AU2007203160A1 - 5-phenylthiazole derivatives and use as P13 kinase inhibitors - Google Patents

Description

Australian Patents Act 1990 Regulation 3.2A

NO

ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title derivatives and use as PI3 kinase inhibitors" The following statement is a full description of this invention, including the best method of performing it known to us:- P/00/011 Q,\OPER\MAL\2007\JuIy\30262358 Novarti div 6 Julydoc .6/7/07 -1I- DERIVATIVES AND USE AS P13 KINASE INHIBITORS This is a divisional of Australian Patent Application No. 2003214080, the entire contents of which are incorporated herein by reference.

The present invention relates to organic compounds, their preparation and their use as INC pharmaceuticals.

a first aspect, the present invention provides compounds of. formula I R 2 R 5

I-

S> R1 or a salt thereof, wherein RL is arninocarbonyl optionally substituted by nittile, or R' is Ci-Ce-alkylcarbonyl optionally substituted by hal ogen, hydroxy, amino, C 1 -Caalkylanmizo, carboxy, Cl-Cs-aikoxycarbonyl, nitrile, phenyl, Cl-Ca-haloallcyl, or by Ci-Cs-alkyl optionally substituted by hydroxy, or R' is Cl-Ca-aJlkyLaninocarbonyl, optionally substituted by halogen, hydroxy, amino, CI-Csalkylamino, di(Ci-Ca-alkyl) amino, carboxy, Ci-Co-alkoxycarbonyl, nitrile, phenyl, C 1 -C8haloalcyl, or by Cl-Cs-alkyl optionally su~bstituted by hydroxy, or R1 is Gi-Ca-alkylcarbonyl or Ci-Ca-alkylaminocarbonyl either of which being optionally substituted by C 3 -Cs-cycloalkyl optionally substituted by hydroxy, or RI is Ci-Cs-alkylcarbonyl or Ci-Cs--allclamninocarbanyl. either of which being optionally substituted by Ci-CA-ailcoxy optionially substituted by hydroxy, or RI is Ci-Ca-alkylcarbonyl or Ci-Cs-alkylarninocarbonyl either of which being optionally substituted by phenyl optionally substituted by hydroxy or Ci-Co-alkyl, or~ RI is Ci-Ca-alkykcarbonyl optionally substituted by a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hemero atoms selected from the group conisisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Ci-CR-alkyl or Cl-Cs-alkoxy, or R' is Ci-Ce-alkylarninocarbonyl. optionally substituted by a 5- ox 6-menibered heterocyclic ring having one or more ring herero atoms selected from th~e group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Cl-Ce-ailcyl or C 1 -Csalkoxy, or 1L 1 is where a is 0 or I and Het denotes a 5- or 6-membered heterocyclic ring having one or more ring herero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, CI-CK-alkyl, Ci-Cs-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring herero atoms selected from the group consisting of oxygen, nitrogen and sulphur, Or R1 is where b is 0 or 1 and T denotes Cs-cycloalkyl optionally substituted by hydroxy, CI-Cs-akl, Ci-Cg-alkoxy, or by C 1 -Cs-alkyl substituted by hydroxy, nor T denotes plienyl substituted by hyciroxy, Ci-Cs-alkyl, Ci-Cs-ailkoxy, or by CI-Ca-alkyl 0 substituted by hydroxy;.

R2 is Cl-C3-alkyl or halogen; one of RI and R 4 is R 6 and the other is R 7

R

5 is hydrogen or hilogen; R's is hydrogen, hydroxy, amino, -SORS, -S0 1

R

8 -SOi-NI12, -SO2NBYR' 0 -CORO, -CONHRS, -NHS02zRR, nicrilc, carboxy, -OR3 or Ci-Ca-haloalkyl;

R

7 is hydrogen, R 11 halo, carboxy, -S02R 8 cyano or Cj-haloaltkyl, or, when R 4 is

R

7

PL

7 can also be -NRIzR'3, R1 4 or -OR' 4 R8 and R11 are i ndependently Gi-Ca-alkyl or C3-Ca-cycloalkyl, optionally substituted by halogen, hydroxy, Ci-CB-ailkoxy, nitrite, amino, Cj-C&-alkylaniino or di(CI-Ca-alkyl) amino; either R 9 is Ci-Cs-alkyl or C 3 -Cs-cydloalkyl, optionally substiruted by hydroxy, Ci-C-alkoxy, nitrite, amino, Cj-Cs-alkylamino, di(CI-Ca-alky[) amino or a 5- or 6-membered heterocyclic ring having one or m~ore ring hetero atoms selected from the group consisting of oxygen, nitrogari and sulphur, that ring being optionally substituted by Ci-Cs-alkyl, and RIO is hydrogen or C 1 Cg-ailcyl; or R 9 2and RIO together with the nitrogen atom to which they are attached form a or 6-membered heterocyclic ring that contains one or more furthcr hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl; either R2 2 is Ci-Cs-alkyl or C3-C-eycloaikyl optionally substituted by hydroxy, amino, C 1 -Csalkylarriho or di(Ci-C&-alkyl)amino, and R11 is hydrogen 6r Ci-Os-alkyl; or R1 2 and R1 3 together with the nitrogen atom to which they are attached form a 5- or 6- memnbered heterocyclic ring that contains one or more further herero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 .Csalkyl; and RI 4 is Ci-Cs-alkyl optionally substituted by hydroxy or -NR1R1 3.

Terms used in the specification have the following meanings: "Optionally substituted" as *used herein means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.

"cAminocarbonyl") as used herein denotes amino attached through the nitrogen atom to a carbonyl group.

S "Cl-Cs-alkyl" denotes straight chain or branched C-Cs-alkyl, which may be, for example, o methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched CK pentyl, straight or branched hexyl, straight or branched heptyl, or straight or branched octyl.

Preferably, Cl-Cs-alkyl is CI-C 4 -alkyl.

"C3-Cs-cycloalkyl" denotes cycloalkyl having 3 to 8 ring carbon atoms, for example a monocyclic group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloeptyl or cyclooctyl, any of which can be substituted by one or more, usually one or two, Ci-C 4 -alkyl groups, or a bicyclic group such as bicycloheptyl or bicyclooctyl. Preferably "C3-Cscycloalkyl" is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

C' "C-Cs-alkoxy" denotes straight chain or branched Ci-Cs-alkoxy which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branched hexyloxy, straight or branched heptyloxy, or straight or branched octyloxy. Preferably, CI-Cs-alkoxy is CI-C4-alkoxy.

"Ci-Cs-haloalkyl" denotes Ci-Cs-alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms, preferably fluorine or chlorine atoms. Preferably Ci-Cs-haloalkyl is CI-C 4 -alkyl substituted by one, two or three fluorine or chlorine atoms.

"Ci-Cs-alkylcarbonyl", "Ci-CB-alkoxycarbonyl" and "Ci-Cs-haloalkylcarbonyl" and denote Ci-Ce-alkyl, Ci-Cs-alkoxy or Cl-Ce-haloalkyl respectively as hereinbefore defined attached by a carbon atom to a carbonyl group.

"Ci-Cs-alkylamino" and "di(Ci-Cs-alkyl)amino" denote amino substituted respectively by one or two Ci-Cs-alkyl groups as hereinbefore defined, which may be the same or different.

Preferably C 1 -Cs-alkylamino and di(CI-Cs-alkyl)amino are respectively C1-C4-alkylamino and di(C1-C4-alkyl)amino.

"C3-Cs-cycloalkyl" denotes cycloalkyl having 3 to 8 ring carbon atoms, for example a monocyclic group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any of which can be substituted by one or more, usually one or two, CI-C 4 -alkyl groups, or a bicyclic group such as bicycloheptyl or bicycloocyl. Preferably "C 3 -Cscycloalkyl" is cyclopropyl, cyclobuyl, cyclopentyl, cyclohexyl, cycloheptyl or cycloocty.

r> "Halogen" or "halo" may be fluorine, chlorine, bromine or iodine; preferably it is fluorine or 0 chlorine.

S 5- or 6-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur" as used herein may be, for example, azetidine, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole,, C) thiadiazole, isothiazole, oxadiazole, pyridine, oxazole, isoxazole, pyrazine, pyridazine, pyrimnidine, piperazine, morpholino, triazine, oxazine or thiazole. Preferred heterocyclic rings S include piperazine, morpholino, imidazole, isotriazole, pyrazole, pyridine, furan, oxazole, isoxazole and azetidine.

C1 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.

Preferred compounds of the present invention include compounds of formula I in free or salt form, wherein RI is arninocarbonyl optionally substituted by nitrile, or RI- is Ci-Co-alkykcarbonyl optionally substituted by halogen, hydroxy, carboxy, Cv 1 -Cealkoxycarbonyl, nirrile, phenyl, Cl-Ca-haloalkyl, or by Ci-Cs-alkyl optionally substituted by hydroxy, or RI is Ci-Cs-alkylaminocarbonyl optionally substituted by halogen, hydroxy, di(CI-CRalkyl)ainino, carboxy, CI-Cs-allcoxycarbonyJ, nitrile, phenyl, Ci-Ca-haloalcyl, or by C 1

-CS-

alkyl optionally substituted by hydroxy, or RI is Ci-Co-alkylaminoiarboriyl optionally substituted by C3-Cs-cycloalk, or RI is Ci-Cs-alkylcarbonyl or Ci-Cs-alkylaminocarbonyl either of which being optionally substituted by Ci-Cs-alkoxy optionally substituted by hydroxy, or R' is Ci-Co-alkcylcarbonyl optionally substituted by a 5- or 6-rnembered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Cx-Cs-alkyl, or R1 is CI-Ga-alikylaminocarbonyl optionally substituted by a 5- or 6-mernbercd heterocyclic ring having one or imore ring herero atoms selected from the group consisting of oxygen, n~itrogen and sulphur, that ring being optionally substituted by Ci-Ce-alkyl, or RI is where a is 0 or 1 and Het denotes a 5- or 6-membered Nheterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Ci-Cs-alkyl, Ci-Cs-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atom s selected from the group consisting of oxygen, nitrogen and sulphur, or R1 is *here T denotes C3-Cn-cycloalcyl optionally substituted by hydroxy, Ci-Ca-aJlkyl, or by Ci-Cs-alkyl subsrirured. by hydroxy, or T denotes phenyl suibstituted by hydroxy, Ci-CR-alkcyL,.or by CL-Co-alkyl substituted by hydroxy; 0 is Ci-C;-alkl; one of R 3 and R4 is W and the other it R 7 RY is hydrogen or halogen; RI is hydrogen, hydroxy, amino, -SORs, -SOzNHi, -SOMNR1RI, -NHSORS, cyano, carboxy, -OR$ or Ci-Q-haloalcyl;

R

7 is hydrogen, -OR] fluorine, chlorine, bromidne, nitrile or Ci-Q-haloalkyl, or, when R 4 is R7, P%7 can also be -NR12R13 or -OR14; RB and R" are independently Ci-Co-alkyl; either RI is Ci-Cs-alkyl optionally substitued by hydroxy, Ca-Ca-cydloaflcl optionally substituted by hydroxy, CI-C8-alkoxy, nitrile, di(Cu-Co.allcyl)-amino or a 5- or 6-membered heterocyclic ring having one or more ring hetcro atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Ci-Cs-alkyl, and R'D is hydrogen or C,-Cs-alkyl; or R9 and RIO together with the nitrogen atom to which they are attached form a 5- or 6-mezabered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and :nitrogen, that ring being optionally substituted by C 1 Cl-alkyl;I either R12 is Ci-Cg-alkyl optionally substituted by cfi(Ci-Ce-alyl)axnino, and R 1 3 is hydrogen or Ci-CR-alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached form a or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Cj- Ca-alkyl; and R14 iS Ci-Ca-alkyl.

Further preferred compounds of formula I in free or salt form include those wherein RI is arninocarbonyl optionally substituted by nitrile, or RI iS Cl-C4-alkylcarbonyl optionally substituted by halogen, hydroxy, carboxy, CI-CV alkoxycarbonyl, nitrile, phenyl, Ci-C4-baloalkyl, or by Ci-C4-alkyl optionally substituted by hydroxy, or RI is Ci-C4-alklaminocarbonyl optionally substituted by halogen, hydroxy, di(C 1

-C

4 alkyl)arnino, carboxy, Ci-C4-alkoxycarbonyl, nitrile, phenyl, Ci-Q~-haloalkyl, or by Ci-Qalkyl. optionally substituted by hydroxy, or RI is Ci-C4-alkylaminocarbonyl optionally substituted by C3-Cs-cycloalkyl, or RI is Ci-C 4 -alkylcatbonyl or C1-C4-alkylarninocarbonyl either of which being optionally substituted by CI.C4-allcoxy optionally substituted by hydroxy, or RI is CI-C4-alkylcarbonyl optionally substituted by a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hatero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cv-alkyl, or RI is Cl-C4-alkylamtinocarbonyl optionally substitued by a 5- or 6-ruembered heterocyclic ring having one or more ring hecero atoms selected from the group consisting of oxygen, nitrogen arnd sulphur, that ring being optionally substituted by Ci-C 4 -alkyl, or RI is -(C=O)-(N4H)rHet where a is 0 or 1 and H-et denotes a 5- or 6-membered Nheterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, CI-C 4 -alkyl,.

CI-C

4 -alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring herero atoms selected from the group consisting of oxygen, nitrogen and su lphur, or RI is where T denotes C3-Cs.-cycloalkyl optionally substituted by hydroxy, C-q4-alkyl, or by Cl-C4-alkyl substituted by hydroxy, or T denotes phenyl substituted by hydroxy, Ci-C 4 -2lkyl, or by Ci-Q-alkYl substituted by hydroxy; R2 is Cl-C3-alcyl; one of R.

3 and R.

4 is R6 and the other is R 7 Rs is hydrogen or halogen; R6 is hydrogen, hydroxy, amino, S02aRS, S0?aNH 2 S02NR9RW0, NHSOIRS, nitrile, carboxy,

OR

8 or Ci-C 4 -hlaloalkyl;

R

7 is hydrogen, -OR" 2 fluorine, chlorine, bromine, cyano or Ci-Q-haloalkyl, or, when R 4 is

R

7

R

7 Can also be -NR17R13 or 0R14.

R3 and R11 are independently Cl-C 4 -alkyl; either RV is Ci-C 4 -alkyl optionally substituted by hydroxy, Ci-Cs-cycloaukyl optionally substituted by hydroxy, Cl-C 4 -alkoxy, nitrile, di(QC4-alkyl)aniino or a 5- or 6-membered heterocyclic ring having one or more ring hctero atoms selected from the group consisting of IDoxygen and nitrogen, that ring being optionally substirtuted by CI-C4-allcyl, azid RIO is hydrogen or CI-C 4 -alkyl; or W~ and RIO together with the nitrogen atom n to which they are atrached form a 5- or 6-nlembered heterocyclic ring that contains one or more further heero, atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Cj- C4-alkyl; r-either R12 is Ci-Cq-alkyl optionally substituted by di(QC4-alkyl)arnino, and RI3 is hydrogen or 0 Ci-C4-alkyl; or RL' and R13 together with the nitrogen atom to which they are attached form a or 6-niembered heterocyclic: ring that contains one or more fu~rther hetero, atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Cj- C4-alkyl; and R14 is Ci -4 alkyl.

In a second aspect, the present invention provides compounds of formula I in free or salt form, wherein RI is arninocarbonyl, or R' is Ca-Cs-alkylcarbonyl optionally su.bstituted by hydroxy, amino, Cl-Cs-alkylamino, carboxy, Ci-Ca-alkyl optionally substituted by hydroxy, or by halogen, or RI is Ci-Cs-alkylaminocarbonyl optionally substituted by laydroxy, amino, Cj-C&alkylanino, di(Ci-Cs-allcyl(arnino), carboxy, Ci-Ce-alkyl optionally substituted by hydroxy, or by halogen, or RI is Ci-Ce-alkylcarbonyl or Ci-Co-alkylaminocarbonyl. either of which being optionally substituted by Ca-Cs-cydloalkyl optionally substituted by hydroxy, CI-C 8 -alkoxy optionally substituted by hydroxy, Ci-Cs-alkoxycarbonyl, nitrile, halogen, phenyl optionally substituted by hydroxy or Ci-Cs-alkyl, or R 1 is Ci-Ci-allcylcarbonyl optionally substituted by a 5- or 6-menbered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Cl-Co-alkyl or Ci-Co-alkoxy, or RI is Ci-Ce-alkylaminocarbonyl optionally substituted by a S- or 6-membered heterocyclic ring havin~g one or more ring herero atoms selected fromt the group consisting of oxygen, nitrogen and sulphur, rhat ring being optionally substituted by hydroxy, QCRs-a.kyl or C 1 -Cr ailcoxy, or R 1 is where a is 0 or 1 and Het denotes a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consising of oxygen, nitrogen and sulphur, that ring being optionally substituted by hiydroxy, Ci-Ca-alkyl or QCs-, alkoxy; R2 is Cl-C3-alkyl or halogen; one of R 3 and R4~ is R6 and Ehe other is R7; R.s is hydrogen or halogen; R.9 is hydrogen, hydroxy, amino, -SORS, -SO 1 RS, -SOiNI- 2 -SOaNRIO, -CORI, -CONHRO,

-NH-SO

2 nitrile, carboxy, -OR' or CI-Cs-haloalkyl;

R.

7 is hydrogen, Ri!, -ORUl, halo, carboxy, -SO2.R9, cyano or Ci-Cs-haloalkyl, or, when R.

4 is R7, R7 can also be -NRZRI3, R 14 or -OR' 4 and R1 1 are independently Ci-Cs-alkyl or C3-Ce-cycloalkyl, optionally substituted by halogen, hydroxcy, Ci-Cs-alkoxy, nitrile, amino, Ci-Co-allcylamino or di(C,-Cs-alkyl)ainino; either V' is Ci-Cs-alkyl or C3-Cs-cycloaikyl, optionally substituted by hydroxy, Ci-CB-alkoxy, nitrile, amino, Ci-C-alkylaio, di(Cj-Cs-alkyl)amino or a S- or 6-xnerbered heterocyclic ring having onc or more ring herero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally subsritut~d by Ci-Cs-alkyl, and RIO is hydrogen or C 1 Cs-alkyl; or R9 and RIO 0 togerher with. the nitrogen atom to which they are attached form a or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl; either R 1 7 is Ci-CH-alkyl or C3-Cs-cyd~oalkyl optionally substituted by hydroxy, amino, C 1 -Csallcylamino or di(Ci-Ca-alkyl)amjno, and R1 3 is hydrogen or Ci-Ca-alkyl; or R12 and R 1 3 together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocycic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by QCsalkyl; and R14 is Ci-Cs-alkyl optionally substituted by hydroxy or -NR1-'Ri3.

Preferred compounds include compounds of formula I wherein RI is aminocarbonyl, or RI is Ci-Cv-alkylcarbonyl optionally substituted by hydroxy, carboxy, Ci-C-alkyl IND optionally substituted by hydroxy, or by halogen, or RI is Ci-Ca-alkylarninocarbonyl optionally substituted by hydroxy, di(Ci-Cs-alkylainino), carboxy, CI-Cs-alkyl optionally substituted by hydroxy, or by halogen, or RI is Ci-Ca-alkylcarbonyl or Cl-Ca-alkylaminocarbonyl either of which being optionally substituted by C3-Ca-CYClOalkyl optionally substituted by hydroxy, CI-Ca-alkoxy optionally substituted by hydroxcy, Ci-Cralkoxycarbonyl, nitrile, halogen, phenyl optionAy substituted by hydroxy or Ci-Ca-Akyl, or RI is Ci-Cs-alkylcarbonyl optionally substituted by a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero, atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substirorcd by Ci-Cs-alkyl or Ci-Cealkoxy, or RI is CI-Cs-alkylaminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring herero atoms selected from the group consisting of ox~ygen, nitrogen and sulphur, that ring being optionally substituted by QCfi-alkcyl or CI-Ce-alkoxy, or RI is whcre a is 0 or 1 and Het denotes a 5- or 6-rnembered Nheterocyclic ring optionally substituted by hydfoxy, Ci-Cs-alkyl or Ci-Ca-alkoxy;

R

1 is Ci-Ci-alkyl; one'of R3 and R4 is R 6 and the other is R 7 is hydrogen or halogen; R6 is hydrogen, hydroxy, amino, -SO2R8, -SOzNHz, -SOaNR 9 RO, -NHSO2RO, cyanko, carboxy, -OR' or C1-C4-haloalkyl; is hydrogen, -OR" 1 fluorine, chlorine, bromine, cyano or Ci-C 4 -halaalcyl, or, when R 4 is R7', R7 can also be -NRllR23 or -0R 14 R& and R11 are independently CI-CII-alkyl; either RP is Ci-Ce-ailcyl optionally substituted by hydroxy, C3-Cs-cycloalkyl optionally substituted by hydroxy, Ci-Cs-alkoxy, nitrile, di(C,-Cs-alkyl)am-ino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionially substituted by Ci-Cs-allcl, and RIO is--hydrogen,, or Ci-Cs-ailcyl; or RI and. RIO together with the nitrogen atom to which they-are attached. formi a 5- or 6-mcmbered heterocyclic ring that contains one or more further hetero atoms selected 0 from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Cl- Co-alkyl; 0either R11 is Ci-Ca-alkyl optionally substituted by di(Ci-Ca-aUkyl)arnino, and R 1 3 is hydrogen or Ci-Ca-alkyl; or R1 2 and R 13 together with the nitrogen atom to which they are attached form a or 6-nicmbcred heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 Cs-alkyl; and R1 4 is Ct-Ca-alkyl.

In a third aspect, the present invention provides compounds of formula 1 RI is Ci-CB-alkylcarbonyl or Cl-C8-alkylaninocarbonyl optionally substituted by amino, carboxy, Cj-Cs-alkoxy, Ci-C8-alkoxycarbonyl, nitrile; or by halogen, or R1 is Cl-Cs-alklcarbonyl optionally substituted by a 5 or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Cl-Cs-alkyl, or RI is Ci-Cs-alkylaminocarbonyl, optionally substituted by a 5 or 6-xnembered heterocyclic ring having one or more ring herero atom's selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-ailkyl; R2 is Ci-C 3 -alkyl or halogen; one of R 3 and R 4 is R 6 and the other is R 7 is hydrogen or halogen;

R

6 is hydrogen, hydroxy, amino, SORO, MI 2 R% SO 2 NJ.1, SO2NR-9RIO, CORO; CONHRB, NHS02R8, nitrile, carboxy, ORB or Ci-Cs-haloalkyl;

R

7 is hydrogen, R11, OR", halo, cyano, carboxyi SO 2 RR,, or Ci-Ce-haloalkyl, or, when R4 isR,

R

7 can also be NRI 2 R'3 R 1 4 or OR' 4

;I

RO and R1 1 are independently Ci-Cs-alkyl or C3-Cs-cycloaLkyl, optionally substituted by halogen, hydroxy, Ci-CR-alkoxy, nitrile, amino, Ci-Cs-ailcylamino or di(Cz-Co-alkyl) amino; either is Ci-Cs-alkyl or Cs-Cs-cycloalkyl, optionally substituted by hydroxy, Ci-Cf-alkoxy, nitrile, amino, Ci-Ce-alkylamino, di(Cl-Cs-alkyl)amino or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms sciected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-CR-alkyl, and RIO is hydrogen or C,- Co-alkyl; orRW and RIO together with the nitrogen atom to which they are attached form a 5 or 6- membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, thar ring being optionally substituted by Gi-Cs-alkyl; either R 1 2 is Ci-Cs-alkyI or C3-Cs-cycloalkyl optionally substituted by hydroxry, amnino, CI-Csalkylamino or di(Cr-Cs-aLkyl)amino, arnd RI" is hydrogen or Ci-Cl-alkyl; or R' 1 and R1 3 together with the nitrogen atom to which they are attached form a 5 or 6- mnemnbered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Caalkyl; and R'M is Ci-Ce-alkyl optionally substituted by hydroxy or NRZR13.

Preferred compounds include compounds of formula 1, wherein R, is Ci-Cs-alkylcarbonyl or CI-CQ-alkylarminocarbony1 optionally substituted by carboxy or Ci-Ca3-alkoxycarbonyl; RZ is Ci-Ci-alkyl; one of W 3 and R 4 is R6 and the other is R 7 RS is hydrogen or halogen; R6 is hydrogen, hydroxy, amino, SO-.Rg, SO 2 NI-1 2 SOaNR-RIOS

NHSO

2 cyano, carboxy, ORB or Cl-C4-haloalkyl;

R

7 is hydrogen 1 OR"l, fluorine, chlorine, bromine, cyano or Cl-C4s-haloalk-yl, or, when Rl is

R

7 can also be NRU-RI3 or O)U14 RI and R 11 are independently Ci-Cs-alkyl; either R9 is Ci-Cs-alkyl or C3-Ca-cycloalkyl, optionally substituted by hydroxy, Ci-Cs-alkoxy, nitrile, di(Ci-C8-alkyl)amino or a 5 or 6-mernbered heterocyclic ring having one or more ring hetero, atoms selected from rho group consisting of oxygen and nitrogen, that ring being optionally substituted by Cl-Cs-alky1, and R3O is hydrogen or Ci-Co-alkyl; or R9 and R11) together with the nitrogen atom to which they are attached form a 5 or 6- membered hererocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring* being optionally substituted by Ci-CR-alkyl; either R 12 is Ci-Cs-alkyl optionally substituted by di(Cj-CB-alkyl)aznino, and R1 3 is hydrogen or C,-CH-alkl; or R1 2 and R13 together with the nitrogen atom to which they are attached form a or 6- membered heterocyclic ring that contains one or more further hcrero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Ci- Co-alkyl; and R14 is Ci-Ca-alkyl.

Many of the compounds represented by formula I are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid S addition salts of the compound of formula I include those of inorganic acids, for example, O hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic \0 monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and c butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, C. dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic C- hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene- 2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures.

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. These salts may be prepared from compounds of formula I by known salt-forming procedures.

In those compounds where there is an asymmetric carbon atom the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures. The present invention embraces both individual optically active R and S isomers as well as mixtures, e.g. racemic or diastereomeric mixtures, thereof.

Specific preferred compounds of formula I are described hereinafter in the Examples.

The invention provides, in another aspect, a process for preparing a compound of formula I in free or salt form which comprises the steps of: for the preparation of compounds of formula I where R' is CI-Cs-alkylcarbonyl or Ci-Cs-alkylaminocarbonyl optionally substituted by amino, carboxy, C 1 -Cs-alkoxy, Ci-Cs-alkoxycarbonyl, nitrile or halogen, 13or R' is Ci-Cg-alkylcarbonyl optionally substituted by a 5 or 6-membered Sunsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl, 0 or R' is Ci-Ce-alkylaminocarbonyl optionally substituted by a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by SCi-Cs-alkyl, reacting a compound of formula II

II

BrB S R wherein R 1 and R 2 are as hereinbefore defined, with a compound of formula III

R

5

B(OH)

2

R

3 R4 wherein R 3

R

4 and R 5 are as hereinbefore defined, in the presence of a transition metal catalyst; for the preparation of compounds of formula I where R 3 or R 4 is -SO 2

NH

2 or -SO2NRR

O

reacting a compound of formula IV

R

2 7N S O R 3 R

V

CI

wherein R 1

R

2

R

5 and R 7 are as hereinbefore defined and the -SOzCI group is meta or para to the thiazole ring, with ammonia or a compound of formula R'R 1 0

NH;

for the preparation of compounds of formula I where R 3 or R 4 is NHS0 2

R

8 reacting a compound of formula I where one or R 3 and R 4 is NH 2 with a sulfonyl chloride of formula R'SOzCI; -14for the preparation of compounds of formula I where R 4 is NRi 2

R

13 reacting a compound of formula I where R 4 is halogen and R 3 is SO 2

R

8 with a compound of t formula V \12 0

R\

R/NH

V

O R13 S where R 1 2 and R 13 are as hereinbefore defined; for the preparation of compounds of formula I where R 1 is optionally substituted 0 Ci-Cs-alkylaminocarbonyl, reacting a compound of formula I where R 1 is hydrogen with a compound of formula VI R1l-N=C=O VI R's-N=C=O, wherein R 1 5 is Ci-Cs-alkyl optionally substituted by carboxy or CI-Csalkoxycarbonyl; for the preparation of compounds of formula I where one of R 3 and R 4 is amino and the other is hydrogen or halogen and at least one of R 3

R

4 and R 5 is halogen, halogenating a compound of formula I where R 3 or R 4 is amino and the other is hydrogen; reacting a compound of formula VII R 0

VII

R

3

R

4 wherein R 2

R

3

R

4 and R 5 are as hereinbefore defined and X is halogen, with a compound of formula VIII

NH

2 S CN/H

VIII

R

wherein R 1 is as hereinbefore defined; for the preparation of compounds of formula I where R 3 or R 4 is -SO 2 RS and R 8 is methyl, reacting a compound of formula IV wherein R 2

R

5 and R 7 are as S hereinbefore defined and the -SOzCl group is meta or para to the thiazolyl ring, with an alkali metal sulphite and an alkali metal bicarbonate, followed by reaction Swith bromoacetic acid or an alkyl halide;

\O

for the preparation of compounds of formula I where RI is Ci-Cs-alkylamino- 0 carbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and 0 sulphur, that ring being optionally substituted by Ci-Cs-alkyl or Ci-Cs-alkoxy, or where R 1 is where a is 0 and Het denotes a 5- or 6-membered C heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Ci-Cs-alkyl, Ci-Cs-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or where RI is where b is 0 and T denotes C3-Cs-cycloalkyl either of which optionally substituted by hydroxy or T denotes phenyl substituted by hydroxy, C I-Cs-alkyl, Ci-Cs-alkoxy, or by Ci-Cs-alkyl substituted by hydroxy, reacting a compound of formula I where RI is hydrogen with a compound of formula

IX

R1'-C 0

IX

O-H

where R 1 6 is Ci-Ca-alkyl substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl or Ci-Ce-alkoxy, or R 16 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Ci-C-alkyl, Ci-Ca-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 6 is C 3 -Cs-cycloalkyl optionally substituted by hydroxy, Ci-Cs-alkyl, Ci-Cg-alkoxy, or by C 1 -Cs-alkyl substituted by hydroxy, 15A or R16 is phenyl substituted by hydrogy, Ci-Cs-alcyl, Ci-Ca-alkoxy, or by Ci- Cg-alkyl substituted by hydroxy, or for the preparation of compounds of formula I where

R

1 is Ci-Co-alkylaminocarbonyl optionally substituted by halogen, hydroxy, amino, CI- Cs-ailcylamino, di(.Cx-Cs-alkyl)aminoj carboxy, Ci-Ca-alkoxycarbonyl, nitrile, phenyl, Ci-Cs-haloalkyl, or by C-Cs-alcyl optionally substituted by hydroxy, or~ R 1 is Ci-Ce-ailcylaminocarbonyl optionally substituted by Ci-Cs-cycloalkyl optionally substituted by hydroxy, or RI is Ci-Cs-alkylaminocarbonyl optionally substituted by Ct-Ce-allcoxy optionally substituted by hydroxy, or RI is Ci-Cs-alkylaminocarbonyl optionally substituted by phenyl. optionally substituted by hydroxy or Ci-Cs-allcyl, or RI is Ci-Cs-alkylaminocarbonyl optionally substituted by a 5- or 6-membered hecerocydic ring having one or more ring herero atoms selected from the group, consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, CI-Cs-alkyl or Ci-Cs-alkoxy, or R 1 is where a is 0 or 1 and Het denotes a 5- or 6-znembered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxcy, Q -Cs-alkyl, Ci-Cs-alkoxy or -by a 5- or 6-membered hererocyclic ring having one or more ring hetero, atoms selected from the group consisting of oxygen, nitrogen and sulphur, or RI is where b is 0 or 1 and T1 denaotes C3-CR-cycloallcyl optionally substituted by hydroxy, C2-G5-alkyl, Ci-Cs-alkoxy, or by CI-Cs-'alkyl substituted by hydroxy, or T denotes phenyl substitu~ted by hydroxy, C1-CR-alkyI, CI-Ca-alkoxy, or by Ci-Ca-alkyl substituted by hydroxy, reacting a compound of formula X 1 ~N S

X

Fl 3 wherein R2, R 3

K

4 and R 5 are as hereinbefore defined, with a compound of forrmula Ml I/NH X1 R 1 -Iwhere RIT and R's are selected from hiydrogen, hydrox-y, amino, C 1 -Gs-alkylatnino, di(CI-Cv-aflkyl(arn-ino), carboxy, Ci-Cs-alyl optionally substituted. by hydroxy, nhalogen, Cs-Cscycloalkyl optionally substitued by hydroxy, CI-Cs-alkoxy optionally substituted by hydroxy, CI-Cs-allcoxycarbonyl, nitrile, halogen, phenyI optionally substituted by hydroxy or CI-Cs-allcyl, and a 5. or 6-membercd heterocyclic ring having one or more ring hetero atoms selected from the grouip consistig of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydlroxy, QCC-alkyl or C-3 alkoxy, or when RI is R 1 is hydrogen and RIB is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Ci-Cs-alkyl, Ci-Ci-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atorns selected from the group consisting of oxygen, nitrogen and sulphur, or when R1 is R 17 Is hydrogen and RIB is either C 3 -CR-cycloalkyl optionally substituted by hydroxy, QC 1 -Cu-atkyl, C2-Cs-alkoxy, or by CI-Cs-alkyl substituted by hydroxy, or RIB is phenyl substituted by hydroxy, C 1 -Cs-allcyl, C 1 -Csalkoxy, or by C 1 -Cl-alkyl substituted by hydroxy; and Ui) recovering the -resultant compound of formula I in free or salt form.

Process variant may be carried out using known Suzuki reaction procedures, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent such as dimethoxyethane (DME) usually in the presence of aqueous alkali metal carbonate. The reaction temperature may be from room temperature to 1000 C, but conveniently 800 C. The palladium catalyst may be, for example, a bis(triarylphosphine) S palladium halide.

Process variant may be carried out using known procedures for preparation of sulphonamides from sulfonyl chlorides, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an aqueous solvent or an organic solvent, e.g. an ether such as dioxane, usually in the presence of an alkali metal carbonate. The reaction temperature may N be from 00 C to 1000 C, but conveniently room temperature.

NC Process variant may be carried out using known procedures for reaction of amines with sulfonyl chlorides, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent, e.g. dimethylformamide (DMF), usually in the presence of an alkali metal carbonate. The reaction temperature may be from 0 0 C to 1000 C, but conveniently room temperature.

Process variant may be carried out using known procedures for reaction of aryl halides, ortho to an electron withdrawing group, with primary or secondary amines, or analogously, e.g. as hereinafter described in the Examples. It may be carried out either neat or in an organic solvent, e.g. dimethylsulphoxide. The reaction temperature may be from 1000 C to 1700 C but conveniently about 120 o C to 1400 C.

Process variant may be carried out using known procedures for reaction of amines with acylating agents or isocyanates, or analogously, e.g. as hereinafter described in the Examples.

It may be carried out in an organic solvent, e.g. dimethylformamide. The reaction temperature may be from 00 C to 1000 C, but conveniently room temperature.

Process variant may be carried out using known procedures for halogenating anilines, or analogously, e.g. as hereinafter described in the Examples. Chlorination may be carried out using hydrogen peroxide, acetic acid and hydrochloric acid, for example as described in S.

Mukhopadhyay, K.H. Chandnani and S.B.Chandalia, Organic Process Research Development, 1999, 3, 196-200. The reaction temperature may be from 0° C to 50° C, but conveniently room temperature. Mono-bromination may be carried out by reaction with Nbromosuccinimide (NBS) in an organic solvent, preferably dimethylsulphoxide. But mono- or di-bromination may be carried out by reaction with bromine in an organic solvent, e.g. an CN ether such as dioxane. In both cases the reaction the reaction temperature may be from 00 C to 50° C, but conveniently room temperature.

Process variant may be carried out using known procedures for preparing aminothiazoles, or analogously, e.g. as hereinafter described in the Examples. The halogen X is preferably I0 bromine. The reaction may be carried out in an organic solvent, e.g. an alcohol such as CM ethanol. The reaction temperature may be from room temperature to the reflux temperature of CN the solvent, but conveniently from about 500 C to 600 C Process variant may be carried out using the procedure known in R. W. Brown, Journal of Organic Chemistry, 1991, 56, 4974 for converting sulfonyl halides to sulfones, or analogously, e.g. as hereinafter described in the Examples. It may be carried out with the alkali metal sulphite, e.g. sodium sulphite, and the alkali metal bicarbonate, e.g. sodium bicarbonate in water at a temperature from 200 C to 1000 C, but conveniently at about 75° C. The reaction with bromoacetic acid may be carried out at temperature from 50° C to 1500 C, but conveniently at about 1000 C. An alkyl halide, e.g. iodomethane may be used in place of bromoacetic acid Process variant may be carried out using known procedures for reacting amines with carboxylic acids, or analogously, e.g. as hereinafter described in the Examples. The reaction may be carried out in an organic solvent, e.g. dichloromethane, in the presence of a coupling agent, e.g. HATU, and a base, e.g. triethylamine. The reaction temperature may be from 00 C to 50° C, but conveniently room temperature.

Process variant may be carried out using known procedures for reacting isocyanates with amines, or analogously, e.g. as hereinafter described in the Examples. The reaction may be carried out in an organic solvent, e.g. dioxane or DMF. The reaction temperature may be an elevated temperature, for example from 50O C to 1000 C, but preferably about 800 C.

Process variant may be carried out using known procedures for converting alkylcarbonylamines to amines, or analogously, e.g. as hereinafter described in the Examples.

The reaction may be carried out in an organic solvent, e.g. ethanol, in the presence of a base, preferably a strong base such as sodium hydroxide. The reaction temperature may be an elevated temperature, for example from 50 C to 100° C, but preferably about 900 C.

0O

IND

The compounds of formula I in free or salt form can be recovered from reaction mixtures and purified in a conventional manner. Isomer mixtures can be separated into individual isomers, e.g. enantiomers, in a conventional manner, e.g. by fractional crystallisation.

Compounds of formula II may be prepared by the method known in Garreau, Bull. Soc. Chim.

Fr, 1954,1048, or analogously, e.g. as hereinafter described in the Examples.

Compounds of formula III are commercially available.

Compounds of formula IV may be prepared by reacting a compound of formula XII wherein R 1

R

2

R

5 and R 7 are as hereinbefore defined, with nitrous acid to give a diazo compound which is then reacted with sulphur dioxide in the presence of copper chloride, for example by the method described in E. E. Gilbert, Synthesis 1969,1-10, to give the corresponding sulfonyl chloride of formula IV.

Compounds of formula IV may also be prepared by reacting a compound of formula XIII R2 Rs H R S

XIII

RR

wherein R 2

R

5 are as hereinbefore defined and R 7 is halogen or OR" with chlorosulfonic acid or analogously, e.g. as described in the Examples.

Compounds of formula V are either available commercially or may be prepared by known methods.

Compounds of formula VI are either available commercially or may be prepared by known methods.

Compounds of formula VII may be prepared by reacting a compound of formula XIV R 3

XIV

wherein R 2

R

3

R

4 and R 5 are as hereinbefore defined, with an halogenating agent, for example bromine, or analogously, e.g. as described in the Examples.

Compounds of formula VIII are commercially available or may be prepared by known methods.

Compounds of formula IX are commercially available or may be prepared by known methods.

Compounds of formula X may be prepared by reacting a compound of formula I wherein R' is hydrogen with phosgene, or analogously, e.g. as described in the Examples.

Compounds of formula XI are commercially available or may be prepared by known methods.

Compounds of formula XII may be prepared by reduction of compounds of formula XV Rp2 o wherein R 2

R

5 and R 7 are as hereinbefore defined, using standard techniques known for the reduction of aromatic nitro compounds to anilines, for example catalytic hydrogenation using a transition metal catalyst, preferably palladium on carbon, in an organic solvent, e.g.

ethyl acetate, under an atmosphere of hydrogen.

Compounds of formula XIII may be prepared by reacting the corresponding ketone of formula

XVI

S wherein R 2

R

3

R

4 and R 5 are as hereinbefore defined and X is halogen, with a compound of formula VIII wherein R I is as hereinbefore defined, or analogously, e.g. as described in the NO Examples.

0 S Compounds of formula XIV where either R 3 or R 4 is independently SO 2

NH

2 or SO 2

NR

9

R

1 0 IND may be prepared by reacting a compound of formula XII where R I and R 2 are as hereinbefore M defined and one of R 5 or R 7 is hydrogen, the other being halogen or OR", with chlorosulfonic C acid followed by treatment with an amine or ammonia, or analogously, e.g. as described in the S Examples.

O

(N

Compounds of formula XIV may also be obtained from commercially available compounds of formula XVII

H

R

s

CO

I XVII

R

by known methods, for example as described in R.V. Heinzelman, Organic Synthesis 1963, IV, 573.

Compounds of formula XV may be prepared as described in process variant or by known procedures, for example as described in J. Liebscher, E. Mitzner, Synthesis, 1985, 4, 414-417.

Compounds of formula XVI may be prepared by reacting a compound of formula XVIII R CO

R

7 R[ R 7 XVIl wherein R 2

R

5 and R 7 are as hereinbefore defined, with an halogenating agent, for example bromine, or analogously, e.g. as described in the Examples.

Compounds of formula XVII where R 3 is SO 2

CH

3 are available from commercial sources or may be prepared from compounds of formula XVI where R 3 is halogen, for example by the method described in A. Ulman and E. Urankar, J. Org. Chem., 1989, 54, p 4691-4692.

S Compounds of formula XVIII are commercially available or may be prepared by known methods.

\O0 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 _0 hydrates or solvates containing a solvent used for crystallization. Compounds of formula I can CC be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as C1 enantiomers, may be obtained in a conventional manner, e.g. by fractional crystallization or 0 asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, CN1 starting materials.

Compounds of formula I and their pharmaceutically acceptable salts, hereinafter referred to alternatively as agents of the invention, are useful as pharmaceuticals. In particular, they exhibit inhibition of phosphatidylinositol 3-kinase (Pi3 kinase) enzymes, especially the gamma isoform (p1lOy), which are responsible for generating phosphorylated signalling products. The inhibitory properties of compounds of formula I may be demonstrated in the following test procedures: Baculovirus expressing different fragments of PI3Ky fused to GST have been previously described by Stoyanova, Bulgarelli-Leva, Kirsch, Hanck, Klinger, Wetzker, Wymann, M.P. (1997) Lipid- and protein kinase activities of G protein-coupled PI 3-kinase g: structure-activity analysis and interactions with wortmannin. Biochem. 324:489.

Residues 38-1102 of human PI3Ky are subcloned into the BamH1 and EcoR1 sites of the transfer vector pAcG2T (Pharmingen) to create a GST-PI3Ky lacking the first 37 residues of PI3Ky. To express the recombinant protein, Sf9 (Spodoptera frugiperda 9) insect cells are routinely maintained at densities between 3 X 10 5 and 3 X 106 cells/ml in serum containing TNMFH medium (Sigma). Sf9 cells, at a density of 2 X 106 are infected with human GST- PI3KyA34 baculovirus at a multiplicity of infection of 1 for 72 hours. The infected cells are harvested by centrifugation at 1400 g for 4 minutes at 4' C and the cell pellets are frozen at -80' C. Both Sf9 and Sf21 cells work equally well. Sf9 cells (1X10 9 are resuspended in 100 ml cold C) lysis buffer (50 mM Tris-HCI pH 7.5, 1% Triton X-100, 150 mM NaCI, 1 mM NaF, 2 mM DTI and protease inhibitors. Cells are incubated on ice for 30 minutes then centrifuged at 15000 g for 20 minutes at 4" C. Purification of the supernatant sample is carried out at 4" C by affinity chromatography using SEPHAROSETM agarose gel beads coupled to glutathione (from Amersham Pharmacia Biotech). A cell lysate/GST resin ratio of 50:1 is used.

'4 The GST resin is firstly pre-rinsed to remove ethanol preservative and then equilibrated with lysis buffer. Cell lysate (supernatant) is added (usually as 50 ml lysate to 1 ml GST resin in IN ml tubes) and gently rotated on a mixer at 4' C for 2-3 hours. The unbound flow through sample is collected by centrifugation at 1000g for 5 minutes at 4' C using a DENLEY

M

S centrifuge. The 1 ml GST resin containing bound material is transferred to a 15 ml I FALCON T M centrifuge tube for subsequent washing and elution steps. Firstly a series of 3 cycles of washings (mixing by gentle inversion) is performed with 15 ml ice cold wash Buffer A r1 (50 mM Tris-HCl pH 7.5, 1% Triton X-100, 2 mM DTT) interspersed with centrifugation at 0 1000g for 5 minutes at 4" C. A final single wash step is performed with 15 ml ice cold wash CN Buffer B (50mM Tris-HCl pH 7.5, 2 mM DTT) and then centrifuged at l000g for 5 minutes at 4" C. The washed GST resin is finally eluted with 4 cycles of 1 ml ice cold elution buffer mM Tris-HCl pH 7.5, 10 mM reduced glutathione, 2 mM DTT, 150 mM NaCI, 1 mM NaF, ethylene glycol and protease inhibitors) interspersed with centrifugation at 1000g for minutes at 4' Samples are aliquoted and stored at -20° C.

An in vitro kinase assay was established that measures the transfer of the terminal phosphate of adenosine triphosphate to phosphatidylinositol. The kinase reaction is performed in a white 96 well microtitre plate as a Scintillation Proximity Assay. Each well contains 10 pl test compound in 5% dimethylsulphoxide and 20 pl assay mix (40 mM Tris, 200 mM NaCI, 2 mM ethyleneglycol-aminoethyl-tetraacetic acid (EGTA), 15 pg/ml phosphatidylinositol, 12.5 pM adenosine triphosphate (ATP), 25 mM MgCl 2 0.1 pCi 33 P]ATP). The reaction is started by the addition of 20 pl of enzyme mix (40 mM Tris, 200 mM NaCI, 2 mM EGTA containing recombinant GST-pllOy). The plate is incubated at room temperature for 60 minutes and the reaction terminated by the adding 150 pl of WGA-bead stop solution (40 mM Tris, 200 mM NaCI, 2 mM EGTA, 1.3 mM ethylene diamine tetraacetic acid (EDTA), 2.6 pM ATP and mg of Wheat Germ Agglutinin-SPA beads (Amersham Biosciences) to each well. The plate is sealed, incubated at room temperature for 60 minutes, centrifuged at 1200 rpm and then counted for 1 minute using a scintillation counter. Total activity is determined by adding 10 pl of 5% dimethylsulphoxide (DMSO) and non-specific activity is determined by adding 10 pl mM EDTA in place of the test compound.

Compounds of the Examples hereinbelow have ICso values below 0.6 pM in the aforementioned assay. For example the compounds of Examples 8, 48, 80, 138, 156, 165 and 178 have ICso values of 0.009, 0.018, 0.013, 0.005, 0.002, 0.019 and 0.040 respectively.

Having regard to their inhibition of phosphatidylinositol 3-kinase enzymes, compounds of formula I in free or pharmaceutically acceptable salt form, hereinafter alternately referred to as ID "agents of the invention", are useful in the treatment of conditions which are mediated by the activation of the Pi3 kinase enzymes, particularly inflammatory or allergic conditions.

Treatment in accordance with the invention may be symptomatic or prophylactic.

M Accordingly, agents of the invention are useful in the treatment of inflammatory or obstructive C1 airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodelling or disease progression. Inflammatory or obstructive Ci airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".) Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. 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. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALl), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other

C

N inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, acute, arachidic, catarrhal, croupus, chronic or IND phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the

O

present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether 0 chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, M including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, o silicosis, tabacosis and byssinosis.

N Having regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, agents of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophilrelated disorders of the airways consequential or concomitant to L6ffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.

Agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.

Agents 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, treatment of diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology, including autoimmune haematological disorders haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune S inflammatory bowel disease ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, IN multiple sclerosis, primary billiary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including IN idiopathic nephrotic syndrome or minal change nephropathy).

M Other diseases or conditions which may be treated with agents of the invention include septic C1 shock, rheumatoid arthritis, osteoarthritis, proliferative diseases such as cancer, athersclerosis, O allograft rejection following transplantation, stroke, obesity, restenosis, diabetes, e.g. diabetes NC1 mellitus type I (juvenile diabetes) and diabetes mellitus type II, diarrheal diseases, ischemia/reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygeninduced retinopathy, and conditions characterised by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.

The effectiveness of an agent of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal model, e.g. a mouse or rat model, of airways inflammation or other inflammatory conditions, for example as described by Szarka et al, J. Immunol. Methods (1997) 202:49-57; Renzi et al, Am. Rev.

Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J. Clin. Invest. (1995) 96:2924-2931; and Cernadas et al (1999) Am. J. Respir. Cell Mol. Biol. 20:1-8.

The agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine 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. An agent of the invention may be mixed with the 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 an agent of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory or antihistamine drug substance, said agent of the invention and said drug substance being in the same or different pharmaceutical composition. Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone, ciclesonide or mometasone, LTB4 antagonists such as those described in US5451700, LTD4 antagonists such as montelukast and zafirlukast, dopamine receptor agonists such as cabergoline, S bromocriptine, ropinirole and 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]-sulfonyl]ethyl]amino]ethyl]-2(3H)-benzothiazolone and pharmaceutically acceptable salts thereof (the INO hydrochloride being Viozan® AstraZeneca), and PDE4 inhibitors such as Ariflo® (GlaxoSmith Kline), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma) and PD189659 (Parke-Davis). Such _0 bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular CM ipratropium bromide, oxitropium bromide and tiotropium bromide, and beta-2 adrenoceptor C' agonists such as salbutamol, terbutaline, salmeterol and, especially, formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of PCT International patent publication No. WO 00/75114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula

O

H CH 3

HO

OH

and pharmaceutically acceptable salts thereof. Co-therapeutic antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride. Combinations of agents of the invention and steroids, beta-2 agonists, PDE4 inhibitors or LTD4 antagonists may be used, for example, in the treatment of COPD or, particularly, asthma. Combinations of agents of the invention and anticholinergic or antimuscarinic agents, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonists may be used, for example, in the treatment of asthma or, particularly, COPD.

Other useful combinations of agents of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCRS, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5Hbenzocyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4aminium chloride (TAK-770), and CCR-5 antagonists described in US 6166037 (particularly S claims 18 and 19), WO 00/66558 (particularly claim and WO 00/66559 (particularly claim 9).

O

The agents 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 0 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 KN in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory S bowel disease.

O

The present invention also provides a pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor. The composition may contain a co-therapeutic agent such as an anti-inflammatory, bronchodilatory 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 HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanol (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 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. 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 an agent of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form, an inhalable medicament comprising an agent of the invention in inhalable form; a pharmaceutical product comprising such an agent of the invention in inhalable form in association with an inhalation device; and an inhalation device containing an agent of the invention in inhalable form.

Dosages of agents 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 oral administration are of the order of 0.1 to 10 mg/kg.

EXAMPLES

Compounds of formula I which are also of formula XIX

H

3

C\

are shown in the Table 1 below, the method of preparation being described thereafter. The table also shows mass spectrometry data. The examples are in free form.

29 TABLE 1 Compounds of the invention

Ex. Ra R b Rc RrI/sH se0H H 427.3

CH/CH

3CH I' 26 0I clC H 337.8 27 0I clC 408.9 0 NH2 0_ C3 28 OCH 3 0 H 370.9 29OCH 3 \0H 0C 414.9 0l

CH

3

OCH

3 H -~CH 3 341.9 0 NH0 31 OCH 3 H ~CH 3 413.0 H 0 32 OCH 3 0 H "Y CH 3 400.0 01' 0 33 OCH 3 'o H CH 3 425.0 Q) 0 34 OCH 3 0 H CH 3 427.0 sH H1 N 0 0 10 32 Ex. Rb Rc MH+ 00H 3 0H C. H 3 427.0 0 0

IND~

36 OCH 3 /0H OH 3 469.0 0/ 0 37OCH 3 0H ~CH3 439.0 sH NH 0Y 0

N-)

OCH

3 0o H OH 3 36.0

S

39 OH 3 3 0IHC 3 41.

1x R R b Rc MH+ 42 OCH 3 0 H NCH 3 371.0 0 43 OCH 3 o H CH O 3 385.1 44 OCH 3 H ~CH 3 366.0 071

N

H H OH 3 310.97 o H 3 0 46 H 0 H C3 335.97 0

N

47 F \H ~CH 3 328.97 oCH 3 0 48 CI H C3 344.94 CH3 0H 49 H H, ,o H H 3 312.0 H

H

HCH

3 395.0 0 51 H 0o H '~CH 3 397.0 N 0

C/

S

0

CH/~

N-CH 3

CH'

S! 0 0 CH 3 Ex. Ra R b Re MH+ 61 H H37.

H

3 62o H H 384.0 CH 0 M 63 \oBr H CHO 3 388.8 64I 0~ F H >CH 329.02 OH H 3 0 \o CF 3 H OH 3 378.5

CH

3 0 66 cI H OH 3 344.7

OCH

3 67 0H OH 3 409.14 C~H

N

CH

3 68 0o H N..CH 3 411.11

N

OH

3 690H CH3 411.14 3 0 CH" CH 3 36 C1 n/s Ex. Ra Rb Rc MH+ 0 H C3 425.02 3

OH)

71 0 H 3 439.15 0 O 3 3 0III c-I

OH

3 72 \o:1 F H H 286.99 C3 73 0F H H358.04 o H O 3 0 CH 3 74 OH H H OY H 3 277.0 o 0 H -~CH 3 320.1 0 ~OH0 76 H H H '~CH 3 329.1 O 0 0

N

Preparation of Specific Examples Abbreviations used are as follows: DCM is dichioromethane, DIPEA is diisopropylethyla mine DME is dimethoxyethane, HATU is 7-azabenzotriazol- 1-yl)-N, N'-tetramethyluroniumn hexafluorophophate, NBS is N-bromosuccinimide and THF is tetrahydrofuran.

Example 1 N-S-( 4 -Methanesulfonylamino-1phenyl)-4-methyl-thiazo[-2ylla cetamide: 1 a) N [5-(4--Amino-phenyl )-4-methyl-thiazol-2-yl] -acetamide: (I4 N-[4-Methyl-5-(4-nitro-phenyl)-thiazol-2-yl]-acetamide Liebscher, E. Mitzner, Synthesis, 1985, p 414) (10.0g, 3.6 mmol) is dissolved in ethyl acetate THF 600 ml) and IO stirred at room temperature under an atmosphere of argon. The solution is then treated with palladium on carbon (10 The reaction mixture is purged three times with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture is then filtered through ND celite T filter material and the catalyst is washed with tetrahydrofuran (600 ml). The solvent is C removed in vacuo to leave N-[S-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide as an off- C white solid.

C1 lb) N-[S-(4-Methanesulfonylamino-phenyl)-4-methyl-thiazol-2-yl]-acetamide: N-[S-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (0.05 g, 0.20 mmol) is dissolved in dimethylformamide (1 ml) and treated by a solution of methylsulfonyl chloride (0.0232 g, 0.20 mmol) in dry dimethylformamide (1 ml) followed by 2M aqueous sodium carbonate solution (0.20 ml, 0.40 mmol). The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is purified by chromatography to give the title compound. MH+ (ESMS): 326.1 Example 2: N-{5-[4-(Butane-l-sulfonylamino)-phenyll-4-methyl-thiazol-2-yl}-acetamide: This is prepared as described in example lb by replacing methylsulfonyl chloride with nbutylsulfonyl chloride. MH* (ESMS): 368.1 Example 3 N-[4-Methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide: 3a) 4 2 -Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride: N-[5-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example la) (7.9 g, 31.9 mmol) in suspension in glacial acetic acid (250 ml) is treated with a 32 aqueous HCI solution (40 ml).

The resulting solution is then cooled approximately to 100 C and treated dropwise with a solution of sodium nitrite (2.2 g, 31.9 mmol) in water (2 ml). After 10 minutes the reaction mixture is added to a stirred solution of S0 2 /AcOH/CuCl 2 /H20 (200 ml) (the preparation of the reagent is described below). The reaction mixture is allowed to warm to room temperature and is stirred overnight.

The reaction mixture is then poured into water (1000 ml) and extracted with ethyl acetate (3 x 300 ml). The combined organic layers are washed with water (2 x 250 ml) followed by brine C1 (200 ml) and dried over MgSO4. After filtration the solvent is removed in vacuo to give 4-(2chloride. MH+ (TOF, MS 248.1 Preparation of the reagent SOz/AcOH/CuCI2/H 2

O:

According to the reported procedure E. Gilbert, Synthesis 1969, 1-10, p6), glacial acetic I\D acid (100 ml) vigorously stirred at room temperature is treated by bubbling SOz gas. Once a saturated solution is achieved (approximately 10 g per 100 ml), the solution is treated with S copper (II) chloride (4 g) in water (5 ml). The resulting mixture is allowed to settle to give a green solution.

O

3b) N-[4-Methyl-S-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide: 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (3a) (3.8 g, 11.5 mmol) is dissolved in dioxane (50 ml) with stirring. Sodium carbonate (2.45 g, 23 mmol) is added followed by a solution of ammonia in dioxane (50 ml, 0.75 After stirring for 2 hours at room temperature diethyl ether (120 ml) is added and the solid precipitate is removed by filtration. The solid is stirred in tetrahydrofuran (200 ml) and the mixture is then filtered through celite T filter material to remove inorganic material. Removal of the solvent affords

N-[

4 -methyl-5-(4-sulfamoyl-phenyl)-thiazol-2-yl]-acetamide.

Example 4 N-[5-(4-Amino-3-chloro-phenyl)-4-methyl-thiazol-2-yll-acetamide: Following a general procedure for chlorination of anilines Mukhopadhyay, K. H.

Chandnani, S. B. Chandalia, Organic Process Research Development, 1999 3, p196) hydrogen peroxide (27 solution in water, 5.1 ml, 40 mmol) is added dropwise over minutes to N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide la (5.0 g, 20 mmol) stirred in acetic acid (30 ml) and concentrated hydrochloric acid (6.7 ml) at room temperature.

When the addition is complete the mixture is poured onto ice water and the pH adjusted to alkaline by addition of 4M aqueous sodium hydroxide solution. The mixture is then extracted with ethyl acetate, followed by dichloromethane. The combined organic extracts are dried (MgSO4) and the product mixture is absorbed on silica. Chromatography on silica eluting with hexane ethyl acetate affords three fractions: The first fraction is identified as 4 -amino-3,5-dichloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 4a). MH* (TOF, MS ES+) 316.1, 318.1, 320.1. The second fraction is identified as the title compound, N-[S- 4 -amino-3-chloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 4b). MH* 282, 284 The third fraction is unreacted starting material (Example la).

(I Examples 5 to 8 These products are obtained in a two step sequence from the corresponding anilines (4a, 4b, ID 7a, 8a) following analogous conditions to those described for the conversion of N-[5-(4-aminophenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) to the corresponding sulfonamide (Example 3b).

M Example 5 3-Chloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yll-acetamide: N1 Using N-[S-(4-amino-3-chloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 4b) affords the title compound as an orange solid. MH+. (TOF, MS ES+) 345.9, 347.9 Example 6 3.S-Dichloro-4-sulfamoyl-phenyl )-4-methyl-thiazol-2-yll-acetamide: Using N-[S-(4-amino-3,5-dichloro-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 4a) affords the product as a white crystalline solid. NM+ (TOF, MIS ES+) 380.0, 382.0, 384.0 Example 7: N-[5-(3-Bromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yll-acetamide: 7a) N-[5-(4-Amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide: NBS (2.52 g, 14.7 mmol) is added to a stirred solution of N-[S-(4-amino-phenyl)-4-methylthiazol-2-yll-acetamide (Example 1a) (3.5 g, 14.7 mmol) in dry dimethylsulphoxide (50 ml) at 100 C. After 10 minutes the solution is diluted with water (200 ml) and the resulting precipitate is removed by filtration. Crystallisation from ethyl acetate methanol affords the title compound. NM+ (TOF, MS 325.9, 328.9 7b) N- [S-(3-Bromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide: The title compound is obtained from N-t5-(4-amino-3-bromo-phenyl)-4-methyl-thiazol-2-y]acetamide (Example 7a) to give a cream solid. MI-V (TOF, MS ES+) 390.1, 391.1, Example 8 :N-f S-(3,5-Dibromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yll-acetamide: 8a) N-[IS-(4-Amino-3,-dibromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide: Bromine (0.083 ml, 1.6 mmol) is added dropwise over 10 minutes to a stirred solution of N- [5-(4-amino-phenyl )-4-methyl-thiazol-2-yl]-acetamide (Example 1 a) (0.20 g, 0.81 mmol) in 1,4-dioxane (S ml). When the addition is complete the mixture is diluted with saturated sodium hydrogen carbonate solution (30 ml) and extracted with dichloromethane (2 x 30 ml).

The combined organic extracts are dried (MgSO 4 filtered, and the solvent removed to give a dark solid. Crystallisation from methanol dichioromethane yields the title compound. MWH (TOF, MS 403.7, 405.6, 407.6 8b) 3,S-Dibromo-4-sulfamoyl-phenyl)A4-methyl-thiazol-2-yl]yacetamide: Using N-[S-(4-amino-3,S-dibromo-phenyl)-4-methyl-thiazol-2-yl..acetamide (8a) affords the ID title compound. MWH (TOF, MS 467.8, 469.8, 471.8 Example 9: 4 -(2-Acetylamino-4-methyl-thiazol-5-yl)-2,6-dibromo-benzenesulfonic acid: This compound is obrained as a minor component in the preparation of example 5 from 4 -amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide; The crude product mixture obtained in the preparation of example 8 is filtered through celiteTM filter material washing with tetrahydrofuran to give 3,S-dibromo-4-sulfamoyl-phenyl)-4-methyl-thiazol-2y].

acetamide Washing the celite'm filter material with ethanol then affords the title compound. M-H+ 466.7, 468.6, 470.6 Example 10: N-[ 4 -Methyl-5-(4-methylsulfamoyl-12henyl)-thiazol-2-yll-acetamide: 4 2 -Acety lam ino-4-methyl-thi1azol-5-yl)-benzenesulfonyl chloride (Example 3a) (0.05 g, 0.15 mmol) is dissolved in dioxane (1 ml). The solution is treated with 2M aqueous sodium carbonate (0.15 ml, 0.24 mmol) followed by the addition of a 33% solution of methylamine in ethanol (0.08 ml, 0.6 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by prep LC-MS i.e. liquid chromatography mass spectrometry to give N-[ 4 -Methyl-S-( 4 -methylsulfamoyl-phenyl)-thiazol-2.yl]-acetamide.

MHW

(ESMS): 326.1 Examples 11 to 16 These compounds, namely 4 -dimethylsulfamoyL-phenyl)-4-methyl-thiazol-2-yl].

acetamide (Mp 279-281o N-5(-tyslaolpey)4-ehltizl2y]aeaie N-[5-(4-cyclopropylsulfamoyl-phenyl )-4-methyl-thiazol-2-yl]-acetamide, N-1S-[4-(2-hydroxyethylsulfamoyl)-phenyl] -4-methyl-thiazol-2-yl)-acetamide, N-{5-[4-(2-cyano-ethylsulfamoyl)phenyl]-4-methyl-thiazol-2-yl)-acetamide and 4 2 -methoxy-ethylsulfamoyl)-phenyl-4methyl-thiazol-2-yl}-acetamide respectively, are prepared in an analogous manner to Example by reaction of the appropriate amine with 4 -(2-acetylamino-4-methyl-thiazol-5-yl)benzenesulfonyl chloride (3a).

Example 17: N-S-(4-Methanesulfonyl-12henyl)-4-methy-thiazol-2-yl]acetamide: 17a) N-(4-Methyl-thiazol-2-yl)-acetamide: 2-Amino-4-methylthiazole (10.0 g, 87.6 mmol) is dissolved in dry pyridine (75 ml) at room NO temperature. This solution is then treated dropwise with acetyl chloride (6.3 ml, 87.6 mmol).

After 2 hours, the reaction mixture is poured into water (1000 ml), and extracted with ethyl acetate (3 x 250 mi). The combined organic layers are washed with water (2 x 200 ml), brine IO (200 mi), dried over MgSO 4 filtered and concentrated in vacuo. The residue is dissolved in M toluene (200 mi) followed by the removal of the solvent in vacuo. The solid thus obtained is 0 CN dried in vacuo to give the title compound.

S17b) N-(S-Bromo-4-methyl-thiazol-2-yl)-acetamide: N-(4-Methyl-thiazol-2-yl)-acetamide (Example 17a) (4.0 g, 25.6 mmol) is dissolved in glacial acetic acid (100 ml) at room temperature. This solution is then treated portionwise with N-bromosuccinimide (4.6 g, 25.6 mmol). After 48 hours the reaction mixture is poured into water (1000 ml) and extracted with ethyl acetate (3 x 250 ml). The combined organic layers are washed with water (200 ml), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in toluene (100 ml) followed by the removal of the solvent in vacuo. This is repeated twice more and the resulting solid is dried in vacuo at 400 C to give N- (5-bromo-4-methyl-thiazol-2-yl)-acetamide.

17c) N-[5-(4-Methanesulfonyl-phenyl)-4-mehyl-thiazol-2-yl]-acetamide: N-(5-Bromo-4-methyl-thiazol-2-yl)-acetamide (Example 17b) (0.1 g, 0.43 mmol) is dissolved in DME (2 ml) at room temperature. This solution is treated with [(4-methylsulfonyl) phenyl] boronic acid (0.172 g, 0.86 mmol), followed by 2M aqueous Na2CO 3 (0.63 ml, 1.29 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.03 g, 0.043 mmol). The mixture is then heated at 800 C for 4 hours. The solvent is removed in vacuo and the residue is purified by preparative LCMS to give 4 -methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide.

MH(ESMS): 311.0, Mp 251-253oC Examples 18 to 23 These compounds, namely 4 -acetyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, N-[4methyl-5-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-acetamide, N-[S-(4-hydroxy-phenyl)-4methyl-thiazol-2-yl]-acetamide, 3 4 -dimethoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide, N-[S-(3-cyano-phenyl)-4-methyl-thiazol-2-yl]-acetamide and N-[4-methyl-5-(3-trifluoromethylphenyl)-thiazol-2-yl]-acetamide respectively, are prepared in an analogous manner from the appropriate boronic acid following the procedure described for Example 17.

C

N Example 24 3 4 -Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yll-ureido)-acetic acid: ethyl ester 24a) 4-(2-Amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide: Concentrated hydrochloric acid (15 ml) is added to a stirred suspension of ND dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (example 11) (6.26 g, 18.5 mmol) c in ethanol (120 ml). The reaction is heated at 850 C until no starting material remains (4 Cg hours). The reaction is allowed to cool and the solvent removed to give the hydrochloride salt as a yellow solid. Aqueous sodium hydroxide (4M) is added and the mixture is stirred vigorously for 30 minutes before extracting with chloroform followed by ethyl acetate. The combined organic extracts are dried (MgSO 4 filtered and the solvent is removed to give the title compound. MH* (TOF, MS, 427.3 24b) (3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido)-acetic acid ethyl ester: 4 2 -Amino- 4 -methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and ethyl isocyanatoacetate (0.05 ml, 0.34 mmol) are stirred in dimethylformamide at 1000 C for 3 hours. The mixture is then partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic extract is washed with brine, dried over MgSO 4 and the solvent removed in vacuo. Purification by preparative HPLC affords the title compound. MH (TOF, MS, 441.4 Example 25 3-{3-[5-(4-Dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-propionic acid ethyl ester: Using 4 2 -amino- 4 -methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and replacing ethyl isocyanatoacetate with ethyl 3-isocyanatopropion-ate (0.05 ml, 0.34 mmol) in the above reaction affords the title compound.

Example 26 4 2 -Amino- 4 -methyl-thiazol-5-yl)-2.6-dichloro-benzenesulfonamide: A solution of 3 ,5-dichloro-4-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) (0.70 g, 1.84 mmol) in aqueous hydrochloric acid (5M, 10 ml) and ethanol ml) is heated at reflux for 90 minutes. When cool, the mixture is concentrated to remove ethanol and the aqueous solution is brought to pH 9 by addition of aqueous sodium hydroxide The product is extracted with n-butanol (50 ml) and the organic extract is dried over MgSO 4 Removal of the solvent followed by chromatography on silica (eluting with ethyl acetate hexane, 2:1 increasing to 4:1) affords the title compd. MH+ (MS, 337.8, 339.5 Example 27 ,2,6-Dichloro-4-[2-( 3 -ethyl-ureido)-4-methyl-thiazol-S-yll-benzenesulfonamide Ethyl isocyanate 0.015 ml, 0.19 mmol) is added to a stirred solution of 4 -(2-amino-4-methyl- ID thiazol-S-yl)-2,6-dichloro-benzenesulfonamide (Example 26) (0.043 g, 0.127 mniol) in dry dimethylformamide (1.0 ml) under argon. After heating at 850 C for 3 hours more ethyl isocyanate (0.015 ml, 0.19 mmol) is added and heating continued for a further hour. The ID reaction is concentrated in vacuo and the product is purified by chromatography on silica M eluting with ethyl acetate hexane 1 increasing to 4: 1) to give the title compound. MH+ (TOF, MS, 408.9, 410.9, 412.8 Example 28 5-[ 2 3 -Ethyl-ureido)-4-methyl-thiazol-5-yll-2-methoxy-benzenesulfonamide 2 8a) N-[S-(4-Methoxy-phenyl)-4-methyl-thiazo-2yl..acetamide: 4-methoxyphenylacetone (10 g, 60.9 mmol), N-acetylthiourea (7.2g, 60.9 mmol) and iodine (15.46 g, 60.9 mmol) in pyridine (50 ml) are stirred at 70 0 C for 16 hours. The mixture is concentrated and the residue is purified by chromatography on silica with iso-hexane-ethyl acetate to give the titled compound.

2 8b) S-( 4 -Methoxy-phenyl)-4-methyl-rhiazol-2-ylamine: A solution of concentrated hydrochloric acid HC1 (20 ml) in water (30 ml) is added to Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 28a) (2 g, 7.63 mmol) in ethanol. After 5 hours at reflux, the reaction is poured into water (600 ml) and the pH is adjusted to 9/10 with 2.5 M NaOH. The aqueous layer is then extracted with ethyl acetate (3 x 200 ml). The combined organic layers are dried over MgSO 4 filtered and concentrated to afford S-(4-Methoxy-phenyl)-4-methyl-thiazol-2-ylamine.

28c) 1 -Ethyl-3- [5-(4-methoxy-phenyl)-4-methyl-thiazol-2-ylJ urea: Ethyl isocyanate (1.2 ml, 14.18 mmol) is added to S-(4-methoxy-phenyl)-4-methyl-thiazol-2ylamine (Example 28b) (1.56 g, 7.09 mmol) in dioxane (100 ml). After Shours at reaction mixture is concentrated to yield I -ethyl-3-[S-(4-methoxy-phenyl)-4-methyl-thiazol-2yl]urea as a brown solid.

28d) 5-2(-ty-rio--ehltizl5y]2mtoybneeufnlhoie A suspension of 1-.ethyl-3- [S-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl] urea (Example 28c) g, 3.44 mmol) in dichloromethane (15 ml) is added portionwise to chiorosulfonic acid ml, excess) cooled at -100 C. The temperature is kept below 00 C throughout the addition. The reaction mixture is left to warm up to room temperature. After 3 hours, the reaction mixture is poured carefully onto ice (2 litres). Once ice is melted, the aqueous layer is extracted with I dichloromethane (DCM) (3 x 200 ml). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated to afford 5-[ 2 -(3-ethyl-ureido)-4-methyl-thiazol- 5-yl]-2-methoxy benzenesulfonylchloride.

S28e) 3 -Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamide: N To a stirred solution of S-[ 2 3 -ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesulfonylchloride (Example 28d) (0.2 g, 0.514 mmol) in dioxane (10 mi) is added 2 M S Na 2

CO

3 (0.515 ml) followed by 0.5 M NH 3 in dioxane (2.06 mi). After 2 hours at room temperature, the reaction mixture is poured into water (200 ml) then extracted with ethyl acetate (3 x 50 ml). The combined organic layers are dried over MgSO 4 filtered and concentrated to afford S-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxybenzenesulfonamide as a yellow powder.

Example 29: 5-[2-(3-Ethyl-ureido)-4-methyl-thiazol-5-ll-.N.-(2-hydroxy-ethylbenzenesulfonamide To 5-[ 2 -(3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesu Ifonylchloride (Example 28d) (0.2g, 0.514 mmol) in dioxane (10 ml) is added 2M Na 2

CO

3 (0.515 ml) followed by ethanolamine (0.031 ml, 0.514 mmol). After 2 hours at room temperature, the reaction mixture is poured into water (150 ml) ethylacetate (50 ml) and sonicated. The layers are separated then the aqueous layer is extracted with ethyl acetate (3 x 50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford a sticky oil which is dissolved in a minimum amount of DCMI methanol and dried at reduced pressure to afford 2 3 -ethyl-ureido)- 4 -methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-2-methoxy-benzenesulfonamide as a yellow foam.

Example 30 N-1S-( 4 -Methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-vll-acetamide: 2 -Methoxy-5-(2-oxo-propyl)-benzenesulfonamide: 4 -methoxyphenylacetone (5 g, 30 mmol) is added dropwise to chlorosulfonic acid (14.25 ml, 0.21 mol) at below 00 C and the mixture is stirred at room temperature for 2 hours. The mixture is poured into crushed ice and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over Na 2

SO

4 After removal of the solvent, the residue is dissolved in tetrahydrofuran (50 ml) and concentrated ammonia (8 ml) is added dropwise. The '4 mixture is stirred at room temperature overnight and concentrated. To the residue is added water, the precipitates are collected by filtration and recrystallised from methanol to give the ID titled compound.

0 30b) S-(l1-Bromo-2-oxo-propyl)-2-methoxy-benzenesulfonamide: IND 2-Methoxy-5-(2-oxo-propyl)-benzenesulfonamide (Example 30a) (0.5g, 2.05 mmol) in dry M THF (15 ml) is added dropwise to a solution of 2-carboxyethyltriphenylphosphonium N1 perbromide (1.24 g, 2.15 mmol) in dry THF (10 ml). The mixture is stirred at room temperature for 3 hours, filtered and then concentrated. The residue is purified by richromatography on silica with hexane ethyl acetate to give the titled compound.

N-[S-(4-Methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide: 5-(l1-Bromo-2-oxo-propyl)-2-methoxy-benzenesulfonamide (Example 30b) (0.2 g, 0.64 mmol) and N-acetylthiourea (0.075 g, 0.64 mmol) in ethanol (3 ml) are stirred at 700 C for 4 hours.

The mixture is concentrated and the residue is recrystallised from ethanol to give an off-white solid. MH+ (ESMS): Mp 341.90 C Example 31 N-15-[3-(2-Dimethylamino-ethylsulfamoyl)-4-mnethoxcy-p2henyll-4-methyl-thiazol- 2-yll-acetamide: 31 a) N- [5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide: 4-methoxyphenylacetone (10 g, 60.9 mmol), N-acetylthiourea (7.2 g, 60.9 mmol), iodine (15.46 g, 60.9 mmol) in pyridine (SO ml) are stirred at 70 0 C for 16 hours. The mixture is concentrated and the'residue is purified by chromatography on silica with hexane-ethyl acetate to give the titled compound.

31 b) [3-(2-Dimethylamino-ethylsulfamoyl)-4-methoxy-phenyl]-4-methyl-thiazol-2-yl)acetamide: To N-[S-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 28a) (0.0947 g, 0.361 mmol) is added at 00 C chlorosulfonic acid (3 ml) followed by dichloromethane (1 ml). The reaction mixture is stirred below 00 C for 2 hours then poured into crushed ice and extracted with dichloromethane (3 x 5 ml). The organic layers are combined and dried over MgSO 4 The solvent is removed to give S-( 2 -acetylamino-4-methyl-thiazol-S-yl)-2-methoxy-benzenesulfonyI chloride, which is dissolved into dioxane (2 ml). To this solution is added NN-dimethylethylenediamine (0.0636 g, 0.72 mmol) and 2M NaZCO 3 (0.5 ml). The reaction mixture is stirred at room temperature for 2 hours. The mixture is concentrated and the residue is taken Z into water (2 ml) and extracted with dichioromethane (3 x 5 ml). The combined organic layers ID are dried over MgSO 4 After filtration the solvent is removed in vacuo to give the titled compound which is dried overnight in vacuum oven at 250GC. MH-I (ESMS): Mp 413.00 C.

ID Examples 32 to These compounds namely 4 -methoxy-3-(2-methoxy-ethylsulfamoyl)-phenyl]-4-methythiazol-2-yI}-acetamide, N-(S-[4-methoxcy-3-(4-methyl-piperazine-l1-sulfonyl)-phenyl]-4-methylthiazol-2-yl)-acetamide, 3 -dimethylamino-propylsulfamoyl)-4-methoxy-phenyl]-4methyl-thiazol-2-yl)-acetamide, N-(S-(3-[(2-dimethylamino-ethyl)-methyl-sulfamoyl]-4methoxy-phenyl}-4-methyl-thiazol-2-yl)-acetamide, N-{S-[4-methoxy-3-(3-morpholin-4-ylpropylsulfamoyl)-phenyl]-4-methyl-thiazol-2-yl)-acetamide, N-(5-14-methoxy-3-[3-(4-methylpiperazin- 1-yl)-propylsulfamoyl]-phenyl)-4-methyl-thiazol-2-yl )-acetamide, N-{S-[4-methoxy-3- (2-pyrroli din- 1 -yl-ethylsulfamoyl) -phenyl]l-4-methyl-thiazol-2-ylj-acetamide, N-1S-[4-methoxy- 3-(3-methoxy-propylsulfamoyl)-phenyl]-4-methyl-thiazol-2-ylJ-acetzamide and hydroxy-ethylsulfamoyl )-4-methoxy-phenyll-4-methyl-thiazol-2-yl)-acetamide respectively, are prepared by replacing NN-dimethylethylenediamine with the appropriate amine in the above procedure described for the preparation of N-(S-[3-(2-dimethylamino-ethylsulfamoyl)-4methoxy-phenyl]-4-methyl-thiazol-2-yl)-acetamide (Example 31 b) to afford the title compounds.

Example 41 N- 3-Methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-yll-acetamide 41 a) S-( 2 -Acetylamino-4-methyl-thiazol-5-yl)-2-methoxy-benzenesulfony chloride: To chlorosulfonic acid (25 ml, excess), cooled at -100 C, is added portionwise a suspension of N-[S-(4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 31 a) (1.0 g, 3.8 mmol) in DCM (10 ml). The temperature is kept below 00 C throughout the addition. The reaction mixture is left to warm up to room temperature. After 2 hours, the reaction mixture is poured carefully onto ice (500 ml). Once the ice is melted, the aqueous layer is extracted with DCM (3 x 200 ml). The combined organic layers are washed with brine (150 ml), dried over MgSO 4 filtered and concentrated to afford S-( 2 -acetylamino-4-methyl-thiazol-S-yl)-2-methoxybenzenesulfonyl chloride.

41 b) 3 -Methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-y]-acetamide: S To a stirred solution of sodium sulfite (1.05 g, 8.31 mmol) and sodium hydrogen carbonate (0.71 g, 8.31 mmol) in water (10 ml) at 700 C is added a solution of 5-(2-acetylamino-4- ID methyl-thiazol--yl)-2-methoxy-benzenesulfonyl chloride (Example 41a) (1.5 g, 4.16 mmol) in 1,4-dioxane (20 mi). After 30 minutes, the reaction mixture is concentrated to yield the sodium sulfinate intermediate as an off-white solid. To the sulfinate intermediate (0.5 g, 1.43 IN mmol) in DMF (10 ml) is added iodomethane (0.09 ml, 1.43 mmol). After 2 hours at 400 C, C the reaction mixture is poured into water (250 ml) and extracted with ethyl acetate (3 x 50 mi).

SThe combined organic layers are dried over MgSO 4 filtered and concentrated to afford N-[S- (3-methanesulfonyl-4-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide.

Examples 42 to 44 These compounds, namely N-{5-[3-(2-hydroxy-ethanesulfonyl)-4-methoxy-phenyl]-4-methylthiazol-2-yl}-acetamide, N-(S-[3-(3-hydroxy-propane- 1 -sulfonyl)-4-methoxy-phenyl]-4-methylthiazol-2-yl)-acetamide, and N-[S-(3-Cyanomethanesulfonyl-4-methoxy-phenyl)-4-methylthiazol-2-yl]-acetamide respectively, are synthesised following the same procedure as 41, replacing methyl iodide in the above procedure with the appropriate alkyl iodide Example 45: N-[5-(3-Methanesulfonyl-phenvl)-4-methyl-thiazol-2-yll-acetamide:

N-[

4 -Methyl-S-(3-nitro-phenyl)-thiazol-2-yl]-acetamide (Example 49b) is converted into the aniline using the procedure described in Example la and this material is converted into the title compound following the procedure described in Example 41b.

Example 46: 3 -Cyanomethanesulfonvyl-phenyl)-4-methyl-thiazol-2-yll-acetamide: N-[4-Methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-acetamide (49b) is converted into the aniline using the procedure described in Example la and this material is converted into the title compound following the procedure described in Example 41b, replacing methyl iodide in this procedure with iodoacetonitrile.

Example 47: N-S5-( 4 -Fluoro- 3 -methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-acetamide 47a) 2 -Fluoro-5-(2-oxo-propyl)-benzenesulfonyl chloride: To chlorosulfonic acid (25 ml, excess) cooled at -100 C is added dropwise 4-fluorophenyl acetone (1.0 g, 6.57 mmol). The temperature is kept below 00 C throughout the addition. The reaction mixture is then left to warm up to room temperature overnight. The reaction mixture is poured carefully onto ice (1500 ml). Once ice is melted, the aqueous layer is extracted with CN DCM (3 x 250 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford the titled compound as an off-white solid.

47b) 1-(4-Fluoro-3-methanesulfonyl-phenyl)-propan-2-one: To a stirred solution of sodium sulfite (0.5 g, 3.99 mmol) and sodium hydrogen carbonate I\D (0.34 g, 3.99 mmol) in water (10 ml) at 700 C is added a solution of 2 -fluoro-5-(2-oxo-propyl)- Mc benzenesulfonyl chloride (Example 47a) (0.5 g, 1.99 mmol) in 1,4-dioxane (20ml After 1 C hour, the reaction mixture is concentrated to yield the sulfinate intermediate. To the sulfinate intermediate (0.47 g, 1.97 mmol) in DMF (20 ml) is added iodomethane (0.12 ml, 1.97 mmol).

After 1 hour at 400 C, the reaction mixture is poured into water (400 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers are dried over MgSO 4 filtered and concentrated. The residue is left overnight in the vacuum oven to afford the titled compound as a viscous oil.

47c) 1-Bromo-l-(4-Fluoro-3-methanesulfonyl-phenyl)-propan-2-one: To l-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (Example 47b) (0.23 g, 1 mmol) in dry THF (5 ml) is added under inert atmosphere and dropwise a solution of 2carboxethyltriphenylphosphonium tribromide (0.6 g, 1.05 mmol). After 2.5 hours at room temperature the reaction mixture is filtered then concentrated to give a viscous orange oil which is purified by chromatography eluting with isohexane-ethyl acetate (4:1 then 2:1) to give the titled compound.

47d) N-[5-(4-Fluoro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide: A mixture of 1-bromo-l-(4-fluoro-3-methanesulfonyl-phenyl)-propan-2-one (Example 47c) (0.17 g, 0.55 mmol) and N-acetylthiourea (0.065 g, 0.55 mmol) in ethanol is heated at 700 C for 3 hours then at room temperature over two days. The reaction mixture is poured into water (200 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers are dried over MgSO 4 filtered and concentrated to afford a viscous solid. This solid in a minimum amount of ethyl acetate is sonicated to give a suspension which is then heated until all solid has dissolved then left to cool to room temperature overnight. The white crystalline solid is filtered off to afford the titled compound.

Example 48: N-[5-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-acetamide The title compound is prepared following the same route as N-[5-(4-Fluoro-3methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-aceramide (Example 47) by replacing 4- ID fluorophenyl acetone with 4-chlorophenyl acetone.

0Example 49: N-[ 4 -Methyl-5-(3-sulfamoyl-phenyl)-thiazol-2-yll-acetamide M 49a) l-Bromo-1-(3-nitro-phenyl)-propan-2-one: A stirred solution of 3-nitrophenylacetone (0.5 g, 13.9 mmol) in TI-ff (10 ml) at room temperature is treated with polymer supported pyridine hydrobromide perbromide (1.4 g, 2 mmol Br3-/g). The reaction mixture is stirred overnight, then filtered and concentrated in vacuo. The residue is purified by chromatography on silica with iso-hexane-ethyl acetate (6:1) to give the titled compound.

49b) N-[4-Methyl-S-(3-nitro-phenyl)-thiazol-2-yll-acetamide: A mixture of 1-bromo-1-(3-nitro-phenyl)-propan-2-one (Example 49a) (0.5 g, 1.94 minol) and N-acetylthiourea (0.23 g, 1.94 mxnol) in ethanol (10 ml) is stirred at 70 0 C for 2 hours. After cooling the reaction to room temperature, the precipitated product is removed by filtration and dried under vacuum to give the titled compound (0.28 g).

49c) N-[ 4 -Methyl-5-(3-sulfamoyl-phenyl)-thiazo[-2.yl].acetamide: 3-nitro-phenyl)-thiazol-2-ylI-acetamide (Example 49b) is converted into the aniline using the procedure described in Example 1Ia and this material is converted into the corresponding sulfonamide following the procedure described in Example 3.

Examples 50 to 54 These compounds, namely N-(4-methyl-S- 3 -(4-methyl-piperazine-l1-sulfonyl)-phenyl]-thiazol- 2-yl)-acetamide, 3 -dimethylamino-propylsulfamoyl)-phenylJ.4-methyl-thiazol-2yi).

acetamide, N-{4-methyl-S- 3 3 -morpholin-4-yI-propylsulfamoyl)-phenyl]-thiazol-2-yl.

acetamide, 3 3 -methoxy-propylsulfamoyl)-phenyl]-4-methy-thiazo-2-yl..acetamide and N-1S-[ 3 2 -hydroxy-ethylsulfamoyl)-phenyl]-4methyl..thiazol-2yi).acetamide respectively, are prepared as described for Example 49 by replacing ammonia in the final reaction with the appropriate amine.

Example 55 N-( 3 -Dimethylamino-ropyl)-3-2-3-ethy-ureido)4methylthiazols.yl benzenesulfonamide CN The title compound was prepared from Example 51 using hydrolysis conditions described in example 26 followed by reaction with ethyl isocyanate as described in Example 27.

Example 56 [5S-( 4 -Fluoro-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yll-acetamide The title compound is prepared from 4-fluorophenyl acetone via 2-fluoro-5-(2-oxo-propyl)- I benzenesulfonyl chloride (Example 47a) following an identical sequence of reactions used for M the synthesis of N-[S-(4-methoxy-3-sulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 30) from 4-methoxyphenyl acetone.

Example 57: N-[5-(4-Chloro-3-sulfamovl-phenvl)-4-methyl-thiazol-2-yll-acetamide: Replacing 4-fluorophenyl acetone with 4-chlorophenyl acetone in the above procedure (Example 56) affords the title compound.

Example 58 5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine: 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-benzenesulfonyl chloride (Example 3a) (0.5 g, mmol) in dioxane (2 ml) is added dropwise to a stirred solution of sodium sulfite (0.378 g, mmol) and sodium hydrogen carbonate (0.252 g, 3.0 mmol) in water at 750 C. After 1 hourat 750 C, bromoacetic acid (0.417 g, 3.0 mmol) is added and heating continued for 1 hour at 1000 C. Sodium hydroxide (0.24 g, 6.0 mmol) in water (0.25 ml) is then added and the mixture is heated with stirring at 91 0 C for 16 hours. The reaction mixture is allowed to cool, diluted with water (100 ml) and extracted with dichloromethane (3 x 75 ml). The combined organic extracts are washed with brine (75 ml), dried (MgSO 4 filtered, and the solvent removed to give the title compound. MH+ 268.9.

Example 59: 1-Ethyl-3-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-urea: Ethyl isocyanate (0.09 ml, 1.1 mmol) is added to a stirred solution of 5-(4-methanesulfonylphenyl)-4-methyl-thiazol-2-ylamine (Example 58) (0.10 g, 0.37 mmol) in dimethylformamide mi). The mixture is heated at 850 C for 90 minutes followed by removal of the solvent.

The residue is crystallised from ethyl acetate methanol to afford the title compound. MH* 340.0.

Ex. 60: (3-[5-(4-Methanesulfonyl-phenvl)-4-methyl-thiazol-2-yll-ureidol-acetic acid ethyl ester Replacing ethyl isocyanate in Example 59 with ethyl isocyanoacetate affords the title compound as a white solid. MH+ 398 S Example 61: 13-[5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido-acetic acid: Aqueous sodium hydroxide (2M, 0.5 ml) is added to a stirred solution of \O methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido)-acetic acid ethyl ester (Example (0.14 g, 0.00035 mmol) in methanol (2 ml). After stirring at room temperature for 18 hours the solvent is removed and dilute HCI is added. The resulting yellow solid is removed by IO filtration and recrystallised from ethanol to afford the title compound. MH+ 370.0

O

1 Example 62: 3 1 3 4 -Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-ureido)-propionic acid: S Replacing ethyl isocyanate in Example 59 with ethyl 3-isocyanatopropionate affords I3-[5-(4- S methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido)-propionic acid ethyl ester as a white solid. This is treated with aqueous sodium hydroxide for 18 hours as described in Example 61 to afford the title compound as a white solid. MH* 384.0 Example 63 N-[5-(3-Bromo-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-acetamide: N-[5-(4-amino-3-bromo-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 7a) (1.0 g, 3.07 mmol) is converted into the corresponding sulfonyl chloride by the procedure described for the conversion of aniline (Example la) to sulfonyl chloride (Example 3a). A sample of this crude sulfonyl chloride (1.0 g, 2.4 mmol) is dissolved in dioxane (5 ml) and the resulting solution is added to a stirred solution of sodium sulfite (0.615 g, 4.9 mmol) and sodium hydrogen carbonate (0.41 g, 4.9 mmol) in water (5 ml) at 750 C. After 1 hour at 750 C bromoacetic acid (0.679 g, 4.9 mmol) is added. The reaction is stirred for an additional 6 hours at 750 C. When cool the mixture is diluted with water (200 ml) and extracted with dichloromethane (3 x 100 ml). The combined organic extracts are washed with brine (100 ml, dried (MgSO 4 and the solvent removed. Purification by chromatography on silica (EtOAc) affords the title compound.

Example 64: 3 -Fluoro- 4 -methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-acetamide: 64a) 3-Fluoro-4-methanesulfonyl-benzaldehyde: Methane sulfinic acid sodium salt (20.1 g, 200 mmol) is added to a stirred solution of 3,4difluorobenzaldehyde (22.5 g, 158 mmol) in dry DMSO (200 ml) at 750 C. After 2 hours the reaction is poured onto ice-water (200 ml). The precipitate is filtered, washed with water and dissolved in chloroform (400 ml). The organic extract is washed with water (2 x 200 ml), dried over MgSO 4 filtered, and the solvent is removed to give the title compd as a white solid.

C( 64b) 2 -Fluoro-l-methanesulfonyl-4-(2-nitro-propenyl)-benzene: A stirred mixture of 3-fluoro-4-methanesulfonyl-benzaldehyde (Example 64a) (24 g, 0.119 I\N mol), nitroethane (70 ml, 0.97 mol) and ammonium acetate (2.75 g, 35 mmol) is heated at reflux under argon for 24 hours. The mixture is concentrated to give an oil which is dissolved in chloroform (200 ml) and washed with water (2 x 200 ml), followed by brine (100 ml). The IN organic extract is dried (MgSO 4 filtered and the solvent removed to give the product as an c orange oil. This was used immediately in the next step.

64c) 1-( 3 -Fluoro-4-methanesulfonyl-phenyl)-propan-2-one: S Iron powder (25 g, 0.45 mol) is added to a stirred mixture of freshly prepared 2-fluoro-1methanesulfonyl-4-(2-nitro-propenyl)-benzene (Example 64b) (29 g, 0.112 mol) in THF ml). Water (110 ml) is added and the mixture is heated to 600 C. Concentrated hydrochloric acid (50 ml) is added slowly over lh at 60-900 C. The reaction is then stirred at 1000 C for hours then diluted with cold water (500 ml) and filtered through celite T filter material washing with chloroform (500 ml). The organic extract is washed with water (200 ml) followed by brine (200 ml). After drying (MgSO 4 the mixture is absorbed on silica and purified by chromatography, eluting with hexane ethyl acetate to give the title compound.

64d) N-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide: 1-( 3 -Fluoro-4-methanesulfonyl-phenyl)-propan-2-one (Example 64c) (1.0 g, 4.34 mmol) is dissolved in dioxane (35 ml) and the solution is cooled to 100 C at which point the mixture is semi frozen. Bromine (0.067 ml, 1.2 mmol, 0.3 eq.) is added slowly and the mixture is stirred for an additional 15 min in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil containing starting material and 1bromo-l-( 3 -fluoro-4-methanesulfonyl-phenyl)-propan-2-one. This material is dissolved in ethanol (30 ml) and N-acetylthiourea (0.369 g, 3.1 mmol) is added in one portion. The mixture is stirred at 600 C for 30 minutes then allowed to cool whereupon the product crystallised.

Filtration affords the title compound as a white solid.

Ex 65 N-[5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-yl-acetamide The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluorobenzaldehyde with 3-fluoro-4-trifluoromethylbenzaldehyde.

(NI Example 66 N-F5-(3-Chloro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-acetamide The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4- IND methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4difluorobenzaldehyde with 3,4-dichlorobenzaldehyde.

IND Example 67 :N1(5- [4-Methanesulfonyl-3-(4-methyl-piperazin-1I-yl)-p2henyll-4-methyl-thiazol-2yllJ-acetamide A stirred mixture of N-f 3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylJacetamide (Example 64) (0.05 g, 0.15 mmol) and 1-methylpiperazine (0.1 ml, 0.9 mmol) in dry DMSO (1 ml) is heated under argon at 1150 C for 1 hour. The solvent is removed and water ml) is added. The product is extracted with ethyl acetate (2 x 30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO 4 Removal of the solvent and trituration with diethyl ether affords the title compound as a yellow solid.

Examples 68 to 71 These compounds, namely N-(5-(3-[(2-dimethylamino-ethyl)-methyl-amino]-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl)-acetamide, N-(S-[3-(3-dimethylamino-propylamino)-4methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl)-acetamide, N-{S-[3-(2-diethylamino-ethylamino)-4-methanesulfonyl-phenyl]-4-methyl-thiazol-2-yl)-acetamide and N-(S-(3-[(2-diethylamino-ethyl)-methyl-amino] -4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl)-aceramide respectively, are prepared by the same procedure as Example 67, replacing 1-methylpiperazine in this example with the appropriate amine.

Example 72 3-Fluoro-4-methanesulfonyl-p2henyl)-4-methyl-thiazol-2-ylamine This material is prepared from 3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2ylJ-acetamide (Example 64) using hydrolysis conditions described in Example 26.

Example 73 1 -Ethyl-3-15-( 3-fluoro-4-niethanesulfonyl-phenyl)-4-methyl-thiazol-2-ylk-urea A mixture of S-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (0.40 g, 1.4 mmol) and ethyl isocyanate 121 ml, 1.5 mmol) in dry DMF (3 ml) is heated at 85 0 C for 1 hour. The solvent is removed and the product is purified by chromatography on silica eluting with hexane ethyl acetate to give the title compound.

Example 74 4-(2-Acerylamino-4-methyl-thiazol-5-yl)-benzoic acid: N 74a) 3-(1-Bromo-2-oxo-propyl)-benzoic acid: A stirred solution of 4-(2-oxopropyl)benzoic acid (1.0 g, 5.6 mmol) in THF (30 ml) at room IN temperature is treated with polymer supported pyridine hydrobromide perbromide (2.8 g, 2mmol Br3-/g). After 3 hours at room temperature, the reaction mixture is filtered through celite T M filter material and the solvent removed under vacuum to give the titled compound.

74b) 4 -(2-Acetylamino-4-methyl-thiazol-5-yl)-benzoic acid: S A mixture of 3-(1-bromo-2-oxo-propyl)-benzoic acid (1.4 g, 5.4 mmol) and N-acetylthiourea (0.64 g, 5.4 mmol) in ethanol is stirred at 700 C for 2 hours. The reaction mixture is cooled to S room temperature. The precipitated product is removed by and dried under vacuum to give the titled compound.

Example 75 4 2 -Acetylamino-4-methyl-thiazol-5-yl)-N-(2-hydroxv-ethyl)-benzamide: To 4 2 -acetylamino-4-methyl-thiazol-5-yl)-benzoic acid (Example 74b) (0.1 g, 0.36 mmol) in DMF (1 ml) is added HATU (0.14 g, 0.36 mmol) followed by DIPEA (0.07 ml, 0.36 mmol) and ethanolamine (0.022 ml, 0.36 mmol). After 5 hours, the reaction mixture is filtered and the precipitated product is washed with ethanol and dried under vacuum to give the titled compound.

Example 76 4-(2-Acetylamino-4-methyl-thiazol-5-yl)-N-(2-cyano-ethyl)-benzamide: The title compound is prepared following the procedure outlined in Example 75 by replacing ethanolamine with 3-aminopropionitrile.

Agents of the invention also include compounds of formula XIX where Ra, Rb, R and R' are as shown in the Table 2 below, the method of preparation being described thereafter. The table also shows mass spectrometry data. The examples are in free form.

TABLE 2 Compounds of the invention

OH

3 "Y

CH

3 0 I CH,

N

0

H

3

OH

3 0

IND

rn/s Ex. Ra R b Rc R' MH+ 136 cI H CH 3 452.9 ovS OH 3

N

137 Cl 0H F F 441.9 o11 CH- 3 fHj 138 CI 0o H NH 2 345.8 o H 3 0 139 Cl 0 OH H 0 140 Cl 0~ H T H 3 403.97 s yN O"

OH

3 015,s CH3 N

OH

141 CI o H' O 415.94 CH__ 3_ 0 142 01 0 H 417.94 O OH 3 143 CI 0o H H ce 316.99 3 0 144 010 H 411.9 Oll O H 3 0 N-HJ 146 01 \os: H T 3373.9 Oll O H 3 0Y O" H 3 147 I \oH H 373

HO

(I Preparation of Specific Examples ID Abbreviations used are as follows: DCM is dichioromethane, DIPEA is diisopropylethylamine 0 DME is dimethoxyethane, HATU is O-(7-azabenzotriazol-1-yl)-N, N'-tetramethyluroniumn hexafluorophophate, NES is N-bromosuccinimide and THF is tetrahydrofuran.

M Example 77: 1 -(5-13-[(2-Dimethlamino-ethyl)-methyl-aminol-4-methanesulfonyl-phenyl-4methyl-thiazol-2-yl)-3-ethyl-urea A stirred mixture of 1 -Ethyl-3- 3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl] urea (Example 73) (0.05 g, 0.14 mmol) and NNN'-Trimethylethylenediamine (0.25 ml, 2.1 mmol) in dry DMSO (0.5 ml) is heated under argon at 1200 C for 2 hours. The solvent is in v 'acuo removed and the product is purified by chromatography on silica eluting with ethanoltriethylamine (98:1) to give the titled compound. MHW: 440.1051 Ex 78 N-fS-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll.2-tetrazol--yl.acetamide 5-(4-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 58) (0.08 g, 0.3 mmol) is added to a solution of HATUJ (0.113 g, 0.3 mmol) and 1-tetrazole acetic acid 0 0 3 9 g, 0.31 mmol) in DCM. Triethylamine (0.104 ml, 0.75 mmol) is then added and the reaction mixture is left to stir at r~oom temperature overnight. The product is purified by chromatography on silica eluting with methanol DCM (96:4) to give the titled compound.

Example 79 N- 4 -Methanesulfonyl-12henyl)-4-methyl-thiazol-2-yll-2-pyridin-3-y-acetamide This is prepared as described in Example 78 by replacing 1-tetrazole acetic acid with 3pyridineacetic acid.

Example 82 4 -Methanesulfonyl-phenyl)-4-methyl.thiazol.2.ylb2-pyridin.4.y[acetamide This is prepared as described in Example 78 by replacing 1-tetrazole acetic acid with 4pyridineacetic acid.

Ex 80 3-Imidazol-1I-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll .acetamide A stirred mixture of 3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]acetamide (Example 64) (0.1 g, 0.30 mmol), imidazole (0.069 g, 0.90 mmol) and caesiumn carbonate (0.198 g, 0.60 mmol) in dry DM50 is heated under argon at 140 0 C for 2 hours.

The solvent is removed and water (30 ml) is added. The product is extracted with ethyl acetate (2 x 30 ml) and the combined organic extracts are washed with brine (20 ml) and dried (MgSO 4 Removal of the solvent and trituration with methanol affords the titled compound as an orange solid. MH+: 377.9721 Examples 81. 84 to 87. 103 and 104 The compounds, namely N-[5-(4-niethanesulfonyl-3- [1 ,2,4lrriazol- 1-yl-phenyl)-4-methyl- IND thiazol-2-yl]-acetamide, N-{S-[4-methanesulfonyl-3-(4-methyl-imidazol- 1-yl)-phenyl]-4-methylthiazol-2-yl}-acetamide, N-(5-[4-methanesulfonyl-3-(2-methyl-imidazol- 1-yl)-phenylj-4-methyl- NK thiazol-2-yl)-acetamide, N-{S-[3-(2-ethyl-imidazol- 1-yl)-4-methanesulfonyl-phenyl]-4-methylthiazol-2-yll-acetamide, [4-methanesulfonyl-3-(4-methyl-pyrazol- l-yl )-phenyl]-4-methylthiazol-2-yll-acetamide, N-{S-[4-methanesulfonyl-3-(2-propyl-imidazol-1 -yl)-phenyll-4-methylthiazol-2-yl)-acetamide and N-IS-f 3-(2-isopropyl-imidazol-1 -yl )-4-methanesulfonyl-phenylj-4methyl-thiazo1-2-yl)-acetamide respectively, are prepared by the same procedure as Example replacing 1-methylpiperazine in this example with the appropriate 5-membered ring nitrogen heterocycle.

Example 83 :5-(4-Chloro-3-methanesulfonyl-phenyl)-4-nethyl-thiazol-2-ylamine This compound is made via an analogous procedure to N-[S-(4-Chloro-3-methanesulfonylphenyl)-4-methyl-rhiazol-2-yl]-acetamide (Ex.4 8) by replacing N-acetylthiourea with thiourea.

Example 88 :1-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-3-(2-hydroxcyethyl)-urea 8 8a) 3-fluoro-4-methanesulfonyl-phenly)-2-isocyanato-4-methyl-thiazole: 5S-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yla mine (Example 72) (1.74 mmol, g) is added to acetonitrile (15 ml) and treated with phosgene (20% solution in toluene, 6.99 mmol, 3.7 ml). The reaction mixture is heated to reflux (85 0 C) for 30 minutes. After cooling to room temperature the solvent is removed in vacuo to leave 5-(3-fluoro-4methanesulfonyl-phenly)-2-isocyanato-4-methyl-thiazole as an orange solid.

88 b) 1 3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)urea: 3 -fluoro-4-methanesulfonyl-phenly)-2-isocyanato-4-methyl-thiazole (88a)(0.5 8 mmol, 0.183 g) is dissolved in dioxane (S ml) and treated with 2-aminoethanol (0.64 mmol, 0.039 ml) under argon. The reaction mixture is stirred and heated to 80CC for 1 hour. The solvent is then removed and the residue dissolved in EtOAc and washed with water (2 x 20 ml) followed by brine (20 ml) and dried over MgSO 4 After filtration, the solvent is removed in vacuo and the (NI residue purified by chromatography on silica eluting with ethyl acetate methanol to give the title compound.

Examples 89. 91 to 94 and 96 These compounds, namely 1 2 -cyano-ethyl)-3-[S-(3-fluoro-4-methanesulfonyl-phenyl)-4 IND methyl-thiazol-2-yl]-urea, 1 3 -fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazo[-2yI.3- (3-hydroxy-propyl)-urea, 1 -[5-(3-fluoro-4-methanesulfonyl-phenyl )-4-methyl-thiazol-2-yl]-3pyridin-2-ylmethyl-urea, 1 -[S-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2yl]-3(2pyridin-2-yl-ethyl)-urea, 1- 3 -Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazolz..yl].3(2pyridin-3-yl-ethyl)-urea and 1 3 -Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol.2-yl..

3-(4-hydroxy-butyl)-urea respectively are prepared by the same procedure as Example 88 replacing 2-aminoethanol (part 88b) in this example with the appropriate amine.

Examples 97. 99 to 101 and 105 to 116 The compounds namely, 1- [5-(4-chloro-3-methanesulfonyl-phenyl )-4-methyl-thiazol-2-yl]-3propyl-urea, 1- 4 -chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl1-3-furan-2ylmethyl-urea, 1- 4 -chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl1.3-(2.cyanoethyl)-urea, 1 -IS-(4-chloro-3-methanesulfonyl-phenyl )-4-methyl-thiazol-2-yl]-3-(2,S-dimethyl- 2H-pyrazol-3-yl)-urea, 1 4 -chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazo[-2yl..3 pyridin-2-ylmethyl-urea, 1- 4 -chloro-3-methanesulfony-phenyl)-4-methyl.thiazo2yl].3 isopropyl-urea, 1 -butyl-3- 4 -chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yJ.urea, 1 4 -chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazo-2-yl].3-cyclobuy..urea, azetidine- 1 -carboxylic acid 4 -chloro- 3 -methanesulfonyl-pheny)-4-methyl-thiazol2yl]-amide, 1 4 -chloro- 3 -methanesulfonyl-phenyl)-4methylthiazol2yl].3-pyridin-4ylmethyl-urea, 1 choo3mtaeufnipey)4mty-tizl2yl3prdn3ymty-ra 1 chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl.3-( 3-imidazol-1 -yl-propyl)-urea, pyrrolidine-1-carboxylic acid 4 -chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol.2-y] amide, 1- 4 -chloro- 3 -methanesulfonyl-phenyl)-4-methylrhiazol2yll-3cyclopropylmethylurea, I 4 -chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol2yl].i..[2( 1-methylpyrrolidin-2-yl)-ethyl]-urea, 1 [-4clr--ehneufnlpey)4mehltizl2yl3 furan-3-ylmethyl-urea respectively are prepared by the same procedure as Example 88 replacing 3 -fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol.2yla mine (Example 72) with S-(4-chloro-3-methanesulfonyl-phenyl )-4-methyl-thiazol-2-ylamine (Example 83) and by replacing 2-aminoethanol (part 88b) with the appropriate amine.

(I Examples 117 to 147 The compounds namely, 1 -[S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(2- ID hydroxy-ethyl)-urea, I -[S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3.(3hydroxy-propyl)-urea, 1- [S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((S)- 1 -hydroxymethyl-propyl)-urea, l-[S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2- ID yl]-3-(4-hydroxy-cyclohexyl)-urea, 1- 4 -chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol- M2-yl]-3-( (R)-2-hydroxy-1 -methyl-ethyl)-urea, 1 -[S-(4-chloro-3-methanesulfonyl-phenyl)-4- Nmethyl-thiazol-2-yll-3-((S)-2-hydroxcy- 1-methyl-ethyl)-urea, 1 -II-(4-chloro-3-methanesulfonylphenyl)-4-methyl-thiazol-2-yl]-3-[2-(2-hydroxy-ethoxy).ethyl]-urea, 1 -[S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-(3-diethylamino-propyl)-urea, 1 -[S-(4-chloro-3methanesulfonyl-phenyl )-4-methyl-thiazol-2-yl]-3-pyridin-3-yl-urea, 1 -[S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylI-3-pyridin-4-yl-urea, 1 -[S-(4-chloro-3-methanesulfonylphenyl)-4-methyl-rhiazol-2-yl]-3-(2-methyl-2H-pyrazol-3-yl)-urea, 1 -[S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-( 1,3,5-trimethyl-l1H-pyrazol-4-yl )-urea, 1 chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol2yl-3-(5-methyl-soxazol.3ylmethyl).

urea, 1 4 -chloro-3-methanesulfonyl-phenyl)-4-merhyl-thiazol-2-yl]-3-(4,6-dimerhyl-pyridin- 2-yi)-urea, 1 -[S-(4-chloro-3-methanesulfony-phenyl)-4-methyl-thiazol-2-ylJ-3-( 6-methylpyridin-2-yl)-urea, 1 -[5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-((S)-2hydroxy-2-phenyl-ethyl)-urea, I -[S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2- 3-hydroxymethyl-2-methyl-phenyl)-urea, R)-sec-butyl)-3-[S-(4-chloro-3-methanesulfonyl-phenyl )-4-methyl-thiazol-2-ylJ-urea, 1- [S-(4-chloro-3-methanesulfonyl-phenyl)-4methyl-thiazol-2-ylI-3-(6-methoxy-pyridin-3-yl)-urea, I -[S-(4-chloro-3-methane-sulfonylphenyl)-4-methyl-thiazol-2-yl]-3-(2-methox-pyridin-3yl)urea, 1- [5-(4-chloro-3-methanesulfonyl-phenyl 4 -methyl-thiazol-2-yII-3-(3,3,3-trifluoro-propyl)-urea, [5-(4-chloro-3methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea, 1- I5-(4-chloro-3-methanesulfonylphenyl)-4-methyl-thiazol-2-yl]-3-methyl-urea, 3-[5-(4-chloro-3-methanesulfonyl-phenyl)-4methyl-thiazol-2-y]-1 -(2-hydroxy-ethyl)- 1-methyl-urea, (R)-3-hydroxy-pyrrolidine- 1carboxylic acid [S-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide, 1- chloro-3-merhanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]y3-(4.hydroxy-butyl).urea, I chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl].3-( 5-hydroxy-pentyl )-urea, 1-f S-(4chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl].3.(l1H-pyrazol-3-yl)-urea, 1 chloro- 3 -methanesulfony-phenyl)-4-methyl-thiazol-2-yl..3cyclopropyl-urea, I -[5-(4-chloro-3methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-urea and 3- [S-(4-chloro-3 -methanesulfonyl-phenyl)-4-methyl-rhiazol-2-yl]- 1,1 -dimethyl-urea respectively, are prepared by the N same procedure as Example 88 replacing 2-amninoethanol (part 88b) in this example with the appropriate amine and by replacing dioxane with dimethyl formamide.

Example 90: N-[S-(3,4-Bis-methanesulfonyl-p1henyl)-4-methyl-thiazol-2-yl]-acetamide This is isolated as a minor by product in the synthesis of N-[S-(3-Fluoro-4-metbanesulfonyl- ID phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) when excess methane sulfinic acid sodium salt is added in the first step of the synthesis (64a). The resulting aldehyde is converted into the title compound by the procedure described in parts 64b-d.

Example 95: N-(5-(3,5-Difluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-acetamide The title compound is made via an analogous procedure to N-[5-(3-Fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluorobenzaldehyde in part 64a of the procedure with 3,4,S-trifluorobenzaldehyde.

Example 98: 3-t2-(3-Ethyl-ureido)-4-methyl-thiazol-5-yll-N-(2-hydroxy-ethyl)benzenesulfonamide 98a) 1 -Bromo-lI-( 3-nitro-phenyl)-propan-2-one: A stirred solution of 3-nitrophenylacetone (2.5 g, 14.0 mmol) in dry TI-F (50 ml) at room temperature is treated with polymer supported pyridine hydrobromide perbromide (7.0 g, 14.0 mmol) and left to stir overnight. The reaction mixture is then filtered and the solvent removed in vacuo. The residue is purified by chromatography on silica eluting with 1:4 ethyl acetate hexane to give the titled compound.

98b) 4-Methyl-S-( 3-nitro-phenyl)-thiazol-2-ylamine: A stirred solution of 1-Bromo-1-(3-nitro-phenyl)-propan-2-one (98a) (2.4 g, 9.3 mmol) in ethanol (20 ml) at room temperature is treated with thiourea (0.71 g, 9.3 mmol). The reaction mixture is heated to 70 0 C for 10 minutes. The resulting precipitate is removed by filtration and dried under vacuum to give the titled compound.

98c) 1 -Ethyl-3-[4-methyl-S-(3-nitro-phenyl )-thiazol-2-yl]-urea: The title compound is made via an analogous procedure to Example 88 by, first of all, replacing S-(3-Fluoro-4-methancsulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (part 8 8a) with 4-Methyl-S-( 3-nitro-phenyl)-thiazol-2-ylamine and secondly, by replacing 2-aminoethanol with ethylamine (part 88b).

(NI 98d) I -[S-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-urea: A stirred solution of l-Ethyl-3-[4-methyl-S-(3-nitro-phenyl)-thiazol-2-yl]-urea (98c) (0.55 g, IND 1.8 mmol) in THF (25 ml) and EtOAc (50 ml) under Argon is treated withl0% palladium on carbon (1.0 g).The reaction mixture was placed under an atmosphere of hydrogen for 2 hours.

The mixture was then filtered through celitem filter material and the solvent removed in vacuo IND to yield the titled compound.

N 98e) 3-Ethyl-ureido)-4-methyl-thiazol-5-yl]-N-(2-hydroxy-ethyl)-benzenesulfonamide: The titled compound is made via an analogous procedure to N-14-methyl-S-(4-sulfamoylphenyl)-thiazol-2-yl]-acetamide (Example 3) by replacing N-[S-(4-amino-phenyl)-4-methylthiazol-2-yl]-acetamide with 1 -[S-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-3-ethyl-urea (part 3a) and by replacing ammonia with ethanolamine (part 3b).

Example 102 N-[5-(3,5-Dichloro-phenyl)-4-methyl-thiazol-2-yll-acetamide The title compound is made via an analogous procedure to N-[S-(3-Fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-ylI-acetamide (Example 64d) by replacing 1-(3-Fluoro-4methanesulfonyl-phenyl)-propan-2-one with 3,S-Dichloro-phenyl)-propan-2-one.

Example 148: 3-Imidazol-l1-yl- 4 -methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine A stirred solution of N- 3-imidazol-1 -yl-4-methanesulfoniyl-phenyl)-4-methyl-thiazol-2-yl]acetamide (Example 80) (0.80 g, 2.13 mmol) in ethanol (15 ml) and 7M aqueous HGI (20 ml) is heated at 90 0 C for 2 hours. The solution is allowed to cool, brought to pH 10 by addition of aqueous NaOH and extracted with n-butanol. The organic extract is dried (MgSO 4 the solvent is removed and the residue is triturated with ethanol to give the titled compound as a yellow solid.

Ex. 149: 4 -Methanesulfonyl-3-(2-propyl-imidazol1-yl)phenyll.4-methyl-thiazol..2-vamine This is prepared by an analogous procedure to Ex. 148, replacing N-[5-(3-imidazol-1-yl-4methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (example 4) with N-15-[4-methanesulfonyl-3-(2-propyl-imidazol-1yl)phenyl]4methyl.thiazol2yl)-acetamide (Ex. 103).

Example 150: 1 -(2-Cyano-ethyl)-3-f 3-imidazol-1 -vl-4-methanesulfonyl-phenyl )-4-methylthiazol-2-yll-urea ri 150a) Imidazole- 1-carboxylic acid [S-(3-imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methylthiazol-2-yli-amide: Sodium hydride (60% dispersion in oil, 0.137g, 3.42 mmol) is added to a stirred suspension of 3-Imidazol- 1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (148) (1.04 g, 3.1 mmol) in dry dimethylformamide (10 ml) at room temperature under argon. 1,1'-Carbonyl diimidazole (0.757 g, 4.67 mmol) is added and the stirred suspension is heated to 40 0 C for 1h.

The reaction mixture is cooled and the resulting solid filtered and washed with DCM and ether to afford the title compound.

150~b) 1 -(2-Gyano-ethyl)-3-[5-( 3-imidazol- 1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2yl]-urea: The titled compound is prepared by the same procedure as example 88, replacing 2aminoethanol (part 88b) in this example with 3-aminopropionitrile and replacing S-(3-fluoro- 4-methanesulfonyl-phenly)-2-isocyanato-4-methyl-thiazole (88a) with Imidazole-1-carboxylic acid [S-(3-imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (150~a) Examples 151 to 155 These compounds, namely 3-hydroxy-propyl)-3-[S-(3-imidazol-1 -yl-4-methanesulfonylphenyl)-4-methyl-thiazol-2-yl]-urea, 1 -(4-hydroxcy-butyl)-3-[S-(3-imidazol-1-y1-4-methanesulfonyl-phenyl )-4-methyl-thiazol-2-yl]-urea, I -cyano-3- 3-imidazol- 1-yl-4-methanesulfonylphenyl)-4-methyl-thiazol-2-ylJ-urea, 1-(2-cyano-ethyl)-3-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl )-4-methyl-thiazol-2-yl]-1 -methyl-urea and 1-(2-cyano-ethyl)-l1-ethyl-3-[S-(3imidazol- 1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea respectively are prepared by the same procedure as Example 150 by replacing 3-aminopropionitrile (part 150b) in that Example with the appropriate amine.

Example 156: N-5-[4-Chloro-3-(2-hydroxv-ethylsulfamoyl)-phenyll-4-methyl-thiazol-2-ylLacetamide The title compound is made via an analogous procedure to N-[S-(4-Methoxy-3-sulfamoylphenyl)-4-methyl-thiazol-2-yl] -acetamide (Example 30) by replacing 4-methoxyphenyl acetone (in example 30a) with 4-chiorophenyl acetone; and ammonia with 2-amino ethanol.

Agents of the invention also include compounds of formula XIX where Ra, Rb, Rc and RI are as shown in the Table 3 below, the method of preparation being described thereafter. The table also shows mass spectrometry data. The examples are in free form.

69 TABLE 3 Compounds of the invention

IND

IND

IN 0 CH g c~I 179 F H 0 y CH3 0H 180 0F H H490 o H 3

_N

CH,

181 F H H 439.07 o H O 3 H Preparation of Specific Examples Example 157: 2-Chloro-N-[5-( 3-imidazol-l1-yl-4-methanesulfonyl-phenyl )-4-methyl-thiazol-2yll-acetamide 3-Imidazol- 1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) (0.537 g, 1.60 mmol) and chloroacetyl chloride (S ml) are heated together for 2 hours. The reaction mixture is allowed to cool to room temperature and the solid filtered and washed with saturated sodium bicarbonate solution (3 x 100 ml) and water (2 x S0 ml) to yield the titled compound.

Example 158: N-[5-(4-Methanesulfonl-3-trifluoromethyl-phenyl)-4-methyl-thiazo[-2yl12.

methoxy-acetamide 1 58a) S-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thia zol-2.yla mine: The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluorobenz- (NI aldehyde with 3-fluoroA4-trifluoromethylbenzaldehyde (part 64a) and by replacing N-acetalthiourea with thiourea (part 64d).

158b) N- [S-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-y]-2-methoxyacetamide: S-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazo.2-ylamine (15 8a) (0.1 g, 0.3 mmol) is added to a solution of HATU (0.226 g, 0.6 mmol), methoxyacetic acid (0.046 ml, 0.6 mmol) and DIPEA (0.lml, 0.6 mxnol) in DMF (7.5 ml). The reaction mixture was left to stir for 3 days at room temperature. The reaction mixture is filtered through basic alumina. The solvent is removed in vacuo and the product is purified by chromatography on silica eluting with ethyl acetate-hexane to give the titled compound.

Example 159: N- [S-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-propionamide (3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yla mine (Example 72) (1 g, 3.39 mmol) is suspended in propionic anhydride (12.5 ml) and heated to 70 0 G for 1 hour. The reaction mixture is cooled to room temperature and the solvent removed in vacuo. The solid is triturated with ether to yield the titled compound.

Example 160: N-[S-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)V4-methyl-thiazol-2-yllpropionamide The title compound is prepared via an analogous procedure to N-[5-(3-imidazol-1-yl-4methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 80) by replacing 3fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in this example with 3 -Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylJ-propionamide (159).

Example 161: N-[5-(4-Fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yll-acetamide 161 a) 1 -(4-Fluoro-3-methoxy-phenyl)-propan-2-one: The title compound is prepared via an analogous procedure to 1-((3-fluoro-4-methanesulfonylphenyl)-propan-2-one (64c) (steps 64b-64c) by replacing 3-fluoro-4-methanesulfonyl-benzaldehyde in step 64b with 4-fluoro-3-methoxy-benzaldehyde.

161ib) 1 -bromo-l1-(4-fluoro-3-methoxy-phenyl)-propan-2-one: A stirred solution of l-( 4 -fluoro-3-methoxy-phenyl)-propan-2-one (161a) (0.5 g, 2.74 mmol) in dry THF (5 ml) is treated dropwise with a solution of 2-carboxyethyltriphenylphosphonium C1 perbromide (1.66 g, 2.88 mmol) in THF. The reaction mixture is allowed to stir at room temperature for 1.5 hours and then filtered. The fitrate is concentrated in vacuo to yield the titled compound.

0 161c) N-[5-(4-Fluoro-3-methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide: IND 1-Bromo-l-(4-fluoro-3-methoxy-phenyl)-propan-2-one (161b) (0.72 g, 2.74 mmol) is dissolved C< in ethanol (20 ml) and N-acetylthiourea (0.324 g, 2.72 mmol) is added in one portion. The 0 mixture is stirred at 80*C overnight then allowed to cool whereupon the product crystallised.

Filtration affords the title compound as a white solid.

Example 162: 3-Hydroxy-azetidine-l-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-amide 162a) 1-Benzhydryl-3-(tert-butyl-diphenyl-silanyloxy)-azetidine: A stirred solution of 1-Benzhydrylazetan-3-ol (2.0 g, 8.4 mmol) in DMF (20 ml) at 0°C is treated with imidazole (0.57 g, 8.4 mmol) and t-butylchlorodiphenyl silane (2.31 g, 8.4 mmol).

The reaction mixture is allowed to warm up to room temperature and stirred overnight. The mixture is poured into water (250 ml) and extracted with EtOAc (3 x 100 ml). The combined organic extracts are washed with water (2 x 100 ml), brine (100 ml) and dried over MgSO4.

The solvent is removed in vacuo to yield the titled compound.

162b) 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine: A stirred solution of 1-benzhydryl-3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162a) (4.0 g, 8.4 mmol) in DCE (60 ml) at room temperature is treated with 1-chloroethylchloroformate (1.2 ml, 10.9 mmol) and the reaction mixture is heated to 80 0 C. After 2 hours, the solvent is removed in vacuo and the residue is dissolved in methanol (60 ml) and heated to reflux. After 1 h the reaction mixture is poured into water (250 ml), acidified with hydrochloric acid (1M solution) and washed with EtOAc (3 x 75 ml). The aqueous solution is basified with saturated sodium bicarbonate solution and extracted with EtOAc (3 x 75 ml). The combined organic layers are washed with water (2 x 50 ml), brine (50 ml), dried over MgSO 4 The solvent is removed in vacuo to yield the titled compound.

162c) 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine-l-carboxylic acid [5-(4-chloro-3methanesulfonyl-phenyl)-4-methyl-thiazole-2-yl]amide: N1 A stirred solution of S-( 4 -chloro-3-methanesulfonyl-phenyl)-2-isocyanato-4-mehy..thiazole [prepared by the same procedure as example 88a replacing S-(3-fluoro-4-methanesulfonyl- ID phenyl)-4-methyl-thiazol-2-ylarniine (Example 72) in this example with S-(4-chloro-3methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83)1 (0.2 g, 0.61 mmol) in DMF is treated with 3-(tert-butyl-diphenyl-silanyloxy)-azetidine (162b) (0.25 g, 0.8 mmol) and ID the reaction mixture is heated to 120*C. After 30 minutes, the reaction is complete. The product is purified by chromatography on silica eluting with ethyl acetate-hexane to give the titled compound.

1 62d) 3-Hydroxy-azetidine-1-carboxylic acid [S-(4-chloro-3-methanesulfonyl-phenyl)-4methyl-thiazol-2-yl]-amide: A strirred solution of tert-butyl-diphenyl-silanyloxy)-azetidine-l1-carboxylic acid chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazole2yl]amide (1 62c) (0.15 g, 0.23 mmol) in THF (2 ml) at room temperature is treated with terabutylammonium fluoride (1.0 M in THF, 0.23 ml, 0.23 mmol). After 30 minutes, the reaction was complete. Purification by preparative LC-MS affords the titled compound.

Example 163: 4 -Ghloro-3-methanesulfonyl-12henyl)-4-methyl-thiazol-2yl.3-(6morpholin-4-yI-pyridin-3-yI )-urea The title compound is prepared by the same procedure as 1-[S-(3-fluoro-4-methanesulfonylphnl--ehltizl2y]3(-yrx-ty)ue (Example 88) replacing 3-fluoro-4methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with S-(4-chloro-3methanesulfonyl-phenyl)-4-methyl-thiazol.2ylamine (Example 83) and by replacing 2aminoethanol (part 88b) with 6-morpholinopyridin-3-amine.

Example 164: 4-1 3 3 -Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol.2-yl1..ureidobbutyric acid ethyl ester 3 -Fluoro- 4 -methanesulfony-phenyl)-4-methyI-thiazol-2ylamine (Example 72), (0.1 g, 0.31 mmol) DIPEA (0.039 ml, 0.34 mmol), ethyl-4-isocyanatobutyrate (0.046 ml, 0.31 mmol) in DCM (2 ml) are heated together at reflux overnight. The reaction mixture is diluted with DCM ml) and washed with 1M hydrochloric acid (15 ml), water (2 x 15 ml), brine (15 ml), dried over MgSO 4 filtered and concentrated in vacuo to yield the titled compound as an off white solid.

(Nj1 Example 165: 3-f 3-fS-(3-Fluoro-4-methanesulfonyl-p2henyl)-4-methyl-hiazol-2-yll-uridolpropionic acid ethyl ester ID The title compound is prepared by the same procedure as 4-{3-[S-(3-Fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-yl]-ureido)-butyric acid ethyl ester (Example 164) by replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.

M Example 166: 3 -I3-f5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-mehylthiazol2yllureidol-p2ropionic acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-yl]-ureido)-buryric acid ethyl ester (Example 164) by replacing S-(3fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with S-(4methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (15 8a) and replacing ethyl-4-isocyanatoburyrate with 3-isocyanato-propionic acid ethyl ester.

Example 167: 4i3-[5-(4-Methanesulfonyl-3-trifluoromethyl-henyl)4-methylthiazo2yl..

ureidol-butyric acid ethyl ester The title compound is prepared by the same procedure as 4 -(3-[5-(3-fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-ylI-ureido)-butyric acid ethyl ester (Example 164) by replacing S-(3fluoro-4-methanesulfonyl-phenyl )-4-methyl-thiazol-2-ylamine (Example 72) with S-(4methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (15 8a).

Example 168: 3 -13-[5-(3-lmidazol-1-yl-4-methanesulfonyl-p2henyl-4-methyl-thiazol-2-y1ureidol-propionic acid ethyl ester The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-yl] -ureido)-butyric acid ethyl ester (Example 164) by replacing 3fluoro- 4 -methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 3imidazol- 1 -yl-4-metha nesulIfonyl-phenyl) -4-methyl-thi azol-2-yla mine (Example 148) and replacing ethyl-4-isocyanatoburyrate with 3-isocyanato-propionic acid ethyl ester.

Example 169: 4 -1 3 3 -Imidazol-1-yl-4-methanesulfonyl-phenyl).4-methyl-thiazo[-2YI1.

ureidol-butyric acid ethyl ester The title compound is prepared by the same procedure as 4-(3-[S-(3-fluoro-4-methanesulfonylpheriyl)-4-methyl-thiazol-2-yl]-ureido)-butyric acid ethyl ester (Example 164) by replacing 3fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 3imidazol-1I-yl-4-methanesul fonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148).

(I Example 170: 3-1 3-II-(4-Chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl-ureidol.

Z propionic acid ethyl ester ID The title compound is prepared by the same procedure as 4 3 -[S-(3-fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-yl]-ureido)-but-yric acid ethyl ester (Example 164) by replacing S-(3fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with S-(4-chloro- IND 3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 83) and replacing ethyl-4isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.

Example 171: 3-13-f S-(3.5-Dichloro-4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2yl..

ureidol-propionic acid ethyl ester 171 a) N- [5-(3,-ihoo4dmtyslfmy hnl--ehlthao--l-ctrie The title compound is prepared by an analagous procedure to N-[S-(3,5-dichloro-4-sulfamoylphenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 6) by replacing ammonia with dimethylamine.

171 b) 4 2 -Amino- 4 -methyl-tbiazol-5-yI)-2,6-dichloro-N,N-dimethyi-benzenesulfonamide: The title compound is prepared by the same procedure as 4 2 2,6-dichloro-benzenesulfonamide (Example 26) by replacing N-[5-(3,S-dichloro-4-sulfamoylphenyl)-4-methyl-thiazoL-2-yl]-acetamide (Example 6) with N- 3,S-dichloro-4dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]yacetamide (171 a).

171 c) 3-f 3 ,S-Dichloro.- 4 -dimethylsulfamoyl-phenyl)-4-methyl-thiazo[-2yl]ureido)-.

propionic acid ethyl ester: The title compound is prepared by the same procedure as 4 3 -[S-(3-Fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-yl] -ureido)-butyric acid ethyl ester (Example 164) by replacing 3fluoro-4-methanesulfonyl-phenyl )-4-methyl-thiazol-2-ylamine (Example 72) with 4-(2-amino- 4 -methyl-thiazol-S-yl)-2,6-dichloro-N,q-dimethyl-benzenesulfonamide (171 b) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.

Example 172: 4 3 -Fluoro- 4 -methanesulfonyl-phenyl)-4-methl-thiazol-2-ylcarbamoyll butyric acid methyl ester Methyl-4-(chloroformyl) butyrate (4.0 mmol) is added to a stirred solution of S-(3-fluoro-4methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) (0.77 g, 2.69 mmol) and heated to 60*C for 1.5 hours. The reaction mixture is allowed to cool to room temperature CN and the solvent removed in vacuo. The residue is washed with saturated sodium bicarbonate solution (2 x 50 ml) and water (1 x 50 ml) The product is extracted with ethyl acetate (2 x I\ 50 ml) and the combined organic extracts dried (MgSO4). Removal of the solvent followed by recrystallisation from ethyl acetate affords the titled compound.

N0 Example 173: 3-f3-f5-(4-Dimethylsulfamoyl-phenyl)- 4 -methyl-thiazol-2-yll-ureido)-propionic m acid o Cy To a stirred solution of 3-{3-[5-(4-dimethylsulfamoyl-phenyl)-4-methyl-thiazol-2-yl]-ureido)propionic acid ethyl ester (Example 24) in methanol (5 ml) is added dropwise sodium C, hydroxide (2M, 3 ml) over 2 minutes. The reaction mixture is heated at reflux overnight and then allowed to cool to room temperature. The mixture is neutralised with hydrochloric acid (2M, 3ml) and the resulting precipitate is filtered, washed with water (20 ml) and dried in vacuo to yield the titled compound.

Example 174: 1-(5-[4-Chloro-3-(4-methyl-piperazine-l-sulfonyl)-phenyl-4-methyl-thiazol-2yll-3-ethyl-urea 174a) 2-Chloro-5-(2-oxopropyl)-benzenesulphonyl chloride: To chlorosulfonic acid (25 ml, excess) cooled at -100 C is added dropwise 4-chlorophenyl acetone (1.0 g, 5.93 mmol). The temperature is kept below 00 C throughout the addition. The reaction mixture is then left to warm up to room temperature overnight. The reaction mixture is poured carefully onto ice (1500 ml). Once the ice is melted, the aqueous layer is extracted with dichloromethane (3 x 250 ml). The combined organic layers are dried over MgSO 4 filtered and concentrated to afford the titled compound as an off-white solid.

174b) 1-[4-Chloro-3-(4-methyl-piperazine-l-sulfonyl)-phenyl]-propan-2-one: 2 -Chloro-S-(2-oxopropyl)-benzenesulphonyl chloride (174a) (2.0 g, 7.5 mmol) is dissolved in dioxan (50 ml) with stirring. Sodium carbonate (7.5 ml, 2M solution, 2 eq.) is added followed by 1-methyl piperazine (0.75 g,7.5 mmol). After 30 min the reaction mixture is poured onto water (250 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts are washed with water (2 x 100 ml) followed by brine (100 ml) and dried (MgSO 4 After filtration the solvent is removed and the product is purified by chromatography on silica, eluting with ethyl acetate hexane to afford the titled compound.

174c) 1-Bromo-l-[4-chloro-3-(4-methyl-piperazine-l-sulfonyl)-phenyl]-propan-2-one: (I A stirred solution of 1-[4-chloro-3-(4-methyl-piperazine-1 -sulfonyl)-phenyl]-propan-2-one (174b) (0.5 g, 1.22 mmol) in dry THF (5 ml) is treated dropwise with a solution of 2- ID carboxyethyltriphenylphosphonium perbromide (0.84 g, 1.44 mmol) in THF. The reaction mixture is allowed to stir at room temperature for 1.5 hours and then filtered. The fitrate is concentrated in vacuo to yield the titled compound.

M1 74d) 5-[4-Chloro-3-(4-methyl-piperazine-l1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylamine: The title compound is prepared as an HBr salt by the same procedure as N-[S-(4-fluoro-3methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (161 c) by replacing 1 -bromo-lI-(4-fluoro-3methoxy-phenyl)-propan-2-one (161 b) with 1-bromo-lI-[4-chloro-3-(4-methyl-piperazine- 1sulfonyl)-phenyll-propan-2-one (171 c) and N-acetylthiourea with thiourea.

1 74e) I -{S-[4-Chloro-3-(4-methyl-piperazine-l1-sulfonyl)-phenyl]-4-methyl-thiazol-2-yl)-3ethyl-urea: A stirred solution of 5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol- 2-ylamine hydrobromide (174d) (0.1 g, 0.26 mmol) in DMF (1 ml) at room temperature is treated with DIPEA (0.07 g, 0.52 mmol) and ethyl isocyanate (0.025 ml, O.33mmol). The reaction mixture is heated to 120'C for 1 hour and then allowed to cool to room temperature.

Purification by preparative LC-MS affords the titled compound.

Example 175: N-[5-(3-Cya no-4-methanesulfonyl-p2henyl)-4-methyl-thiazol-2-yll-acetamide The titled compound was prepared by an identical procedure to N-[S-(3-fluoro-4methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) replacing 3,4difluorobenzaldehyde in this procedure with 2-fluoro-S-formylbenzonitrile.

Examples 176: 3-13-f 5-(3-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-ureidol-p2ropionic acid ethyl ester 1 76a) 1 -(4-Chloro-3-methanesulphonyl-phenyl)-propan-2-one: A stirred solution of 2-Chloro-S-(2-oxo-propyl)-benzenesulphonyl chloride (prepared as described in Example 174a) (20.0 g, 74.9 mmol) in dioxane (300 ml) at room temperature is treated with a solution of sodium sulphite (18.9 g, 150 mmol) and sodium hydrogen carbonate (12.6 g, 150 mmol) in water (200 ml). The reaction mixture is heated to 75*C for 10 minutes and then allowed to cool to room temperature. The solvent is removed in vacua and the residue dissolved in DMF (200 ml). The solution is stirred at room temperature and treated N1 with iodomethane (21.2 g, 150 mmol). After stirring for 20 minutes, the reaction mixture is diluted with water (1000 ml) and extracted with ethyl acetate (3 x 250 ml). The combined organic layers are washed with water (2 x 200 ml), brine (100 ml), dried over MgSO 4 and concentrated in vacuo to yield the titled compound.

176b) 1-(3-Methanesulphonyl-phenyl)-propan-2-one: S A solution of 1-(4-chloro-3-methanesulphonyl-phenyl)-propan-2-one (5.49 g, 22.28 mmol) in C methanol (250 ml) is stirred under hydrogen in the presence of 10% Pd on carbon (3 g) for 2 hours. The reaction mixture is filtered and concentrated in vacuo to yield a yellow oil of the C, titled compound.

176c) 1-Bromo-l-(3-methanesulphonyl-phenyl)-propanone: A stirred solution of 1-(3-methanesulphonyl-phenyl)-propan-2-one (176b) (0.25 g, 1.18 mmol) in dioxane (10 ml) at 5°C is treated with bromine (0.131 g, 0.82mmol) added in two portions.

The reaction is stirred and allowed to warm up to room temperature. The solvent is removed in vacuo to yield an orange oil of the titled compound.

176d) 5-(3-Methanesulphonyl-phenyl)-4-methyl-thiazol-2-ylamine hydrobromide: A stirred solution of 1-bromo-l-(3-methanesulphonyl-phenyl)-propanone (176c) (0.32 g, 1.01 mmol) is treated with thiourea (0.067 g, 0.88 mmol) added in one portion. The reaction mixture is allowed to stir at room temperature over two days. The product precipitates out and is filtered to yield the tittle compound as while solid.

176e) 3-{3-[5-(3-Methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido)-propionic acid ethyl ester: A stirred suspension of 5-(3-methanesulphonyl-phenyl)-4-methyl-thiazol-2-ylamine hydrobromide (176d) (0.172 g, 0.64 mmol) in DCM (15 ml) is treated with Hunigs base (0.45 ml, 2.36 mmol) followed by ethyl-3-isocyanatopropionate (0.092 g, 0.64 mmol). The reaction mixture is stirred and heated to 60 0 C for 10 hours and then the solvent in removed in vacuo.

The product is purified by chromatography on silica to give the titled compound Examples 177: [5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yll-urea 177a) Imidazole-1-carboxylic acid [5-(3-fluoro-4-methanesulfonyl-phenyl0-4-methyl-thiazol-2yl]-amide: Ni The title compound is prepared by the same procedure as imidazole-1-carboxylic acid Z imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (Example 150~a) by t replacing S-(3-imidazol-1 -yl-4-methanesulfonyl-phenyl)A4-methyl-thiazol-2-ylamine (Example 148) with 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) C 1 77b) [S-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea: The title compound is prepared by the same procedure asl-[S-(3-fluoro-4-methanesulfonyl- 0 phenyl)-4-methyl-thiazol-2-yl]-3-(2-hydroxy-ethyl)-urea (Example 88) by replacing 2aminoethanol (part 88b) in this example with ammonia.

Examples 178: 1 -[2-(5-Ethyl-oxazol-2-yl)-ethyll-3- [5-(3-fluoro-4-methanesul fonyl-phenyl 1-4methyl-thiazol-2-yll-urea The title compound is prepared by the same procedure as-[S-(3-fluoro-4-methanesulfonylphenyl)-4-methyl-thiazol-2-yli-urea (Example 177) by replacing ammonia (part 177b) with the hydrochloride salt of 2-(5-Ethyl-oxazol-2-yl)-ethylamine (details of preparation procedure follows below), by replacing dioxane with DMF and by using triethylamine as a base.

2-(5-Ethyl-oxazol-2-yl)-ethylamine): Step 1) 2 2 -Hydroxy-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester: A mixture comprising Z-Beta-Ala-OH (9.0 g, 40.3 mmol), EDCI.HCI (10.0 g, 52.4 mmol), hyrdoxybenzotriazole (5.45 g, 40.3 mmol), triethylamine (7.3 ml, 52.4 mmol) in DCM (150 ml) is stirred at 0 0 G for 30 minutes. 1-Amino-2-butanol (4.2 ml, 44.3 mnnol) is added in one portion and stirring is continued for 1 hour. The reaction mixture is diluted with water (150 ml) and extracted with dichloromethane (2 x 150 ml) The organic layers are combined, dried over MgSO4, filtered and concentrated in vacuo to yield a crude white solid. The product is purified by chromatography on silica eluting with ethanol-ethyl acetate (1:10) to give the titled compound.

Step 2) [2-(2-Oxo-burylcarbamoyl)-ethyll-carbamic acid benzyl ester: To a stirred solution of oxalyl chloride (2 M in DCM) (13.35 ml, 26.5 mmol) in dry DCM at 78'C is added dropwise DMSO (2.5 ml, 35.4 mmol). After stirring for 15 minutes, the reaction mixture is treated with a solution of (2-hydroxy-butylcarbamoyl) -ethyl] -carbamic acid benzyl ester (step 1) (6.5 g, 22.1 mol) in dry DGM (40 ml). Triethylamine (13 ml) is added after 1 hour and after stirring at -78'C for 90 minutes, the reaction mixture is allowed to warm to room temperature. The reaction is diluted with DCM (100 ml) and washed with HCI (1M, 200 ml), saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine (200 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as a white solid.

Step 3) [2-(5-Ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester: To a stirred suspension of polymer supported triphenylphosphene (19.6 g, 58.9 mmol) in DCM (250 ml) is added iodine (14.95 g, 58.9 mmol). After stirring at room temperature for minutes, the mixture is treated with triethylamine (16.4 ml, 117.5 mmol) followed by a solution of [2-(2-oxo-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester (step 2) (6.88 g, 23.5 mmol) in DCM (50 ml). The reaction mixture is stirred overnight and then filtered through celite, washed through with DCM (500 ml) and the solvent removed in vacuo to yield the titled compound as a brown solid.

Step 4) 2-(5-Ethyl-oxazol-2-yl)-ethylamine (hydrochloride salt): A solution of [2-(5-ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester (step 3) (0.

4 1g, 1.49 mmol), 2M HCI (0.75 ml) in ethanol (40 ml) is stirred under hydrogen in the presence of Pd on carbon (0.041 g) for 5 hours. The reaction mixture is filtered and concentrated in vacuo to yield the titled compound.

Examples 179: 1-2-(4-Ethyl-oxazol-2-yl)-ethyll-3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4methyl-thiazol-2-yll-urea The title compound is prepared by the same procedure as 1-[2-(S-ethyl-oxazol-2-yl)-ethyl]-3-[5- 3 -fluoro- 4 -methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 178) by replacing 2- (S-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of 2-(4ethyl-oxazol-2-yl)-ethylamine. This is prepared by the same procedure as 2-(S-ethyl-oxazol-2yl)-ethylamine hydrochloride (step 4) by replacing 1-amino-2-butanol (step 1) with 2-amino-1butanol.

Example 180: 1-5-(3-Fluoro-4-methanesulfonyl-phenl)-4-methyl-thiazol-2-yll-3-[2-(5-methyloxazol-2-l)-ethyll-urea The title compound is prepared by the same procedure as l-[ 2 -(5-ethyl-oxazol-2-yl)-ethyl]-3-[5- 3 -fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl-urea (Example 178) by replacing 2- (S-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of methyl-oxazol-2-yl)ethylamine. This is prepared by the same procedure as 2-(5-ethyl-oxazol-2yl)-ethylamine hydrochloride (step 4) by replacing 1-amino-2-butanol (step 1) with 1-amino-2propanol.

S Example 181: 1-15-( 3 -Fluoro-4-methanesulfonl-phenyl).-4methyl-thiazol-2-yl]-.3-2-(4-methyloxazol-2-yl)-ethyll-urea The title compound is prepared by the same procedure as 1-[2-(S-ethyl-oxazol-2-yl)-ethyl]-3-[5- (3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-urea (Example 178) by replacing 2- 0 (5-ethyl-oxazol-2-yl)-ethylamine hydrochloride (step 4) with the hydrochloride salt of 2-(4methyl-oxazol-2-yl)ethylamine. This is prepared by the same procedure as 2-(5-ethyl-oxazol-2- O yl)-ethylamine hydrochloride (step 4) by replacing l-amino-2-butanol (step 1) with 2-amino-1propanol.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "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.

Claims (11)

1. 2. A compound according to claim 1 or a salt thereof wherein RI is arninocarbonyl. optionally substituted by nitrike, Or RI is Ci-Cs-ailcylcarbonyl optionally substituted by halogcn, hydroxy, carboxy, Cl.Ca- alkoxycarboniyl, nitrile, phenyl, Cl-Cs-haloaikyl, or by Ci-Co-allcyl optionally substituted by hydroxy, or RI is Gi-Ca-alkylaminocarbonyl optionally substituted by halogen, bydroxy, di(Gi-Ca- allcyl)amino, carboxy, Ci-Cs-alkoxycarbonyJ, nitrile, phenyl, Ci-Ca-haloalkyl1, or by C 1 -Cs- IND alkyl optionally substituted by hydroxy, or XI is Ci-Cralkylaniinocarbonyl optionally substituted by C3-Cs-cydoalkyl, 0 or R' is Ci-C8-alkylcarbonyl or Ci-Ca-alkylarninocarbonyl either of which being optionally sulbstituted by Ct-Cs-alkoxy optionally substituted by hydroxy, or R 1 is Ci-Cs-ailcylcarbonyl optionally substituted by a 5- or 6-membered unsarurated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, itrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl, or RI is Ci-Gs-alkylaminocarbonyl optionally substituted by a 5- or 6-memnbered hererocyclic ring having one or more ring hereto atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl, or RI is where a is 0 or 1 and Het denotes a 5- or 6-membered N- hieterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, CI-Cv-alkyl, Ci-Ce-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R1 is where T denotes C3-CH-cycloalkyl optionally substituted by hydroxy, Ci-C3-alkyl, or by Ci-Ce-alkyl substituted by hydroxy, or T denotes phenyl substituted by hydroxy, Ci-C-alky1, or by CI-Cls-alkyl substitutcd by hydroxy; is Ci-C3-alkyli one of R 3 and R 4 is R6 and the other is* R 7 Rs is hydrogen or halogen; RI is hydrogen, hydroxy, amino, -SO7.R 8 -SO 2 NH.- 2 -SO2aNR9R'O, -NHSOiR', cyano, carboxy, -M'V or Ci-Q4-haloalcyl; R 7 is hydrogen, fluorine, chlorine, bromine, nitrile or Ci-C4-haloalcyl, or, when R4~ is R 7 R7 can also be -NRMR13 or -R4 RI and R'1 are independently Ci-Coralkyl; either K 9 is Ci-Cg-alcyl optionally substituted by hydroxy, C3-Ce-cycloallcyl optionally substituted by hydroxy, Ci-Cs-alloxy, riitrile, di(Ci-CB-allcyl)arnino or a 5- or 6-membered heterocyclic ring having one or more ring hetro atoms selected from the group consisting of Q--)oxygen and nitrogen, that ring being optionally substituted by Cz-Cs-alkyl, and RIO is hydrogen or Ci-Ca-alkyl; or R9 and RIO together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further hetero atoms selected C) from the group consisting of oxygen and nitrogen, that ring being optionally substituted by C 1 Cv-alkyl; either Riz is Cx-Cs-alkyl optionally substituted by di(Ci-Ca-alkyl)amnino, and R13 is hydrogen~ or C1-CR-a~kyl or R 12 and R 13 together with the nitrogen atom to which they are attached form a or 6-membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Cj- Ca-aIlkyl; and R1 4 iS Ci-Cs-alkyl.
2. 3. A compound according to claim 1 or 2, or a salt thereof, wherein R' is aminocarbonyl optionally substituted by nitrile, or R 1 L is Ci-C4-alkylcarbonyl optionally substituted by halogen, hydroxy, carboxy, Ci-C 4 alkoxycarbonyl, nitrile, phenyl, Cj-C 4 -baloalkyl, or by Cl-C 4 -alkyl optionally substituted by hydroxy, or RI is CI-C4-alkylaminocarbonyl optionally substituted by halogen, hydroxy, di(Cl-C 4 alkyl)arnino, carboxy, Ci-Cv-aloxycarbonyl, nitrile, phenyl, Ci-Q~-haloalkyl, or by CI-C 1 ailcyl optionally substituted by hydroxy, or R' is Ci-C4-alkylaxinocarbonyl optionally substituted by C3-Cs-cycloalkyl, or RI is Ci-C4-alkylcatbonyl or Cl-C4-alkylaminocarbonyl either of which being optionally substituted by Ci-C4-alkoxy optionally substituted by hydroxy, or R1 is Gi-C4-alkylcarbonyl optionally substituted by a or 6-membered unsaturated heterocyclic ring having one or more ring hetero, atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by CI-C4-alkyl, or RI is CI-C4-alkylaminocarbonyl optionally substituted by a 5- or 6-meinbered heterocyclic ring having one or more ring herero atoms selected from rhe group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by CI-C 4 -alkyl, or RI is 3 -Het where a is 0 or 1 and HcLt denotes a 5- or 6-menibered N- heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Cl-C 4 -alkyl, Ci-C 4 -alkoxy or by a 5- or 6-.membered heterocyclic ring having one or more ring herero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or RI is where T denotes C3-CS-cycloalkyl optionally substituted by hydroxy, CI-q,-alkyl, or by Ci-C 4 -alkyl substituted by hydroxy, or T denotes phenyl substituted by hydroxcy, Ci-C4-aikyl, or by Ci-C4-aJlkyl substituted by hyciroxy; Rz is CI-C3-alkyl; one of R 3 and R 4 is R6' and the other is R 7 is hydrogen or halogen; R6 is hydrogen, hydroxy, amnino, SO 2 .R8, SO2NH2, SO2NR.9RU, Nl-SOiRB, nirrile, carboxcy, OR 8 or G1-C4-haloallcyl; R 7 is hydrogen, -OR"3, fluorine, chlorine, bromine, cyano or Ci-Q4-haloalkyl, or, when R 4 is R7, R7 can also be -NR1IR13 or -OR 14 R8 and R" are independently Ci-0 4 -alkyl; either R' is GI-C4-alkyl optionally substituted by hydroxy, C3-Os-cycloallcyl optionally substituted by hydroxy, Cl-G4-alkoxy, nitrile, di(Cl-C4-alkyl)antino or a 5- or 6-membered heterocyclic ring having one or mnore ring hctero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Cl-C 4 -alkyl, afid RIO 0 is hydrogen or Cl-C4-alkyl; or Rt 9 and RIO together with the nitrogen -atom to which they are attached form a 5- or 6-membered heterocyclic ring that contains one or more further herero atom~s selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by CI- C 4 -alkyl; either R17 is Cl-Ci-alkyl optionally substituted by di(C1-CQ-alkyl)arnino, and R'3 is hydrogen or Ci-C4-alkyl; or R12 and R13 together with the nitrogen atom to which they are artachcd form a or 6 -membcred-heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of ox'ygen and nitrogen, chat ring being optionally substituted by Cj- C4-a.Lkyl; and
3. 4. A compound of formula I according to claim 1 or a salt thereof, wherein RI is arninocarbonyl, or R' is Ci-Cs-alkylcarbonyl optionally saibstituted by hydroxy, amino, Cl-Ca-alkylarnino, carboxy, Ci-C&-alkyl optionally substituted by hydroxy, or by halogen, or R1 L; Ci-Co-alkylaminocarbonyl optionally substituted by Iaydroxy, amino, CI-Cs- alkylamnino, di(Cl-Ce-atkyl (amnino), carboxy, C2-CO-ailcyl optionally substituted by hydroxy, or by halogen, or RI is Ci-Co-ailcylcarbonyl or Ci-G.-alkylaminocarbonyl either of which being optionally substituted by C3-C8-cYd~oallcYl Optionally substituted by hydroxy, Ci-C 1 -alkoxy optionally substituted by hydroxy, Ci-Calkoxycarbonyl, nitrile, halogen, phenyl. optionally substituted by hydroxy or Ci-Ca-alkyl, or RI is Ci-Cu-ilkylcarbonyl optionally substituted by a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Cl-Co-alkyl or Cl-Cs-alkoxy, or RI is Ci-Ce-alkylaminocarbonyl optionally substituted by a 5- or 6-mcrnbered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy,* Ci-CR-allcyl or Ci-Cb- alkox-y, or RI is where a is 0 or 1 and Het denotes a 5- or 6-rnembered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Gi-Ca-ailkyl or Ci-Cs- alkoxy; R2~ is Cl-C 3 -alkyl or halogen; one of R3 and R4 is R6 and the other is R7; Rs is hydrogen or halogen; R6 is hydrogen, hydroxy, amino, -SORR, -SO!R8, -SOiNH 2 -SOiNR9RO, -COR', -CONURS, -NIISO 2 nitrile, carboxy, -OR' or CI-Cr-haloalkyl; R 7 is hydrogen, RuI, halo, carboxy, -S02RI, cyano or Cl-Ca-haloalkyl, or, when R 4 is R7 R7' can also be -NR12R13,I R 14 or -OR' 4 R 8 and Ril are independently Ci-Cs-alkyl or Cs-Ce-cycloalkyl, optionally substituted by halogen, hydroxy, Ci-Cs-alkoxy, nitrile, amino, Cl-Co-alkylamino or di(C,-Co-alkyl)amino; either K9 is CI-Ce-ailcyl Or C3-Cs-cycloalkyl, optionally substituted by hydroxy, Cl-Cs-alkoxy, nitrile, amino, Ci-Co-alkylamino, di(CI-Cs-allcyl)amino or a 5- or 6-niembered heterocyclic ring having onc or more ring heetro atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl, and R11 is hydrogen or Ci- Cs-alkyl; or R-9 aad RIO together with the nitrogen atomn to which they are attached form a or 6-inembered heterocyclic ring that contains one or more futher hetero atoms selected from the group consisting of oxygen, nitrogen and sulphuir, chat ring being optionally substituted by Ci-Ca-alkyl; either R 12 is Ci-GR-alkyl or C3-Cs-cyd oalkyl optionally substituted by hydroxy, amino, C 1 -Cs- alkylamino or di(Cu-Ca-alkyl)arpjno, and R 1 3 is hydrogen or Ci-C&-ailkyl; or R12 and R13 rogether with the nitrogen atom to which they are attached form a 5- or 6. membered heterocyclic ring that contains one or more further hereto atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Cl-Ca- alicyl; and R14 is Ci-Cs-alkyl optionally substituted by hydroy or -NR12R13. A compound according to claim 4 or a salt thereof wherein R 1 is aminocarbonyl, or R 1 is CL-Cv-alkylcarbonyl optionally substituted by hydroxy, carboxy, Ci-Cs-alkyl optionally substituted by hydroxy, or by halogen, or R1 is Ci-Ca-allcylaminocarbonyl optionally substituted by hyciroxy, di(Ci-Cs-alkylamino), carhoxy, Ci-Cs-alkyl optionally substituted by hyctroxy, or by halogen, or RI is Ci-Cs-alkylcarbonyl or Cl-Co-alkylantinocarbonyl either of which being optionally substituted by C3-Ca-cycloalkyl optionally substituted by hydroxy, Ci-Cs-alkoxy optionally substituted by hydroxy, Ci-Cs-alkoxycarbonyl, nitrile, halogen, phenyl optionally substituted by hydroxy Or CI-CR-allcyl, or R' is Ci-Ca-allylcarbonyl optionally substituted by a 5- or 6-membered unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl or Ci-Ca- alkoxy, or R 1 is Ci-Co-alkylaminocarbony1 optionally substituted by a 5- or 6-membered hererocydic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl or Cl-Ca-alkoxy, or R1 is where a is 0 or 1 and Her denotes a 5- or 6-ruembered N- heterocyclic ring optionally substituted by hydroxy, Ci-Cs-alkyl or CI-Ce-alkoxy; RI IS Cl-C3-aikyl; one of R 3 and R 4 is R6 and tho other is R 7 Rs is hydrogen or halogen; R6 is hydrogen, hydroxy, amino, -SO 2 RB, -SO 2 NH2, -SO2,NRR1O, -NHSOiRB, cyano, carboxy, -OR, or Cl-C4-haloalkyl; R' is hydrogen, -OR" 1 fluorine, chlorine, bromine, cyano or Cl-C4-haloalkyl, or, when R1 is R7 7 R' can also be -NR12R13 or -0R14; R9 and R 1 1 are independently Ci-Cs-alkyl; either R9 is Ci-CB-alkyl optionally substituted by hydroxy, C3;-CB-ycloalkyl optionally substituted by hydroxy, Ci-Cs-alkoxy, nitrile, di(Ci-Cs-alkyl)amino or a 5- or 6-niembered heterocyclic ring having one or more ring hetero atoms selected from The group consisting of oxygen. and nitrogen, that ring being optionally substituted by CI-Cs-alky1, aind RIO is hydrogen.,, or Q -Co-alcyl; or RI and. RIO together with the nitrogen atom to which they are attached form a or 6-incmbered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Ci- Ca-alkyl; either R 1 2 is Cl-Cs-alkyl optionally substituted by di(Ci-Cralkyl)aMino, and R13 is hydrogen or Ci-Ce-alkyl; or R1 2 and R 13 together with the nitrogen atom to which they are attached form a S- or 6-mcmbcred heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Ci- Cs-alky!; and R1 4 is GI-CR-ailcyl.
4. 6. A compound of formula I according to claim 1, or a salt thereof, wherein R 1 is% C-Cs-alkylcmbonyl or Ci-Co-ailcylaniinocarbonyl optionally substituted by amino, carboxy, Cl-Cs-alkoxy, Gi-Cs-alkoxycarbonyl, nitrile, or by halogen, or R1 is Ci-Cs-alkylcarbonyl optionally substituted by a 5 or 6-membefed unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by CL-C3-alkyl, or RI is Cl-Cs-alkylaininor-arbonyl optionally substituted by a 5 or 6-inembered heterocyclic ring having one or more ring hetro atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Gi-Cs-alkyl; R 2 is CI-Cs-alkyl or halogen; one of R 3 and R 4 is R6 and the othaer is R 7 R 5 is hydrogen or halogen; R6 is hydrogen, hydroxy, amino, SORB, S0 2 Rs, SOzNH2, SO2NR9R0, COR', CONHRB, N1-fSO 2 R8', nitrile, carboxy, OR 9 or Ci-Cs-haloalkyl; R 7 is hydrogen, R1 1 OR", halo, cyano, carboxy, SOzR',, or Ci-Ce-haloalkyl, or, when R4 is R7Z, R 7 can also be NR 12 R' 3 R 1 4 or OR 14 R8 and R11 are independently Ci-Co-alkyl or G3-Cs-cyclo-alkyl, optionally substituted by halogen, hydroxy, Ci-GR-alkoxy, nitrile, amino, Ci-Cs-akylarnino or di(Ci-Ca-allcyl)arnino; either R-9 is Ci-Ca-alkyl Or C3-Cs-cycloalkyI, optionally substituted by hydroxy, Cl-Ge-alkoxy, nitrile, amino, Ci-Ca-alkylarnino, di(Ci-Cs-alkyl) amino or a 5 or 6-mernbered heterocyclic ring having one or more ring hetero atoms sclected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl, and RIO is hydrogen or Ci- Ce-alkyl; or R9 and RIO together with the nitrogen atom to which they are attached form a 5 or 6- mnembered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by 0 Gx-CB-alkyl; either R12 is Gi-Gs-alkyl or C-C-yclalkyl optionally substituted by hydroxy, arnino, Cj-C3- alkylamino or di(Ci-C&-alkyl) amino, and R) 3 is hydrogen or Ci-Cv-Alkyl; or R1 2 and R1 3 together with the nitrogen atom to which they are attached form a 5 or 6- memnbered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen, nitrogen and sulphuf, that ring being optionally substituted by C 1 -G 8 C alkyl; and R1 4 is GI-CS-alkyl optionally substituted by hydroxy or NRI2R13.
5. 7. A compound according to claim 6 or a salt thereof wherein k, is Ci-Ce-alkylearbonyl or Ci-Cs-alkylantinocarbonyl optionally substituted by carboxy or Ci-Ce-alkoxycarbonyl; R 2 is Cl-C 3 -alkyl; one of R 3 and R 4 is R6 and the other is R 7 Rs is hydrogen or halogen; R1 is hydrogen, hydroxcy, amino, 5O2RR, SO 2 ,NI-1 2 SOaNR 9 RIO, NHSO 2 R8, cyano, carboxy, ORB or Ci-C 4 i-haloalkyl; R 7 is hydrogen, ORl", fluorine, chlorine, bromine, cyano or Ci-C4-haloalkyl, or, when R 4 is R7., R 7 can also be NRl2RU3 or OR' 4 RS and R 11 are indepen~dently Ci-Co-alcyli cither is Ci-Cs-.alkyl or C3-CB-cycloalkyl, optionally substituted by hydroxy, Cl-Cs-alkoxy, nitrile, di(Ci-Cs-ayl)amino, or a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Ci-C8-alkyl, and RIO is hydrogen or Ci-Ca-alkyl; or R' and RIO together with the nitrogen atom to which they are attached form a 5 or 6- membered heterocyclic ring that contains one or more further herero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Ci-Ce-alkyl; either R12 is Ci-Co-alkyl optionally substituted by di(Ci-Cs-atkyl)arnino, and R1 3 is hydrogen or Ci-CR-alkyl; or R 12 and RA 3 together with the nitrogen atom to which they are attached form a or 6- membered heterocyclic ring that contains one or more further hetero atoms selected from the group consisting of oxygen and nitrogen, that ring being optionally substituted by Ci- Cs-alkyl; and R 1 4 is Ci-Cs-alkyl.
6. 8. A compound according to claim 1, that is also a compound of formula XIX H 3 C '-N Rb or a salt thereof, wherein Rb, Re and RI are as shown in the following table: Rb I Ra 9n Ra R b H H C -CH CHY CHP 0 H H CHO H; H H CH 3 0 H H H HX~ 0 H H 0 0H H H N. (C, COCH 3 H H %Y CH CF 3 H H C OH H H H QCH 3 OCH 3 H O' H3 H ON H Or H 3 H CF 3 H CHO Ru R _Re RI o0SNCH3 CH/ 0 4-N-CHS CH/ H H m N CH 3 N O H 0 CH OCH 3 OCH 3 OC 3 Cl Cr ,o s 0 NH2 X04 0 /0 H H H H H H I 0 a OCH 3 OCH 3 'Y CH 3 0 "YrCH 3 0 N'Y H 3 0 I c-I Rb Rc OCH 3 H H 00 H DH 0H OCH 3 H GH3 0 OCH 3 H H 0 OCH 3 H C- HS NHN OCH 3 H HH 0~0 0 2007203160 06 Jul 2007 IND OV\CHS 0 CH3 0 CH-1 N CH 3 H SI CHN 0 H H~0 H C F HC H H 0FH H H yC1 0 0 H- H H
7. 9. A compound according to claim 1, that is also a compound of formula XIX NE/ OH 0C H H C; NS 0l l I or a salt thereof, wherein R1, Rb, Re and R 1 are as shown in the following table: R b Re CH 3 p0 F H H 0 CH 3 0 F HH CH3 0 H o CH 3 0 H 0 I FH OH s oF H o CH 3 oF H o CH 3 F H 0 ACH 3 \,oF F O o CH 3 FH OH o11 CH 3 cl0 HH H H \oH H 011 O CH 3 0 IND IND CH 3 CHS IND IND Rh Rb R R_ CI H H 3 0CH 3" C 0H N o CH 3 N 0 0 H o CH 3 H 0H NHO 0 H H S/O I I Y n 7# CH H o OH 3 N 0 H0 CCH 3 CHH CHO 3 A compound according to claim 1, that is also a compound of formula XIX 107 Re NR R XIX Ra IND or a salt thereof, wherein Ra, Rb, Rc and RI are as shown in the following table: iw I I Re J _H IND IND ;o CH3 P \OPER\MAL\2(l7il2417910 Ispa doc-/A,72rx) S-109- R" Rb R O RI H s H H \o F H NH2 0 CH 3 O H F H C; CHO NH 3 O SCHC o O F H N CH o F H o OH 3 C 1 1. A compound according to any one of claims 1 to 10 for use as a pharmaceutical.
8. 12. Pharmaceutical compositions comprising a compound according to any one of claims 1 to
9. 13. The use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis, Crohn's disease, septic shock, proliferative disorders such as cancer, athersclerosis, allograft rejection following transplantation, diabetes, stroke, obesity or restenosis. r IOPEP.ALUK)7,I245:,c; 1 po JOSf 1/:/2XJ7 -110-
10. 14. A method of treating respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, 0 rheumatic disorders, psoriasis, ulcerative colitis, Crohn's disease, septic shock, Sproliferative disorders such as cancer, athersclerosis, allograft rejection following N transplantation, diabetes, stroke, obesity or restenosis including the step of administering M 5 an effective amount of a compound according to any one of claims 1 to A process for the preparation of a compound of formula I as defined in claim 1, in free 1 or salt form which comprises the steps of: for the preparation of compounds of formula I where R' is Ci-Cs-alkylcarbonyl or C 1 -Cs-alkylaminocarbonyl optionally substituted by amino, carboxy, Ci-C 8 -alkoxy, C -Cs-alkoxycarbonyl, nitrile or halogen, or R' is Ci-Cs-alkylcarbonyl optionally substituted by a 5 or 6-membered. unsaturated heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -Cs-alkyl, or R' is Ci-Cs-alkylaminocarbonyl optionally substituted by a 5 or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl, reacting a compound of formula II 2IN Br S R P:\OPERMALUI07\12487910 spa doc-.3M1/207 -111- wherein R I and R 2 are as hereinbefore defined, with a compound of formula III R B(OH) 2 III R 3 R 4 wherein R 3 R 4 and R 5 are as hereinbefore defined, in the presence of a transition metal catalyst; for the preparation of compounds of formula I where R 3 or R 4 is -SO 2 NH 2 or -SO 2 NR'R' 0 reacting a compound of formula IV 2 R' Rs N OS R CI wherein R 1 R 2 R 5 and R 7 are as hereinbefore defined and the -SO 2 Cl group is meta or para to the thiazole ring, with ammonia or a compound of formula R 9 Ri'NH; for the preparation of compounds of formula I where R 3 or R 4 is NHSO 2 R 8 reacting a compound of formula I where one or R 3 and R 4 is NHz with a sulfonyl chloride of formula RSSOzCI; -112- for the preparation of compounds of formula I where R 4 is NR 12 R 1 3 reacting a compound of formula I where R 4 is halogen and R 3 is SO 2 R S with a compound of formula V ID O R 1 2 SR N/NH V Swhere R 1 2 and R 1 3 are as hereinbefore defined; for the preparation of compounds of formula I where R' is optionally substituted O Ci-Cs-alkylaminocarbonyl, reacting a compound of formula I where R 1 is hydrogen with a compound of formula VI R S-N=C=O VI R'S-N=C=O, wherein R is is Ci-Cs-alkyl optionally substituted by carboxy or CI-Cs- alkoxycarbonyl; for the preparation of compounds of formula I where one of R 3 and R 4 is amino and the other is hydrogen or halogen and at least one of R 3 R 4 and R 5 is halogen, halogenating a compound of formula I where R 3 or R 4 is amino and the other is hydrogen; reacting a compound of formula VII R X0 I VII R 3 R 4 wherein R 2 R 3 R 4 and R 5 are as hereinbefore defined and X is halogen, with a compound of formula VIII NH 2 S NH VIII R wherein R 1 is as hereinbefore defined; for the preparation of compounds of formula I where R 3 or R 4 is -S0 2 R 8 and R 8 is methyl, reacting a compound of formula IV wherein R 2 R s and R 7 are as -113- hereinbefore defined and the -SO 2 Cl group is meta or para to the thiazolyl ring, with an alkali metal sulphite and an alkali metal bicarbonate, followed by reaction with bromoacetic acid or an alkyl halide; ID for the preparation of compounds of formula I where R 1 is Ci-Cs-alkylamino- carbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and Ssulphur, that ring being optionally substituted by Ci-Cs-alkyl or Ci-Cs-alkoxy, or where R 1 is where a is 0 and Het denotes a 5- or 6-membered Oheterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Ci-Cs-alkyl, Ci-Cs-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or where R' is where b is 0 and T denotes C3-Cs-cycloalkyl either of which optionally substituted by hydroxy or T denotes phenyl substituted by hydroxy, C i-Cs-alkyl, CI-Cg-alkoxy, or by Ci-Cs-alkyl substituted by hydroxy, reacting a compound of formula I where R' is hydrogen with a compound of formula IX R 0 IX O-H where R 6 is Ci-Cs-alkyl substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by Ci-Cs-alkyl or Ci-Cg-alkoxy, or R 1 6 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Ci-Cs-alkyl, Ci-Cs-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 6 is C3-Cs-cycloalkyl optionally substituted by hydroxy, Ci-Cs-alkyl, Ci-Cs-alkoxy, or by Ci-Cs-alkyl substituted by hydroxy, -114- or R 16 is phenyl substituted by hydrogy, Ci-Cs-allcyl, Ci-Ca-alkoxy, or by Ci-.Cs-alicyl substituted by hydroxy; or ()for the preparation of compoundt of formula I where IND R1is Cl-Ca-alkylaininocarbonyl optionlally substituted by halogen, hydroxy, amino, CI- Cs-allcylamnino, di(CI-Ca-alkyl)aminoj carboxy, Ci-Cs-alkoxycarbonyl, nitrile, phenyl, Ci-Cj-haloalkyl, or by Ci-Ca-alkyl optionally substituted by hydroxy, or RI is Ci-Ce-allcylaminocarbonyl optionally substituted by C3-Cs-cycloalkyl optionally substituted by hydroxy, or RI is Ci-Ca-alkylaminocarbonyl optionally substituted by Ci-CB-alkoxy optionally substituted by hydroxy, or RI is Gi-C3-alkylaininocarbonyl optionally substituted by phenyl. optionally substituted by hydroxy or C-i-Ga-alkyl, or RI is Ci-Cs-alkylaminocarbonyl optionally substitutecd by a 5- or 6-nernbered heterocyclic ring having one or more ring herero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Ci1-Ca-alkyl or Ci-Ca-alkoxy, or RI is where a is 0 or 1 and Het denotes a 5- or 6-inembered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by hydroxy, Q -Ca-alkyl, Ci-Cs-alkoxy or -by a 5- or 6-xnembered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or RI is where b is 0 or I and TI denotes C3-Ca-cycloalkyl optionally substituted by hydroxy, CQ-Cs-allcyl, Ci-Ca-alkoxy, or by Ci-Ca-:a~yl substituted by hydroxy, or T denotes phenyl substituted by hydroxy, Ci-CR-allcyl, CI-Crallcoxy, or by Ci-Cs-alkyl substituted by hydroxy, reacting a compound of formula X k NC=O 8 x wherein R2, RI, R 4 and Rs are as hereinbefore defined, with a compound of formula ME NH X1
11. 115- where R1 7 and R18 are selected from hydrogen, hydroxy, amino, Gi-Cs-alkylamino, di(CI-Cv-alkyl(amino), carboxy, Ci-Ce-alkyl optionally substituted by hyciroxy, halogen, C 3 -Cg-CYClOalkyl optionally substituted by hydroxy, C-i-C3-alkoxy optionally substituted by hydroxy, Ci-Cs-alkoxycarbonyl, nittile, halogen, phenyl optionally substituted by hydroxy or CI-CV-allcYl, and -a 5- or 6-membercd heterocyclic ring having one or more ring hetero atoms selected from dhe grouip consistig of oxygen, nitrogen and sulphur, that ring being optionally suibstituted by hydroxy, Ci-Ce-alkyl or C-s alkoxy, or when R' is RV 7 is hydrogen and RIO is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally subscirated by hydroxy, Ci-Ce-alkyl, Ci-Cs-alkoxy or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or when R1 is R 17 is hydrogen and RIB is either C 3 -Ca-cycloalkyl optionally substituted by hydroxy, CL-Cq-alkyl, Ci-Cs-alkoxy, or by CI-Ga-alkyl substituted by hydroxy, or RIB is phenyl substituted by hydroxy, Cl-C8-alkyl, G 1 -Cs- alkoxy, or by Ci-Curalkyl substituted by hydroxy; and (ii) recovering the-resultant compound of formula I in free or salt form.