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Definitions

• the present invention relates to certain heterocyclic compounds, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.
• Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved cysteine motif. At the present time, the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the C-X-C, C-C and C-X 3 -C families. The C-X-C and C-C families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues. The C-X 3 -C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the NH-proximal pair of cysteine residues.
• the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (EL-8) and neutrophil- activating peptide 2 (NAP-2).
• EL-8 interleukin-8
• NAP-2 neutrophil- activating peptide 2
• the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils.
• Examples include human monocyte chemotactic proteins 1- 3 (MCP-I, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins l ⁇ and l ⁇ (MIP- l ⁇ and MIP- l ⁇ ).
• the C-X 3 -C chemokine (also known as fractalkine) is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells.
• chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3 -C family.
• These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
• WO 2004/011443 we disclosed amino-substituted pyrimidine sulfonamides for use as modulators of chemokine receptors.
• the present invention now provides a compound of formula (1), or a pharmaceutically acceptable salt, solvate or in vivo hydro lysable ester thereof:
• R 1 is a group selected from C 3-7 carbocyclyl, Ci.salkyl, C 2 _6alkenyl and C 2- 6alkynyl; wherein the group is optionally substituted by 1 , 2 or 3 substituents independently selected from fluoro, nitrite, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 , -COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 5 R 6 , -NR 8 SO 2 R 9 , phenyl or heteroaryl; wherein phenyl and heteroaryl are optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, -OR 4 , - NR 5 R 6 , -CONR 5 R 6 , -COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 -
• X is -CH 2 -, a bond, oxygen, sulphur, sulphoxide, or sulphone;
• R 2 is C 3-7 carbocyclyl, optionally substituted by 1, 2 or 3 substituents independently selected from: fluoro, -OR 4 , -NR 5 R 6 -CONR 5 R 6 , -COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 5 R 6 , -NR 8 SO 2 R 9 ; or R 2 is a 3-8 membered ring optionally containing 1, 2 or 3 atoms selected from O, S, -NR 8 and whereby the ring is optionally substituted by 1 ,2 or 3 substituents indepedently selected from Ci ⁇ alkyl, fluoro, -OR 4 , -NR 5 R 6 -CONR 5 R 6 , -COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 5 R 6 , -NR 8 SO 2 R 9 ; or R 2 is
• R 3 is trifluoromethyl or a group-NR 5 R 6 ,
• R is phenyl, napthyl, monocyclic or bicyclic heteroaryl wherein a heteroring may be partially or fully saturated and one or more ring carbon atoms may form a carbonyl group, and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, phenyl, heteroaryl, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 , -COR 7 , , -COR 20 ,--COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 5 R 6 , -NR 8 SO 2 R 9 , trifluoromethyl or Q- ⁇ alkyl [optionally further substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, -OR 20 , -COOR 20 , -COR 20 ,
• R 3 is a group selected from C 3-7 carbocyclyl, C ⁇ aUcyl, C 2 - 6 alkenyl and C 2 .6alkynyl whereby the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 , -COR 7 ,-COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 5 R 6 , -NR 8 SO 2 R 9 , phenyl or monocyclic or bicyclic heteroaryl, wherein a heteroring may be partially or fully saturated; and wherein each phenyl or monocyclic or bicyclic heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 , -COR 7
• R 4 is hydrogen or a group selected from C ⁇ aUcyl and phenyl, wherein the group is optionally substituted by 1 or 2 substituents independently selected from halo, phenyl, -OR 11 and - NR 12 R 13 ;
• R 5 and R 6 are independently hydrogen or a group selected from C 1-6 alk;yl and phenyl and monocyclic or bicyclic heteroaryl, wherein a heteroring may be partially or fully saturated; wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, phenyl, -OR 14 ,-NR 15 R 16 , -COOR 14 , -CONR 15 R 16 , -NR 15 COR 16 , -SO 2 R 10 , - SO 2 NR 15 R 16 and NR 15 SO 2 R 16 ; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to
• R 10 is hydrogen or a group selected from C ⁇ aUcyl or phenyl, wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, phenyl, -OR 17 and - NR 15 R 16 ; and each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 R 15 , R 16 , R 17 is independently hydrogen, Ci-6alkyl or phenyl.
• R 18 , R 19 , and R 20 are hydrogen or a group selected from C ⁇ aUcyl or heteroaryl (wherein a heteroring may be partially or fully saturated) or phenyl, wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, nitro, -CN, -OR 4 , - NR 8 R 9 , -CONR 8 R 9 , -COR 7 ' -COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 8 R 9 , -NR 8 SO 2 R 9 , C 1-6 alkyl or heteroaryl.
• Certain compounds of formula (1) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (1) and mixtures thereof including racemates.
• the present invention relates to the compounds of formula (1) as hereinbefore defined as well as to the salts thereof.
• Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (1) and their pharmaceutically acceptable salts.
• Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of the compounds of formula (1) as hereinbefore defined which are sufficiently basic to form such salts.
• Such acid addition salts include for example salts with inorganic or organic acids affording pharmaceutically acceptable anions such as with hydrogen halides (especially hydrochloric or hydrobromic acid of which hydrochloric acid is particularly preferred) or with sulphuric or phosphoric acid, or with trifluoro acetic, citric or maleic acid.
• Suitable salts include hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, tartrates, oxalates, methanesulphonates or/?-toluenesulphonates.
• Pharmaceutically acceptable salts of the invention may also include basic addition salts of the compounds of formula (1) as hereinbefore defined which are sufficiently acidic to form such salts. Such salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
• Such salts with inorganic or organic bases include for example an alkali metal salt, such as a lithium, sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or an organic amine salt, for example a salt with methylamine, dimethylamine, trimethylamine, triethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• alkali metal salt such as a lithium, sodium or potassium salt
• an alkaline earth metal salt such as a calcium or magnesium salt
• an ammonium salt or an organic amine salt for example a salt with methylamine, dimethylamine, trimethylamine, triethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
• Other basic addition salts include aluminium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, trometh
• a selection of in-vivo hydrolysable ester forming groups for hydroxy include Ci-ioalkanoyl, for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, Q-ioalkoxycarbonyl (to give alkyl carbonate esters), for example ethoxycarbonyl; di-(Cr4)alkylcarbamoyl and N-(di-(Cr4)alkylaminoethyl)-//- (Cr 4 )HUCyICaTbBmOyI (to give carbamates); di-(Ci- 4 )alkylaminoacetyl and carboxyacetyl.
• Ci-ioalkanoyl for example acetyl; benzoyl; phenylacetyl; substituted benzoyl and phenylacetyl, Q-ioalkoxycarbonyl (to give alkyl carbonate est
• ring substituents on phenylacetyl and benzoyl include aminomethyl, (Ci. 4 )alkylaminomethyl and di-((Ci-4)alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.
• Other interesting in- vivo hydrolysable esters include, for example, R ⁇ C(O)O(Ci -6 )alkyl- CO-, wherein R ⁇ is for example, benzyloxy-(Ci- 4 )alkyl, or phenyl).
• Suitable substituents on a phenyl group in such esters include, for example, 4-(Ci- 4 )piperazino-(Ci- 4 )alkyl, piperazino- (Ci-4)alkyl and morpho lino -(Cr 4 ) alky 1.
• alkyl includes both straight-chain and branched- chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched-chain alkyl groups such as f-butyl are specific for the branched chain version only. For example, "Ci.
• C 3 . 7 carbocyclyl is a saturated, partially saturated or unsaturated, monocyclic ring containing 3 to 7 carbon ring atoms wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
• Suitable examples of “carbocyclyl” are cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, 4-oxocyclohex-l-yl and 3-oxocyclohept-5-en-l-yl.
• halo refers to fluoro, chloro, bromo and iodo.
• Examples of "Ci- ⁇ alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, 1-ethylpropoxy and hexyloxy.
• Examples of "Ci- 6 alkylamino” include methylamino, ethylamino, propylamino, butylamino and 2-methylpropyhnino.
• Examples of "di(Ci. 6 alkyl)amino” include dimethylamino, N-methyl-N-ethylamino, diethylamino, N- propyl-N-3-methylbutylamino. Examples of 'W-(Ci.
• 6 alkyl)-N-(phenyl)amino include N- methyl-N-phenylamino, N-propyl-N-phenylamino and N-(2-methylbutyl)-iV-phenylamino.
• Examples of 'W-(Ci -6 alkyi)carbamoyr are iV-methylcarbamoyl, N-ethylcarbamoyl and N-(2- ethylbutylcarbamoyl.
• Examples of 'W-(C 1 -6alkyl)-N-(phenyl)carbamoyl include N-methy ⁇ -N- phenylcarbamoyl, JV-butyl-N-phenylcarbamoyl and ⁇ (3-methylpentyl)-N-(phenyl)carbamoyl.
• Examples of 'W.N-d ⁇ C ⁇ ealky ⁇ carbamoyl” include ⁇ N-dimethylcarbamoyl, N-methyl-iV- ethylcarbamoyl and iV-propyl-N-(2-methylbutyl)carbamoyl.
• Examples of "Ci- ⁇ alkylthio” include methylthio, ethylthio, propylthio, butylthio and 2-methylbutylthio.
• ' ⁇ eteroaryl is a monocyclic or bicyclic aryl ring, containing 5 to 10 ring atoms of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulphur or oxygen.
• heteroaryl include pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxadiazolyl, oxadiazolyl, isothiadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyridinonyl, pyrimidindionyl, benzfuranyl, benzthieno, indolyl, benzimidazolyl, benzoxazolyl, benzthiazoly
• heteroaryl is selected from imidazolyl, pyrazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, isoxazolyl, or indazolyl.
• Fully saturated heterocyclic rings include examples such as oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, isoxazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, piperazinonyl, morpholinyl, thiomorpholinyl, thiomo ⁇ holinyl-1 -oxide, thiomorpholiny 1-1,1 -dioxide, oxazinanonyl, quinuclidinyl, homopiperidinyl and homopiperazinyl, 9-methyl-3,9-diazabicyclo[4.2.1]nonanyl and tetrahydropyridinyl.
• R 1 is Ci- ⁇ alkyl, wherein the group is substituted by phenyl optionally substituted by 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, methoxy, methyl and trifluoromethyl.
• X is -CH 2 -, a bond, oxygen , sulphur, sulphoxide, or sulphone;
• R is C 1-8 alkyl wherein the group is optionally substituted by 1, 2 or 3 substituents independantly selected from d- ⁇ alkoxy, hydroxy and fluoro; or R is a 5-6 membered ring optionally containing 1,2 or 3 heteroatoms selected from O, S, -
• R 3 is C 3 - 7 carbocyclyl, d-salkyl, -NR 5 R 6 , phenyl, monocyclic or bicyclic heteroaryl wherein a heteroring may be partially or fully saturated and one or more ring carbon atoms may form a carbonyl group, and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from cyano, heteroaryl, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 ,
• R 4 is hydrogen or Ci -6 alkyl
• R 5 and R 6 are a group selected from d- ⁇ alkyl or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally containing a further heteroatom selected from oxygen and nitrogen atoms.
• R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 R 15 , R 16 , R 17 are independently hydrogen, Ci -6 alkyl or phenyl.
• R 18 -R 20 Convenient values of R 18 -R 20 are as follows: R 18 , R 19 and R 20 are hydrogen, phenyl, heteroaryl, or d- ⁇ alkyl (optionally further substituted by NR 8 R 9 ). Preferred values of R 1 , R 2 , R 3 , and X are as follows:
• R 1 is Ci- 3 alkyl (such as -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH 2 (CH 3 )- or -CH 2 (CH 3 )CH 2 -) wherein the group is substituted by phenyl optionally substituted by 1, 2 or 3 substituents independently selected from fluoro and chloro. Benzyl is particularly preferred.
• X is -CH 2 -, a bond, oxygen, or sulphur. Oxygen is particularly preferred.
• R 2 is C 1-8 alkyl, such as C 1-4 alkyl, wherein the group is optionally substituted by 1 or 2 substituents independently selected from Ci. 3 alkoxy (such as methoxy, ethoxy, cyclopropyloxy or isopropyloxy), hydroxy and fluoro, hydroxy is particularly preferred; or R 2 is a 5-membered ring optionally containing a heteroatom selected from O or -NR 8 and wherby the ring is optionially substituted by -OR 4 .
• R 3 is C 1-3 alkyl (such as methyl, ethyl, isopropyl or cyclopropyl) or -NR 5 R 6 (such as azetidinyl, pyrolidinyl, morphotinyl, piperidinyl, piperazinyl) or phenyl or a monocyclic or bicyclic heteroaryl group (such as 1-methylimidazolyl or 1,2-dimethylimidazolyl).
• Preferred values of R 4 -R 17 are as follows: R 4 is hydrogen, or C 1-3 alkyl (such as methyl, ethyl, cyclopropyl or isopropyl)
• R 5 and R 6 are a group selected from C 1-2 alkyl (such as methyl and ethyl) or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring (such as azetidinyl, pyrolidinyl, piperidinyl) or optionally containing a further heteroatom selected from oxygen (such as morpholinyl) or nitrogen (such as . piperazinyl).
• C 1-2 alkyl such as methyl and ethyl
• R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring (such as azetidinyl, pyrolidinyl, piperidinyl) or optionally containing a further heteroatom selected from oxygen (such as morpholinyl) or nitrogen (such as . piperazinyl).
• R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 R 15 , R 16 , R 17 are independently hydrogen, or C 1-2 alkyl (such as methyl or ethyl).
• R 18 -R 20 are as follows: R 18 , R 19 and R 20 are hydrogen or C 1-6 alkyl (optionally further substituted by NR 8 R 9 ). Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
• Particular compounds of the invention include:
• the present invention further provides a process for the preparation of compounds of formula (1) as defined above which comprises:
• R 1 , R 2 and X are as defined in formula (1) and L is a leaving group such as halogen with sulfonamides (R 3 SO 2 NH 2 ) where R 3 is as defined in formula (1). and optionally thereafter (i), ( ⁇ ), (in), (iv), or (v) in any order: i) removing any protecting groups; ii) converting the compound of formula (1) into a further compound of formula (1) iii) forming a salt iv) forming a prodrug v) forming an in vivo hydrolysable ester.
• Reaction of compounds of formula (2a) wherein R 1 , R 2 and X are as defined in formula (1) with sulfonamides (R 3 SO 2 NH 2 ), where R 3 is as defined in formula (1), can be carried out in the presence of a suitable base, solvent and catalyst heated thermally or by microwaves.
• suitable bases include metal carbonates such as those from cesium, potassium, lithium or sodium. Most preferably Cesium carbonate is used.
• Suitable solvents include toluene and ethers such as anisole, tetrahydrofuran, 1,4-dioxane, glyme and diglyme. Preferably 1,4-dioxane is used.
• the temperature of the reaction can be performed between 1O 0 C and 12O 0 C, preferably at 100 0 C.
• suitable catalysts include a suitable palladium(O) source such as palladium tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), or tetrakistriphenylphosphinepalladium (Pd(PhJ) 4 ) (either in 0.01-0.5 mol equivalents) in the presence of a suitable ligand such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenyl- phosphine (Xantphos), or 2-dicyclohexyl-phosphino-2'-(N,N-dimethylamino)biphenyl or 2- dicyclohexyl-phosphino-2',4',6'-tri-isopropyl,l,r-biphenyl (XP ⁇ OS)
• R 1 and R 3 are as defined in formula (1)
• L is a leaving group such as halogen
• PG is a convenient protecting group or hydrogen and where X is oxygen or sulphur, with alcohols ⁇ OR 2 or thiols ⁇ SR 2 respectively wherein R 2 is as defined in formula (1) in the presence of a suitable base and solvent, and optionally thereafter (i), (ii), (in), (iv), or (v) in any order: i) removing any protecting groups; ii) converting the compound of formula (1) into a further compound of formula (1) iii) forming a salt iv) forming a prodrug v) forming an in vivo hydrolysable ester.
• Suitable bases include the alkali metal hydrides such as Na or K, or metal alkoxides such as Li, Na or K-tert-butoxide, alkali metal hexamethyldisilazides such as Li, Na or K-hexamethyldisilazide, or metal carbonates such as Na, K, Cs.
• Suitable solvents include iV.iV-dimethylamides, l-methyl-2-pyrolidinone, toluene and ethers such as anisole, tetrahydrofuran, 1,4-dioxane, glyme and diglyme.
• compounds of formula (1) wherein R'and R 3 are as defined in formula (1), L is a leaving group such as halogen, PG is a convenient protecting group or hydrogen and X is - CH 2 - or a bond can be prepared from compounds of formula (2b) wherein R 2 is as defined in formula (1) by 'treatment with a suitably protected alkene under "Heck coupling" type reaction conditions (Synlett, 2003, no 8 ppl 133- 1136) or with a suitably protected boronic acid or ester under "Suzuki coupling" type reaction conditions (JACS, 1999, no 121, pp9550-9561, JACS 2001, no 123, ppl0099- 10100) in the presence of a suitable palladium catalyst, ligand, salt, base and solvent with thermal or microwave heating.
• suitable palladium catalysts, salts, bases and solvents include tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), or palladium di- acatate (Pd(OAc) 2 ); added salts include potassium chloride, tetra-n-butylammonium chloride; and bases include tri-n-butylamine or di-isopropylethylamine; and solvents include N,N- dimethylformamide or N-methyl-pyrrolidin-2-one.
• Suitable palladium catalysts, ligands, salts, bases and solvents include palladium di-acetate; with ligands tri-cyclohexylphosphine, or 2,2'bis-dicyclohexyl-phosphino- 1 , 1 '-biphenyl or di-t-butyl-phosphino- 1 , 1 '-biphenyl or tri-t- butylphosphine; with salts potassium phosphate (K 3 PO 4 ) or potassium fluoride in solvents tetrahydrofuran or 1,4-dioxane.
• Suitable bases include the alkali metal hydrides such as Na or K, or metal alkoxides such as Li, Na or K-tert-butoxide, alkali metal hexamethyldisilazides such as Li, Na or K-hexamethyldisilazide, or metal carbonates such as Na, K, Cs.
• Suitable solvents include ⁇ iV-dimethylamides, l-methyl-2-pyrolidinone, ethers such as tetrahydrofuran, 1,4-dioxane, glyme and diglyme.
• sodium hydride in tetrahydrofuran at ambient to reflux temperature is employed.
• compounds of formula (2a) wherein R*and R 2 are as defined in formula (1), and X is -CH 2 - or a bond can be prepared from compounds of formula (3) wherein R 1 is as defined in formula (1) and L is a leaving group such as halogen, by treatment with a suitably protected alkene under "Heck coupling" type reaction conditions (Synlett, 2003, no 8 ppl 133- 1136) or with a suitably protected boronic acid or ester under "Suzuki coupling" type reaction conditions (JACS, 1999, no 121, pp9550-9561, JACS 2001, no 123, ppl0099- 10100) in the presence of a suitable palladium catalyst, ligand, salt, base and solvent with thermal or microwave heating.
• suitable palladium catalysts, salts, bases and solvents include tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), or palladium di- acatate (Pd(OAc) 2 ); added salts include potassium chloride, tetra-n-butylammonium chloride; and bases include tri-n-butylamine or di-isopropylethylamine; and solvents include N,N- dimethylformamide or N-methyl-pyrrolidin-2-one.
• palladium di-acetate, with salt tetra-n-butylammonium chloride, with base tri-n-butylamine in solvent NN,- dimemylformamide at 95°C is employed.
• Suitable bases include the alkali metal hydrides such as Na or K, or metal alkoxides such as Li, Na or K-tert-butoxide, alkali metal hexamethyldisilazides such as Li, Na or K-hexamethyldisilazide, or metal carbonates such as Na, K, Cs.
• Suitable solvents include acetonitrile, tetrahydrofuran, 1,4-dioxane, glyme and diglyme. The temperature of the reaction can be performed between 10°C and 12O 0 C.
• Suitable catalysts include a suitable palladium(0) source such as tetrakistriphenylphosphinepalladium (Pd(Pl ⁇ ) 4 ) or tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) in the presence of a suitable ligand such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenyl-phosphine (Xantphos), or 2- dicyclohexyl-phosphino-2'-(N,N-dimethylamino)biphenyl or 2-dicyclohexyl-phosphino- 2 ⁇ 4',6'-tri-isopropyU,l'-biphenyl (XP ⁇ OS).
• a suitable palladium(0) source such as tetrakistriphenylphosphinepalladium (Pd(Pl ⁇ ) 4 ) or tris(dibenzyliden
• Compounds of formula (3) wherein R 1 is as defined in formula (1) and L is halogen may be prepared from compounds of formula (3) wherein R 1 is as defined in formula (1) and L is OH by reaction with a halogenating agent such as phosphorous oxychloride. The reaction may be carried out in the presence of N,N-dimethylaniline at reflux.
• a halogenating agent such as phosphorous oxychloride. The reaction may be carried out in the presence of N,N-dimethylaniline at reflux.
• (4) may be prepared from compounds of formula (4) wherein L is OH by reaction with alkylhalides (R 1 A) where R 1 is as defined in formula (1) and A is halogen in the presence of a suitable base and solvent.
• Suitable bases include the alkali metal hydroxides such as Li, Na, or K, or metal carbonates such as Li, Na, K or Cs, or metal acetates such as Li, Na, K or Cs, or metal alkoxides such as Li, Na, K tert-butoxide.
• Suitable solvents include water, N,N- dirnethylamides, l-methyl-2-pyrolidinone, ethers such as tetrahydrofuran, 1,4-dioxane, glyme -23-
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt, solvate or in vivo hydro lysable ester thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (1), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the pharmaceutical compositions may be administered topically (e.g.
• the compounds of the invention are administered orally.
• the compounds of formula (1) and their pharmaceutically acceptable salts, solvate or in vivo hydrolysable esters are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effect of chemokine modulation activity in labatory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
• the invention further relates to combination therapies wherein a compound of formula (1) or a pharmaceutically acceptable salts, solvate or in vivo hydrolysable ester thereof, or a pharmaceutical composition or formulation comprising a compound of formula (1) is administered concurrently or sequentially with therapy and/or an agent for the treatment of any one of asthma, allergic rhinitis, cancer, COPD, rheumatoid arthritis, psoriasis, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis or osteoporosis.
• the compounds of the invention may be combined with agents such as TNF- ⁇ inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D.sub2.E.sub7.) and TNF receptor immunoglobulin molecules (such as EnbreLreg.), non ⁇ selective COX-I / COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as -24- naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as -24- naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen), f
• the present invention still further relates to the combination of a compound of the 10 invention together with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenol hydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L- 15 739,010; 2-cyanoquinoline compounds such as L-746,530; indole and quinoline compounds such as MK-591, MK-886, and BAY x 1005.
• the present invention still further relates to the combination of a compound of the invention together with a receptor antagonist for leukotrienes LTB.sub4., LTC.suM., LTD.suM., and LTE.suM. selected from the group consisting of the phenothiazin-3-ones 20 such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG- 12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
• the present invention still further relates to the combination of a compound of the 25 invention together with a PDE4 inhibitor including inhibitors of the isoform PDE4D.
• the present invention still further relates to the combination of a compound of the invention together with a antihistaminic H.subl. receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
• a antihistaminic H.subl. receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
• the present invention still further relates to the combination of a compound of the 30 invention together with a gastroprotective H.sub2. receptor antagonist.
• the present invention still further relates to the combination of a compound of the invention together with an ⁇ .subl.- and ⁇ .sub2. -adrenoceptor agonist vasoconstrictor -25- sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride.
• -adrenoceptor agonist vasoconstrictor -25- sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride,
• the present invention still further relates to the combination of a compound of the invention together with anticholinergic agents such as ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine.
• anticholinergic agents such as ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine.
• the present invention still further relates to the combination of a compound of the invention together with a ⁇ .subl.- to ⁇ .sub4.
• -adrenoceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; or methylxanthanines including theophylline and aminophylline; sodium cromoglycate; or muscarinic receptor (Ml, M2, and M3) antagonist.
• Ml muscarinic receptor
• the present invention still further relates to the combination of a compound of the invention together with an insulin- like growth factor type I (IGF-I) mimetic.
• IGF-I insulin-like growth factor type I
• the present invention still further relates to the combination of a compound of the invention together with an inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate.
• the present invention still further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), Le., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase- 1 (MMP- 1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP- 12.
• MMPs matrix metalloproteases
• the present invention still further relates to the combination of a compound of the invention together with other modulators of chemokine receptor function such as CCRl,
• CCRIl for the C-C family
• CXCRl, CXCR3, CXCR4 and CXCR5 for the C-X-C family
• CX 3 CRl for the C-X 3 -C family.
• the present invention still further relates to the combination of a compound of the invention together with antiviral agents such as Viracept, AZT, aciclovir and famciclovir, and antisepsis compounds such as Valant. -26-
• the present invention still further relates to the combination of a compound of the invention together with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
• cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
• the present invention still further relates to the combination of a compound of the invention together with CNS agents such as antidepressants (such as sertraline), anti ⁇ parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), and anti- Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
• CNS agents such as antidepressants (such as sertraline), anti ⁇ parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitor
• the present invention still further relates to the combination of a compound of the invention together with (i) tryptase inhibitors; (ii) platelet activating factor (PAF) antagonists; (iii) interleukin converting enzyme (ICE) inhibitors; (iv) IMPDH inhibitors; (v) adhesion molecule inhibitors including VLA-4 antagonists; (vi) cathepsins; (vii) MAP kinase inhibitors; (v ⁇ i) glucose-6 phosphate dehydrogenase inhibitors; (ix) kinin-B.subl. - and B.sub2.
• -receptor antagonists include anti-gout agents, e.g., colchicine; (xi) xanthine oxidase inhibitors, e.g., allopurinol; (xii) uricosuric agents, e.g., probenecid, sulfinpyrazone, and benzbromarone; (xiii) growth hormone secretagogues; (xiv) transforming growth factor (TGF ⁇ ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) Tachykinin NK.subl.
• anti-gout agents e.g., colchicine
• xi xanthine oxidase inhibitors, e.g., allopurinol
• NK.sub3. receptor antagonists selected from the group consisting of NKP-608C; SB-233412 (talnetant); and D- 4418; (xx) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; (xxi) TNFD converting enzyme inhibitors (TACE); (xxii) induced nitric oxide synthase inhibitors (iNOS) or (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (CRTH2 antagonists).
• TACE TNFD converting enzyme inhibitors
• iNOS induced nitric oxide synthase inhibitors
• chemoattractant receptor-homologous molecule expressed on TH2 cells, (CRTH2 antagonists chemoattractant receptor-homologous molecule expressed on TH2 cells, (CRTH2 antagonists).
• the compounds of the invention may also be used in combination with existing therapeutic agents for the treatment of osteoarthritis.
• Suitable agents to be used in combination include standard non-steroidal anti- inflammatory agents (hereinafter NSAID's) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and etoricoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc and P2X7 receptor antagonists.
• NSAID's standard non-steroidal anti-
• antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine and paclitaxel (Taxol®); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine,
• inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morphohnopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(
• vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and WO02/08213;
• antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
• gene therapy approaches including for example approaches to replace aberrant genes such as aberrant ⁇ 53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
• GDEPT gene-directed enzyme pro-drug therapy
• immunotherapy approaches including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as -29- cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
• cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
• EL- 8 human, recombinant was purchased from Amersham, U.K. with a specific activity of 2,000Ci/mmol. All other chemicals were of analytical grade. High levels of hrCXCR2 were expressed in HEK 293 cells (human embryo kidney 293 cells ECACC No. 85120602) (Lee et al. [YWl) J. Biol. Chem. 267, ppl 6283- 16291). hrCXCR2 cDNA was amplified and cloned from human neutrophil mRNA. The DNA was cloned into PCRScript (Stratagene) and clones were identified using DNA.
• the coding sequence was sub-cloned into the eukaryotic expression vector RcCMV (Invitrogen). Plasmid DNA was prepared using Quiagen Megaprep 2500 and transfected into HEK 293 cells using Lipofectamine reagent (Gibco BRL). Cells of the highest expressing clone were harvested in phosphate-buffered saline containing 0.2%(w/v) ethylenediaminetetraacetic acid (EDTA) and centrifuged (20Og, 5min.).
• EDTA ethylenediaminetetraacetic acid
• the cell pellet was resuspended in ice cold homogenisation buffer [1OmM HEPES (pH 7.4), ImM dithiothreitol, ImM EDTA and a panel of protease inhibitors (ImM phenyl methyl sulphonyl fluoride, 2 ⁇ g/ml soybean trypsin inhibitor, 3mM benzamidine, 0.5 ⁇ g/ml leupeptin and lOO ⁇ g/ml bacitracin)] and the cells left to swell for 10 minutes.
• the cell preparation was disrupted using a hand held glass mortar/PTFE pestle homogeniser and cell membranes harvested by centrifugation (45 minutes, 100,000g, 4°C).
• the membrane preparation was stored at -7O 0 C in homogenisation buffer supplemented with Tyrode's salt solution (137mM NaCl, 2.7mM KCl, 0.4mM NaH 2 PO 4 ), 0.1%(w/v) gelatin and 10%(v/v) glycerol.
• the assay was initiated with the addition of membranes and after 1.5 hours at room temperature the membranes were harvested by filtration using a Millipore MultiScreen vacuum manifold and washed twice with assay buffer (without bacitracin). The backing plate was removed from the MultiScreen plate assembly, the filters dried at room temperature, punched out and then counted on a Cobra ⁇ -counter.
• Human neutrophils were prepared from EDTA-treated peripheral blood, as previously described (BaIy et al. (1997) Methods in Enzymology 287 pp70-72), in storage buffer [Tyrode's salt solution (137mM NaCl, 2.7mM KCl, 0.4mM NaH 2 PO 4 ) supplemented with 5.7mM glucose and 1OmM HEPES (pH 7.4)].
• the chemokine GRO ⁇ (human, recombinant) was purchased from R&D Systems (Abingdon, U.K.). All other chemicals were of analytical grade. Changes in intracellular free calcium were measured fluorometrically by loading neutrophils with the calcium sensitive fluorescent dye, fluo-3, as described previously (Merritt et al. (1990) Biochem. J. 269, pp513- 519). Cells were loaded for 1 hour at 37°C in loading buffer (storage buffer with 0. l%(w/v) gelatin) containing 5 ⁇ M fluo-3 AM ester, washed with loading buffer and then resuspended in Tyrode's salt solution supplemented with 5.7mM glucose, 0.
• loading buffer storage buffer with 0. l%(w/v) gelatin
• bovine serum albumin BSA
• CaCl 2 1.8mM CaCl 2
• ImM MgCl 2 The cells were pipetted into black walled, clear bottom, 96 well micro plates (Costar, Boston, U.S.A.) and centrifuged (20Og, 5 minutes, room temperature).
• step i) To a mixture of the the subtitle product of step i) (101.5g) with benzyltriethylammonium chloride (8.6g) in 1,2-dimethoxyethane (550ml) was added phosphorus oxychloride (70ml) and the mixture heated at 85 0 C for 5h. The reaction was allowed to cool and solvents and excess phosphorus oxychloride were removed in vacuo before partitioning between ethyl acetate and ice water. The layers were separated and the dried (MgSO 4 ) organics concentrated in vacuo to afford the crude product as a pale brown oil which solidified on standing.
• the solution was cooled and added to mixture of palladium(II) acetate, potassium phosphate (1.16g), (biphenyl-2-yl)dicyclohexyl- phosphine (0.14g) and 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (1.5g) stirred under nitrogen.
• the mixture was heated in a microwave at 70°C, 250W for a total of 1.5h, then 7O 0 C on a hot-plate for 2 days.
• a solution of the product of step i) (109mg), tris(dibenzylideneacetone)dipalladium(0) (14mg), azetidine-1-sulphonamide (145mg), 2-dicyclohexyl-phosphino-2',4',6'-tri- isopropyl,l,r-biphenyl (XPHOS)(14mg) and cesium carbonate (120mg) in anhydrous dioxane (2.3ml) was heated at 100 0 C for 45min. The reaction mixture was partitioned between ethyl acetate and water.
• the title compound was prepared according to the procedure outlined in example 4 using a mixture of azetidine- 1-sulfonamide (150mg), tris(dibenzylideneacetone)dipalladium (0) (25 mg), 2-dicyclohexylphos ⁇ nino-2',4',6'-tri-isopropyl-l,l'-biphenyl (XPHOS) (25mg), cesium carbonate (244mg) and (25,3S)-3-( ⁇ 6-chloro-2-[(2,3-difluorobenzyl)thio] ⁇ yrimidin-4- yl ⁇ oxy)butan-2-ol (200mg) in anhydrous dioxane (10ml).
• the subtitle compound was prepared according to the procedure outlined in example 4 step (i) using (25,35)-butane-2,3-diol (250mg) and 4,6-Dichloro-2-[(2,3- difluorobenzyl)thio]pyrimidine (the product of example 1 step (U)) (427mg) in anhydrous tetrahydrofuran (20ml) and 60% sodium hydride (33.4mg) to give the subtitle compound as a colourless gum. Yield: 440mg.
• the subtitle compound was prepared according to the procedure outlined in example 1 step iii) using (25)-l,4-dioxaspiro[4.5]decane-2-methanol (0.46g) and 4,6-Dichloro-2-[(2,3- difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii) (0.75g) in THF (8mL) and 60% sodium hydride (39mg) to give the subtitle compound as a pale yellow solid. Yield: 0.7Og. MS: APCI(+ve) 403/405 [M+H + ] -42-
• the subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine- 1- sulfonamide (prepared according to patent WO 2004/011443, 0.25g), tris(dibenzylideneacetone)dipaUadium (0) (83rng), 2- dicyclohexylphosphino-2',4',6'-tri-wopropyl-l,r-biphenyl (XPHOS) (43mg), cesium carbonate (0.44g) and 4-chloro-2-[[(2,3-difluoro ⁇ henyl)methyl]thio]-6-[(25)-l,4- dioxaspiro[4.5]dec-2-ylmethoxy]-pyrimidine (0.4Og) in dioxane (8mL).
• azetidine- 1- sulfonamide prepared according to patent WO 2004/011443, 0.25g
• the subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 2,2-dimethyl-(4 ⁇ )-l,3-dioxolane-4-methanol (0.26g) and 4,6-Dichloro-2-[(2,3- difluorobenzyl)thio]pyrimidine (the product of example 1 step ⁇ ) (0.5Og) in THF (5mL) and 60% sodium hydride (79mg) to give the subtitle compound as a clear, colourless oil. Yield: 0.47g.
• the subtitle compound was prepared according to the procedure outlined in example 1 step iii) using ⁇ , ⁇ -2,2-tetramethyl-(4/?)-l,3-dioxolane-4-methanol (0.32g) and 4,6-Dichloro-2- [(2 > 3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ⁇ ) (0.56g) in THF (5mL) and 60% sodium hydride (80mg) to give the subtitle compound as a pale yellow oil. Yield: 0.43g.
• the subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine- 1- sulfonamide (prepared according to patent WO 2004/011443, 0.2Og), tris(dibenzylideneacetone)dipalladium (0) (91mg), 2- dicyclohexyl ⁇ hosphino-2',4',6'-tri-/r ⁇ propyl-l,r-biphenyl (XPHOS) (42mg), cesium carbonate (0.49g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[l-[(4/?)-2,2-dimethyl- l,3-dioxolan-4-yl]-l-methylethoxy]-pyrimidine (0.43g) in dioxane (8mL).
• azetidine- 1- sulfonamide prepared according to patent WO 2004/011443, 0.2Og
• the subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine-1- sulfonamide (prepared according to patent WO
• the subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 2,2,5-trimethyl-l,3-dioxan-5-ol (as prepared in Synthesis, 1998, p879) (0.29g) and
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1- sulfonamide (prepared according to patent WO
• the subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 2-hydroxy-(2/?)-propanoic acid ethyl ester (1.45mL) and 4,6-Dichloro-2-[(2,3- difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (3g) in THF (4OmL) and 60% sodium hydride (0.55g) to give the subtitle compound as a clear, colourless oil. Yield: 2.85g.
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 2-thiazolesulfbnamide (0.17g), tris(dibenzylideneacetone)dipalladium (0) (64mg), 2-dicyclohexylphosphino-2',4',6'-tri-wo ⁇ ropyl-l,r-biphenyl (XPHOS) (33mg), cesium carbonate (0.34g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4- pyrimidtnyl]oxy]-(2 ⁇ )- propanoic acid ethyl ester (0.27g) in dioxane (5mL).
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iii) using (2R)- l-(triphenylrnethoxy)-2-propanol ( 1.35g) and 4,6-Dichloro-2-[(2,3- drfluorobenzyl)thio]pyrimidine (the product of example 1 step (ii) (Ig) in THF (15mL) and 60% sodium hydride (0.18g) to give the subtitle compound as a pale yellow oil. Yield: 1.8g. MS: APCI(+ve) 589 [M+H + ]
• the title compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine-1 -sulfonamide (prepared according to patent WO 2004/011443, 0.17g), tris(dibenzylideneacetone)dipalladium (0) (75mg), 2-dicyclohexylphosphino-2',4',6'- trw,r ⁇ propyl-l,l'-biphenyl (XPHOS) (40mg), cesium carbonate (0.4Og) 4-chloro-2-[[(2,3- difluorophenyl)methyl]thio]-6-ethoxy-pyrimidine (the product from step i) (0.26g)) in dioxane (5mL).
• azetidine-1 -sulfonamide prepared according to patent WO 2004/011443, 0.17g
• tris(dibenzylideneacetone)dipalladium (0) 75mg
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-(aminosulfonyl)-l-piperazinecarboxylic acid-l,l-dimethylethyl ester (the product from step i) (0.29g), tris(dibenzylideneacetone)dipalladium (0) (67mg), 2- dicyclohexylphosphino-2',4',6'-tri-i,yopropyl-l,r-biphenyl (XPHOS) (35mg), cesium carbonate (0.36g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-ethoxy-pyrimidine (the product from example 14, step i) (0.23g) in dioxane (5mL).
• the subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 2,2,2-trifluoroethanol (0.16mL) and 4,6-Dichloro-2-[(2,3- difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (0.6Og) in THF (6mL) and 60% sodium hydride (94mg) to give the subtitle compound as a clear, colourless oil. Yield: 0.6g.
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-(aminosulfonyi)-l- ⁇ iperazinecarboxylic acid-l,l-dimethylethyl ester (the product from example 15, step i), 0.4Og), tris(dibenzylideneacetone)dipalladium (0) (91mg), 2-dicyclohexylphos ⁇ l ⁇ no-2 ⁇ 4 ⁇ 6 ⁇ ri-iM ⁇ ro ⁇ yl-l,l > -biphenyl (XPHOS) (48mg), cesium carbonate (0.49g) and 4-chIoro-2-[[(2,3-difluorophenyl)methyl]thio]-6-(2,2,2- trifluoroethoxy)-pyrimidine (the product from example 16, step i) (0.37g) in dioxane (6mL).
• the subtitle compound was prepared from azetidine-1 -sulfonamide (prepared according to patent WO 2004/011443, 0.1 Ig) and 4-Chloro-2-[[(2,3-difluoro ⁇ henyl)methyl]thio]-6-[(2- phenyl-l,3-dioxan-5-yl)thio]pyrimidine (the product of step i) (0.17g ) according to the procedure outlined in Example 1, step iv). The residue was purified by flash chromatography on silica gel, eluting with EtOAc/w ⁇ -hexane (2:8) to give the subtitle compound as a colourless oil. Yield: 0.1 Ig MS: APCI(+ve) 567 [M+H] -61-
• a mixture of 4-(aminosulfonyl)- 1,1-dimethylethyl ester- 1 -piperazinecarboxylic acid (the product of example 15 step i) (0.4Og), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2- dicyclohexylphosphino-2',4',6'-tri-ir ⁇ propyl-l,r-biphenyl (XPHOS) (50mg), cesium carbonate (Ig) and (2R)- propanoic acid-2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4- pyrimidinyl]oxy]-, ethyl ester (the product from example 11 step i) (0.4Og) in dioxane (2OmL) was heated at reflux in a microwave at 100 0 C, 300W, open vessel with cooling for 20min.
• reaction mixture was then heated in a microwave at 50 0 C, 300W, open vessel with cooling for lOmin.
• the reaction mixture was then quenched with 2N HCl and the volatiles evaporated.
• the residue was then separated between EtOAc (20OmL) and H 2 O (20OmL), the aqueous was then further extracted with EtOAc (2x200mL).
• the combined organic layers were dried (MgSO 4 ), filtered and evaporated and the residue purified by reverse phase HPLC using a TFA (0.2%)/MeCN method to give the title compound as a clear on.
• the subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2, 3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii)
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1 -sulfonamide (prepared according to patent WO 2004/011443, 0.13g), tris(dibenzylideneacetone)dipalladium (0) (58mg), 2- dicyclohexylphosphino-2',4',6'-tri-ir ⁇ propyl-l,r-biphenyl (XPHOS) (42mg), cesium carbonate (0.3 Ig), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]- (25)-propanoic acid ethyl ester (product of step i) (0.25g) and dioxane (1OmL).
• azetidine-1 -sulfonamide prepared according to patent WO 2004/011443, 0.13g
• the title compound was prepared according to the procedure outlined in example 24 using a mixture of 2-[[2-[[(2,3-dMuorophenyl)methyl]tMo]-6-[(4-mo ⁇ hoh ⁇ ylsulfonyl)amino]-4- pyrimidinyl]oxy]-(22?)-propanoic acid ethyl ester, (the product of step i) (0.34g), THF (8mL) and 2M lithium borohydride in THF (ImL). Purification was by reverse phase HPLC
• the subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of 4-mor ⁇ holinesulfonamide (prepared according to patent WO 2004/011443, 0.19g), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2- dicyclohexylphosphino-2',4',6'-tri-i5opropyl-l,r-biphenyl (XPHOS) (52mg), cesium carbonate (0.38g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]- -72-
• the title compound was prepared according to the procedure outlined in example 24 using a mixture of 2-[[2-[[(2,3-difluorophenyl)methyl]tMo]-6-[(l-pyrrolidinylsulfonyl)amino]-4- ⁇ yrirnidinyl]oxy]-(2/?)-propanoic acid ethyl ester, (the product of step i) (O.38g), THF (8mL) and 2M lithium borohydride in THF (1.3mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase).
• the subtitle compound was prepared according to the procedure outlined in example 1, step iv) using a mixture of 1-pyrrolidinesulfonamide (prepared according to patent WO 2004/011443, 0.19g), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2- dicyclohexylphosphino-2',4',6'-tri-J5Opropyl-l,r-biphenyl (XPHOS) (52mg), cesium carbonate (O.38g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrirnidinyl]oxy]- (2/?)-propanoic acid ethyl ester (the product of Example 23 step i) (0.3Og) and dioxane (1OmL).
• 1-pyrrolidinesulfonamide prepared according to patent WO 2004/011443, 0.19g
• the title compound was prepared according to the procedure outlined in example 24 using 2- [[6- [(cyclopropylsulfony i)arnino] -2- [ [(2,3-difluorophenyl)methyl] thio] -4-pyrimidinyl] oxy] - (2 ⁇ )-propanoic acid ethyl ester, (the product of step i) (0.3Og), THF (8mL) and 2M lithium borohydride in THF (2mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA /acetonitrile as the mobile phase).
• the title compound was prepared according to the procedure outlined in example 24 using 2- [[2-[[(2,3-difluorophenyl)methyl]tWo]-6-[[(l-methyl-lH-imidazol-4-yl)sulfonyl]amino]-4- pyrimidinyl]oxy]-(2/?)-propanoic acid ethyl ester (the product of step i) (0.28g), T ⁇ F (8mL) and 2M lithium borohydride in T ⁇ F (0.8ImL). Purification was by reverse phase ⁇ PLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase).
• the subtitle compound was prepared according to the procedure outlined in example 1, step iv) using a mixture of l-methyl-lH-imidazole-4-sulfonamide (0.19g), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2-dicyclohexylphosphino-2',4',6'-tri- i ⁇ r ⁇ pro ⁇ yl-l,l'-biphenyl (XP ⁇ OS) (52mg), cesium carbonate (0.38g), 2-[[6-chloro-2-[[(2,3- difluorophenyl)methyl]tiiio]-4-pyrirnidinyl]oxy]-(2/?)-propanoic acid ethyl ester (the product of Example 23 step i) (0.30g) and dioxane (1OmL).
• the subtitle compound was prepared according to the procedure outlined in example 1 step iv) using 4,6-Dichloro-2-[(2, 3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.43g), (2/?)-l-[[(l,l-dimethylethyl)dimethylsilyl]oxy]-3-ethoxy-2-propanol (product of step iii) (0.47 g), THF (2OmL) and 60% sodium hydride (67mg), to give the subtitle compound as a colourless oil.
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1- sulfonamide (prepared according to patent WO 2004/011443, 0.29g), tris(dibenzylideneacetone)dipalladium (0) (O.13g), 2- dicyclohexylphosphino-2',4',6'-tri-/5 ⁇ propyl-l,r-biphenyl (XPHOS) (93mg), cesium carbonate (0.68g), 4-chloro-2-[[(2,3-difluoro ⁇ henyl)methyl]thio]-6-[(l/?)-2-[[(l,l- dimethylethyl)dirnethylsilyl]oxy]-l-(ethoxymethyl)ethoxy]-pyrirnidine (the product of step iv) (0.7Og) and dioxane (15mL). Purification was by column chromatography on silica gel -
• step iv The title compound was prepared according to the procedure outlined in example 1, step iv).
• a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.15 g), tris(dibenzylideneacetone)dipalladium (0) (44mg), 2-dicyclohexylphos ⁇ hino-2'4'6'-tri- /s ⁇ -propy 1-1,1 'biphenyl (44mg), cesium carbonate (0.36g) and 4-chloro-2-[[(2,3- difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of step i) (0.23g) in dioxane (7.2mL).
• the subtitle compound was prepared from 1,1 -dimethylethyl 4-sulfamoylpiperazine-l- carboxylate (the product of example 15, step i), 0.22g) and 4-Chloro-2-[[(2,3- difluoro ⁇ henyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25g) according to the procedure outlined in Example 1, step iv).
• the crude material was purified by column chromatography on silica gel using EtOAc/jr ⁇ hexane (2:8) as eluent.
• the title compound was prepared from morpholine-4-sulfonamide (prepared according to patent WO 2004/011443, 0.2Og) and 4-Chloro-2-[[(2,3-drfluorophenyl)metliyl]thio]-6- methoxypyrimidine (the product of Example 35, step i) (0.25g) according to the procedure outlined in Example 1, step iv).
• the crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.26g.
• step i) (0.25g) according to the procedure outlined in Example 1, step iv).
• the crude material was purified by column chromatography using EtOAc/is ⁇ hexane (2:8) as eluent.
• the subtitle compound was prepared from azetidine-1- sulfonamide (prepared according to patent WO 2004/011443, 0.22g) and 1,1-Dimethylethyl (S)-4-[6-chloro-2-[[(2,3- difluorophenyl)methyl]tWo]pyrimidin-4-yloxy]-isoxazolidine-2-carboxylate (the product of step i) (0.13g) according to the procedure outlined in Example 1, step iv).
• the crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.14g -84-
• the title compound was prepared from 1,1-dimethylethyl [(R)-2-[6-azetidine-l-sulfonyl a ⁇ iino)-2-[[(2,3-dMuorophenyl)methyl]tWo]pyrirnidin-4-yloxy]propyl ⁇ carbamate (0.26g) (the product of step ii) according to the procedure outlined in Example 41.
• the crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.1 Ig
• the subtitle compound was prepared from azetidine-1 -sulfonamide (prepared according to patent WO 2004/011443, 0.1 Ig) and 1,1-Dimethylethyl [(R)-2-[6-chloro-2-[[(2,3- difluorophenyl)methyl]thio]pyrimidin-4-yloxy]propyl]carbamate (the product of step i) (0.2g) according to the procedure outlined in Example 1, step iv).
• the crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.14g MS: APCI(-ve) 544 [M-H]
• the title compound was prepared from azetidine-1- sulfonamide (prepared according to patent WO 2004/011443, 0.15g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4- pyrimidinyl]oxy]- ⁇ f, ⁇ f-dimethyl-l-propanamine (the product of step i) (0.29g) according to the procedure outlined in Example 1, step iv).
• the reaction product was purified by reverse phase HPLC eluting with acetonitrile / aq. 0.1% ammonium acetate mixtures to give the title compound as a pale yellow solid. Yield: 0.30g MS: APCI(+ve) 474 [M+H]
• the subtitle compound was prepared according to the procedure outlined in Example 41 step i) using l-dimethylamino-2-propanol (80mg), 4,6-Dichloro-2-[(2,3- difluorobenzyl)thio]pyrimidine (the product of Example 1 step ⁇ ) (0.25g) and 60% sodium -87- hydride (30mg) in THF (2mL) at room temperature for 2d to give the subtitle compound as a pale yellow gum. Yield: 0.29g. MS: APCI(+ve) 374 [M+H]
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iii) using (l/?)-l-[(45)-2,2-dimethyl-l,3-dioxolan-4-yl]ethanol (prepared according to Liebigs. Ann. Chem. 1987, 7-14) (0.25g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrirnidine (the product of example 1 step ⁇ ) (0.53g) in THF (2OmL) and 60% sodium hydride (80mg).
• the subtitle compound was prepared from 1,1-dimethylethyl 4-sulfamoylpiperazine-l- carboxylate (the product of example 15, step i), 0.26g) and 4-chloro-2-[(2,3- difluorobenzyl)tMo]-6- ⁇ (l/?)-l-[(45)-2,2-dimethyl-l,3-dioxolan-4-yl]ethoxy ⁇ pyrirnidine (the product of Example 47, step i) (0.2Ig) according to the procedure outlined in Example 1, step iv). Yield: 0.28g MS: APCI(-ve) 644 [M-H]
• the subtitle compound was prepared from 5-(azetidin-l-ylcarbonyl)furan-2-sulfonamide (the product of step ⁇ i) (0.4Og) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(li?)-l- methyl-2-(triphenyhnethoxy)ethoxy]-pyrimidine (the product of Example 13, step iii) (0.4Ig) according to the procedure outlined in Example 1, step iv). Yield: 0.25g MS: APCI(-ve) 781 [M-H]
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 5-(arninosulfonyl)-N-(terf-butyl)-2-furamide (0.25g), tris(dibenzylideneacetone)dipalladium (0) (58mg), 2-dicyclohexylphosphino-2',4',6'-tri- is ⁇ propyl-l,l'-biphenyl (XPHOS) (30mg), cesium carbonate (0.65g) and 2-[[6-chloro-2- [[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2/?)- propanoic acid ethyl ester (product of Example 11 step i) (0.26g) in dioxane (1OmL). Purification was trituration with Et 2 O to give the subtitle compound as a white solid. Yield: 0.25g MS: APCI(+ve)
• the subtitle compound was prepared from 5-cyanofuran-2-sulfonamide (the product of step i) (0.29g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(l/?)-l-methyl-2- (triphenyhnethoxy)ethoxy]-pyrimidine (the product of Example 13, step ii) (0.15g) according to the procedure outlined in Example 1, step iv). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:4 to 2:3 gradient) to give the subtitle compound as a pale yellow solid. Yield: 0.25g MS: APCI(-ve) 723 [M-H]
• the subtitle compound was prepared according to the procedure outlined in example 15 step i) using 2-piperazin-l-ylpyrimidine (3.Og) and sulfamide (1.2g) in dioxane (3OmL) to give the subtitle compound as a white solid. Yield: 2.06g.
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of methane sulfonamide (0.25g), tris(dibenzylideneacetone)dipalladium (0) (55mg), 2-dicyclohexyl ⁇ hosphino-2',4',6'-tri-/r ⁇ propyl-l,l'-biphenyl (XPHOS) (29mg), cesium carbonate (0.3Og) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6- ⁇ (l/?)-l-[(45)-2,2- dimethyl-l,3-dioxolan-4-yl]ethoxy ⁇ pyrimidine (the product of Example 47, step i) (0.25g) in dioxane (5ml).
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-morpholine sulfonamide (prepared according to patent WO 2004/011443) (0.15g), tris(dibenzylideneacetone)dipalladium (0) (55mg), 2- dicyclohexylphosphino-2',4',6'-tri-ir ⁇ propyl-l,r-biphenyl (XPHOS) (29mg), cesium carbonate (0.30g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6- ⁇ (l/?)-l-[(45)-2,2-dimethyl- l,3-dioxolan-4-yl]ethoxy ⁇ pyrimidine (the product of Example 47, step i) (0.25g) in dioxane (5ml).
• a mixture of azetidine- 1-sulfonamide (prepared according to patent WO 2004/011443, 0.32g), tris(dibenzylideneacetone)-dipalladium (0) (33mg), 2-dicyclohexylphosphino-2',4',6'- tri-iiOpropyl-l,r-biphenyl (XPHOS) (17mg), cesium carbonate (0.58g) and 4-chloro-2-[(2,3- difluorobenzyl)thio]-6-(methylthio)pyrimidine (the product of example 57, step i) (0.38g) in dioxane (1OmL) was heated at 100 0 C for 18h.
• the layers were separated and the aqueous material extracted with further DCM.
• the combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated.
• TFA (ImI) and DCM (4ml) were added to the residue and the reaction mixture stirred at room temperature for 2d.
• the mixture was partitioned between saturated aqueous sodium bicarbonate and DCM, then neutralised with 2M aqueous hydrochloric acid, the layers -109- separated and the aqueous material extracted with further DCM.
• the DCM extracts were allowed to slowly evaporate and the resulting solid washed with minimal cold DCM to afford the title compound as a white powder.
• the subtitle compound was prepared according to the procedure outlined in Example 62 step i) using 2-oxopiperazine (0.5g) and sulfamide (0.45g) to give a beige solid. Yield: 0.83g.
• reaction mixture was reduced in vacuo and the residue -117- redissolved in EtOAc (20ml) before reducing in vacuo directly onto silica and purifying by column chromatography on silica 50%EtOAc/50% /s ⁇ -hexane to give the title compound as a white solid.
• reaction mixture was purified by loading onto SCX and eluting with 7N NH 3 ZMeOH (200ml). The eluent was then reduced in vacuo to yield 9-methy 1-3,9- diazabicyclo[4.2.1]nonane-3-sulfonamide (0.13g) as a yellow solid. A mixture of 9-methyl- 3,9-diazabicyclo[4.2.
• a mixture of 4-sulfamoyl-l,4-diazepane-l-carboxylic acid tert-butyl ester (the product from example 68 step i) (0.54Ig), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2- dicyclohexyl ⁇ hosphino-2',4',6'-tri-ir ⁇ propyl-l,r-biphenyl (XPHOS) (50mg), cesium carbonate (0.55 g) and (2i?,3i?)-3-( ⁇ 6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4- -130- yl ⁇ oxy)butan-2-ol (the product of example 4 step i), 0.54Ig) in dioxane (4OmL) was heated at reflux in a microwave at 100 0 C, 300W, open vessel with cooling for 15 mins.
• N-(tert-Butyl)-2-(trifluoroacetyl)- 1 ,2,3,4-tetrahydroisoquinoline-7-suh c onamide (the product from step i), 1.78g) was dissolved in TFA and stirred at room temperaturefor 96h. The reaction was reduced in vacuo and the residue purified by column chromatography on silica gel 50% EtO Ac/50 % /.r ⁇ -hexane to give the subtitle compound as a white solid.
• the subtitle compound was prepared according to the procedure outlined in example 34 step iii) using (2S)-3-ir ⁇ propoxypro ⁇ ane-l,2-diol (0.8Og) (the product from step ( ⁇ ) in DCM (1OmL), tert-butyldimethylsilyl chloride (1.59g), triethylamine (1.43mL) and 4- (dimethylamino)pyridine (50mg) at 0°C to give the subtitle compound as a clear, colourless oH. Yield: 1.86g
• the subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2, 3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.46g), (22?)-l- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -3-/r ⁇ propoxypropan-2-ol (product of step iii) (0.66g), THF (5mL) and 60% sodium hydride (80mg), to give the subtitle compound as a colourless oil. Yield: 0.56g
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1 -sulfonamide (prepared according to patent WO -136-
• Example 80 iV- ⁇ 2-[(2,3-Difluorobenzyl)thio]-6-[(l/?)-2-hydroxy-l-methylethoxy]pyrimidin-4-yl ⁇ -l,2- dimethyl- lH-iiiiidazole-4-sulfonaniide
• the subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of l,2-Dimethyl-lH-imidazole-4-sulfonic acid amide (0.19g), tris(dibenzylideneacetone)dipalladium (0) (56mg), 2-dicyclohexylphosphino-2 ' ,4' ,6' -tri- /r ⁇ propyl-l,l'-biphenyl (XPHOS) (41mg), cesium carbonate (0.32g), 2-[[6-chloro-2-[[(2,3- difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2/?)-propanoic acid ethyl ester (the product of example 11 step i) (0.24g) and dioxane (2OmL).

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