CHEMICAL COMPOUNDS 635 : PYRIDOPYRIMIDINEDIONES AS PDE4 INHIBITORS

The present invention concerns pyridopyrimidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.

Pharmaceutically active pyridopyrimidine derivatives are disclosed in EP-A- 0260817, WO 98/02162, WO 93/19068 and WO 0045800.

Phosphodiesterases (PDEs) work by converting cAMP or cGMP to AMP and GMP, or the inactive nucleotide forms incapable of activating downstream signalling pathways. The inhibition of PDEs leads to the accumulation of cAMP or cGMP, and subsequent activation of downstream pathways. PDEs comprise a large family of second messengers with 11 families and over 50 isoforms. In addition splice variants have been described for each isoform. The PDEs can be cAMP-specific (PDE4, 7, 8, 10), cGMP specific (PDE5, 6, 9) or have dual specificity (PDEl, 2, 3, 11). cAMP is generated from ATP at the inner leaflet of the plasma membrane through the action of GPCR-regulated adenylate cyclase. Once cAMP is generated, the only way to terminate the signal is through phosphodiesterase action, degrading cAMP into 5'-AMP. Increased concentrations of cAMP are translated into cellular responses mainly by activation of cAMP-dependent protein kinase (PKA). The specific activity of PKA is in part regulated by the sub-cellular localization of PKA, which limits the phosphorylation of PKA to substrates in its near vicinity. The downstream events caused by activation of PKA appear poorly elucidated and involve many components in the initiation of signalling cascades. PDE4s have been shown to have abundant roles in regulating cell desensitisation, adaptation, signal cross-talk, cAMP compartmentalization and feedback loops, and are major regulators of cAMP homeostasis.

The physiological role implicated for elevated cAMP levels include: 1) broad suppression the activity of many imunocompetent cells; 2) induction of airway smooth muscle relaxation; 3) suppression of smooth muscle mitogenesis; and, 4) has beneficial modulatory effects on the activity of pulmonary nerves.

PDE4 has been found to be the predominant cAMP metabolising isozyme family in immune and inflammatory cells and, along with the PDE3 family, a major contributor to cAMP metabolism in airway smooth muscle.

Over the last two decades significant attention has been devoted into the development of PDE4 selective inhibitors for the treatment of inflammatory and immune disorders including asthma, rhinitis, bronchitis, COPD, arthritis and psoriasis. A number of compounds (for example rolipram, tibenelast and denbufylline) have been reported to have impressive effects in animal models of inflammation, especially pulmonary inflammation.

Rolipram Denbufylline

Unfortunately the clinical utility of these inhibitors has been limited by PDE4 related side-effects, including nausea, vomiting and gastric acid secretion. Recently a second generation of PDE4 inhibitors (for example cilomilast, roflumilast and AWD 12- 281) has been described having significantly reduced risk of emetic side effects in animal models of emesis, thus providing the potential for an increased therapeutic ratio.

Cilomilast Roflumilast AWD 12-281

The present invention discloses novel pyridopyrimidine derivatives that are inhibitors of human PDE4 and are thereby useful in therapy.

The present invention provides a compound of formula (I):

wherein: E is N or CE ¹ ; W is (CH ₂ ) _n ; Y is (CH ₂ ) _p ; n and p are, independently 0 or 1;

R ²⁴ is tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl S-oxide or tetrahydrothiopyran-4- yl S-dioxide; or aryl or heteroaryl, each of which is optionally substituted by halogen, cyano, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , OCF ₃ , Ci _-4 alkylthio, S(O)(Ci _-4 alkyl), S(O) ₂ (Ci _-4 alkyl) or C(O) ₂ (Ci _-4 alkyl);

R ² is hydrogen, Ci _-6 alkyl (optionally substituted by heteroaryl), optionally substituted aryl or optionally substituted heteroaryl;

R ¹ is C _1-6 alkyl (optionally substituted by hydroxyl, Ci _-6 alkoxy, aryl, aryloxy, phenyl(Ci- ₆ alkoxy), heteroaryl, C _3-I0 cycloalkyl, CO ₂ H, CO ₂ (Ci _-6 alkyl), NHC(O)O(Ci _-6 alkyl) or NHC(O)R ³ ), C _3-6 cycloalkyl (optionally substituted by hydroxy, Ci _-6 alkyl, phenyl, phenyl(Ci _-6 alkyl), heteroaryl or heteroaryl(Ci _-6 alkyl)), heterocyclyl (optionally substituted by Ci _-6 alkyl, C(O)NH ₂ or phenyl(Ci _-6 alkyl)), aryl or heteroaryl; R ³ is Ci _-6 alkyl or phenyl; the foregoing phenyl, aryl and heteroaryl moieties of R ¹ , R ² and R ³ are, independently, optionally substituted by: halogen, oxo, cyano, nitro, hydroxy, S(O) _q R ⁴ , OC(O)NR ⁵ R ⁶ , NR ⁷ R ⁸ , NR ⁹ C(O)R ¹⁰ , NR ¹¹ C(O)NR ¹² R ¹³ , S(O) ₂ NR ¹⁴ R ¹⁵ , NR ¹⁶ S(O) ₂ R ¹⁷ , C(O)NR ¹⁸ R ¹⁹ , C(O)R ²⁰ , CO ₂ R ²¹ , NR ²² CO ₂ R ²³ , d. ₆ alkyl, Ci _-6 hydroxyalkyl, Ci _-6 haloalkyl, Ci _-6 alkoxy(C _1-6 )alkyl, N(Ci _-6 alkyl)C(O)O(Ci _-6 alkyl), di(Ci _-6 )alkylamino(Ci _-6 )alkyl, heterocyclyl(Ci _-6 alkyl) (optionally substituted by Ci _-6 alkyl or C(O)NH ₂ ), Ci _-6 alkoxy (optionally substituted by C(O)NH ₂ ), di(Ci _-6 )alkylamino(Ci _-6 )alkoxy, heterocyclyl(Ci _-6 alkoxy), Ci _-6 haloalkoxy, Ci _-6 alkoxy(Ci _-6 )alkoxy, hydroxy(Ci _-6 )alkoxy, Ci _-6 alkylthio, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl (itself optionally substituted by

Ci- ₄ alkyl or oxo), C _3-1 O cycloalkyloxy (itself optionally substituted by Ci _-4 alkyl or oxo), methylenedioxy, difluoromethylenedioxy, 1,2-ethylenedioxy, ethyleneoxy, heterocyclyl (optionally substituted by Ci _-6 alkyl or C(O)NH ₂ ), phenyl, phenyl(C _1-4 )alkyl, phenoxy, phenylthio, phenyl(Ci. ₄ )alkoxy, heteroaryl, heteroaryl(C _1-4 )alkyl, heteroaryl(Ci. ₄ alkylthio), heteroaryloxy or heteroary^C^alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(O) ₁ (Ci _-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , cyano, Ci _-4 alkyl, Ci _-4 alkoxy, C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(O)N(Ci _-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(Ci _-4 alkyl), NHS(O) ₂ (Ci _-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ ; E ¹ and G ¹ are, independently, hydrogen, halogen, cyano, hydroxy, Ci _-4 alkyl, Ci _-4 alkoxy, CF ₃ or OCF ₃ ; q and r are, independently, O, 1 or 2;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ are, independently, Ci _-6 alkyl {optionally substituted by halogen, hydroxy, Ci _-6 alkoxy, NH ₂ , NH(Cj _-6 alkyl), N(Ci _-6 alkyl) ₂ or heterocyclyl} , CH ₂ (C _2-6 alkenyl), phenyl {itself optionally substituted by halogen, hydroxy, nitro, NH ₂ , NH(Ci _-4 alkyl), N(Ci _-4 alkyl) ₂ , S(O) ₂ (Ci _-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , cyano, Ci _-4 alkyl, Ci _-4 alkoxy, C(O)NH ₂ , C(O)NH(Cj _-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (Ci _-4 alkyl), NHC(O)(Ci _-4 alkyl), NHS(O) ₂ (Ci _-4 alkyl), C(O)(Ci _-4 alkyl), CF ₃ or OCF ₃ ) or heteroaryl {itself optionally substituted by halogen, hydroxy, nitro, NH ₂ , NH(Ci _-4 alkyl), N(C _1-4 alkyl) ₂ , S(O) ₂ (C _1-4 alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(C _1-4 alkyl), S(O) ₂ N(C _1-4 alkyl) ₂ , cyano, C _1-4 alkyl, C _1-4 alkoxy, C(O)NH ₂ , C(O)NH(C _1-4 alkyl), C(O)N(C _1-4 alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _1-4 alkyl), NHS(O) ₂ (C _1-4 alkyl), C(O)(C _1-4 alkyl), CF ₃ or OCF ₃ ); R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ can also be hydrogen; or a N-oxide thereof; or a pharmaceutically acceptable salt thereof.

Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions. Enantiomerically pure forms are particularly desired. When in solid crystalline form a compound of formula (I) can be in the form of a co-crystal with another chemical entity and the invention encompasses all such co-crystals.

A pharmaceutically acceptable salt of a compound of formula (I) includes a salt prepared from a pharmaceutically acceptable non-toxic base, such as an inorganic or organic base. A salt derived from an inorganic base is, for example, an aluminium, calcium, potassium, magnesium, sodium or zinc salt. A salt derived from an organic base is, for example, a salt of a primary, secondary or tertiary amine, such as arginine, betaine, benzathine, caffeine, choline, chloroprocaine, cycloprocaine, N',N'- dibenzylethylenediamine, diethanolamine, diethylamine, 2-diethyl-aminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylendiamine, N-ethyl-morpholine, N-ethyl piperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, tertiary butylamine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine or thanolamine.

A pharmaceutically acceptable salt of a compound of formula (I) also includes a quaternary ammonium salt, for example where an amine group in a compound of formula (I) reacts with a C _1-1 O alkyl halide (for example a chloride, bromide or iodide) to form a quaternary ammonium salt.

A pharmaceutically acceptable salt also includes a salt of pharmaceutically acceptable organic acid, such as a carboxylic or sulphonic acid, for example: an acetate, adipate, alginate, ascorbate, aspartate, benzenesulphonate (besylate), benzoate, butyrate, camphorate, camphorsulphonate (such as [(lS,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept- l-yl]methanesulfonic acid salt), camsylate, citrate, p-chlorobenzenesulphonate, cyclopentate, 2,5-dichlorobesyalte, digluconate, edisylate (ethane- 1,2-disulfonate or ethane- 1 -(sulfonic acid)-2-sulfonate), esylate, ethanesulphonate, fumarate, formate, 2- furoate, 3-furoate, gluconate, glucoheptanate, glutamate, glutarate, glycerophosphate, glycolate, heptanoate, hexanoate, hippurate, 2-hydroxyethane sulfonate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulphonate, 2- naphthalenesulfonate, napadisylate (naphthalene-l,5-disulfonate or naphthalene- 1- (sulfonic acid)-5-sulfonate), nicotinate, oleate, orotate, oxalate, pantothenate, pamoate, pamoic, pectinate, 3-phenylpropionate, pivalate, propionate, pivolate, pyruvate, saccharinate, salicylate, stearate, succinate, tartrate, p-toluenesulphonate, transcinnamic acid, trifluoroacetate, xinafoate, xinofolate, xylate (p-xylene-2-sulphonic acid), undecanoate, 2-mesitylenesulphonate, 2-naphthalenesulphonate, D-mandelate, L- mandelate, 2,5-dichlorobenzenesulphonate, cinnamate or benzoate; or a salt of an

inorganic acid such as a hydrobromide, hydrochloride, hydroiodide, sulphate, bisulfate, phosphate, nitrate, hemisulfate, thiocyanate, persulfate, phosphate or sulphonate salt. In another aspect of the invention the stoichiometry of the salt is, for example, a hemi- salt, or a mono- or di-salt or tri-salt. A pharmaceutically acceptable salt of a compound of formula (I) can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound or N-oxide with a suitable organic or inorganic acid and isolating the salt thus formed.

Alternatively, a suitable salt can be a quaternary ammonium salt formed by the reaction of a primary, secondary or tertiary amine group in a compound of formula (I) with, for example, a C _1-6 alkyl halide (such as methyl iodide or methyl bromide).

The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.

For example an acid addition salt is a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, malonate, succinate, tartrate, citrate, oxalate, methanesulfonate or/7-toluenesulfonate.

Halogen includes fluorine, chlorine, bromine and iodine. Halogen is, for example, fluorine or chlorine.

Alkyl moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl or tert-butyl. Haloalkyl is, for example C ₂ Fs, CF ₃ or CHF ₂ . Alkoxy is, for example, methoxy or ethoxy; and haloalkoxy is, for example OCF ₃ or OCHF ₂ .

Alkenyl is, for example, vinyl or prop-2-enyl. Alkynyl is, for example, propargyl.

Cycloalkyl is a mono- or bi-cyclic ring systemwhich is saturated or unsaturated but not aromatic. It is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[3.1.1]heptenyl. C _3-7 Cycloalkyl(Ci _-4 alkyl) is, for example, cyclopentylCH ₂ . Cycloalkyloxy is, for example, cyclopropyloxy, cyclopentyloxy or cyclohexyloxy. Cycloalkylalkoxy is, for example, (cyclopropyl)methoxy or 2-(cycloρropyl)ethoxy.

Heterocyclyl is a non-aromatic 5- or 6-membered ring optionally fused to one or more other non-aromatic rings and optionally fused to a benzene ring, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur.

Heterocyclyl is, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isoindolyl, morpholinyl, 3,8-diazabicyclo[3.2.1]octyl, 8-azabicyclo[2.2.2]octyl, 2-oxa-6- azabicyclo[5.4.0]undeca-7,9,l 1-trienyl, 7-oxa-10-azabicyclo[4.4.0]deca-l,3,5-trienyL 6-

thia-l,4-diazabicyclo[3.3.0]octa-4,7-dienyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, 1,2,3,4-tetrahydroquinolinyl, 1 ,4-diazepinyl, quinuclidinyl, 9-oxa-2,8-diazaspiro[4.4]non- 7-enyl, 1 ,2-dihydroquinazolinyl, 2,4,10-triazabicyclo[4.4.0]deca-l,3,5,8-tetraenyl or 2-oxa- 5-aza-bicyclo[4.4.0]deca-7,9,l l-trienyl. Hydroxyalkyl is, for example, CH ₂ OH; Ci _-6 alkoxy(Ci- ₆ )alkyl is, for example

CH3OCH2; and, Ci-6 alkoxy(C] _-6 )alkoxy is, for example, CH ₃ OCH ₂ O. Dialkylaminoalkyl is, for example (CH ₃ ) ₂ NCH ₂ or (CH ₃ )(CH ₃ CH ₂ )NCH ₂ .

Aryl is, for example, phenyl, naphthyl, indanyl or a tetralin (for example 1,2,3,4- tetrahydronaphthyl). For example aryl is phenyl. Heteroaryl is, for example, an aromatic 5- or 6-membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S- dioxide thereof. Heteroaryl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [1,2,3]- thiadiazolyl, [l,2,4]-triazolyl, [l,2,3]-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), indazolyl, benzimidazolyl, 1,2,3-benztriazolyl, benzoxazolyl, 1,3-benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2a]pyridinyl), thieno[3,2-b]pyridin-6-yl, 1,2,3-benzoxadiazolyl (also known as benzo[ 1 ,2,3]thiadiazolyl), 2, 1 ,3-benzothiadiazolyl, benzofurazan (also known as 2,1,3- benzoxadiazolyl), quinoxalinyl, a pyrazolopyridine (for example lH-pyrazolo[3,4- b]pyridinyl or pyrazolo[l,5-a]pyridinyl), an imidazopyridine (for example imidazo[l,2- a]pyridinyl), a dihydropyrido[2,3-d]pyrimidine (for example l,4-dihydropyrido[2,3- d]pyrimidinyl), quinolinyl, isoquinolinyl, a naphthyridinyl (for example [l,6]naphthyridinyl, [l,7]naphthyridinyl or [l,8]naphthyridinyl), 1,2,3-thiadiazolyl, IH- pyrrolo[2,3-b]pyridinyl, thieno[2,3-b]pyridinyl, thieno[2,3-b]pyrazinyl, [l,2,4]triazolo[l,5- a]pyrimidinyl or 6,7-dihydro-5H-[l,3]thiazolo[3,2-a]pyrimidinyl; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.

In one particular aspect the present invention provides a compound of formula (I) wherein the phenyl, aryl and heteroaryl moieties of R ¹ , R ² and R ³ are, independently, optionally substituted by: halogen, oxo, cyano, nitro, hydroxy, S(O) _q R ⁴ , OC(O)NR ⁵ R ⁶ , NR ⁷ R ⁸ , NR ⁹ C(O)R ¹⁰ , NR ¹¹ C(O)NR ¹² R ¹³ , S(O) ₂ NR ¹⁴ R ¹⁵ , NR ¹⁶ S(O) ₂ R ¹⁷ , C(O)NR ¹⁸ R ¹⁹ , C(O)R ²⁰ , CO ₂ R ²¹ , NR ²² CO ₂ R ²³ , Ci _-6 alkyl, Ci _-6 hydroxyalkyl, C _-6 haloalkyl, Ci. ₆

alkoxy(C _1-6 )alkyl, N(Ci _-6 alkyl)C(O)O(C, _-6 alkyl), di(Ci _-6 )alkylamino(Ci _-6 )alkyl, heterocyclyl(Ci _-6 alkyl) (optionally substituted by Ci _-6 alkyl or C(O)NH ₂ ), Ci-6 alkoxy (optionally substituted by C(O)NH ₂ ), di(Ci- ₆ )alkylamino(Ci. ₆ )alkoxy, heterocyclyl(Ci_6 alkoxy), Cj _-6 haloalkoxy, Ci _-6 alkoxy (C i. ₆ )alkoxy, hydroxy(Ci ^alkoxy, Ci-6 alkylthio, C _2-6 alkenyl, C _2-6 alkynyl, C _3-I o cycloalkyl (itself optionally substituted by C _M alkyl or oxo), C _3-I o cycloalkyloxy (itself optionally substituted by Cj _-4 alkyl or oxo), methylenedioxy, difluoromethylenedioxy, 1,2-ethylenedioxy, heterocyclyl (optionally substituted by C _]-6 alkyl or C(O)NH ₂ ), phenyl, phenyl(Ci_ ₄ )alkyl, phenoxy, phenylthio, phenyl(Ci-4)alkoxy, heteroaryl, heteroaryl(Ci_ ₄ )alkyl, heteroaryl(Ci_ ₄ alkylthio), heteroaryloxy or heteroaryl(Ci _-4 )alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(0) _r (Ci_ ₄ alkyl), S(O) ₂ NH ₂ , S(O) ₂ NH(Ci _-4 alkyl), S(O) ₂ N(Ci _-4 alkyl) ₂ , cyano, Ci _-4 alkyl, Ci _-4 alkoxy, C(O)NH ₂ , C(O)NH(Ci _-4 alkyl), C(0)N(C _M alkyl) ₂ , CO ₂ H, CO ₂ (C _1-4 alkyl), NHC(O)(C _-4 alkyl), NHS(O) ₂ (Ci _-4 alkyl), C(O)(Ci _-4 alkyl), CF ₃ or OCF ₃ ; wherein q, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² and R ²³ are as defined above.

In a further aspect the present invention provides a compound of formula (I) wherein R ² is hydrogen, Ci _-6 alkyl, optionally substituted aryl or optionally substituted heteroaryl. In another aspect the present invention provides a compound of formula (I) wherein

E is CE ¹ . E is, for example, CH or CF.

In a further aspect the present invention provides a compound of formula (I) wherein Y and W are both CH ₂ .

In another aspect the present invention provides a compound of formula (I) wherein E ¹ and G ¹ are, independently, hydrogen or halogen (for example fluoro). For example G ¹ is hydrogen. For example E ¹ is fluoro.

In yet another aspect the present invention provides a compound of formula (I) wherein R ²⁴ is tetrahydrothiopyran-4-yl.

In a further aspect the present invention provides a compound of formula (I) wherein R ¹ is Ci _-6 alkyl mono-substituted by phenyl, naphthyl, phenoxy or heteroaryl; the phenyl, naphthyl and heteroaryl moieties being optionally substituted by halogen (such as fluoro or chloro), cyano, hydroxyl (when hydroxyl is on a heteroaryl ring the whole system may tautomerise such that the hydroxyl appears as an oxo group), Cj _-4 alkyl (such as

methyl), Ci _-4 alkoxy (such as methoxy), CF ₃ , phenyl, phenylthio, heteroaryl, phenyl(Ci _-2 alkyl), C3-6 cycloalkyl, C _3-6 cycloalkyloxy, methylenedioxy, difluoromethylenedioxy, 1,2- ethylenedioxy, ethyleneoxy or NHR*; R* is Ci _-6 alkyl optionally substituted by N(C _M alkyl) ₂ ; wherein the immediately foregoing phenyl and heteroaryl moieties are optionally substituted by halogen (such as fluoro or chloro), cyano, hydroxyl, Ci _-4 alkyl (such as methyl) or C _M alkoxy (such as methoxy).

In another aspect the present invention provides a compound of formula (I) wherein heteroaryl is thiazolyl, pyrazolyl, imidazolyl, pyridinyl, benzo[b]furyl (also known as benzfuryl), benzimidazolyl, 1,3-benzthiazolyl, imidazo[l,2a]pyridinyl) or quinolinyl. In a still further aspect the present invention provides a compound of formula (I) wherein R ¹ is benzyl or (CH ₂ )heteroaryl; the phenyl and heteroaryl moieties being optionally substituted by halogen (such as fluoro or chloro), cyano, hydroxyl, CM alkyl (such as methyl), C _M alkoxy (such as methoxy), phenyl or phenyl(CH ₂ ); wherein the immediately foregoing phenyl moieties are optionally substituted by halogen (such as fluoro or chloro) or cyano.

In yet another aspect the present invention provides a compound of formula (I) wherein heteroaryl is imidazolyl, pyridinyl, imidazo[l,2a]pyridinyl) or quinolinyl.

In a still further aspect the present invention provides a compound of formula (I) wherein R ¹ is Ci _-6 alkyl (optionally substituted by hydroxy, aryl, C _3-7 cycloalkyl, CO ₂ (C] _-6 alkyl) or NHC(O)R ³ ), aryl or heteroaryl (for example pyridyl, benzimidazolyl, furyl or 1,4- dihydropyrido[2,3-d]pyrimidinyl); and R ³ is phenyl. Aryl is, for example, phenyl.

In another aspect the present invention provides a compound of formula (I) wherein the foregoing phenyl, aryl and heteroaryl moieties of R ¹ and R ³ are, independently, optionally substituted by: halogen, hydroxy, CO ₂ (Ci-O alkyl), Ci _-6 alkyl, C] _-6 hydroxyalkyl or C i-6 alkoxy.

In yet another aspect the present invention provides a compound of formula (I) wherein R ¹ is heterocyclyl (optionally substituted by Ci _-6 alkyl), for example R ¹ is pyrrolyl, piperidinyl or morpholinyl, each optionally substituted by Ci _-6 alkyl (such as methyl or ethyl). In another aspect the present invention provides a compound of formula (I) wheein

R ² is hydrogen or CH ₂ (heteroaryl); the heteroaryl being optionally substituted by halogen, hydroxy, CO ₂ (Ci _-6 alkyl), Ci _-6 alkyl, Ci _-6 hydroxyalkyl or Ci _-6 alkoxy (for example the

heteroaryl is optionally substituted by halo, such as fluoro). In yet another aspect R ² is hydrogen. The heteroaryl of R ² is, for example, imidazo[l,2-a]pyridinyl.

Compounds of the invention are described in the Examples. Each of the compounds of the Examples is a further aspect of the present invention; and, a pharmaceutically acceptable salt of each of the compounds of the Examples is a still further aspect of the present invention

The compounds of the present invention can be prepared as described below, by using or adapting the methods described in the Examples, or by using or adapting methods known in the art. Intermediates are either know in the art or can be prepared by using or adapting methods described in the art.

In a further aspect the invention provides a process for the preparation of a compound of formula (I) wherein R ² is hydrogen and R ¹ is CH ₂ -R", where R" is the remainder of the R ¹ group, which comprises removing the Boc protecting group from a compound of formula (II)

wherein G ¹ , E, Y, W and R ²⁴ are as defined in formula (I), (for example with an acid such as trifluoroacetic acid or hydrochloric acid) and reacting the product so formed with a suitable carbaldehyde R"CH(O) wherein R" is as defined above, in a suitable solvent (such as methanol or N-methyl-pyrrolidinone), in the presence of an acid catalyst (such as acetic acid), optionally in the presence of trimethyl orthoformate, and then adding a suitable reducing agent (such as a borohydride, for example sodium cyanoborohydride or sodium triacetoxyborohydride); the process being conducted at room temperature (such as from 0- 3O ⁰ C).

A compound of formula (II) wherein G ¹ , E, Y, W and R ²⁴ are as defined in formula (I), can be prepared by condensing a compound of formula (IV):

wherein G ¹ , E, Y, W and R ²⁴ are as defined in formula (I), with a suitable carbonylating agent such as carbonyl diimidazole or ethyl chlorformate in the presence of a suitable base such as sodium hydride. The process is carried out at a suitable temperature, generally between 0 ⁰ C and the boiling point of the solvent, in a suitable solvent such as tetrahydrofuran.

A compound of formula (IV) wherein G ¹ , E, Y, W and R ²⁴ are as defined in formula (I), can be prepared by reacting a compound of formula (V):

wherein R ²⁴ , G ¹ and E are as defined in formula (I), with an amine of formula (VI)

wherein Y and W are as defined in formula (I). The process is carried out at a suitable temperature, generally between 0 ⁰ C and the boiling point of the solvent, in a suitable solvent such as dichloromethane. The process is optionally carried out in the presence of a base and a coupling reagent such as HATU, HOAT, HOBT or DIEA.

A compound of formula (V) wherein m, G ¹ and E are as defined in formula (I), can be prepared by reacting a compound of formula (VII):

(VII)

wherein G and E are as defined in formula (I) and Hal represents a halogen atom, with R ²⁴ -NH2. The process is carried out at a suitable temperature, generally between 50 °C and the boiling point of the solvent, in a suitable solvent such as dimethylformamide. The process is optionally carried out in the presence of a base such as potassium carbonate. The preparations of various intermediates are described in the literature or can be prepared by routine adaptation of methods described in the literature.

In the above processes it may be desirable or necessary to protect an acid group or a hydroxy or other potentially reactive group. Suitable protecting groups and details of processes for adding and removing such groups may be found in "Protective Groups in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts.

In another aspect the present invention provides processes for the preparation of compounds of formula (I).

The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of PDE 4 receptor activity, and may be used in the treatment of inflammatory diseases, asthma or COPD.

Examples of disease states that can be treated with a comkpound of the invention are:

1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due

to respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus; or eosinophilic esophagitis;

2. bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; osteoporosis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;

3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthritides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis); 4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,

pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber- Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;

5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo- vaginitis; Peyronie's disease; erectile dysfunction (both male and female);

9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;

10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;

11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;

12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes;

13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; or,

15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.

According to a further feature of the present invention there is provided a method for treating a PDE 4 mediated disease state in a mammal, such as man, suffering from, or at risk of, said disease state, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. In another aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy (for example modulating PDE 4 enzymatic activity).

The invention further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:

1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust- induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus; or eosinophilic esophagitis;

2. bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; osteoporosis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including

idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle- Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;

3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthritides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis); 4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber- Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;

5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory- disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;

6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);

7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and thinner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);

9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;

11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;

12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes; 13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as

Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; or, 15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema; in a mammal (for example man).

In a further aspect the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; or COPD.

In a still further aspect a compound of formula (I), or a pharmaceutically acceptable salt thereof, is useful in the treatment of COPD. The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper- responsiveness)}; or COPD. In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of a mammal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.

In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will, for example, comprise from 0.05 to 99 %w (per cent by weight), such as from 0.05 to 80 %w, for example from 0.10 to 70 %w, such as from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), inhalation, oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art. A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.

Each patient may receive, for example, a dose of 0.001 mgkg ^"1 to 100 mgkg ^"1 , for example in the range of 0.1 mgkg ^'1 to 20 mgkg ^'1 , of the active ingredient administered, for example, 1 to 4 times per day.

The invention further relates to a combination therapy wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with agents listed below. Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including nonselective cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist

or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline. In addition the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl ,

CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX ₃ CRl for the C-X ₃ -

C family.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; for example collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-11) and MMP-9 and MMP- 12, including agents such as doxycycline. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the phenothiazin-3-yls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agent including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine,

glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically- applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a

fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agents, paracetamol, or a non-steroidal anti-inflammatory agent. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof. A compound of the present invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subl. - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiϋ) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK.subl. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of p38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS; or (xxviii) a glucocorticoid receptor (GR-receptor) agonist.

In a further embodiment the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore described, and at least one further active ingredient selected from:-

• a β2. adrenoceptor agonist,

• a modulator of chemokine receptor function, • an inhibitor of kinase function,

• a protease inhibitor,

• a steroidal glucocorticoid receptor agonist,

• an anticholinergic agent, and a

• a non-steroidal glucocorticoid receptor agonist.

The pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture. Alternatively, the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof. The pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.

Examples of a β ₂ -adrenoceptor agonist that may be used in the pharmaceutical product according to this embodiment include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate), pirbuterol or indacaterol. The β ₂ -adrenoceptor agonist of this embodiment may be a long-acting β ₂ -agonists, for example salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g. as hydrochloride), carmoterol (TA 2005, chemically identified as 2(1H)-Quinolone, 8- hydroxy-5-[ 1 -hydroxy-2-[[2-(4-methoxy-phenyl)- 1 -methylethyl] -amino] ethyl] - monohydrochloride, [R-(R* ,R*)] also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S. Patent No 4,579,854), indacaterol (CAS no 312753-06-3; QAB-149), formanilide derivatives e.g. 3-(4-{[6-({(2R)-2-[3- (formylamino)-4-hydroxyphenyl]-2-hydroxyethyl} amino)hexyl]oxy} -butyl)- benzenesulfonamide as disclosed in WO 2002/76933, benzenesulfonamide derivatives e.g. 3-(4- { [6-( {(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethyl} amino)- hexyl]oxy}butyl)benzenesulfonamide as disclosed in WO 2002/88167, aryl aniline receptor agonists as disclosed in WO 2003/042164 and WO 2005/025555, indole derivatives as disclosed in WO 2004/032921 and US 2005/222144, and compounds GSK 159797, GSK 159802, GSK 597901, GSK 642444 and GSK 678007.

Examples of a modulator of chemokine receptor function that may be used in the pharmaceutical product according to this embodiment include a CCRl receptor antagonist. Examples of an inhibitor of kinase function that may be used in the pharmaceutical product according to this embodiment include a p38 kinase inhibitor and an IKK inhibitor.

Examples of a protease inhibitor that may be used in the pharmaceutical product according to this embodiment include an inhibitor of neutrophil elastase or an inhibitor of MMP12.

Examples of a steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17- propionate or 17,21-dipropionate esters), ciclesonide, loteprednol (as e.g. etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g. as acetonide), flunisolide, zoticasone, flumoxonide, rofleponide, butixocort (e.g. as propionate ester), prednisolone, prednisone, tipredane, steroid esters e.g. 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-l lβ-hydroxy- 16α-methyl-3-oxo-androsta-l,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α,9α- difluoro- 11 β-hydroxy- 16α-methyl-3-oxo- 17α-propionyloxy-androsta- 1 ,4-diene- 17β- carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester and 6α,9α-difluoro-l lβ-hydroxy- 16α-methyl- 17α-[(4-methyl- 1 ,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta- 1 ,4-diene- 17β- carbothioic acid S-fluoromethyl ester, steroid esters according to DE 4129535, steroids according to WO 2002/00679, WO 2005/041980, or steroids GSK 870086, GSK 685698 and GSK 799943. Examples of an anticholinergic agent that may be used in the pharmaceutical product according to this embodiment include for example a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a M3 antagonist) for example ipratropium (e.g. as bromide), tiotropium (e.g. as bromide), oxitropium (e.g. as bromide), tolterodine, pirenzepine, telenzepine, glycopyrronium bromide (such as R,R- glycopyrronium bromide or a mixture of R,S- and S,R-glycopyrronium bromide); mepensolate (e.g. as bromide), a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2- dithien-2-ylacetoxy)- 1 -(3 -phenoxypropy I)- 1 -azonia-bicyclo [2.2.2] octane bromide as disclosed in US 2003/0055080, quinuclidine derivatives as disclosed in WO 2003/087096 and WO 2005/115467 and DE 10050995; or GSK 656398 or GSK 961081. Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include those described in WO2006/046916.

A compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a

nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5 α-reductase such as finasteride;

(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erb b2 antibody trastuzumab, or the anti-erb bl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyi)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-a mine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;

(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);

(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or, (ix) an agent used in an immunotherapeutic approach, for example ex- vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:

The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: (i) when given, ¹ H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300MHz or 400MHz using perdeuterio DMSO-D6 (CD ₃ SOCD ₃ ) or CDCI ₃ as the solvent unless otherwise stated; (ii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe. Where indicated ionisation was effected by electrospray ionisation (ES), or atmospheric pressure chemical ionisation (APCI), or multimode ionisation, a combination of ES ionisation and APCI. Where values for m/z are given, generally only ions which indicate the parent mass are reported, and the mass ions quoted are the positive or negative mass ions: [M] ⁺ , [M+H] ⁺ or [M-H] ^' ; (iii) the title and sub-title compounds of the examples and methods were named using the index name program from Advanced Chemistry Development Inc, version 8.00 or were named using the index name program from Ogham and stereochemical descriptors added by hand. (See www.evcsopcn.com/products/applications/ogham.html)

(iv) unless stated otherwise, reverse phase HPLC was conducted using a Symmetry™, NovaPak™ or Xterra™ reverse phase silica column, all available from Waters Corp. (vi) the following abbreviations are used:

The starting materials for the Examples below are either commercially available or readily prepared by standard methods from known starting materials (The compounds are named using the index name program from Advanced Chemistry Development Inc, version 8.00)

Preparation 1

5-Fluoro-2-(tetrahydro-2H-thiopyran-4-yl acid.

2-Chloro-5-fluoronicotinic acid (5.27 g, 30 mmol), K ₂ Cθ ₃ (5 g, 36 mmol) was added to dry DMF (30 ml) under argon atmosphere. Copper (95 mg, 1.8 mmol), methanol- washed dried copper(I)bromide (215 mg, 1.5 mmol) and tetrahydro-2H-thiopyran-4-amine (6 g, 51 mmol) were added and the mixture was stirred at 150 ⁰ C for four hours. Ethyl

acetate was added and the crude product was washed twice with 0.5 M aqueous citric acid, the organic solvents dried over Na ₂ SO ₄ , filtrated and removed in vacuum to afford the title compound (6 g, 78 %).

¹ H NMR (400 MHz, DMSO-^): δ 13.43 (IH, brs), 8.31 (IH, d), 7.97 (IH, brd), 7.91 (IH, dd), 3.99 (IH, brs), 2.76-2.61 (4H, m), 2.21 (2H, m), 1.64-1.53 (2H, m). APCI-MS m/z: 257 [MH ⁺ ].

Preparation 2 tert-Butyl [cw-4-({[5-fluoro-2-(tetrahydro-2H-thiopyran-4-ylamino)pyrid in-3- yl]carbonyl} amino)cyclohexyl]carbamate.

A mixture of 5-fluoro-2-(tetrahydro-2H-thiopyran-4-ylamino)nicotinic acid (5.9 g, 23 mmol), tert-butyl (cώ-4-aminocyclohexyl)carbamate (5.42 g, 25.3 mmol), HATU (9.6 g, 25.3 mmol), HOAT (3.44 g, 25.3 mmol) and DIEA (12 ml, 70 mmol) in NMP (100 ml) was stirred for 10 min at room temperature (at pH 8-9 adjusted with DIEA). Ethyl acetate was added and the crude product was washed twice with 0.5 M aqueous citric acid, aqueous sodium hydrogencarbonate and water. The organic solvents dried over Na ₂ SO ₄ , filtrated and removed in vacuum. The residue was purified by flash chromatography on silica using ethyl acetate/heptane (1:3) as eluent to give the title compound (8.45 g, 81 %). ¹ H NMR (400 MHz, DMSO-^ ₆ ): δ 8.22 (IH, d), 8.17 (IH, brd), 8.16 (IH, brd),

7.96 (IH, dd), 6.61 (IH, brs), 3.92 (IH, brs), 3.77 (IH, brs), 3.40 (IH, brs), 2.74-2.60 (4H, m), 2.18 (2H, m), 1.70 (4H, m), 1.54 (6H, m), 1.39 (9H, s).

APCI-MS m/z: 453 [MH ⁺ ].

Preparation 3 tert-Buty 1 {cis-4- [6-fluoro-2 ,4-dioxo- 1 -(tetrahydro-2H-thiopyran-4-yl)- 1 ,4- dihydropyrido[2,3-d]pyrimidin-3(2H)-yl]cyclohexyl} carbamate.

To a solution of tert-butyl [cw-4-({[5-fluoro-2-(tetrahydro-2H-thiopyran-4- ylamino)pyridin-3-yl]carbonyl}amino)cyclohexyl]carbamate (3.9 g, 8.58 mmol) and 1,1'- carbonyldiimidazole (4.17 g, 25.7 mmol) in dry NMP (100 ml) under an argon atmosphere was added 50% NaH in oil (1.24 g, 25.7 mmol) in ten portions over a period of an hour. The mixture was stirred at room temperature for two days. Ethyl acetate was added and the crude product was washed twice with 0.5 M aqueous citric acid, aqueous sodium hydrogencarbonate, and water. The organic solvents were dried over Na ₂ SO ₄ , filtered and concnetrated in vacuo. The residue was purified by flash chromatography on silica using ethyl acetate/heptane (1:4) as eluent to give the title compound (1.95 mg, 48 %) and 0.9 g (23%) of recovered starting material.

¹ U NMR (400 MHz, DMSO-^): δ 8.78 (IH, d), 8.21 (IH, dd), 6.58 (IH, brs), 5.20 (IH, brs), 4.72(1H, bit), 3.56 (IH, brs), 2.84-2.68 (6H, m), 2.58 (2H, q), 2.01-1.86 (4H, m), 1.49 (2H, bit), 1.42 (HH, brs).

APCI-MS m/z: 379 [MH ⁺ - tBOC].

Preparation 4

3-(cz5-4-Aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiop yran-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione hydrochloride.

A mixture of tert-butyl {c/s-4-[6-fluoro-2,4-dioxo-l-(tetrahydro-2H-thiopyran-4- yl)-l,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl]cyclohexyl}ca rbamate (0.36 g, 0.75

mmol) and 4 M HCl in 1,4-Dioxane (10 ml) was stirred at room temperature for one hour. The solvents were removed and the pure crude product was used directly. APCI-MS m/z: 379 [MH ⁺ ].

Example 1

6-fluoro-3- {cis-4-[(imidazo[ 1 ,2-a]pyridin-2-ylmethyl)amino]cyclohexyl} - 1 -(tetrahydro- 2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidine-2,4( 1 H,3H)-dione.

3-(cis-4-aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiop yran-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (26 mg, 0.06 mmol), imidazo[l,2-a]pyridine-2- carbaldehyde (11 mg, 0.075 mmol) and acetic acid (one drop) were dissolved in methanol (1 ml) and the mixture stirred at room temperature for 30 min. Sodium cyanoborohydride (6.48 mg, 0.1 mmol) was then added and the reaction mixture was stirred at room temperature overnight.

Reaction was subsequently repeated on larger scale: 3-(cis-4-aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiopyra n-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (180 mg, 0.476 mmol), imidazo[l,2-a]pyridine-2- carbaldehyde (76.5 mg, 0.524 mmol) and acetic acid (28.58 mg, 27.25 ul, 0.476 mmol) were dissolved in methanol (10 ml) and the mixture stirred at room temperature for 30 min. Sodium cyanoborohydride (45 mg, 0.714 mmol) was then added and the reaction mixture was stirred for 2h.

The two reactions were combined, and the solvents evaporated. The residue was partitioned between ethyl acetate and water, and the combined organic extracts were dried (anhydrous sodium sulphate), filtered and evaporated. The crude material (141mg) was purified by reverse phase HPLC (25-95% acetonitrile in aqueous ammonia) to afford the title compound (44 mg, 18%) and the bis compound 3-{cis-4-[bis(imidazo[l,2-a]pyridin-2-

ylmethyl)amino]cyclohexyl} -6-fluoro- 1 -(tetrahydro-2H-thiopyran-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (Example 2) (7 mg, 2%).

¹ H NMR (400 MHz, DMSO-J ₆ ): δ 8.77 (d, IH), 8.51 (d, IH), 8.22 (dd, IH), 7.85 (s, IH), 7.48 (d, IH), 7.19 (td, IH), 6.84 (t, IH), 5.21 (broad s, IH), 4.79 - 4.72 (m, IH), 3.83 (d, 2H), 3.32 - 3.29 (m, IH), 2.81 - 2.71 (m, 8H), 1.97 - 1.87 (m, 4H), 1.51 - 1.44 (m, 2H), 1.38 - 1.33 (m, 2H) APCI (Multimode) m/z: 509 [M+H] (for Example 1)

Example 2 3- {cis-4-[bis(imidazo[ 1 ,2-a]pyridin-2-ylmethyl)amino]cyclohexyl} -6-fluoro- 1 -

(tetrahydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidine-2,4 (lH,3H)-dione.

This compound was a by-product from the reaction above (Example 1).

¹ H NMR (400 MHz, DMSO-J ₆ ): δ 8.80 (s, IH), 8.58 (d, 2H), 8.34 (dd, IH), 8.10 (s, 2H), 7.50 (d, 2H), 7.19 (t, 2H), 6.86 (t, 2H), 4.96 - 4.84 (m, IH), 4.01 (s, 2H), 2.97 - 2.77 (m,

6H), 2.60 - 2.52 (m, 4H), 2.40 - 2.33 (m, 4H), 2.05 - 1.99 (m, 2H), 1.50 - 1.35 (m, 4H)

APCI (Multimode) m/z: 639 [M+H]

Example 3

6-fluoro-3-(cis-4-{[2-(2-hydroxyethoxy)benzyl]amino}cyclo hexyl)-l-(tetrahydro-2H- thiopyran-4-yl)pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione.

2-(2-Hydroxy-ethoxy)-benzaldehyde (66 mg, 0.4 mmol) was dissolved in NMP (2 ml) and 3-(cis-4-aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiopyra n-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (150 mg, 0.4 mmol) was added, followed by acetic acid (24 mg, 23 ul, 0.4 mmol), and trimethyl orthoformate (504 mg, 0.52 ml, 4.75 mmol), and the mixture was stirred at room temperature for Ih. Sodium triacetoxyborohydride (186 mg, 1 mmol) was added and the reaction mixture allowed to stir at room temperature overnight. The mixture was concentrated in vacuo and the residue adsorbed onto SCX resin, washing with methanol then eluting with 20% aqueous ammonia in methanol. The solvents were evaporated and the residue was purified by reverse phase HPLC (25-95% acetonitrile in aqueous ammonia) to afford the title compound (70 mg, 33%). ¹ H NMR (300 MHz, DMSO-J ₆ ): δ 8.77 (d, IH), 8.21 (dd, IH), 7.33 (d, IH), 7.21 (dd, IH), 6.99 - 6.89 (m, 2H), 5.20 (s, IH), 4.91 (s, IH), 4.74 (t, IH), 4.04 (t, 2H), 3.76 - 3.69 (m, 4H), 2.84 - 2.66 (m, 9H), 1.97 (s, 2H), 1.89 - 1.76 (m, 3H), 1.48 - 1.30 (m, 4H) APCI (Multimode) m/z: 529 [M+H]

Example 4

6-fluoro-3-(cis-4-{[4-(2-morpholin-4-ylethoxy)benzyl]amin o}cyclohexyl)-l-(tetrahydro- 2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione.

4-(2-Morpholin-4-yl-ethoxy)-benzaldehyde (93 mg, 0.4 mmol) was dissolved in NMP (2 ml) and 3-(cis-4-aminocyclohexyl)-6-fluoro- 1 -(tetrahydro-2H-thiopyran-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (150 mg, 0.4 mmol) was added, followed by acetic acid (24 mg, 23 ul, 0.4 mmol), and trimethyl orthoformate (504 mg, 0.52 ml, 4.75 mmol), and the reaction mixture was stirred at room temperature for Ih. Sodium triacetoxyborohydride (186 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue adsorbed onto SCX resin washing with methanol then eluting with 20% aqueous ammonia in methanol. The solvents were evaporated and the residue was purified by reverse phase HPLC (25-95% acetonitrile in aqueous ammonia) to afford the title compound (85 mg, 36%).

¹ H NMR (300 MHz, DMSO-J ₆ ): δ 8.76 (s, IH), 8.22 (d, IH), 7.29 (d, 2H), 6.90 (d, 2H), 5.20 (s, IH), 4.74 (t, IH), 4.07 (t, 2H), 3.64 - 3.57 (m, 6H), 2.85 - 2.67 (m, HH), 2.49 - 2.45 (m, 3H), 2.03 - 1.82 (m, 4H), 1.75 - 1.64 (m, IH), 1.46 - 1.30 (m, 4H) APCI (Multimode) m/z: 598 [M+H]

Example 5

3- {cis-4-[(l -benzylpiperidin-3-yl)amino]cyclohexyl} -6-fluoro- 1 -(tetrahydro-2H-thiopyran- 4-yl)pyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione.

l-Benzyl-piperidin-3-one (89 mg, 0.4 mmol) was dissolved in NMP (2 ml) and 3-(cis-4- aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiopyran-4-yl)py rido[2,3-d]pyrimidine- 2,4(1 H,3H)-dione (150 mg, 0.4 mmol) was added, followed by acetic acid (24 mg, 23 ul, 0.4 mmol) and trimethyl orthoformate (504 mg, 0.52 ml, 4.75 mmol), and the reaction mixture was stirred at room temperature for Ih. Sodium triacetoxyborohydride (186 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue adsorbed onto SCX resin washing with methanol then eluting with 20% aq. ammonia in methanol. The solvents were evaporated and the residue was purified by reverse phase HPLC (25-95% acetonitrile in aqueous ammonia) to afford the title compound (23mg, 10%).

¹ H NMR (300 MHz, DMSO-J ₆ ): δ 8.77 (d, IH), 8.23 (d, IH), 7.37 - 7.26 (m, 4H), 7.27 - 7.22 (m, IH), 5.32 (t, IH), 4.77 (s, IH), 3.16 (d, IH), 2.87 - 2.68 (m, 6H), 2.63 - 2.58 (m, 2H), 2.45 - 2.37 (m, 3H), 2.00 - 1.90 (m, 3H), 1.85 - 1.59 (m, 5H), 1.50 - 1.39 (m, 3H), 1.34 - 1.27 (m, 3H), 1.21 - 1.13 (m, 2H), 1.09 - 1.05 (m, IH) APCI (Multimode) m/z: 552 [M+H]

Example 6

6-fluoro-3-(cis-4- {[(6-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)methyl]amino} cyclohexyl)- 1 - (tetrahydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidine-2,4(lH ,3H)-dione.

Step (a) 6-fluoroimidazo[l,2-a]pyridin-2-yl)methanol.

6-Fluoro-imidazo[l,2-a]pyridine-2-carboxylic acid (900 mg, 5 mmol) was suspended in THF (10 ml) and IM borane/THF solution (25 ml, 25 mmol) added. The reaction was heated at reflux for 3h, cooled to room temperature. Methanol (20 ml) added and mixture heated at reflux for a further Ih. The solvent was removed by evaporation, and the residue dissolved in methanol (25ml). Concentrated hydrochloric acid (5 ml) was added and the mixture heated at reflux for Ih. Mixture cooled to room temperature and purified by adsorbing onto SCX resin, washing with methanol, then eluting with aqueous ammonia in methanol, and the solvent evaporated to give the sub-title compound. This was used without further purification

¹ H NMR (400 MHz, DMSO-^ ₅ ): δ 8.73 (ddd, IH), 7.73 - 7.90 (m, IH), 7.52 (dd, IH), 7.16 - 7.38 (m, IH), 5.20 (t, IH), 4.58 (d, 2H)

Step (b) 6-fluoroimidazo[l,2-a]pyridine-2-carbaldehyde.

6-fluoroimidazo[l,2-a]pyridin-2-yl)methanol was dissoved in DCM (20 ml) and manganese dioxide (5 g, 57 mmol) added and the reaction mixture heated at reflux for Ih. Mixture cooled to room temperature and filtered through celite, the filtrate evaporated and the residue purified by flash chromatography on silica using hexane:ethyl acetate (3:1) as eluent to afford the sub-title compound (170 mg, 20%).

¹ HNMR (300 MHz, DMSO-^ ₅ ): δ 10.03 (s, IH), 8.84 (dd, IH), 8.61 (d, IH), 7.67 - 7.92 (m, IH), 7.35 - 7.62 (m, IH)

Step (c) 6-fluoro-3-(cis-4-{[(6-fluoroimidazo[l,2-a]pyridin-2-yl)meth yl]amino}cyclo hexyl)-l-(tetrahydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidi ne2,4(lH,3H)-dione.

3-(cis-4-aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiop yran-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (180 mg, 0.48 mmol), 6-fluoro-imidazo[l,2-a]pyridine-2- carbaldehyde (75 mg, 0.46 mmol), and acetic acid (275 ul, 4.5 mmol) were dissolved in methanol (10 ml) and stirred at room temperature for 30 min. Sodium cyanoborohydride (45 mg, 0.71 mmol) was added and the reaction stirred for a further Ih. The solvent was removed by evaporation and the residue pardoned between ethyl acetate and water. The organic extract was separated and evaporated. The residue was purified by reversed phase HPLC (35-65% acetonitrile in aqueous ammonia) to afford the title compound (65 mg,

¹ H NMR (300 MHz, DMSO-J ₆ ): δ 8.77 (d, 2H), 8.21 (dd, IH), 7.88 (s, IH), 7.55 (dd, IH), 7.28 (t, IH), 5.20 (s, IH), 4.74 (d, IH), 3.84 (s, 2H), 2.61 - 2.94 (m, 9H), 1.79 - 2.03 (m, 5H), 1.20 - 1.60 (m, 4H) APCI (Multimode) m/z: 527 [M+H]

Example 7

3-(cis-4- {bis[(6-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)methyl]amino} cyclohexyl)-6-fluoro- 1 - (tetrahydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidine-2,4(lH ,3H)-dione.

3-(cis-4-aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiopyra n-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (180 mg, 0.476 mmol), 6-fluoro-Imidazo[l,2-a]pyridine-2- carbaldehyde (200 mg, 1.22 mmol) and acetic acid (28.58 mg, 27.25 ul) was dissolved in dichloroethane (10 ml) and stirred at room temperature for 30 min. Sodium

triacetoxyborohydride (210 mg, 1 mmol) was added and the reaction mixture was stirred for 16h. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The combined organic extracts were dried (anhydrous sodium sulphate), filtered and evaporated. The residue was purified using prep HPLC (25-95% acetonitrile in aqueous ammonia) to afford the title compound (45 mg, 14%).

¹ H NMR (400 MHz, DMSO-^): δ 8.79 (t, 3H), 8.37 (dd, IH), 8.11 (s, 2H), 7.58 (dd, 2H),

7.28 (dddd, 2H), 5.30 (s, IH), 4.88 (m, IH), 3.98 (s, 4H), 2.83 (m, 9H), 2.36 (m, 2H), 2.02

(m, 2H), 1.43 (m, 4H)

APCI (Multimode) m/z: 675 [M+H]

Example 8 3 -(cis-4- { [(6-chloroimidazo[ 1 ,2-a]pyridin-2-yl)methyl]amino} cyclohexyl)-6-fluoro- 1 -

(tetrahydro-2H-thiopyr -dione.

Step (a) 6-chloroimidazo[l,2-a]pyridine-2-carbaldehyde

6-Chloro-imidazo[l,2-a]pyridine-2-carboxylic acid (0.4 g, 2 mmol) was dissolved in dry THF (10 ml) and 1.0M borane/THF solution (5 ml, 5 mmol) was added, and the mixture heated at reflux for 2h. Mixture was quenched with methanol (2 ml), acidified with 3 drops of concentrated hydrochloric acid and heated at reflux for 15 min. The mixture was then adsorbed on to SCX resin, washed well with methanol and the crude alcohol intermediate eluted with 10% aqueous ammonia in methanol. This intermediate (0.4 g, 2.2 mmol) was mixed with manganese dioxide (2 g, 23 mmol) in dichloromethane (50 ml) and was heated at reflux for 30 min. The inorganics were removed by filtration and the filtrate evaporated to dryness to afford the sub-title compound (0.32 g, 89%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 10.22 (s, IH), 8.33 (s, IH), 8.09 (s, IH), 7.64 (d, IH), 7.27 (dd, IH)

Step (b) 3-(cis-4- { [(6-chloroimidazo[ 1 ,2-a]pyridin-2-yl)methyl]amino} cyclohexyl)-6- fluoro-l-(tetrahydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidi ne-2,4(lH,3H)-dione 3-(cis-4-aminocyclohexyl)-6-fluoro-l-(tetrahydro-2H-thiopyra n-4-yl)pyrido[2,3- d]pyrimidine-2,4(lH,3H)-dione (160 mg, 0.42 mmol), 6-chloro-imidazo[l,2-a]pyridine-2- carbaldehyde (76.5 mg, 0.425 mmol ) and acetic acid (28.58 mg, 27.25 ul) were dissolved in methanol (10 ml) and stirred at room temperature for 30 min. Sodium cyanoborohydride (449 mg, 7.12 mmol) was added and the reaction mixture was stirred for 2h. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The combined organic extracts were dried (anhydrous sodium sulphate), filtered and evaporated and the residue was purified using prep HPLC (25-95% acetonitrile in aqueous ammonia) to afford the title compound (181 mg, 79%). ¹ H NMR (300 MHz, DMSO-^ ₅ ): δ 8.81 (dd, IH), 8.77 (d, IH), 8.22 (dd, IH), 7.86 (s, IH), 7.54 (d, IH), 7.26 (d, IH), 5.20 (s, IH), 4.75 (tt, IH), 3.83 (d, 2H), 2.90 - 2.63 (m, 10H), 2.04 - 1.71 (m, 5H), 1.57 - 1.22 (m, 4H) APCI (Multimode) m/z: 543 [M+H]

The following examples were prepared in a similar manner to Example 3. {The compounds were named were named using the index name program from Ogham and stereochemical descriptors added by hand. (See www.cvesopen.com/products/applications/ogham.html)) R ¹ in the structural fragment presented in the table below shows the point of attachment to the structure directly below.

R ¹

EXAMPLE 235 Human Phosphodiesterase B2 Radiometric Assay

The assay uses recombinant Human Phosphodiesterase B2 (PDE4B2) produced in house (PrAZLO 163), stored at -20 ⁰ C. This assay is based on the observation that 5'AMP, the product of the reaction catalysed by PDE4, binds preferentially to yttrium silicate SPA beads (Amersham Biosciences, UK) compared to the substrate, cAMP. Compounds at the appropriate concentration were preincubated at 30C for 30 min with an assay buffer containing 50 mM HEPES (pH 7.5), 8.3 mM MgC12, 1.7 mM EGTA, 0.01% (w/v) Brij ^® 35 and 0.1 μg/mL recombinant PDE4B2. The reaction was started by the addition of [3H]cyclic AMP to give a final concentration of 8 nM, and was stopped 20 minutes after the addition of the substrate by the addition of yttrium silicate SPA beads containing 18mM Zn SO4. Bound [3H]cyclic AMP was measured using a Topcount NXT (Packard

Bioscience, UK). IC ₅₀ values (presented in Table 2) were determined using Xlfit3 curve fitting, using model 205.

TABLE 2