH; in the presence of a palladium catalyst. The reaction may be conveniently carried out in a solvent such as toluene at an elevated temperature, e.g. the reflux temperature, using a catalyst such as tris(dibenzylideneacetone)- dipalladium(0), a phosphine ligand such as 2,2'-bis(diphenylphosphino)-1,1’- binaphthyl, and a base such as caesium carbonate. Where desired, alternative reaction conditions may be used, for example as described in the literature [Luker ef al., Tetrahedron Lett., 2001, 41, 7731; Buchwald, S.L., J.

Org. Chem., 2000, 65, 1144; Hartwig, J.F., Angew. Chem. Int. Ed. Engl., 1998, 37, 2046]. intermediates of formula (7) may be prepared by reaction of a compound of formula (8) with an alkylating agent of formula Cy'(AKk')aZ, where Z is a leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethylsulphonyloxy, or arylsulphonyloxy, e.g. phenylisulphonyloxy, group.

The reaction may be performed in the presence of a solvent, for example a substituted amide such as N,N-dimethylformamide, optionally in the presence of a base, for example an inorganic base such as sodium hydride, or an organic base such as an organic amine, 8.0. a cyclic amine such as 1,5 diazabicyclo[4.3.0]Jnon-5-ene, or a resin-bound organic amine such as resin- bound 2-tert-butylimino-2-diethylamino-1 .3-dimethylperhydro-1,3,2-diaza- phosphorine (PS-BEMP), at an elevated temperature, for example 80 to 100°C.

Intermediates of formula (6) may be prepared by the reaction of a compound of formula (8) with a boronic acid of formula Cy'B(OH). in which Cy' is an aryl or heteroaryl group. The reaction may be performed in an organic solvent, for example a halogenated hydrocarbon such as dichloromethane or dichloroethane, in the presence of a copper reagent, for example a copper(l) salt such as Cul, or for example a copper(ll) reagent such as copper(ll) acetate, optionally in the presence of an oxidant, for example 2,2,6,6- tetramethylpiperidine-1-oxide or pyridine-N-oxide, optionally in the presence of a base, for example an organic amine such as an alkylamine, eq. triethylamine, or an aromatic amine, e.g. pyridine, at a temperature from around ambient to the reflux temperature [see for example Chan, D.T. et al.,

Tetrahedron Letters, 1998, 2933; Lam, P.Y.S. et al, Tetrahedron Letters, 2001, 3415).

Intermediates of formula (6) where Cy' is an aryl or heteroaryl group may also be prepared by nucleophilic aromatic substitution of a suitably activated aryl or heteroaryl halide with a compound of formula (8). The reaction may be performed in a dialkylamide solvent such as DMF in the presence of a base such as a metal hydride, e.g. sodium hydride, at a temperature from around ambient to 100°C. Suitably activated aryl or heteroaryl halides are those with an electron-withdrawing substituent such as a nitro, cyano or ester group, e.g. a chioro- or fluoro-nitrobenzene or 2-chloro-5-nitropyridine.

Alternatively a nitrogen-containing heteroaryl halide can be activated to nucleophilic substitution by N-oxidation, e.g. 2-chloropyridine N-oxide.

It will be appreciated that if desired the reactions just described may be carried out in the reverse order so that the amination using ANH: is performed first with the intermediate of formula (8) followed by alkylation/arylation to yield the compound of formula (6). It may be necessary to protect the nitrogen function of compounds of formula (8) during the course of these reactions. Such protection may be achieved by O- alkylation with an alkyl halide, e.g. cyclopropylmethyl bromide, or an arylalkyl bromide, e.g. benzyl bromide, as shown in Scheme 4.

Scheme 4 r r —Ar oA 0 oi 60” SE gy OE A ee” 670” SN” 8 (34) OB!

Where G = Anyt or alkyl group | deprotection

Ar — Ar roe Alkylation arylation re

Sl OEt 07 NT 8 OEt fh, (5) nos) cy'

The O-alkylation reaction may be performed in an organic solvent such as

DMF in the presence of a base, for example an inorganic base such as

Cs,COj3 or an organic base such as an amine, e.g. a cyclic amine such as 1,5-diazabicyclo[4.3.0]non-5-ene, at an elevated temperature, e.g. 80 to 100°C, to give a compound of formula (13). Reaction of the protected compound (13) with ArNH2 under palladium catalysis can then be performed as previously described to give a compound of formula (14). Deprotection can then be achieved by treating a solution of this compound in an alcohol, e.g. MeOH, with a mineral acid such as concentrated HCI at an elevated temperature, e.g. the reflux temperature, to give a compound of formula (15).

Alternatively when benzyl protection is employed then this group may be removed reductively by treating a solution of compound (14) in an organic solvent such as EtOH using a palladium or platinum catalyst, e.g. palladium on carbon or PtO,, under an elevated pressure of hydrogen at a temperature from around ambient to 60°C. Compounds of formula (15) can then undergo alkylation/arylation reactions as previously described to give compounds of formula (5).

Intermediate pyridinones of formula (8) may be prepared from pyridine N- oxides of formula (9) by sequential reaction with an anhydride, for example acetic anhydride, at an elevated temperature, for example the reflux temperature, followed by reaction with an inorganic base, for example a carbonate such as aqueous potassium carbonate, in a solvent such as an ether, for example a cyclic ether, e.g. tetrahydrofuran, at around ambient temperature. Alternatively the reaction may be performed using trifluoroacetic anhydride in N,N-dimethylformamide from 0°C to ambient temperature conditions [see for example Konno et al., Heterocycles, 1986, 24, 2169].

Pyridine N-oxides of formula (9) may be formed by oxidation of pyridines of formula (10) using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid or m-chloroperoxybenzoic acid in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, or an alcohol, e.g. tert butanol, at a temperature from the ambient temperature to the reflux temperature.

Intermediate pyridines of formula (10) in Scheme 3 may be obtained by standard methods such as for example by the Sandmeyer reaction. Thus, for example, a bromide of formula (10) may be prepared by treatment of an aryl amine of formula (11) with an alkyl nitrite, for example tert-butyl nitrite, and a copper salt, for example copper(ll) bromide, in the presence of a solvent, for example a nitrile such as acetonitrile, at a temperature from about 0° fo around 65°C.

Amines of formula (11) may be formed from 2-halopyridine-3-carbonitriles of formula (12) by reaction with a reagent such as ethyl 2-mercaptoacetate.

The reaction may be performed in the presence of a solvent such as a substituted amide, for example N,N-dimethylformamide, or an ether, e.g. a cyclic ether such as tetrahydrofuran, or an alcohol such as ethanol, in the presence of a base, for example an inorganic base such as sodium

Claims (12)

Claims:

1. A compound of formula (1): NHAr = OX Y i NG) Lg Alk') Cy | ( CY (RY ) wherein: Y is a linking group -C(O}- or -S(O)2-; nis zero or the integer 1; m is the integer 1, 2, 3 or 4; p is the integer 1, 2, 3 or 4; RY is an -OH, -(Alk?)OH (where AIK? is a straight or branched C14 alkylene chain), -OR" (where R' is a straight or branched C1. alkyl group), -(AI®)OR’, -NR?R® (where RZ and R® may be the same or different and Is each independently a hydrogen atom or a straight or branched C1. alkyl group), -(AIk?)NR?R? or straight or branched C1. alkyl group; AIK! is a straight or branched Ci.4 alkylene chain; Cy' is an optionally substituted cycloaliphatic, aromatic or heteroaromatic group; and Ar is an optionally substituted aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof.

2. A compound as claimed in claim 1 wherein RY is -OH, -(Alk*)OH, -(AIJOR', -NRZR® or -(AIk3NR?R?, in which All, R', R? and R® are as’ defined in claim 1.

3. A compound as claimed in claim 1 or claim 2 wherein Alk? is -CHa- or -C(CHg3).-.

4. A compound as claimed in any one of the preceding claims wherein R'is methyl.

5. A compound as claimed in any one of the preceding claims wherein R? is hydrogen or methyl.

6. A compound as claimed in any one of the preceding claims wherein R® is hydrogen or methyl.

7. A compound as claimed in any one of the preceding claims wherein Cy' is phenyl, fluorophenyl, chlorophenyl, methylphenyl or cyclopropyl.

8. A compound as claimed in any one of the preceding claims wherein Ar is phenyl, difluorophenyl, (chloro)(fluoro)phenyl, (fluoro)(methyl)phenyl, chlorophenyl, cyanophenyi or methylphenyl.

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

10. A pharmaceutical composition comprising a compound of formula (1) as defined in claim 1, or a pharmaceutically acceptable salt, solvate, hydrate ar N-oxide thereof, in association with a pharmaceutically acceptable carrier.

11. The use of a compound of formula (1) as defined in claim 1, or a phamaceutically acceptable salt, solvate, hydrate or N-oxide thereof, for the manufacture of a medicament for the treatment and/or prevention of a disorder for which an inhibitor of p38 MAP kinase is indicated.

© WO 2004/113347 PCT/GB2004/002621

12. A compound of formula (1) as defined in claim 1, or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof for use in a method for the treatment and/or prevention of a disorder for which an inhibitor of p38 MAP kinase is indicated. -126 - Amended sheet: 29 January 2007