ZA200302411B - Morpholin-acetamide derivatives for the treatment of inflammatory diseases. - Google Patents

Description

MORPHOLIN-ACETAMIDE DERIVATIVES FOR THE TREATMENT OF INFLAMMATORY DISEASES , This invention relates to novel chemical compounds, processes for their . preparation, pharmaceutical formulations containing them and their use in therapy. ¢ Inflammation is a primary response to tissue injury or microbial invasion and is characterised by leukocyte adhesion to the endothelium, diapedesis and activation within the tissue. Leukocyte activation can result in the generation of toxic oxygen species (such as superoxide anion), and the release of granule products (such as peroxidases and proteases). Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue.

The primary function of leukocytes is to defend the host from invading organisms, such as bacteria and parasites. Once a tissue is injured or infected, a series of events occurs which causes the local recruitment of leukocytes from the circulation into the affected tissue. Leukocyte recruitment is controlled to allow for the orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction. There is increasing evidence that the bronchial inflammation which is characteristic of asthma represents a specialised form of cell-mediated immunity, in which cytokine products, such as IL-4 and IL-5 released by Th2 T lymphocytes, orchestrate the accumulation and activation of granulocytes, in particular eosinophils and to a lesser extent basophils. Through the release of cytotoxic basic proteins, pro-inflammatory mediators and oxygen radicals, eosinophils generate mucosal damage and initiate mechanisms that underlie bronchial hyperreactivity. Therefore, blocking the recruitment and activation of Th2 cells and eosinophils is likely to have anti-inflammatory properties in asthma. In addition, eosinophils have been implicated in other disease types such as rhinitis, eczema, irritable bowel syndrome and parasitic infections. " Chemokines are a large family of small proteins which are involved in trafficking \ 30 and recruitment of leukocytes (for review see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are released by a wide variety of cells and act to attract and activate various cell types, including eosinophils, basophils, neutrophils, macrophages, T and B lymphocytes.

There are two major families of chemokines, CXC- (a) and CC- (B) chemokines, classified according to the spacing of two conserved cysteine residues near to the amino terminus of the chemokine proteins. Chemokines bind to specific cell surface receptors belonging to the family of G-protein-coupled seven transmembrane-domain proteins (for review see Luster, , 1998). Activation of chemokine receptors results in, amongst other responses, an increase in intracellular calcium, changes in cell shape, increased expression of cellular adhesion molecules, degranulation and promotion of cell migration (chemotaxis).

To date, 9 members of CC chemokine receptors have been identified (CCR-1 to 9). Of particular importance to the current invention is the CC-chemokine receptor-3 (CCR- 3), which is predominantly expressed on eosinophils, and also on basophils, mast cells and

Th2 cells (Luster, 1998). Chemokines that act at CCR-3, such as RANTES, MCP-3 and

MCP-4, are known to recruit and activate eosinophils. Of particular interest are eotaxin and eotaxin-2, which specifically bind fo CCR-3. The localization and function of CCR-3 chemokines indicate that they play a central role in the development of allergic diseases such as asthma. Thus, CCR-3 is specifically expressed on all the major cell types involved in inflammatory allergic responses. Chemokines that act at CCR-3 are generated in response to inflammatory stimuli and act to recruit these cell types to sites of inflammation, where they cause their activation (e.g. Griffiths et al., J. Exp. Med., 179, 881-887 (1994),

Lloyd et al, J. Exp. Med., 191, 265-273 (2000)). In addition, anti-CCR-3 monoclonal antibodies completely inhibit eotaxin interaction with eosinophils (Heath, H. et al., (1997) J.

Clin. Invest. 99 (2), 178-184), while an antibody for the CCR-3 specific chemokine, eotaxin, reduced both bronchial hyperreactivity and lung eosinophilia in an animal model of asthma (Gonzalo et al., J. Exp. Med., 188, 157-167 (1998). Thus, many lines of evidence indicate that antagonists at the CCR-3 receptor are very likely to be of therapeutic use for the treatment of a range of inflammatory conditions.

A number of patent applications relating to CCR-3 antagonists have published before the filing date of this application. For example, EP 0 903 349, FR 2785902, WO 00/29377, WO 00/31032 and WO 00/31033 (all in the name of F.Hoffmann-La-Roche AG) disclose pyrrolidine, piperidine and piperazine based compounds which are all distinct from the compounds of the present invention.

WO 99/55324, WO 00/04003, WO 00/27800, WO 00/27835, WO 00/27843, WO 00/41685 * 30 and WO 00/53172 (all in the name of SmithKline Beecham Corporation) describe a variety of y compounds as CCR-3 antagonists which are unrelated to the compounds of the present ) invention.

WO 00/34278 (Toray Industries Inc.) describe fused triazolo derived compounds as chemokine inhibitors.

and WO 00/35877 (Du Pont Pharmaceuticals Company) describe N-ureidoalkyl and heterocyclic piperidine compounds as CCR-3 antagonists.

WO 00/51607 and WO 00/51608 (Merck & Co. Inc.) describe a series of pyrrolidine \ 5 modulators of chemokine receptor activity.

WO 00/53600 (Banyu Pharmaceutical Co. Ltd.) describes piperidine derivatives as inhibitors at the CCR-3 receptor.

WO 01/14333 (AstraZeneca UK Ltd.) describe substituted piperidine compounds as modulators of chemokine receptor activity.

EP 0 760 362 (Nisshin Flour Milling Co. Ltd.) describes morpholinoalkylurea derivatives which are disclosed as being useful in the treatment of digestive tract diseases.

JP 04208267A (Mitsui Seiyaku Kogyo KK) also describes morpholinoalkylurea derivatives which are disclosed as being useful as antiemetics, for activating peristalsis and ameliorating gastrointestinal function.

EP 243959A (Dainippon Pharm KK) describes O-substituted N-morpholinyl-alkyl-benzamide derivatives useful as gastrointestinal motility enhancing agents.

JO 1117-882-A (Dainippon Pharm KK) describes heterocyclic morpholiny! alkylenyl carboxamide derivatives useful as anti-emetics.

WO 00/71518 (Sepracor Inc) describes morpholinoalkylamide derivatives useful in the treatment of pain, drug addiction and tinnitus.

WO 97/48695 and WO 97/48397 (Klinge Pharma Gmbh) describe pyridyl alkane, alkene and/or alkyne acid amide compounds useful as cytostatic, immunomodulatory or immuno- suppressive agents.

Kato et al, (1992) Chem. Pharm. Bull. 40(3), 652-660, Kato et al., (1991) J. Med. Chem. 34(2), 616-624 and Kato et al., (1990) J. Med. Chem. 33(5), 1406-1413 describe a series of morpholine benzamides which are disclosed as being selective and potent gastrokinetic agents.

We have now found a novel group of CCR-3 antagonist compounds which block migration/chemotaxis of eosinophils, consequently effecting anti-inflammatory properties. ¢ 30 These compounds are therefore of potential therapeutic benefit, especially in providing ' protection from eosinophil, basophil and Th2-cell-induced tissue damage in diseases where “ such cell types are implicated, particularly allergic diseases, including but not limited to bronchial asthma, allergic rhinitis and atopic dermatitis.

In addition to a key role in inflammatory disorders, chemokines and their receptors also play a role in infectious disease. Mammalian cytomegaloviruses, herpes viruses and . pox viruses express chemokine receptor homologues, which can be activated by human CC chemokines such as RANTES and MCP-3 (for review see Wells and Schwartz, Curr. Opin. . 9 Biotech., 8, 741-748, 1997). In addition, human chemokine receptors, such as CXCR-4,

CCR-5 and CCR-3, can act as co-receptors for the infection of mammalian cells by microbes such as human immunodeficiency viruses (HIV). CCR-3 serves as a co-receptor for certain clinical strains of HIV-1 and facilitates viral entry (e.g Choe, H.et al, Cell, 1996, 85, 1135- 1148). A key ligand for CCR-3, eotaxin, blocked the process of HIV entry. Thus, chemokine receptor antagonists, including CCR-3 antagonists, may be useful in blocking infection of

CCR-3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.

Thus, according to one aspect of the invention, we provide compounds of formula on:

O]

Fhe

N“R* : ()

RS wherein:

R' represents C, alkyl, C,, alkenyl, C,, alkynyl, Cs alkynyl-Y'-, aryl-Y'-, heteroaryl-Y'-, aryl-(O)-aryl-Y'-, aryl-(O)-heteroaryl-Y'-, heteroaryl-(O)-aryl-Y'-, heteroaryl-(O)-heteroaryl-Y'-, C,; alkenyl-Y'-, aryl-O-Y'-, heteroaryl-O-Y'-,

Cs alkyl-SO,-Y'-, M-Y'-, J%-Y'-, -CN or C,, cycloalkyl-Y'- or C,4 cycloalkenyl-Y'-, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C,; alkyl groups;

R?represents hydrogen or C, 4 alkyl; . X represents ethylene or a group of formula CR°R’ wherein R® and R' independently represent hydrogen or C,, alkyl or R® and R" may together with the carbon atom to which w 25 they are attached form a C;; cycloalkyl group;

R?® and R* independently represent hydrogen or C,_, alkyl;

Z represents a bond, CO, §O,, CR°R%(CH,),, (CH,),CR°R®, CHR®(CH,),0, CHR®CH,),S,

CHR¥(CH,),0CO, CHR®*(CH,),CO, COCHR®(CH,), or SO,CHRS(CH,),;

R® represents C, alkyl, C.s alkenyl, aryl, heteroaryl, aryl-C,; alkenyl- or a group of formula -Y2-J', . R® represents hydrogen, Cy, alkyl, CONR’R® or COOC,; alkyl; a and b represent 1 or 2, such that a+b represents 2 or 3; . DO n represents an integer from 0 to 4;

J" and J? independently represent a moiety of formula (K): x! x? wherein X' represents oxygen, NR™ or sulphur, X? represents CH,, oxygen, NR' or sulphur, m' represents an integer from 1 to 3 and m? represents an integer from 1 to 3, provided that m'+m? is in the range from 3 to 5, also provided that when both X' and X? represent oxygen,

NR™, NR" or sulphur, m' and m? must both not equal less than 2, wherein K is optionally substituted by one or more (eg. 1 or 2) -Y*-aryl, -Y*-heteroaryl, -Y*-CO-aryl, -COC,_ scycloalkyl, -Y3-CO-heteroaryl, -C,; alkyl, -Y3-COOC, ; alkyl, -Y3-COC,; alkyl, -Y3-W, -Y3-CO-

W, -Y3-NR"R", -Y3-CONR'"'R"?, hydroxy, oxo, -Y>-SO,NR"'R", -Y*-S0O,C, alkyl, -Y°-

SO,aryl, -Y*-SO,heteroaryl, -Y*-NR™C, 4 alkyl, -Y3-NR"SO,C, ; alkyl, -Y>-NR"“CONR"R", -

Y3-NR“COOR?" or -Y*-OCONR"'R" groups, and is optionally fused to a monocyclic aryl or heteroaryl ring;

R’, R® R% R'" R"™ R"and R" independently represent hydrogen or C, alkyl;

R" and R" independently represent hydrogen or Cs alkyl or R'' and R'" together with the nitrogen atom to which they are attached may form a morpholine, piperidine or pyrrolidine ring;

M represents a C,;5 cycloalkyl or a C5 cycloalkenyl group fused to a monocyclic ary! or monocyclic heteroaryl group;

W represents a saturated or unsaturated, non-aromatic 5-7 membered ring containing between 1 and 3 heteroatoms selected from nitrogen, oxygen or sulphur, optionally “ substituted with one or more C, 5 alkyl, halogen or hydroxy groups; t represents 0 or 1. = Y', Y? and Y® independently represent a bond or a group of formula —(CH,),CRRYCHj),- wherein R° and R? independently represent hydrogen or C,4 alkyl or R® and RY may together with the carbon atom to which they are attached form a C;5 cycloalkyl group, and p and q independently represent an integer from 0 to 5 wherein p + q is an integer from 0 to 5;

and salts and solvates thereof.

Specific groups of compounds of formula (1) which may be mentioned are those as defined above with the proviso that the compound of formula (I) is not a compound of formula ()*:

N 0]

RY RY H N RA

I rR" wherein R* represents hydrogen, halogen, nitro, SO,NH,, or mono- or di-(C,, alkylsulphamoyl;, R" represents hydrogen, halogen, amino, nitro, -N(CH.), or Cs alkanoylamino (provided that at least one of R* and R" is not hydrogen); R® represents halogen, hydroxy, C,; alkoxy, cyano, C,, cycloalkyl, -SCH,, amino or C, alkoxycarbonyl; X' represents methylene or ethylene; b' represents 1 or 2; R¥ and R represent hydrogen or C,_, alkyl; and wherein the moiety —Z-R® represents heteroarylC,; alkyl (wherein heteroaryl represents furyl, thienyl, pyridyl or 1,2-benzisoxazolyl), phenyl-C,5 alkenyl, naphthyl, -C, alkylenenaphthyl, -C,s alkyleneOnaphthyl, -C,; alkyleneCOnaphthyl, phenyl, -C,; alkylenephenyl, -C,; alkyleneOphenyl or -C,; alkyleneCOphenyl (wherein phenyl is substituted by one to five members each independently selected from the group consisting of a halogen, C,, alkyl, trifluoromethyl, C,, alkoxy, nitro, cyano or amino) (compounds of formula (1)* are described in EP0243959A1); and/or the proviso that the compound of formula (1) is not a compound of formula (1)®: ai Q

R I i hy Yee

N

% Us ksi : + 20 wherein Het represents a heteroaryl moiety; R*, R™ and R® represent hydrogen, halogen,

C.s alkyl, C4 alkoxy, amino or NMe,; X' represents methylene or ethylene; R¥ represents ° hydrogen or C,, alkyl; b® represents 1 or 2; and wherein the moiety —Z"-R% represents optionally substituted aryl-C,.s alkyl- (compounds of formula (I)° are described in J01117- 882A); and/or the proviso that the compound of formuia (1) is not a compound of formula (1): 0 . EN Ali

RH

: N zi (Ne

RS . wherein R"™ represents C, alkyl, C,; cycloalkyl, heteroaryl or aryl; R?" represents C,, alkyl;

CX represents ethylene or a group of formula CR®"Rf wherein R® and R™ independently represent hydrogen or C,, alkyl; R%! represents hydrogen or C,, alkyl; b" represents 1 or 2;

Z" represents CR¥R®(CH,),; (wherein R® represents hydrogen or C,, alkyl and R® represents hydrogen or C,; alkyl and niii represents 0 to 3); and Ri represents C,; alkyl, aryl, heteroaryl or C, alkenyl (compounds of formula (1)¢ are described in WO00/71518A2); and/or the proviso that the compound of formula (1) is not a compound of formula (1)% aiv R™ .

R rr ° :

N = dll x O Yo a

Lan bY Jp

N RA

LT

RW wherein R* represents hydrogen, halogen, -CN, -CF,, -OH, -CONH,, -COOH, C, alkyl, Cos alkenyl, -C, alkoxy, -SCH,;, Cj, cycloalkyl, -COOC, alkyl, -NHCOC,; alkyl, -CON(C,, alkyl), -N(CH,),; R®™ represents hydrogen, halogen, -CN, OH, -CF,, C,; alkyl or C4 alkoxy;

Re represents hydrogen, halogen, C,, alkyl, -CFs; Y'" represents C,; alkylene; R2 represents hydrogen or Cg alkyl; X" represents methylene or ethylene; R® represents hydrogen or C,, alkyl; R*" represents hydrogen or C, alkyl; b" represents 2; ZV represents

CR™R®(CH,)u, CHR®™(CH,),,,CO (wherein R® represents hydrogen or C,, alkyl and R® ’ represents hydrogen or methyl and niv represents 0 ta 3) or SO,CHR®Y(CH,),,, (wherein R%" represents hydrogen and niv represents 0); and R® represents C,, alkyl, C,¢ alkenyl, “ phenyl, J' or heteroaryl (wherein said phenyl or heteroaryl may be optionally substituted by 1-3 halogen, CN, Cs alkyl, -CF;, Cs cycloalkyl, hydroxy, C,; alkoxy, -SCH;, COOH,

COOC, alkyl, nitro, amino or -N(CH,),) (compounds of formula (I)? are described in

WO97/48695A1 and WO97/48397A1); and/or the proviso that the compound of formula (I) is not a compound of formula (1)®: 0 . R* 0 ) N

XL

RY RY N

? ye

R% : wherein R® represents chlorine; RY represents amino; R® represents methoxy or ethoxy; and the moiety —~Z'-R* represents phenyl or C, alkyl (such compounds of formula (I)° are described in Kato et al., (1992) Chem. Pharm. Bull. 40(3), 652-660); also wherein R™ represents chlorine; R™ represents amino; R™ represents methoxy or ethoxy; and the moiety —Z'-R* represents —CH,-phenyl wherein phenyl is substituted by 2-, 3- or 4-chlorine, 2-, 3- or 4-fluorine, 3- or 4-CF;, 3- or 4-methoxy, 4-methyl, 4-nitro, 4-amino, 4-carboxymethyl, 3- or 4-cyano, 3,4-dichloro, 2,4-difluoro, 3,4-difluoro, 3,5-difluoro, 2,4,6- trimethyl! (such compounds of formula (1)® are described in Kato et al., (1991) J. Med. Chem. 34(2), 616-624); also wherein R* represents hydrogen, bromine, chlorine, nitro or SO,NH,; R™ represents amino, -NMe,, -NEt, or -NHCOCH;;, R™ represents methoxy, ethoxy, hydroxy or chlorine; and the moiety —Z'-R™ represents —CH,-pheny! (such compounds of formula (I)° are described in Kato et al., (1990) J. Med. Chem. 33(5), 1406-1413).

A preferred set of compounds of formula (1) include compounds wherein R’ represents Cs alkyl, C, alkenyl, C, alkynyl, C, alkynyl-Y'-, aryl-Y'-, heteroaryl-Y'-, aryl- (O)raryl-Y'-, aryl-(O)-heteroaryl-Y'-, heteroaryl-(O)-aryl-Y'-, heteroaryl-(O)-heteroaryl-Y'-,

Cy alkenyl-Y'-, aryl-O-Y'-, heteroaryl-O-Y'-, C, ; alkyl-SO,-Y'-, M-Y'- or C,, cycloalkyl-Y'- or

Cs, cycloalkenyl-Y'-, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C, alkyl groups; and

J! represents a moiety of formula (K): :

RY wherein X' represents oxygen, NR™ or sulphur, X? represents CH,, oxygen, NR" or sulphur, m' represents an integer from 1 to 3 and m? represents an integer from 1 to 3, provided that m'+m? is in the range from 3 to 5, also provided that when both X' and X? represent oxygen,

NR™, NR" or sulphur, m' and m?* must both not equal less than 2, wherein K is optionally 9 substituted by one or more (eg. 1 or 2) -Y*-aryl, -Y*-heteroaryl, -Y>-CO-aryl, -Y>-CO- heteroaryl, -C,; alkyl, -Y>-COOC, ; alkyl, -Y3-COC, alkyl, -Y>-W, -Y3-CO-W, -Y®-NR''R", -

Y*-CONR'R™2, hydroxy, oxo, -Y*-SO,NR"'R", -Y3-SO,C, alkyl, -Y3-80.aryl, -Y3-

SO;heteroaryl, -Y’-NR"C, alkyl, -Y3-NR"SO,C, alkyl, -Y>-NR™CONR''R?, -Y*-

NR™COOR"™ or -Y*-OCONR"'R* groups, and is optionally fused to a monocyclic ary! or heteroaryl ring.

A preferred subset of compounds of formula (1) include compounds wherein R' represents C,; alkyl, C,5 alkenyl, C, alkynyl, aryl-Y'-, heteroaryl-Y'-, aryl-(O)q-ary!l-Y'-, aryl- (O)r-heteroaryl-Y'-, heteroaryl-(O)-aryl-Y'-, heteroaryl-(O)-heteroaryl-Y'-, C,, alkenyl-Y'-, aryl-O-Y'-, heteroaryl-O-Y'-, C, alkyl-SO,-Y'-, M-Y'- or C,; cycloalkyl-Y'- or C,, cycloalkenyl-Y’-, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C, alky! groups; :

Z represents a bond, CO, CR°R%(CH,),, CHRYCH,),0, CHR%(CH,),S, CHR®(CH,),0CO,

CHR®(CH,),CO:; and

J! represents a moiety of formula (K):

OR wherein X' represents oxygen, nitrogen, NR or sulphur, X? represents CH,, oxygen, nitrogen, NR™ or sulphur, m' represents an integer from 1 to 3, m? represents an integer from 1 to 3, provided that m'+m? is in the range from 3 to 5, also provided that when X2 represents oxygen, nitrogen, NR" or sulphur, m'and m? must both not equal less than 2, -wherein K is optionally substituted by one or more (eg. 1 or 2) -Y*-aryl, -Y*-heteroaryi, -Y3- , CO-aryl, -Y>-CO-heteroaryl, -C,.¢ alkyl, -Y3-COOGC, alkyl, -Y*>-COC, ¢ alkyl, -Y3-W, -Y3-CO-W, -Y®-NR"'R™, -Y*>-CONR''R", hydroxy, oxo, -Y*-SO,NR"'R", -Y*-80,C, alkyl, -Y*-SQ,aryl, - w Y3.SO heteroaryl, -Y>-NR"C,; alkyl, -Y3-NR"S0,C,, alkyl, -Y*-NR*CONR'"'R™, -Y3-

NR"COOR?"™ or -Y*-OCONR"R" groups, and is optionally fused to a monocyclic aryl or heteroaryl ring.

References to ‘aryl’ include references to monocyclic carbocyclic aromatic rings (eg. phenyl) and bicyclic carbocyclic aromatic rings (e.g. naphthyl) and references to ‘heteroaryl’ include references to mono- and bicyclic heterocyclic aromatic rings containing 1-3 hetero atoms selected from nitrogen, oxygen and sulphur. References to ‘heteroaryl’ may also be extended to include references to mono- and bicyclic heterocyclic aromatic rings containing 4 hetero atoms selected from nitrogen, oxygen and sulphur. Examples of monocyclic heterocyclic aromatic rings include e.g. pyridinyl, pyrimidinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, imidazolyl. Further examples of monocyclic heterocyclic aromatic rings include pyrazinyl or tetrazolyl. Examples of bicyclic heterocyclic aromatic rings include eg. benzimidazolyl, quinolinyl or indolyl. Further examples of bicyclic heterocyclic aromatic rings include eg. benzotriazolyl, pyrrolopyridine, benzothiazolyl and quinoxalinyl. Carbocyclic and heterocyclic aromatic rings may be optionally substituted, e.g. by one or more C, alkyl, C, alkenyl, halogen, C, alkoxy, cyano, hydroxy, nitro, amino, W, -N(CH,),, -NHCQC, ; alkyl, -OCF,, -CF,, -COQC, alkyl, -OCHF,, -

SCF, -SO,N(CH;),, -SO,CH3, -SCH,, -CONR'™R" or -SO,NR"R"” groups (wherein R' and

R" independently represent hydrogen or C, alkyl; R* and R" may also independently represent C5 cycloalkyl). Further substituents of carbocyclic and heterocyclic aromatic rings include —COOH and -NHSO,CHs. Yet further substituents include -N(C,.salkyl)SO,C, salkyl, -

N(SO.C.salkyl),, -NHCOCH,N(C, alkyl), -NHCONHC, qalkyl, -<CONH(CH,),0C, alkyl, -

CONH(CH,),N(Calkyl),, CON(C, galkyl),, Cscycloalkyl, morpholinyl, ~COmethylpiperazinyl and COmorpholinyl.

Examples of group J include indolinyl, which may be optionally substituted.

Examples of group J? include thiomorpholinyl and piperidiny!, which may be optionally substituted, for example by t-butoxycarbonyl.

Examples of group M include tetrahydronaphthalenyl.

Examples of group W include piperidinyl, pyrrolidinyl, morpholinyl and piperazinyl which may be optionally substituted.

References to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl. It will be appreciated that references to alkylene * 30 and alkoxy shall be interpreted similarly.

References to C;, cycloalkyl include references to all alicyclic (including - branched) isomers of the corresponding alkyl.

Preferably, R' represents C, alkyl (particularly butyl and —(CH,),CH(CHs),), C. alkenyl, C, alkynyl, aryl-Y'-, heteroaryl-Y'-, aryl-(O)qaryl-Y'-, aryl-(O)-heteroaryl-Y'-

(particularly wherein aryl represents phenyl and heteroaryl represents tetrazolyl, oxadiazolyl, thiazolyl or oxazolyl), heteroaryl-(O)-aryl-Y'-, heteroaryl-(O)-heteroaryl-Y'- (particularly ~ wherein heteroaryl represents oxazolyl, thiazolyl, thiophenyl, pyrazolyl, pyrazinyl, furanyl, ’ pyridinyl or tetrazolyl), C,¢ alkenyl-Y'-, aryl-O-Y'- (particularly wherein aryl represents phenyl), heteroaryl-O-Y"-, C, alkyl-SO,-Y'- (particularly wherein C,. alkyl represents methyl), M-Y'-, -CN, J*-Y'- or C, ; cycloalkyl-Y'- (particularly cyclopropyl! and cyclohexyl) or

Css cycloalkenyl-Y'-, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxy! or C, alkyl groups. } | Particularly, R' represents C, alkyl, C,.¢ alkenyl, C,¢ alkynyl, aryl-Y'- heteroaryl-

Y'-, aryl-(O)aryl-Y'-, aryl-(O)-heteroaryi-Y'-, heteroaryl-(O)-aryl-Y'-, heteroaryl-(O)-heteroaryl-Y'-, C, alkenyl-Y'-, aryl-O-Y'-, heteroaryl-O-Y'-,

Cis alkyl-8O,-Y'-, M-Y'- or C5 cycloalkyl-Y'- or C4 cycloalkenyl-Y'-, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C,; alkyl groups.

More preferably, R" represents aryl-Y'-, aryl-O-Y'-, heteroaryl-Y'-, aryl-(O), heteroaryl-Y'- or heteroaryl-(O)-heteroaryl-Y'-, especially aryl-Y'-, heteroaryl-Y?, heteroaryl-(O)-heteroaryl-Y'- or aryl-(O)-heteroaryl-Y'-. In this definition, aryl preferably represents phenyl optionally substituted by one or more -SO,-N(CH,),, -SO,CH,, halogen (especially fluorine or chlorine), C4 alkyl! (especially methyl), CH,CONH-, -CF;, CH,0-, -CONH,, (CH3),N- or -SCH; groups. Further preferred phenyl substituents include -NHSO,CH,, -COOH, -COOCH; and -CONH-cyclopropyl. Yet further preferred phenyl substituents include ~SO,NHcyclopropyl, -SO,NHCH,CH,, -SO,NHCH,, -N(CH,)SO,CH;, -

N(SO,CHa), -NHCOCH,N(CH;),, -NHCOCH(CH,),, -NH,, -SO,NH,, -NHCONHCH,, -NO,, -

CONH(CH,),0CH,;, -CONHCH(CH,),, -CONH(CH,),OH, -CONH(CH,),N(CH;),, -CON(CHs),, -CONHCH,CH;, -CONHCHj,, -COCH,, -COCH(CHj),, -CN, -OH, —CO-4-methyl-1-piperazinyl and -COmorpholinyl. Heteroaryl preferably represents indolyl, thiophenyl, oxazolyl, pyrazolyi, thiazolyl, pyrimidinyl or furanyl optionally substituted with one or more C,; alkyl (especially methyl), CH;O- or halogen (especially bromine) groups. Heteroaryl also preferably represents tetrazolyl or pyrazinyl. Further preferred groups which heteroaryl may represent include benzotriazolyl, pyrrolopyridine, benzothiazolyl, pyridinyl, quinoxalinyl and imidazolyl. » 30 Suitable heteroaryl substituents include halogen (especially bromine), -COCH,, -COOCH,, -

CH, -CH(CH)., morpholinyl, cyclopropyl, -CH,CH(CH,), and -CH=C(CH,),. * A most particularly preferred group of compounds are those in which R' is aryl- (O)¢heteroaryl-Y'- especially wherein heteroaryl represents optionally substituted oxazolyl, (especially oxazolyl substituted by methyl), aryl represents phenyl and t represents 0.

Especially preferred R' is aryl-Y'-, particularly when aryl represents phenyl optionally substituted by any of the above substituents, most especially phenyl substituted by ~SONH,.

Preferably, Y' represents a bond, C, alkylene, C, 4 cycloalkyl or ~-CHCH,, + © particularly C, alkylene or C,; cycloalkyl, most preferably methylene, ethylene or cyclopropyl, especially methylene or cyclopropyl, most especially methylene.

Preferably, R? represents hydrogen.

Preferably, X represents methylene.

Preferably, R* and R* independently represent hydrogen or methyl, especially hydrogen.

Preferably, Z represents a bond, CO, CR°R%CH,),, CHR*CH,),0, CHR®(CH,),S,

CHR®(CH,),0CO or CHR%(CH.),CO. :

More preferably, Z represents a bond, CO, CHR®(CH,),, CHR®(CH,),O (particularly (CH),0) or CHR®(CH,),CO, more particularly CHR¥CH,), or CHR®CH,),CO, most preferably CH,, (CH,)s, CHCH, or CH,CO, especially CH, or CH,CO, most especially CH,.

Preferably, R® represents C,; alkenyl! (particularly —CH,CH(CH,;)=CH,), aryl, heteroaryl or a group of formula —Y2-J', more preferably aryl, heteroaryl or a group of formula ~Y2-J", most preferably monocyclic aryl, heteroaryl or a group of formula —Y?-J', especially aryl or —Y3-J', particularly phenyl which may be optionally substituted. We also especially prefer R® to represent heteroaryl, particularly thiophenyl which may be optionally substituted.

Other groups which heteroaryl preferably represents include benzoxadiazolyl, benzothiadiazolyl or benzothiophenyl which may be optionally substituted. We most particularly prefer R® to represent phenyl optionally substituted by one or more (eg. 1, 2 or 3) halogen groups. Other preferred substituents for phenyl include -CN and -CF;. We also most particularly prefer R® to represent thiophenyl optionally substituted by one or more (eg. 1, 2 or 3) halogen groups.

Especially preferred R® groups are dichlorophenyl, difluorophenyl, fluorophenyl, chlorothiophenyl, chlorophenyl and trifluorophenyl, most especially dichlorophenyl, difluorophenyi, fluorophenyl and chlorothiophenyl.

Most preferred R® is dichlorophenyl (particularly 3.4-dichlorophenyl, 2,3- dichlorophenyl and 2,5-dichlorophenyl), 4-fluorophenyl and 3,4-difluorophenyl. ¢ Most especially preferred R® is dichlorophenyl, particularly 3,4-dichlorophenyl.

Preferably, Y? represents a bond.

Preferably, J represents indolinyl, particularly indolin-1-yl.

Preferably, J* represents optionally substituted piperidinyl (particularly piperidinyl substituted by -COOC,qalkyl eg. ~COOC(CH,),) or thiomorpholinyl (particularly dioxidothiomorpholinyl) or dioxidothiomorpholinyl.

Preferably, Y* represents a bond.

Preferably, R® represents hydrogen.

Preferably, R” and R® represent hydrogen.

Preferably, R® represents hydrogen.

Preferably, R" and R* independently represent hydrogen or methyl, especially hydrogen.

Preferably, R" and R'? independently represent hydrogen or methyl or R' and R" together with the nitrogen atom to which they are attached may form a morpholine, piperidine or pyrrolidine ring, especially hydrogen or methyl.

Preferably, R' and R* independently represent hydrogen or methyl.

Preferably, R'® and R"” independently represent hydrogen, methyl, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, cyclopropyl or 2-(dimethylamino)ethyl. Most preferably, R™ : and R" independently represent hydrogen or cyclopropyl.

Preferably, R® and R? independently represents hydrogen or methyl, most preferably hydrogen or R°® and R? together with the carbon atom to which they are attached preferably forms cyclopropyl.

Preferably, R® and R' both represent hydrogen.

Preferably, a and b both represent 1.

Preferably, n represents 0, 1 or 2, more preferably 0.

Preferably, p and q independently represent 0 or 1 such that p+q represent 0-1.

Most preferably, p and q both represent 0.

Preferably, t represents 0.

Preferably, W represents pyrrolidinyl or piperidinyl, especially pyrrolidinyl.

Preferably, X' represents sulphur, oxygen or NR". More preferably, X' represents oxygen or NR".

Preferably, X* represents CH,, oxygen or NR, » 30 Preferably, m' and m* independently represent an integer from 1 to 2, such that m' + m?is in the range from 3 to 4. ‘ Suitable salts of the compounds of formula (I) include physiologically acceptable salts and salts which may not be physiologically acceptable but may be useful in the preparation of compounds of formula (I) and physiologically acceptable salts thereof. If appropriate, acid addition salts may be derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates, maleates, 1-hydroxy-2-naphthoates, palmoates, methanesulphonates, formates or trifluoroacetates. Examples of solvates include hydrates. . 5 When compounds of formula (I) contain chiral centres, the invention extends to mixtures of enantiomers (including racemic mixtures) and diasterecisomers as well as to individual enantiomers. Generally it is preferred to use a compound of formula (1) in the form of a single enantiomer.

The compounds of formula (I) and salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention.

A process according to the invention for preparing a compound of formula (1) which comprises: (a) acylation of a compound of formula (11)

Ho _X._ _O

LR oo

R Wa

NTR

J (mn ie or a protected derivative thereof wherein R?, R3, R* R® X, Z, a and b are as described above, with a compound of formula R'COOH or an activated derivative thereof, wherein R' is as described above; or (b) reacting a compound of formula (lil)

O

REN “Qe , og

N~ RY 4 (mn or a protected derivative thereof wherein R', R?, R? R* X, a and b are as defined above, . with a compound of formula

L'-Z-R®, wherein Z and R® are as defined above and L' represents a suitable leaving group: “ or (c) deprotecting a compound of formula (I) which is protected; or (d) interconversion of other compounds of formula (1).

We also provide a further process according to the invention for preparing a compound of formula (I) which comprises: (e) forming a compound of formula (I) wherein R' represents heteroaryl-Y'-, aryl-(O)- heteroaryl-Y'- or heteroaryl-(O)rheteroaryl-Y'- (wherein said Y' group is attached to heteroaryl via a heterocyclic nitrogen atom) and R? represents hydrogen which comprises reacting a compound of formula (IV) 0 phe “h

IT she ? (IV)

RS or a protected derivative thereof wherein R?, R*, R®, X, Y', Z, a and b are as defined above,

L? represents a suitable leaving group, such as a halogen atom eg. bromine and P! represents a solid phase resin bound protecting group, such as one described for process (c), with a heterocyclic compound defined by the R' groups heteroaryl, aryl-(O)¢-heteroaryl or heteroaryl-(O)-heteroaryl above wherein said heteroaryl group contains at least one NH atom, followed by removal of the solid phase resin bound protecting group; or ® forming a compound of formula (I) wherein Z represents CR°R%(CH,), and R® represents hydrogen which comprises reacting a compound of formula (lll) or a protected derivative thereof with a compound of formula R®CO(CH,),R?, followed by reduction of the resultant imine; or (9) forming a compound of formula (I) wherein Z represents CO by reacting a compound of formula (lll) or a protected derivative thereof with a compound of formula

R°COOH or an activated derivative thereof.

Process (a) may be effected simply by the reaction of a compound of formula (1) with R'COOH which may typically be achieved using an oven eg. a microwave oven at a power of 600W for 4 minutes. Examples of activated derivatives of R'COOH which may be employed in this reaction include acid halides and anhydride derivatives (eg. the acid > 25 chloride). Alternatively, process (a) may be performed in the presence of O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethylammonium hexafluorophosphate (HATU) and a ‘ suitable base, eg. N,N-diisopropylethylamine in a suitable solvent, eg. N,N- dimethylformamide at a suitable temperature, eg. room temperature. Process (a) may also be performed in the presence of 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-

ethylcarbodiimide hydrochloride in the presence of a suitable base, eg. N,N- diisopropylethylamine and a suitable solvent, eg. dichloromethane or N,N- dimethylformamide, at a suitable temperature, eg. room temperature. Further, process (a) may be performed in the presence of 1,1'-carbonyldiimidazole in the presence of a suitable solvent, eg. N,N-dimethylformamide at a suitable temperature, eg. room temperature.

Process (a) may also be performed in the presence of a suitable base such as polyvinylpyridine and a suitable solvent, such as dichloromethane at a suitable temperature such as room temperature.

Process (b) may be performed in the presence of a suitable solvent eg. N,N- dimethylformamide, optionally in the presence of N N-diisopropylethylamine at a suitable temperature eg. room temperature. Examples of suitable leaving groups (L') include halogen, eg. chlorine. :

In process (c), examples of protecting groups and the means for their removal can be found in T. W. Greene and P.G.M. Wuts ‘Protective Groups in Organic Synthesis’ (J.

Wiley and Sons, 3rd Ed. 1999). Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. benzyloxycarbony! or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate. Other suitable amine protecting groups include triflucroacetyl (-COCF,) which may be removed by base catalysed hydrolysis, or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6- dimethoxybenzyl group (Ellman linker) or a 2,6-dimethoxy-4-[2- (polystyrylmethoxy)ethoxylbenzyl, which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.

Process (d) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic aromatic substitution, ester hydrolysis or amide bond formation. Alternative conditions for process (d) include t- butoxycarbonyl group addition or removal and sulphonylation.

Process (e) may be performed using a suitable base, eg. potassium tert-butoxide and a suitable solvent, eg. N,N-dimethyiformamide, at a suitable temperature, eg. 60°C.

Process (f) may be performed in the presence of a suitable acid eg. acetic acid + 30 and a suitable reducing agent, eg. sodium triacetoxyborohydride in a suitable solvent, eg. dichloromethane at a suitable temperature, eg. room temperature. ) Process (g) may be performed in the presence of suitable reagents, eg. 1,-(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and 1-hydroxybenzotriazole in the presence of a suitable base, eg. N,N-diisopropylethylamine and a suitable solvent eg. N,N- dimethylformamide at a suitable temperature, eg. room temperature.

Compounds of formula (I) may be prepared according to the following process:

PAN 0] o NPR 0 wo Hi Es ;

GE STI EO SE A i R L1-Z-R5 | R

Ho f, (yp ’ a wherein R? R? R% R® X, a, b and Z are as defined above and L' represents a suitable leaving group eg. chlorine and P? represents a suitable protecting group eg. one mentioned above, such as -COCF,. Step (i) comprises the use of a suitable solvent eg. N,N- dimethyiformamide in the presence of suitable reagents eg. sodium iodide and potassium carbonate at a suitable temperature eg. room temperature. Alternatively step (i) may comprise the use of a suitable solvent eg. N,N-dimethylformamide, in the presence of a suitable base such as N,N-diisopropylethylamine at a suitable temperature eg. room temperature. Step (ii) comprises deprotection under conventional conditions appropriate for the protecting groups. When P? represents —COCF;, deprotection may be achieved by the use of water and methanol in the presence of potassium carbonate at room temperature.

Compounds of formula (1) may also be prepared by reductive amination of compounds of formula (V) in an analogous manner to that described in process (f) above.

Compounds of formula (ll) wherein R? represents hydrogen, X represents methylene, a and b represent 1 and R® and R* are both attached to the morpholine ring at the 5-position may be prepared according to the following process:

R’ 3 H 0 wo. A wo AH Step (i) TY Le

RO 20» RY] A NTR! . vi iL 0) i (n= . R® wherein R®, R* and R® and Z are as defined above and L' represents a suitable leaving : group eg. chlorine. Step (i) comprises heating in the absence of solvent at between 50 and 60°C. Step (ii) comprises heating with 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione at 80°C under nitrogen, followed by stirring with concentrated sulphuric acid at 150°C.

Compounds of formula (il) wherein R? represents H may be prepared according to the following process: lo} o [J UE « (T° (VIII) (IX) ) | a

Step (ii) i I Je

N R

Ho

H X Oo H 7 1 Nei Step (iii) « [7 0 bo

Ho Oey ge L1-Z-RS T Per 2 ap rr

IP Hoo wherein R?, R%, R® X, a, b and Z are as defined above and L' represents a suitable leaving group eg. chlorine. Step (i) comprises heating a compound of formula (Vill; Merrifield Resin) with sodium carbonate in a suitable solvent eg. dimethylsulphoxide at a suitable temperature eg. 150°C. Step (ii) comprises reacting a compound of formula (IX) with a compound of formula (X) in the presence of a suitable solvent eg. tetrahydrofuran at a suitable temperature eg. room temperature. Step (iii) comprises the use of suitable solvent eg. N,N- dimethylformamide and a suitable base eg. N,N-diisopropylethylamine at a suitable temperature eg. 70°C, followed by deprotection under conventional conditions appropriate for the Merrifield resin protecting group eg. acid catalysed hydrolysis.

Compounds of formula R'COOH used in process (a) above (and activated derivatives thereof) are either known compounds or may be synthesised by known methods.

For example, compounds of formula R'COOH wherein R' represents heteroaryl- . Y', aryl-(O)-heteroaryl-Y'- or heteroaryl-(O)-heteroaryl-Y'- (wherein the heteroaryl moiety linked to Y' represents 1,3-oxazol-4-yl and t represents 0) may be prepared according to the . following process:

RA Jig J 20, —~Y 0” TY 1 5 ae ’ Hal RN, R XIV) ’ (Xn) (Xun : - (ii)

N Y.. _OH

I hil 0 Np 5 xv) wherein R" represents a suitable substituent described above for a heteroaryl group, especially Cs alkyl, R* represents C,; alkyl, aryl or heteroaryl, R* represents C,, alkyl, especially ethyl, Hal represents a halogen atom, especially bromine and Y' is as defined above.

Compounds of formula (XII) may be prepared by following the procedure described in

Svendsen and Boll (1973) Tetrahedron 29, 4251-4258. :

Step (i) may typically be performed in the presence of a suitable solvent, eg. toluene at a suitable temperature eg. at 140°C and using suitable conditions, eg. Dean-Stark conditions.

Step (ii) may typically be performed in the presence of a suitable alkali, eg. sodium hydroxide and suitable solvents, eg. water and ethanol at a suitable temperature, eg. 70°C.

Compounds of formula R'COOH wherein R' represents heteroaryl-Y', aryl-(O) heteroaryl-Y'- or heteroaryi-(O)-heteroaryl-Y'- (wherein the heteroaryl moiety linked to Y' represents 1,3-oxazol-4-yl and t represents 0) may also be prepared according to the following process:

HO. 0 . oO 0

LA it JAK " —_———— 0 X 1 v

ML R N Y OR

HN Y'"" “or 2 A H : XVI) xvi (XVII) 0 0

Me BY Step (ii)

R* 0 R" (x9

RY

0) 0 w i" R 0 ed JL Step (iii) 0 0

Be Sa ed

N Y'" “oR PR J

R" N Y'"" Tor’ (XX) H (XX)

Step (iv) rR" o 0 r—4& J

N Y'"" “oH (Xv) wherein R' represents C,, alkyl, especially methyl, R¥ represents a suitable substituent described above for a heteroaryl group, especially C, alkyl, R* represents C, alkyl, aryl or heteroaryl, Hal represents a halogen atom, especially chlorine and Y' is as defined above.

Step (i) may typically be performed in the presence of a suitable base, eg. pyridine, at a suitable temperature, eg. from 0°C to room temperature.

Step (ii) may typically be performed in the presence of a suitable base, eg. pyridine at a suitable temperature, eg. 90°C, followed by the addition of water at a suitable temperature, eg. 90°C.

Step (iii) may typically be performed in the presence of a suitable reagent, eg. phosphorus . oxychloride and a suitable solvent, eg. toluene, under suitable conditions, eg. 110°C.

Step (iv) may typically be performed in the presence of a suitable alkali eg. 2M aqueous sodium hydroxide, and a suitable solvent, eg. ethanol at a suitable temperature, eg. room temperature.

Compounds of formula (lll) as the R-isomer, wherein R? represents hydrogen, X represents methylene, a and b represent 1 and R® and R*both represent hydrogen may be prepared according to the following process: . * 1 b, o (S) 0 s)] Step (i) R' NT © Step (ii) ,(R)

L R'COOH " [) eo )

PF (XX) ps (XX) N (nea wherein R' is as defined above and P* is a suitable protecting group, eg. benzyl.

Compounds of formula (XXII) may be prepared as described in EP0995746. / Step (i) typically comprises the use of 1-hydroxybenzotriazole and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the presence of a suitable base, eg. N,N-diisopropylethylamine and a suitable solvent, eg. N,N-dimethylformamide, at a suitable temperature, eg. room temperature.

Step (ii) typically comprises a simple deprotection reaction, eg. which may comprise the use of 10% palladium on activated carbon in the presence of ammonium formate and a suitable solvent, eg. ethanol.

Compounds of formula (Ill) as the S-isomer, wherein R' is as defined above, may be prepared by an analogous process.

Compounds of formula (IV) may be prepared according to the following process: 0

RAE: , Step (i) 1 AL XO lL k R —_— Y N do 3

Po Or ox L2-Y'-COOH bi T Be R

NTR z

R® (IP 7,

Rw wherein R®, RY, R®, X, Y', Z, a and b are as defined above, L? represents a suitable leaving group, such as a halogen atom, eg. bromine and P' represents a solid phase resin bound protecting group, such as one described in process (Cc).

Step (i) typically comprises the use of a suitable reagent, eg. 1,3- diisopropylcarbodiimide in the presence of one or more suitable solvents, eg. dichloromethane and N,N-dimethyiformamide.

Compounds of formula (V), (VI), (VII), (X), (XII), (XID), (XVI), (XVII), (XIX) and (XXII) are either known or may be prepared in accordance with known procedures.

Compounds of formula L'-Z-R°, RSCO(CH,),R®, R°COOH, L2Y'-COOH and heterocyclic compounds defined by the R' groups heteroaryl, aryl-(O)-heteroaryl or heteroaryl-(O)-heteroaryl above are also either known or may be prepared in accordance with known procedures.

Compounds of formula (Ill) may be prepared in accordance with processes analogous to those described above for compounds of formula (I), employing suitable protection for the morpholine (or analogue) NH, e.g. t-butoxycarbonyl! protection.

Compounds of formula (11), (Il) and (IV) in their protected and deprotected form and salts and solvates thereof are also claimed as an aspect of the invention.

Compounds of the invention may be tested for in vitro and in vivobiological activity in accordance with the following assays. (a) CCR-3 Binding Assay

A CCR-3 competition binding SPA (scintillation proximity assay) was used to assess the affinity of novel compounds for CCR-3. Membranes prepared from K562 cells stably expressing CCR-3 (2.5ug/well) were mixed with 0.25mg/well wheat-germ agglutinin SPA beads (Amersham) and incubated in binding buffer (HEPES 50 mM, CaCl, 1 mM, MgCl, 5 mM, 0.5% BSA) at 4°C for 1.5 hr. Following incubation, 20 pM of ['*I] eotaxin (Amersham) and increasing concentrations of compound (1pM to 30uM) were added and incubated in a 96 well plate for 2 hr at 22°C then counted on a Microbeta plate counter. The total assay volume was 100 pl. Competition binding data were analysed by fitting the data with a four parameter logistic equation. Data are presented as the mean plCs, values (negative logarithm of the concentration of compound which inhibits ['*l]eotaxin binding by 50%) from at least two experiments. (b) Eosinophil chemotaxis Assay.

Compounds were evaluated for their inhibitory effect on eosinophil chemotaxis. Eosinophils were purified from human peripheral blood by standard CD16 cell depletion using a Miltenyi i cell separation column and a magnetic Super Macs magnet as previously described (Motegi & Kita, 1998; J.Immunology. 161:4340-6). Cells were re-suspended in RPMI 1640/10% FCS . solution and incubated with calcein-AM (Molecular Probes) at 37°C for 30 mins. Following incubation, the eosinophils were centrifuged at 400g for 5 min and re-suspended in

RPMI/FCS at 2.2 million/ml. Cells were then incubated in the presence of increasing concentration of compounds (1 pM to 30 pM) at 37°C for 30 mins. For control responses cells were incubated with RPMI/FCS only. The agonist eotaxin (either a concentration response curve or for the functional inhibition curves an EC, concentration) was added to the lower chamber of a 96 well chemotaxis plate (5 pm filter: Receptor Technologies).

Eosinophils (50 pl of 2 million/ml cells) were added to the top chamber of the filter plate and incubated at 37°C for 45 mins. Cells remaining on top of the chemotaxis filter were removed and the number of eosinophils which had migrated were quantified by reading the plate on a fluorescent plate reader. Inhibition curves for the effect of compounds on eosinophil chemotaxis were analysed by fitting the data with a four parameter logistic equation. Functional pK; values (fpK;) were generated using the equation below (Lazareno &

Birdsall, 1995. Br.J.Pharmacol 109: 1110-9). foKi=— Cx 1+ Agora]

EC, (c) Guinea-pig Ovalbumin Model

Inhibition of Eosinophil Infiltration and Hyper-Reactivity in the Guinea Pig

In a method based on that described by Danahay et al., 1997, ovalbumin sensitised guinea pigs were dosed with mepyramine (30mg kg" ip) to protect against anaphylactic bronchospasm. Test compounds, dissolved in 10% DMSO and 90% PEG200, were given by the oral route, 30 minutes before ovalbumin challenge (10 minutes breathing of an aerosol generated from a 0.5% solution of ovalbumin). Hyper-reactivity of the airways to the thromboxane mimetic U46619, was measured 24 hours after ovalbumin challenge in un- restrained animals using a whole body plethysmograph (Buxco Ltd., USA). The guinea pigs were then sacrificed and the lungs lavaged. Total and differential leukocyte counts were then obtained for the bronchoalveolar lavage fluid and the percentage reduction in eosinophil accumulation determined (Sanjar et al., 1992). Data was presented as the inhibitory effect of the specified dose expressed as a percentage of the vehicle control response.

Examples of disease states in which the compounds of the invention have potentially beneficial anti-inflammatory effects include diseases of the respiratory tract such as bronchitis (including chronic bronchitis), asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD) and rhinitis. Another disease of the respiratory tract in which the compounds of the invention have potentially beneficial effects is sinusitis. Other relevant disease states include diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure. Furthermore, compounds of the invention may be used to treat nephritis, skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions and diseases of the central nervous system which have an } 5 inflammatory component eg. Alzheimer’s disease, meningitis, multiple sclerosis and AIDS dementia. Compounds of the present invention may also be of use in the treatment ofnasal polyposis, conjunctivitis or pruritis. Additionally, the compounds of the present invention may be of use in the treatment of viral diseases such as HIV.

Further examples of disease states in which compounds of the invention have potentially beneficial effects include cardiovascular conditions such as atherosclerosis, peripheral vascular disease and idiopathic hypereosinophilic syndrome. Other diseases for which the compounds of the present invention may be beneficial are other hypereosinophilic diseases such as Churg-strauss syndrome. Additionally, eosinophilia is commonly found in parasitic diseases, especially helminth infections, and thus the compounds of the present invention may be useful in treating inflammation arising from hyper-eosinophilic states of diseases such as hydatid cyst (Echinococcus sp.), tapeworm infections (Taenia sp.), blood flukes (schistosomiasis), and nematode (round worms) infections such as:- Hookworm (Ancylostoma sp.), Ascaris, Strongyloides, Trichinella, and particularly lymphatic filariasis including Onchocerca, Brugia, Wucheria (Elephantiasis).

Compounds of the invention may be useful as immunosuppressive agents and so have use in the treatment of auto-immune diseases such as allograft tissue rejection after transplantation, rheumatoid arthritis and diabetes.

Compounds of the invention may also be useful in inhibiting metastasis.

Diseases of principal interest include asthma, COPD and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis. Preferred diseases of principle interest include asthma and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis. Further diseases also of principle interest include inflammatory diseases of the gastrointestinal tract such as inflammatory bowel disease.

It will be appreciated by those skilled in the art that reference herein to treatment - 30 extends to prophylaxis as well as the treatment of established conditions.

As mentioned above, compounds of formula (1) are useful as pharmaceuticals, in particular as anti-inflammatory agents.

There is thus provided as a further aspect of the invention a compound of formula (1) or a physiologically acceptable salt or solvate thereof for use as pharmaceuticals, particularly in the treatment of patients with inflammatory conditions, eg. asthma or rhinitis.

According to another aspect of the invention, there is provided the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory conditions, eg. asthma or rhinitis.

In a further or alternative aspect there is provided a method for the treatment of a human or animal subject with an inflammatory condition eg. asthma or rhinitis, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in anti-inflammatory therapy, comprising a compound of formula (1) or a physiologically acceptable salt or solvate thereof together, if desirable, with one or more physiologically acceptable diluents or carriers.

There is also provided a process for preparing such a pharmaceutical formulation which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, parenteral or rectal administration, preferably for oral administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or ~ 30 oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid ’ preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p- ) hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate.

For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

The compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.

The pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example anti-inflammatory agents (such as corticosteroids (e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide) or NSAIDs (eg. sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) or beta adrenergic agents (such as salmeterol, salbutamol, formoterol, fenoterol or terbutaline and salts thereof), anti-histamines (eg methapyrilene or loratadine) or antiinfective agents (eg. antibiotics, antivirals).

It will be appreciated that when the compounds of the present invention are + 30 administered in combination with other therapeutic agents normally administered by the inhaled or intranasal route, that the resultant pharmaceutical composition may be ’ administered by the inhaled or intranasal route.

Compounds of the invention may conveniently be administered in amounts of, for example, 0.001 to 500mg/kg body weight, preferably 0.01 to 500mg/kg body weight, more preferably 0.01 to 100mg/kg body weight, 1 to 4 times daily. The precise dose will of course depend on the age and condition of the patient and the particular route of administration chosen. ) The compounds of the invention have the advantage that they may be more . 5 efficacious, show greater selectivity, have fewer side effects, have a longer duration of action, be more bioavailable when administered by the oral route, have more ready and economic synthesis, or have other more desirable properties than similar known compounds.

The invention may be illustrated by reference to the following examples:

Examples

General Experimental Details

Standard Automated Preparative HPLC column, conditions and eluent

Automated preparative high performance liquid chromatography (autoprep. HPLC) was carried out using a Supelco+ 5um (100mm x 22mm internal diameter) column eluted with a 16 mixture of solvents consisting of i) 0.1% trifluoroacetic acid in water and ii) 0.1% trifluoroacetic acid in acetonitrile, the eluent being expressed as the percentage of ii) in the solvent mixture, at a flow rate of 4ml per minute.

Mass Directed Automated Preparative HPLC column, conditions and eluent

Mass directed automated preparative high performance liquid chromatography was carried out using an LCABZ+ Sum (5cm x 10mm internal diameter) column, employing gradient elution using two solvent systems, (A) 0.1% formic acid in water, and (B) 95% acetonitrile and 0.5% formic acid in water, at a flow rate of 8ml min. Mass spectrometry was carried out using a VG Platform Mass Spectrometer, with an HP1100 Diode Array Detector and

Accurate Flow Splitter.

Normal Phase Automated Preparative HPLC Column - conditions

Normal phase automated preparative high performance liquid chromatography (normal phase autoprep HPLC) was carried out using a Nucleosil silica 5pm (100mm x 20mm internal diameter) column eluted with an ethyl acetate:heptane two-step gradient (iy 0% to 25% ethyl acetate over 7min followed by (ii) 25% to 100% ethyl acetate over 5.5min; at a flow rate of 30ml/min.

LC/MS System

Three alternative Liquid Chromatography Mass Spectroscopy (LC/MS) Systems were used:

System A

This system used a 3um ABZ+PLUS (3.3cm x 4.6mm internal diameter) column, eluting with solvents:A —~ 0.1%viv formic acid + 0.077% w/v ammonium acetate in water; and B — 95:5 acetonitrile:water + 0.05%v/v formic acid, at a flow rate of 3 ml per minute. The following i 5 gradient protocol was used: 100% A for 0.7mins; A+B mixtures, gradient profile 0 — 100% B over 3.5mins; hold at 100%B for 1.1mins; return to 100% A over 0.2mins.

System B .

This system used a 3um ABZ+PLUS (3.3cm x 4.6mm internal diameter) column, eluting with solvents:A — 0.1%v/v formic acid + 0.077% w/v ammonium acetate in water: and B — 95:5 acetonitrile:water + 0.05%v/v formic acid, at a flow rate of 1 ml per minute. The following gradient protocol was used: 100% A for 1.0min; A+B mixtures, gradient profile 0 — 100% B over 9.0mins; hold at 100%B for 3.0mins; return to 100% A over 2.0mins.

System C

This system used a 3pm ABZ+PLUS (3.3cm x 4.6mm internal diameter) column, eluting with solvents:A — 0.1%v/v formic acid + 0.077% w/v ammonium acetate in water; and B — 95:5 acetonitrile:water + 0.05%vV/v formic acid, at a flow rate of 1 ml per minute. The following gradient protocol was used: 100% A for 2.0mins; A+B mixtures, gradient profile 0~-100% B over 20mins; hold at 100%8B for 5.0mins; return to 100% A over 2.0mins; hold at 100% A for 1.0mins.

All LC/MS systems (apart from the Mass Directed Automated Preparative HPLC system) used a micromass spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u.

Thermospray Mass Spectra

Thermospray Mass Spectra were determined on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures 120°C (stem), 190°C (tip), detection mass range 100-850 a.m.u. Compounds were injected in 10pl of a mixture of solvents comprising 65% methanol and 35% 0.05M aqueous ammonium acetate, at a flow rate of 0.7ml/min.

Normal phase analytical HPLC method © 30 Normal phase automated analytical high performance liquid chromatography (normal phase analytical HPLC) was carried out using a Nucleosil silica 3um (150mm x 4.6mm internal diameter) column eluted with an ethyl acetate:heptane two-step gradient (i) 0% to 40% ethy! acetate over 7 min followed by (ii) 40% to 100% ethyl acetate over 2.5 min; at a flow rate of 2mi/min.

Standard chiral analytical HPLC system

This system used a 250 x4.6mm Chiralpak AD 10um column, eluting with absolute ethanol:heptane mixtures at a flow rate of 1m! per minute, with UV detection at 215nm.

Standard chiral preparative HPLC system

This system used a Chiralpak AD column (2cm x 25cm), eluting with absolute ethanol:heptane mixtures (15ml/min over 25mins, UV detection at 215nm).

Solid phase extraction (ion exchange) 'SCX refers to Isolute Flash SCX-2 sulphonic acid solid phase extraction cartridges.

Organic/aqueous phase separation with hydrophobic frits "Hydrophobic frit’ refers to a Whatman polypropylene filter tube fitted with a PTFE frit, pore size 5.0um.

All temperatures are in °C. :

Intermediates intermediate 1: [4~(3,4-Dichlorobenzylmorpholin-2-yijmethylamine

A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (Chem Abs No. 40172-06-3, 0.980g) and 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (1.10g) was heated at 80°C under nitrogen for 3h. The resulting solid mass was treated with concentrated sulphuric acid (1.5ml) then : stirred at 150°C for 24h. The mixture was treated with water (100ml) then washed with ethyl acetate (2x100ml). The dark aqueous phase was basified to ~pH 12 using 5M aqueous sodium hydroxide, then extracted with ethyl acetate (2x100ml). The combined organic extracts were washed with water and brine, dried (Na,SO,) and concentrated under vacuum to give the title compound as a brown oil (1.023). :

LC-MS (System A): Rt 1.6min.

Intermediate 1 (Alternative procedure): [4-(3,4-Dichlorobenzyhmorpholin-2-ylimethylamine

To a stirred solution of Intermediate 42 (2.979) in methanol (15ml) and water (5ml) was added potassium carbonate (5.53g). The mixture was stirred at 22°C for 18h before the methanol was removed in vacuo. Water (25ml) was added and the mixture extracted with ethyl acetate (3 x 30ml). The combined organic phases were washed with water (5ml) and saturated aqueous sodium chloride solution (10ml) before drying over sodium sulphate, + 30 filtering and evaporation of the solventin vacuo to give a pale yellow oil. The oil was purified by Biotage flash chromatography on a 90g silica cartridge eluting with 75:8;1 ) dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compoundas a colourless oil (1.85).

LC/MS (System A) R, 1.77 min, Mass Spectrum m/z 275 [MH"].

Intermediate 1A: [4-(3.4-Dichlorobenzyl)morpholin-2-yljmethylamine salt with para- toluenesulphonic acid 1:1

A solution of 2.{(3,4-dichlorobenzylyaminojethanol (2.25g) and 2-chloroacrylonitrile (1.0ml) in tetrahydrofuran (3ml) was heated at 40°C for 66h. The solvent was evaporated in vacuo to a: leave a gum. The residue was redissolved in tetrahydrofuran (20m) and cooled to 0-5°C.

Potassium tert-butoxide (1.2g) was added portionwise to this solution over 10min and the mixture was stirred at 0-5°C for a further 45min. The mixture was diluted with water (20m) and ethyl acetate (20ml), the phases were separated and the organic phase was washed with 20% w/w aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo to leave a gum (2.75g).

A portion of this gum (0.229) in tetrahydrofuran (1ml) was treated dropwise with a 1M solution of borane.tetrahydrofuran complex in tetrahydrofuran-(2.44mi) at 15-25°C. The mixture was stirred at 15-25°C for 16h, and methanol (3ml) was added dropwise. The mixture was stirred for a further 5h and the solvent was evaporated in vacuo. The residue was redissolved in ethyl acetate (4ml) and p-toluenesulfonic acid monohydrate (0.123g) was added. The mixture was heated at 50°C for 20min, and the suspension was cooled to 15- 25°C and stirred for 15min. The mixture was filtered, washed with ethyl acetate and dried to give the title compound (0.123g) as a white solid.

LC/MS (System A) R,; 1.75 min. Mass spectrum m/z 275/277 [MH]

Intermediate 2: 2-[(3,4-Dichlorobenzyl)amino]-2-methylpropan-1-ol 3,4-Dichlorobenzyl chloride (3.95g) was added to 2-amino-2-methylpropan-1-ol (17.8g) and the mixture was stirred at 60°C under nitrogen for 2h. Excess amine was removed by distillation under vacuum and the residue was partitioned between saturated aqueous sodium bicarbonate (100ml) and ethyl acetate (100ml). The phases were separated, the organic layer was washed with water (4x100ml) and brine (100ml), dried (Na,SO,) and concentrated under vacuum to give the title compound as a white solid (4.7g).

LC-MS (System A): Rt 2.07min.

Intermediate 3. 1-[4-(3,4-Dichlorobenzyl)-5,5-dimethylmorpholin-2-yljmethanamine

A mixture of Intermediate 2 (0.260g) and 2-(oxiran-2-yimethyl)-1H-isoindole-1,3(2H)-dione © 30 (0.205g) was heated at 80°C under nitrogen for 3h. The mixture was treated with concentrated sulphuric acid (0.3ml) then stirred at 150°C for 18h. The mixture was treated ’ with water (25ml) then washed with ethyl acetate (2x25ml). The dark aqueous phase was basified to ~pH 11 using 5M aqueous sodium hydroxide then extracted with ethyl acetate

(2x25ml). The combined organic extracts were washed with water and brine, dried (Na;SO,) and concentrated under vacuum to give the title compound as a brown oil (0.225g).

LC-MS (System A): Rt 1.92min.

Co Intermediate 4: _ 2-[(3,4-Dichlorobenzyf)amino]propan-1-ol 3,4-Dichlorobenzyl chloride (0.988g) was added to 2-amino-1-propanol (4.10g) and the mixture was stirred at 50°C under nitrogen for 2h. The mixture was partitioned between saturated aqueous sodium bicarbonate (100ml) and ethyl acetate (100ml) and the phases were separated. The organic layer was washed with water (4x100ml) and brine, dried (Na;SO,) then concentrated under vacuum to give the title compound as a white solid (0.935g).

LC-MS (System A): Rt 2.13min.

Intermediate 5: 1-[(cis)-4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yljmethanamine (2:1 mixture with trans isomer)

A mixture of Intermediate 4 (0.470g) and 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.4109) was heated at 80°C under nitrogen for 5h. The mixture was treated with concentrated sulphuric acid (0.6ml) then stirred at 150°C for 42h. The mixture was treated with water (50ml) then washed with ethyl acetate (2x50ml). The dark aqueous phase was basified to ~pH 11 using 5M aqueous sodium hydroxide then extracted with ethyl acetate (2x50ml). The combined organic extracts were washed with water and brine, dried (Na,SO,) and concentrated under vacuum to give the title compound as a brown oil (0.42g).

LC-MS (System A): Rt 1.74min.

Intermediate 6. 2-{{3-(3,4-Dichlorophenyl)propyljamino}ethanol 4-(3-Bromopropyl)-1,2-dichlorobenzene (Chem Abs No. 29648-26-8, 1.30g) was added to ethanolamine (2.8ml) and the mixture stirred at 60°C under nitrogen for 2h. The mixture was concentrated under vacuum at 80°C and the residue was partitioned between saturated aqueous sodium bicarbonate (100ml) and ethyl acetate (100ml). The phases were separated, the aqueous layer was re-extracted with ethyl acetate (100ml) and the combined organic extracts were washed with water (2x100ml) and brine then dried (Na,SQ,). The solution was concentrated under vacuum to give the title compound as a pale yellow liquid ~ 30 (1.109).

LC-MS (System A): Rt 2.40min. “ Intermediate 7: 1-{4-[3-(3,4-Dichlorophenyl)propylimorpholin-2-yl}methanamine

A mixture of Intermediate 6 (1.05g) and 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione ) (1.10g) were heated at 80°C under nitrogen for 2h. The mixture was treated with concentrated sulphuric acid (1.5ml) then stirred at 150°C for 18h. The mixture was treated with water (100ml) then washed with ethyl acetate (2x100ml). The dark aqueous phase was basified to ~pH 11 using 5M aqueous sodium hydroxide then extracted with ethyl acetate ) (2x100ml). The combined organic extracts were washed with water and brine, dried (Na,S0,) and concentrated under vacuum to give the title compound as a brown oil (0.980g).

LC-MS (System A): Rt 2.05min.

Intermediate 8: 1-[4-(2,3-Dichlorobenzyl)morpholin-2-yljmethanamine hydrochloride

A mixture of chioromethylpolystyrene-divinylbenzene (Merrifield resin, loaded at 4.0 mmol g") (5.0g) and sodium hydrogen carbonate (14.59) in dimethylsulphoxide (80ml) was heated at 150°C for 8h. The solution was allowed to cool, left to stand for 24h, then filtered. The solid was washed successively with water (3 x 100ml), tetrahydrofuran (3 x 100ml) and diethyl ether (3 x 100ml), then dried in vacuo to give the formylpolystyrene as a yellow solid which was not characterised. A portion of this solid (1.0g) was washed with tetrahydrofuran (5x10mi) and transferred to a round bottomed flask. 1-Morpholin-2-ylmethanamine dihydrochloride (0.435g) was dissolved in methanol (10ml) and loaded equally onto two solid phase extraction columns (Isolute SCX sulphonic acid, 10g each) which had been prepared by application of methanol. Elution with methanol, then .880 ammonia:methanol 10:90 gave a clear colourless oil (0.280g). This was added in tetrahydrofuran (2.3m) to the round bottomed flask containing formylpolystyrene and the mixture stirred for 24h at 20°C. The mixture was then filtered, and the solid washed with tetrahydrofuran:methanol 1:1 to leave N- {[4-(polystyrene resin)phenyl]methylidene}-1-morpholin-2-yimethanamine as a yellow solid which was not characterised. Two portions of this solid (2x50mg) in two thick walled glass vials (Reactivials) were each treated with N,N-dimethyiformamide (1.25mi), N,N- diisopropylethylamine (0.097ml) and 1,2-dichloro-3-(chloromethyl)benzene (0.076ml), and the mixture was stirred at 70°C for 20h, then allowed to cool. The mixtures were combined, filtered and washed sequentially with N,N-dimethylformamide (10x10ml) and tetrahydrofuran (5x10mi), then treated with tetrahydrofuran:2M aqueous hydrochloric acid solution 3:1 (3ml).

After 2h shaking at 20°C, the mixture was filtered, washed with tetrahydrofuran (4x5ml) and the filtrate and washings concentrated in vacuo to give the title compoundas white crystals ~30 (0.060g).

THNMR (MeOD) 7.85 (1H,dd, aromatic CH), 7.78 (1Hdd,aromatic CH), 7.53 (1H.t,aromatic : CH), 4.72 (2H,AB,CH,), 4.30 — 4.23 (2Hm,2xCH), 4.05 (1H,br.t,CH), 3.65 (1H,br.d,CH), 3.58 (1H,br.d,CH), 3.47 (1H,dd,CH), 3.30 — 3.22 (2H,m,2xCH), 3.08 (1H,br.m,CH).

Intermediate 9: 1-[(25)-4-(3,4-Dichlorobenzylymorpholin-2-y[Jmethanamine

Intermediate 1 (racemic mixture, 8g) was separated into its single enantiomers by preparative chiral-HPLC. The separation was carried out using a 2" x 22cm Chiralpak AD 20pm column, Merck self pack DAC system, eluting with 95:5:0.1 (v/v) heptane : absolute ethanol: diethylamine (flow rate: 55ml/min over 40min, UV detection 225nm); sample load preparation: 400mg sample in 20ml 3:2 (v/v) absolute ethanol: system eluent.

The title compound (2.49g) was obtained with preparative HPLC retention time 23.0 min.

Intermediate 9A: 1] (25)-4-(3,4-Dichlorobenzyl)morpholin-2-yljmethanamine salt with D- tartaric acid 1:1 35% Hydrazine in water (1.8ml) was added to a slurry of Intermediate 41 (5g) in industrial methylated spirits (75ml), and the mixture was heated to reflux. Chloroform (75mi) was added and the mixture was heated under reflux for 65h. The reaction mixture was cooled to 0-4°C and allowed to stand for 15min. The by-product phthalhydrazide was removed by vacuum filtration and washed with chloroform (50m). The filtrate was washed with water (50ml, 25m), dried (MgSQ,), and the solvent evaporated in vacuo to give an oil. This was dissolved in methanol (20ml), which was evaporated in vacuo to give an oil. The oil was dissolved in methanol (100ml) and D-tartaric acid (1.05g) was added. The mixture was heated to and maintained at reflux for 30min. The solution was cooled to 45-50°C, then seeded. The slurry was held at this temperature for 30min, then cooled to 0-4°C and allowed to stand for 30min. The product was isolated by filtration to give the title compound as a white solid (2.599).

A sample of the crude D-tartrate salt (500mg) was dissolved in water (1.4ml). Methanol (23ml) was added to give a slurry which was heated to reflux to give a solution. The mixture was stirred at reflux for 30min, then cooled slowly, seeding at 55°C. The resultant slurry was cooled to 0-4°C and allowed to stand 30min. The product was isolated by filtration to give the title compound as a white solid (0.355g). ee: 91.6%ee

LC/MS (System A) R; 1.75 min. Mass spectrum m/z 275/277 [MH]

Chiral analytical HPLC (Chiralpak AD column, 4.6 x 250mm, eluent 50:50:0.1 MeOH: EtOH: - 30 Butylamine, flow rate 0.5ml/min, UV detection at 220nm), Rt 8.9min.

Intermediate 9A (Alternative Procedure): 1-{(2S)-4-(3,4-Dichlorobenzyl)morpholin-2- ' yljmethanamine salt with D-tartaric acid 1:1

Intermediate 1 (0.613g) was dissolved in methanol (12.3ml). D-Tartaric acid (0.335g) was added and the slurry was heated to reflux for 50min. The mixture was allowed to cool to O- 5°C and the precipitate isolated by filtration to give the title compound as a white solid (0.49). ee: 76%ee

Chiral analytical HPLC (Chiralpak AD column, 4.6 x 250mm, eluent50:50:0.1 MeOH: EtOH:

Butylamine, flow rate 0.5mi/min, UV detection at 220nm), Rt 8.9min.

Intermediate 10: 1-{(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yljmethanamine

Intermediate 10 was prepared in an analogous manner to Intermediate 9 yielding the title compound (2.24g) with preparative HPLC retention time 27.8 min.

Intermediate 10A: 1-[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yljmethanamine salt with L- tartaric acid 1:1 [4-(3,4-Dichlorobenzyl)morpholin-2-ylimethylamine (Intermediate 1) (0.500g) was dissolved in methanol (5ml). L-Tartaric acid (0.273g) was added and the mixture was heated to ~65°C to give a milky slurry, and maintained at this temperature for 1h. Further methanol (5ml) was added and the mixture left to cool slowly to 15-25°C, then cooled further to 0-4°C. The mixture was stirred for 30min at this temperature and the product isolated by filtration to give the title compound as a white solid (0.38g). ee: 78%

LC/MS (System A) R; 1.75 min. Mass spectrum m/z 275/277 [MH"]

Chiral analytical HPLC (Chiralpak AD column, 4.6 x 250mm, eluent 50:50:0.1 MeOH: EtOH:

Butylamine, flow rate 0.5mi/min, UV detection at 220nm), Rt 10.5min. intermediate 11. Ethyl [2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]acetate

A suspension of 4-fluorobenzamide (12.9g) and ethyl 4-bromo-3-oxopentanoate (Chem Abs

No. 36187-69-6; 5.249) in anhydrous toluene (120ml) was heated at 140°C for 19 h, using a

Dean-Stark trap. The solution was allowed to cool, filtered, and the residual solid washed with toluene (30ml). The combined filtrate and washings were concentrated in vacuo to give a brown oil, which was purified by Biotage flash chromatography on silica gel (90g column), eluting with ethyl acetate:cyclohexane (5:95, 7.5:92.5, 10:90), to give thetitle compound as a yellow solid (2.98). "30 LC/MS (System A) Rt 3.26 min. Mass spectrum m/z 264 [MH"].

Intermediate 12: [2-(4-Fluorophenyl)-5-methyl-1,3-oxazol-4-yljacetic acid

Intermediate 11 (2.989) in ethanol (25ml) was treated with aqueous sodium hydroxide (2.5M, : 18ml) and the solution stirred at 70°C for 3.5h then allowed to cool. The material was concentrated in vacuo to remove the ethanol, then the aqueous phase was washed with ethyl acetate (30ml). The aqueous phase was adjusted to pH1 by addition of aqueous hydrochloric acid (5M) and the desired acid was extracted into ethyl acetate (1 x 100ml, 1 x 50ml). The combined organic phases were washed with dilute aqueous sodium chloride, ) dried (Na,SO,), filtered and the solution concentrated in vacuo to give the title compound as a cream solid (2.549).

LC/MS (System A) Rt 2.85 min. Mass Spectrum m/z 236 [MH*].

Intermediate 13: 1-{4-[(5-Chlorothien-2-yl)methy{]morpholin-2-yl}methanamine

Intermediate 13 was prepared in an analogous manner to Intermediate 1 (Alternative procedure) from Intermediate 19 and 2-chloro-5-(chloromethyi)thiophene, followed by a deprotection reaction yielding the title compound.

Intermediate 14: 1-{(2S)-4-[(5-Chiorothien-2-yl)methyljmorpholin-2-yl}methanamine

Intermediate 13 was separated into its single enantiomers by chiral preparative HPLC to give the title compound in an analogous manner to the separation of Intermediate 1to yield

Intermediate 9.

LCMS (system A) R, 25.2min.

Chiral Preparative HPLC retention time 25.2min

Intermediate 14A: 1-{(2R)-4-[(5-Chlorothien-2-yl)methyljmorpholin-2-yl}methanamine

Intermediate 14A was prepared in an analogous manner to Intermediate 14yielding the title compound.

LCMS (system A) R, 34min.

Chiral Preparative HPLC retention time 34min.

Intermediate 15: N-{[(2S)-4-Benzylmorpholin-2-ylmethyl}-2-(5-methyl-2-phenyl-1,3-oxazol- 4-yl)acetamide

A mixture of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (0.263g), 1-hydroxylbenzotriazole (0.163g), and N,N-diisopropylethylamine (0.211ml) in N,N-dimethyiformamide (3ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.232g). The mixture was stirred for Smin, treated with 1-[(2S)-4-benzylmorpholin-2-yljmethanamine (prepared in accordance with EP 0 995 746 A1; 0.1929), and the solution was stirred at 22°C for 18h. The mixture was partitioned between dichloromethane (20ml) and saturated - 30 aqueous sodium hydrogen carbonate (10ml). The phases were separated in a hydrophobic frit; the organic phase was loaded onto a solid phase extraction cartridge (10g SCX) and : eluted with methanol, followed by .880 ammonia:methanol 10:90 to give thetitle compound as a colourless gum (0.394g).

LC/MS (System A) R, 2.42 min. Mass spectrum m/z 406 [MH"]. }

Chiral analytical HPLC, eluent 10% EtOH/n-heptane, R, 18.55 min.

Intermediate 15A: N-{[(2R)-4-Benzylmorpholin-2-ylimethyl}-2-(5-methyl-2-phenyl-1,3- oxazol-4-yl)acetamide

Prepared in an analogous manner to Intermediate 15 from 1-[(2R)-4-benzylmorpholin-2- yllmethanamine (prepared in accordance with EP 0 995 746 A1) to obtain the R isomer.

Chiral analytical HPLC eluent 10% EtOH/n-heptane, R, 16.296 min.

Intermediate 16: 2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-N-[(2R)-morpholin-2- yimethyllacetamide

A mixture of Intermediate 15 (0.192g) and ammonium formate (0.4g) in absolute ethanol” (2ml) was treated with 10% palladium on activated carbon (0.1g). After 1.5h the mixture was treated with ammonium formate (0.6g) and stirred under nitrogen for a further 15.5h.

The mixture was filtered through celite and the residue washed with absolute ethanol (20m).

The solvent was removed at reduced pressure to leave a gum. The residue was partitioned between ethyl acetate (20ml) and 2N sodium hydroxide (20ml). The phases were separated and the aqueous phase extracted with ethyl acetate (10ml). The combined organic extracts were filtered through Whatman silicone treated filter paper and the solvent removed at reduced pressure to give the title compound (0.0779) as a colourless gum.

LC/MS (System A) R, 2.14 min. Mass spectrum m/z 316 [MH].

Intermediate 17: 2-(5-Methyl-2-phenyl-1,3-oxazol-4-y!)-N-[(2S)-morpholin-2- yimethyllacetamide

Intermediate 17 was prepared in an analogous manner to Intermediate 16 from Intermediate 15A yielding the title compound.

Intermediate 18: {3-[(Methylsulfonyl)amino]phenyl}acetic acid

Methanesulphonylchloride (1.70ml) was added to a stirred mixture of 3-aminophenylacetic acid (3.29) and sodium carbonate (5.44g) in water (36ml), and the mixture was heated at 85°C with stirring for 4h, allowed to cool and acidified with conc. hydrochloric acid to pH2.

After leaving to stand at approximately 4°C for 18h, a solid was filtered off, and the residue washed with water and ether. The aqueous and ether filtrates were combined and evaporated in vacuo to give a solid, which was dissolved in hot water; the solution was © 30 filtered whilst still hot and the filtrate left to cool before standing at 4°C for 18h. The precipitated solid was filtered, washed with a small quantity of cold water and dried in vacuo to give the title compound as a pale yellow solid (0.4179). 'H nmr (400MHz, d; DMSO) 12.35 (1H, br, s, COOH), 9.74 (1H s, NH), 7.27 (1H, dd, CH), 7.13-7.08 (2H, m, 2xCH), 6.99 (1H, br, d, CH), 3.54 (2H, s, CH,), 2.98 (3H, s CH,)

LCMS (system A) R, 2.07min. Mass Spectrum m/z =247 [MNH,*] m/z =228 [MH].

Intermediate 19: 2,2,2-Trifluoro-N-(morpholin-2-ylmethyl)acetamide

To a stirred solution of morpholin-2-ylmethylamine (3.1g) in methanol (70ml) under nitrogen ) was added an ethereal solution of ethyl-a, a, a-trifluoroacetate (5ml in 20ml ether) which had been washed with saturated aqueous sodium bicarbonate, water and brine, and dried. The mixture was stirred for 30 min at 22°C before removal of all volatilesin vacuo. The residue was dissolved in methanol (10ml) and the volatiles again removed in vacuo to give the title compound as a white crunchy foam (4.9g).

Thermospray Mass Spectrum m/z 213 [MH].

Intermediate 20: 1-[4-(3,4-Difluorobenzyl)morpholin-2-yljmethanamine

Intermediate 20 was prepared in an analogous manner to Intermediate 1 (Alternative

Procedure) from Intermediate 19 and 3,4-difluorobenzyl bromide, followed by deprotection to yield the title compound.

Intermediate 21: 1-[4-(4-Fluorobenzyl)morpholin-2-yljmethanamine

Intermediate 21 was prepared in an analogous manner to Intermediate 1 (Alternative

Procedure) from Intermediate 19 and 4-fluorobenzyl chloride, followed by deprotection to yield the title compound.

Intermediate 22: 1-[(2S)-4-(4-Fluorobenzyl)morpholin-2-yljmethanamine

Intermediate 21 was separated into its single enantiomers by chiral preparative HPLC to give the title compound in an analogous manner to the separation of Intermediate 1to yield

Intermediate 9.

LCMS (system A) R, 18.43min.

Chiral Preparative HPLC Retention time 18.43min.

Intermediate 23: 1-[(2R)-4~(4-Fluorobenzyl)morpholin-2-yljmethanamine

Intermediate 23 was prepared in an analogous manner to Intermediate 22yielding the title compound.

LCMS (system A) R, 26.56min.

Chiral Preparative HPLC Retention time 26.56min.

Intermediate 24: [(28)-4-(3-chlorobenzylmorpholin-2-ylmethylamine + 30 Intermediate 24 was prepared in an analogous manner to Intermediate 9

Preparative chiral HPLC retention time 26.1min ’ Intermediate 25: [(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yljmethylamine

Intermediate 25 was prepared in an analogous manner to Intermediate 9

Preparative chiral HPLC retention time 25.3min

Intermediate 26: [(25)-4-(3 4-difluorobenzyl)morpholin-2-yljmethylamine

Intermediate 26 was prepared in an analogous manner to Intermediate 9

Preparative chiral HPLC retention time 28.3

Intermediate 27: 1-{(cis)-4-(2,5-dichlorobenzyl)-5-methylmorpholin-2-yljmethanamine (2:1 mixture with frans isomer)

Intermediate 27 was made in an analogous manner to Intermediate 5

LC-MS (System A): Rt 1.88mins ~~ Mass Spectrum m/z 289 [MH"]

Intermediate 28: 2-[2-(4-fluorophenyl)-5-methyl-1 ,3-0xazol-4-yl}-N-{(2R)-morpholin-2- ylimethyllacetamide

Intermediate 28 was prepared in an analogous manner to Intermediate 16

LC-MS (System A): Rt 2.21mins ~~ Mass Spectrum m/z 334 [MH"]

Intermediate 29: [4-(3-Fluorobenzylhmorpholin-2-yljmethylamine

A mixture of Intermediate 19 (0.3009) and N,N-diisopropylethytamine (0.372ml) in N,N- dimethylformamide (5ml) was treated with 3-fluorobenzyl bromide (0.295g). The solution was stirred at 20°C under nitrogen for 24h. The mixture was partitioned between dichloromethane (10ml) and saturated aqueous potassium carbonate (10m). The phases were separated and the organic phase applied to an ion exchange cartridge (1 0g Isolute

SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (400ml) followed by 10% 0.880 ammonia in methanol (40ml) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in methanol (2ml) and treated with aqueous 2N sodium hydroxide (2ml). The solution was stirred at 20°C for 24h. The mixture was partitioned between dichloromethane (15m) and water (20ml). The aqueous extract was washed with dichloromethane (15ml) and the combined organic extracts concentrated to give the title compound as a colourless gum (0.150g).

Thermospray Mass spectrum m/z 225 [MH*].

Intermediate 30: _tert-Butyl [(25)-4-(3,4-dichlorobenzoyl)morpholin-2-ylJmethylcarbamate

A mixture of 3,4-dichlorobenzoic acid (0.5g), 1-hydroxybenzotriazole (0.3769), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.4329), and N,N- diisopropylethylamine (0.485ml) in N,N-dimethylformamide (10ml) was stirred at 20°C for "30 10min. The mixture was treated with tert-butyl (2R)-morpholin-2-yimethylcarbamate (0.500g, known compound WO 9639407A1) and stirred at 20°C for 24h. The mixture was partitioned between ethyl acetate (75ml) and 2N aqueous hydrochloric acid (50ml). The phases were separated and the organic extract washed with 2N aqueous hydrochloric acid (50mi),

saturated aqueous sodium hydrogen carbonate (2x50ml), dried (MgS0,) and filtered. The solvent was removed in vacuo to give the title compoundas a yellow oil, (0.7749).

LCMS (system A) R; 3.24min Mass Spectrum m/z 389 [MH].

Intermediate 31: 1 -[(28)-4-(3,4-dichlorobenzoylmorpholin-2-yljmethanamine hydrochloride . 5 Intermediate 30 (0.770g) was treated with 4.0M hydrogen chloride in dioxane (8ml). The mixture was stirred at 20°C for 30min. The solvent was removed in vacuo to give the title compound as a white solid (0.592g).

LCMS (system A) R, 2.04min Mass Spectrum m/z 289 [MH']

Intermediate 32: Methyl 4-oxo-3-[(pyridin-3-ylcarbonyl)amino]pentanoate

Nicotinyl chloride hydrochloride (178mg) was added to a stirred suspension of aspartic acid

B-methyl ester hydrochloride (183mg) in pyridine at 0°C with stirring under nitrogen, and the mixture was stirred at 0°C for 1.5h and at room temperature for 0.5h. Acetic anhydride (0.37ml) was added, and the mixture was heated at 90°C for 2h. Water (0.6ml) was added and heating continued for 15min before the mixture was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was evaporated in vacuo to give a yellow oil (110mg).

LC-MS (System A) Rt 1.86min. Mass Spectrum m/z 251 [MH"].

Intermediate 33: Methyl (5-methyl-2-pyridin-3-yl-1 ,3-0xazol-4-yl)acetate

Intermediate 32 (110mg) was treated with phosphorous oxychloride (0.51ml) in toluene (2ml) 20° and the mixture heated under reflux for 3.5h. The mixture was poured into ice cold saturated aqueous sodium bicarbonate (30ml) and extracted with dichloromethane (20ml). The organic layer was evaporated in vacuo to give a yellow gum (111mg).

LC-MS (System A) Rt 2.30min. Mass Spectrum m/z 233 [MH"].

Intermediate 34: (5-Methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)acetic acid

Intermediate 33 (111mg) was dissolved in tetrahydrofuran (2ml) and water (0.2ml) and lithium hydroxide (12mg) added. The mixture was stirred at 22°C for 17h and heated at 60°C for 2h. Ethanol (3ml) and 2N aqueous sodium hydroxide (1ml) were added, and stirring was continued at 22°C for 2h. The mixture was applied to a sulphonic acid ion exchange cartridge (10g Isolute SCX) and eluted with methanol followed by 10% triethylamine in methanol. © 30 Evaporation of the triethylamine containing fraction gave the title compound as a gum (46mg). ) LC-MS (System A) Rt 2.12min. Mass Spectrum m/z 219 [MH].

Intermediate 35: Ethyl 4-(methylthio)butanoate

Claims (1)

1. ~ PCT/GBO1/04345 ~~ CLAIMS

   1. A compound of formula (I): : (o] X O EN ) l, >Re R a ‘ ya EU) : S wherein: R' represents Cys alkyl, Cs alkenyl, C.. alkynyl, Cs alkynyl-Y'-, aryl-Y'- , heteroaryl-Y'-, aryl-(O)qaryl-Y'-, aryl-(O)-heteroaryl-Y'-, heteroaryl-(O)-aryl-Y'-, heteroaryl-(O)cheteroaryl-Y'-, Co; alkenyl-Y'-, aryl-O-Y'-, heteroaryl-O-Y'-, C5 alkyl-SOzY'-, M-Y'-, J2-Y'- -GN or Cs cycloalkyl-Y'- or Cs 5 cycloalkenyl-Y'-, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or Cs alkyl groups; oo R?represents hydrogen or Cs. alkyl; X represents ethylene or a group of formula CR°R wherein R® and Rf independently represent hydrogen or Cs alkyl or R® and R’ may together with the carbon atom to which they are attached form a Cas cycloalkyl group; : R? and R* independently represent hydrogen or C, alkyl; Z represents a bond, CO, CHR(CHz)n, CHR¥(CH;).0 or CHR®(CH,).CO; RS represents phenyl which may be optionally substituted or thiophenyl which may be optionally substituted; R® represents hydrogen, C4 alkyl, CONR'R® or COOC, 5 alkyl; _ a and b both represent 1; ] . : : . n represents an integer from O to 4; : J? represents a moiety of formula (K): x} be : NS ow wherein X' represents oxygen, NR" or sulphur, X? represents CH,, oxygen, NR™® or sulphur, m' represents an integer from 1 to 3 and m? represents an integer from 1 to 3, provided that m'+m? is in the range from 3 to 5, also provided that 84 : Co AMENDED SHEET CLEAN COPY :

   Lo PCT/GB01/04345 when both X* and X? represent oxygen, NR™, NR" or sulphur, m*! and m? must both not equal less than 2, wherein K is optionally substituted by one or more - : Y?-aryl, -Y*-heteroaryl, -Y*-CO-aryl, -COC3 scycloalkyl, -Y3-CO-heteroaryl, -Cy alkyl, -Y>-COOC;s alkyl, -Y*-COC;. alkyl, -Y3-W, -Y3-CO-W, -Y3-NRVR2, -y2. CONRYR'™, hydroxy, oxo, -Y?-SO.NR"'R™, -Y*-S0,C alkyl, -Y3-SO,anyl, -Y*- SOzheteroaryl, -Y-NR™C, alkyl, -Y-NR'"S0,C, alkyl, -Y:-NR™CONR''R'2, - ~ Y®-NR™COOR?™ or -Y-OCONR''R" groups, and is optionally fusedtoa monocyclic aryl or heteroaryl ring; : R’, R%, R%, R", R™, R" and R* independently represent hydrogen or C,. alkyl; ~ R" and R™ independently represent hydrogen or Cy alkyl or R" and R™2 together with the nitrogen atom to which they are attached may form a morpholine, piperidine or pyrrolidine ring; M represents a C35 cycloalkyl or a C54 cycloalkenyl group fused to a : : monocyclic aryl or monocyclic heteroaryl group; W represents a saturated or unsaturated, non-aromatic 5-7 membered ring containing between 1 and 3 heteroatoms selected from nitrogen, oxygen or sulphur, optionally substituted with one or more Cs alkyl, halogen or hydroxy groups; ~ trepresents Oor 1; : Y' represents methylene, ethylene, or cyclopropyl; : Y2and Y3 independently represent a bond or a group of formula — (CHZ),CR°R¥(CHy)s- wherein R® and R® independently represent hydrogen or Cy alkyl or R® and R? may together with the carbon atom to which they are attached form a Ca cycloalkyl group, and p and q independently represent an integer from : 0 to 5S wherein p + q is an integer from 0 to 5; and salts and solvates thereof;-

   2. A compound of formula (1) according to claim 1 wherein R! represents C,. s alkyl, C. alkenyl, Cz alkynyl, aryl-Y'-, heteroaryl-Y'-, aryl-(O)caryl-Y'-, aryi- (O)-heteroaryl-Y'-, heteroaryl-(O)-aryl-Y'-, heteroaryl-(O)-heteroaryl-Y'-, Coq alkenyl-Y'-, aryl-0-Y'-, heteroaryl-O-Y'-, C1 alkyl-SO,-Y'-, M-Y'-, -CN, J2-Y'-, Css cycloalkyl-Y'-, or C4 cycloalkenyl-Y'-, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C,. alkyl groups.

   : 3. A compound of formula (1) according to claim 1 or claim 2 wherein R' represents Ci alkyl, Cz alkenyl, C,¢ alkynyl, aryl-Y'-, heteroaryl-Y'-, aryl-(O)- aryl-Y'-, aryl-(O)-heteroaryl-Y'-, heteroaryl-{O)raryl-Y'-, heteroaryl-(O)- 85 AMENDED SHEET : A ‘CLEAN COPY - SE

   © PCTIGB01/04345 oo heteroaryl-Y'-, C,. alkenyl-Y'-, aryl-O-Y'-, heteroaryl-O-Y'-, C.¢ alkyl-SO-Y'-, M-Y*- or Css cycloalkyl-Y'- or Cs cycloalkenyl-Y'-, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C1. atkyl groups. :

   4. A compound of formula (1) according to any one of claims 1 to 3 wherein X represents methylene.

   8 5. A compound of formula (1) according to any one of claims 110 4 wherein | : Z represents CHR®(CHy), or CHR®(CH,),CO. :

   - 6. A compound of formula (1) according to any one of claims 1 to 5 wherein 3 Z represents -CH-. : ’

   7. A compound of formula (I) according to any one of claims 1 to 6 wherein : 'R® represents phenyl optionally substituted with one or more halogen atoms. :

   8. A compound of formula (1) according to any one of claims 1 to 7 wherein R® represents 3,4-dichlorophenyl.

   S. A compound of formula (I) according to any one of claims 1 to 8 selected from the list consisting of: N-{[4-(3.4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-phenylacetamide; : N-{[4-(3,4-Dichlorobenzyl)morpholin-2-ylJmethyl}-2-[4- (methyisulfonyl)phenyllacetamide salt with formic acid (1:1); N-{[4-(3,4-Dichlorobenzy!)morpholin-2-ylJmethyi}-2-(3-flucrophenyl)acetamide; N-{[4-(3 ,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2~(4-flucrophenyl)acetamide; no N-{[4~(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-[4- (methylthio)phenyllacetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-ylimethyl}-2-(3,4- : difluorophenyl)acetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yljmethy}-2-(4- i [(dimethylamino)sulfonyllphenyllacetamide salt with formic acid (1:1); 2-(3-Chiorophenyl)-N-{{4-(3,4-dichlorobenzyl)morpholin-2-yfjmethylacetamide; : N-{[4-(3 ,4-Dichlorobenzyf)morpholin-2-yljmethyl}-2~(4-methylphenyl)acetamide; 4-[2-({I4-(3,4-Dichlorobenzyi)morpholin-2-yljmethyl}amino)-2- : oxoethyllbenzamide; 2-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylimethyljacetamide; 86 : AMENDED SHEET CLEAN COPY 5 h

   : ‘ PCT/GB01/04345 LJ N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyi}-2-[4- (dimethylamino)phenyllacetamide salt with formic acid (1:1); N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-(2,5- dichlorophenyl)acetamide; N-{[4-(3,4-Dichlorabenzyl)morpholin-2-yijmethyl}-2-[4- (trifluoromethyl)phenyflacetamide; N-{{4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyi}-2-(3,4- dichlorophenyl)acetamide; 2-{2-Chlorophenyl)-N-{J4-(3,4-dichlorobenzyl)morpholin-2-yijmethylacetamide; : 2-[3,5-Bis(trifluoromethyl)phenyl}-N-{[4~(3,4-dichlorobenzyl)marpholin-2- yijmethyl}acetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2:(2,4- - ~ dichlorophenyl)acetamide; : N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-(4-flucro-2- methylphenyl)acetamide; N-{[4-(3,4-Dichiorobenzyl)morpholin-2-yljmethyl}-2-(2,6- dichlorophenyl)acetamide; : : N-{{4~(3,4-Dichlorobenzyl)morpholin-2-ylimethyl}-2-phenoxyacetamide:. N-{[4-(3,4-Dichlorobenzyl)morphofin-2-ylimethyf}-2-(4-methoxyphenyl)acetamide; 2-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)-5,5-dimethylmorpholin-2- yiimethyl}acetamide; N-{I{cis}4—(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yljmethyl}-2- phenylacetamide; N-{[(trans)-4~(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yljmethyl}-2- phenylacetamide; 2-(4-Chloropheny!)-N-{I(cis)-4-(3,4-dichlorobenzyl)-5-methyimorpholin-2- ylimethyl}acetamide; 2-(4-Chlorophenyl)-N-{[(trans)-4~(3,4-dichlorobenzyl)-5-methylmorpholin-2- ylimethyllacetamide; N-({4-{3-(3,4-Dichlorophenyi)propyljmorpholin-2-yl}methyl)-2-phenylacetamide; 5 2-(4-Chlorophenyl)-N-{[4-(2,3-dichlorobenzyl)morpholin-2-ylimethyf}acetamide : trifluoroacetate; : 1-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyf)morpholin-2- yljmethyl}cyclopropanecarboxamide trifluoroacetate; N-{[4-(3,4-Dichiorobenzyl)morpholin-2-yi] methyl}-2-(5-methoxy-2-methyl-1H- indol-3-yl)acetamide; N-{{4-(3.4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-thien-3-ylacetamide: N-{{4~(34-Dichiorobenzyl)morpholin-2-yljmethyi}-2-(5-methyl-2-phenyl-1 3 oxazol-4-yhacetamide; = a

   87 . AMENDED SHEET oC CLEAN COPY Co

   PCT/GBO1/ 04345 ® ~ N~{[4(3,4-Dichlorobenzyi)morpholin-2-yljmethyl}-2-(5-methyl- 1-phenyl-1H- : pyrazoi-4-yl)acetamide; 2-(4-Bromo-3,5-dimethyl- 1H-pyrazol-1-yl)}-N-{J4-(3,4-d ichlorobenzyl)morpholin-2- . yllmethyl}acetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyi}-2-(2-pheny}-1,3-thiazol-4- : yl)acetamide; N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-(2-pyrazin-2-yl-1,3-thiazol-4- yl)acetamide; | : N-{[4-(3,4-Dichlorobenzyi)morpholin-2-yljmethyf}-2-(2-furyl)acetamide; N-[(2S)-4-(3,4-Dichiorobenzyl)morpholin-2-yljmethyl}-2-[4- (methylsulfonyl)phenyljacetarnide; : a N-{[(2R)-4~(3,4-Dichlorobenzyl)morpholin-2-yljmethy}-2-}4- SL (methylsulfonylphenyllacetamide; . : N-{I4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-[2-(4-flucrophenyl)-5-methyl- ~ 1,3-oxazol-4-yljacetamide; N-{[(25)-4-(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-(2-pyrazin-2-yi-1,3- ~ thiazol4-yl)acetamide; N-{I[(2R}-4~(3,4-Dichlorobenzyl)morpholin-2-ylimethyl}-2«(2-pyrazin-2-yl-1,3- - thiazol-4-yl)acetamide; N-{[(2S5)-4~(3,4-Dichlorobenzyl)morpholiin-2-yljmethyl}-2-(5-phenyl-2H-tetraazol- 2-yl)acetamide; B N-{[4-(3,4-Difluorobenzyl)morpholin-2-yllmethyi}-2-{4- IE [(methyisulfonyl)amino]phenyl}acetamide; N-{[(2S)-4-(4-Fluorobenzyl)morpholin-2-yljmethyl}-2-{4- [(methylsulfonyl)amino]phenyf}acetamide; : : N-{{(2R)-4~(4-Fluorobenzyl)morpholin-2-yljmethyl}-2-{4-

   - [(methylsulfonyl)amino)phenyf}acetamide; N-{[4-(4-Fluorobenzyl)morpholin-2-y{jmethyl}-2-{4- [(methyisulfonyl)amino)phenyl}acetamide;

   } N-{{(2S)4-[(5-Chlorothien-2-yl)methyljmorpholin-2-yl}methyl)-2-{3- [(methylsulfonyl)amino}phenyl}acetamide; : N-({(2R)-4-[(5-Chlorothien-2-yl)methyllmorpholin-2-yl}methyl)-2-{3- - [(methylsulfonyl)amino]phenyl}acetamide; : : N-({4-[(5-Chlorothien-2-yl)methylJmorpholin-2-yl}methyl)-2-{3- [(methylsulfonyl)amino]phenyf}acetamide; N-{[4~(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2~(2,6- NE

   : difluorophenyl)acetamide; N-Cyclopropyl-3-{2-({{4-(3.4-dichlorobenzyf)morpholin-2-y{Jmethyf}amino)-2- oxoethyllbenzamide; 88 a AMENDED SHEET : ' CLEAN COPY oo .

   PCT/GB01/04345 @ N-{[(2S)-4~(3,4-Dichlorobenzyl)morpholin-2-yljmethyl}-2-(5-methyl-2-phenyl-1 3- oxazol-4-yl)acetamide; 'N-{[(2R)-4~(3 4-Dichiorobenzyl)morpholin-2-ylJmethyl}-2-(5-methyl-2-phenyl-1,3- : oxazol-4-yl)acetamide; + Methyl 3-[2-({[4~(3,4-dichlorobenzyl)morpholin-2-ylJmethyflamino)-2- BE oxoethyllbenzoate; 3-[2-({{4-(3.,4-Dichiorobenzyl)morpholin-2-yllmethyl}amino)-2-oxoethyl]benzoic acid compound with N,N,N-triethylamnine (1:1);. 2-[3-(acetylamino)phenyl}-N-{[4-(3,4-dichiorobenzyl)morpholin-2- ylimethyl}acetamide; oo 2-(3-acetyl-1-benzothien-4-yl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2- yllmethyl}acetamide trifluoroacetate; Lo

   _. 2-(5-bromopyridin-3-yi)-N-{{4~(3,4-dichlorobenzyl)morpholin-2- ~ yilmethyl}acetamide compound with formic acid (1:1); N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylimethyl}-2-(2,3-dimethylquinoxalin-6- yl)acetamide; 2-(4-acetylphenyi)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylJmethylacetamide triflucroacetate; 2-(4-acetylphenyl}-N-{[4~(3,4-dichlorobenzyl)morpholin-2-yljmethyl}acetamide; N-{{4-(3,4-dichlorobenzyf)morpholin-2-yllmethyl}-2-(4-isobutyrylphenyl)acetamide : trifluoroacetate; oo methyl 4-[2-({f4-(3,4-dichiorobenzyl)morpholin-2-yljmethylarnino)-2- oxoethyl]benzoate trifluoroacetate; © methyl 4-[2-({[4~(3,4-dichlorobenzyl)morpholin-2-yljmethy}amino)-2- oxoethyllbenzoate; 2-{(4-cyanophenyl}-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}acetamide : trifluoroacetate; } : 2-(4-cyanophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}acetamide; N-{[(2S,5R)-4~(3 4-dichlorobenzyl)-5-methylmorpholin-2-yljmethyl}-2- phenylacetamide; nN 2-(4-chlorophenyl}-N-{[(2S; 5R)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2- ylimethyl}acetamide; N-{[4-(3,4-dichiorobenzyl)morpholin-2-yljmethyl}-2-(3-fluoro4- . hydroxyphenyl)acetamide trifluoroacetate; N-{{(25)-4-(3,4-dichlorobenzyl)morpholin-2-ylimethyl}-2-(2-fury)acetamide; N-{[4~(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-{4-[(4-methylpiperazin-1- yl)carbonyllphenyl}acetamide; 4-[2-({{4-(3.4-dichiorobenzyl)morpholin-2-yljmethyl}amino)-2-oxoethyl}-N-[2- (dimethylamino)ethyl]benzamide; aE

   89 . AMENDED SHEET " CLEAN COPY : }

   PCT/GB01/04345 : ® 4-[2-({]4-3,4-dichlorobenzyl)morpholin-2-ylimethyl}amino)-2-oxoethyl}-N,N- : dimethylbenzamide; . : 4-{2-{{]4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}amino)-2-oxoethyl}-N- : ethylbenzamide; : 4-[2-({]4-(3,4-dichlorobenzyl)morpholin-2-y]Jmethyl}Jamino)-2-oxoethyl}-N-(2- hydroxyethyl)benzamide; N-{[4~(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-[4-(morpholin-4-- ylcarbonyl)phenyljacetamide; : N-{[(2S)-4~(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-{3- [(dimethylamino)sulfonyllphenyl} acetamide; N-{[(2R)-4~(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-{4- a. - [(dimethylamino)sulfonyl]pheny} : acetamide; N-{[(2S)-4~(3,4-dichiorobenzyl)morpholin-2-yljmethyl}-2-{4- [(dimethylamino)sulfonyflphenyi} acetamide; 4-{2-({14-(3,4-dichlorobenzyl)morpholin-2-y[jmethyl}amino)-2-oxoethyl}-N- : : methylbenzamide; 4-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}amino)-2-oxoethyi}-N- isopropylbenzamide; N-cyclopropyi-4-{2-({[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyamino)-2- oxoethyllbenzamide; : 4-[2-({14~(3.4-dichiorobenzyl)morpholin-2-ylJmethyl}amino)-2-oxoethyl}-N-(2- methoxyethyl)benzamide; oo N-{{4-(3,4-dichlorobenzyl)morpholin-2-yllmethyl}-2-(5-phenyl-2H-tetraazol-2- yl)acetamide; Co oo 2-(4-bromo-1H-imidazol-1-yl)}-N-{[4-(3,4-dichlorobenzy)morpholin-2- yllmethyllacetamide; : oo N-{{4-(3,4-dichlorobenzyl)mompholin-2-yljmethyl}-2-(4-nitrophenyl)acetamide; EI N-{[4+3 4-dichlorobenzyl)morpholin-2-yjmethyl}-2-(3-nitrophenyl)acetamide; 2-[3-(acetylamino)phenyl}-N-{[4-(3-fluorobenzy)morpholin-2-ylJmethyl}acetamide:; N-{[4-(3-fluorobenzyl)morpholin-2-yljmethyl}-2-{4- : [(methylsulfonyl)amino}phenyl}acetamide; 2-{3-(acetylamino)phenyl}-N-{[4-(3,4-difluorobenzyl)morphofin-2- yllmethyl}acetamide; : 2-[4-(acetylamino)phenyl}-N-{{4-(3,4~diflucrobenzyl)morpholin-2- yllmethyl}acetlamide; N-{[4-(3.4-difluorobenzyl)morpholin-2-yljmethyl}-2-(2-pyrazin-2-yi-1,3-thiazol-4- Co yl)acetamide; Co

   . AMENDED SHEET oo * CLEAN COPY oo

   SU oo PCT/GB01/04345 - N-{4-(3,4-difluorobenzyf)morpholin-2-yljmethyi}-2-{3- : [(methylsulfonyl)aminolphenyl} oo acetamide; N-{[4-(3,4-difluorobenzyl)morpholin-2-yljmethyl}-2-{3- (methylsulfonyl)phenyllacetamide; N-{[4-(3-chlorobenzyl)morpholin-2-yljmethy}-2-[4- : - (methylsulfonyf)phenylJacetamide; " N-H{[4-(3-chiorobenzyl)morpholin-2-yljmethyi}-2-[3- ~ (methyisulfonyl)phenyllacetamide; 2-[3-(acetylamino)phenyl}-N-{[4-(4-flucrobenzylmorpholin-2-yljmethyl}acetarmide; x : 2-[4-(acetylamino)phenyl]-N-{[4-(4-fluorobenzyl)morpholin-2-yljmethyl}acetamide; N-{[4-(4-fluorobenzyl)morpholin-2-yljmethyl}-2-(2-pyrazin-2-y-1,3-thiazo-4- oo yl)acetamide; . : N-{[4-(2,3-dichlorobenzyl)morpholin-2-yljmethyl}-2-[4- ~ (methylsulfonyl)phenylJacetamide; a oo : oo 2-[3-(acetylamino)phenyl}-N-{[4-(2,3-dichlorobenzyl)morpholin-2- : yllmethyl}acetamide; © N-{J4-(2,3-dichlorobenzyl)morpholin-2-yljmethyl}-2-{4- [(methyisulfonyl)aminojphenyi} acetamide; } } N-{[4~(2,3-dichlorobenzyl)morpholin-2-yljmethyl}-2-(4- {[(methylamino)carbonyljaminc} : phenyl)acetamide; N-{J4-(2,3-dichlorobenzyl)morpholin-2-yfjmethyl}-2-(2-pyrazin-2-yi-1 3-thiazol-4- : yl)acetamide; N-({4-[(5-chiorothien-2-yl)methyljmorpholin-2-yf}methyl)-2-[4- (methylsulfonyl)phenyllacetamide; 2-[3-(acetylamino)phenyl}-N-({4-[(S~chlorothien-2-yl)methyljmorpholin-2- ylimethyl)acetamide; Co N-{{4-[(5-chlorothien-2-yl)methylJmorpholin-2-yljmethy)-2-{4- . : [(methyisulfonyi)amino]phenyl} acetamide; N-({4-](5-chlorothien-2-yl)methyl] morpholin-2-yl}methyl)-2-(2-pyrazin-2-yi-1,3- . thiazol-4-yl)acetamide; 2-[3-(acetylamino)phenyl}-N-{[4-(3-chlorobenzyl)morpholin-2- yllmethyl}acetamide; : N-{[4~{3-chlorobenzyl)morpholin-2-yfjmethyf}-2-{4-[(methylsulfenyl)amino]phenyl} -acetamide; 2-[4-(acetylamino)phenyi}-N-{[4-(3-chlorobenzyl)morpholin-2- yllmethyl}acetamide; 91 AMENDED SHEET : CLEAN COPY B

   RE - | PCT/GB01/04345 @ | : N-{J4-(3-chlorobenzyl)morpholin-2-ylimethyl}-2-(4- | - {[{(methylamino)carbonyljamino} EE phenyl)acetamide; : N-{[4~(3-chlorobenzyhmorpholin-2-yljmethyl}-2-(2-pyrazin-2-yi-1 ,3-thiazol-4- yl)acetamide; 2-{4-(acetylamino)phenyl}-N-{{4-(2,3-dichlorobenzyl)morpholin-2- : : ylimethyl}acetamide; : N-{[4-(2,3-dichlorobenzy!)morpholin-2-yljmethyl}-2-{3- (methyisulfonyl)phenyllacetamide; : 2-[4-(aminosulfonyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2- yljmethyl}acetamide; : 2-[2-(acetylamino)phenyl}-N-{[4~(3,4-dichlorobenzyl)morpholin-2- : ylimethyf}acetamide; - oo 2-(3-cyanophenyl)-N-{J4-(3,4-dichlorobenzyl)morpholin-2-ylimethyljacetamide; : - N-{[(2S,5R)4~(2,5-dichlorobenzyt)-5-methyimorpholin-2-yljmethyl}-2- : phenylacetamide; 2-(4-chlorophenyl)-N-{[(2S,5R)-4(2,5-dichlorobenzyl}-S-methyimorpholin-2- ylimethyl}acetamide; : N-{4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}-2-(2-fluorophenylacetamide; N-{4-(3,4-dichlorobenzyl)morpholin-2-yljmethyi}-2~(2,3-difluorophenyl)acetarnide; : NH{[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-(2,4-diflucrophenyl)acetaride; N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylimethyl}-2-(2,5-diflucrophenyl)acetamide; 3-{2-({[4-(3.4-dichlorobenzyl)morpholin-2-yljmethyl}amino)-2-oxoethyl}-N-(2- methoxyethyl)benzamide; 3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}amino)-2-oxoethyl}-N- ethylbenzamide; 342-({[4-(3.4-dichlorobenzyl)morpholin-2-yjmethylamino)-2-oxoethyl]-N,N- ~ dimethylbenzamide; . 3-[2-({I4-(3.4-dichlorobenzyl)morpholin-2-yljmethyllamino)-2-oxoethyl}-N-{2- : : (dimethylamino)ethyllbenzamide; oo N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylimethyl}-2-{3-[(4-methylpiperazin-1- : yi)carbonyllphenyl}acetamide; - 2-(3-aminophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}acetamide; E 2-(4-aminophenyl)-N-{[4-(3,4-dichlorobenzy)morpholin-2-yljmethyljacetamide; N~[(28)-4-(3.4-dichlorobenzyl)morpholin-2-yljmethyl}-2-(5-methyl-2-phenyl-1 3 oxazol-4-yl)acetamide hydrochloride; N-{[(25)-4-(3.4-dichlorobenzyl)morpholin-2-yljmethyi}-2-(5-methyl-2-phenyl-1 3 oxazol-4-yl)acetamide fumarate salt; 2-{4-(acetylamino)phenyl}-N-{4-(3,4-dichlorobenzyl)morpholin-2- * ylimethyDacetamide; 92 AMENDED SHEET - "CLEAN COPY a | | PCT/GB01/04345 N-{4-12-({[4-(3,4-dichlorobenzyl)morpholin-2-ylimethylJamino)-2-oxoethyllphenyl}- ‘2-methylpropanamide; N-{3-{2-{{14~(3.4~dichlorobenzyl)morpholin-2-yljmethyl}amino)-2-oxoethyllphenyi}- 2-methylpropanamide; . N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}-2-{3- oo [(methyisulfonyl)amino]phenyflacetamide; 2-[4-(acetylamino)phenyl]-N-{[4-(3, 4-dichlorobenzyl)morpholin-2- ylimethyl}acetamide; N-{4-[2-({4-(3.4-dichlorobenzyl)morpholin-2-yllmethyl}amino)-2-oxoethyljphenyl}- 2-methylpropanamide; N-{3-{2-{{[4-(3,4-dichiorobenzyl)morpholin-2-ylJmethyllamino)-2-oxoethyljphenyl}- ~~ 2-methylpropanamide; Bh N-{T4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}2-{3- [(methyisulfonyl)amino}phenyl}acetamide; . N-{[(2S,5R)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2-yllmethyl}-2-(5-methyi-2- : phenyl-1,3-oxazol-4-yl)acetamide; N-{]4-(3,4-dichlorobenzyl)morphofin-2-yfjmethyl}-2-{4- : [(methylsulfonyl)amino]phenyl} : iE acetamide; N-{3-{2-{{I4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}amino)-2-oxoethyl}pheny)- 2-(dimethylamino)acetamide; 2-{4-[bis(methylsulfonyl)aminojphenyl}-N-{[4-(3,4-dichlorobenzyl)morpholin-2- yllmethyl}acetamide; : N-{I4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-(5-methyl-2-phenyl-1 3- thiazol-4-yl)acetamide; N-{[4~(3,4-dichlorobenzy!)morpholin-2-yi] methyf}-2-(5-methyl-2-pyrazin-2-yi-1,3- : thiazol-4-yl)acetamide; N-{[4~(3,4-dichlorobenzyl)morpholin-2-yljmethy}-2-[3- (methyisulfonyl)phenyljacetamide; N-{{4-(3,4-dichlorobenzyi)morpholin-2-yljmethyi}-2-[4-(methyisulfonyi)-2- nitropheny(Jacetamide; N-{]4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-(2-hydroxyphenyl)acetamide: N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylimethyl}-2-(2-phenyi-1,3-oxazol4- ~ yl)acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-{4- [methyl{methylsulfonyl)amino] oo phenyllacetamide; : N-{[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyf}-2-{3- [methy)(methylsulfonyl)amino}phenylacetamide; EA 93

   ~. AMENDED SHEET oo ' CLEAN COPY : y

   PCT/GB01/04345 ® N-{[(2S)~4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-4-- {methylsulfonyl)butanamide; to N-{[4-(3,4-dichlorobenzyl)morphoiin-2-yljmethyl}-2-[5-methyl-2~5-methylthien-2- yl}-1,3-oxazol-4-yl)acetamide; : 2-[2-amino-4-(methylsulfonyl)phenyl}-N-{[4-(3,4-dichlorobenzyl)morphoiin-2- oo yllmethyDacetamide; N-{{4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}-2~(5-methy}-2-thien-2-yi-1,3- oxazol-4-yl)acetamide; oo N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}-2-[2-(2-furyl)-5-methyk1,3- oxazol-4-ylJacetamide; oo N-{l4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}pent-4-ynamide; N-{I(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-ylJmethyl}-2-(5-methyl-2-pyridin-3-yl- 1,3-oxazol-4-yl)acetamide compound with formic acid (1:1); N-{[(28}-4~(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}-2-(2-isopropyt-5-methyi- 1,3-oxazol-4-yl)acetamide; : N-{[(25)-4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-{4- [(methylamino)sulfonyl}phenyf} : : acetamide; : N-{[{28)4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-{4- : : [(ethylamino)sulfonyllphenyl} acetamide; a 2-[3-(Aminosulfonyl)phenyl}-N-{[(2S)4-(3,4-dichlorobenzyl)morpholin-2- ‘yllmethyl}acetamide; 2-[3-(Aminosulfonyl)phenyl}-N-{[4~(34-dichlorobenzyl)morpholin-2- yllmethyllacetamide; 2-{3-[(cyclopropylamino)sulfonyl]phenyl}-N-{[(2S)-4~(3,4~ dichlorobenzyl)morpholin-2-yljmethyljacetamide; : N-{I(2S)-4~(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-{3- - [(ethylamino)sulfonyfjphenyf} } acetamide; Co N-{I(25)-4~(3,4~dichlorobenzyl)morpholin-2-yljmethy-2-{3- [(methylamino)sulfony{Jphenyl} _ acetamide; N-{[(2S)-4-(3,4~dichlorobenzyl)morpholin-2-yljmethyl}-2-(5-methyl-2-morpholin-4- _yi-1,3-oxazol-4-yl)acetamide; 2-[4-(aminosulfonyl)phenyl}-N-{{4-(3,4-dichlorobenzyl)morpholin-2- ~ ylimethyllacetamide; : 2-{4-{(cyclopropylamino)sulfonyl]phenyl}-N-{[4-(3,4-dichlorobenzyf)morpholin-2- : yijmethyl}acetamide; : a. ’ 94 ~ AMENDED SHEET oo "* CLEAN COPY oo -

   PCT/GB01/04345 ® methyl 2-[2-({J4~(3.4-dichlorobenzyi)morpholin-2-ylJmethyl}amino)-2-oxoethyl}- 2H-1,2,3-benzotriazole-5-carboxylate; : a oo N{[4-(3 4-dichlorobenzyl)morpholin-2-ylimethyf}-2~ 1H-pyrrolo[2,3-blpyridin-1- yl)acetamide; : : N-{[4-(3,4-dichlorobenzyl)morpholin-2-yllmethyl}-2-(5-pyridin-2-yl-2H-tetraazol-2- yl)acetamide; N-{[4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-(5-pyridin-3-yi-2H-tetraazol-2- ylacetamide; N-{J4~(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}-2-[5-(3-formylphenyl)-2H-

   tetraazol-2-yllacetamide; methyl 1-[2-({[4-(3.4-dichlorobenzyl)morpholin-2-yllmethyl}amino)-2-oxoethyl}- 1H-1,2,3-benzotriazole-5-carboxylate, compound with methyl 1-[2-({{4-(3.4-

   dichlorobenzyl)morpholin-2-yljmethyllamino)-2-oxoethyl}-1 H-1,2,3-benzotriazole-

   - 6-carboxylate (1:1); : | = -

   oo * N-{[(2S)-4-(3,4-dichiorobenzyl)morpholin-2-ylmethyl}-2-[2-(2-furyl)-5-methyl-1,3- oxazol-4-yljacetamide; N-{[(2S)-4-(3,4-dichiorobenzyl)morpholin-2-yljmethyl}-2-(5-methyl-2-thien-2-yi- 1,3-oxazol4-yl)acetamide; N-({(28)-4-{(5~chlorothien-2-y)methylJmorpholin-2-yl}methyl)-2-(5-methy}-2- phenyl-1,3-oxazol-4-yl)acetamide; =~ N-{[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-ylJmethyl}-2-(5-methyl-2-phenyl-1,3- oxazol-4-yl)acetamide; :

   - N-{{(2S)-4-[(5-chlorothien-2-yl)methyljmorpholin-2-yl}methyl)-2-[2-(4- fluorophenyl)-5-methyl-1,3-oxazol-4-yllacetamide; N-{[(2S)-4-(4-fluorobenzyl)morpholin-2-yljmethyl}-2-[2-(4-fluorophenyi)-5-methyl- 1,3-oxazol-4-yllacetamide; N-{[(2S)-4~(2,3-dichlorobenzyl)morpholin-2-ylmethyl}-2-[2-(4-fluorophenyl)-5- methyl-1,3-oxazol-4-ylJacetamide; oo co N-({(2S)-4-[(5-chlorothien-2-yl)methyljmorpholin-2-yl}methyl)-2-(2-phenyl-1,3- oxazol-4-yl)acetamide; : : N-{[(2S)-4-(4-fluorobenzyl)morpholin-2-yljmethyl}-2-(2-phenyl-1,3-oxazol-4- yhacetamide; : g N-{[(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yljmethyl}-2-(2-phenyl-1,3-oxazol-4- yl)acetamide; N-{[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yljmethyl}-2-(5-methyl-2-phenyl-1,3- oxazol-4-yl)acetamide; N-{[(2S)-4~(3-chlorobenzyl)morpholin-2-yljmethyf}-2-(5-methyl-2-phenyl-1,3- oxazol-4-yl)acetamide;

   © N-[(2S)-4-(3,4-diflucrobenzyl)morpholin-2-yljmethyl}-2-[2-(4-fluorophenyl}-5- : methyl-1,3-oxazol-4-ylJacetamide; oo . 95 So AMENDED SHEET CLEAN COPY oo

   ; PCT/GB01/04345 ® N-{[(25)-4~(3-chlorobenzy!)morpholin-2-ylJmethyl}-2-[2-(4-fluorophenyl)-5-methyi- 1,3-oxazol-4-ylJacetamide; } N-{[(2S)~4-(3,4-difluorobenzyl)morpholin-2-yljmethyl}-2-(2-phenyl-1,3-oxazol-4- yhacetamide; B N-{[(2S)-4-(3-chlorobenzyl)morpholin-2-yljmethyl}-2-(2-phenyi-1 ,3-0xazol-4- - yhacetamide; N-{[(28)4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-[2-(4-fluorophenyi)-5- methyl-1,3-oxazol-4-yfjacetamide; N-{[(2S)~4-(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-(2-phenyl-1,3-oxazol-4- : yhacetamide; : Co N-cyclopropy-3-[2-({[(2S)-4-(2,3-dichlorobenzy!)morpholin-2-yljmethyljamino)-2- oxoethyllbenzamide; : ~. -

   . 3-{2-{({(25)-4-[(5-chlorothien-2-yl)methylJmorpholin-2-y)methyl)amino}-2- oxoethyl}-N-cyclopropyibenzamide; N-cyclopropyl-3-{2-({{(2S)-4-(4-fluorobenzyl)morpholin-2-yljmethyl}amino)-2- oxoethyilbenzamide; To : 3-[2-({I(25)-4~(3-chlorobenzyl)morpholin-2-yljmethyl}amino)-2-oxoethyl}-N- ~ cyclopropylbenzamide; - N-cyclopropyl-3-[2-({[(2S)-4-(3,4-difluorobenzyl)morpholin-2-yljmethyl}amino)-2- oxoethyllbenzamide; : N-cyclopropyl-3-[2~({[(2S)-4-(3,4-dichiorobenzyl)morpholin-2-yljmethyl}amino)-2- oo oxoethyllbenzamide; . N-{I(25)-4-(2,3-dichlorobenzyl)morpholin-2-yljmethyl}-2-(5-phenyl-2H-tetraazol-2- ° yl)acetamide; : : N-{[(2S)-4-(4-fluorobenzyl)morpholin-2-yllmethyl}-2-(5-phenyl-2H-tetraazol-2- yl)acetamide; Co N-{[(2S)-4-(3-chlorobenzyl)morpholin-2-ylimethyi}-2-(5-phenyl-2H-tetraazol-2- yDacetamide; : N-{[(25)-4~(3,4-diflucrobenzy!)morpholin-2-yljmethyl}-2-(5-phenyl-2H-tetraazol-2- vhacetamide; oo . N-{[(25)-4~(3,4-dichlorobenzyl)morpholin-2-yljmethyl}-2-[5-methyl-2-(3- methyithien-2-yl)-1,3-oxazol-4-ylJacetamide; . N-{I(28)4-(3,4-dichlorobenzyl)morpholin-2-yljmethyf}-2-[2-(1 »3-dimethyl-1H- pyrazol-5-yh)-5-methyl- 1, 3-oxazol-4-ylJacetamide; 2-[2-(3-chlorothien-2-yl)-5-methyl-1,3-oxazol-4-yl]-N-{[(2S)-4-(3.4- dichlorobenzyl)morpholin-2-ylimethyl}acetamide; N-({(28)4-[(5-chlorothien-2-yl)methyljmorpholin-2-yl}methyl)-2-(5-phenyl-2H- tetraazol-2-yl)acetamide; . N-{[(25}-4-(3-cyanobenzyf)morpholin-2-y{Jmethyl}-2-[2-(4-fluorophenyl)-5-methyl- 1,3-oxazol-4-yllacetamide; Co

   96 . _ AMENDED SHEET Co "CLEAN COPY Co

   ~ PCT/GB01/04345 N-{[(2S)-4-(2.1,3-benzoxadiazol-5-yimethyl)morpholin-2-ylimethyl}-2-{2-(4- fluorophenyl)-5-methyl-1,3-oxazol-4-yllacetamide; 2-[2-(4-fluorophenyi)-5-methyl-1,3-oxazol4-yl]-N-{[(25}-4-(2.3.4- triftuorobenzyl)morpholin-2-yljmethyl}acetamide; 2-[2-(4-fluorophenyl)-5-methyl-1 3-oxazol-4-yl]-N-({(25)4-{4-fluoro-3- - (trifluoromethyl)benzylJmorpholin-2-ylimethyl)acetamide; N-{[(25)-4(3 4-dichlofobenzyl)morpholin-2-yjmethyl}-2-{5-methyl-2-[4- (methylsulfonyl)phenyl}-1 ,3-oxazol-4-yljacetamide; NH[(25)4-(3,4-dichiorobenzyl)morpholin-2-yljmethyl}-2-(5-methyl-2-phenyi-1 3 thiazol-4-yl)acetamide; : : : N-{[(25)-4~(3.4-dichlorobenzyl)morpholin-2-yljmethyl}-2-{5-methyl-2-pyrazin-2-yl- 1,3-thiazol-4-yl)acetamide; . : N-({(25)-4-[3-(4~chiorophenyl)propyljmorpholin-2-yjmethy)-2{2-(4-flucrophenyl)- oo 5-methyl-1,3-oxazol-4-ylJacetamide; } ) oo * 2-{2-cyclopropyl-5-methyt-1,3-oxazol-4-yI)-N-{[(2S)-4-(3.4- dichlorobenzyl)morpholin-2-yljmethyf}acetamide; N-{[(2S)-4~(3,4-d ichlorobenzyl)morpholin-2-yllmethyl}-2-(2-isob utyl-5-methyl-1,3- oxazol-4-yl)acetamide; oo N-{[(2S)-4~(3 4-dichlorobenzyl)morpholin-2-ylJmethyl}-2-[S-methyi-2-(2- methylprop-1-enyl)-1,3-oxazol-4-ylJacetamide; N-{(2S)~4~(3,4-dichlorobenzyl)morpholin-2-ylJmethyl}-2-(S-methyl-2-pyridin-2-yi-

   1.3-oxazol-4-yl)acetamide compound with formic acid (1:1); oo N-{[(2S)-4~(3 4-dichiorobenzyhmorpholin-2-yljmethyl}-2-{5-(4-fluorophenyi)-2H- Co tetraazol-2-ylJacetamide; - N-{[(2S)-4~(3.4-Dichlorobenzyl)morpholin-2-yi} methyl}-2-[5-(4-fluorophenyl)-1,2,4- oxadiazol-3-yljacetamide; N-{[(2S)-4-(2,1,3-benzothiadiazol-5-yimethyl)morpholin-2-ymethyl}-2-{2-(4- fiuorophenyl)-5-methyl-1 ,3-oxazol-4-yljacetamide; oo 4-4-2-({[(2S4-(3 4-dichlorobenzyl)morpholin-2-yljmethylJamino)-2-oxoethy]-5- methyl-1 ,3-oxazol-2-yl}-N,N-dimethylbenzamide; : 2-{2-]4-(acetylamino)phenyl}-5-methyi-1 ,3-oxazol-4-y-N-{[(25)-4-(3,4- dichlorobenzyl)morpholin-2-yljmethyl}acetamide; a N-{[(25)-4-(1,2,3-benzothiadiazol-6-yimethyl)morpholin-2-ylmethyl}-2-{2-(4- . fluorophenyl)-5-methyl-1,3-oxazol-4-yllacetamide; : oo N-{(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yJmethyl}pentanamide; N-{[(2S)-4~(3,4-dichlorobenzyl)morpholin-2-yljmethyl-4-methylpentanamide; N-{{4-[3-(3,4-dichlorophenyl)propyllmorpholin-2-yl}methyl)-2-phenoxyacetamide; oo 2-cyclohexyl-N-{[4-(3,4-dichiorobenzyl)morpholin-2-ylmethyllacetamide triflucroacetate; 3 2-(4-chlorophenyl)-N-{[4~(3,4-dichiorobenzyl)morpholin-2-ylimethyf}propanamide; - 3 97 oe . AMENDED SHEET s CLEAN COPY Co .

   PCT/GB01/04345 N-{[4-(3,4-dichlorobenzyl)morpholin-2-ylimethyl}- 2-(1, 1-dioxidothiomorpholin- ® 4-yl)acetamide; 2-[2-(4-fluorophenyl)-5-methyl- 1, 3-oxazol-4-yl]-N-({(2S)-4-[2-(4-fluorophenyl)- 2-oxoethyllmorpholin-2-yl}methyl)acetamide; : N-{{(2S)-4-[(3-chloro- 1-benzothien-2-yl)methyllmorpholin-2-yl}methyl)-2-[2~(4- i fluorophenyl)-5-methyl-1,3-oxazol-4-yllacetamide; 2-[2-(4-fluorophenyl)-5-methyl- 1, 3-oxazol-4-yl]-N-{[{2S)-4-(2-methylprop- 2- enyl)morpholin-2-yllmethyl}acetamide; 2-[2-t4-fluorophenyl)-5-methyi-1, 3-oxazol-4-yl}-N-{[{2S)-4-(1- phenylethyl)morpholin-2-yllmethyl} acetamide; N-{[{28)-4-(3-cyano-4-fluorobenzyl)morpholin-2-yllmethyl}-2-[2-(4- fluorophenyl)-5-methyl- 1, 3-oxazol-4-yllacetamide; N-{[{2S)-4-(3,4-dichlorobenzylimorpholin-2-yllmethyl}-2-[2-(4-fluorophenyl)-5- isopropyl-1,3-oxazol-4-yllacetamide; N-{[{2S5}-4-(3,4-dichlorobenzyl)morpholin-2-yllmethyl} cyclopropane carboxamide; N-({(2S)-4-[2-(3-chiorophenoxy)ethyllmorpholin- 2-yl}methyl)-2-[ 2-(4- : fluorophenyl)-5-methyi-1,3-oxazol-4-yllacetamide; N-{[{2S)-4-(3,4-dichlorobenzoylimorpholin-2-yllmethyl}-2-[ 2-(4-fluorophenyl)- 5-methyl-1,3-oxazol-4-yllacetamide, and; tert-butyl 4-[3-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yllmethyl}amino)-3- oxopropyllpiperidine-1-carboxylate.

   10. A compound of formula (I) according to any one of claims 1 to 9 which is 2-[3-(Aminosulfonyl}phenyl]-N-{[{2S)-4-({3,4- dichlorobenzyl)morpholin-2-ylJmethyl}acetamide or a solvate thereof.

   11. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof in admixture with one or more pharmaceutically acceptable diluents or carriers. :

   12. A compound of formula (I) as defined in any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical.

   13. Use of a compound of formula (1) as defined in any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of inflammatory diseases. AMENDED SHEET

   PCT/GB01/04345

   14. A method of prophylaxis of inflammatory diseases eg. asthma which @ comprises administering to a subject an effective amount of a compound of formula (I) as defined in any one of the preceding claims or a : pharmaceutically acceptable salt or solvate thereof.

   156. A process for preparing a compound of formula (I) as defined in claim 1 which comprises: (a) acylation of a compound of formula (ll) Ho _X_ _O NT » . l, R R a re z (in rR wherein R%, R®% R* RS, X, Z, a and b are as defined in claim 1, with a compound of formula R'COOH or an activated derivative thereof, wherein R’ is as defined in claim 1; or (b}) reacting a compound of formula (HI) 0 Pq X<__© R' NT Qs Ro 3 ( N Rr : H on wherein R’, R?, R® R* X, a and b are as defined in claim 1, with a compound : of formula L'-Z-R®, wherein Z and R® are as defined in claim 1 and L' represents a : suitable leaving group; or (c) . deprotecting a compound of formula (I) which is protected; or {(d) interconversion of other compounds of formula {I}.

   16. A process for preparing a compound of formula (I) as defined in claim 1 which comprises: (e) forming a compound of formula (I) wherein R' represents heteroaryl- Y'-, aryl-(O)-heteroaryl-Y'- or heteroaryl-(O) -heteroaryl-Y'- (wherein said Y’ group is AMENDED SHEET

   PCT/GB01/04345 : attached to heteroaryl via a heterocyclic nitrogen atom) and R? represents hydrogen which comprises reacting a compound of formula (IV)

   o . . 12 J xX © : Ny N~ % , I, , R i 4 wv) oo fs } or a protected derivative thereof wherein R®, RY, RS, X,Y", Z aand b are as defined in claim 1, L? represents a suitable leaving group, such as a halogen . atom eg. bromine and P' represents a solid phase resin bound protecting group, with a heterocyclic compound defined by the R' groups heteroaryl, aryl-(O)- heteroaryl or heteroaryl-(O)heteroaryl above wherein said heteroaryl group, contains at least one NH atom, followed by removal of the solid phase resin : bound protecting group; or (f) - forming a compound of formula (1) wherein Z represents CR®R®(CH,). and R® represents hydrogen which comprises reacting a compound of formula (lil) or . a protected derivative thereof with a compound of formula R®CO(CH.).R®, followed by reduction of the resultant imine; or . (9) forming a compound of formula (I) wherein Z represents CO by reacting a compound of formula (lif) or a protected derivative thereof with a compound of formula R°COOH or an activated derivative thereof.

   17. A compound of formula (IV) } | o 12 J X o : Sy nN" Ya oo - I Ro : NTR z ov) h . Rr? wherein R23, R*, RS, X, Y*, Z, a and b are as defined in claim 1, L2 represents @_ suitable leaving group, such as a halogen atom eg. bromine and P' represents a solid phase resin bound protecting group, or a salt or solvate thereof. 100 :

   oo . AMENDED SHEET CLEAN COPY :

   PCT/GB01/04345

   18. Use of a compound of formula (l) as defined in any one of the @ preceding claims or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a preparation for treatment. : : 19. A substance or composition for use in a method of treatment, said substance or composition comprising a compound of formula (1) as defined in any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof, and said method comprising administering said substance or composition.

   20. A substance or composition for use in a method of treatment or prophylaxis of inflammatory diseases eg. asthma, said substance or composition comprising a compound of formula (I) as defined in any one of the preceding claims or a pharmaceutically acceptable sait or solvate thereof, and said method comprising administering to a subject an effective amount of said substance or composition.

   21. A compound according to any.one of claims 1 to 10, 12 or 17, substantially as herein described and illustrated.

   22. A composition according to claim 12, substantially as herein described and illustrated.

   23. Use according to claim 13 or claim 18, substantially as herein described and illustrated. 24, A method according to claim 14, substantially as herein described and illustrated. :

   25. A process according to claim 15 or claim 16, substantially as herein described and illustrated.

   26. A substance or composition for use in a method of treatment or prophylaxis according to claim 19 or claim 20, substantially as herein described and illustrated.

   27. A new compound, a hew composition, a new use of a compound as claimed in any one of claims 1 to 10, a new non-therapeutic method of treatment, a new process for preparing a compound, or a substance or composition for a new use in a method of treatment or prophylaxis, substantially as herein described. AMENDED SHEET