3,4-DI-SUBSTITUTED CYCLOBUTENE-l, 2-DIONBS AS CXCR2 RECEPTOR ANTAGONISTS

The present invention relates co organic compounds, e.g. compounds of formula (I), and to uses thereof.

In one aspect the present invention provides a compound of formula I ) or solvates, hydrates or pharmaceutically acceptable salts thereof, wherein

R ¹ is H or Ci-Cs alkyl, wherein the alkyl group is optionally substituted by one or more halogen atoms;

R ² is a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups or a 3 fo 10 membered heterocyclic group optionally substituted by one or more Z groups; or

R ^J and R ² together with the carbon arom to which they are attached form a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups or a 3 to 10 membered heterocyclic group including one or more heteroatoms independently selected from N, O and

S, wherein rhe heterocyclic group is optionally substituted by one or more Z groups;

Ar is phenyl, naphthyl or benzotriazolyl; optionally substituted by one, two or three R' groups; each R ³ is independently selected from OH, halogen, cyano, C) -Q alkyl, CO2H, CChCr

Qalkyl, C(O)N(C ₁ -Cs alkylfc, CH(OH)(CFj) ₂ , NO ₂ , tetrazolyl, and C(O)Ph optionally substituted by halogen; p is zero or 1 ;

R ⁴ is H, Ci-Cs alkyl, Ci-Cs cycloaikyl, Cs-O cycloalkertyj or (Ci-Q alkylJ-R ⁶ , wherein the alkyl groups are each optionally substituted by one or more halogen atoms;

R ^s is Ci-O alkyl, CrQ alkyl-O CVCg aikyl, C ₁ -Cs alkyl O-Ph, Cj-Cw cycloaikyl, Cs-Ci ₀ cvcloalkenyl, a 3 to 10 membered heterocyclic group, (Cj-O aikyl)-Os-Cio cycloaikyl or (C1-C4 alkyl}-Cj-Cιo cycloaikenyl, wherein the aikyl groups and ring systems are each optionally substituted by one or more halogen atoms, OH or CFj groups; or R ⁴ and K ^s _t together with the nitrogen atom to which they are attached, form a 5 to 10 membered heterocyclic group optionally containing one or more additional heteroatoms and optionally substituted by one or more Z groups, provided that the heterocyclic ring does not include an oxygen atom adjacent to the sulfonamide nitrogen;

R ⁶ is selected from a 3 to 10 membered carbocyclic group optionally substituted by one or more Z groups, a 3 to 10 membered heterocyclic group optionally substituted by one or more

Z groups, NR ⁷ R ⁹ , NR ⁷ (SO ₂ )R', (SO ₂ )NR ⁷ R*, (SO ₂ )R*, NR ⁷ C(O)R ⁹ , C(O)NR ⁷ R ⁹ ,

NR ⁷ C(O)NR ^S R*, NR ⁷ C(O)OR ⁹ , C(O)OR ⁷ , C(O)R*, SR ⁷ , CN and NO ₂ ;

R ⁷ and R ^s are each independently selected from H, Ct-Cs alkyl, C3-C.0 cycloalkyl, Cs-Cio cycloalkenyl and -(Ci-Ca alkyleneJ-Cs-Cio cycloalkyl;

R' is selected from H, Ci-Gs alkyl, -(Ct-C? alkylene)-CvCio cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclic group, wherein each of the alkyl groups and ring systems is optionally substituted by OH, halo, C1-C3 alkyl and Ci-Q alkoxy;

Z is independently selected from OH, a 3 to 10 membered carbocyclic group, a 3 to 10 membered heterocyclic group, benzyl, Q-Q alkyl optionally substituted by one or more halogen atoms or OH groups, Q-O alkox7 optionally substituted by one or more halogen atoms or OH groups, -O-aryl, -O-aralkyl, -0(CH ₂ )^C(O)E, NR^(SO ₂ )R ¹ *, (SO ₂ )NR ^W R ⁱ S

(SO ₂ )R ⁱ *, NR ^iO QO)R" QO)NR ^W R ^H , NfR ^iβ QO)NR"R«, NR ^iO C(O)OR ^1Z , NR»°R«

C(O)OR ¹⁰ , C(O)R", SR"\ CN, NO ₂ , and halogen; a is 0, 1, 2, 3 or 4, wherein the alkylene group is optionally substituted by OH or NH ₂ when a is 1, 2, 3 or 4;

E is NR ^O R ¹² Or OR ¹² ; each R ^U) and R" are independently selected from H, Ci-Q alky!, O-Cjo cycloalkyl, CVCio cycloalkenyl and -(Ci-Cj alkyleneJ-Cj-Cio cycloalkyl; and each R ^t * is selected from H, Ci -C« alkyl, -(Ci Cjs alkylene) Cv-Cio cycloalkyl, a 3 to 10 membered carbocyclic group and a 3 to 10 membered heterocyclic group, wherein each of the ring systems is optionally substituted by OH, halo, CrCj alkyl and Ci-Q alkoxy, provided that when Ar is phenyl which is bonded to the amine nitrogen in the 1 -position, is substituted by OH at the 2-po.sition and is further substituted at the 3-position, then R ² is not a 5-membered non-aromatic carbocyclic group or Ri and R ₂ Together with the -CH group to which they are attached do not form a non-aromatic 5 -membered unsubstituted or one- or morefold substituted heterocyclic ring system having 1. to 4 heteroatoms selected from O and

S. In an embodiment of the invention, R ¹ is H or Ci-O alkyl, suitably methyl or ethyl, especially ethyl, and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R ^z is a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R ¹ and R ² , together with the carbon atom to which they are attached form a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R ¹ is H or CV C4 alfcyl; R ² is a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups; or R ^f and R ² , together with the carbon atom to which they are attached form a 4 to 6 membered carbocyclic group optionally substituted by one or more Z groups or a 4 to 6 membered heterocyclic group optionally substituted by one or more Z groups.

In a further embodiment of the invention, when p is 1, R ² is a 4 to 6 membered heterocyclic group, suitably a 5 membered heterocyclic group, more suitably an oxygen-containing heterocyclic group, such as a furanyl or tetrahydrofuranyl group, more suitably a furanyl group, optionally substituted by one or more Z groups, suitably a Ci-Q alkyl group, such as a methyl group; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, when p is 0, K ^λ is a 4 to 6 membered carbocyclic group, suitably a phenyl group, optionally substituted by one or more Z groups, suitably halogen such as fluorine, or a 4 to 6 membered heterocyclic group, suitably a 5 membered heterocyclic group, more suitably a nitrogen or an oxygen-containing heterocyclic group, such as a piperidtnyl, pyranyl, furanyl or tetrahydrofuranyl group, more suitably a furanyl group, optionally substituted by one or more Z groups, suitably a Ci-C» alkyl group, such as a methyl group; and the other variables are as defined anywhere herein. In a further embodiment of the invention, when p is 0, R ¹ and R ² , together with the carbon atom to which they are attached form a 4 to 6 membered heterocyclic group, suitably a 5 membered heterocyclic group, more suitably a sulfur-containing heterocyclic group, such as a terrahydrothiophenyl group, optionally substituted by one or more Z groups, suitably an unsubstituted tetrahydrothiophenyl group; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R ² is furanyl substituted by methyl.

In a further embodiment of the invention, when p is zero, Ar is phenyl, naphthyl or benzotriazoiyl; optionally substituted by one or two R ³ groups; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, when p is 1, Ar is phenyl; optionally substituted by one or two R ³ groups; and the other variables are as defined anywhere herein.

In a further embodiment of the invenrion, when p is zero and Ar is phenyl, the phenyl group is substituted by one or two R ³ groups; and the other variables are as defined anywhere herein.

in a further embodiment of the invention, when p is 1 and Ar is phenyl, the phenyl group is substituted by one or two R ³ groups; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, when p is 1 and Ar is phenyl, the sulfonamide substituetu is in the meta- position; and the other variables are as defined anywhere herein.

In a further embodiment of the invenrion, when p is 1 and Ar is phenyl, the phenyl group is substituted by two R ^s groups, one of which is OH; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, when p is 1 and Ar is phenyl, the phenyl group is substituted in the ortho- position by OH and in the meta- position by the sulfonamide substituent; and the other variables are as defined anywhere herein. In a further embodiment of the invention, when p is 1 and Ar is phenyl, the phenyl group is substituted in the ortho- position by OH, in the meta- position by the sulfonamide substituent and in the para- position by R ³ , suitably chlorine; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R ³ is OH, halogen, suitably fluorine or chlorine, Ci- C ₄ alkyl, CO ₂ OH, COiO-Oalkyl, C(0)N(Ci-Oalkylh, CH(OH)(CF ₃ )I, NO ₂ , tetrazolyl, and C(O)Ph substituted by halogen, suitably chlorine; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R ⁴ is H, Ct-O alkyl, C3-O cycloalkyl or (Ci-Q alkyty-Cv-O cycloalkyl, more suitably R* is H or CVQ alkyl; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, R ⁵ is Ci-O alkyl, Ci-Ce alkyl (O) Cj-Q alkyl, Ci-Cg alkyl (O)Ph, C3-C10 cycloalkyl, O-Cto cycloalkenyl, including phenyl, a 3 to 10 membered heterocyclic group, wherein the alkyl groups and ring systems are each optionally substituted by one or more OH or CF3 groups; and the other variables are as defined anywhere herein.

In a further embodiment, R ⁴ and R ⁵ , together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic group, optionally containing one or more additional heteroatoms, suitably a nitrogen atom, and optionally substituted by one or more Z groups, suitably OH or a 3 10 10 membered carbocyclic group, more suitably OH or a 5 membered carbocyclic group; and the other variables are as defined anywhere herein.

In a further embodiment of the invention, Z is selected from Ci-O alkyl, OH, halogen such as fluorine, or a 3 to 10 membered carbocyclic group; and the other variables are all as defined anywhere herein.

Reference to "the other variables are all as defined anywhere herein" will be understood to mean that all of the other variables used in the definition of the compounds of Formula I can have any of the definitions applied to them hereinabove or in the claims. Thus, combinations of sub-defintions of the variables are considered to be within the scope of the invention, in particular, the definition of a variable in an embodiment of the invention may he combined with the definition of a second variable from a separate embodiment of the invention.

In a further embodiment, the present invention provides a compound of formula (ϊ) selected from:

3-{2-[(R)-l~(4-Fluoro-phenyl}-ethylamino]-3,4-dioxo-cyclo bαt-l-enylamino)-2-hydroxy-N,N- dimethyl-ben-iamide;

3-{3,4-Dioxo-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-cycl obut-l-enylamino}-2-hydroxy-N _>

N-dimethyi- benzarnide;

2-Hydroxy-N _> N-dimethyI-3-{2-[{ 1 •methyi-piperidin-3-ylmethyI)-aminoJ-3,4-dioxo<yclobut •• 1 - enylamino}-ben;_amide;

3-(3-Hydroxy-phenyIamino)"4-|(R)-l-{5-mechyl-furan-2-yl)" propylamino}-cyclobut-3-ene-t,2- dione;

3-((R)-l-(5-Methyl-furan-2-yi)-propylamino] -4-j2-(2,2,2-trifluoro-ϊ-hydroxy-i- trifluoromethyl~ethyl)-phenylamjno|-cyctobut-3~ene-l,2-dione ;

3-{2-Hydroxy-4-methyl-phenylamino)-4-{{S)-{tetrahydro-dii ophen-3-yl)amino} cyclohut-3-ene-

1,2-dione;

3-(2-Fluoro-ρhenylamino)-4-{tetrahydro-thiophen-3~ylamin o)-cycIobut-3-ene-l,2-dJone;

2-{3,4-Dioxo-2-[($)-(tetrahydro •chiophen-3-yl)ajιninoJ-cyclobut- 1 -enylaminoj-benzoic acid;

2-{3,4-^i<3XO-2-[(S)-(tetrahydro-thk)phen-3-yi)amino)- cyclobut-l-enylamijio}"5 fluoro-benzoic acid;

3-(2-Fluoro-phenylamino)-4-{tetrahydro-thiophen-3-ylamino )-cyclobut-3-ene-J,2-dionc;

6-Ch{oro-2-hydroxy-3-{2-[(R)-l-(5 methyi-furan-2-yI)-propylamino]-3 _> 4-dioxo-cyclobut-l- enylatninoJ-NjN-bis^ljl^^^-pentadeijrerO'ethyiJ-bcnxenesulfo namidc;

6-Chloro-2-hydroxy-3-{2-[{R)-i-(5-merhy|-furan-2-yl)-prop ylaminoj-3,4-dioxo-cycIobut-l- enylaπύτio)-N-pyridin-yl benzenestilfonamidej

2-{3 ₎ 4-Dioxo-2-[(S) (tetrahyd.ro-thiophen-3-yl)amino3-cyclobut-l-enybrnino}-5-fl uoro bt'nzok acid;

2-{3,4 J>ioxo-2-[{S)-(tetrahydro-thiopheπ"3-yl)amino|-cyclobυt -1-enylamino}-4-fluoro-benzoic acid;

2-{3,4-Dioxo-2-(($)-(tetrahydro-thiophen-3-yi)amino] cyc!obut-l-enylamino}-6-methyl- benzoic acid;

2-{3,4-Dioxo-2-|{S) (tetrahydro-thiophen-3-yI)aminoj-cyclobut-l-enylarnino}-naph tha}ene-2- carboxylic acid; 3-{2-Hydroxy-5-nUro-phenylamino)-4-[{S)-(tetrahydro-thiophen --3-yl)ainmoJ-cyclobut-3-ene'- 1,2-dione;

3-(5-teit-Butyl-2-hydroxy-pheiiyiaiΩino)^-[(S)-{tetrabyd ro-thiophen-3-yl)amlnoj-C)'clobuf-3- ene- 1,2-dione;

6-Chloro-2-hydroxy-3-{2-[{R)-l-((2R _r 5R)-5-methy}-retrahydro-furan-2»yi)-ρropylamino]-3,4 - dioxo-cycbbut-l-enylamino}-N-|4-(2,2,2-trJfiuoro-l-hydroxy-l -trifluoromethyl-ethyl)- pheny.i]-benzene.sulfoiiamide;

3-( 1 H-Benzotriazol-4-y lamino)-4-f (R)-I -((2R,5R)-5-methyi-fctrahydro-furan-2-yI)- propylamino)-cyclobut-3-ene-l,2-dione;

6-Chloro-2-hydroxy-N-(2-methoxy-ethyl)-3-{2-[(R)-l-{(2R, JR)-J-methyi-tet.rahydro-fυraiι-2- y!)-propylamiπo)-3 _> 4-dioxo-cyclobut-l-enyiamiπo)-bcnzcnesulfonamid€;

6-Chloro-N-cycloρcntyl-2-hydcoxy-3-{2-[(R)-l-{{2R,5R)-5- methyl-tetrahydro-fu.ran-2-yl)- propyiamino]-3,4-dioxo-cyclobut-l-enyIamino}-benzenesuIfonam ide;

6-ChIoro-2-hydroxy-N-(3 methoxy-proρy!)-3-{2-[(R)-l-{{2R _> 5R)-5 merhyI-tetrahydfo>-furaπ-2- yl)-ρropylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzenesul fonamide;

6-Chloro-2-hydroxy-N-(4-hydroxy-cyclohexyl)-3-{2-{(R)-l-{ 2R,5R)-5-methyl-cetrahydro- furan-2-yl)-propyiaminol-3,4-dioxo-cyclobut-l-enyIamino)-ben zenesuJfonamide;

6-Chloro-2-hydroλ7-3-(2-[{R)-l-((2R,5R)-5-raechyl-tetrah ydro-furan-2-yi)-propylamino)-3,4- dioxo-cyclobtu l-enylaminoJ-N-ftetrahydro-pyran^-ylJ-benzenesulfonainide;

6 Chloro-N-(3-ethoxy-propyl)-2-hydrox. ^y -3-{2-[(R)-l-{(2R,5R)-5 rnethyl-tetrahydro-furan-2" y! )-propylaminoJ-3,4-dioxo-cyc!obut- 1 -enylaminoj-bcnzenesulfonamjde;

6-Chloro-2-hydroxy-3-{2-[(R)-i-((2R,5R)-5-methyI-terrahyd ro-turan-2-yI)-piOpylamino}-3 _> 4- dioxo-cyclobuC-l-enylaminol-N^l-propoxy-ethylJ-benzenesulfon amide;

6-Ch!oro-2 hydroxy-N-(2-isopropoxy-ethyl)-3-{2-[(R) l-{2R,5R)-5-meιhyl-terrahyd.ro-furan-

2 yl} propylamino]-3 _> 4-dioxo-cycIobut-l-enyIaπύnoj-benzencsυlfonamide;

6-Chloro-2-hydroxy-N"(3-hydroxy-ρheπyl)-3-{2-[(R)-1-(2R ,5R)-5-merhyi-t:etrahydro-jfuran-2- yO-propylaminol-S^-dioxo-cyclobυt-l-enylaminoJ-benzenesulfo πaraide;

N-fS-Bucoxy -propylJ- ^β' -chloro-l-hydroxyO ^-I^RJ-l ^iRjSRJ-S-methyl tetrahydro-furan-l- yl )-propylamino]-3,4-dioxo-cyclobut- ^' l -enylamino) -benzencsulfonam ide;

6-Chkn.o-2-hydroxy- N-{lH-indazoi-4-yl)-3-{2-[(R)-i-(2R,5R)-5-merhyl-tecrahydro- furan-2- y ⁽ )-propylaπiino|-3,4-dioxo-cyclobut-i-enyiamino}-beiue nesulfonaιnide;

6-C ^' h!oro-2-hydroxy-3-{2-|(R)-! -({2R,5R)-5-methyl-tetrahydro-furan-2-yl) propylaniinoj -3,4- dJoxo cyclobut- !-eny!ainino}-N,N-bis-(l, 1,2,2,2 •pentadeutero-ethyl)-berøeπe.sulfonaniide; 6-Chlo.ro-2-hydroxyO-(2-((R)-^((2R,5R)-5-methyI-tetrahydro-f uran-2-y!)-p^opylamino]-3,4- dioxo-cyclobut-l-enylaminol-N-fl-phenoxy-ethylJ-benzenesulfo namide;

6-Chloro-2-hydroxy-N-{5-hydroxy-adamantan-2-yl)-3-{2-|{R) -l-((2R,5R)-5-niethyl- t€trahydro-furan^-yD-propylaminol-S^-dioxo-cyclobut-l-enyl am.noJ-beiizenesulέonamide;

3-[4-Cfaloro-3-(4-cycIopenϊyJ-pipera2ine-l-suIfonyi)-2-h ydroxy-phenylaminoJ-4-[(R)-l-

((2R,5R)-5-tnethyi-tetrahydfo-furan-2-yl)-propyiammo]-cyc lobut-3-ene-l,2-dione;

3-[4-Chioro-2-hydroxy-3~((S)"3-hydfaxy-pyrroiidine--l-sul fonyi)-pheny!ainino)-4-l{R)-l-

({2R _> 5R)-5-merhyl-tetrahydro-/uraπ-2-y!)-propylaminoJ-cyci obuc-3-ene-l,2-dionc;

3-{3-ChIoro-2-hydroxy-phenylamino)-4-[(R)-l-(5-methyl-fur an-2-yl)-propykπiino]-cyclobut-

3-ene-l,2-dione;

2-Chbro-6-{2-[{R)-l-{5-methyl-fur«αn-2-yl) ^» propylarninoj-3 _t 4-dioxo-cyciobut-l-enyiamino}- benzoic acid;

3-P-Chloro-2-(2lJ-te£razol-.S-yl)-phenylamino3-4-|(R)-l- (5-methyl-.furan-2-y!)~propylarnino}- cyclobut-3-ene- 1 ,2-dione; and

5-Fiuoro-2-(2-'[(R)-1-{5-methyl-furan-2-y{)-propylamino}- 3,4-dioxo-cyc!obut-l-enylamino} - benzoic acid methyl ester.

If not otherwise defined herein:

- "Alkyl" includes linear or branched Ci-Cs alkyl, such as Ci-Cs alkyl or Ci-O alkyl, e.g. Cj- Cz alkyl, including unsυbstituted or substituted alkyi, e.g. alkyl substituted by groups which are conventional in organic chemistry, e.g. halogen, OH, NH∑ or haio{Cu)aikyl,

- "Halogen" includes fluoro, chloro, bromo, iodo, e.g. fluoro, chloro, bromo, suitably chloro,

- "Carbocyclic group" denotes a ring system consisting of the relevant number of carbon atoms, e.g. 3, 4, 5, 6, 7, 8, 9 or 10. The ring system may be a single ring, a fused ring system or a spirocyclic ring system. Furthermore, the carbocyclic group may be saturated, partially unsaturated or aromatic. In particular, it may include a saturated or partially unsaturated ring fused to an aromatic ring or a second saturared or partially unsaturated ring; or it may include two aromatic rings fused together. Thus, "carbocyclic group" includes, for example, cycloalkenyl, cycloalkyl, phenyl, indane, indene, naphthalene, tetralin and azulene.

- "Heterocyclic group" denotes a ring system consisting of the relevant number of member atoms, e.g. 3, 4, 5, 6, 7, 8, 9 or 10, including at least one heteroatom selected from N ₅ O and S. The ring system may be a single ring, a fused ring system or a spirocyclic ring system. Furthermore, the heterocyclic group may be saturated, partially unsaturated or aromatic (i.e. heterocyclic includes heterocycloalkyl, heterocycloalkenyl and heteroaryl). In particular, it may include a saturated or partially unsaturated ring fused to an aromatic ring or a second saturated or partially unsaturated ring; or it may include two aromatic rings fused together. In addition, the heterocyclic group includes a heterocyclic ring fused to a cnrbocyclic ring, e.g. benzofused heterocyclic groups. Suitably, the heterocyclic group includes 1, 2 or 3 heteroatoms selected from N, C ⁾ and S.

- "optionally substituted by one or more Z groups" denotes that the relevant group may include one or more subsrituents, each independently selected from the groups included within the definition of Z. Thus, where there are two or more Z group substituents, these may be the same or different.

- "-(Ci-G alkylene)-" or "-(CrQ alkylene)-* denote a hydrocarbon linking group having the relevant number of carbon atoms,

Throughout this specification and in the claims that follow, unless the context requires otherwise, the word "comprise", or variations, such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Compounds of formula (ϊ) in free or pharmaceutically acceptable salt form are hereinafter referred to alternatively as compounds of the invention.

Compounds of formula ϊ that contain a basic centre are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, caprylic acid, dichloroacetic acid, hippuric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, gluconic acid, mandelic acid, dicarboxylic acids such as maleic acid or succinic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, malonic acid, sebacic acid, aromatic carboxylic acids such as benzoic acid, p-chloro- bcnzoic acid, nicotinic acid, diphenylacetic acid or triphenyfacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1 -hydroxynaphthalene-2- carboxylic acid or 3-hydroxynaphtha!ene-2-carboxyUc acid, and sulfonic acids such as methanesυlfonic acid or benzenes ulfonic acid, ethanesulfonic acid, ethane- 1, 2 -disuffonic acid, 2-hydroxy-erhanesulfonic acid, {+) camphor- 10-sulfoπic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5-disulfonic acid or p-toluenesulfønic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures. Pharmaceutically acceptable solvates are generally hydrates.

Compounds of formula I which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine, arginine, benethamme, benzathine, dierhanolamine, 4-{2-hydroχy«ethyl)morρholme, 1 -(2-hydroxyethy l)pyrrolidine, N-meihyl glutamine, piperazine, methanol-amine, choline or tromethamine. These salts may be prepared from compounds of formula I by known salt-forming procedures. Compounds of formula I that contain acidic, e.g. carboxyl, groups may also exist as zwitterions with the quaternary ammonium centre.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallisation may be isotopkally substituted e.g. DzO, d^acerone or d$- DMSO.

Compounds of formula I in free form may be converted into salt form, and vice versa, in a conventional manner. The compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallisation. Compounds of formula I can be recovered from reaction mixtures and purified iτ\ a conventional manner. Isomers, such as eπantiomers, may be obtained in a conventional manner, e.g. by fractional crystallisation or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.

Some compounds of the invention contain at least one asymmetric carbon atom and thus they exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic mixtures. In cases where additional asymmetric centres exist the present invention also embraces both individual optically active isomers as well as mixtures, e.g. diostereomerk mixtures, thereof. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or; by stereospecific or asymmetric syntheses. Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at feast 85%, especially at least .98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1 %, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.

The invention includes all pharmaceutically acceptable isotopicaily-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention inducfe isotopes of hydrogen e.g. ² H and ³ H, carbon e.g. ¹¹ C, ¹³ C and ¹⁴ C, chlorine e.g. ³⁶ Cl, fluorine e.g. ¹⁸ F, iodine e.g. ^m l and ¹²⁵ I, nitrogen e.g. ^1J N and ^{! S} N, oxygen e.g. ¹⁵ 0, ¹⁷ O and ^O, and sulfur e.g. ^3S S.

Certain isotopicaily-labelled compounds of formula I, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium ( ^} H) and carbon- 14 ( ¹⁴ C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium ( ¹ H) may afford certain therapeutic advantages that result from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ^U O, and ⁿ N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy,

Isotopicaily-labelled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously used.

Some of the compounds of Formula I may exist in different tautomeric forms. Tautomerism is well known to those skilled in the art and the skilled person will readily appreciate which groups are able to tautomerise to form the different tautomeric forms. The invention includes all tautomeric forms of the compounds of Formula I.

Any compound described herein, e.g. a compound of the present invention, may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein. Starting materials are known or may be prepared according, e.g. analogously, to a method as conventional or as described herein.

A compound of formula I thus obtained may be converted into another compound of formula I, e.g. or a compound of formula I obtained in free form may be converted into a salt of a compound of formula ϊ and vice versa.

Any compound described herein, e.g. a compound of the present invention, may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein. Starting materials are known or may be prepared according, e.g. analogously, to a method as conventional or as described herein.

In another aspect the present invention provides a process for the preparation of a compound of the present invention comprising:

(A) reacting a compound of formula II

Ii wherein Ar, p, R ⁴ and R ⁵ are as defined above, with a compound of formula UI

HE wherein Ri and Kz are as defined above, under appropriate conditions, e.g. in the presence of triethylamine, acetonitrile, methanol, for an appropriate time, e.g. 2 to 24 hours, at appropriate temperatures, e.g. room temperature, to obtain a compound of formula (ϊ) of the invention.

In a further aspect the present invention provides a process for the preparation of a compound of the present invention comprising:

(B) reacting a compound of formula (IV)

E

IV wherein R' and R ² are as defined above, with a compound of formula (V)

2

V wherein Ar, p, R ⁴ and R ^? are as defined above, under appropriate conditions, e.g. in the presence of triethylamine, ethanoi, for an appropriate time, e.g. 2 to 24 hours, at appropriate temperatures, e.g. 50 - 80°C, to obtain a compound of formula (I) of the invention.

In a further aspect the present invention provides a process for the preparation of a compound of the present invention comprising:

(C) reacting a compound of formula (Vf)

Vl with a compound of formula (III) wherein R ¹ and R ² together with the carbon arom to which they are attached form a 3 to 10 membered carbocyciic group optionally substituted by one or more Z groups or a 3 to 10 membered heterocyclic group optionally substituted by one or more Z groups, and a compound of formula (V) wherein Ar, p, R ⁴ and R ⁵ are as defined above, under appropriate conditions, e.g. in the presence of triethylamine, ethanol, for an appropriate time, e.g. 2 to 24 hours, at appropriate temperatures, e.g. room temperature, to obtain a compound of formula (I) of the invention.

A compound of formula ϊ thus obtained may be converted into another compound of formula I, e.g. or a compound of formula I obtained in free form may be converted into a salt of a compound of formula I and vice versa.

Compounds of the invention, are useful as pharmaceuticals. Accordingly the invention also provides a compound of formula I in free or phsirmaceuticaiiy acceptable salt form for use as a pharmaceutical.

In another aspect the present invention provides the use of a compound of foπnula(I) wherein the substituenrs are as defined above as a pharmaceutical.

The compounds of the invention act as CXCR2 receptor antagonists, thereby inhibiting the infiltration and activation of inflammatory cells, in particular neutrophils, monocytes and CD8+ T cells and mediators involved in chronic obstructive pulmonary disease (COPD). The compounds of the invention therefore provide symptomatic relief and reduce disease progression.

The airways of subject with COPD exhibit an inflammatory response which is predominantly neutrophilic. When the airways are exposed to cigarette smoke macrophages, CD8+ T cells and epithelial ceils are activated and release pro-inflammatory mediators, oxidants, cytokines and neutophilic chemotactic factors _. , IL-8, GROα, ENA-78 and teukαtrienes. 11,-8, GROα and ENA-78 are selective chemoattractants for neutrophils. In human neutrophils IL-8 binds two distinct receptors with similar affinity, CXCRl and CXCR2. Closely related chemokines including GROα, β, y, NAP-2 and ENA-78 bind only to CXCR2. Inhibiting neutrophil recruitment is therefore a recognised therapeutic strategy for treating several lung diseases. Blocking the binding of IL-8, GROα and ENA-78 to the cheπiokine receptor CXCR2 can provide beneficial effects in patients with COPD by suppressing the infiltration and activation of key inflammatory cells, thereby reducing subsequent tissue damage, mucus secretion, airflow obstruction and disease progression.

The IL-8 and GROtt chemokiήe inhibitory properties of compounds of the invention can be demonstrated in the following assays:

Receptor Binding Assay

[ ¹²⁵ I] IL-8 {human recombinant) are obtained from Amersham Pharmacia Biotech, with specific activity 2000 Ci/mmol. All other chemicals are of analytical grade. Human recombinant CXCR2 receptor expressed in Chinese hamster ovary cells (CHO-Kl) is purchased from Euroscreen, The Chinese hamster ovary membranes are prepared according to protocol supplied by Euroscreen. Membrane protein concentration is determined using a Bio- Rad protein assay. Assays are performed in a 96-weli micro plate foπnat according the method described in White, et al., J Biol Chem., 19.98, 273, 10095). Each reaction mixture contains 0.05 mg/rnl CXCR2 membrane protein in 20 mM Bis-Tris-propane, pH 8.0, containing 1.2 mM MgSO ₄ , 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS. In addition, compound of interest pre-dissolved in dimerhylsulphoxide (DMSO) so as to reach a final concentration of between 10 μM and 0.0005 μM (final concentration of DMSO 2 % (v/v)) is added. Binding is initiated by addition of 0.02 iiM ¹²⁵ I-IL-S. After 2 hours at room temperature the plate is harvested using a Brandell™ 96-weli harvester onro glass fibre filter plate (GF/c) blocked with 1% polyethyleneimine + 0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCI, 1 mM MgSO ₄ , OJ mM EDTA, 0.03% CHAPS, pH 7.4. The filter is dried at 5O ⁰ C overnight. Backseal is applied to the plate and 50 μl of liquid scintillation fluid added. The counts are measured on the Packard Topcount ^'<M scintillation counter.

P ⁵ Sj-GTIY? binding assay for human CXCR2 receptor using SPA technology [ ³⁵ Sj-GTTyS (with .specific activity 1082 Ci/mmol) and wheat germ agglutinin poly vinyl toluene scintillation proximity beads are purchased from Amershaxn Pharmacia Biotech. The Chinese hamster ovary cell (CHO-Kl) membranes expressing human CXCR2 receptors are purchased from Biosignal Packard Inc. All other chemicals are of analytical grade. White non- binding surface 96 well Optiplate™ microplates are obtained from Packard. Recombinant human IL-8 is synthesised, cloned and expressed in Escherichia coli as described previously (Lindiey I, et al., Proc. Nad. Acad. ScL, 1988, 85{23):9199).

The assay is performed in duplicate in 96 well Optiplate™ microplate in a final volume of 250 μl per well. Compounds are diluted in DMSO (0.5% final concentration) and incubated in 20 πiM FIEPES buffer pH 7.4 containing 10 mM MgQ ₂ , 100 mM NaCI, 1 mM EDTA plus 100 nM IL-8, 50 μM GDP and 500 pM FS}GTPγS per well. SPA beads (1 mg/well final concentration) were pre-mixed with the membranes (10 μg/well final concentration) in assay buffer: 20 mM HEPES buffer pH 7.4 containing 10 mM MgO ₂ , 100 mM NaCI, 1 mM EDTA. The bead membrane mixture is added to each well, plates are sealed and incubated at room temperature for 60 minutes. The plate is centrifuged and read on Packard TopCount ^T1 * scintillation counter, program [ ^3S S dpm j for 1 πύn/well. Data are expressed as the % response to 100 nM IL-8 minus basal.

Chemotaxis Assay

The in vitro inhibitory properties of these compounds are determined in the neutrophil chemotaxis assay. Assays are performed in a 96- well plate format according to previously published method (Frevert C W, et al., J Immunology Methods, 1998, 213, 41 ). 96-well chemotaxis chambers 5 μm are obtained from Neuro Probe, all cell buffers are obtained from Invitrogen Paisley, UK, dextran -T500 and Ficoll-Paque Plus™ density gradient centrifugation media are purchased from Pharmacia Biotech Buckinghamshire, UK. Calcein-AM dye is obtained from Molecular Probes. Neutrophils are isolated as previously described (Hasiett, C, et al. Am) Path., 1985, 1.19:101). Citrated whole blood is mixed with 4% (w/v) dextran- T500 and allowed to stand on ice for 30 minutes to remove erythrocytes. Granulocytes (PMN) ate separated from peripheral blood mononuclear cells by layering 15 ml of cell suspension onto 15 ml Ficoll-Paque PLUS density gradient and centrifuged at 250 xg for 25 minutes. Following centrifugation any erythrocytes contamination of PMN pellet is removed by hypotonic shock lysis using 10 ml ice-cold endoioxin-free sterile water for 50 seconds arid neutralised with 10 ml of cold 2.x phosphate buffered saline. Isolated neutrophils (1 xlO ⁷ ) are labelled with the ffuorochrome calcein-AM (5 μg) in a total volume of 1 ml and incubated for 30 minuses at 37 ⁰ C. The labelled cells are washed with RPMI without phenol red + 0.1 % bovine serum albumin, prior co use the cells are counted and adjusted to a final concentration of 5 x 10* cells /ml. The labelled neutrophils are then mixed with test compounds (0.001-1000 nM) diluted in DMSO (0.1 % final concentration) and incubated for 10 minutes at room temperature. The chemoattractants (29 μl) are placed in the bottom chamber of a 96-well chemotaxis chamber at a concentration between (0.1-5 nM). The polycarbonate filter (5 μm) is overlaid on the plate, and the cells (25 μl) are loaded on the top filter. The cells are allowed to migrate for 90 minutes at 37° C in a humidified incubator with 5% CCb.. At the end of the incubation period, migrated cells are quantified using a multi-well fluorescent plate reader (Fluroskan 11™, labsystems) at 485 nm excitation and 538 nm emission. Each compound is tested in quadruplet using 4 different donors. Positive control cells, i.e. cells that have not been treated with compound, are added to the bottom well. These represent the maximum chetnotactic response of the cells. Negative control cells, i.e. those that have not been stimulated by a chemoattractant, are added to the bottom chamber. The difference between the positive control and negative control represents the chemotactic activity of the cells.

The compounds of the Examples herein below have ICso values below 10 μM in the [ ^3S S]~ GPTyS binding assay. For instance, Table A provides the iC.to values for a selection of compounds.

Table A

Name

Ex. Structure Kb

,(uMl

6-Chioro-2-hydroxy-3-{2-[{ R)-I-

(5-methyl-furan-2-yi)- propylarnino]-3,4-dioxo- n < ^*

OH 0.01 cyclobut-l-cnylamiπo} -N,N-bis-

( 1,1 ,2,2,2-ρentadeurero-ethyl)- benzenesulfonamide 3-[4-Chloro-2-hydroxy-3-ttS)-3- hydroxy-pyr rolidine- 1 -sul fonyi)- phenylamino]-4-[(R)-l-

(βR^RK-methyl-tetrahydro- furan-2-yl)-propylamino ^' j- cyc!obut-3-ene-1.,2-dione

3-{3-Chloro-2-hydroxy- phenylamino)-4*[(R)-l-(5- methyl-f uran-2-yl ) - propylamϊnoj-cyclobut-3-ene- 1 ,2-diσne

2-Chk>ro-6-{2-j<R>- 1 -<5-methyl- ruran-2-yl)-propylamino}-3,4- dioxo-cyclαhtit- 1 -eny I amino}- benzoic acid

Having regard to their inhibition of binding of CXCR2, compounds of the invention are useful in the treatment of conditions or diseases mediated by CXCR2, for example inflammatory or allergic conditions or diseases, particularly chronic obstructive pulmonary airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, bronchiolitis obliterans syndrome and severe asthma. Compounds of the present invention are further useful in the treatment of various diseases, such as cancer, e.g. ovarian cancer, prostate cancer, melanoma including metastatic melanoma, lung cancer, e.g. non small cell lung cancer, renal cell carcinoma; tumour angiogenesis, ischaeπύa/reperfusion injury, delayed graft function, osteoarthritis, myeloid metaplasia with myelofibrosis, λdetiomyosis, contact hypersensitivity (skin), and in wound healing. Treatment in accordance with the invention may be symptomatic or prophylactic.

Prophylactic efficacy in the treatment of chronic bronchitis or COPD will be evidenced by reduced frequency or severity, will provide symptomatic relief and reduce disease progression, improvement in lung function. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory. Other inflammatory or obstructive airways diseases and conditions to which the invention is applicable include acute lung injury (ALI), acure/adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis, fibroid I ting, airway hyperresponsiveness, dyspnea, pulmonary fibrosis, allergic airway inflammation, small airway disease, lung carcinoma, acute chest syndrome in patients with sickle cell disease and pulmonary hypertension, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tahacosis and byssinosis.

Compounds of the invention are also useful for treating respiratory viral infections, which exacerbate underlying chronic conditions such as asthma, chronic bronchitis, COPD, otitis media, and sinusitis. The respiratory viral infection treated may be associated with secondary bacterial infection, such as otitis media, sinusitis or pneumonia.

Compounds of the invention are also useful in the treatrnent of inflammatory conditions of the skin, for example psoriasis, atopic dermatitis, lupus erythematosus, and other inflammatory or allergic conditions of the skin.

Compounds of the invention may also be used for the treatment of other diseases or conditions, in particular diseases or conditions having an inflammatory component, for example, diseases affecting the nose including allergic rhinitis, e.g. atrophic, chronic, or seasonal rhinitis, inflammatory conditions of the gastrointestinal tract, for example inflammatory bowel disease such as ulcerative colitis and Crohn's disease, diseases of the bone and joints including rheumatoid arthritis, psoriatic arthritis, and other diseases such as atherosclerosis, multiple sclerosis, and acute and chronic allograft rejection, e.g. following transplantation of heart, kidney, liver, lung or bone marrow. Compounds of the invention are also useful in the treatment of endotoxic shock, glomerulonephritis, cerebral and cardiac ischemia, Alzheimer's disease, cystic fibrosis, virus infections and the exacerbations associated with them, acquired immune deficiency syndrome (AIDS), multiple sclerosis (MS), Helicobacter pylori associated gastritis, and cancers, particularly the growth of ovarian cancer.

Compounds of the invention are also useful for treating symptoms caused by viral infection in a human which is caused by die human rhinovirus, other enterovirus, coronavirus, herpes viruses, influenza virus, parainfluenza virus, respiratory syncytial virus or an adenovirus. Compounds of the invention are also useful for treating pancreatitis .

The effectiveness of a compound of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal model, e.g. mouse, rat or rabbit model, of airway inflammation or other inflammatory conditions, for example as described by Wada et al,/. Exp. Med (1994) 180:1135-40; Sekido et al, Nature (1993) 365:654-57; Modelska et al., Am, ]. Respir. Crit. Care. Med (1999) 160r 1450-56; and Laffon et al (1999) Aw. /. Reφir. Crit Care Med. 160:1443-49.

The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A compound of the invention may be mixed with rhe other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particular giucocorticosteroids such as budesonide, beclamethasoπe dipropionate, fluticasone propionate, cidesonkk' or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11., 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO 04/19935 and WO 04/26248; LTD4 antagonists such as montelukast and zafirlυkast; PDE4 inhibitors such ciiomilast (Arifio® GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayex), SCH-351591 (Schering-Plough), Arofylline (Alrmrall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 {Asta Mcdica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/1.9751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; A ₂ A agonists such as those described in EP 1052264, EP 1241176, EP 409595A2, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, and WO 03/086408; and A» antagonists such as those described in WO 02/42298.

Suitable bronchødiiatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, US 3714357, US 5171744, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/018422, WO 04/05285, WO2004096800, WO2006048225 and WO200802554Ϊ; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salrneterol fenorerol, procaterol, and especially, forrnoterot, carmoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula 1 of WO 00/751 14, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula

and pharmaceutically acceptable salts thereof, as well as compounds {in free or salt or solvate form) of formula I of WO 04/16601, and also compounds of EP 1440966, JP 05025045, WO 93/18007, WO 99/64035, US 2002/0055651, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/ 70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618 WO 04/46083 and WO 04/80964.

Such antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarare, promethazine, loratidine, desloraridine, diphenhydramine and fexofenadine hydrochloride.

Combinations of compounds of the invention and anticholinergic or antimuscarinic compounds, steroids, beta-2 agonist*;, PDE4 inhibitors, dopamine receptor agonists, LTD4 antagonists or LTB4 antagonists may also be used. Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with other antagonists of chemokinε receptors, e.g. CCR-I, CCR-3, CCR-4, CCR-S, CCR-6, CCR-7, CCR-8, CCR-9 and CCRlO, CXCRl, CXCR2, CXCR3, CXCR4, CXCRS, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351 125, SCH-55700 and SCH-D, Takeda antagonists such as N-([4-{{(6,7-dihydrθ"2"{4"methylphenyl)-5H-benzocyclohepten -8-yl|carbonyl)amino|phenylJ- methylj-tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770), CCR-5 antagonises described in US 6166037 (particularly claims 18 and 19), WO 0066558 (particularly claim 8), and WO 0066559 (particularly claim 9).

In accordance with the foregoing, the invention also provides a method for the treatment of a condition or disease mediated by CXCR2, for example an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease, which comprises administering to a subject, particularly a human subject, in need thereof an effective amount of a compound of formula 1 in a free or pharmaceutically acceptable salt form as hereinbefore described. In another aspect the invention provides the use of a compound of formula I, in free or pharmaceutically acceptable salt form, as hereinbefore described for the manufacture of a medicament for the treatment of a condition or disease mediated by CXCR2, for example an inflammatory or allergic condition or disease, particularly an inflammatory or obstructive airways disease. In another aspect the invention provides a compound of formula I, in free or pharmaceutically acceptable salt form, as hereinbefore described for the treatment of a condition or disease mediated by CX CR2, for example an inflammatory or allergic condition or disease, particularly an inflammatory or obstructive airways disease.

The compounds of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.

In a further aspect _* the invention also provides a pharmaceutical composition comprising as active ingredient a compound of formula ϊ in free or pharmaceutically acceptable salt form, optionally together with a pharmaceutically acceptable diluent or carrier therefor. The composition may contain a eo-therapeutic compound such as an anti-inflammatory bronchodilarory or antihistamine drug as hereinbefore described. Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches. Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.

When the composition comprises an aerosol formulation, it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant such as HFAl 34a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanoi (up to 20% by weight), and/or one or more surfactants such as oleic acid or sorbitan trioleate, and/or one or more bulking agents such as lactose. When the composition comprises a dry powder formulation, it preferably contains, for example, the compound of formula I having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture, e.g. magnesium stearare. When the composition comprises a nebulised formulation, it preferably contains, for example, the compound of formula i either dissolved, or suspended, in a vehicle containing water, a co-solvent such as ethanol or propylene glycol and a stabiliser, which may be a surfactant.

The invention includes (A) a compound of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form, (B) an inhalable medicament comprising a compound of the invention in inhalable form; (C) a pharmaceutical product comprising such a compound of the invention in inhalable form in association with an inhalation device; and (D) an inhalation device containing a compound of the invention in inhalable form.

Dosages of compounds of the invention employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for administration by inhalation are of the order of 0.01 to 1 mg/kg per clay while for oral administration suitable daily doses are of the order of 0.005 to JOO mg/kg of total body weight. The daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.

The invention is illustrated by die following Examples.

EXAMPLES

Especially preferred compounds of the present invention include compoundsS of formula I

are shown in Table 1 bdow. The method of preparation being described hereinafter. TABLE 1

General Methods;

Referring to the examples that follow, compounds of the preferred embodiments are synthesized using the methods described herein, or other methods, which are known in the art.

It should be understood that the organic compounds according to the preferred embodiments raay exhibit the phenomenon of tautomerisrh. As the chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood chat the preferred embodiments encompasses any tautomeric form of the drawn structure.

It is understood that the invention is not limited to the embodiments set fbrrh herein for illustration, but embraces all such forms thereof as come within the scope of the above disclosure.

General Conditions:

Mass spectra were run on LCMS systems using electrospray ionization. These were either Agilent 1100 ϊlPLQMicrornass Platform Mass Spectrometer combinations or Waters Acquity UPLC with SQD Mass Spectrometer. {M+HJ ⁺ refers to mono-isotopic molecular weights.

NMR spectra were run on open access Bruker AVANCE 400 NMR spectrometers using ΪCO N-NMR. Spectra were measured at 298 K and were referenced using the solvent peak.

The various starting materials, intermediates, and compounds of the preferred embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures.

In addition various trade reagents and materials available have been utilized. Such reagents and materials include: Isolute™ (available from Biotage), Hyflo™, Ceiite™ and can be readily obtained from the suppliers indicated.

For the examples below as well as throughout the application, the following abbreviations have the following meanings. If nor defined, the terms have their generally accepted meanings.

Abbreviations:

DCM dichloromethane

DMSO dimethyl sulfoxide

Et ₂ O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

HCl hydrochloric acid

HiO water

KjCO ₅ potassium carbonate

LCMS liquid chromatographic mass spectroscopy

MeCN acetonitrile

MeOH methanol

MgSO ₄ magnesium sulphate

NaOH sodium hydroxide

Na ₂ SO ₄ sodium sulphate

RT room temperature

TEA triethyiamine

TFA trifluoroacetic acid

T HF terrahydrofuran

Preparation of final compounds

Example 1 3-|2r{,(l!U~M^PfaQTQ"Pheπyl)~Cthylamino)^ dimethyl-benzamide

To a stirred solution of 3^2-ethoxy-3,4-dioxo-cyclobut-l-enylamino)-2-hydroxy-N.,N- dimethyl-benzamide (Intermediate A) (60mg, 0.20 mmol) in dry MeCN (1 ml) was added A- fluoropheπyiethyl amine (33mg, 0.24 mmol) and triethylamine (33μl, 0.24 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The crude product was triturated using diethyl ether. The resultant solid was purified by chromatography on silica, eluting with EtOAc/Iso-hexane 1/1 to yield the title compound as an off-white solid |M+Hj* 398. ¹ H NMR (400 MHz, DMSO-d6) S 9.95 (IH, s), 9.25 (IH, s), 8.70 (I H, d), 775 (IH, ni), 7.45 (2H, m), 7.25 (2H, m), 6.90 (2H, m), 5.35 (IH, m), 2.95 (6H, s), 1.6 (3H, d)

Examples 2-3

These compounds namely*

^-{.^^-Dioxo-l-Jttetrahydro-pyran^-ylmethyO-aminol-cyclob ut-l-enylamiiioJ-l hydroxy-N,

N-diraethyl-benzamide; ¹ HNMR oH (400MHz DMSO) 9.90 (s, IH), 8.30 (t, IH), 7.82 (d.

IH), 6.85 (m, 2H), 3,85 (q, 2H), 3.50 (U 2H), 2.90 (s, 6H), 1.75 (m. IH), 1.62(m, 2H), 1.20

(m, 2H).

2-Hydroxy-N,N-dimethyl-3-{2-| ^' (l -methyl-piperidin -3-ylroethyl)-amino)-3,4-dioxo-cyclobut-l - enylamino)-benzamide were prepared by an analogous procedure to Example I by replacing 4-aminotetrahydropyran with the appropriate amine.

Example 4

3' ⁽ 3'Hydrpxy-phenyføm|np)-4-{(R)- l-(5-methyl-furan-'2-yl)-propytamino ^' }-cyclobμt*3"ene"1)2- dione

To a stirred solution of 3 aminopheno! hydrochloride (83 mg, 0.57 mmol) in EtOH (5 ml) at room temperature was added 3-ethoxy-4"f(R)-l-(5-methyl-furaπ-2-yl)-propylaminoj"Cyciob ut- 3-ene-l,2-dione (intermediate B) (lOOmg, 0.38 mmol). Trierhylamine (0.159 ml, 1.14 mmol) was added and the reaction mixture was heated at 50 ⁰ C for 1 h. The reaction temperature was then increased to 80 ⁰ C and the reaction mixture was stirred at RT overnight. The mixture was concentrated in vacuo then dissolved in EtOAc (20 ml) and washed with 0.1 M HCi. The aqueous phase was extracted with EtOAc (3x25 ml), the organics werecombined, dried (MgSO*) and concentrated in vacuo. The crude product was triturated using EtOAcZEt ₂ O to yield the title compound as an off-white solid. (M+HJ* 327. ¹ H NMR (400 MH*. MeOD) 67.15 (IH, t), 7.00 (JH, s), 6.90 (IH, d), 6.50 (IH, d), 6.20 (IH, s), 6.00 (IH, s), 5.20 ( IH, m), 2.30 (3H _> s), 2.00 (2H, m), 1.05 (3H, t)

Example 5

3-[(ft ⁾ -ϊ- ⁽ 5-Methyl-furan-2-yl)-propy).4pμnol-4-f2-(2 _f 2 _τ 2-trif{uoro-l"hydroxy'1- trifluoromethyl-ethylVphcnylaminol-cyclobut^-ene-i^-dipfte

This compound was prepared by an analogous procedure to Example 4 by replacing 3- aminophenol hydrochloride with 2-(2-aminophenyl)-l,l ,l,3,3,3-hexafluoropropan-2-oL

Example 6

3-/2-Hvdroxv-4-methyl'phen ^γ la.mino ⁾ -4-f<S ⁾ -<tetrahvdrt>-thiophen-3-ylkminol cyclobut-3-ene- |,2-dione

To a stirred solution of 3-ethoxy-4-(2-hydroxy-4-methyl-phenyiamino)-t:yclobut-3 ene-l _> 2- dione (50 mg, 0.20 rnmol) (Tntermediate C) in EtOH (3ml) at room temperature was added (S)-(tetrahydro-thiophen-3-yl)amine (21 mg, 0.20 mmol) (Intermediate D2) followed by triethylamine (0.028 ml, 0.20 .mmol). The reaction mixture was stirred at room temperature overnight. A precipitate forms which was removed by filtration. The filtrate was evaporated to dryness in vacuo and the residue was purified by chromatography on silica during with CH ₂ CVMeOH (9/1) to yield the title compound as a yellow solid. [M.+H]* 305. ¹ H NMR (400 MHx., DMSO-d6) δ 10.00 (IH, s), 9.20 (IH, s), 8.35 (IH, d), 7.60 (IH, d), 6.70 (IH, s), 6.60 (IH, d), 4.85 (IH, $), 3.10 (IH, m), 2.90 (2H _> m), 2.85 (IH ₁ m), 2.20 (3H, s), 2.10 (2H, m)

Example 7

3-(2-Fluorθ"phenylamino ⁾ -4 (tetrahydrp-thtophen-3-ylamino)-cycbbut-3-ene-l _τ 2"dione Tlie. title compound was prepared by an analogous procedure to Example 6 by replacing 3- ethoxy-4-(2-hydroxy-4 methyl-phenykmino)-cyclobut-3-ene-i ,2-dione with Intermediate CB. IM+H1* 293. Example 8

2-f3.4>DiQxo-2-[(S)-{^yr^hydrQ-?hiPphPiπ^^-yl)Affliπ P3-<^ctobμ^V^nylamino}-l^nzok' acid

The tide compound was prepared by an analogous procedure to Example 6 by replacing 3- ethoxy-4-(2-hydroxy-4-m€thy!-phenyiamino)-cyc!obut-3-ene-l ,2-dione with Intermediate CD. (M ₊ H]* 319.

Example 9 2-(3 _f 4-Dioxo-2-[^$)'(τeff _f ihydrP-^hiθph^'3-yQg'^'"Q) ^j cyci<>but-l-enylaniino}-5-fluoro-benzoic

3£iU

S-fS-iΦChloro-benzoylj-S-fluoro-Z-hydroxy-phenylaminoj^- ethoxy-q'clobut-S-ene-l^-dione (intermediate CA) was dissolved in MeCN (1 ml) and triethylamine (0.167 ml, 1.195 mmoi) was added. {R)-l-(5-Mcthyl-furan-2-yl)-propylafn»ne toluenesulfonate salt (279 rng, 0.896 ^' mmol) (prepared according to the procedure described in US 2004/0209946 page J 9) was added and the reaction mixture was heated at 50 "C for 16 h. The solvent was evaporated in vacuo and the crude product was purified by reverse phase chromatography (Isofute™ Mash C18 50 g column) using a FlashMaster Personal™ with a GradientMaster™ eluting with 0- 100% MeCN in water. The product fractions were combined and evaporated to dryness in vacuo to yield the tide compound. |M+H]* 483. ¹ H NMR (400 MHz, MeOD) § 8.30 (IH, άά\ 7.75 (2H, d), 7.60 (2H, d), 6.95 (IH, dd), 6.25 (IH, s), 6.00 (IH, s), 5.25 (IH, t), 2.30 (3H, β), 2.05 (2H, m), 1.05 (3H, t)

Examples 10-12

These compounds namely,

3-(2-Fluoro-phcnylamiπo) ^-{tetrahydro-thiophen •3~yla.mino)-cyclobut-3-ene-l ,2-dione

[M+H]* 413.

6-Chloro-2-hydroxy-3-{2-((R)-l-(5-πit ^> thyl-furan-2-yl)-propylamino]"3,4»dioxo-cycbbut- ^' l • enylaminoj"N,N"biS"(l,l,2,2,2-pentadeurero-ethyJ)-ben7.enesu lfonamide JM+HJ* 506.

6-Chloro-2 hydroxy-3-{2-[(R)- 1 -(5-merhyl-furan-2-yl)-propylaniino]-3 _> 4-dioxo-cydobut-l - enylamino)-N-pyridin-yl-benzenesulfonamide jM+Hj* 517. were prepared by an analogous procedure to Example 9 by replacing 3-[3-(4-dhloro-benzoyi)-

5-fluoro-2-hydroxy-phenylaniino}-4-ethoxy-cyclαbur-3-ene -] ,2-dione with Intermediates CC,

HM and HN respectively. Examplc 13

^-{^AP'Oxo-^-HSVt^trghydro-thiophcn-S-yUaminol-cyςio^ut^ -enylarniiiiffi-^-fluoro-benzoic acid

To 2-amino-5-fIuorobenzoic acid (19 mg, 0.12 mmol) was added triethylamine {0.084 ml, 0.60 mmol) in EtOH (0.5 ml), followed by 3,4-diethox7-3-cyclobuten-l,2-dione (20 mg, 0.12 mmol). The reaction mixture was shaken at room temperature overnight. To the reaction mixture was added a solution of (S}-(tetrahydro-thiophen-3-yl) amine (14 mg, 0.14 mmol) (Intermediate D2) in EtOH (0.5 ml). The reaction mixture was shaken at room temperature overnight. The reaction mixture was evaporated to dryness using a Genevac™. The residue obtained was purified by preparative LC-MS (MeCN/H∑O containing 0.1% TFA) to yield the title compound. [M+H] ⁺ 337.

Examples 14-18

These compounds namely,

2-{3,4~Dioxo-2-[(sS)-(tetrahydπ>-thiophen-3-yl)amino) »cyciobut-l-eιiyiamino} -4-f{uoro-benzoic acid ¹ H NMR (400 MHz, DMSO-dά) δ 13.60 (IH, s), 10.45 (IH, s), 8.95 (IH, m), 8.00 (IH, r), 7.45 (IH, m), 6.95 (IH, m), 4.35 (IH, m), 3.15 (IH, q) 2.40 (2H, m), 2.35 (IH, m), 2.10

(2H, m),

2 {3,4-Dioxo-2-|(S)-(tetrahydro-thiophen-3-yi)amino]-cyclobut- l-enylami.no}-6-methyl- benzoic acid,

2-(3,4-Dioxo-2 -f(S)-(fetrahydro-thiophen-3"y{)amino]-cyc!obut-l-enylamino} -naphthalene-2- carboxylic acid,

3-(2-Hydroxy-5-nitro-phenylainino)"4-[(S)-(tetrahydro-thi ophen»3-yl)amino)-cyclobut-3 ene-

1 ,2-dione,

3-(5-tert Butyl-2-hydroxy-pheny{am»no)-4-|(S)-{tetrahydrθ"i:hiophen- 3-yl)aminoj"Cyc!obut-3- ene-1 ,2-dione, were prepared by an analogous procedure to Example 13 by replacing 2-amim>-5- fluorobenzoic acid with the appropriate amine.

Example 19

6-ChlQro-2-hydroxy-3-{2-[rR)-l-((2R.5R)-5-methyl-tetrahyd ro-furan-2-vπ-propvlaminol-3.4- di9χp<yclobιιtr1 eny)amino)-N _' l4-(2 _f 2.2"rrifluorp-^-hydroxy-l-trif{uoromethyl-ethyl)- phenyπ-benzenesuifonamtde 6-ChIoro-3-(2-ethoxy-3,4-dioxo-cycIobut-1-enylamino)--2-hy&l t;iroxy-N-i4-{2,2,2-trifl[uoro-l- hydroxy-l-trifluoromethyl-ethyi)-phenyl3-benzenesulfonamid� � (85 mg, 0.144 mmol) (intermediate H3) was dissolved in MeCN (5 ml) and (R)- l-((2R,5R)-5-methyl-tetrahydro- furan-2-yl)-propylamine p-toluenesulfonate salt {55 mg, 0.173 mmol) (Intermediate F3) was added, followed by triethylamine (40μl, 0.289 mmol). The reaction mixture was stirred ar room temperature for 48 h. The reaction mixture was partitioned between EtOAc (50 ml) and IM HCl (20 ml) and the organic layer was separated, dried (MgSθ4) and filtered. Silica gel (2 g) was added to the filtrate and evaporated to dryness in vacuo. The compound was dry- loaded onto a silica column (12 g) and was purified by chromatography eluting with EtOAc in iso-hexane (0-60%) using an JSCO CombiFlash™ system to yield the title compound as brown crystals. [M ₊ H) ⁺ 687. ³ H NMR (400 MHz, DMSO-d6) δ 11.45 (IH, s), 10.50 (IH, s), 9.50 (IH, s), 8.60 (IH, s), 8.25 (IH, d), 7.95 (IH, d), 7.60 (2H, d), 7.20 (2H, d), 7.10 (IH, s), 4.00 (IH, m), 3.90 (2H, m), 3.15 (IH, s), 1.95 (2H, m), 1.60 (3H, m), 1.30 (IH, m), 1.20 (3H, d), 0.90 (3H, t)

Examples 20-34

These compounds namely,

3"(lH-Berøόtriazo}4-ylamino)-4-[(R) -l -((2R,5R)"5 -methyl"ϊetrahydro-furan-2-yi)- propylaminoJ-cyclobur-S-ene-l^-dione,

6-Chloro-2-hydroxy-N-(2-methoxy-ethyl)-3-{2-ϊ(R)-l-((2R, 5R)-5 -methyl-fetrahydro-fur«'in-2- ylhpfopylaminoj-S^-dioxo-cyclobut-l-enylaminoj-benzenesulfon amide,

6-Chloro-N-cycIαpentyl-2-hydroxy-3-{2-[(R)-l-((2R _J ,5R)-5-methyl-tecrahydro-furan-2-yI)- propylaminoJ-.^^-dioxo-cyclobut-i enylarniπol -ben/enesulfonamide,

6-Chloro-2-hydroxy-N (3 methoxy-propyl)-3-{2-|(R)-l-((2R,5R)-5-methyt-tetrahydro-fur an-2- yl)-propyiamino)-3,4-dioxo<yclobut-l-enylamino{-ben7enesu lio.namide,

6-Chloro-2-hydroxy N-(4-hydroxy-cyclohexyl)-3-{2-[(R)-l-(2R _> 5R)-5-methyl-tetrahydro- furaH-2-yi)-propylainJno}-3,4-dioxo cyclobut l-enylamino} -benzenesulfonamide _>

6-Chk>ro-2-hydroxy-3-{2-((R)-l-((2R,5R)-5-mcπhyl-retr ahydro-furan-2-yl)-propylamino]-3,4- dioxo-cyclobut-l-enyla.mino}-N (tetrahydiO-ρyran-4-yl)-l>enϊ:enesulfonamide,

6 Chloro-N-(3-ethoxy-propyl)-2-hydroxy -3 {2 j(R)-l-((2R,5R)-5-methyl-tetrahydro-furan-2- yl)-propylamino)-3,4-dioxo-cyclobut-l-enylamino}-benzenesnlf onamide _>

6-ChlotO-2-hydroxy-3-{2-[(R) l-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-piOpylainino]-3 ₎ 4- dioxo-cyclobut-l -enylamino}-N-(2-propoxy evliyl) -benzenesulforiamide, e-Chiortvl-hydro^-N-U-isopropoxy-ethylJ-a-fl-ftRj-l-fZH^RJ-S -πicthyl-tetrabydrø-furan-

Z-yO-propybminol-S^-dioxo-cyclobut-i-enylaminoJ-benzenesu lfonamide,

6-Chloro-2-hydroxy-N-{3-hydroxy-pheny ^{ )-3-{2-[(R)-i-(2R,5R)~5-methyl-tetrahydro-furan-2- yl)-propylamitio|-3,4-dioxθ'Cyclobut-l-enylaπiino)-benzene sulfonamide,

N-(3-Butoxy-propyi)-6-chioro-2-hydroxy-3-{2-[(R)-l-(2R,5R )-5-methyl-tetrahydro-fuian-2- y!)-propylajninoj*3,4-dioxo-cyclobut-1.-eny!amino}-benzenesu {fonamide,

6-Chbro-2-hydroxy-N-{ 1 H-ind«zoI-4-yl)-3-{2-|[(RM -(2R,5R)-5-methyl-εetraKydro-furan-2- ylj-propylaininoj- ^j ^-dioxo-cyclobut-i-enylaminoj-benzenesulfonamide,

6-αiloro-2-hydroxy-3-{2-[(R)-I-{{2R,5R)-5-methyl-tetrahy dro-furan-2-yl)-propylamino)-3,4- dioxo-cyclobur-l-enylaπiinoj NjN-bis^ljl^^^-pentadeutero-ethyD-benzenesiilfonamidc,

6-Chioro-2-hydroxy-3~{2-l(R)-l-{(2R,5R)-5-merhyl-tetrahyd rθ"furan-2-yi)-propylaminoJ-3,4- dioxo-cyclobut-l-enyfaminoJ-N ^-pKenoxy-ethyO-benzenesulfonamide,

6-Chloro-2-hyd«o ^χ y-N-( 5-hydroxy-adamantan-2-yl)-3- (2-1(R)- 1 -((2R,5R)-5-αιethyl- tetrahydro-furan-2 yl)φropylarninoj-3,4-dioxo cyclobut-1-enyIamino)-benzenesuifonamidc,

3-f4-Chloro-3-{4-cyclopentyl~pipera7<ine-l-sulfonyl)-2 -hydroxy-phenylamino)-4-|(R)-1-

((2R,5R)-5-methy!-terrahydiO-furan-2"yl)-propylamino|-cyc lobυt-3-ene-l,2-dione,

3-[4~Chloro-2-hydroxy-3-{(S) ⁱ -3-hydroxy-pyrroUdine-l-sulfonyl)-phenyiamino)-4-[{R)- l-

({2R,5R)-5-methyl ιetrahydro-fαran-2-y{)-propylamino]-c>τlobut-3-enc-l ,2- dione, were prepared by an analogous procedure to Example 19 by replacing 6-chloro-3-{2-ethoxy-

3,4-dioxo-cydobu t- 1 -enylam jno) •2-hydroxy-N-{4-(2,2,2-trifl«oro- 1 -hydroxy- 1 - trifiuoromethyl-ethyD-pheny! J-benzeπesulfonaniide with the appropriate intermediate.

Example 37

3- ⁽ 3-Chtoro-2-hydroxy-phcMiylaniino ⁾ -4-|rR ⁾ -l-L5-methyl-furan-2-yl)φropykminol-cvcbbut-

3-ene-1 _^ 2-dione fλ^-t-Hh 361

The title compound was prepared by an analogous procedure to Example 9 by replacing 3-(3-

(4-chloro-beπzoyl)-5 fluoro-2 ^» hyd.roxy-phenylaminoj-4-ethoxy-cyclobut-.J-ene- 1,2-dione with intermediate (^E

Example 38

2- Chkm>- ⁽ >-i2-U R)- 1 -(S-roethyl-furan^ vn-propylaminol-S^-dtoxo-cvclobut- 1 -enylaminof- benzoic acid [M ₊ H]* 389 The title compound was prepared by an analogous procedure to Example 9 by replacing 3-[3- {4-dϊloro-benzoyl)-5-fluoro-2-hydroxy-phenylami-ioJ-4-ethox y-cycIobut-3-ene-1,2-dione with Intermediate CF

Example 39

3-[3-Chlorp-2-(2H _' tetrazol-5-yn^henylaminol-4-{(R)4-f5-methyl-furan-2-yl )-propylamtrio)- cvclobut-3-cne-l .2-dione [M+H]* 413

The title compound was prepared by an analogous procedure to Example 9 by replacing 3-{3- (4-chloro-ben2oyl)-5-fluoro-2-hydroxy-phenybmino]-4-ethoxy-c yclobut-3-ene-l,2-dione with Intermediate CG

Example 40

^-f|uoro^2-(2-l ^' (RWl-(5-methy| ₇ furan-^-yl)-propylaiτιino)-3.4^oxo<yciobttt- _. ^' |,-enylflφinoj.- benzoic acid methyl ester {M+H|* 387

To a mixture of intermediate j (80mg, 0.22 rnmol) in dry DMF (4 mi) was added potassium carbonate (60mg, 0.43 rnmol) and iodomethane (27μf, 0.43 rhmol). The stirring reaction mixture was heated at 40 ⁰ C for 4 hours. The resultant mixture was concentrated in vacuo. The crude material was dissolved in EtOAc and washed with aqueous acid, H2O and brine. The organic layer was evaporated and purified by chromatography on silica, eluting with iso- hexane/EtOAc 2/1 to yield the title compound as a yellow solid [M+H]' 387. ¹ H NMR (400 MHz, CDCI3) δ 10.65 (IH, β), 8.20 (IH, m), 7.15 (IH, dd), 7.30 (IH, m), 6.20 (IH, s), 5.90 (IH, s), 5.60 (IH, β), SΛ5 (IH, s), 3.95 (3H, s), 2.30 {SH, s), 2.05 (IH, m), 2.00 (IH, m), 1.05 (3H, t).

Preparation of intermediate compounds Intermediate A

Al: Preparation of intermediate Al: 2-hydroxy-N, N-dimethyl-3-nitro-benzamide 2 Nitrosalicylic acid (65 g, 0.35 mαl) was dissolved in acetonirrile (650 ml) and thionyl chloride (39 ml, 0.54 mol) was added. The reaction mixture was stirred for 3 h at 70 ⁰ C. The reaction mixture was then cooled to 5 ⁰ C and IM dimethylamine solution in THF (700 ml, 0.70 mol) was added dropwise. The reaction mixture was heated slowly to 35 °C and stirred for 30 minutes. The reaction mixture obtained was acidified to pH 2 with IM sulphuric acid and extracted with EtOAc (2 x 500 ml). The organic layers obtained were washed with HkO (300 ml), dried over NaiSO*, filtered and evaporated in vacuo, to give the title compound.

A2: Preparation of intermediate A2: 3-(2-Ethoxy-3,4-cUoxo-cydobut-l-enylamino)-2-hydroxy- N,N-dimethyl-benzamide

2~Hydroxy-N,N«dimethyl-3-nitro-bεnzaπiide {67.5 g, 0.32 mol) was dissolved in ErOH/AcOH (1 L) and degassed (4x) by evacuating and purging with argon. 7.5 g of Ru/C {7,5 g) was added and the reaction mixture was degassed (4x) by evacuating and purging with argon. The reaction mixture was healed to reflux and hydrazine inonohydrate (25 nil, 0-51 mol) was added slowly. At 1 h intervals, 3 further portions of hydrazine monohydrate (25 ml, 0.51 mol) were added. The reaction mixture was cooled to room temperature, filtered over Hyflo™ and washed with EtOH. The filtrate was evaporated in vacuo azeoptroping with toluene (4x). The residue obtained was taken up in H2O (1 L) and EtOAc (1 L). The aqueous layer was extracted with EtOAc (3x). The organic layers were washed with brine (2x), dried over Na∑SO-i, filtered and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica (500 g), eluting with EtOAc/hexane (1/1) to yield 3-aniino-2- hydroxy-N,N-dimethyl-benzarnide.

3-Amino~2-hydrpxy-N,N-dimethyl«benzamide (44 g, 0.24 mol) was dissolved in EtOH {880 ml). 3,4-diethoxy-3-cyck>buten-l,2 dione (46 g, 0.27 mol) and KiCOi (4.4 g, 0.032 mol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo. The residue obtained was purified by chromatography on silica (500 g) using CFbCh/MeOH (98/2) as the eluent. The product was suspended in iMeOH (1 L) and filtered. This process was repeated a further 3 times to to yield the title compound. [Mn-Hj ⁺ 305.

Intermediate B

S-Ethoxv^-KR^I -fi-methyl-furan^-ylt-propylanunol-cvclobut^^-ene-l.a-dioπe

3,4-diethoxy-3-cyclobute.n-l,2-dione (2.0 g, 11.5 mmol) was dissolved in EtOH (100ml). The solution was cooled to -5 ⁰ C (ice-acetone bath). 1.6 g of (R)-l-(5-methyl-furaii-2-yl)- propylamine (1.6 g, 5.1 mmol) in EtOH (100 ml) was added dropwise over 30 minutes. After warming to room temperature and stirring for 2 days, the solvenr was evaporated and the resulting oil was purified by chromatography on silca eluting with 5-10% EK-)Ac in iso- hcxaπe to afford the title compound; IH NMR OH (400MHz MeOD) 6.18 (d, IH), 5.95 (s, IH), 4.75 (in, 2H), 4.12 (q, IH), 2.05 {in, 2H), 1.92 (m, IH), 1.48 (s, 3H) 1.25 (r, 2H), 1.0 {t, 3H).

Intermediate C

3*Ethoxy-4-(2-hydroxy-4-iiiethyl-phenylami^ϋ)-ςyclobut- 3-t'!ne-l _r 2-dione To a solution of 6-amino-m-cresol (200 mg, 1.62 nimol) in EtOH (5 ml) at room temperature was added 3,4-dieεhoxy-3-cyclobuten-l,2-dione (0.24 mi, 1.62 mmol) followed by triethylamine (0.226 ml, 1.62 mmol). The reaction mixture was stirred at room temperature overnight. A precipitate was formed which was filtered and the filtrate was evaporated in vacuo. The residue formed was dissolved in EtOAc, washed with water (2x), brine and dried over MgSO* filtered and evaporated in vacuo to give the title compound as a light brown solid. (MfH]* 248.

Intermediate CA

3-f3- ⁽ 4-Chioro-ben2oyl ⁾ -5-flι>oro-2 hydroxy-p,henylarnino|-4-ethoxy-cyclohυt-3-ene l _f 2-dione The title compound was prepared analogously to Intermediate C by replacing 6-amino-m- cresol with (3-amino-5-fluofo-2-hydroxy-phenyl)'4 chIoro-phenyl)-methanone (prepared according to the procedure described in EP 65874 page 34). [M+H]* 390.

Intermediate CB

3 Ethoxv-4^2 fluoro-phenvlamino)-cvclobut-3-ene-l _r 2 dione

The title compound was prepared analogously to Intermediate C by replacing 6-amino-m- cresol with 2-fluoroaniJine. (MfH]* 236.

Intermediate CC

3-^2-Et,hoxy-3 _T 4-dipxp-cyc|obut-l-enyl|arnino)-phthalic acid 1 -methyl ester

The title compound was prepared analogously to Intermediate C by replacing 6 amino-m- cresol with Intermediate E. |M+Hj* 320.

Intermediate CD

2- ⁽ 2-Methoxy-3,4-d,ipχo-cyclobut-ϊ-enylaπunp)"benyΛ&g t;ic acid The title compound was prepared analogously to Intermediate C by replacing 6-amino-m- cresol with anthranilic acid.

IH NMR δn (400MHz DMSO) 13.85 {bs, IH), 11.25 (s, IH), 8.0 (d, IH), 7.80 (d, IH), 7.65 (t, IH), 7.22 (t, IH).

Intermediate CE

3"(3-Chloro-2-hydro ^χy -phenylam-no)-4-ethoχy-cyelobut-3-ene-^2-dione

The title compound was prepared analogously to Intermediate C by replacing 6-ainino-m- cresol with 2-amino-6-chloro-phenol |M+H] ⁺ 268.

Intermediate CF 2-Chlor9-6^2-ethoxy"3 _t 4-dtoxo-ςyς|obut-l-enylamino)-benzoic acid

The title compound was prepared analogously to Intermediate C by replacing 6-amino-m- cresol with 2-amino-<5-chloro-benzoic acid [M+H} ⁺ 296 Intermediate CG

3-{3-Ch}Qfo-2- ⁽ 2H"tetrazol-5-vπ-phenylamino)-4-ethoxy-cyck)but-3-enc -l _τ 2--dtθ-ie

The title compound was prepared analogously to Intermediate C by replacing 6-amino-m- cresol with intermediate ϊ [M+Hj* 320

Intermediate CH 2-(2-^tho?ff-3.4 dioxo-cy'ciobut-1 -enytan-ino)-5-fluorϋ ben/oic acid

The title compound was prepared analogously to Intermediate C by replacing 6-amino-m- cresol with 2-amino-5-fluorobem.oic acid [M+H]* 280

Intermediate D

($)-(yetrahydro-thiophen-3-yl)amine

Dk Preparation of Intermediate Dl: {S)-4 (2-Methylsutfanyi-ethyi)-2-phenyl-4,5-dihydro- oxazole L-Methioninol (1O g, 73,9 mmol), zinc bromide (0.042 g, 0.185 lπinol) and benzonitrile (16.8 g, 163 .mmol) were heated in an Anton Paar Synthos™ 3000 microwave reactor at 150 °C for 1.5 h. Excess benzonicriJe was evaporated in vacuo and the residue was purified by chromatography on silica (330 g column) using an 1SCO™ system eluting with a gradient of 0-100% EtOAc in iso-hexane over 70 min. The product fractions were evaporated in vacuo to yield the title product as a yellow liquid. [M+H] ⁺ 222.

U.Zλ Preparation of intermediate D2: (S)-(tetxahydro-thiophen-3-yl)amine (S)-4-{2-Meεhyl$ulfanyt-cthyl)~2-phenyl ^« 4,5~dihydro- oxazole (5.4 g, 24.2 mmol) (intermediate

Dl) was dissolved in SM HCl (30 ml). The reaction mixture was divided between two microwave vials in an Anton Paar Synthos™ 3000 microwave reaccor and heated at 140 ⁰ C for Ih. After this time, the reaction mixtures were pooled together for work-up. ErOAc (50 ml) was added to the pooled suspensions. The aqueous layer was separated and evaporated m vacuo to dryness. 20% aqueous NaOH was added to the oily residue and the emulsion was extracted with CHiCU (3x). The combined QHfeClj layers were dried over MgSO«, filtered and evaporated to dryness in vacuo (700 mbar) to afford the title product as a dark oil. IH NMR δ»ι (400MHz CDCIJ) 3.75 (m, IH), 3.05 (m, IH), 2.93(m, 4H), 2.65 (m, IH), 2.05 (m, IH), 1.92 (m, IH).

Intermediate E

3-Amino-phthatic acid 1-rnethyl ester

1.25M HCl in MeOH (1 ml, L25 mmol) was added to a solution of 3-aminophthalic acid (200mg, J.I mmol) in dry MeOH (8 ml). The reaction mixture was heated at 60 ⁰ C for 5 h and then left: stirring at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica eluting with OhCfe/MeOH (9/1) to yield the ritle product as a light yellow oil. IH NMR δ» (400MHz DMSO) 8.50 {be, 2H), 7.20 (t, ihll 6.86 (d, IH), 6.64 (d, IH), 3.70 (s, 3H).

Intermediate F

{(RV r ((2R.5R)-5-methv4-tetrahvdro-fι>ran-2--vU-propylamine para-toluenes;ulfonate sak FIi Preparation of intermediate FJ: {(R)-1-(5-Methyl-furan-2-yl)-propyI)-carbamic acid tert- butyl ester (M ₊ H]* 332

An ice-cooled solution of (RH-(5-methyl-furan-2-yl)-propylamine PTSA salt (591 mg, 1.90 mmol) {prepared according to the procedure described in UvS 2004/0209946 page 19) and Et ₃ N (0.264ml, 1.90 mmol) in dry MeCHM (4ml) was treated with BOC anhydride (456 mg, 2.09 mmol) at room temperature under an inerr atmosphere of nitrogen. The reaction mixture was stirred at 0 ⁰ C for 30 minutes and then allowed to warm to room temperature. The solvent was evaporated in vacuo and the resulting oil was dissolved in EtOAc (20 ml) and washed with IM HCl UO ml), N32SO4 (JO ml), brine (10 ml), dried over MgSO* and concentrated in vacuo. The resulting oil was dissolved in a minimal volume of EtOH and triturated with EtOAc/EtaO to afford the title compound.

F2; Preparation of intermediate F2: [(R)-l-(2R,5R)<(5-MethyI tetrahydro-furan-2-yl)-propyi3- carbamic acid tert-butyl ester

10% Pd/C (55 mg) was added to a solution of [(R)-l-{2R,5R)-(5-methyl {-uran-2-yI)-propyl]- carbamjc acid tert-butyl ester (453 mg, 1.89 mmol) (intermediate Fl) in dry MeOH (20 ml) at room temperature under an inert atmosphere of nitrogen. The resulting mixture was placed under a positive atmosphere of hydrogen and stirred vigorously. The catalyst was removed by filtration and the filtrate was reduced in vacuo to afford the title compound as a mixture of two diastereomers.

FJJi Preparation of intermediate F3: ((R)-I ■•((2R,5R)-5-methy--tetrahydro-furari-2-yl)- propylamine para-toluenesulfortate salt

To an ice-cooled solution of |(R)-l-(2R,5R)-(5-meεhyI-tetrahydro-furan-2-yl)-ρropyl}- carbamic acid tert-butyl ester (416 mg, 1.71 mmol) (Intermediate F2) in dry DCM (4 ml) was added TFA (200 μl, 1.41 mmol) under an inert atmosphere of nitrogen. After stirring at room temperature for 3 h, the mixture was diluted with EtOAc (15 ml) and washed with saturated aqueous NaiCXb. The organic portion was dried over Na?SO« and then para-toiuenesulfonic acid (147 mg, 0.77 mmol) was added. After stirring, the solvent was removed in vacuo and recrystallisation from MeCN affords the title compound as a white solid.

Intermediate G

^^J.B-^n ^y ^ffi.a^oM-ylMύno^^^hQxyi^y.clobPt^-eηe-La-dionς Gl; Preparation of intermediate Gl: 3-Bromo-6-nifro-bertzene-l,2-diamine

To a stirring solution of 2-bromo-5-nitro-amline (7.41 g, 0.034 mol) in DMSO (370 ml) at room temperature was added 1,1,1-trimethylhydrazinium iodide (6.89 g, 0.034 moi) in one portion, followed by sodium cert-pentoxide (11.27 g, 0.102 mol) porfionwise. The reaction mixture was stirred at room temperature under argon overnight. The reaction mixture was poured into ice/water. Acidified to pH 3 with 10% HCl and extracted in small batches (due to emulsion formation) with CH2CI2. The combined organic layers were dried over NazSO4 and concentrated in vacuo. The crude material was run through a silica plug using BtOAc/hexanes (1/3) as the elnent. IH NMR δ _H (400MHz DMSO) 7.32 (s, 2H), 7.30 (d, IH), 5.48 (s, 2H).

Q2ά Preparation of Intermediate G2: 7-Bromo-4-nitro-lH-ben2otriazole NaNOi (81 mg, 1.17 rnmol) was added portionwise to a solution of 3-Bromo-6-nitro- benzenε- 1,2 diamine (250 mg, 1.08 mmol) (Intermediate Gl) in AcOH (30 ml) at room temperature. The reaction mixture was heated at 60-70 ⁰ C for 1 h followed by room temperature for 1 h. The solvent was removed in vacuo then azeorroped with toluene (40 ml) to remove AcOH. The material was taken on crude to the next step. [M+Hj* 243.

GJt Preparation of intermediate G3: lH-benzotriazol-4-ylamine

To 7-bromo-4-nirro-lH -benzotriazole (250 mg, 1.03 mmol) (Intermediate G2) in dry MeOH (20 ml) at room temperature under an inert atmosphere was added 10% Pd/C (30 mg) portionwise. The reaction mixture was placed under a positive atmosphere of hydrogen and stirred at room temperature overnight. The reaction mixture was filtered through Celite™ (filter material) and concentrated in vacuo* The crude material was prcabsorbed onto silica and purified by chromatography on silca during with EtO Ac/iso- hexane (2/1) to afford the title compound as a pale brown solid. IH NMR δ _H (400MHz DMSO) 5.85 (bs, 2H), 6.35 (d, IH), 6.75 (bs, JH), 7.10 (t, IH)

.04.: Preparation of intermediate G4: 3-{lH-Benzσtria2θt-4-ylamino)-4-ethoxy-cyc-ϋbut-3-ene- \ ,2-dtone

The title compound was prepared by an analogous procedure to Intermediate C by replacing 6-amino-m-cresol with IH-benxotriazol-4-ylamine (Intermediate G3). [M +HJ ⁺ 259. Intermcdiate H

6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut- 1 -enylamtno)-2-hydroxy-N-(4-{2,2,2-trif luoro-1 - hydroxy-l-triftuoromεthyl-ethyl)-phenylj-benzenesulfonamide

HIi Preparation of Intermediate Ht; 2-rert-Butyl-6-chloro-ben*zooxazole-7-sul- ^: onic acid [4-{2,2,2-trifluoro-l -hydroxy-1 -trifluoromethyl-ethy I )~ρhenyl]-amide

2-tert-Buryl-6-chJoro-ben20oxazole-7-sulfonyl chloride (500 mg, 1.62 mmo.) {prepared according to the procedure described in US 2007/067088 page 17} , 2-(4-aminophenyl)- l,l,l,3,3,3-hexafluoropropan-2-ol (420 mg, 1.62 mmol) and triethylamine (0.226 ml, 1.62 mmol) were combined in THF (5 ml) to give a yellow solution. The reaction, mixture was stirred at room temperature for 2 h then heated at 50 ⁰ C for 48 h. The reaction mixture was partitioned between EtOAc (20 ml) and IM HCI (10 ml), live organic layer was washed with brine (10 ml), dried (MgSO-O, filtered and added to silica gel (4 g) then carefully evaporated in vacuo. The silica gel was dry-loaded onto an (Isolure™ Flash Si II 25 g) column for purification by chromatography, eluting with iso-hexane/ErOAc (10/1). The product fractions were combined and evaporated to dryness in vacuo to yield the title product. IH NMR 6 _H (400MHz DMSO) 8.55 (s, IH), 7.94 (d, IH), 7.61 (d, IH), 7.49 (d, 2H) 7.19 <d, 2H), 1.28 {$, 9H).

UZl Preparation of Intermediate H2: 3-Amino-6-chloro-2-hydroxy-N-[4-(2,2,2 trifluoro-l- hydroxy-l-triiluoromethyl-ethyO-phenylj -benzeiiesulfonamide

2-teκ-Butyl •6-ch-oro-benzoox;izole-7-sulfonic acid (4-(2,2,2 trifluoro- 1-hydroxy- i - trifluoroπκ ^> thyl-ethyi)-p.henyl)-amidc (intermediate Hl) (420 mg, 0.79 mmol), sulphuric acid (1 ml, J 8.76 mmol), 1,4-dioxane (5 ml) and water ( I ml) were combined to give a yellow solution. The reaction mixture was stirred at 100 ⁰ C overnight. The reaction mixture was extracted with EtOAc (20 ml) and the pH adjusted to pH 5 with IM NaOH (-20 mi). The organic layer was separated, dried (MgSO^ _. , filtered and concentrated in vacuo to give a brown oil. The product was purified by chromatography on silca during with iso- hexanc/EtOAc (4/1) to afford the title compound as off-white crystals; IH NMR δ"n (400MHz DMSO) 7.64 (d, 2H), 7.20 (d, 2H), 6.84 (d, IH), 6.72 (d, IH). H3: Preparation of intermediate H3: o-Chlpro-S-tl-ethoxy-S^-tiioxo-cyclobut-i-enylamipo)-

2-hy<jroxy-N-[4-(2 _t 2.2-trif!uoro-l-hydroxy-l-trifluorornetl>yl-ethyl)- phenyl]- bcnzcnesulfonamide

The tide compound was prepared analogously to Intermediate C by replacing 6-amino-m- cresol with 3-amino-6-chbro-2-hydroxy-N-f4-(2,2 _> 2-trifluoro- 1-hydroxy-l-tr.ifluoromethyi- cthyl)-phenyl]-benzenesulfonamide (Intermediate H2). IH NMR δn (400MHz DMSO, DaO)

7.52 (d, 2H), 7.38 (d, IH), 7.19 (d, 2H), 6.73 {be, IH), 4.68 (q, 2H) 1.36 (c, 3H).

Intermediates HA - HN

These compounds, namely

6-Chioro-3'(2-ethoxy-3,4-dioxo-cyclobut-l-enylamiπo)-2-h ydroxy-N-(2-methoxy -ethyl)- benzenesulfonamide (intermediate HA). [M+HJ* 405.

6-Chloro-N-cycIopentyI-3-(2-ethoxy-3 _> 4-dioxo-cyclobut- 1 ~enylamino)-2 -hydroxy • benzenesulfonamide (intermediate HB). [M+HJ* 415.

6'Chloro-3-(2-ethoxy-3 _> 4-dioxo-t7clobut-l-enylamino)-2-hydroxy-N-(3-methoxy-p ropyi)- benzeneswifbnamidc (intermediate HC) . [M+H ^' j* 41.9.

6-Chloro-3-(2-ethoxy-3,4-dioxo-cyc!obut-i-enyiamino)-2 hydroxy-N (4-hydroxy-cyclohexyl)- ben?.enesulfonamide (intermediate HD). [M+H] ⁺ 445.

6"Chloro-3-(2-ethoxy-3,4-diθλ*o-cyclobut-l-enylamino) -2-hydroλ7-N"(tetrahydro-ρyraJi-4-yl)- benzenesulfonamidc (intermediate HE). [M+H}* 431.

6 Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-l-enylamino)-N (3-ethoxy-propy])-2 -hydroxy- benzenesulfonamide (intermediate HF). [M.+HJ* 433.

6-Ch!oro-3-(2-ethoxy-3,4-dioxo cyck)but-l-enylamino)-2-hydroxy-N-(2 propoxy-ethyI)- benzenesulfonamide (intermediate HG). f M+Hj* 433.

6-Chloro- 3- (2-ethoxy-3,4-dioxo-cyclobvtt~ 1 enylamino)-2-hydroxy-N-(2-propoxy-ethyl)- benzenesuifonamide (intermediate HI). | ^' M+H]* 433.

6-Chloro -3 -(2-ethoxy-3,4-dioxo-cyclobuM "enylamiriio)-2-hydroxy-N-(3-hydroxy-phenyl)- l>enzenesulfonamide (intermediate Hj). {M+H] ⁺ 439.

N-(3 Butoxy-propyl)-6-chloro-2-hydroxy ^• 3-(2-methoxyraethyl-3,4-dicyclobut- 1 -enylamino)- benzenesulfonamide (intermediate HK). [M +H]~ 461.

6-C^hloro-3-(2 elhoxy-3,4-dioxo-cyc{obuE-l-enylamitκ>)»2-hydroxy N-(l H-iπclazol-4-yl)- benzenesulfonamide (intermediate HL). |M+HJ* 463. 6-Cbioro-2-hydroxy-3-{2-((R)- 1 -(5-merhyi-furan-2-yl)-proρylaπ}ino]-3,4-dioxo-cyclobut- 1 • enylaπαino}-N,N-(bis-l ,l,2,2,2-pentadeutero-ethyl)-benzenesul.fonaniide (intermediate HM).

(M ₊ H] ⁺ 413.

6-Chloro-3-{2-ethoxy-3,4-dioxo-cyclobut-l-enylamino)-2-hy droxy-N-pyridin-4-yI- benzenesulfonam.de (intermediate HN). {M+HJ* 424.

6-Cbloro-3-(2-ethoxy-3,4-dk>xo-cycJobυt-l-enylaππno )-2-hydroxy-N-{2-phenoxy-ethyl)- benzenesulfonarnide (intermediate HO). [M ₊ H] ⁺ 467.

6-Chloro-3-(2-cthoxy-3,4-dioxo-cyclobut-l-eny ^{ amino)-2-hydroxy-N-(5-hydroxy-adamaπtan-

2-yl)-bεnzenesuifortamide (intermediate HP}. (M ₊ H]* 497.

3-{4-Chlorø-3-(4-cyc ^{ opentyl-piperazine-l-suIfonyl)-2-hydroxy-pbenylam ino]-4-ethoxy ^» cyclobut-3-ene-l.,2-dione (intermediate HQ) [M+H} ⁺ 484

3-[4-Chloro-2-hydiOxy-3-((S)-3-hydroxy-pyrrolidine-l -sαlfonyl)-phenylamino)-4-eclϊθxy- cycbbut-3-ene-1,2-dione (intermediate HR) [M ₊ Hj ⁺ 417 were prepared by an analogous procedure to intermediate H by replacing 2-{4-aminophenyi)- ijljljSjS^-hexaftuoroproparv^-oi with the appropriate amine.

Intermediate I

3-Chbro-2^{2J-foemi2ol-5-yl)-phenylamme

To a suspension of 2-amino-6-chloroben/onitrile (350 rng, 2.29 mmoi) in dry toluene (5 ml) was added sodium azide (225mg, 3.44 mmoi) and triethylamine hydrochloride (475mg, 3.44 nrmoi). The mixrure was heated ar 100 ⁰ C for 12 hours then allowed to cool. The resultant mixture was extracted with HjO, and the aqueous layer was acidified. The resultant precipitate was collected by filtration and dried to yield the title compound as a white solid [M ₊ H] ⁺ 196

Intermediate J

5"Fluoro-2-(2-((R ⁾ -l-(5-π)ethyl"furan-2->4)-propylamino]-3 _t 4-dioxo-cycbbut-l-enylamino}- btttfgfejKid

Intermediate J was prepared by an analogous procedure to Example .9 by replacing 3-[3-(4» chloro-be ^j uoylJ-sS-fluoro^-hydroxy-phenylaminoM-ethoxy-cyclobut^ ^' J-ene-lj^ dione with

Intermediate CH; (M ₊ Hj* 373. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.