WO2003059893A1 - N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases - Google Patents

N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases Download PDF

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Publication number
WO2003059893A1
WO2003059893A1 PCT/SE2003/000041 SE0300041W WO03059893A1 WO 2003059893 A1 WO2003059893 A1 WO 2003059893A1 SE 0300041 W SE0300041 W SE 0300041W WO 03059893 A1 WO03059893 A1 WO 03059893A1
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WO
WIPO (PCT)
Prior art keywords
pyrazinyl
methoxy
dichloro
benzenesulphonamide
chloro
Prior art date
Application number
PCT/SE2003/000041
Other languages
French (fr)
Inventor
Andrew Baxter
Timothy Johnson
Nicholas Kindon
Bryan Roberts
Michael Stocks
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0200119A external-priority patent/SE0200119D0/en
Priority claimed from SE0201857A external-priority patent/SE0201857D0/en
Priority to IL16267803A priority Critical patent/IL162678A0/en
Priority to ES03700655T priority patent/ES2375107T3/en
Priority to AT03700655T priority patent/ATE534635T1/en
Priority to AU2003201802A priority patent/AU2003201802A1/en
Priority to EP03700655A priority patent/EP1467976B1/en
Priority to KR10-2004-7010982A priority patent/KR20040073566A/en
Priority to CA002472204A priority patent/CA2472204A1/en
Priority to MXPA04006806A priority patent/MXPA04006806A/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to JP2003559997A priority patent/JP4504021B2/en
Priority to NZ533750A priority patent/NZ533750A/en
Priority to BR0306922-2A priority patent/BR0306922A/en
Priority to UA20040705311A priority patent/UA79255C2/en
Priority to US10/501,510 priority patent/US7662825B2/en
Publication of WO2003059893A1 publication Critical patent/WO2003059893A1/en
Priority to IS7348A priority patent/IS7348A/en
Priority to NO20043370A priority patent/NO20043370L/en
Priority to HK05101480.0A priority patent/HK1068885A1/en
Priority to US12/435,864 priority patent/US20100081670A1/en

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Definitions

  • the present invention relates to a sulphonamide compound, 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 four cysteine motif. At the present time, the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C), Cys-Cys (C-C) and Cys-X 3 -Cys (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 (IL-8) and neutrophil-activating peptide 2 (NAP -2).
  • IL-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 chemo tactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins l ⁇ and l ⁇ (MIP-1 ⁇ and
  • MIP-1 ⁇ Thymus and Activation Regulated Chemokine
  • TARC Thymus and Activation Regulated Chemokine
  • MDC Macrophage Derived Chemokine
  • 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, CCRIO and CCRl 1 (for the C-C family); CXCR1 , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 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.
  • the present invention therefore provides a compound of formula (I) and pharmaceutically acceptable salts, solvates or N-oxides thereof:
  • R 1 , R 2 and R 3 are independently hydrogen, halogen, cyano, CF 3 , OCF 3 , OC 1-6 alkyl or C 1-6 alkyl;
  • R 4 is halogen, CO 2 R 12 ,
  • alkyl group may forai a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
  • OC ]-6 alkylR 11 or OC 2-6 alkyl-X-R 11 where the alkyl group may fo ⁇ n a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR 14 R 15 , SR 13 , S(O) 2 R 13 , S(O)R 13 or COR 13 ; OCi.6 alkylR 16 ;
  • R 5 and R 6 are independently hydrogen, cyano, halogen, CO 2 R 12 , CONR I4 R 15 ;
  • C 1-6 alkyl optionally substituted by hydroxy, NR 14 R 15 , or 1-3 fluorines;
  • n 1 ,2, 3, 4 or 5;
  • q 2, 3, 4, 5 or 6;
  • X is NR 13 , O, S 3 S(O), S(O) 2 ;
  • R 14 and R 15 are independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or (CH 2 )qOH,
  • R 14 and R 15 together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from mtrogen, oxygen and sulphur and optionally substituted by C 1-6 alkyl, C 1-6 alkyl-OH, or hydroxy; and
  • R 4 is halogen or C 1- alkoxy and R 5 is hydrogen, halogen, C 1-4 alkyl,
  • the tenn aryl includes phenyl and naphthyl.
  • the terai alkyl whether alone or as part of another group, includes straight chain and branched chain alkyl groups.
  • Examples of 5- to 7-membered heteroaromatic ring containing 1 to 4 heteroatoms include thienyl, furanyl, py ⁇ olyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
  • saturated 4- to 8-membered rings containing 1 to 3 heteroatoms include morpholine, piperidine and azetidine. Substituents on any rings can be present in any suitable ring position including suitable substituents on nitrogen atoms.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of fo ⁇ m ⁇ la (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also fonn an aspect of the present invention.
  • halogen groups for R 1 , R 2 and R 3 are chloro, bromo and fluoro.
  • R 1 , R 2 and R 3 are chloro, bromo and fluoro.
  • R and R is hydrogen and the other is chloro, bromo or methyl. More preferably R and R 2 are chloro at the 2- and 3-positions of the phenyl ring and R 3 is hydrogen (i.e. 2,3- dichlorophenyl), R 1 and R 3 are chloro at the 2- and 4-positions of the phenyl ring and R 2 is hydrogen (i.e. 2,4-dichlorophenyl) or R 1 is chloro at the 2-position and R 2 is methyl at the 3-position of the phenyl ring and R 3 is hydrogen (i.e 2-chloro-3-methylphenyl). Most preferably R 1 and R 2 are chloro at the 2- and 3-positions of the phenyl ring and R 3 is hydrogen (i.e. 2,3-dichlorophenyl).
  • the invention provides a compound of formula (I) as defined above but without the provisos where R 1 and R 2 are chloro at the 2- and 3-positions of the phenyl ring and R 3 is hydrogen (i.e. 2,3-dichlorophenyl), R 1 and R 3 are chloro at the 2- and 4-positions of the phenyl ring and R 2 is hydrogen (i.e. 2,4-dichlorophenyl) or R 1 is chloro at the 2- position and R 2 is methyl at the 3-position of the phenyl ring and R 3 is hydrogen (i.e 2- chloro-3 -methylphenyl) .
  • examples of C 3-6 alkynyloxy include OCH 2 CCH
  • examples of OC 1-6 alkyl-O-C 1-6 alkyl include OCH 2 CH 2 OMe
  • examples of OC 1-6 alkylR 11 include OCH 2 R n
  • examples of OC 1-6 alkylR 16 include OCH 2 pyrrolidine.
  • R 4 examples include C 1-6 alkoxy such as methoxy, 2-furanylmethoxy, bromo, chloro, 2-methoxyethoxy, (5-methyl-3-isoxazolyl)methoxy, 2-, 3- or 4-pyridylmethoxy, 3-pyridazinylmethoxy, methoxy, 2-(l-imidazolyl)ethoxy, (2-methyl-4-oxazolyl)methoxy and 4-methoxyphenylmethoxy. More preferably R 4 is methoxy.
  • NR 14 R 15 includes morpholine, pyrrolidine, NMe 2 , NHCH 2 CH 2 OMe, NHMe, and the groups below:
  • Examples of X-(CH 2 )qNR 1, R ⁇ :> include SCH 2 CH 2 NH 2 and SCH 2 CH 2 NMe 2
  • examples of (CH 2 )nNR ]4 R 15 include CH 2 morpholine
  • examples of X-R 12 includes SMe, OMe, OEt, OH, SO 2 Me
  • examples of X-C 1-6 alkylR 16 includes OCHbpyrrolidine
  • examples of X- (CH 2 )nCO 2 R 12 includes SCH 2 CO 2 H, SCH 2 CO 2 Me, SCH 2 CH 2 CO 2 Me
  • examples of X- (CH 2 )nCONR 14 R 15 includes SCH 2 CONH 2 , SCH 2 CONHMe, OCH 2 CONEt 2
  • examples of X-(CH 2 )n n includes the groups below:
  • Examples of X-(CH 2 ) n CN includes SCH 2 CN, examples of X-(CH 2 )qOR . 1 i 2;includes OCH 2 CH 2 OMe, examples of (CH 2 )nOR 12 includes CH 2 OH, CH 2 OMe, examples of X-(CH 2 )qNHC(O)NHR 12 includes SCH 2 CH 2 NHC(O)NHEt, and examples of X-(CH 2 )qNHC(O)R 12 includes NHCH 2 CH 2 NHC(O)Me.
  • Examples of NHC(O)C 1-6 alkyl optionally substituted by one or more hydroxy groups includes NHCOCH 2 OH.
  • R 5 examples include hydrogen, halogen such as bromo and chloro, phenyl, d- ⁇ alkyl such as methyl, CH 2 OH, cyano and 2-aminothanethiol. More preferably R 5 is hydrogen, methyl, CH 2 OH or halogen such bromo or chloro.
  • Preferred groups for R 6 include hydrogen, C 1-6 alkyl, CH 2 OH and halogen, more preferably hydrogen, methyl, CH 2 OH or chloro.
  • the invention provides a compound of foraiula (IA):
  • R 1 , R 2 and R 3 are independently hydrogen, halogen, cyano, CF 3 , OCF 3 , C 1-6 alkenyl or
  • R 4 is halogen, C ⁇ e alkoxy or OR 9 ;
  • R 5 and R 6 are independently hydrogen, halogen, C 1-6 alkoxy, C 1-6 alkylthio, cyano, R 9 ,
  • R 9 and R 10 are independently hydrogen, C 1-6 alkyl optionally substituted by hydroxy, C 1-6 alkoxy or NHCOC 1-6 alkyl, or R 9 and R 10 are optionally substituted aryl, C ⁇ . 6 alkyl-aryl or C 1-6 alkyl-R 11 or R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 8-membered saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C 1-6 alkyl or C 1-6 alkyl-OH; and R 11 is a 5- to 7-membered heteraromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C 1-6 alkyl; and R 12 and R 13 are independently hydrogen or C 1-6 alkyl.
  • R , R and R are independently hydrogen, halogen, cyano, CF 3 , OCF 3 , C 1-6 alkenyl or C 1-6 alkyl, preferred halogen groups being chloro.
  • R 1 , R 2 and R 3 is methyl, ethenyl, cyano, chloro, fluoro, iodo or two are chloro or all three are fluoro. More preferred are compounds where R 1 - R 3 together with the phenyl group to which they are attached fo ⁇ n a 3-chloro-2-methylphenyl or a 2,3-dichlorophenyl group.
  • R 4 preferred groups for R 4 include halogen such as bromo and chloro, C 1-6 alkoxy such as methoxy and ethoxy, C 1-6 alkyl or OR 9 where R 9 is CH 2 R ⁇ where R 11 is a 5- or 6-membered heteraromatic ring containing 1 or 2 heteroatoms.
  • R 4 is methoxy, halogen, such as chloro, or OR 9 where R 9 is CH R n where R 11 is furanyl, 5-methyl-3 -isoxazolyl, pyridyl optionally substituted by methyl, pyridazinyl, pyrazinyl, 1 -methyl-6-oxo- 1 ,6-dihydro-3-pyridinyl.
  • R 5 is hydrogen, methyl, bromo, chloro, methoxy, morpholinyl, pyrrolinyl, dimethylamino, hydroxy, 2-methoxy ethoxy, pyrazinyl, pyrimidinyl, O-Ph-CO 2 H, 2-hydroxyethylamino, 2-methoxyethylamino, NHCH 2 CH 2 NHCOMe, cyano, 4-hydroxymethyl-l-piperidinyl, SMe, NHMe, or 2,4- difluorophenyl.
  • R 6 is hydrogen or chloro.
  • Preferred compounds of formula (I)/(IA) include those exemplified herein both in free base form and as pha ⁇ naceutically acceptable salts.
  • R 4 , R 5 and R 6 are as defined in formula (I) or are protected derivatives thereof with a compound of fo ⁇ nula (III):
  • R 1 , R 2 and R 3 are as defined in fonnula (I) or are protected derivatives thereof and LG is a leaving group, and optionally thereafter • removing any protecting groups,
  • Preferred leaving groups LG include halogen such as chloro.
  • the reaction between compounds (II) and (III) is carried out by treating compound (II) with a base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as 1,2- dimethoxyethane or tetrahydrofuran.
  • Wliere R 4 is C 1-6 alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
  • OC 1-6 alkylR 11 or OC 2-6 alkyl-X-R 11 where the alkyl group may fo ⁇ n a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR 14 R 15 , SR 13 , S(O) 2 R 13 , S(O)R 13 ; or
  • compounds of fo ⁇ nula (II) can be prepared by treating a compound of the formula (IV), where LG is a leaving group (such as chlorine or bromine):
  • R 4 is C 1-6 alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
  • OC 1-6 alkylR 11 or OC 2-6 alkyl-X-R 11 where the alkyl group may fo ⁇ n a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR 14 R 15 , SR 13 , S(O) 2 R 13 , S(O)R 13 ; or
  • compounds of fo ⁇ nula (I) can be prepared by treating a compound of the formula (VI), where LG is a leaving group (such as chlorine or bromine):
  • a suitable solvent such as 1,2-dimethoxyethane, NN-dimethylfonnamide or tetrahydrofuran
  • a suitable base such as sodium hydride or potasssium tert-butoxide at a suitable temperature such as 25°C to 60°C.
  • Vlll Compounds of structure (Vlll) can be prepared by taking a compound of formula (Nil) where LG is a leaving group (such as chlorine or bromine) and protecting the sulfonamide as for example the trimethylsilyethoxymethyl ether (SEM) or methoxymethyl ether (MOM) by the standard literature methods (such as SEM-chloride or MOM-chloride) in a suitable solvent (such as tetrahydrofuran) with a suitable base (such as triethylamine) at a suitable temperature (such as 0-20°C) to afford compound of the fo ⁇ nula (Vlll) :
  • LG is a leaving group (such as chlorine or bromine)
  • MEM methoxymethyl ether
  • R 5 -H is a primary or secondary amine, thiol or alcohol as defined above (i.e. where R 5 is a group containing an X moiety where X is ⁇ R 13 , O or S), in a suitable solvent (such as tetrahydrofuran or acetonitrile) with or without a suitable base (such as sodium hydride, caesium carbonate or triethylamine) at a suitable temperature ranging from 25-85°C to afford compound of the fo ⁇ nula (X):
  • a suitable solvent such as tetrahydrofuran or acetonitrile
  • a suitable base such as sodium hydride, caesium carbonate or triethylamine
  • the protecting group (P) can then be removed by standard methods to afford compound of fonnula (1).
  • Compounds of structure (11) or (1), where R 5 is an optionally substituted aryl or heteroaryl ring as defined in the claims, can be prepared by taking a compound of formula (XI) or (Nil) where LG is a suitable leaving group such as bromine, chlorine or iodine and reacting it with an aryl or heteroaryl boronic acid such as phenyl boronic acid, a palladium catalyst such as [1,1 '-bis(diphenylphosphino)ferrocene]palladium (11) chloride, a suitable base such as caesium fluoride, sodium acetate or caesium carbonate and a suitable solvent such as methanol or ethanol and heating between 40-80°C
  • R 5 or R 6 is CO 2 R 13
  • R 13 can be prepared by reacting a compound of formula (11) or (1), where R 5 or R 6 is bromine or iodine, in a suitable solvent such as R 13 OH or dioxane containing R 13 OH, a suitable tertiary amine such as triethylamine, a suitable palladium catalyst such as
  • Compounds of fonnula (11) and (1) where R 5 or R 6 is CO ⁇ R 14 R 15 can be prepared by reacting a compound of fo ⁇ nula (11) or (1), where R 5 or R 6 is bromine or iodine, in a suitable solvent such as dioxane containing NHR 14 R 15 , a suitable tertiary amine such as triethylamine, a suitable palladium catalyst such as
  • Compounds of fo ⁇ nula (1) where R 5 or R 6 is CH 2 OH can be prepared from compounds of fonnula (1) where R or R is CO2R by reduction using a suitable reducing agent such as lithium triethylborohydride in a suitable solvent such as tetrahydrofuran at a temperature of 0-10°C.
  • Compounds of fo ⁇ nula (1) where R 5 or R 6 is CHO can be prepared from compounds of fo ⁇ nula (1) where R 5 or R 6 is CH 2 OH by oxidation using a suitable oxidising agent such as manganese dioxide or pyridinium chlorochromate (PCC) in a suitable solvent such as tetrahydrofuran or dichloromethane at a temperature of 0-50°C.
  • a suitable oxidising agent such as manganese dioxide or pyridinium chlorochromate (PCC) in a suitable solvent such as tetrahydrofuran or dichloromethane at a temperature of 0-50°C.
  • Compounds of fo ⁇ nula (1) where R 5 or R 6 is CH(OH)R n or CH(OH)(Cl-5)alkyl can be prepared from compounds of fonnula (1) where R 5 or R 6 is CHO by reaction with a compound of fo ⁇ nula (XII) where M is a metal such as magnesium or lithium in a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature of 0-10°C
  • a compound of fonnula (XV) can be made by reacting a compound of fonnula (XIII), where R 4 is preferrably chloro, bromo or alkoxy and LG is a suitable leaving group such as chloro or bromo, with a compound of fonnula (XIV) using a suitable base such as potassium carbonate or caesium carbonate in a suitable solvent such as NN- dimethylfonnamide at a temperature of 40-90°C
  • Intennediate compounds of fo ⁇ nula (II) and (III) can be prepared using standard chemistry or are available commercially.
  • the compounds of fonnula (I) above may be converted to a phannaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
  • a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine
  • an acid addition salt such as a hydrochloride
  • the compounds of fo ⁇ nula (I) above may be converted to a phannaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
  • a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine
  • an acid addition salt such as a hydrochloride,
  • the compounds of formula (I) has activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR4) activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of chemokines.
  • conditions/diseases include:
  • obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, fanner's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
  • COPD chronic obstructive
  • Neurodegenerative diseases and dementia disorders e.g. Alzheimer's disease, amyotrophic lateral sclerosis and other motor neuron diseases, Creutzfeldt- Jacob's disease and other prion diseases, HIN encephalopathy (AIDS dementia complex), Huntington's disease, frontotemporal dementia, Lewy body dementia and vascular dementia; polyneuropathies, e.g. Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, plexopathies; C ⁇ S demyelination, e.g.
  • multiple sclerosis multiple sclerosis, acute dissemmated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis
  • neuromuscular disorders e.g. myasthenia gravis and Lambert- Eaton syndrome
  • spinal diorders e.g. tropical spastic paraparesis
  • stiff-man syndrome paraneoplastic syndromes, e.g. cerebellar degeneration and encephalomyelitis
  • C ⁇ S trauma migraine
  • stroke and correctum diseases such as meningitis
  • AIDS Acquired Immunodeficiency Syndrome
  • lupus erythematosus systemic lupus, erythematosus, Hashimoto's thyroiditis
  • type I diabetes nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, and idiopathic thrombocytopenia pupura
  • post-operative adhesions and sepsis.
  • Cancer carcinoma & tumour metastasis, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin, especially non-small cell lung cancer (NSCLC), malignant melanoma, prostate cancer and squamous sarcoma.
  • NSCLC non-small cell lung cancer
  • malignant melanoma prostate cancer and squamous sarcoma.
  • Hematopoietic tumors of lymphoid lineage including acute lymphocytic leukemia, B cell lymphoma and Burketts lymphoma, Hodgkins Lymphoma, Acute Lymphoblastic Leukemia.
  • Hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias and promyelocytic leukemia.
  • Tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma, and other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
  • Reproductive Diseases e.g. Disorders of ovulation, menstruation and implantation, Pre-tenn labour, Endometriosis
  • the present invention provides a compound of fonnula (I), or a pharmaceutically- acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the compound of the invention are used to treat diseases in which the chemokine receptor belongs to the CC chemokine receptor subfamily, more preferably the target chemokine receptor is the CCR4 receptor.
  • Particular conditions which can be treated with the compound of the invention are asthma, rhinitis and inflammatory skin disorders, diseases in which there are raised TARC, MDC or CCR4 levels. It is preferred that the compound of the invention is used to treat asthma and rhinitis, especially asthma.
  • the present invention provides the use of a compound of fonnula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the present invention provides the use of a compound of fonnula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity, particularly CCR4 activity, is beneficial.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the te ⁇ ns “therapeutic” and “therapeutically” should be construed accordingly.
  • the invention still further provides a method of treating a chemokine mediated disease wherein the chemokine binds to a chemokine (especially CCR4) receptor, which comprises administering to a patient a therapeutically effective amount of a compound of fonnula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • a chemokine especially CCR4
  • the invention also provides a method of treating a respiratory disease, such as athma and rhinitis, especially asthma, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a phannaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • a respiratory disease such as athma and rhinitis, especially asthma
  • administering to the patient a therapeutically effective amount of a compound of formula (I), or a phannaceutically acceptable salt or solvate thereof, as hereinbefore defined.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the compound of formula (I) and phannaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the fo ⁇ n of a phannaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a phannaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a phannaceutically acceptable salt or solvate 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 phannaceutical composition of the invention which comprises mixing a compound of fonnula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a phannaceutically acceptable adjuvant, diluent or carrier.
  • the phannaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the fonn of solutions, suspensions, heptafluoroalkane aerosols and dry powder fonnulations; or systemically, e.g. by oral administration in the fo ⁇ n of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the fo ⁇ n of suppositories or transde ⁇ nally.
  • the compound of the invention is administered orally.
  • the present invention provides the use of a compound or formula (I), or a phannaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy in combination with drugs used to treat asthma and rhinitis (such as inhaled and oral steroids, inhaled ⁇ 2-receptor agonists and oral leukotriene receptor antagonists).
  • drugs used to treat asthma and rhinitis such as inhaled and oral steroids, inhaled ⁇ 2-receptor agonists and oral leukotriene receptor antagonists.
  • Example 2 Prepared by the method of Example 1 (reaction performed at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (0.16g) and 2,3,4-trifluorobenzenesulphonyl chloride (0.25g). Yield 0.08g. m/e 352/4 (M-l + , 100%) 1H NMR (D6-DMSO) ⁇ 7.93-7.80 (IH, m), 7.89 (IH, s), 7.60-7.50 (IH, m), 3.91 (3H, s).
  • N-bromosuccinamide (6.9g) was added portionwise over 0.5h to a stined solution of 6- chloro-2-pyrazinamine (5.0g) in chloroform (200mL) heated under reflux. After the addition was complete the reaction mixture was allowed to cool, washed with water and evaporated to give a 3:1 mixture of 5-bromo-6-chloro-2-pyrazinamine and the subtitle compound which were separated by silica gel chromatography eluting with dichloromethane. Yield 2.0g. Used directly.
  • Example 2 Prepared by the method of Example 1 (reaction performed at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (O.lg) and 2,3-dichlorobenzenesulphonyl chloride (0.15g). Yield 0.05g. m/e 366/8/370/2 (M-l + , 100%) 1H NMR (D6-DMSO) ⁇ 8.15 (IH, d), 7.93 (IH, d), 7.79 (IH, s), 7.58 (IH, t), 3.93 (3H, s).
  • Example 2 Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0.2g) and 3,5-dichlorobenzenesulphonyl chloride (0.24g). Yield 0.012g. m/e 410/2/4/6 (M-l + , 100%) ⁇ NMR (D6-DMSO) ⁇ 7.96-7.91 (4H, m), 3.93 (3H, s).
  • Example 2 Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0.2g) and 2,4-dichlorobenzenesulphonyl chloride (0.24g). Yield 0.059g. m/e 410/2/4/6 (M-l + , 100%) ] H ⁇ MR (D6-DMSO) ⁇ 8.07 (IH, d), 7.85 (2H, d), 7.64 (IH, dd), 3.92 (3H, s).
  • tetrabutylam onium hydroxide (0.28g of 40% aqueous solution) was added to a solution of 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ benzenesulfonamide (0.25g) in 1,2-dimethoxyethane (3. OmL) at room temperature. After 16h, the solution was diluted with ethyl acetate (20mL). The organic solution was washed with aqueous citric acid (lOmL) and brine, dried (MgSO ) and evaporated.
  • Example 87 Prepared by the method of Example 86 using 2,3-dichloro-N-[5-chloro-3-(4- ⁇ yridinylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 87) (O.lg). Yield 0.4g. m/e 462 (M+l + , 100%)
  • Example 74 Prepared by the method of Example 31 using 2-methylsulphanylethanol (0.05g) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (O.lg). Yield 0.06g. m e 427 (M-l + , 100%) 1H ⁇ MR (D6-DMSO) ⁇ 11.50-12.00 (lH, br s), 8.09 (IH, d), 7.95 (IH, d), 7.81 (IH, s), 7.60 (IH, t), 4.47 (2H, t), 2.86 (2H, t), 2.14 (3H, s) MP 140-141°C
  • Example 74 Prepared by the method of Example 31 using (6-methyl-2-pyridinyl)methanol (0.15g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.15g).
  • Example 89 Prepared by the method of Example 86 using 2,3-dichloro-N-[5-chloro-3-(2- pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 89) (0.2g). Yield O.lg. m/e 462 (M+l + , 100%)
  • 3,5-Dichloro-2-pyrazinamine (l.Og) was added to a stined suspension of pyridine-3- methanol (1.3g) and sodium hydride (0.70g of 60% dispersion in oil) in 1,2- dimethoxy ethane (lOmL). After 0.5h, 5% aqueous citric acid was added and the mixture extracted with ethyl acetate. Chromatography on silica gel eluting with ethyl acetate/zso- hexane mixtures gave the title compound as a white solid (0.2g). Used directly.
  • Example 95a 5- chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 95a) (O.lg) and 3-chloro-2- methylbenzenesulphonyl chloride (0.09g). Yield 0.012g. m/e 425 (M+l + , 100%)
  • Example 95a 5- chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine
  • Example 95a 5- chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine
  • Example 95a 3-chloro-2- fluorobenzenesulphonyl chloride
  • Example 4a 3- bromo-5-chloro-2-pyrazinamine (Example 4a) (1.2g) and 2,3-dichlorobenzenesulphonyl chloride (1.4g). Yield 1.5g. m/e 418 (M+l + , 100%)
  • Example 98 Prepared by the method of Example 31 using pyridine-3 -methanol (0.22g) andN-(3- bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.2g). Yield 0.04g. m/e 445 (M+l + , 100%)
  • Example 98 Prepared by the method of Example 31 using pyridine-2 -methanol (0.22g) andN-(3- bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.2g).
  • Example 36 Prepared by the method of Example 66a using 2,3-dichloro-N-[5-chloro-3-(3- pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 36) (0.5g). Yield 0.68g. Used directly.
  • Example 107b Preparedby the method of Example 107b using 2,3-dichloro-N-[5-chloro-3-(3- fonnylphenylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 107a) (O.lg) and 2- aminoethanol (0.05g). Yield 0.035g. m/e 517 (M+l + , 100%)
  • Example 110a 2,3-dichloro-N-[5-chloro-4-(3- formylphenylmethoxy)-2-pyrazinyl]benzenesulphonamide (0. lg) and 2- aminoethanol (0.05g). Yield 0.028g. m/e 517 (M+l + , 100%)
  • N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 8) (6.5g) and dichloro[l,r-bz diphenylphosphino)ferrocene]palladium(ll) dichloromethane adduct (0.7g) in methanol (30mL) and triethylamine (lOmL) was heated at 100°C under an atmosphere of carbon monoxide (6 bar). After 5h, the mixture was filtered and evaporated. The residue was dissolved in ethyl acetate. The organic solution was washed with brine, aqueous citric acid, dried (MgSO ) and evaporated.
  • Methylmagnesium bromide (3mL of a 3M solution in diethyl ether) was added over 3 minutes to a stirred solution of 5-(2,3-dichlorobenzenesuphonylamino)-6- methoxypyrazine-2-carboxylic acid, methyl ester (Example 113) (0.3g) in tetrahydrofuran (lOmL) cooled in an ice/water bath. After a further 5 minutes, aqueous citric acid was added and the mixture extracted with ethyl acetate. The organic solution was evaporated to dryness. Chromatography on silica gel eluting with methanol/dichloromethane mixtures gave the title compound as a white solid (0.15g). m/e 392 (M+l + , 100%)
  • Example 66a Prepared by the method of Example 66a using 2,3-dichloro-N-(5-chloro-3-methoxy-2- pyrazinyl)benzenesulphonamide (Example 5) (7.0g). Yield 9.8g. Used directly.
  • Example 115a (trimethylsilyl)ethoxy]methyl ⁇ benzenesulphonamide (0.25g) was added to a mixture of ethanolamine (0.05mL) and sodium hydride (0.035g of a 60% dispersion in oil) in 1 ,2-dimethoxyethane (15mL) at room temperature. After 2h, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO ) and evaporated to dryness.
  • Example 118b A solution of 3,5-dibromo-6-methyl-2-pyrazinamine (Example 118b) (0.9g) was added to a solution of sodium (0.39g) in methanol (30mL) was heated at reflux for 18h. After removal of solvent in vacuo, the residue was partitioned between water and dichloromethane, and the organic phase dried (MgSO ), filtered and evaporated to give the title compound as a pale yellow solid (0.58g). m/e 218/220 (M+l + , 100%)
  • Example 118 Prepared by the method of Example 113 using 2,3-dichloro-N-[5-bromo-3-methoxy-6- methylpyrazinyl)benzenesulphonamide (Example 118) (0.35g). Yield 0.27g. m/e 404/406 (M-r, 100%)
  • Example 121a 5,6- dichloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (0.27g) and 2,3- dichlorobenzenesulphonyl chloride (0.27g). Yield 0.17g. m/e 479 (M+l + , 100%)
  • Example 121a Prepared as for Example 121a using 3-chloro-2-aminopyrazine (0.5 g), pyridine-3- methanol (0.42g) and sodium hydride (0.3 lg of a 60% dispersion in oil) inN- methylpyrrolidinone (5 mL) to afford the sub-titled compound as a solid (0.62 g).
  • ⁇ ⁇ MR (CDCI 3 ) ⁇ 8.73 (IH, d), 8.60 (IH, d), 7.78 (IH, d), 7.60 (IH, d), 7.42 (IH, d), 7.32 (IH, dd), 5.43 (2H, s), 4.77 (2H, br).
  • Example 125a 3-methoxy-5- bromo-6-chloro-2-pyrazinamine (Example 125a) (0.5g) and 2,3-dichlorobenzenesulphonyl chloride (2.21 g). Yield 3.2g. m/e 445, 447 (M-l + , 100%)
  • Example 125 N-(5-bromo-6-chloro-3-methoxypyrazin-2- yl)-2,3-dichlorobenzenesulfonamide (Example 125) (l.Og). Yield 0.92g. m/e 426, 428 (M-l + , 100%)
  • Example 126 Prepared as for Example 120 using 3-chloro-5- ⁇ [(2,3-dichlorophenyl)sulphonyl]amino ⁇ -6- methoxypyrazine-2-carboxylic acid, methyl ester (Example 126) (0.105g). Yield 0.072g. m/e 397, 399 (M-l + , 100%)
  • Example 28b Prepared by the method of Example 28b using 2,3-dichloro-N-(3-chloro-2- pyrazinyl)benzenesulphonamide (Example 28a) (0.338g) and (6-methoxy-3- pyridinyl)methanol (0.2 lg). Yield 0.23g. m/e 439, 440 (M-l + , 100%)
  • Example 2 By the method outlined in Example 1 (reaction performed at room temperature) using 3- chloro-2-pyrazinamine (1.29g), 3-fluorobenzenesulphonyl chloride (2.13g). The crude adduct was reacted with a solution of sodium methoxide (lOmL of a 25% solution in methanol) in methanol (20mL) to afford the sub-titled compound (2.36g) as a solid. m e 284 (M+l + , 100%) MP 142-143°C
  • Example 131a 3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 131a) (0.283g), lithium di-zso-propylamide (prepared from di-z ' 50-propylamine
  • Example 2 By the method outlined in Example 1 (reaction perfonned at room temperature) using 3- chloro-2-aminopyrazine ( 0.83 g), 3-methoxybenzenesulfonyl chloride (1.44 g) .
  • the crude adduct was reacted with a solution of sodium methoxide (10 mL of a 25% solution in methanol) in methanol (20mL) to afford the sub-titled compound (1.41g) as a solid.
  • m/e 296 M+l + , 100%
  • Example 34 N-[5-bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide (Example 34).(0.2g) and bis(triphenylphosphine)palladium(ll) dichloride (O.lg). Yield 0.14g. m/e 469(M+ ⁇ + , 100%) ⁇ ⁇ MR (D6-DMSO) ⁇ 8.83 (IH, s), 8.61 (IH, d), 8.15-8.05 (3H,m), 7.90 (IH, d), 7.60- 7.50 (2H, m), 5.48 (2H, s), 3.82(3H, s). MP 209-210°C
  • Example 115 using N-(5-chloro-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- ( ⁇ 2-[(trimethylsilyl)oxy] ethoxy ⁇ methyl)benzenesulphonamide (Example 115a) (0.25 g), allyl alcohol (0.06g) and sodium hydride (0.035g of a 60% dispersion in oil) inNN- dimethylformamide (5mL) stirred at room temperature for 5 days. Purification was by silica gel chromatography eluting with ethyl acetate/z's ⁇ -hexane mixtures to give the title compound with SEM attached. Yield 0.18g.
  • N-methylpyrrolidinone (2mL). After 0.5h, chloropyrazine (0.013mL) was added and the mixture heated at 60°C for 3h. Aqueous acetic acid was added and the mixture extracted with ethyl acetate. The organic solution was dried ( ⁇ a 2 SO ) and evaporated.
  • Example 74 Prepared by the method of Example 31 using (5-bromo-3-pyridinyl)methanol (0.2g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.25g). Yield 0.17g. m/e 523(M-1 + , 100%)
  • Example 74 Prepared by the method of Example 3 lb using (2-methyl-4-oxazolyl)methanol (0.08g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.26g).
  • Examples 146-165 were prepared using the following procedure:

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Abstract

The invention provides N-pyrazinyl-phenylsulphonamides of formula (I) for use in the treatment of chemokine mediated diseases. Particularly inflammatory diseases, such as asthma.

Description

N-PYRAZINYL-PHENYLSULPHONAMIDES AND THEIR USE IN THE TREATMENT OF CHEMOKINE MEDIATED DISEASES
The present invention relates to a sulphonamide compound, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.
Certain sulphonamide compounds are known in the art, for example see GB2295616, US patent 2002143024, WO 01/44239, EP 749964 and Esche, J; Wojahn, H. Arch. Pharm. (1966), 299(2), 147-153.
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 four cysteine motif. At the present time, the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C), Cys-Cys (C-C) and Cys-X3-Cys (C-X3-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-X3-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 (IL-8) and neutrophil-activating peptide 2 (NAP -2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils. Examples include human monocyte chemo tactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins lα and lβ (MIP-1 α and
MIP-1 β), Thymus and Activation Regulated Chemokine (TARC, CCL17) and Macrophage Derived Chemokine (MDC, CCL22).
The C-X3-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. Studies have demonstrated that the actions of 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, CCRIO and CCRl 1 (for the C-C family); CXCR1 , CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X3-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.
The present invention therefore provides a compound of formula (I) and pharmaceutically acceptable salts, solvates or N-oxides thereof:
Figure imgf000003_0001
(I) in which:
R1, R2 and R3 are independently hydrogen, halogen, cyano, CF3, OCF3, OC1-6 alkyl or C1-6 alkyl;
R4 is halogen, CO2R12,
C1-6 alkoxy where the alkyl group may forai a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
C3-6 alkenyloxy or C3-6 alkynyloxy where either may be optionally substituted with hydroxy or NR14R15;
OCι-6 alkyl-X-C1-6 alkyl where the alkyl groups may foπn a 3-6 membered saturated ring;
OC]-6 alkylR11, or OC2-6 alkyl-X-R11 where the alkyl group may foπn a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)2R13, S(O)R13 or COR13; OCi.6 alkylR16;
R5 and R6 are independently hydrogen, cyano, halogen, CO2R12, CONRI4R15 ;
C1-6 alkyl optionally substituted by hydroxy, NR14R15, or 1-3 fluorines;
Cι.6 alkylR11 or XCH(Rn)C1-6 alkyl or XCH(R16)C1-6 alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NR14R15;
NR14R15; N(R11)R11; X-(CH2)qNRI4R15; (CH2)nNR14R15; NHC(O)d.6 alkyl optionally substituted by one or more hydroxy groups,
C3-6 alkynyl or C3-6 alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O;
R11; X-R11; X-R12; X-C1-6alkylR16; X-R16; X-(CH2)nCO2R12; X-(CH2)nCONR14R15; X-(CH2)nRπ; X-(CH2)nCN; X-(CH2)qOR12; (CH2)nOR12; (CH2)n-X-Rπ; X-(CH2)qNHC(O)NHR12; X-(CH2)qNHC(O)R12; X-(CH2)qNHS(O)2R12; X-(CH2)qNHS(O)2R1 ! ; X-C3-6alkenyl; X-C3-6alkynyl;
n is 1 ,2, 3, 4 or 5;
q is 2, 3, 4, 5 or 6;
X is NR13, O, S3 S(O), S(O)2;
R11 is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR14R15 5 C(O)OR12, hydroxy, =O, =S, CN, NO2, COR13, NR14R15, X(CH2)qNR14R15, (CH2)nNR14R15, (CH2)nOH, SR13, S(O)R13, S(O)2R13 C1-6 alkyl-X-Cι-6 alkyl, C1-6 alkyl or C1-6 alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)R13, S(O)2R13; R12 and R13 are independently hydrogen or C1-6 alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered ring;
R14 and R15 are independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)qOH,
or R14 and R15 together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from mtrogen, oxygen and sulphur and optionally substituted by C1-6 alkyl, C1-6 alkyl-OH, or hydroxy; and
R16 is a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O,
provided that: • when R4 is halogen or C1- alkoxy and R5 is hydrogen, halogen, C1-4alkyl,
C1-2alkoxy, C1-2alkylthio, trifluoromethyl or ethynyl and when one of R1, R2 or R3 is C1-6alkyl or C1-6alkoxy and is meta to the sulphonamide group then the group ortho to both the sulphonamide group and the C1-6alkyl or C1-6alkoxy group is not hydrogen, • when R4 is halogen or Cι- alkoxy and R5 is hydrogen, halogen, C1-4alkyl,
C1-2alkoxy, C1-2alkylthio, trifluoromethyl or ethynyl and when one of R , R or R is C1-6alkyl or C1-6alkoxy and is ortho to the sulphonamide group then the group ortho to the Ci-όAlkyl or C^alkoxy and also meta to the sulphonamide group is not hydrogen, • when two of R1, R2, R3 are hydrogen and the other is a methyl group para to the sulphonamide and R4 is methoxy then R5 is not hydrogen or bromo, and • when R5 is methyl and R6 is methoxy and one of R1, R2 or R3 is bromo or iodo and the other two are both hydrogen, then the bromo or iodo group is not ortho to the sulphonamide group.
The tenn aryl includes phenyl and naphthyl. The terai alkyl, whether alone or as part of another group, includes straight chain and branched chain alkyl groups. Examples of 5- to 7-membered heteroaromatic ring containing 1 to 4 heteroatoms include thienyl, furanyl, pyπolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl. Examples of saturated 4- to 8-membered rings containing 1 to 3 heteroatoms include morpholine, piperidine and azetidine. Substituents on any rings can be present in any suitable ring position including suitable substituents on nitrogen atoms.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of foπmαla (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also fonn an aspect of the present invention.
Preferred halogen groups for R1, R2 and R3 are chloro, bromo and fluoro. Preferably one
1 9 ^ 1 of R , R and R is hydrogen and the other is chloro, bromo or methyl. More preferably R and R2 are chloro at the 2- and 3-positions of the phenyl ring and R3 is hydrogen (i.e. 2,3- dichlorophenyl), R1 and R3 are chloro at the 2- and 4-positions of the phenyl ring and R2 is hydrogen (i.e. 2,4-dichlorophenyl) or R1 is chloro at the 2-position and R2 is methyl at the 3-position of the phenyl ring and R3 is hydrogen (i.e 2-chloro-3-methylphenyl). Most preferably R1 and R2 are chloro at the 2- and 3-positions of the phenyl ring and R3 is hydrogen (i.e. 2,3-dichlorophenyl).
In a further aspect the invention provides a compound of formula (I) as defined above but without the provisos where R1 and R2 are chloro at the 2- and 3-positions of the phenyl ring and R3 is hydrogen (i.e. 2,3-dichlorophenyl), R1 and R3 are chloro at the 2- and 4-positions of the phenyl ring and R2 is hydrogen (i.e. 2,4-dichlorophenyl) or R1 is chloro at the 2- position and R2 is methyl at the 3-position of the phenyl ring and R3 is hydrogen (i.e 2- chloro-3 -methylphenyl) .
For the group R4 examples of C3-6 alkenyloxy include OCH2CH=CH2, examples of C3-6 alkynyloxy include OCH2CCH, examples of OC1-6 alkyl-O-C1-6 alkyl include OCH2CH2OMe, examples of OC1-6 alkylR11 include OCH2Rn, and examples of OC1-6 alkylR16 include OCH2pyrrolidine.
Preferred groups for R4 include C1-6 alkoxy such as methoxy, 2-furanylmethoxy, bromo, chloro, 2-methoxyethoxy, (5-methyl-3-isoxazolyl)methoxy, 2-, 3- or 4-pyridylmethoxy, 3-pyridazinylmethoxy, methoxy, 2-(l-imidazolyl)ethoxy, (2-methyl-4-oxazolyl)methoxy and 4-methoxyphenylmethoxy. More preferably R4 is methoxy.
For R5 and R6 examples of NR14R15 includes morpholine, pyrrolidine, NMe2, NHCH2CH2OMe, NHMe, and the groups below:
Figure imgf000007_0001
Examples of X-(CH2)qNR1, Rι:> include SCH2CH2NH2 and SCH2CH2NMe2 , examples of (CH2)nNR]4R15 include CH2morpholine, examples of X-R12 includes SMe, OMe, OEt, OH, SO2Me, examples of X-C1-6alkylR16 includes OCHbpyrrolidine, examples of X- (CH2)nCO2R12 includes SCH2CO2H, SCH2CO2Me, SCH2CH2CO2Me, examples of X- (CH2)nCONR14R15 includes SCH2CONH2 , SCH2CONHMe, OCH2CONEt2, examples of X-(CH2)n n includes the groups below:
Figure imgf000007_0002
Examples of X-(CH2)nCN, includes SCH2CN, examples of X-(CH2)qOR . 1i2;includes OCH2CH2OMe, examples of (CH2)nOR12 includes CH2OH, CH2OMe, examples of X-(CH2)qNHC(O)NHR12 includes SCH2CH2NHC(O)NHEt, and examples of X-(CH2)qNHC(O)R12 includes NHCH2CH2NHC(O)Me. Examples of NHC(O)C1-6 alkyl optionally substituted by one or more hydroxy groups includes NHCOCH2OH.
Preferred groups for R5 include hydrogen, halogen such as bromo and chloro, phenyl, d-β alkyl such as methyl, CH2OH, cyano and 2-aminothanethiol. More preferably R5 is hydrogen, methyl, CH2OH or halogen such bromo or chloro.
Preferred groups for R6 include hydrogen, C1-6 alkyl, CH2OH and halogen, more preferably hydrogen, methyl, CH2OH or chloro.
In a further aspect the invention provides a compound of foraiula (IA):
Figure imgf000008_0001
(IA)
in which
R1, R2 and R3 are independently hydrogen, halogen, cyano, CF3, OCF3, C1-6 alkenyl or
C1-6 alkyl;
R4 is halogen, C^e alkoxy or OR9;
R5 and R6 are independently hydrogen, halogen, C1-6 alkoxy, C1-6 alkylthio, cyano, R9,
OR , NR » 9*rR> 1ι0υ, SR , S(CH2)nCO2H, S(CH2)nCO2R , 1l2, S(CH2)nCONR12R13, S(CH2)„Rn or a 5- to 7-membered heteroaromatic or saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur; n is 1, 2 or 3;
R9 and R10 are independently hydrogen, C1-6 alkyl optionally substituted by hydroxy, C1-6 alkoxy or NHCOC1-6 alkyl, or R9 and R10 are optionally substituted aryl, Cι.6 alkyl-aryl or C1-6 alkyl-R11 or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C1-6 alkyl or C1-6 alkyl-OH; and R11 is a 5- to 7-membered heteraromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C1-6 alkyl; and R12 and R13 are independently hydrogen or C1-6 alkyl.
1 ^
For compounds (IA) R , R and R are independently hydrogen, halogen, cyano, CF3, OCF3, C1-6 alkenyl or C1-6 alkyl, preferred halogen groups being chloro. Preferably one of R1, R2 and R3 is methyl, ethenyl, cyano, chloro, fluoro, iodo or two are chloro or all three are fluoro. More preferred are compounds where R1 - R3 together with the phenyl group to which they are attached foπn a 3-chloro-2-methylphenyl or a 2,3-dichlorophenyl group.
For compounds (IA) preferred groups for R4 include halogen such as bromo and chloro, C1-6 alkoxy such as methoxy and ethoxy, C1-6 alkyl or OR9 where R9 is CH2Rπ where R11 is a 5- or 6-membered heteraromatic ring containing 1 or 2 heteroatoms. More preferably R4 is methoxy, halogen, such as chloro, or OR9 where R9 is CH Rn where R11 is furanyl, 5-methyl-3 -isoxazolyl, pyridyl optionally substituted by methyl, pyridazinyl, pyrazinyl, 1 -methyl-6-oxo- 1 ,6-dihydro-3-pyridinyl.
For compounds (IA) preferably R5 is hydrogen, methyl, bromo, chloro, methoxy, morpholinyl, pyrrolinyl, dimethylamino, hydroxy, 2-methoxy ethoxy, pyrazinyl, pyrimidinyl, O-Ph-CO2H, 2-hydroxyethylamino, 2-methoxyethylamino, NHCH2CH2NHCOMe, cyano, 4-hydroxymethyl-l-piperidinyl, SMe, NHMe, or 2,4- difluorophenyl.
For compounds (I A) preferably R6 is hydrogen or chloro.
Preferred compounds of formula (I)/(IA) include those exemplified herein both in free base form and as phaπnaceutically acceptable salts.
According to the invention there is also provided a process for the preparation of compound (I) which comprises reaction of a compound of formula (II):
Figure imgf000009_0001
(II)
where R4, R5 and R6 are as defined in formula (I) or are protected derivatives thereof with a compound of foπnula (III):
Figure imgf000009_0002
(HI) where R1, R2 and R3 are as defined in fonnula (I) or are protected derivatives thereof and LG is a leaving group, and optionally thereafter • removing any protecting groups,
• fonning a pharaiaceutically acceptable salt.
Preferred leaving groups LG include halogen such as chloro. Preferably the reaction between compounds (II) and (III) is carried out by treating compound (II) with a base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as 1,2- dimethoxyethane or tetrahydrofuran.
Wliere R4 is C1-6 alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
C3-6 alkenyloxy or C3-6 alkynyloxy where either may be optionally substituted with hydroxy or NR14R15;
OC1-6 alkyl-X-d-6 alkyl where the alkyl groups may foπn a 3-6 membered saturated ring;
OC1-6 alkylR11, or OC2-6 alkyl-X-R11 where the alkyl group may foπn a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)2R13, S(O)R13; or
OCι-6 alkylR16; compounds of foπnula (II) can be prepared by treating a compound of the formula (IV), where LG is a leaving group (such as chlorine or bromine):
Figure imgf000010_0001
(IN)
with a compound of foπnula (V)
R4-H
(N)
in a suitable solvent (such as 1,2-dimethoxyethane, NN-dimethylformamide or tetrahydrofuran) with a suitable base such as sodium hydride or potasssium tert-butoxide at a suitable temperature such as 25°C to 60°C. Where R4 is C1-6 alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
C3-6 alkenyloxy or C3-6 alkynyloxy where either may be optionally substituted with hydroxy or NR14R15;
OC1-6 alkyl-X-C1-6 alkyl where the alkyl groups may foπn a 3-6 membered saturated ring;
OC1-6 alkylR11, or OC2-6 alkyl-X-R11 where the alkyl group may foπn a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)2R13, S(O)R13; or
OCι-6 alkylR16; compounds of foπnula (I) can be prepared by treating a compound of the formula (VI), where LG is a leaving group (such as chlorine or bromine):
Figure imgf000011_0001
(VI)
with a compound of foπnula (V)
in a suitable solvent (such as 1,2-dimethoxyethane, NN-dimethylfonnamide or tetrahydrofuran) with a suitable base such as sodium hydride or potasssium tert-butoxide at a suitable temperature such as 25°C to 60°C.
Compounds of structure (Vlll) can be prepared by taking a compound of formula (Nil) where LG is a leaving group (such as chlorine or bromine) and protecting the sulfonamide as for example the trimethylsilyethoxymethyl ether (SEM) or methoxymethyl ether (MOM) by the standard literature methods (such as SEM-chloride or MOM-chloride) in a suitable solvent (such as tetrahydrofuran) with a suitable base (such as triethylamine) at a suitable temperature (such as 0-20°C) to afford compound of the foπnula (Vlll) :
Figure imgf000012_0001
(NH) (Vlll)
Compound of foπnula (Vlll) could then be treated with compounds of formulae (IX):
R5-H
(IX)
where R5-H is a primary or secondary amine, thiol or alcohol as defined above (i.e. where R5 is a group containing an X moiety where X is ΝR13, O or S), in a suitable solvent (such as tetrahydrofuran or acetonitrile) with or without a suitable base (such as sodium hydride, caesium carbonate or triethylamine) at a suitable temperature ranging from 25-85°C to afford compound of the foπnula (X):
Figure imgf000012_0002
(X)
The protecting group (P) can then be removed by standard methods to afford compound of fonnula (1).
Compounds of structure (11) or (1), where R5 is an optionally substituted aryl or heteroaryl ring as defined in the claims, can be prepared by taking a compound of formula (XI) or (Nil) where LG is a suitable leaving group such as bromine, chlorine or iodine and reacting it with an aryl or heteroaryl boronic acid such as phenyl boronic acid, a palladium catalyst such as [1,1 '-bis(diphenylphosphino)ferrocene]palladium (11) chloride, a suitable base such as caesium fluoride, sodium acetate or caesium carbonate and a suitable solvent such as methanol or ethanol and heating between 40-80°C
Figure imgf000013_0001
(XI) (11)
Figure imgf000013_0002
(NH) (1)
Compounds of formula (11) and (1) where R5 or R6 is CO2R13 can be prepared by reacting a compound of formula (11) or (1), where R5 or R6 is bromine or iodine, in a suitable solvent such as R13OH or dioxane containing R13OH, a suitable tertiary amine such as triethylamine, a suitable palladium catalyst such as
[1,1 '-bis(diphenylphosphino)feπocene]palladium (11) chloride under an atmosphere of carbon monoxide usually at 2-10 bar, ideally at 4-6 bar and at a temperature of 70-120 °C. Compounds of fonnula (11) and (1) where R5 or R6 is COΝR14R15 can be prepared by reacting a compound of foπnula (11) or (1), where R5 or R6 is bromine or iodine, in a suitable solvent such as dioxane containing NHR14R15, a suitable tertiary amine such as triethylamine, a suitable palladium catalyst such as
[l,l'-bis(diphenylphosphino)ferrocene]palladimn (11) chloride under an atmosphere of carbon monoxide usually at 2-10 bar, ideally at 4-6 bar and at a temperature of 70-120 °C. Compounds of foπnula (1) where R5 or R6 is CH2OH can be prepared from compounds of fonnula (1) where R or R is CO2R by reduction using a suitable reducing agent such as lithium triethylborohydride in a suitable solvent such as tetrahydrofuran at a temperature of 0-10°C.
Compounds of foπnula (1) where R5 or R6 is CHO can be prepared from compounds of foπnula (1) where R5 or R6 is CH2OH by oxidation using a suitable oxidising agent such as manganese dioxide or pyridinium chlorochromate (PCC) in a suitable solvent such as tetrahydrofuran or dichloromethane at a temperature of 0-50°C.
Compounds of foπnula (1) where R5 or R6 is CH(OH)Rn or CH(OH)(Cl-5)alkyl can be prepared from compounds of fonnula (1) where R5 or R6 is CHO by reaction with a compound of foπnula (XII) where M is a metal such as magnesium or lithium in a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature of 0-10°C
C1-5 alkylM or RπM
Figure imgf000014_0001
(XIII) (XIV) (XV)
A compound of fonnula (XV) can be made by reacting a compound of fonnula (XIII), where R4 is preferrably chloro, bromo or alkoxy and LG is a suitable leaving group such as chloro or bromo, with a compound of fonnula (XIV) using a suitable base such as potassium carbonate or caesium carbonate in a suitable solvent such as NN- dimethylfonnamide at a temperature of 40-90°C
Intennediate compounds of foπnula (II) and (III) can be prepared using standard chemistry or are available commercially.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intennediate compound may need to be protected by protecting groups. Thus, the preparation of the compound of fonnula (I) may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of functional groups is fully described in 'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of fonnula (I) above may be converted to a phannaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
Certain compounds of foπnula (II) and (III) are believed to be novel and fonn a further aspect of the invention.
The compounds of foπnula (I) above may be converted to a phannaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
The compounds of formula (I) has activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR4) activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of chemokines. Examples of such conditions/diseases include:
(1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, fanner's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
(2) (bone and joints) gout, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and
Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis;
(3) (skin) pruritis, scleroderma, otitus, psoriasis, atopical dermatitis, contact deπnatitis and other eczmatous dermitides, seborrhoetic dennatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodennas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis, lupus;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, ileitis and enteritis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
(5) (central and peripheral nervous system) Neurodegenerative diseases and dementia disorders, e.g. Alzheimer's disease, amyotrophic lateral sclerosis and other motor neuron diseases, Creutzfeldt- Jacob's disease and other prion diseases, HIN encephalopathy (AIDS dementia complex), Huntington's disease, frontotemporal dementia, Lewy body dementia and vascular dementia; polyneuropathies, e.g. Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, plexopathies; CΝS demyelination, e.g. multiple sclerosis, acute dissemmated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; neuromuscular disorders, e.g. myasthenia gravis and Lambert- Eaton syndrome; spinal diorders, e.g. tropical spastic paraparesis, and stiff-man syndrome: paraneoplastic syndromes, e.g. cerebellar degeneration and encephalomyelitis; CΝS trauma; migraine; stroke and correctum diseases such as meningitis
(6) (other tissues and systemic disease) hepatitis, vasculitis, spondyloarthopathies, vaginitis, glomerulonephritis, myositis, atherosclerosis,
Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, and idiopathic thrombocytopenia pupura; post-operative adhesions, and sepsis.
(7) (allograft and xenograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease;
(8) Cancer, carcinoma & tumour metastasis, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin, especially non-small cell lung cancer (NSCLC), malignant melanoma, prostate cancer and squamous sarcoma. Hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B cell lymphoma and Burketts lymphoma, Hodgkins Lymphoma, Acute Lymphoblastic Leukemia.
Hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia. Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma, and other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma.
(9) All diseases that result from a general inbalance of the immune system and resulting in increased atopic inflammatory reactions.
(10) Cystic fibrosis, re-perfusion injury in the heart, brain, peripheral limbs and other organs.
(11) Burn wounds & chronic skin ulcers
(12) Reproductive Diseases (e.g. Disorders of ovulation, menstruation and implantation, Pre-tenn labour, Endometriosis)
(13) thrombosis
(14) infectious diseases such as HIV infection and other viral infections, bacterial infections. Thus, the present invention provides a compound of fonnula (I), or a pharmaceutically- acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
Preferably the compound of the invention are used to treat diseases in which the chemokine receptor belongs to the CC chemokine receptor subfamily, more preferably the target chemokine receptor is the CCR4 receptor.
Particular conditions which can be treated with the compound of the invention are asthma, rhinitis and inflammatory skin disorders, diseases in which there are raised TARC, MDC or CCR4 levels. It is preferred that the compound of the invention is used to treat asthma and rhinitis, especially asthma.
In a further aspect, the present invention provides the use of a compound of fonnula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In a still further aspect, the present invention provides the use of a compound of fonnula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity, particularly CCR4 activity, is beneficial.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The teπns "therapeutic" and "therapeutically" should be construed accordingly.
The invention still further provides a method of treating a chemokine mediated disease wherein the chemokine binds to a chemokine (especially CCR4) receptor, which comprises administering to a patient a therapeutically effective amount of a compound of fonnula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
The invention also provides a method of treating a respiratory disease, such as athma and rhinitis, especially asthma, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a phannaceutically acceptable salt or solvate thereof, as hereinbefore defined. For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
The compound of formula (I) and phannaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the foπn of a phannaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a phannaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a phannaceutically acceptable salt or solvate 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 phannaceutical composition of the invention which comprises mixing a compound of fonnula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a phannaceutically acceptable adjuvant, diluent or carrier.
The phannaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the fonn of solutions, suspensions, heptafluoroalkane aerosols and dry powder fonnulations; or systemically, e.g. by oral administration in the foπn of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the foπn of suppositories or transdeπnally. Preferably the compound of the invention is administered orally.
In a further aspect, the present invention provides the use of a compound or formula (I), or a phannaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy in combination with drugs used to treat asthma and rhinitis (such as inhaled and oral steroids, inhaled β2-receptor agonists and oral leukotriene receptor antagonists). The following examples illustrate the invention.
Example 1 2,3-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-benzenesulphonamide
Figure imgf000021_0001
Sodium hydride (O.lg of 60%) was added to 3-methoxy-5-methyl-2-pyrazinamine (0.07g) in 1,2-dimethoxyethane (3mL) under nitrogen at room temperature. After 1 hour at 50°, 2,3-dichlorobenzenesuphonyl chloride (0.15g) was added. After stirring for 30 minutes, 5% aqueous citric acid was added and the product extracted with ethyl acetate (X3). The combined extracts were washed with saturated brine, dried (MgSO ) and the solvent was evaporated. Chromatography on silica eluting with dichloromethane/methanol mixtures gave the title compound as a white solid (0.08g). m e 346/8/350 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 11.27 (IH, s), 8.06 (IH, d), 7.93 (IH, d), 7.60-7.55 (IH, br s), 7.58 (IH, t), 3.87 (3H, s), 2.28 (3H, s).
Example 2 N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,3,4-tifluorobenzenesulphonamide
Figure imgf000021_0002
Prepared by the method of Example 1 (reaction performed at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (0.16g) and 2,3,4-trifluorobenzenesulphonyl chloride (0.25g). Yield 0.08g. m/e 352/4 (M-l+, 100%) 1H NMR (D6-DMSO) δ 7.93-7.80 (IH, m), 7.89 (IH, s), 7.60-7.50 (IH, m), 3.91 (3H, s).
Example 3 3-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide
Figure imgf000022_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (0.16g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.23g). Yield 0.15g. m/e 346/8/50 (M-l+, 100%)
1H NMR (D6-DMSO) δ 8.05 (IH, d), 7.85 (IH, s), 7.75 (IH, d), 7.47 (IH, t), 3.92 (3H, s),
2.66 (3H, s).
Example 4 2,3-Dichloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
a) 3-Bromo-6-chloro-2-pyrazinamine
Figure imgf000022_0002
N-bromosuccinamide (6.9g) was added portionwise over 0.5h to a stined solution of 6- chloro-2-pyrazinamine (5.0g) in chloroform (200mL) heated under reflux. After the addition was complete the reaction mixture was allowed to cool, washed with water and evaporated to give a 3:1 mixture of 5-bromo-6-chloro-2-pyrazinamine and the subtitle compound which were separated by silica gel chromatography eluting with dichloromethane. Yield 2.0g. Used directly.
b) 6-Chloro-3-methoxy-2-pyrazinamine and 3-bromo-6-methoxy-2-pyrazinamine
Figure imgf000023_0001
3-Bromo-6-chloro-2-pyrazinamine (l.Og), sodium methoxide (3mL of 25% solution in methanol) and methanol (lOmL) were heated at reflux for 3 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and brine. The organic layer was separated dried (MgSO4) and the solvent was evaporated to give a mixture of the sub-title compounds (ratio 10:1). Purification was by silica gel chromatography eluting with dichloromethane. Yield 0.5g. Used directly.
c) 2,3-Dichloro-N-(6-Chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000023_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (0.24g) and 2,3-dichlorobenzenesulphonyl chloride
(0.32g). Yield 0.24g. m e 366/8/370/2 (M-l+, 100%)
1H NMR (D6-DMSO) δ 8.14 (IH, d), 7.96 (IH, d), 7.89 (IH, s), 7.62 (IH, t), 3.91 (3H, s).
Example 5 2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000023_0003
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (O.lg) and 2,3-dichlorobenzenesulphonyl chloride (0.15g). Yield 0.05g. m/e 366/8/370/2 (M-l+, 100%) 1H NMR (D6-DMSO) δ 8.15 (IH, d), 7.93 (IH, d), 7.79 (IH, s), 7.58 (IH, t), 3.93 (3H, s).
Example 6 N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,5-dichlorobenzenesulphonamide
Figure imgf000024_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0.2g) and 2,5-dichlorobenzenesulphonyl chloride
(0.24g). Yield 0.14g. m/e 410/2/4/6 (M-l+, 100%)
1H NMR (D6-DMSO) δ 8.04 (IH, d), 7.86 (IH, s), 7.73 (IH, dd), 7.66 (IH, dd), 3.91 (3H, s).
Example 7 N-(5-Bromo-3-methoxy-2-pyrazinyl)~3,5-dichIorobenzenesulphonamide
Figure imgf000024_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0.2g) and 3,5-dichlorobenzenesulphonyl chloride (0.24g). Yield 0.012g. m/e 410/2/4/6 (M-l+, 100%) Η NMR (D6-DMSO) δ 7.96-7.91 (4H, m), 3.93 (3H, s).
Example 8
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
Figure imgf000025_0001
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (O.lg) and 2,3-dichlorobenzenesulphonyl chloride
(0.2g). Yield 0.045g. m/e 410/2/4/6 (M-l+, 100%) 1H NMR (D6-DMSO) δ 8.06 (IH, dd), 7.93 (IH, dd), 7.82 (IH, s), 7.57 (IH, t), 3.92 (3H, s).
Example 9 N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide
Figure imgf000025_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0.2g) and 2,4-dichlorobenzenesulphonyl chloride (0.24g). Yield 0.059g. m/e 410/2/4/6 (M-l+, 100%) ]H ΝMR (D6-DMSO) δ 8.07 (IH, d), 7.85 (2H, d), 7.64 (IH, dd), 3.92 (3H, s).
Example 10 N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,4-dichlorobenzenesulphonamide
Figure imgf000026_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0.15g) and 3,4-dichlorobenzenesulphonyl chloride
(0.15g). Yield 0.09g. m/e 410/2/4/6 (M-l+, 100%)
1H NMR (D6-DMSO) δ 8.14 (IH, s), 8.00-7.85 (3H, m), 3.94 (3H, s).
Example 11 N-(5-Bromo-3-methoxy-2-pyrazinyl)-4-chlorobenzenesulphonamide
Figure imgf000026_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (O.lg) and 4-chlorobenzenesulphonyl chloride (0.13g). Yield 0.13g. m/e 376/8/380 (M-l+, 100%)
1H NMR (D6-DMSO) δ 11.3 (IH, br s), 7.97 (2H, d), 7.91 (IH, s), 7.66 (2H, d), 3.93 (3H, s). Example 12 N-(5-Bromo-3-methoxy-2-pyrazinyl)-3-chlorobenzenesulphonamide
Figure imgf000027_0001
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0. Ig) and 3-chlorobenzenesulphonyl chloride (0.13g). Yield 0.14g. m/e 376/8/380 (M-l+, 100%) 1H NMR (D6-DMSO) δ 8.00-7.90 (3H, m), 7.75 (IH, d), 7.64 (IH, t), 3.94 (3H, s).
Example 13
N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-fluorobenzenesulphonamide
Figure imgf000027_0002
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2- fluorobenzenesulphonyl chloride. m/e 298 (M+l+, 100%)
1H NMR (D6-DMSO) δ 11.05 (lH, br s), 7.85-7.95 (IH, m), 7.65-7.75 (lH, m), 7.50-7.60
(IH, m), 7.35-7.45 (IH, m), 3.90 (3H, s), 2.30 (3H, s). MP 150-152°C
Example 14 N-(3-Methoxy-5-methyl-2~pyrazinyl)benzenesulphonamide
Figure imgf000028_0001
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and benzenesulphonyl chloride MP 138-139°C
Example 15 N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide
Figure imgf000028_0002
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2- iodobenzenesulphonyl chloride.
1H NMR (D6-DMSO) δ 10.75 (IH, br s), 8.05-8.15 (2H, m), 7.65-7.75 (2H, m), 7.30 (IH, dt), 3.90 (3H, s), 2.30 (3H, s). MP 140-141°C
Example 16
N-(3-Methoxy-5-methyl-2-pyrazinyl)-3-fluorobenzenesulphonamide
Figure imgf000029_0001
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 3- fluorobenzenesulphonyl chloride. MP 95-97°C
Example 17 2-[[(3-Methoxy-5-methyl-2-pyrazinyl)amino]sulphonyl]benzonitrile
Figure imgf000029_0002
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2- cyanobenzenesulphonyl chloride. m/e 305 (M+l+, 100%)
1H NMR (D6-DMSO) δ 8.15 (IH, dd), 8.05 (IH, dd), 7.85 (IH, dt), 7.80 (IH, dt), 7.60 (IH, s), 3.85 (3H, s), 2.30 (3H, s).
Example 18
N-(5-Bromo-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000029_0003
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine and benzenesulphonyl chloride m/e 344 (M+l+, 100%) Example 19 N-(5-Bromo-3-methoxy-2-pyrazinyl)2-iodobenzenesulphonamide
Figure imgf000030_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine and 2-iodobenzenesulphonyl chloride, m/e 470 (M+l+, 100%)
1H NMR (D6-DMSO) δ 11.30 (IH, br s), 8.0-8.1 (2H, m), 7.80 (IH, s), 7.60 (IH, dt), 7.30 (IH, dt), 3.95 (3H, s).
Example 20
2,3-Dichloro-N-[3-(2-furanylmethoxy)-5-ιnethyl-2-pyrazinyl]benzenesulphonamide
ethyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
Figure imgf000030_0002
Prepared by the method of Example 1 using 3-bromo-5-methyl-2-pyrazinamine (0.84g) and 2,3-dichlorobenzenesulphonyl chloride (l.lg). Yield 0.92g.
b) 2,3-Dichloro-N-[3-(2-furanylmethoxy)-5-methyl-2-pyrazinyl]benzenesulphonamide
Figure imgf000031_0001
Sodium hydride (0.04g of a 60% dispersion in oil) was added to furfurylalcohol (0.034g) in 1,2-dimethoxyethane (lmL). After 5 minutes N-(3-Bromo-5-methyl-2-pyrazinyl)-2,3- dichlorobenzenesulphonamide (Example 20 part a) (O.lg) was added and the mixture heated at 40 °C. After 16h, 5% aqueous citric acid (lOmL) was added and the mixture extracted with ethyl acetate (2x5 OmL). The combined extracts were washed with brine, dried (MgSO ) and the solvent evaporated. Chromatography on silica gel eluting with dichloromethane gave the title compound as a white solid (0.02g) m/e 412 (M-l+, 100%)
Η ΝMR (D6-DMSO) δ 11.33 (IH, br s), 8.01 (IH, d), 7.90 (IH, d), 7.70 (IH, s), 7.62 (IH, br s), 7.54 (IH, t), 6.61-6.58 (IH, m), 6.50-6.45 (IH, m), 5.33 (2H, s), 2.32 (3H, s) MP 127-129°C
Example 21 2,3-Dichloro-N-[5-methyl-3-(5-methyl-3-isoxazolylmethoxy)-2- pyrazinyljbenzenesulphonamide
Figure imgf000031_0002
Prepared by the method of Example 20 using (5-methyl-3-isoxazolyl)methanol (0.05g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (O.lg). Yield 0.05g. m/e 429 (M+l+, 100%)
Η NMR (D6-DMSO) δ 11.39 (IH, br s), 8.03 (IH, d), 7.91 (IH, d), 7.64 (IH, br s), 7.47
(IH, t), 6.33 (IH, s), 5.37 (2H, s), 2.41 (3H, s), 2.29 (3H, s)
MP 155-156°C
Example 22 2,3-Dichloro-N-[5-methyl-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000032_0001
Prepared by the method of Example 20 using pyridine-2-methanol (0.05g) and N-(3- bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (O.lg). Yield 0.07g. m e 425 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.57-8.54 (IH, m), 8.05 (IH, d), 7.89 (IH, d), 7.83 (IH, dt), 7.65- 7.50 (2H, m), 7.56 (IH, t), 7.35-7.30 (IH, m), 5.44 (2H, s), 2.26 (3H, s)
Example 23
2,3-Dichloro-N-[5-methyl-3-(6-methyl-2-pyridinylmethoxy)-2- namide
Figure imgf000032_0002
Prepared by the method of Example 20 using 6-methylpyridine-2-methanol (0.05g) and N- (3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (O.lg). Yield 0.023g. m/e 439 (M+F, 100%)
1H NMR (D6-DMSO) δ 8.05 (IH, dd), 7.89 (IH, dd), 7.70 (IH, t), 7.59 (IH, br s), 7.54
(IH, t), 7.34 (IH, d), 7.19 (IH, d), 5.39 (2H, s), 2.47 (3H, s), 2.26 (3H, s)
MP 164-165°C
Example 24
2,3-Dichloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000033_0001
Prepared by the method of Example 20 using pyridine-3-methanol (0.05g) and N-(3- bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (O.lg). Yield 0.023g. m/e 425 (M+l+, 100%)
Η ΝMR (D6-DMSO) δ 8.74 (IH, d), 8.55 (IH, dd), 8.03 (IH, dd), 7.95-7.85 (2H, m), 7.59 (IH, br s), 7.54 (IH, t), 7.42 (IH, dd), 5.41 (2H, s), 2.29 (3H, s) MP 160-161°C
Example 25 2,3-Dichloro-N-[5-methyl-3-(4-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000033_0002
Prepared by the method of Example 20 using pyridine-4-methanol (0.05g) and N-(3- bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (O.lg). Yield 0.009g. m/e 425 (M+l+, 100%)
1H MR (D6-DMSO) δ 8.57 (2H, d), 8.05 (IH, dd), 7.89 (IH, dd), 7.60 (IH, s), 7.55 (IH, t), 7.50 (2H, d), 5.43 (2H, s), 2.26 (3H, s) MP 183-184°C
Example 26
2,3-Dichloro-N-[5-methyl-3-(3-methyl-2-pyridinylmethoxy)-2- pyrazinyljbenzenesulphonamide
Figure imgf000034_0001
Prepared by the method of Example 20 using 3-methylpyridine-2-methanol (0.05g) and N- (3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobeιrzenesulphonamide (O.lg). Yield 0.021g. m/e 439 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.36 (IH, d), 8.05 (IH, dd), 7.83 (IH, dd), 7.64 (IH, d), 7.60 (IH, br s), 7.49 (IH, t), 7.31 (IH, dd), 5.40 (2H, s), 2.33 (3H, s), 2.29 (3H, s) MP 137-138°C
Example 27
2,3-Dichloro-N-[5-methyl-3-(3-pyridazinylmethoxy)-2 -pyrazinyljbenzenesulphonamide
Figure imgf000035_0001
Prepared by the method of Example 20 using pyridazine-3 -methanol (O.lg) and N-(3- bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.15g). Yield 0.038g. m/e 424 (M-l+, 100%) 1H ΝMR (D6-DMSO) δ 11.47 (lH, br s), 9.21 (IH, dd), 8.05 (IH, dd), 8.00-7.95 (IH, m), 7.88 (IH, d), 7.80-7.75 (IH, m), 7.62 (IH, br s), 7.54 (IH, t), 5.65 (2H, s), 2.27 (3H, s) MP 119-124°C
Example 28 2,3-Dichloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000035_0002
2,3-Dichloropyrazine (2.6g), 2,3-dichlorobenzenesulphonamide (4.0g) and potassium carbonate (lO.Og) in NN-dimethylformamide (50mL) was heated at 75°C. After 16h, 5% aqueous citric acid (30mL) was added and the mixture extracted with ethyl acetate (2xl00mL). The combined extracts were washed with brine, dried (MgSO4) and the solvent evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound (1.5g).
b) 2,3-Dichloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000036_0001
Sodium hydride (0.05g of a 60% dispersion in oil) was added to pyridine-2-methanol (0.088g) in 1,2-dimethoxyethane (3.0mL). After 5 minutes, 2,3-dichloro-N-(3-chloro-2- pyrazinyl)benzenesulphonamide (O.lg) was added and the mixture heated at 70°C. After 4h, 5% aqueous citric acid (lOmL) was added and the mixture extracted with ethyl acetate (2x50mL). The combined extracts were washed with brine, dried (MgSO ) and the solvent evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.06g). m e 411 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.57 (IH, d), 8.13 (IH, d), 7.93 (IH, d), 7.90-7.75 (2H, m), 7.75- 7.65 (IH, m), 7.65-7.55 (2H, m), 7.40-7.30 (IH, m), 5.49 (2H, s) MP 167-168°C
Example 29 2,3-Dichloro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000036_0002
Prepared by the method of Example 28 using pyridine-3 -methanol (0.09g) and 2,3- dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (O.lg). Yield 0.042g. m/e 409 (M-l+, 100%) 1H NMR (CDCI3) δ 8.70 (IH, s), 8.65 (IH, d), 8.28 (IH, dd), 7.79 (IH, d), 7.70-7.67 (2H, m), 7.61 (IH, d), 7.40-7.35 (2H, m), 5.45 (2H, s) MP 138-139°C
Example 30 -methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000037_0001
2,3-Dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28 part a) (0.2g) in 10% sodium methoxide in methanol (lOmL) was heated at 85°C. After 4h, 5% aqueous citric acid (50mL) was added and the mixture extracted with ethyl acetate (2xl50mL). The combined extracts were washed with brine, dried (MgSO4) and the solvent evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.12g) m/e 334 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 11.54 (IH, br s), 8.10 (IH, d), 7.94 (IH, d), 7.85-7.75 (IH, m), 7.70-7.55 (IH, m), 7.59 (IH, t), 3.90 (3H, s) MP 183-184°C
Example 31 N-[5-Bromo-3-(2-pyrazinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000037_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 3,5- dibromo-2-pyrazinamine (2.9g) and 2,3-dichloro benzenesulphonyl chloride (2.8g). Yield
4.4g. b) N-[5-Bromo-3-(2-pyrazinyhnethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000038_0001
Sodium hydride (0.05g of a 60% dispersion in oil) was added to pyrazine-2 -methanol
(0.04g) in 1 ,2-dimethoxyethane (3ml). After 5 minutes, 2,3-Dichloro-N-(3,5-dibromo-2- pyrazinyl)benzenesulphonamide
(0.12g) was added. After 0.5h, 5% aqueous citric acid (lOmL) was added and the mixture extracted with ethyl acetate (2x3 OmL). The combined extracts were washed with brine, dried (MgSO4) and the solvent evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.06g). m/e 489 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 9.00 (IH, s), 8.66 (2H, s), 8.08 (IH, dd), 7.92 (IH, dd), 7.91 (IH, s), 7.56 (IH, t), 5.53 (2H, s)
MP 207-209°C
Example 32
N-[5-Bromo-3-(l-methyl-6-oxo-l,6-dihydro-3-pyridinylmethoxy)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
Figure imgf000039_0001
Prepared by the method of Example 31 using 5 -hydroxymethyl-1 -methyl- lH-pyridin-2-one
(O.lg) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (0.16g). Yield
0.035g. m/e 521 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.04 (IH, dd), 7.91 (IH, dd), 7.90-7.87 (2H, m), 7.60-7.50 (2H, m), 6.42 (IH, d), 5.10 (2H, s), 3.41 (3H, s)
MP 169-170°C
Example 33
N-[5-Bromo-3-(3-pyridazinyllmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000039_0002
Prepared by the method of Example 31 using pyridazine-3 -methanol (0.07g) and 2,3- dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulρhonamide (0.15g). Yield 0.06g. m/e 489 (M-l+, 100%) 1H NMR (D6-DMSO) δ 9.23 (IH, d), 8.08 (IH, dd), 7.99 (IH, dd), 7.92 (IH, dd), 7.91
(IH, s), 7.80 (IH, dd), 7.56 (IH, t), 5.67 (2H, s)
MP 115-120°C
Example 34
N-[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000040_0001
Prepared by the method of Example 31 using pyridine-3 -methanol (0.44g) and 2,3- dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (l.Og). Yield 0.6g. m/e 491 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.78 (IH, d), 8.58 (IH, dd), 8.06 (IH, d), 7.99 (IH, dt), 7.91 (IH, d), 7.88 (IH, s), 7.55 (IH, t), 7.55-7.50 (IH, m), 5.44 (2H, s) MP 204-206°C
Example 35
N-[5-Bromo-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000040_0002
Prepared by the method of Example 31 using pyrimidine-5 -methanol (0.035g) and 2,3- dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (0.16g). Yield 0.028g. m/e 490 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 9.21 (IH, s), 9.02 (2H, s), 8.07 (IH, dd), 7.92 (IH, dd), 7.91 (IH, s), 7.56 (IH, t), 5.45 (2H, s)
MP 208-209°C
Example 36
N-[5-Chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000041_0001
Prepared by the method of Example 31 using pyridine-3-methanol (0.13g) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.3g). Yield
0.19g. m/e 447 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.78 (IH, s), 8.59 (IH, dd), 8.06 (IH, dd), 7.96 (IH, dt), 7.91
(IH, dd), 7.83 (IH, s), 7.55 (IH, t), 7.47 (IH, dd), 5.44 (2H, s)
MP 200-204°C
Example 37
N-[5-Chloro-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000042_0001
Prepared by the method of Example 31 using pyrimidine-5 -methanol (0.035g) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.07g). Yield
0.015g. m/e 448 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 9.21 (IH, s), 9.02 (2H, s), 8.08 (IH, dd), 7.92 (IH, dd), 7.86 (IH, s), 7.56 (lH, t), 5.46 (2H, s)
MP 205-206°C
Example 38
2-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide
Figure imgf000042_0002
Prepared by the method of Example 1 (reaction performed at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (O.lg) and 2-chlorobenzenesulphonyl chloride (0.13g). Yield 0.1 lg. m/e 332 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.15 (IH, d), 7.86 (IH, s), 7.70-7.50 (3H, m), 3.91 (3H, s)
MP 172-173°C
Example 39
3-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide
Figure imgf000043_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (O.lg) and 3-chlorobenzenesulphonyl chloride (0.13g).
Yield 0.14g. m e 332 (M-l+, 100%)
1H NMR (D6-DMSO) δ 8.05 (IH, d), 7.93 (IH, dd), 7.90 (IH, s), 7.76 (IH, dd), 7.65 (IH, t) 3.92 (3H, s)
MP 126-127°C
Example 40
4-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide
Figure imgf000043_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (O.lg) and 4-chlorobenzenesulphonyl chloride (0.13g).
Yield 0.13g. m/e 332 (M-l+, 100%)
1H NMR (D6-DMSO) δ 7.99 (2H, dt), 7.89 (IH, s), 7.70 (2H, dt), 3.92 (3H, s)
MP 174-175°C
Example 41 N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenezenesulphonamide
Figure imgf000044_0001
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (0.05g) and 2,4-dichlorobenzenesulphonyl chloride
(O.lg). Yield 0.07g. m/e 368 (M-l+, 100%)
1H NMR (D6-DMSO) δ 8.13 (IH, d), 7.86 (IH, s), 7.85 (IH, d), 7.70 (IH, dd), 3.91 (3H, s)
MP 189-190°C
Example 42
N-(6-Chloro-3-methoxy-2-pyrazinyl)-3,4-dichlorobenezenesulphonamide
Figure imgf000044_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 6- chloro-3-methoxy-2-pyrazinamine (0.05g) and 3,4-dichlorobenzenesulphonyl chloride
(0.09g). Yield 0.08g. m e 368 (M-l+, 100%)
1H NMR (D6-DMSO) δ 8.21 (IH, s), 7.93-7.90 (3H, m), 3.92 (3H, s)
MP 176-177°C Example 43
3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-methylbenezenesulphonaιnide
Figure imgf000045_0001
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine (O.lg) and 3-chloro-2-methylbenzenesulρhonyl chloride (0.19g). Yield 0.08g. m/e 328 (M+l+, 100%) 1H NMR (D6-DMSO) δ 11.09 (IH, br s), 7.95 (IH, d), 7.72 (IH, d), 7.54 (IH, br s), 7.41 (IH, t), 3.88 (3H, s), 2.64 (3H, s), 2.27 (3H, s) MP 133-135°C
Example 44 2-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide
Figure imgf000045_0002
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine (O.lg) and 2-chlorobenzenesulphonyl chloride (0.15g). Yield 0.06g. m/e 314 (M+l+, 100%) 1H NMR (D6-DMSO) δ 11.07 (IH, br s), 8.06 (IH, d), 7.69-7.46 (4H, m), 3.90 (3H, s), 2.24 (3H, s)
Example 45 3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide
Figure imgf000046_0001
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine (O.lg) and 3-chlorobenzenesulphonyl chloride (0.18g). Yield 0.042g. m/e 314 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 10.89 (IH, br s), 7.97 (IH, d), 7.92 (IH, d), 7.73 (IH, d), 7.65- 7.58 (2H, m), 3.90 (3H, s), 2.29 (3H, s) MP 123-125°C
Example 46
4-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide
Figure imgf000046_0002
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine (O.lg) and 4-chlorobenzenesulphonyl chloride (0.18g). Yield 0.06g. m/e 314 (M+l+, 100%)
1H NMR (D6-DMSO) δ 10.83 (IH, br s), 7.96 (2H, d), 7.65 (2H, d), 7.60 (IH, s), 3.88
(3H, s), 2.28 (3H, s) MP 155-156°C
Example 47
2,4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide
Figure imgf000047_0001
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine (O.lg) and 2,4-dichlorobenzenesulphonyl chloride (0.2 lg). Yield 0.04 lg. m e 348 (M+l+, 100%)
1H NMR (D6-DMSO) δ 8.05 (IH, d), 7.83 (IH, d), 7.64 (IH, dd), 7.54 (IH, br s), 3.87
(3H, s), 2.27 (3H, s)
MP 135-136°C
Example 48 3,4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide
Figure imgf000047_0002
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine (O.lg) and 3,4-dichlorobenzenesulphonyl chloride (0.2 lg). Yield 0.046g. m/e 348 (M+l+, 100%)
1H NMR (D6-DMSO) δ 10.97 (IH, s), 8.14 (IH, d), 7.91 (IH, dd), 7.88 (IH, d), 7.63 (IH, s), 3.89 (3H, s), 2.27 (3H, s) MP 148-149°C
Example 49
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2-trifluoromethoxybenezenesulphonamide
Figure imgf000048_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (O.lg) and 2-trifluoromethoxybenzenesulphonyl chloride (0.13g). Yield 0.097g m/e 428 (M-l+, 100%)
1H NMR (D6-DMSO) δ 8.03 (IH, dd), 7.87 (IH, s), 7.82-7.74 (IH, m), 7.60-7.52 (2H, m), 3.92 (3H, s) MP 156-157°C -
Example 50
3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide
Figure imgf000048_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (O.lg) and 3-chloro-2-methylbenzenesulphonyl chloride (0.15g). Yield 0.085g. m/e 346 (M-l+, 100%) 1H NMR (CDCI3) δ 8.17 (IH, d), 7.69 (IH, br s), 7.64 (IH, s), 7.61 (2H, d), 7.30 (IH, t), 4.04 (3H, s), 2.73 (3H, s) MP 150-152°C
Example 51
2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000049_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (O.lg) and 2-chlorobenzenesulphonyl chloride (0.13g).
Yield 0.082g. m/e 332 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.33 (IH, d), 7.82 (IH, s), 7.64-7.62 (IH, m), 7.61 (IH, s), 7.50-7.42
(2H, m), 4.04 (3H, s) MP 190-192°C
Example 52
3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000049_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (O.lg) and 3-chlorobenzenesulphonyl chloride (0.13g). Yield 0.095g. m/e 332 (M+l+, 100%) 1H NMR (CDC13) δ 8.14 (IH, s), 8.03 (IH, d), 7.76 (IH, s), 7.68-7.53 (2H, m), 7.46 (IH, t), 4.02 (3H, s) MP 129-130°C
Example 53 4-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000050_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (O.lg) and 4-chlorobenzenesulphonyl chloride (0.13g).
Yield 0.05g. m/e 332 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.07 (2H, d), 7.75 (IH, s), 7.56 (IH, s), 7.49 (2H, d), 4.02 (3H, s)
MP 179-180°C
Example 54
N-(5-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide
Figure imgf000051_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (O.lg) and 2,4-dichlorobenzenesulphonyl chloride (0.13g). Yield 0.045g. m/e 368 (M-l+, 100%)
1H NMR (CDC13) δ 8.27 (IH, d), 7.78 (IH, s), 7.63 (IH, s), 7.48 (IH, s), 7.43 (IH, d), 4.05
(3H, s)
MP 170-171°C
Example 55
2,3-Dichloro-N-[3-methoxy-5-(4-morpholinyl)-2-pyrazinyl]benzenesulphonamide
a) N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- {[2-
(trimethylsilanyl)ethoxy]methyl}benzenesulphonamide
Figure imgf000051_0002
A mixture of N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 8) (0.40g), diisopropylethyla ine (0.26g) and [2-
(chloromethoxy)ethyl]trimethylsilane (0.25g) in dichloromethane (50mL) was stirred at room temperature. After 2h, the solution was washed with water, dried (MgSO ) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.40g). 1H NMR (CDCI3) δ 8.09 (IH, s), 7.96 (IH, dd), 7.68 (IH, dd), 7.29 (IH, t), 5.24 (2H, s), 3.92 (3H, s), 3.77-3.73 (2H, m), 0.86-0.82 (2H, m), 0.00 (9H, s)
b) 2,3-Dichloro-N-[3-methoxy-5-(4-morpholinyl)-2-pyrazinyl]benzenesulphonamide
Figure imgf000052_0001
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2- (trimethylsilanyl)ethoxy}methyl]benzenesulphonamide
(0.3 Og) and morpholine (0.45 g) in acetonitrile (lOmL) was heated at 50°C. After 16h, the solution was evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound with SEM group attached, as a white solid. The solid was dissolved in trifluoroacetic acid (5. OmL) and dichloromethane (5. OmL). After 2h, the solution was evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.06g). m e 417 (M-l+, 100%)
1H ΝMR (CDCI3) δ 8.17 (IH, d), 7.65 (IH, d), 7.41 (IH, s), 7.34 (IH, t), 7.16 (IH, s), 3.89 (3H, s), 3.80-3.75 (4H, m), 3.40-3.35 (4H, m) MP 167-168°C
Example 56
2,3-Dichloro-N-[3,5-dimethoxy-2-pyrazinyl]benzenesulphonamide
Figure imgf000053_0001
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-
(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.30g) in methanolic sodium methoxide (lOmL of 0.5 molar solution) was strirred at room temperature. After 16h, the solution was evaporated to dryness and dichloromethane (lOmL) and trifluoroacetic acid (lOmL) added. After 2h, the mixture was evaporated to dryness, dichloromethane added and the inorganic salts removed by filtration. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (O.lg). m/e 364 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.21 (IH, d), 7.67 (IH, d), 7.50 (IH, s), 7,37 (IH, t), 7.26 (IH, s), 3.98 (3H, s), 3.87 (3H, s) MP 138-139°C
Example 57 2,3 -Dichloro-N-[3 -methoxy-5 -( 1 -pyπolinyl)-2-pyrazinyl]benzenesulphonamide
Figure imgf000053_0002
Prepared by the method of Example 55 using pyrrolidine (0.4g) and N-(5-bromo-3- methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-
(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.3g). Yield 0.045g. m/e 403 (M+l+, 100%) 1H NMR (CDCI3) δ 8.08 (IH, d), 7.64 (IH, d), 7.30 (IH, t), 7.21 (IH, s), 6.99 (IH, s), 3.81 (3H, s), 3.40-3.35 (4H, m), 2.00-1.95 (4H, m) MP 179-180°C
Example 58
3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide
Figure imgf000054_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6- dichloro-3-methoxy-2-pyrazinamine (O.lg) and 3-chloro-2-methylbenzenesulphonyl chloride (0.14g). Yield 0.13g. m/e 381 (M-l+, 100%)
1H MR (CDC13) δ 8.25 (IH, d), 7.65 (IH, br s), 7.62 (IH, d), 7.35 (IH, t), 4.04 (3H, s),
2.73 (3H, s)
MP 177-178°C
Example 59
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000054_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5,6- dichloro-3-methoxy-2-pyrazinamine (O.lg) and 2,3-dichlorobenzenesulphonyl chloride (0.15g). Yield 0.12g. m/e 402 (M-l+, 100%)
Η NMR (CDC13) δ 8.31 (IH, d), 7.81 (IH, br s), 7.72 (IH, d), 7.45 (IH, t), 4.05 (3H, s)
MP 172-173°C
Example 60
2-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000055_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6- dichloro-3-methoxy-2-pyrazinamine (0.1 gO and 2-chlorobenzenesulphonyl chloride
(0.13g). Yield 0.096g. m/e 367 (M-l+, 100%)
1H ΝMR (CDC13) δ 8.39 (IH, d), 7.79 (IH, br s), 7.58-7.45 (3H, m), 4.04 (3H, s)
MP 217-218°C
Example 61
3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000055_0002
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6- dichloro-3-methoxy-2-pyrazinamine (O.lg) and 3-chlorobenzenesulphonyl chloride (0.13g). Yield 0.047g. m e 367 (M-l+, 100%) 1H NMR (CDCI3) δ 8.19 (IH, s), 8.07 (IH, d), 7.61 (IH, d), 7.59 (IH, br s), 7.50 (IH, t), 4.02 (3H, s) MP 171-172°C
Example 62
4-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000056_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6- dichloro-3-methoxy-2-pyrazinamine (O.lg) and 4-chlorobenzenesulphonyl chloride
(0.13g). Yield 0.09g. m/e 367 (M-l+, 100%)
1H ΝMR (CDCI3) δ 8.11 (2H, d), 7.57 (IH, br s), 7.50 (2H, d), 4.02 (3H, s)
MP 186-187°C
Example 63
2,4-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000056_0002
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6- dichloro-3-methoxy-2-pyrazinamine (O.lg) and 2,4-dichlorobenzenesulphonyl chloride (0.15g). Yield 0.076g. m/e 402 (M-l+, 100%)
1H NMR (CDC13) δ 8.30 (IH, d), 7.76 (IH, br s), 7.50 (IH, s), 7.48 (IH, d), 4.05 (3H, s)
MP 171-172°C
Example 64
3,4-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000057_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6- dichloro-3-methoxy-2-pyrazinamine (O.lg) and 3,4-dichlorobenzenesulphonyl chloride
(0.15g). Yield 0.1 lg. m/e 402 (M-l+, 100%)
1H ΝMR (CDC13) δ 8.30 (IH, s), 8.01 (IH, d), 7.63 (IH, d), 7.58 (IH, br s), 4.03 (3H, s)
MP 189-191°C
Example 65
2,3-Dichloro-N-(3-ιnethoxy-5,6-dimethyl-2-pyrazinyl)benzenesulphonamide
Figure imgf000057_0002
Prepared by the method of Example 1 using 3-methoxy-5,6-dimethyl-2-pyrazinamine (0.07g) and 2,3-dichlorobenzenesulphonyl chloride (0.12g). Yield 0.04g. m/e 360 (M-l+, 100%) Η NMR (CDCI3) δ 8.32 (IH, d), 7.67 (IH, s), 7.65 (IH, d), 7.39 (IH, t), 3.95 (3H, s), 2.28 (3H, s), 2.14 (3H, s) MP 165-166°C
Example 66
2,3-Dichloro-N-(6-chloro-3,5-dimethoxy-2-pyrazinyl)benzenesulphonamide
a) 2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N- {[2- enzenesulphonamide
Figure imgf000058_0001
To a stirred solution of 2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2- pyrazinyl)benzenesulphonamide (0.68g) in dichloromethane (20mL) was added triethylamine (0.49 ImL) followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.328g) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (50mL) and extracted into ethyl acetate (3x20mL). The combined extracts were dried (MgSO ), filtered and concentrated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the sub-title compound as a white solid (0.74g). Η ΝMR (CDCI3) δ 8.02 (IH, dd), 7.70 (IH, dd), 7.34 (IH, t), 5.22 (2H, s), 3.96 (3H, s), 3.73 (2H, dd), 0.91-0.79 (2H, m), -0.03 (9H, s)
b) 2,3-Dichloro-N-(6-chloro-3,5-dimethoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000059_0001
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.1 Og) was dissolved in methanol (1.OmL) and a solution of sodium methoxide in methanol (O.lmL of a 25% solution in methanol) was added. The reaction was stined at room temperature for 30 min and was concentrated. The residue was dissolved in trifluoroacetic acid (2. OmL) and was stirred at room temperature for 30 min. The reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.028g). m e 397 (M-l+, 100%)
1H ΝMR (CDC13) δ 8.26 (IH, d), 7.69 (IH, d), 7.41 (IH, t), 7.41 (IH, br s), 4.02 (3H, s),
3.91 (3H, s)
MP 163-165°C
Example 67
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(4-morpholinyl)-2- pyrazinyl]benzenesulphonamide
Figure imgf000059_0002
2,3-Dichloro-Ν-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.10 g) was dissolved in THF (l.OmL) and a solution of morpholine (0.05g) in THF (O.lmL) was added. The reaction was stirred at room temperature for 30 min and was concentrated. The residue was dissolved in trifluoroacetic acid (2. OmL) and dichloromethane (2. OmL) and was stirred at room temperature for 30 min. The reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.042g). m/e 452 (M-l+, 100%)
1H NMR (CDC13) δ 8.28 (IH, dd), 7.69 (IH, dd), 7.49 (IH, br s), 7.43 (IH, t), 3.96 (3H, s), 3.79 (4H, dd), 3.28 (4H, dd) MP 150-151°C
Example 68
2,3-Dichloro-N-[6-chloro-5-(2-hydroxyethylamino)-3-methoxy-2- pyrazinyljbenzenesulphonamide
Figure imgf000060_0001
Prepared by the method of Example 67 using 2-aminoethanol (0.05g) and 2,3-dichloro-N- (5 ,6-dichloro-3 -methoxy-2-pyrazinyl)-N- { [2-
(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (O.lg). Yield 0.015g. m/e 426 (M-l+, 100%) lH ΝMR (D6-DMSO) δ 10.31 (IH, s), 7.91 (2H, dd), 7.52 (IH, t), 6.89 (IH, br s), 4.71 (IH, t), 3.63 (3H, s), 3.53 (2H, dd), 3.40 (2H, dd)
Example 69
2,3-Dichloro-N-[6-chloro-5-dimethylamino-3-methoxy-2-pyrazinyl]benzenesulphonamide
Figure imgf000061_0001
Prepared by the method of Example 67 using dimethylamine (5mL of a 2M solution in tetrahydrofuran) and 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N- {[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide (O.lg). Yield 0.015g. m/e 410 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 7.99-7.93 (2H, m), 7.56 (IH, t), 3.74 (3H, s), 2.99 (6H, s) MP 145-146°C
Example 70 2,3-Dichloro-N-[6-chloro-3-methoxy-5-(2-methoxyethoxy)-2- pyrazinyl]benzenesulphonamide
Figure imgf000061_0002
Sodium hydride (0.019g of 60% dispersion in oil) was added to a solution of 2,3-dichloro- N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N- {[2-
(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.25g) in 2-methoxyethanol (3.0mL) at room temperature. After 16h, the solvent was evaporated and trifluoroacetic acid (2. OmL) added. After lh, the reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.08g). m/e 442 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.24 (IH, dd), 7.70 (IH, dd), 7.41 (IH, t), 4.50-4.40 (2H, m), 3.96
(3H, s), 3.80-3.70 (2H, m), 3.42 (3H, s)
MP 193-194°C Example 71
2,3-Dichloro-N-[6-chloro-5-hydroxy-3-methoxy-2-pyrazinyl]benzenesulphonamide
Figure imgf000062_0001
tetrabutylam onium hydroxide (0.28g of 40% aqueous solution) was added to a solution of 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulfonamide (0.25g) in 1,2-dimethoxyethane (3. OmL) at room temperature. After 16h, the solution was diluted with ethyl acetate (20mL). The organic solution was washed with aqueous citric acid (lOmL) and brine, dried (MgSO ) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound containing the SEM group, as a white solid (0.08g). The solid was dissolved in trifluroacetic acid (2.0mL) and dichloromethane (2.0mL) and stined at room temperature for lh. The reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.027g). m/e 384 (M+l+, 100%) Η ΝMR (CDC13) δ 12.56 (IH, s), 10.87 (IH, s), 7.96 (2H, t), 7.56 (IH, t), 3.74 (3H, s)
Example 72
2,3-Dichloro-N-[6-methoxy-5-([2,2']bipyrazinylyl)]benzenesulphonamide
Figure imgf000062_0002
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-
(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55 part a) (0.70g), tetra is(triphenylphosphine)palladium(0) (O.lg) and 2-(tributylstannanyl)pyrazine (0.50g) in toluene (20mL) was heated under nitrogen at 100°C. After 16h, chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound protected with the SEM group as a white solid. The solid was dissolved in trifluoroacetic acid (2. OmL) and dichloromethane (2. OmL) and stirred at room temperature for lh. The reaction mixture was concentrated, toluene added and evaporated. The title compound crystallised from acetonitrile to give a white solid (0.38g). m/e 410 (M-l+, 100%)
1H ΝMR (D6 DMSO) δ 9.35 (IH, s), 8.69 (IH, d), 8.67 (IH, d), 8.40 (IH, br s), 8.14 (IH, d), 7.96 (IH, d), 7.61 (IH, t), 4.07 (3H, s) MP 199-200°C
Example 73
4-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyloxy]benzoic acid
Figure imgf000063_0001
4-Hydroxybenzoic acid tert butyl ester (0.13g), N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3- dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55 part a) (0.35g) and caesium carbonate (0.42g) in acetonitrile (lOmL) was heated at 50°C. After 12h, the mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound protected with the SEM group and te7-t butyl group as an oil. The oil was dissolved in trifluoroacetic acid (2. OmL) and stirred at room temperature for 3h. The reaction mixture was concentrated, toluene added and evaporated to give the title compound as a white solid (0.19g). m/e 468 (M-l+, 100%) Η NMR (CDCI3) δ 8.28 (IH, d), 8.11 (2H, d), 7.80 (IH, br s), 7.71 (IH, d), 7.45 (2H, m), 7.12 (2H, d), 3.89 (3H, s) MP 186-187°C
Example 74
2,3-Dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
Figure imgf000064_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 3,5- dichloro-2-pyrazinamine (2.0g) and 2,3-dichloro benzenesulphonyl chloride (2.94g). Yield
3.0g. m/e 372 (M-l+, 100%)
1H ΝMR (D6 DMSO) δ 8.29 (IH, s), 8.06 (IH, dd), 7.94 (IH, dd), 7.57 (IH, t) MP 181-182°C
Example 75
2,3-Dichloro-N-{6-chloro-3-methoxy-5-([2-methoxyethyl)amino]-2- pyrazinyl } benzenesulphonamide
Figure imgf000064_0002
Prepared by the method of Example 67 using 2-methoxyethylamine (3mL) and 2,3- dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulphonamide (0.24g). Yield 0.08g. m/e 439 (M+l+, 100%)
1H NMR (D6-DMSO) δ 10.33 (IH, s), 7.92 (2H, dd), 7.52 (IH, t), 7.00 (IH, s), 3.64 (3H, s), 3.47 (4H, s), 3.24 (2H, dd)
MP 177-178°C
Example 76
N-{2-[3-Chloro-5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-2- pyrazinylamino] ethyl } acetamide
Figure imgf000065_0001
2,3-Dichloro-Ν-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.26g) was dissolved in acetonitrile ( OmL) and N-acetylethylenediamine (0.055mL) and triethylamine (0.19mL) added. After 48h, the reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate gave the title compound protected with the SEM group, as an oil (0.13g). The oil was dissolved in dichloromethane (2. OmL) and boron trifluoride etherate (0.14ml) added. After 2h, ethyl acetate (2 OmL) was added and the mixture washed with 5% aqueous citric acid (5mL), dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate gave the title compound as a solid (0.03 lg). m e 470 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 10.32 (IH, s), 7.93-7.88 (2H, m), 7.52 (IH, t), 7.10 (IH, s), 3.65 (3H, s), 3.40-3.10 (4H, m), 1.75 (3H, s) MP 150-152°C
Example 77
2,3-Dichloro-N-[5-(4-hydroxymethyl-l-piρeridinyl)-3-methoxy-2- pyrazinyljbenzenesulphonamide
Figure imgf000066_0001
Prepared by the method of Example 55 using 4-(hydroxymethyl)piperidine (0.4g) and N- (5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2- (trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.3g). Yield 0.012g. m/e 447 (M+l+, 100%)
1H ΝMR (CDC13) δS.14 (IH, dd), 7.65 (IH, dd), 7.33 (IH, t), 7.20 (IH, s), 4.20 -4.10 (2H, m), 3.86 (3H, s), 3.60-3.50 (2H, m), 2.90-2.70 ( 2H, m), 1.90-1.70 (3H ,m), 1.40-1.20 (3H, m)
Example 78
2,3-Dichloro-N-[5-cyano-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000066_0002
N-[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide (Example 34) (0.15g), tetrakis(triphenylphosphine)palladium(0) (0.04g) and zinc cyanide (0.03g) in NN-dimethylfonnamide (5. OmL) was heated at 70°C. After 5h, the mixture was diluted with ethyl acetate (30mL) and washed with 5% aqueous citric acid (5mL), dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures containing 1% acetic acid gave the title compound as a white solid (0.058g). m/e 436 (M+l+, 100%) 1H NMR (D6 DMSO) δS.70 -7.65 (2H, m), 8.29 (IH, dd), 7.99 (IH, s), 7.78 (IH, d), 7.73 (IH, dd), 7.46 (IH, t), 7.40-7.35 (IH, m), 5.45 (2H, s) MP 222-224°C
Example 79
2,3-Dichloro-N-(6-chloro-3-methoxy-5-methylamino-2-pyrazinyl)benzenesulphonamide
Figure imgf000067_0001
3-Dichloro-Ν-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulphonaιnide (Example 66 part a) (0.25 g) was dissolved in methanol (1.OmL) and methylamine (2. OmL of 40% aqueous solution) was added. After 16h, the solution was partitioned between water and ethyl acetate. The organic layer was dried (MgSO ) and evaporated. The residue was dissolved in dichloromethane (2.0 mL) and boron trifluoride etherate (0.25mL) added. After lh, ethyl acetate (20mL) was added and the solution washed with 5% aqueous citric acid (5mL), dried (MgSO ) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.05g). m/e 395 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 10.27 (IH, s), 7.95-7.87 (2H, m), 7.51 (IH, dd), 7.10-7.00 (IH, m), 3.64 (3H, s), 2.84 (3H, s) MP 185-186°C
Example 80
2,3-Dichloro-N-(3-methoxy-5-methylsulphanyl-2-pyrazinyl)benzenesulphonamide
Figure imgf000068_0001
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2- (trimethylsilanyl)ethoxy]methyl}benzenesulphonamide
(0.30g) and sodium thiomethoxide (0.05g) in acetonitrile (lOmL) was stirred at room temperature. After 2h, the solution was evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound with SEM group attached. The compound was dissolved in trifluoroacetic acid (5mL). After 2h, toluene (20mL) was added and the solution evaporated, . Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.16g). m/e 380 (M+l+, 100%)
1H ΝMR (CDC13) δS.25 (IH, d), 7.70 (IH, s), 7.68 (IH, d), 7.52 (IH, s), 7.39 (IH, t), 4.03 (3H, s), 2.48 (3H, s) MP 141-142°C
Example 81
2,3-Dichloro-N-[5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide
a) 5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinamine
Figure imgf000068_0002
5-Bromo-3-methoxy-2-pyrazinamine (0.3g), cesium fluoride (0.8g), 2,4- difluorobenezeneboronic acid (0.4g) and [l, -bis(diphenylphosphino)ferrocene]palladium (II) chloride (0.04g) in methanol (20mL) was heated at 70°C . After 6h, the solvent was evaporated and the residue purified by chromatography on silica eluting with ethyl acetate/isohexane mixtures to give the sub-title compound (0.2g). b) 2,3-Dichloro-N-[5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide
Figure imgf000069_0001
Prepared by the method of Example 1 using 5-(2,4-difluorophenyl)-3-methoxy-2- pyrazinamine (0.2g) and 2,3-dichlorobenzenesulphonyl chloride (0.2g). Yield 0.06g. m/e 444 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ8.15 (IH, d), 8.05 -7.95 (2H, m), 7.93 (IH, d), 7.60 (IH, t), 7.45-
7.35 (IH, m), 7.30-7.20 (IH, m), 4.03 (3H, s)
MP 169-170°C
Example 82
[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid methyl ester
Figure imgf000069_0002
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-
(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide
(0.40g), mercapto acetic acid methyl ester (O.lg) and caesium carbonate (0.6g) in acetonitrile (lOmL) was stirred at room temperature. After 16h, the solution was diluted with dichloromethane, filtered and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound with SEM group attached. The compound was dissolved in trifluoroacetic acid (5mL). After 2h, toluene (20mL) was added and the solution evaporated, . Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.15g). m/e 438 (M+l+, 100%)
1H NMR (CDC13) δS.26 (IH, dd), 7.73 (IH, s), 7 .68 (IH, dd), 7.59 (IH, s), 7.41 (IH, t),
3.99 (3H, s), 3.80 (2H, s), 3.71 (3H, s)
MP 152-153°C
Example 83
[5-(2,3-Dichlorobenzenesulρhonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid
Figure imgf000070_0001
[5-(2,3-Dichlorobenzenesulρhonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid methyl ester (Example 82) (O.lg) and lithium hydroxide (0.04g) in methanol (5mL) and water (ImL) was stined at room temperature. After 2h, the mixture was evaporated and saturated aqueous citric acid (5mL) added. The white solid was collected, washed with water and dried. Yield 0.07g. m e 424 (M+l+, 100%)
1H NMR (CDCI3) 58.27 (IH, dd), 7.90 (IH, br s), 7.70 (IH, dd), 7.61 (IH, s), 7.40 (IH, t), 3.98 (3H, s), 3.80 (2H, s) MP 138-140°C
Example 84
2,3-Dichloro-N-[5-(2-chlorobenzylsulphanyl)-3-methoxy-2- pyrazinyljbenzenesulphonamide
Figure imgf000071_0001
Prepared by the method of Example 82 using 2-chlorobenzylmercaptan (0.15g) and N-(5- bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-
(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.4g). Yield 0.18g. m e 492 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.26 (IH, dd), 7.73 (IH, s), 7.69 (IH, dd), 7.53 (IH, s), 7.40-7.30 (3H, m), 7.20-7.10 (2H, m), 4.39 (2H, s), 4.02 (3H, s)
MP 119-120°C
Example 85
2,3-Dichloro-N-[6-chloro-5-(3-hydroxy-l-azetidinyl)-3-methoxy-2- pyrazinyl]benzenesulphonamide
Figure imgf000071_0002
2,3 -Dichloro-Ν-(5,6-dichloro-3 -methoxy-2-pyrazinyl)-N- { [2- (trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.20 g), azetidin-3-ol hydrochloride (0.082g) and triethylamine (0.25mL) in acetonitrile (3mL) and water (0.5mL) was stirred at room temperature. After 2h, the mixture was evaporated and triturated with diethyl ether. The ethereal solution was evaporated and the residue dissolved in a 1 molar solution of tetrabutylaimnonium fluoride in THF (6mL). After 16h, the reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate/isohexane mixtures gave the title compound as a white solid (0.024g). m/e 442 (M+l+, 100%)
1H NMR (D6-DMSO) δ 10.58 (IH, s), 7.92 (2H, d), 7.54 (IH, t), 5.66 (IH, s), 4.49 (IH, s), 4.36 (2H, t), 3.88 (2H, m), 3.67 (3H, s) MP 93-95°C
Example 86
2,3-Dichloro-N-[5-methyl-3-(l-oxy-3-pyrazinylmethoxy)-2- pyrazinyl]benzenesulphonamide
Figure imgf000072_0001
2,3-Dichloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl)benzenesulphonamide
(Example 24) (0.2g) and 3-chloroperbenzoic acid (0.35g) in dichloromethane (4mL) was stirred at room temperature. After 0.5h, chromatography on silica gel eluting with 5% methanol in ethyl acetate containing 1 % acetic acid gave the title compound as a white solid (0.16g). m/e 441 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 11.56 (IH, br s), 8.60 (IH, br s), 8.18 (IH, dt), 8.06 (IH, dd), 7.90 (IH, dd), 7.61 (IH, br s), 7.56 (IH, t), 7.50-7.40 (2H, m), 5.36 (2H, s), 2.28 (3H, s)
MP 223-228°C
Example 87 2,3-DichIoro-N-[5-chloro-3-(4-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000073_0001
Prepared by the method of Example 3 lb using pyridine-4-methanol (0.4g) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.4g). Yield 0.47g. m/e 445 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.63 (2H, d), 8.08 (IH, dd), 7.91 (IH, dd), 7.83 (IH, s), 7.60 (2H, d), 7.55 (IH, t), 5.47 (2H, s) MP 226-229°C decomposes
Example 88
2,3-Dichloro-N-[5-chloro-3-(l-oxy-4-pyridinylmethoxy)-2- amide
Figure imgf000073_0002
Prepared by the method of Example 86 using 2,3-dichloro-N-[5-chloro-3-(4- ρyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 87) (O.lg). Yield 0.4g. m/e 462 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.27 (2H, dt), 8.07 (IH, dd), 7.92 (IH, dd), 7.85 (IH, s), 7.60 (2H, d), 7.57 (IH, t), 5.38 (2H, s) MP 208-211°C decomposes
Example 89 2,3-Dichloro-N-[5-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]
Figure imgf000074_0001
Prepared by the method of Example 3 lb using pyridine-2 -methanol (0.2g) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.2g). Yield
O.lg. m/e 445 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.58 (IH, dt), 8.08 (IH, dd), 7.92 (IH, dd), 7.80-7.90 (2H, m),
7.64 (IH, d), 7.56 (IH, t), 7.18-7.20 (IH, m), 5.47 (2H, s)
MP 147-148°C
Example 90
2,3-Dichloro-N-[5-chloro-3-(2-methylsulphanylethoxy)-2- pyrazinyl] benzenesulphonamide
Figure imgf000074_0002
Prepared by the method of Example 31 using 2-methylsulphanylethanol (0.05g) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (O.lg). Yield 0.06g. m e 427 (M-l+, 100%) 1H ΝMR (D6-DMSO) δ 11.50-12.00 (lH, br s), 8.09 (IH, d), 7.95 (IH, d), 7.81 (IH, s), 7.60 (IH, t), 4.47 (2H, t), 2.86 (2H, t), 2.14 (3H, s) MP 140-141°C
Example 91
Figure imgf000075_0001
Prepared by the method of Example 31 using 1-butanol (0.05g) and 2,3-dichloro-N-(3,5- dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (O.lg). Yield 0.037g. m/e 410 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.08 (IH, d), 7.96 (IH, d), 7.79 (IH, s), 7.57 (IH, t), 4.29 (2H, t),
1.60-1.75 (2H, m), 1.40-1.50 (2H, m), 0.95 (3H, t)
MP 133-134°C
Example 92 2,3-Dichloro-N-[5-chloro-3-(2-methyl-3-pyridinylmethoxy)-2- onamide
Figure imgf000075_0002
Prepared by the method of Example 31 using (2-methyl-3-pyridinyl)methanol (0.15g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.15g).
Yield 0.06g m/e 458 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.45 (IH, dd), 8.05 (IH, dd), 7.94 (IH, dd), 7.88 (IH, dd), 7.80
(IH, s), 7.53 (IH, t), 7.32 (IH, dd), 5.40 (2H, s), 2.56 (3H, s)
MP 214-216°C decomposes
Example 93 2,3-Dichloro-N-[5-chloro-3-(6-methyl-2-pyridinylmethoxy)-2-
Figure imgf000076_0001
Prepared by the method of Example 31 using (6-methyl-2-pyridinyl)methanol (0.15g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.15g).
Yield 0.06g. m e 461 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.08 (IH, dd), 7.91 (IH, dd), 7.84 (IH, s), 7.75 (IH, t), 7.55 (IH, t), 7.42 (IH, d), 7.24 (IH, d), 5.42 (2H, s), 2.52 (3H, s) MP 158-159°C
Example 94
2,3-Dichloro-N-[5-chloro-3-(l-oxy-2-pyridinylmethoxy)-2- honamide
Figure imgf000076_0002
Prepared by the method of Example 86 using 2,3-dichloro-N-[5-chloro-3-(2- pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 89) (0.2g). Yield O.lg. m/e 462 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.35-8.40 (IH, m), 8.09 (IH, dd), 7.80-7.90 (2H, m), 7.88 (IH, s), 7.58 (IH, t), 7.40-7.50 (2H, m), 5.51 (2H, s) MP 222-224°C decomposes
Example 95
3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2- methylbenzenesulphonamide
(3-pyridinylmethoxy)-2-pyrazinamine
Figure imgf000077_0001
3,5-Dichloro-2-pyrazinamine (l.Og) was added to a stined suspension of pyridine-3- methanol (1.3g) and sodium hydride (0.70g of 60% dispersion in oil) in 1,2- dimethoxy ethane (lOmL). After 0.5h, 5% aqueous citric acid was added and the mixture extracted with ethyl acetate. Chromatography on silica gel eluting with ethyl acetate/zso- hexane mixtures gave the title compound as a white solid (0.2g). Used directly.
b) 3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2- methylbenzenesulphonamide
Figure imgf000077_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 95a) (O.lg) and 3-chloro-2- methylbenzenesulphonyl chloride (0.09g). Yield 0.012g. m/e 425 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.78 (IH, d), 8.58 (IH, dd), 7.96 (2H, dt), 7.83 (IH, s), 7.72 (IH, d), 7.46 (IH, dd), 7.40 (IH, t), 5.44 (2H, s), 2.63 (3H, s) MP 192-193°C
Example 96 3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-
Figure imgf000078_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 95a) (O.lg) and 3-chloro-2- fluorobenzenesulphonyl chloride (O.lg). Yield 0.034g. m/e 429 (M+l+, 100%)
1H NMR (D6-DMSO) δ 8.78 (IH, d), 8.60 (IH, dd), 7.99 (IH, dt), 7.80-7.90 (3H, m), 7.48
(IH, dd), 7.40 (IH, t), 5.43 (2H, s) MP 177-178°C
Example 97
2,3-Dichloro-N-[5-chloro-3-(4-methoxyphenylmethoxy)-2- pyrazinyljbenzenesulphonamide
Figure imgf000078_0002
Prepared by the method of Example 31 using 4-methoxybenzylalcohol (0.3g) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.5g). Yield
0.4g. m/e 475 (M+l+, 100%) 1H NMR (D6-DMSO) δ 8.05 (IH, dd), 7.91 (IH, dd), 7.81 (IH, s), 7.58 (IH, t), 7.42 (2H, d), 6.94 (2H, d), 5.32 (2H, s), 3.77 (3H, s) MP 163-164°C
Example 98
N-[5-Bromo-6-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000079_0001
Prepared by the method of Example 1 (reaction performed at room temperature) using 3- bromo-5-chloro-2-pyrazinamine (Example 4a) (1.2g) and 2,3-dichlorobenzenesulphonyl chloride (1.4g). Yield 1.5g. m/e 418 (M+l+, 100%)
1H NMR (D6-DMSO) δ 8.07 (IH, dd), 7.90-7.80 (2H, m), 7.53 (IH, t) MP 123-124°C
Example 99
Figure imgf000079_0002
Prepared by the method of Example 31 using pyridine-3 -methanol (0.22g) andN-(3- bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.2g). Yield 0.04g. m/e 445 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.77 (IH, br s), 8.59 (IH, dd), 8.12 (IH, dd), 8.00 (IH, dt), 7.92
(IH, dd), 7.84 (IH, s), 7.58 (IH, t), 7.55-7.50 (IH, m), 5.44 (2H, s)
MP 203-204°C Example 100 loro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000080_0001
Prepared by the method of Example 31 using pyridine-2 -methanol (0.22g) andN-(3- bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.2g).
Yield 0.13g. m/e 445 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.56 (IH, dd), 8.15 (IH, dd), 7.94 (IH, dd), 7.90-7.80 (2H, m),
7.65-7.60 (IH, m), 7.58 (IH, s), 7.40-7.35 (IH, m), 5.48 (2H, s) MP 201-203°C
Example 101
N-[5-(2-Aminoethylsulphanyl)-3-(2-pyridinylmethoxy)-2-pyrazmyl]-2,3- dichlor ob enzenesulphonamide
a) 2,3 -Dichloro-N- [5 -chloro-3 -(3 -pyridinylmethoxy)-2-pyrazinyl] -N- [2- trimethylsilanylethoxymethyl]benzenesulphonamide
Figure imgf000080_0002
Prepared by the method of Example 66a using 2,3-dichloro-N-[5-chloro-3-(3- pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 36) (0.5g). Yield 0.68g. Used directly.
b) N-[5-(2-Aminoethylsulphanyl)-3-(2-pyridinylmethoxy)-2-pyrazinyl]-2,3-
Figure imgf000081_0001
A mixture of 2,3-dichloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-N-[2- trimethylsilanylethoxymethyl]benzenesulphonamide (Example 101a) (0.68g), caesium carbonate (1.9g) and 2-aminoethanethiol hydrochloride (0.2g) in acetonitrile (5mL) was stirred at room temperature for 5h. Ethyl acetate was added and the mixture washed with water and brine. The organic layer was dried (MgSO4) and evaporated. The residue was dissolved in trifluoracetic acid. After lh, toluene was added and the mixture evaporated to dryness. HCl (IM in dioxane) was added and the solid collected by filtration (0.2g). m/e 484 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.65 (IH, s), 8.52 (IH, d), 8.20-7.60 (2H, br s), 7.96 (IH, dd), 7.82 (IH, d), 7.62 (IH, d), 7.42-7.38 (IH, m), 7.35 (IH, t), 7.30 (IH, s), 5.24 (2H, s), 3.05- 3.00 (2H, m), 2.85-2.80 (2H, m)
Example 102
2,3-Dichloro-N-[5-chIoro-3-(6-methoxy-3-pyridinylmethoxy)-2- pyrazmyl]benzenesulphonamide
Figure imgf000082_0001
Preparedby the method of Example 31 using (6-methoxy-3-pyridinyl)methanol (0.3g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.3g).
Yield 0.15g. m/e 474 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.32 (IH, d), 8.04 (IH, dd), 7.91 (IH, dd), 7.85-7.80 (2H, m), 7.86
(IH, d), 7.55 (IH, t), 6.86 (IH, dd), 5.33 (2H, s), 3.87 (3H, s)
Example 103 N-[3-(3-Bromophenylmethoxy)-5-chloro-2-pyrazinyl]-2,3- honamide .
Figure imgf000082_0002
Prepared by the method of Example 3 lb using 3-bromobenzylalcohol (1.3g) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (l.lg). Yield g. m/e 522 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.07 (IH, dd), 7.92 (IH, dd), 7.85 (IH, s), 7.78 (IH, s), 7.60-7.50
(3H, m), 7.37 (IH, t), 5.40 (2H, s) Example 104
3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]benzoic
Figure imgf000083_0001
N-[3-(3-Bromophenylmethoxy)-5-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide (Example 103) (l.Og) and bts(triphenylphospbine)palladium dichloride (0.4g) in methanol (15mL) and triethylamine (7mL) was heated at 100°C under an atmosphere of carbon monoxide (6 ban). After 20h, the mixture was filtered and evaporated. The residue was dissolved in ethyl acetate. The organic solution was washed with brine, aqueous citric acid, dried (MgSO ) and evaporated. Chromatography on silica gel eluting with ethyl acetate/ώo-hexane mixtures gave the title compound as a white solid (0.65g). m e 503 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.11 (IH, s), 8.05 (IH, dd), 7.95 (IH, d), 7.90 (IH, dd), 7.84 (IH, s), 7.80 (IH, d), 7.60-7.50 (2H, ), 5.46 (2H, s), 3.88 (3H, s) MP 175-176°C
Example 105
3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]benzoic acid
Figure imgf000084_0001
A mixture of 3-[6-chloro-3-(2,3-dichlorobenzenesulphonylamino)-2- pyrazinyloxymethyljbenzoic acid methyl ester (Example 104) (0.3g) and lithium hydroxide hydrate (0.2g) in water (5mL) and methanol (5mL) was stirred at room temperature. After 3h, hydrochloric acid (2M) was added to acidify the mixture and the solid product was collected by filtration and dried (0.25g). m/e 489 (M+l+, 100%)
1H NMR (D6-DMSO) δ 13.10-13.00 (IH, br s), 12.00-11.80 (IH, br s), 8.10 (IH, s), 8.05 (IH, dd), 7.85-7.95 (2H, m), 7.82 (IH, s), 7.76 (IH, d), 7.54 (2H, t), 5.46 (2H, s) MP 218-224°C decomposes
Example 106
2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide a) 2,3-Dichloro-N- {5-chloro-3-[3-(tetrahydro-2-pyranyloxymethyl)phenylmethoxy]-2-
Figure imgf000084_0002
Prepared by the method of Example 31 using [3-(tetrahydro-2- pyranyloxymethyl)phenyl]methanol (1.99g) and 2,3-dichloro-N-(3,5-dichloro-2- pyrazinyl)benzenesulphonamide (Example 74) (l.Og). Yield l.Og. Used directly.
b) 2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2-
Figure imgf000085_0001
2,3-Dichloro-N-{5-chloro-3-[3-(tetrahydro-2-pyranyloxymethyl)phenylmethoxy]-2- pyrazinyl}benzenesulphonamide (Example 106a) (l.Og) in acetic acid (40mL), water
(lOmL) and tetrahyrofiiran (2 OmL) was heated at 45°C for 16h and the solution was evaporated to dryness. Chromatography on silica gel eluting with ethyl acetate/zso-hexane mixtures gave the title compound as a white solid (0.6g). m e 475 (M+l+, 100%) Η ΝMR (D6-DMSO) δ 8.05 (IH, dd), 7.91 (IH, dd), 7.82 (IH, s), 7.55 (IH, t), 7.43 (IH, s), 7.40-7.25 (3H, ), 5.39 (2H, s), 4.52 (2H, s)
MP 162-163°C
Example 107 2,3-Dichloro-N-[5-chloro-3-(3-methylaminomethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide a) 2,3-Dichloro-N-[5-chloro-3-(3-formylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide
Figure imgf000086_0001
2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide (Example 106) (0.6g) and manganese dioxide (l.Og) in tetrahydrofuran (5mL) was stirred at room temperature for 16h. The mixture was diluted with dichloromethane and filtered through celite. The solution was evaporated to dryness and the product crystallised from diethyl ether (0.4g). Used directly.
b) 2,3-Dichloro-N-[5-chloro-3-(3-methylaminomethylphenyhnethoxy)-2- pyrazinyl]benzenesulphonamide
Figure imgf000086_0002
A mixture of 2,3-dichloro-N-[5-chloro-3-(3-fonnylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide (Example 107a) (O.lg), methylamine (2mL of a 2M solution in tetrahydrofuran) and acetic acid (0.2mL) in methanol (2mL) was stirred at room temperature. After 2h, sodium cyanoborohydride (0.03g) was added. After 0.5h, water (2mL) was added and the mixture evaporated to dryness. Chromatography on silica gel eluting with methanol/dichloromethane mixtures gave the title compound as a white solid (0.035g). m/e 487 (M+l+, 100%) Η NMR (D6-DMSO) δ 8.90-8.60 (2H, br s), 8.02 (IH, d), 7.90-7.80 (IH, m), 7.80-7.60 (IH, m), 7.59 (IH, d), 7.55-7.40 (4H, m), 5.40 (2H, s), 4.08 (2H, s), 2.59 (3H, s) MP 167-168°C
Example 108
2,3-Dichloro-N-[5-chloro-3-{3-([2-hydroxyethylamino]methyl)phenylmethoxy}-2- pyrazinyl]benzenesulphonamide
Figure imgf000087_0001
Preparedby the method of Example 107b using 2,3-dichloro-N-[5-chloro-3-(3- fonnylphenylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 107a) (O.lg) and 2- aminoethanol (0.05g). Yield 0.035g. m/e 517 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 9.00-8.80 (2H, br s), 7.93 (IH, d), 7.80-7.20 (7H, m), 5.28 (2H, s),
5.21 (IH, t), 4.20 (2H, s), 3.80-3.60 (2H, m), 3.05-2.95 (2H, m) MP 196-198°C
Example 109
2,3-Dichloro-N-[5-chIoro-3-(4~hydroxymethylphenylmethoxy)-2- pyrazinyl] benzenesulphonamide
Figure imgf000088_0001
Prepared by the method of Examples 106a and 106b using [4-(tetrahydro-2- pyranyloxymethyl)phenyl]methanol (2.0g) and 2,3-dichloro-N-(3,5-dichloro-2- pyrazinyl)benzenesulphonamide (Example 74) (l.Og). Yield 0.7g. m/e 474 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.05 (IH, dd), 7.91 (IH, dd), 7.83 (IH, s), 7.55 (IH, t), 7.46 (2H, d), 7.33 (2H, d), 5.38 (2H, s), 4.51 (2H, s) MP 177-178°C
Example 110
2,3-Dichloro-N-[5-chloro-3-{4-([2-hydroxyethylamino]methyl)phenylmethoxy}-2- pyrazinyl]benzenesulphonamide a) 2,3-Dichloro-N-[5-chloro-3-(4-fonnylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide
Figure imgf000088_0002
Prepared by the method of Example 107a using 2,3-dichloro-N-[5-chloro-3-(4- hydroxymethylphenylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 109) (0.65g). Yield 0.64g. Used directly. b) 2,3-Dichloro-N-(5-chloro-3-{4-[(2-hydroxyethylamino)methyl]phenylmethoxy}-2- pyrazinyl]benzenesulphonamide
Figure imgf000089_0001
Prepared by the method of Example 107b using 2,3-dichloro-N-[5-chloro-4-(3- formylphenylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 110a) (0. lg) and 2- aminoethanol (0.05g). Yield 0.028g. m/e 517 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.75 (2H, br s), 7.93 (IH, dd), 7.61 (IH, dd), 7.54 (4H, s), 7.35
(IH, t), 7.26 (IH, s), 5.26 (2H, s), 5.18 (IH, t), 4.18 (2H, s), 3.70-3.60 (2H, m), 3.00-2.95 (2H, m)
MP 202-205°C
Example 111
2,3-Dichloro-N-[3-(4-hydroxymethylphenylmethoxy)-2- pyrazinyl] benzenesulphonamide
a) 2,3-Dichloro-N-{3-[4-(tetrahydro-2-pyranyloxymethyl)phenylmethoxy]-2- pyrazinyl } benzenesulphonamide
Figure imgf000090_0001
2,3-Dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28a) (O.lg), [4- (tetrahydro-2-pyranyloxymethyl)phenyl]methanol (0.27g) and potassium tert-butoxide (2mL of a IM solution in tetrahydrofuran) in N-methylpyπolidinone (ImL) was stirred at 50°C. After 2h, aqueous citric acid was added and the mixture extracted with ethyl acetate. The organic solution was washed with water and brine and evaporated to dryness. Used directly.
b) 2,3-Dichloro-N-[3-(4-hydroxymethylphenylmethoxy)-2- namide
Figure imgf000090_0002
2,3-Dichloro-N-{3-[4-(tetrahydro-2-pyranyloxymethyl)phenylmethoxy]-2- pyrazinyl}benzenesulphonamide (Example 11 la) in acetic acid (lOmL), water (2.5mL) and tetrahydrofuran (5mL) was heated at 45°C for 16h and the solution was evaporated to dryness. Chromatography on silica gel eluting with ethyl acetate/iso-hexane mixtures gave the title compound as a white solid (0.022g). m e 440 (M+l+, 100%) 1H NMR (D6-DMSO) δ 8.08 (IH, dd), 7.91 (IH, dd), 7.90-7.70 (IH, br s), 7.70-7.60 (IH, br s), 7.55 (IH, t), 7.42 (2H, d), 7.31 (2H, d), 5.39 (2H, s), 5.20-5.05 (IH, br s), 4.49 (2H, s)
MP 160-161°C
Example 112
2,3-Dichloro-N-[5-chloro-3-(2-hydroxymethylphenylmethoxy)-2- honamide
Figure imgf000091_0001
2,3-Dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74).
(0.15g), (2-hydroxymethylphenyl)methanol (0.27g) and potassium tert-butoxide (3mL of a IM solution in tetrahydrofuran) in N-methylpyrrolidinone (2mL) was stirred at room temperature. After lh, aqueous citric acid was added and the mixture extracted with ethyl acetate. The organic solution was washed with water and brine and evaporated to dryness. Chromatography on silica gel eluting with ethyl acetate/z'so-hexane mixtures gave the title compound as a white solid (0.027g). m/e 474 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.06 (IH, dd), 7.90 (IH, dd), 7.81 (IH, s), 7.60-7.40 (3H, m), 7.37 (IH, t), 7.29 (IH, t), 5.45 (2H, s), 4.64 (2H, s) MP 145-146°C
Example 113
5-(2,3-DichIorobenzenesuphonyIamino)-6-methoxypyrazine-2-carboxylic acid, methyl ester
Figure imgf000092_0001
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 8) (6.5g) and dichloro[l,r-bz diphenylphosphino)ferrocene]palladium(ll) dichloromethane adduct (0.7g) in methanol (30mL) and triethylamine (lOmL) was heated at 100°C under an atmosphere of carbon monoxide (6 bar). After 5h, the mixture was filtered and evaporated. The residue was dissolved in ethyl acetate. The organic solution was washed with brine, aqueous citric acid, dried (MgSO ) and evaporated. Chromatography on silica gel eluting with ethyl acetate/wo-hexane mixtures gave the title compound as a white solid (4.8g). m/e 392 (M+l+, 100%) 1H ΝMR (D6-DMSO) δ 8.13 (2H, dd), 7.95 (IH, dd), 7.60 (IH, t), 3.95 (3H, s), 3.82 (3H, s)
MP 120-121°C
Example 114 2,3-Dichloro-N-[5-(l-hydroxy-l-methylethyl)-3-methoxy-2- pyrazinyl] benzenesulphonamide
Figure imgf000092_0002
Methylmagnesium bromide (3mL of a 3M solution in diethyl ether) was added over 3 minutes to a stirred solution of 5-(2,3-dichlorobenzenesuphonylamino)-6- methoxypyrazine-2-carboxylic acid, methyl ester (Example 113) (0.3g) in tetrahydrofuran (lOmL) cooled in an ice/water bath. After a further 5 minutes, aqueous citric acid was added and the mixture extracted with ethyl acetate. The organic solution was evaporated to dryness. Chromatography on silica gel eluting with methanol/dichloromethane mixtures gave the title compound as a white solid (0.15g). m/e 392 (M+l+, 100%)
1H NMR (D6-DMSO) δ 11.40-11.30 (lH, br s), 8.07 (IH, dd), 7.93 (IH, d), 7.90-7.80 (IH, br s), 7.59 (IH, t), 5.10-5.05 (IH, br s), 3.88 (3H, s), 1.39 (6H, s)
MP 192-193°C
Example 115 N-[5-(2-Aminoethoxy)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesuIphonamide a) 2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N- {[2- enesulphonamide
Figure imgf000093_0001
Prepared by the method of Example 66a using 2,3-dichloro-N-(5-chloro-3-methoxy-2- pyrazinyl)benzenesulphonamide (Example 5) (7.0g). Yield 9.8g. Used directly.
Figure imgf000093_0002
b) N-[5-(2-aminoethoxy)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 115a) (0.25g) was added to a mixture of ethanolamine (0.05mL) and sodium hydride (0.035g of a 60% dispersion in oil) in 1 ,2-dimethoxyethane (15mL) at room temperature. After 2h, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO ) and evaporated to dryness. Chromatography on silica gel eluting with methanol/dichloromethane mixtures gave the title compound containing the SEM ([2- (trimethylsilyl)ethoxy]methyl) protecting group as an oil (0.14g). Trifluoroacetic acid (ImL) and dichloromethane (3mL) were added. After 0.5h at room temperature, toluene was added and the solution evaporated to dryness. HCl (4M in dioxane) was added and the mixture evaporated to dryness. The product was crystallised from diethyl ether (0.075g). m e 393 (M+l+, 100%)
1H NMR (D6-DMSO) δ 10.90 (IH, br s), 8.07 (2H, br s), 7.99-7.92 (2H, m), 7.56 (IH, t), 7.49 (IH, s), 4.45 (2H, t), 3.84 (3H, s), 3.25-3.20 (2H, m) MP 200-205°C
Example 116
N-{5-[(2-Aminoethyl)thio]-6~chloro-3-methoxy-2-pyrazinyI}-2,3- dichlorobenzenesulfonamide
Figure imgf000094_0001
Prepared by the method of Example 101b using 2,3-dichloro-N-(5,6-dichloro-3-methoxy-
2-pyrazinyl)-N- {[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66a)
(0.27g). Yield 0.055g. m/e 443 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.09 (IH, d), 7.90 (IH, d), 7.58 (IH, t), 3.95 (3H, s), 3.33 (2H, t), 3.14 (2H, t).
MP 185-190°C
Example 117
3-[(5-{[(2,3-Dichlorophenyl)suIphonyl]amino}-6-methoxy-2-pyrazinyI)thio]propanoic acid, methyl ester
Figure imgf000095_0001
Prepared by the method of Example 101b using
2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-{[2-
(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 115a) (0.25g) and 3- mercaptopropionic acid , methyl ester (0.06mL). Yield O.lg. m e 452 (M+l+, 100%)
Η ΝMR (D6-DMSO) δ 11.35 (IH, br s), 8.03 (IH, d), 7.93 (IH, d), 7.66 (IH, s), 7.57
(IH, t), 3.90 (3H, s), 3.58 (3H, s), 3.29 (2H, t), 2.72 (2H, t).
MP 146-148°C
Example 118
2,3-Dichloro-N-[5-bromo-3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide a) 6-Methyl-2-pyrazinamine
Figure imgf000095_0002
Dimethylzinc (lOOmL of a 2M solution in toluene) was added dropwise over 0.5h to a stirred solution of 6-chloro-2-pyrazinamine (12.9g) and [1,3- bz'j,(diphenylphosphino)propane]nickel(II) chloride (5.4g) in dioxane (200mL) under a nitrogen atmosphere. The reaction mixture was heated at reflux for 18h, then cooled to room temperature and quenched cautiously with wo-propanol (3 OmL) and methanol (5 OmL). After removal of solvent in vacuo, the residue was partitioned between dichloromethane and aqueous ammonium chloride. The organic phase was filtered through celite, dried (MgSO4), filtered and evaporated to give the crude product as an orange solid. Chromatography on silica gel eluting with ethyl acetate/methanol mixtures gave the title compound (5.1g). Used directly.
b) 3,5-Dibromo-6-methyl-2-pyrazinamine
Figure imgf000095_0003
A solution of bromine (1.85g) in chlorofonn (5mL) was added dropwise to a stirred solution of 2-amino-6-methylpyrazine (Example 118a) (0.6g) in chlorofonn (50mL). The reaction mixture was stined at room temperature for 0.5h, then washed twice with water, dried (MgSO ), filtered and evaporated to give the crude product as an orange solid. Chromatography on silica gel eluting with dichloromethane gave the title compound (0.95g). Used directly.
Figure imgf000096_0001
A solution of 3,5-dibromo-6-methyl-2-pyrazinamine (Example 118b) (0.9g) was added to a solution of sodium (0.39g) in methanol (30mL) was heated at reflux for 18h. After removal of solvent in vacuo, the residue was partitioned between water and dichloromethane, and the organic phase dried (MgSO ), filtered and evaporated to give the title compound as a pale yellow solid (0.58g). m/e 218/220 (M+l+, 100%)
1H NMR (CDC13) δ 4.70 (2H, br s), 3.97 (3H, s), 2.40 (3H, s)
romo-3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide
Figure imgf000096_0002
Sodium hydride (0.5g of a 60% dispersion in oil) was added to a solution of 5-bromo-3- methoxy-6-methyl-2-pyrazinamine (Example 118c) (0.55g) in N-methylpyπolidinone (25mL). The resultant dark solution was stined at room temperature for 0.5h before a solution of 2,3-dichlorobenzenesulphonyl chloride (0.67g) in N-methylpyrrolidinone (5mL) was added dropwise. The reaction mixture was stirred at room temperature for 3h, then quenched with aqueous aimnonium chloride and partitioned between ethyl acetate and aqueous ammonium chloride (x5). the organic phase was dried (MgSO ), filtered and evaporated to give the crude product. Chromatography on silica gel eluting with dichloromethane/ acetic acid (200:1) gave the title compound as a pale yellow solid (0.38g). m/e 424/426/428 (M-l\ 100%)
1H NMR (CDC13) δ 8.29 (IH, d), 7.69 (2H, d), 7.41 (IH, t), 4.01 (3H, s), 2.27 (3H, s)
MP 146-148°C
Example 119
5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-3-methylpyrazine-2-carboxylic aicd, methyl ester
Figure imgf000097_0001
Prepared by the method of Example 113 using 2,3-dichloro-N-[5-bromo-3-methoxy-6- methylpyrazinyl)benzenesulphonamide (Example 118) (0.35g). Yield 0.27g. m/e 404/406 (M-r, 100%)
1H ΝMR (CDC13) δ 8.32 (IH, br s), 8.10 (IH, br s), 7.70 (IH, d), 7.42 (IH, t) 4.06 (3H, s), 3.90 (3H, s), 2.50 (3H, br s). MP 149-150°C
Example 120 2,3-Dichloro-N-[5-(hydroxymethyI)-3-methoxy-6-methyl-2- pyrazinyl)benzenesulphonamide
Figure imgf000097_0002
To a stined solution of 5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-3- methylpyrazine-2-carboxylic aicd, methyl ester (Example 119) (0.19 g) in tetrahydrofuran (lOmL) under an atmosphere of nitrogen was added a solution of lithium triethylborohydride (1.7mL of a IM solution in tetrahydrofuran). The reaction mixture was stined at room temperature for lh, before quenching with aqueous ammonium chloride and extraction into dichloromethane. The organic phase was dried (MgSO4), filtered and evaporated to give the crude product as a colourless oil. Chromatography on silica gel eluting with dichloromethane/ethyl acetate/acetic acid (150:50:1) gave the title compound as a white solid (0.38g). m/e 378 (M+l+, 100%)
]H NMR (CDC13) δ 8.31 (IH, br d), 7.77 (IH, br s), 7.68 (IH, d), 7.41 (IH, t), 4.55 (2H, d), 4.03 (3H, s), 3.12 (IH, br s), 2.13 (3H, br s). MP 175-177°C
Example 121
2,3-Dichloro-N-[5,6-dichloro-3-(3-pyridinyImethoxy)-2- pyrazinyl] benzenesulphonamide
a) 5,6-Dichloro-3-(3-pyridinylmethoxy)-2-pyrazinamine
Figure imgf000098_0001
To a stirred suspension of sodium hydride (1.20g of a 60% dispersion in oil) in dry dimethoxymethane (40 mL) was added pyridine-3-methanol (2.18g) in 1,2- dimethoxymethane (10 mL). The resulting suspension was stirred at room temperature for 0.5h and then 3,5,6-trichloro-2-aminopyrazine (1.2g) was added and the mixture stirred at 70°C for 4h. The reaction mixture was cooled and cautiously added to water (100 mL) and neutralised with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (2x50 mL), dried (MgSO ), filtered and concentrated. The residue was purified by chromatography on silical gel eluting with ethyl acetate to afford the sub-titled compound as a white solid (0.29 g). 1H NMR (CDC13) δ 8.73 (IH, s), 8.63 (IH, d), 7.8 (IH, d), 7.35 (IH, dd), 5.42 (2H, s), 4.92 (2H, br s).
b) 2,3-Dichloro-N-[5,6-dichloro-3-(3-pyridinylmethoxy)-2- pyrazinyljbenzenesulphonamide
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5,6- dichloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 121a) (0.27g) and 2,3- dichlorobenzenesulphonyl chloride (0.27g). Yield 0.17g. m/e 479 (M+l+, 100%)
1H NMR (D6-DMSO) δ 8.8 (IH, s), 8.63 (IH, d), 8.11 (IH, d), 8.06 (IH, d), 7.58-7.52
(2H, m), 5.41 (2H, s).
Example 122 3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-fluorobenzenesulphonamide
Figure imgf000099_0002
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (0.16g) and 3-chloro-2-fluorobenzenesulphonyl chloride (0.27g). Yield 0.22g. m e 354, 352 (M+l+, 100%)
1H NMR (D6-DMSO) δ 7.94-7.86 (2H, m), 7.82 (IH, s), 7.43 (IH, dt), 3.92 (3H, s).
MP 156-157°C
Example 123 3-Chloro-2-fluoro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide a) 3-(3-Pyridinylmethoxy)-2-pyrazinamine
Figure imgf000099_0003
Prepared as for Example 121a using 3-chloro-2-aminopyrazine (0.5 g), pyridine-3- methanol (0.42g) and sodium hydride (0.3 lg of a 60% dispersion in oil) inN- methylpyrrolidinone (5 mL) to afford the sub-titled compound as a solid (0.62 g). Η ΝMR (CDCI3) δ 8.73 (IH, d), 8.60 (IH, d), 7.78 (IH, d), 7.60 (IH, d), 7.42 (IH, d), 7.32 (IH, dd), 5.43 (2H, s), 4.77 (2H, br). MP 120-122°C
b) 3-Chloro-2-fluoro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000100_0001
To a stirred solution of 3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 122a) (0.404 g) in dichloromethane (5mL) and pyridine (1 mL) was added zso-butylchloroformate (0.3mL) and the resulting solution stined for 20 hours. The reaction mixture was poured into water (20mL) and extracted into ethyl acetate (2x20mL). The combined extracts were dried (MgSO ), filtered and concentrated to afford an oil (0.51 g) that was used without further purification. A portion of the residue (0.15g) was dissolved in 1 ,2-dimethoxymethane (2 mL) and sodium hydride (0.030g of 60% dispersion in oil) added. The resulting suspension was stined for 15 minutes and then 3-chloro-2-fluorobenzenesulfonyl chloride (0.137g) in dimethoxymethane (1 mL) was added. The resulting solution was stirred at room temperature for 6h. The reaction mixture was poured into water (20mL) and extracted into ethyl acetate (2x20mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford an oil that was dissolved into methanol (5mL) and water (2mL) and sodium hydroxide (0.04g) was added. The mixture was heated to 60°C for 1 hour, cooled and was poured into water (20mL) and extracted into ethyl acetate (2x20ml). The combined extracts were dried (MgSO4), filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with ethyl acetate/tso-hexane mixtures followed by ethyl acetate to afford the title compound (0.067g) as a white solid, m/e 395, 397 (M+l+, 100%)
1H ΝMR (CDCI3) δ 8.69 (IH, s), 8.62 (IH, d), 8.06 (IH, t), 7.78 (IH, d), 7.68 (IH, d), 7.69-7.60 (2H, m), 7.34 (IH, dd), 7.26 (IH, dd), 5.43 (2H, s). Example 124
3-{[(2,3-Dichlorophenyl)sulphonyl]amino}pyrazine-2-carboxylic acid, methyl ester
Figure imgf000101_0001
To a stined solution of 2,3-dichlorobenzenesulphonyl chloride (0.246g) and methyl-3- aminopyrazine-2-carboxylate (0.153g) in 1,2-dimethoxymethane (3mL) was added portionwise sodium hydride (O.lg of a 60% dispersion in oil) over 1 hour. The mixture was stined at room temperature for 20h, was poured into water (20mL) and extracted into ethyl acetate (2x20mL). The combined extracts were dried (MgSO ), filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with dichloromethane to afford the titled compound (0.085g) as a white solid, m/e 362/364 (M+l+, 100%)
1H NMR (CDC13) δ 10.97 (IH, s), 8.32 (IH, dd), 8.31 (IH, d), 8.25 (IH, d), 7.68 (IH, dd), 7.42 (IH, t), 4.08 (3H, s). MP 177-178°C
Example 125 N-(5-Bromo-6-chloro-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide a) 3-Methoxy-5-bromo-6-chloro-2-pyrazinamine
Figure imgf000101_0002
A stirred solution of 2-amino-6-chloropyrazine (2.0g) and N-bromosuccinimide (13.71g) in chloro form (100 mL) was heated to reflux for 20 hours. The reaction mixture was cooled and concentrated onto silica gel (20g) and the residue loaded onto a column of silica gel (5cm x 2cm) and the column was eluted with dichloromethane. Concentration afforded 3,5-dibromo-6-chloro-2-aminopyrazine that was dissolved into methanol (200 mL) and sodium methoxide (32g of a 25% solution in methanol) added. The reaction was heated to 70°C for 1.5h, cooled and concentrated to approx. 50 mL capacity. The reaction mixture was poured into water (200mL) and the sub-titled adduct (2.0g) collected as an off-white solid, m/e 235, 237 (M+l+, 100%) b) N-(5-Bromo-6-chloro-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
Figure imgf000102_0001
Procedure as for Example 1 (reaction perfonned at room temperature) using 3-methoxy-5- bromo-6-chloro-2-pyrazinamine (Example 125a) (0.5g) and 2,3-dichlorobenzenesulphonyl chloride (2.21 g). Yield 3.2g. m/e 445, 447 (M-l+, 100%)
1H ΝMR (CDC13) δ 8.32 (IH, dd), 7.79 (IH, br), 7.72 (IH, dd), 7.45 (IH, t), 4.05 (3H, s).
MP 177-178°C
Example 126 3-Chloro-5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2-carboxylic
Figure imgf000102_0002
Prepared by the method of Example 113 using N-(5-bromo-6-chloro-3-methoxypyrazin-2- yl)-2,3-dichlorobenzenesulfonamide (Example 125) (l.Og). Yield 0.92g. m/e 426, 428 (M-l+, 100%)
1H ΝMR (CDC13) δ 8.36 (IH, dd), 8.05 (IH, br), 7.73 (IH, dd), 7.47 (IH, t), 4.09 (3H, s),
3.92 (3H, s). MP 200-201°C
Example 127
2,3-Dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxypyrazin-2- yl] benzenesulphonamide
Figure imgf000102_0003
Prepared as for Example 120 using 3-chloro-5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6- methoxypyrazine-2-carboxylic acid, methyl ester (Example 126) (0.105g). Yield 0.072g. m/e 397, 399 (M-l+, 100%)
Η NMR (CDC13) δ 8.34 (IH, dd), 7.84 (IH, br), 7.74 (IH, dd), 7.45 (IH, t), 4.63 (2H, d),
4.07 (3H, s), 2.83 (IH, t).
MP 145-147°C
Example 128
2,3-Dichloro-N-{3-[(6-methoxy-3-pyridinyl)methoxy]-2- pyrazinyljbenzenesulphonamide
Figure imgf000103_0001
Prepared by the method of Example 28b using 2,3-dichloro-N-(3-chloro-2- pyrazinyl)benzenesulphonamide (Example 28a) (0.338g) and (6-methoxy-3- pyridinyl)methanol (0.2 lg). Yield 0.23g. m/e 439, 440 (M-l+, 100%)
1H ΝMR (CDCI3) δ 8.28-8.26 (2H, m), 7.70-7.65 (3H, m), 7.60 (IH, br), 7.39 (IH, t), 6.80 (2H, d), 5.36 (2H, s), 3.97 (3H, s).
MP 187-188°C
Example 129
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(methoxymethyl)-2- pyrazinyl] benzenesulphonamide /
Figure imgf000103_0002
To a stirred solution of 2,3-dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxy-2- pyrazinyljbenzenesulphonamide (Example 127) (O.lg) in tetrahydrofuran (3mL) was added manganese dioxide (0.13 lg) and the resulting suspension was stirred for 20h, filtered and concentrated. The residue was taken up into methanol (3mL) and acetic acid (O.lmL). To this solution was added ethylamine hydrochloride (0.081g) and sodium cyanoborohydride (0.05 lg). The resulting mixture was stined for 20h and concentrated onto silical gel (1 g) and eluting with methanol/dichloromethane mixtures to afford the titled compound (0.029 g) as a white solid, m/e 412, 414 (M-l+, 100%)
1H NMR (CDC13) δ 8.35 (IH, dd), 7.72 (IH, d), 7.45 (IH, t), 4.45 (2H, s), 4.05 (3H, s), 3.43 (3H, s). MP 193-196°C
Example 130 2-Chloro-N-(5-chIoro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide a) N-(5-Chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide
Figure imgf000104_0001
By the method outlined in Example 1 (reaction perfonned at room temperature) using 5- chloro-3-methoxy-2-pyrazinamine (0.798g) and 3-fmorobenzenesulphonyl chloride (1.17g). Yield 0.64g. m/e 316 (M-l+, 100%)
b) 2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide.
Figure imgf000104_0002
A solution of N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide (Example 130a) (0.159g) in dry tetrahydrofuran (3mL) was added to a stirred solution of lithium di-z'so-propylamide (prepared from di-z'so-propylamine (0.151g) and n-butyl lithium (2.5M in hexanes)) in tetrahydrofuran (7.0mL) at -78°C. The resulting solution was stirred at -78°C for 15 minutes and then hexachloroethane (0.472g) in tetrahydrofuran (2mL) was added and the mixture allowed to attain room temperature over a 5 hour period. The reaction was quenched by the addition of IN hydrochloric acid (lOmL) and extracted into ethyl acetate (2x20mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with ethyl acetate/zsO-hexane mixtures gave the titled compound (0.086 g) as a white solid, m/e 350, 352 (M-l+, 100%) 1H NMR (CDCI3) δ 8.16 (IH, dd), 7.81 (IH, br), 7.62 (IH, s), 7.48-7.37 (2H, m), 4.06 (3H, s)
MP 159-159.5°C
Example 131
2-Chloro-3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
a) 3-Fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000105_0001
By the method outlined in Example 1 (reaction performed at room temperature) using 3- chloro-2-pyrazinamine (1.29g), 3-fluorobenzenesulphonyl chloride (2.13g). The crude adduct was reacted with a solution of sodium methoxide (lOmL of a 25% solution in methanol) in methanol (20mL) to afford the sub-titled compound (2.36g) as a solid. m e 284 (M+l+, 100%) MP 142-143°C
b) 2-Chloro-3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000105_0002
Prepared as for Example 130, 3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 131a) (0.283g), lithium di-zso-propylamide (prepared from di-z'50-propylamine
(0.30g) and zi-butyl lithium (0.96mL of a 2.5M solution in hexanes)) and hexachloroethane
(0.994g) in anhydrous tetrahydrofuran (20mL) afforded the titled compound (0.092g) as a white solid after re-crystallisation from tert-butyl methylether. m/e 318, 320 (M-l+, 100%) 1H ΝMR (CD3OD) δ 8.11-8.08 (2H, m), 7.57 (IH, d), 7.57-7.50 (3H, m), 4.0 (3H, s).
MP 144-145°C
Example 132 2-Chloro-3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide a) 3 -Methoxy-N-(3 -methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000106_0001
By the method outlined in Example 1 (reaction perfonned at room temperature) using 3- chloro-2-aminopyrazine ( 0.83 g), 3-methoxybenzenesulfonyl chloride (1.44 g) .The crude adduct was reacted with a solution of sodium methoxide (10 mL of a 25% solution in methanol) in methanol (20mL) to afford the sub-titled compound (1.41g) as a solid. m/e 296 (M+l+, 100%) MP 133-134°C
b) 2-Chloro-3-methoxy-N-(3-methoxypyrazin-2-yl)benzenesulphonamide
Figure imgf000106_0002
Prepared as for Example 130, 3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
(Example 132a) (0.295g), lithium di-zso-propylamide (prepared from di-wo-propylamine
(0.30g) and n-butyl lithium (0.96mL of a 2.5M solution in hexanes)) and hexachloroethane (0.994g) in anhydrous tetrahydrofuran (20mL) afforded the titled compound (0.152g) as a white solid after re-crystallisation from tert-butyl methylether. m/e 328, 329 (M-l+, 100%)
1H ΝMR (CDC13) δ 7.97 (IH, d), 7.92 (IH, br), 7.65 (IH, d), 7.60 (IH, d), 7.41 (IH, t),
7.15 (IH, t), 3.99 (3H, s), 3.91 (3H, s). MP 151-152°C
Example 133
N-[5-Bromo-3-[(2S)-2-pyrrolidinyImethoxy]-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
Figure imgf000107_0001
Sodium hydride (0.026g of a 60% dispersion in oil) was added to a mixture of 2,3- dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (Example 31a) (O.lg) and 2- hydroxymethylpynolidine-1 -carboxylic acid tert-butyl ester (0.088g) in 1,2- dimethoxyethane (2mL). After 0.5h, the reaction mixture was partitioned between 2Ν hydrochloric acid and ethyl acetate. The organic solution was dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/zso-hexane mixtures gave the title compound protected with the BOC (tert-butoxycarbonyl) group (0.1 lg) as an oil. This product was dissolved in dichloromethane (6mL) and trifluoroacetic acid (2mL). After 2h, toluene was added and the solution evaporated to dryness. Crystallisation from diethyl ether gave the product as a white solid (0.083g). m/e 482 (M+l+, 100%)
1H NMR (D6-DMSO) δ 8.99 (IH, br), 8.65 (IH, br s), 8.13 (lH,d), 7.95 (IH, d), 7.84 (IH, s), 7.59 (IH, t), 4.57(1H, dd), 4.39 (IH, t), 4.0 (IH, br s), 3.3 (2H, d), 2.20-2.05 (IH, m), 2.05-1.90 (2H, m), 1.85-1.75 (IH, m). MP 199-200°C
Example 134
5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2- carboxylic acid, methyl ester
Figure imgf000107_0002
Prepared as for Example 113 using N-[5-bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide (Example 34).(0.2g) and bis(triphenylphosphine)palladium(ll) dichloride (O.lg). Yield 0.14g. m/e 469(M+\+, 100%) Η ΝMR (D6-DMSO) δ 8.83 (IH, s), 8.61 (IH, d), 8.15-8.05 (3H,m), 7.90 (IH, d), 7.60- 7.50 (2H, m), 5.48 (2H, s), 3.82(3H, s). MP 209-210°C
Example 135 5-{[(2,3-Dichlorophenyl)sulphonyl]amino}-6-(3-pyridinylmethoxy)-2- pyrazinecarb oxamide
Figure imgf000108_0001
5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-carboxylic acid, methyl ester (Example 134) (0.05g) was heated at 60°C in 7M ammonia in methanol for 4 days. The solution was evaporated to dryness and the product crystallised from methyl acetate. Yield 0.027g. m e 453(M-1+, 100%)
1H NMR (D6-DMSO) δ 8.72 (IH, s), 8.52 (IH, d), 7.99 (lH,d), 7.90 (IH, d), 7.83 (IH, s), 7.66 (IH, d), 7.56 (IH, s), 7.45-7.35 (2H, m), 5.49 (2H, s).
MP 174-178°C
Example 136
2,3-Dichloro-N-[5-(4-pyridinyl)-3-(3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide
a) [5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl][(2,3- dichloroρhenyl)sulphonyl]carbamic acid, 2-methylpropyl ester
Figure imgf000109_0001
Sodium hydride (0.045g of a 60% dispersion in oil) was added to N-[5-bromo-3-(3- pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide (Example 34) (0.5g) in 1,2-dimethoxyethane (3mL). Zso-butylchloroformate (0.15mL) was added. After 2h, the mixture was partitioned between water and ethyl acetate. The organic layer was dried (Νa2SO ) and evaproated to yield the product (0.65g). Used directly.
b) 2,3-Dichloro-N-[5-(4-pyridinyl)-3-(3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide
Figure imgf000109_0002
[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl][(2,3-dichlorophenyl)sulphonyl]carbamic acid, 2-methylpropyl ester (Example 136a) (0.1 lg), 4-tributylstannanylpyridine (0.067g) and tet7-αfø triphenylphosphine)palladium(0) (0.05g) in toluene (3mL) was heated at 95°C for 16h. Chromatography on silica gel eluting with ethyl acetate/ethanol mixtures gave the title compound protected with the 2-methylpropyl carbonyl group (0.09g). The compound was heated at 60°C in methanol (2mL) and IM sodium hydroxide (0.36mL) for lh. The solution was evaporated. Purification was by reverse phase preparative high pressure liquid chromatography. Yield 0.015g. m/e 488(M+l+, 100%) 1H NMR (D6-DMSO) δ 9.05 (IH, s), 8.85 (2H, d), 8.78 (IH, d), 8.62 (IH, s), 8.44-8.39 (3H, m), 8.17 (IH, dd), 7.96 (lH,dd), 7.87-7.80 (IH, m), 7.64-7.57 (IH, m), 5.74 (2H, s) MP 210°C (dec.)
Example 137
2,3-Dichloro-N-[5-(hydroxymethyl)-3-(3-pyridinylmethoxy)-2- pyrazinyl] b enzenesulphonamide
Figure imgf000110_0001
Lithium aluminium hydride (0.85mL of a IM solution in tetrahydrofuran) was added dropwise to 5-(2,3-dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2- carboxylic acid, methyl ester (Example 134) (0.2g) in tetrahydrofuran (lOmL) cooled to - 65°C. The reaction mixture was allowed to warm to room temperature and stirred for lh. Aqueous acetic acid was added and the mixture extracted with ethyl acetate. The organic solution was dried (MgSO ) and evaporated. Chromatography on silica gel eluting with ethyl acetate/methanol mixtures gave the title compound (0.08g). m/e 441(M+l+, 100%)
]H NMR (D6-DMSO) δ 8.73 (IH, s), 8.55 (IH, d), 8.06 (IH, dd), 7.95-7.85 (2H, m), 7.65 (IH, s), 7.56 (IH, t), 7.64-7.57 (IH, m), 5.41 (2H, s), 5.36 (IH, t), 4.41 (2H, d)
Example 138 roxymethyl)-3-methoxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000110_0002
Prepared as for Example 120 using 5-(2,3-dichlorobenzenesuphonylamino)-6- methoxypyrazine-2-carboxylic acid, methyl ester (Example 113) (0.84g). Yield 0.5g. m/e 364(M+l+, 100%)
1H NMR (D6-DMSO) δ 8.21 (IH, dd), 7.79 (IH, dd), 7.59 (IH, s), 7.51 (IH, t), 4.50 (2H, s), 4.01 (3H, s).
MP 160-161°C .
Example 139
N-(5-Allyloxy-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
Figure imgf000111_0001
Procedure as for Example 115 using N-(5-chloro-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- ({2-[(trimethylsilyl)oxy] ethoxy} methyl)benzenesulphonamide (Example 115a) (0.25 g), allyl alcohol (0.06g) and sodium hydride (0.035g of a 60% dispersion in oil) inNN- dimethylformamide (5mL) stirred at room temperature for 5 days. Purification was by silica gel chromatography eluting with ethyl acetate/z'sσ-hexane mixtures to give the title compound with SEM attached. Yield 0.18g. This compound was dissolved in dichloromethane (4mL) and trifluoroacetic acid (ImL). After 2h, toluene was added and the mixture evaporated to dryness. Purification was by silica gel chromatography eluting with ethyl acetate/wo-hexane mixtures to give the title compound. Crystallised for diethyl ether/wo-hexane mixtures. Yield 0.026g. m/e 390 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 10.81 (IH, s), 8.0-7.9 (2H, m), 7.53 (IH, t), 7.49 (IH, s), 6.07- 7.02 (IH, m), 5.38 (IH, dd), 5.26 (IH, dd), 4.80 (2H, d), 3.82 (3H, s) MP 120-121°C
Example 140
2,3-Dichloro-N-{3-methoxy-5-[(pyrazinyloxy)methyl]-2- pyrazinyljbenzenesulphonamide
Figure imgf000112_0001
Sodium hydride (0.022g of a 60% dispersion in oil) was added to 2,3-dichloro-N-[5-
(hydroxymethyl)-3-methoxy)-2-pyrazinyl]benzenesulphonamide (Example 138) (0.05g) in
N-methylpyrrolidinone (2mL). After 0.5h, chloropyrazine (0.013mL) was added and the mixture heated at 60°C for 3h. Aqueous acetic acid was added and the mixture extracted with ethyl acetate. The organic solution was dried (Νa2SO ) and evaporated.
Chromatography on silica gel eluting with ethyl acetate/zsø-hexane mixtures gave the title compound (0.012g). m/e 442(M+l+, 100%) 1H NMR (D6-DMSO) δ 8.36 (IH, s), 8.23 (2H, d), 8.06 (IH, d), 7.87 (IH, d), 7.68 (IH, s),
7.54 (IH, t), 5.26 (2H, s), 3.86 (3H, s).
MP 155°C (dec) .
Example 141 2,3-Dichloro-N-[5-(3-hydroxy-l-propynyl)-3-methoxy-2~ pyrazinyl] benzenesulphonamide
Figure imgf000112_0002
A mixture of N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[ {2- (trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.52g), propargyl alcohol (0.223mL), copper(I)iodide (0.05g) and bz triphenylphosphine)palladium(ll) chloride (O.lg) in triethylamine (3mL) was stirred at room temperature and under nitrogen for 16h. The solvent was evaporated. Chromatography on silica gel eluting with ethyl acetate/zso-hexane mixtures gave the title compound containing the SEM ([2- (trimethylsilyl)ethoxy]methyl) protecting group (0.38g). 0.074g of this compound was dissolved in dichloromethane (2mL) and trifluoroacetic acid (2mL). After lh the solvent was evaporated. Chromatography on silica gel eluting with ethyl acetate/z'^o-hexane mixtures gave the title compound (0.043g). m/e 386(M-l+, 100%) 1H NMR (D6-DMSO) δ 8.07 (IH, d), 7.93 (IH, d), 7.72 (IH, s), 7.58 (IH, t), 4.29 (2H, s), 3.90 (3H, s).
Example 142 N-{3-[(5-Bromo-3-pyridinyl)methoxy]-5-chloro-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
Figure imgf000113_0001
Prepared by the method of Example 31 using (5-bromo-3-pyridinyl)methanol (0.2g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.25g). Yield 0.17g. m/e 523(M-1+, 100%)
1H ΝMR (D6-DMSO) δ 8.77 (IH, d), 8.71 (IH, d), 8.28 (IH, s), 8.07 (IH, dd), 7.92 (IH, d), 7.85 (IH, s), 7.55 (IH, t), 5.43 (2H, s). MP 199-201°C .
Example 143
2,3-Dichloro-N- [5-chloro-3-{ [6-(hydroxymethyl)-2-pyridinyl] methoxy}^2- pyrazinyl]benzenesulphonamide
Figure imgf000114_0001
Prepared by the method of Example 31 using 2,6-bώ(hydroxymethyl)pyridine (0.1 lg) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.1 lg) in N-methylpyπolidinone (2mL). Yield 0.043g. m/e 475(M+l+, 100%)
1H ΝMR (D6-DMSO) δ 7.97 (IH, d), 7.83 (IH, t), 7.68 (IH , d), 7.43-7.35 (4H, m), 5.44 (IH, s), 5.32 (2H, s), 4.58 (2H, s). MP 220°C
Example 144
2,3-Dichloro-N-{5-chloro-3-[(2-methyl-4-oxazolyl)methoxy]-2- pyrazinyljbenzenesulphonamide
Figure imgf000114_0002
Prepared by the method of Example 3 lb using (2-methyl-4-oxazolyl)methanol (0.08g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.26g).
Yield 0.083g. m/e 449(M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.09 (IH, s), 8.03 (IH, dd), 7.94 (IH , dd), 7.85 (IH, s), 7.55 (IH, t), 5.23 (2H, s), 2.45 (3H, s) MP 172-173°C. Example 145 -methyl-4-oxazolyl)methoxy]-2-pyrazinyl}benzenesulphonamide
Figure imgf000115_0001
Prepared by the method of Example 28 using (2-methyl-4-oxazolyl)methanol (0.3g) and
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (0.89g). Yield 0.035g. m/e 412(M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.06 (2H, dd), 7.92 (IH , dd), 7.85 (IH, br s), 7.70 (IH, br s), 7.56
(IH, t), 5.23 (2H, s), 2.41 (3H, s).
MP 207-209°C.
Examples 146-165 were prepared using the following procedure:
To a solution of N-(3,5-dibromo-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 31) (0.003g) and primary alcohol (0.026mL of a 0.5M solution inN- methylpynolidinone) in N-methylpyrrolidinone (O.lmL) was added potassium tert- butoxide (0.050mL of a IM solution in tetrahydrofuran). The solution was allowed to stand for 24 hours. The reaction mixture was diluted with acetic acid (0.01 OmL) and water (0.1 OmL) and the solvents were evaporated. The residue was redissolved in dimethylsulphoxide (0.5mL) and purified by mass directed high pressure liquid chromatography. The solvent was evaporated to afford a solid.
Example 146 iV-[5-Bromo-3-(phenylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000116_0001
m e 489(M+l+, 100%)
Example 147 s N-[5-Bromo-3-(2-cyclopropylethoxy)pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000116_0002
m/e 467(M+l*, 100%)
Example 148
Figure imgf000116_0003
m e 495(M+l+, 100%)
Example 149 N-{5-Bromo-3-[(2~methyl-3-furanyl)methoxy]-2-pyrazinyl}-2,3-
Figure imgf000117_0001
m/e 493(M+l+, 100%)
Example 150
N-{5-Bromo-3-[(3-furanyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenzenesulphonamide
Figure imgf000117_0002
m/e 479(M+l+, 100%)
Example 151
N-{5-Bromo-3-[(4-fluorophenyl)methoxy]-2-pyrazinyI}-2,3- dichlorobenzenesulphonamide
Figure imgf000118_0001
m e 507(M+l+, 100%)
Example 152
N-{5-Bromo-3-[(3-fluorophenyl)methoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
Figure imgf000118_0002
m e 507(M+l+, 100%)
Example 153
N-{5-Bromo-3-[3-(2-pyridinyI)propoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
Figure imgf000119_0001
m/e 518(M+l+, 100%)
Example 154
N-[5-Bromo-3-(pentyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000119_0002
m/e 469(M+l+, 100%)
Example 155 N-[5-Bromo-3-(propyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000119_0003
m/e 441(M+l+, 100%) Example 156
N-[5-Bromo-3-(2-methoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000120_0001
m/e 457(M+l+, 100%)
Example 157 N-[5-Bromo-3-(2-ethoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000120_0002
m/e 471(M+l+, 100%)
Example 158 N-[5-Bromo-3-(2-fluoroethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000121_0001
m e 445(M+l+, 100%)
Example 159 N-{5-Bromo-3-[2-(lH-imidazol-l-yl)ethoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
Figure imgf000121_0002
m/e 493(M+l+, 100%)
Example 160
N-{5-Bromo-3-[3-(3-pyridinyl)propoxy]-2-pyrazinyl}-2,3-
Figure imgf000121_0003
m e 516(M-l+, 100%)
Example 161 N-[5-Bromo-3-[2-(methylamino)ethoxy]-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
Figure imgf000122_0001
m e 456(M+l+, 100%)
Example 162 N-{5-Bromo-3-[3-(4-hydroxyphenyl)propoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
Figure imgf000122_0002
m e 533(M+1+, 100%)
Example 163 N-[5-Bromo-3-(2-phenoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000123_0001
Example 164
N-[5-Bromo-3-(cyclopropylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000123_0002
m/e 453(M+l+, 100%)
Example 165 N-[5-Bromo-3-(3-phenoxypropoxy)-2-pyrazinyl]-2,3-dichlorobenzenesuIphonamide
Figure imgf000123_0003
m/e 531(M-l+, 100%)
Example 166 2,3-Dichloro-N-(5-ethoxy-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000124_0001
Prepared as for Example 56 using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-
[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.3g) and sodium ethoxide (5mL of a 0.5M solution in ethanol). Yield O.lg. m e 378 (M+l, 100%)
1H ΝMR (CDC13) δ 8.22 (IH, d) , 7.65 (IH, d), 7.49 (IH, s), 7.34 (IH, t), 7.30 (IH, s),
4.24 (2H, q), 3.95 (3H, s), 1.36 (3H, t)
MP 96-97°C
Example 167 2,3-Dichloro-N-[3-methoxy-5-([l,2,4]-l-triazolyl)-2-pyrazinyl]benzenesulphonamide
Figure imgf000124_0002
Prepared as for Example 101b (reaction heated at 50°C) using N-(5-bromo-3-methoxy-2- pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide
(Example 55a) (0.25g) and [l,2,4]triazole (O.lg). The intennediate product containing the
SEM (2-[trimethylsilyl]ethoxymethyl) group was purified by silica gel chromatography eluting with ethyl acetate/z'so-hexane mixtures. Deprotection as for Example 101b gave the title compound. Yield 0.035g. m/e 401 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.92 (IH .s), 8.34 (IH, d), 8.24 (IH, s), 8.08 (IH, s), 8.01 (IH, br s),
7.72 (IH, d), 7.43 (IH, t), 4.14 (3H, t)
MP 248-249°C
Example 168 -[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]-N-
Figure imgf000125_0001
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-
[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.4g) and 2- mercapto-N-methylacetamide (0. lg). The intermediate product containing the SEM (2-
[trimethylsilyl]ethoxymethyl) group was purified by silica gel chromatography eluting with ethyl acetate/wo-hexane mixtures. Deprotection as for Example 101b gave the title compound. Yield 0.05g. m/e 437 (M+l+, 100%) 1H ΝMR (CDC13) δ 8.25 (IH, dd), 7.76 (IH, s), 7.68 (IH, dd), 7.58 (IH, s), 7.40 (IH, t),
6.62 (IH, br s), 3.99 (3H, s), 3.69 (2H, s), 2.86 (3H, d)
MP 150-152°C
Example 169 2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-
Figure imgf000125_0002
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-
[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.2g) and 2- mercaptoacetamide (0.05g). The intennediate product containing the SEM group was purified by silica gel chromatography eluting with ethyl acetate/wo-hexane mixtures.
Deprotection as for Example 101b gave the title compound. Yield 0.03g. m/e 423 (M+l+, 100%)
1H ΝMR (CDCU) δ 7.98 (IH, dd ), 7.75 (IH, d), 7.46-7.42 (3H, m), 7.06 (IH, s), 3.83 (3H, s), 2.59 (2H, s)
MP 163-164°C Example 170
2,3-Dichloro-N-[5-(4-fluorobenzylsulphanyl)-3-methoxy-2- e
Figure imgf000126_0001
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- {[2-(trimethylsilanyl)ethoxy]methyl}benzenesulphonamide (Example 55a) (0.4g) and (4- fluorophenyl)methanethiol (0.13g). The intermediate product containing the SEM group was purified by silica gel chromatography eluting with ethyl acetate/zso-hexane mixtures. Deprotection as for Example 101b gave the title compound. Yield 0.2g m/e 474 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.25 (IH, dd), 7.73 (IH, s), 7.67 (IH, dd), 7.51 (IH, s), 7.38 (IH, t),
7.27 (2H, m), 6.92 (2H, m), 4.24 (2H, s), 4.01 (3H, s)
MP 119-120°C
Example 171
2,3-Dichloro-N-[5-cyanomethylsulphanyl-3-methoxy-2- pyrazinyl]benzenesulphonamide
Figure imgf000126_0002
See example 172 for preparation. m/e 403 (M-l+, 100%)
1H NMR (CDC13) δ 8.28 (IH, dd), 7.84 (IH, s), 7.69 (IH, dd), 7.63 (IH, s), 7.38 (IH, t), 4.11 (3H, s), 3.78 (2H, s)
MP 158-159°C
Example 172
Figure imgf000127_0001
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- [{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.4g), [1,2,4]- 3-oxadiazolylmethanethiol (0.15g) and cesium carbonate (0.5g) at room temperature for 16h. The intermediate products containing the SEM (2-[trimethylsilyl]ethoxymethyl) group was purified by silica gel chromatography eluting with ethyl acetate/zso-hexane mixtures. Deprotection as for Example 101b gave the title compound (0.09g) and 2,3- dichloro-N-[5-cyanomethylsulphanyl-3-methoxy-2-pyrazinyl]benzenesulphonamide (Example 171) (O.lg) which were separated by silica gel chromatography eluting with dichloromethane. m/e 448 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.64 (IH, s), 8.26 (IH, dd), 7.76 (IH, s), 7.67 (IH, dd), 7.57 (IH, s), 7.37 (IH, t), 4.39 (2H, s), 4.04 (3H, s) MP 154-156°C
Example 173 N-[5-(2-Aminoethylsulphanyl)-3-methoxy-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
Figure imgf000127_0002
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- [{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.45g) and 2- aminoethanethiol hydrochloride (0.2g). Yield 0.03g m e 409 (M+l+, 100%) lH ΝMR (D6-DMSO) δ 8.02 (IH, dd), 7.94 (IH, dd), 7.87 (IH, s), 7.70 (IH, s), 7.58 (IH, t), 3.93 (3H, s), 3.48 (2H, br s), 3.28 (2H, t), 3.10-3.03 (2H, m) MP 189-190°C
Example 174 2,3-Dichloro-N-[3-methoxy-5-(5-methyl-3-isoxazolylmethoxy))-2-
s pyrazinyl]benzenesulphonamide
Figure imgf000128_0001
Prepared as for Example 115b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- [{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.3g) and (5- methyl-3-oxazolyl)methanol (0.13g). The intennediate product containing the SEM (2- [trimethylsilyl]ethoxymethyl) group was purified by silica gel chromatography eluting o with ethyl acetate/zsO-hexane mixtures. Deprotection as for Example 115b gave the title compound. Yield 0.2g m/e 445 (M+l+, 100%)
1H ΝMR (CDC13) δ 8.22 (IH, dd), 7.66 (IH, dd), 7.59 (IH, s), 7.38 (2H, t), 6.01 (IH, t), 5.31 (2H, s), 3.97 (3H, s), 2.43 (3H, s) 5 MP 142-143°C
Example 175
2,3-Dichloro-N-[5-(5-dimethylaminomethyl-2-furanylmethoxy)-3-methoxy-2- pyrazinyl]benzenesulphonamide 0
Figure imgf000128_0002
Prepared as for Example 115b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- [{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.3g) and (5- dimethylaminomethyl-2-furanyl)methanol (0.2g). After removal of the SEM (2- [trimethylsilyl]ethoxymethyl) group the title compound was purified by silica gel chromatography eluting with methanol/dichloromethane mixtures Yield 0.23g m/e 487 (M+l+, 100%)
1H NMR (CDC13) δ 8.21 (IH, dd), 7.66 (IH, dd), 7.37 (2H. t), 6.39 (2H, s), 5.20 (2H, s),
4.00 (3H, s), 3.84 (2H, s), 2.51 (6H, s)
MP 114-115°C
Example 176
N-[5-Bromo-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyrazinyI]-2,3-dichloro- benzenesulphonamide
Figure imgf000129_0001
Prepared by the method of Example 31 using (5-dimethylaminoιnethyl-2-furanyl)hιethanol (0.2g) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (Example 31a) (0.2g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures and recrystallised from acetonitrile. Yield 0.058g. m/e 535 (M+l+, 100%) 1H ΝMR (D6-DMSO) δ 7.92 (IH, dd), 7.63 (IH, dd), 7.36 (2H, t), 6.71 (IH, d), 6.68 (IH, d), 5.22 (2H, s), 4.37 (2H, d), 2.75 (6H. s) MP 206-207°C
Example 177
Figure imgf000129_0002
i fjb l h id Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- [{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.2g) and 2- mercaptoethanol (0.2g). After removal of the SEM (2-[trimethylsilyl]ethoxymethyl) group the title compound was purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.015g m/e 410 (M+l+, 100%)
Η NMR (CDC13) δ 8.27 (IH, dd), 7.78 (IH, s), 7.67 (IH, dd) , 7.61 (IH, s), 7.39 (IH. t),
4.04 (3H, s), 3.83 (2H, t), 3.24 (2H, t)
MP 180-181°C ,
Example 178
Figure imgf000130_0001
Ethylisocyanate (0.016g) was added to N-[5-(2-aminoethylsulphanyl)-3-methoxy-2- pyrazinyl]-2,3-dichloro-benzenesulphonamide (Example 173) (0.08g) in dichloromethane (5mL). After lh, the reaction mixture was evaporated to dryness. Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.015g. m/e 480 (M+l+, 100%)
1H ΝMR (CDCI3) δ 8.27 (IH, dd), 7.69 (IH, dd), 7.56 (IH, s), 7.39 (IH, t), 4.60 (IH, br s), 4.18 (IH, br s), 4.04 (3H, s), 3.40-3.30 (2H, m), 3.30-3.2 (2H, m), 3.25-3.20 (2H, m), 1.15 (3H, t)
Example 179
2,3-Dichloro-N-[3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-
Figure imgf000130_0002
razinyl]benzenesulphonamide ^ — Prepared by the method of Example 28 using (5-dimethylaminomethyl-2-furanyl)methanol (0.2g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.4g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.2g. m/e 455 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 7.96 (IH, dd), 7.66 (IH, dd), 7.40 (IH, t), 7.30 (IH, d), 7.24 (IH, d), 6.65 (IH, s), 6.64 (IH, d), 5.23 (2H, s), 4.25 (2H, s), 2.66 (6H, s)
Example 180 2,3-DichIoro-N-[6-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-
Figure imgf000131_0001
Prepared by the method of Example 31 using (5-dimethylaminomethyl-2-furanyl)methanol (0.2g) and N-(3-bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.3g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.1 lg. m/e 491 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.01 (IH, dd), 7.66 (IH, dd), 7.39 (IH, t), 7.11 (IH, s), 6.69 (IH, d), 6.67 (IH, d), 5.20 (2H, s), 4.39 (2H, s), 2.76 (6H, s) MP 209-210°C
Example 181 2,3-Dichloro-N-[6-chloro-3-(5-methylaminomethyl-2-furanylmethoxy)-2-
pyrazinyljb enzenesulphonamide
Figure imgf000131_0002
Prepared by the method of Example 31 using (5-methylaminomethyl-2-furanyl)methanol (0.3g) and 2,3-dichloro-N-(3,5-dichloiO-2-pyrazinyl)benzenesulphonamide (Example 74) (0.4g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.03g. m/e 477 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.98 (2H, br), 7.92 (IH, d), 7.63 (IH, d), 7.35 (IH, t), 7.29 (IH, s), 6.67 (IH, d), 6.64 (IH, d), 5.20 (2H, s), 4.25 (2H, s), 2.59 (3H, s)
MP 211-212°C
Example 182
2,3-Dichloro-N-[5-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2- pyrazinyljbenzenesulphonamide
Figure imgf000132_0001
Prepared by the method of Example 31 using (5-dimethylaminomethyl-2-furanyl)methanol (0.3g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74)
(0.4g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.30g. m/e 491 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 7.93 (IH, dd), 7.65 (IH, dd), 7.36 (IH, t), 7.32 (IH, s), 6.71 (IH, d), 6.69 (IH, d), 5.23 (2H, s), 4.38 (2H, s), 2.75 (6H, s)
MP 209-210°C
Example 183
2,3-Dichloro-N-[3-(5-methylaminomethyl-2-furanylmethoxy)-2- pyrazinyl] benzenesulphonamide
Figure imgf000133_0001
Prepared by the method of Example 28 using (5-methylaminomethyl-2-furanyl)methanol (0.2g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.4g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.12g. m/e 443 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.99 (2H, br s), 7.95 (IH, d), 7.62 (IH, d), 7.35 (IH, t), 7.24 (IH, d), 7.15 (IH, d), 6,88 (IH, d), 6.63 (IH, d), 5.20 (2H, s), 4.24 (2H, s), 2.58 (3H, s) MP 198-199°C
Example 184 N-(5-Bromo-3-methoxypyrazinyl)-2-cyanobenzenesulphonamide
Figure imgf000133_0002
Prepared by the method of Example 1 (reaction performed at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0.2g) and 2-cyanobenzenesulphonyl chloride (0.24g).
Yield 0.059g. m e 369/370 (M+l+), 307/309 (100%)
1H ΝMR (D6-DMSO) δ 8.14 (IH, d), 8.09 (IH, d), 7.93-7.82 (3H, m), 3.93 (3H, s).
MP 190-191.5°C
Example 185 N-(5-Bromo-3-methoxypyrazinyI)-2,3-dichloro-4-fluorobenzenesuIphonamide a) 2,3-Dichloro-4-fluorobenzenesulphonyl chloride
Figure imgf000134_0001
Chlorosulphonic acid (12. ImL) was added dropwise to a solution of 2,3-dichloro-4- fluorobenzene (5.0g) in dichloromethane (12mL) at -40°C. The solution was allowed to slowly wann to room temperature and was stirred for 3 days. The solution was poured onto crushed ice/water, extracted into dichloromethane and concentrated under reduced pressure. Purified by silica gel chromatography eluting with dichloromethane/zso-hexane mixtures. Yield 4.2g m/e 262/264 (M+), 163 (100%).
b) N-(5-Bromo-3-methoxypyrazinyl)-2,3-dichloro-4-fluorobenzenesulphonamide
Figure imgf000134_0002
Prepared by the method of Example 1 (reaction perfonned at room temperature) using 5- bromo-3-methoxy-2-pyrazinamine (0.2g) and 2,3-dichloro-4-fluorobenzenesulphonyl chloride (Example 185a) (0.3 lg). Yield 0.042g.
Figure imgf000134_0003
1H ΝMR (D6-DMSO) δ 8.16-8.12 (IH, m), 7.81 (IH, s), 7.68-7.64 (IH, m), 3.92 (3H, s). MP 208-211°C
Example 186
2,3-Dichloro-N-[3-methoxy-5-(4-morpholinylmethyl)-2- pyrazinyl]benzenesulphonamide
a) 2,3-Dichloro-N-(5-fonnyl-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000135_0001
Prepared as for Example 107a using 2,3-dichloro-N-[5-(hydroxymethyl)-3-methoxy-2- pyrazinyl]benzenesulphonamide (Example 138) (0.6g). Yield 0.53g. Used directly.
b) 2,3-Dichloro-N-[3-methoxy-5-(4-morpholinylmethyl)-2- pyrazinyl]benzenesulphonamide
Figure imgf000135_0002
Prepared as for Example 107b using 2,3-dichloro-N-(5-formyl-3-methoxy-2- pyrazinyl)benzenesulphonamide (Example 186a) (0.26g) and morpholine (3.7mL). Yield 0.057g. m/e 433 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.12 (IH, d), 7.94(1H, d), 7.59 (IH, t), 4.20 (2H, s), 3.96 (3H, s),
3.85-3.65 (5H, m)
Example 187
N-(3-AUyloxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
Figure imgf000135_0003
Prepared by the method of Example 31 using allyl alcohol (lOmL) as solvent and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.35g). Yield 0.32g. m/e 393 (M-l+, 100%) 1H ΝMR (D6-DMSO) δ 11.80 (IH, br s) , 8.08 (IH, dd) , 7.96 (IH ,dd) , 7.82 (IH, dd), 7.58 (IH, t) , 6.10-6.00 (IH, m) , 5.49 (IH, dddd) , 5.29 (IH, dddd) ,4.86 (2H, dddd) MP 145-146°C
Example 188 2,3-Dichloro-N-[5-chIoro-3-(2-propynyloxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000136_0001
Prepared by the method of Example 31 using propargyl alcohol (0.3g) and 2,3-dichloro-N- (3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.35g). Yield 0.2g. m/e 390 (M-l+, 100%) 1H ΝMR (D6-DMSO) δ 8.08 (IH, dd) , 7.95 (IH, dd) , 7.86 (IH, s) , 7.58 (IH, t) , 5.02 (2H, d) , 3.65 (IH, t) MP 138-139°C
Example 189 2,3-Dichloro-N-[3-(2-propynyloxy)-2-pyrazinyl)benzenesulphonamide
Figure imgf000136_0002
Prepared by the method of Example 28 using propargyl alcohol as solvent (3mL), 2,3- dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.3g) and sodium hydride (0.2g of a 60% dispersion in oil) at room temperature for 16h. Yield 0.27g. m/e 356 (M-l+, 100%) 1H NMR (D6-DMSO) δ 11.67 (IH, br s) , 8.10 (IH, dd) , 7.94 (IH , dd) , 7.85 (IH , br) , 7.72 (IH , br) , 7.59 (IH, t) , 5.01 (2H, d) , 3.56 (IH, t) MP 153-154°C
Example 190 o-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000137_0001
Prepared as for Example 78 using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3- dichlorobenzenesulphonamide (Example 8) (O.lg). Yield 0.034g. ' m/e 357 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.15 (IH, s) , 8.14 (IH, dd), 7.95 (IH, dd) , 7.59 (IH, t) , 3.96
(3H, s)
MP 239-240°C
Example 191
2,3-Dichloro-N-{3-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-2- pyrazinyljbenzenesulfonamide hydrochloride
Figure imgf000137_0002
Procedure as for Example 115 using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- ({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 55a) (0.5 g), tert- butyl (2S)-2-(hydroxymethyl)pyιτolidine-l-carboxylate (0.603 g) and sodium hydride (0.12g of a 60%) dispersion in oil) in N-methylpyrrolidinone (20mL). The adduct was deprotected with HCl (4M n dioxane) to afford the titled adduct (0.24 lg) as a white solid, m/e 433, 435 (M-HC1+1+, 100%)
1H ΝMR (D6-DMSO) δ 10.92 (IH, s), 9.45 (IH, br), 8.93 (IH, br), 7.98 (IH, d), 7.93 (IH, d), 7.57(1H, d), 7.52 (IH, d), 4.53 (IH, dd), 4.37 (IH, dd), 3.94-3.86 (IH, m), 3.85 (3H, s), 3.22-3.18 (2H, m), 2.13-2.08 (IH, m), 1.99-1.86 (2H, m), 1.76-1.67 (IH, m). Example 192
2,3-Dichloro-N-{6-chloro-3-methoxy-5-[(2R)-2-pyrrolidinylmethoxy]-2- pyrazinyl}benzenesulphonamide Hydrochloride
Figure imgf000138_0001
Procedure as for Example 115 using 2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-
N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66a) (0.29g), tert- butyl (2S)-2-(hydroxymethyl)pynolidine-l-carboxylate (0.15 g) and sodium hydride
(0.04g of a 60%) dispersion in oil) in N-methylpyrrolidinone (20mL). The adduct was deprotected with HCl (4M in dioxane) to afford the titled adduct (0.2g) as a white solid. m/e 464 (M+H+, 100%)
1H ΝMR (D6-DMSO) δ 11.24 (IH, br s), 9.46 (IH, br s), 8.99 (IH, br s), 8.01 (IH, d),
7.96 (IH, d), 7.59 (IH, m), 4.61 (IH, dd), 4.46 (IH, dd), 3.95 (IH, br s), 3.85 (3H, s), 3.19
(2H, br s), 2.16-2.07 (IH, br s), 2.03-1.94 (IH, br s), 1.92-1.85 (IH, br s), 1.81-1.72 (IH, br s).
MP 200-204°C
Example 193
2,3-Dichloro-N-[3-methoxy-5-(2-pyridinylmethoxy)-2- pyrazinyl] benzenesulphonamide Hydrochloride
Figure imgf000138_0002
Procedure as for Example 115 using N-(5-chloro-3-methoxy-2 -pyrazinyl)-2,3-dichl oro-N- ({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.5 g), pyridine-3 -methanol (0.11 g) and sodium hydride (0.05g of a 60% dispersion in oil) in N- methylpyπolidinone (5mL). Yield 0.23g. m/e 438 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 10.9 (IH, br s), 8.7 (IH, br s), 8.12 (IH, t), 7.99-7.92 (2H, m), 7.74 (IH, d), 7.61 (IH, s), 7.63-7.53 (2H, m), 5.54 (2H, s), 3.73 (3H, s). MP 180-183°C.
Example 194
2,3-Dichloro-N-(3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide
Figure imgf000139_0001
To a solution of 5-bromo-3-methoxy-6-methyl-2-pyrazinamine (Example 118c) (0.8g) and ammonium formate (0.4g) in methanol (20mL) was added palladium on carbon (0.2g) and the reaction mixture heated at reflux for 5h. After cooling to room temperature, the reaction mixture was filtered through a plug of celite, and the filtrate evaporated. The residue was partitioned between dichloromethane and water, and the organic phase dried (MgSO4), filtered and evaporated to give the title compound as a white solid (0.44g). 1H NMR (D6-DMSO) δ 7.10 (IH, s), 6.15 (2H, br s), 3.83 (3H, s), 2.14 (3H, s)
-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide
Figure imgf000139_0002
A solution of 3-methoxy-6-methyl-2-pyrazinamine (Example 194a) (0.050g) and 2,3- dichlorobenzenesulphonyl chloride (0.098g) in pyridine (0.3mL) was stirred at room temperature for 18h. Solvent was evaporated to give a residue which was purified by chromatography on silica gel eluting with dichloromethane/ethyl acetate/acetic acid (200:4:1) giving the title compound as a pale orange solid (0.07 lg). m/e 348/350 (M+H+, 100%)
1H NMR (D6-DMSO) δ 11.44 (IH, br s), 8.14 (IH, dd), 7.92 (IH, dd), 7.65 (IH, br s),
7.61 (IH, t), 3.85 (3H, s), 2.07 (3H, br s).
MP 50-60°C
Example 195
2,3-Dichloro-N-[3-methoxy-5-(lH-l,2,4-triazol-l-ylmethyl)-2- pyrazinyljbenzenesulphonamide a) 2,3-Dichloro-N-[5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]-N-{[2-
Figure imgf000140_0001
To a suspension of 2,3-dichloro-N-[5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]- benzenesulphonamide (l.Og) in dichloromethane (lOOmL) was added diisopropylethylamine (0.57mL) and 2-(trimethylsilyl)ethoxymethyl chloride (0.58mL). The reaction mixture was stined at room temperature for 0.5h, then washed with water. The organic phase was dried (MgSO ), filtered and evaporated to give a yellow oil. This was purified by chromatography on silica gel eluting with dichloromethane/ethyl acetate mixtures to give the title compound as a colourless oil (0.8g).
1H ΝMR (CDC13) δ 8.04 (IH, s), 7.99 (IH, d), 7.66 (IH, d), 7.28 (IH, t), 5.27 (2H, s), 4.74 (2H, d), 3.90 (3H, s), 3.78 (2H, m), 2.58 (IH, t), 0.85 (2H, m), 0.00 (9H, s).
b) 2,3-Dichloro-N-[3-methoxy-5-(lH-l,2,4-triazol-l-ylmethyl)-2-pyrazinyl] benzenesulphonamide
Figure imgf000141_0001
To a solution of 2,3-dichloro-N-[5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]-N-{[2- (trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 195a) (O.lg) and triethylamine (0.056mL) in dichloromethane (5mL) at 0°C was added methanesulphonyl chloride (0.019mL) and the reaction mixture stirred at 0°C for lh and room temperature for lh. The solution was filtered through a plug of silica washing with ethyl acetate and concentrated in vacuo to give a colourless oil (0.082g). This was dissolved inNN- dimethylformamide (0.5mL) and 1,2,4-triazole (0.013g) and sodium carbonate (0.026g) added. The reaction mixture was heated at 60°C for 18h, then partitioned between ethyl acetate and saturated aqueous ammonium chloride (5x). The organic phase was dried
(MgSO4), filtered and evaporated. The residue was dissolved in trifluoroacetic acid (2mL) and dichloromethane (2mL). After 20min, removal of solvent in vacuo gave a residue which was purified by chromatography on silica gel eluting with ethyl acetate/acetic acid mixtures to give the title compound a pale yellow sollid (0.01 lg). m e 413/415 (M-H\ 100%)
1H ΝMR (CDC13) δ 8.27 (2H, m), 8.0 (IH, br s), 7.94 (IH, s), 7.68 (IH, d), 7.58 (IH, br s), 7.41 (IH, t), 5.25 (2H, s), 3.97 (3H, s). MP 95-105°C
Example 196
N-(3-(5-Aminomethyl-2-furanylmethoxy)-5-chloro-2-pyrazinyl)-2,3-dichloro-
Figure imgf000141_0002
Prepared by the method of Example 31 using (5-aminomethyl-2-furanyl)methanol (0.2g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.3g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield O.lg. m e 463 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 8.25 (2H, br s), 7.92 (IH, dd), 7.61 (IH, dd), 7.35 (IH, t), 7.27
(IH, s), 6.66 (IH, d), 6.57 (IH, d), 5.19 (2H, s), 4.14 (2H, s)
MP 201-202°C
Example 197
N-(3-(5-Aminomethyl-2-furanylmethoxy)-2-pyrazinyl)-2,3- dichlorobenzenesulphonamide
Figure imgf000142_0001
repared by the method of Example 28 using (5-aminomethyl-2-furanyl)methanol (0.2g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example 28) (0.3g).
Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures.
Yield 0.2g. m/e 427 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.40 (2H, br s), 7.96 (IH, dd), 7.60 (IH, dd), 7.35 (IH, t), 7.24 (IH, d), 7.15 (IH, d), 6.64 (IH, d), 6,57 (IH, d), 5.20 (2H, s), 4.13 (2H, s)
MP 199-201°C
Example 198 2,3-DichIoro-N-[3-methoxy-5-(2-propyn-l-yloxy)-2-pyrazinyl]benzenesulphonamide
Figure imgf000142_0002
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N- ({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25g), propargyl alcohol (0.025mL) and sodium hydride (0.035g of a 60% dispersion in oil) in NN-dimethylfonnamide (5mL). Yield 0.05g. m/e 388 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 10.90 (IH, s), 7.98-7.94 (2H, m), 7.55 (IH, t), 7.51 (IH, s), 4.97 (2H, d), 3.85 (3H, s), 3.56 (IH, t) MP 110-112°C
Example 199
{ [5-(2,3-Dichlorophenylsulfonylamino)-6-methoxy-2-pyrazinyl] oxy} acetic acid, methyl ester
Figure imgf000143_0001
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N- ( {2-[(trimethylsilyl)oxy] ethoxy} methyl)benzenesulphonamide (Example 115a) (0.26g), methyl glycolate (0.075mL) and sodium hydride (0.035g of a 60% dispersion in oil) in
NN-dimethylfonnamide (5mL). Yield O.lg m/e 422 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 10.89 (IH, s), 7.99-7.92 (2H, m), 7.58-7.53 (2H, m), 4.92 (2H, s), 3.75 (3H, s), 3.68 (3H, s).
MP 185-190°C
Example 200
N-[5-(2,3-Dichlorophenylsulphonylamino)-6-methoxy-2-pyrazinyl]-2- hydroxyacetamide
Figure imgf000144_0001
Procedure as for Example 115 using 2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N- ({2-[(trimethylsilyl)oxy]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25g), glycolamide (0.066g) and sodium hydride (0.035g of a 60%> dispersion in oil) in NN- dimethylfonnamide (5mL). Yield 0.075g. m/e 407 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 11.23 (IH, br s), 9.77 (IH, s), 8.36 (IH, s), 8.05 (IH, dd), 7.94 (IH, dd), 7.58 (IH, t), 4.04 (2H, s), 3.86 (3H, s). MP 153-155°C
Example 201
6-(2,3-Dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxylic acid, methyl ester
a) 6-chloro-3-methoxy-2-pyrazinamine
Figure imgf000144_0002
A mixture of 5-bromo-6-chloro-3-methoxy-2-pyrazinamine (Example 125a) (0.6g), triethylamine (0.72mL), 10% palladium on carbon (0.05g) and ethyl acetate (50mL) were hydrogenated at 0.5 bar until reaction was complete as judged by hydrogen uptake. The reaction mixture was filtered and washed with water (25mL), dried (MgSO4), filtered and evaporated to afford the sub-titled compound (0.33g). Used Directly.
b) 6-Aιnino-5-methoxypyrazine-2-carboxylic acid methyl ester
Figure imgf000145_0001
Prepared as for Example 113 using 6-chloro-3-methoxy-2-pyrazinamine (Example 201a) (0.35g) heated at 120°C for 3h. Yield 0.3g. m/e 184(M+1+, 100%)
c) 6-(2,3-Dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxylic acid, methyl ester
Figure imgf000145_0002
Prepared by the method of Example 1 (reaction performed at room temperature) using 6- amino-5-methoxypyrazine-2-carboxylic acid methyl ester (Example 201b) (0.3g) and 2,3- dichlorobenzenesulphonyl chloride (0.4g). Yield 0.15g. m/e 392 (M+l+, 100%)
1H NMR (D6-DMSO) δ 8.39 (IH, s), 8.25 (IH, dd), 7.93 (IH, dd), 7.65 (IH, t), 3.99 (3H, s), 3.77 (3H, s) MP 90-92°C
Example 202 2,3-Dichloro-N-[6-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide
Figure imgf000145_0003
Prepared as for example 120 using 6-(2,3-dichlorophenylsulphonylamino)-5-methoxy-2- pyrazinecarboxylic acid, methyl ester (Example 201) (0.12g). Yield 0.03g. m/e 364 (M+l+, 100%) 1H NMR (D6-DMSO) δ 11.5 (lH. br s), 8.13 (IH, dd), 7.92 (IH, dd), 7.77 (lH, br s), 7.59 (IH, t), 5.25 (IH, br s), 4.19 (2H, s), 3.87 (3H, s). MP 153-155°C
Example 203
2,3-Dichloro-N-(5-methanesulphonyl-3-methoxy-2-pyrazinyl)benzenesuIphonamide
Figure imgf000146_0001
Oxone (potassium peroxymonosulphate) (0.6g) was added to 2,3-dichloro-N-(3-methoxy-
5-methylsulphanyl-2-pyrazinyl)benzenesulphonamide (Example 80) (0.3g) in methanol (40mL) and water (lOmL) and the mixture heated at 50°C for 4h. After cooling, the mixture was filtered and evaporated. Purified by silica gel chromatography eluting with ethyl acetate/z'sO-hexane mixtures containing 1% acetic acid to give the title compound.
Yield 0.2g. m/e 411 (M-l+, 100%) 1H ΝMR (CDC13) δ 8.33 (IH, s), 8.30 (IH, s), 8.23 (IH, br s), 7.72 (IH , dd), 7.47 (IH, t),
4.14 (3H, s), 3.11 (3H, s)
MP 237-238°C
Example 204 2-[5-(2,3-DichlorobenzenesulphonyIamino)-6-methoxy-2-pyrazinyloxy]-N,N-diethyl- acetamide
Figure imgf000146_0002
Prepared as for Example 115b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- [{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.35g) and NN-diethyl-2-hydroxyacetamide (0.13g). Yield 0.2g m/e 463 (M+l+, 100%)
Η ΝMR (CDCI3) δ 8.22 (IH, dd), 7.68 (IH, dd), 7.52 (IH, s), 7.46 (IH, s), 7.37 (IH, t), 4.88 (2H, s), 3.92 (3H, s), 3.38 (2H, q), 3.30 (2H, q) , 1.20 (3H, t), 1.11 (3H, t) MP 117-118°C
Example 205
2,3-Dichloro-N-{5-[2-(dimethylamino)ethylsulphanyl]-3-methoxy-2- pyrazinyl}benzenesulphonamide
Figure imgf000147_0001
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N- {[2-(trimethylsilanyl)ethoxy]methyl}benzenesulphonamide (Example 55a) (0.3g) and 2- (dimethylamino)ethanthiol hydrochloride (0.2g). Yield 0.25g. m/e 435(M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.05 (IH, dd) , 7.95 (IH, dd) , 7.71 (IH, s) , 7.58 (IH, t ) , 3.98
(3H, s), 3.47 (2H, m), 3.28 (2H, m), 2.77 (6H, s)
MP 117-118°C
Example 206
2,3-Dichloro-N-(5-difluoromethyl-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000147_0002
(Diethylamino)sulphur trifluoride (DAST) (0.15g) and 2,3-dichloro-N-(5-formyl-3- methoxy-2-pyrazinyl)benzenesulphonamide (Example 186a) (0.3g) in dichloromethane (20mL) was stined at room temperature for 4h and then evaporated. Purified by silica gel chromatography eluting with ethyl acetate/zso-hexane mixtures to give the title compound.
Yield 0.06g. m/e 382(M-l+, 100%)
1H ΝMR (D6-DMSO) δ 8.14 (IH, dd), 7.96 (IH, dd), 7.84 (IH, s), 7.60 (IH, t), 6.80 (IH, t), 3.95 (3H, s)
MP 117-118°C
Example 207 2,3-Dichloro-4-fluoro-Ν-(3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000148_0001
Sodium hydride (0.4g of a 60% dispersion in oil) was added to a solution of 3-methoxy-2- pyrazinamine (0.25g) in N-methylpyrrolidinone (lOmL). After 0.5h, 2,3-dichloro-4- fluorobenzenesulphonyl chloride (Example 185a) (0.63g) was added. After 16h at room temperature the reaction mixture was quenched with 2M aqueous HCl, extracted with ethyl acetate, dried (MgSO4) and evaporated. Purification was by silica gel chromatography eluting with ethyl acetate/zso-hexane mixtures. Yield 0.16g. m e 350/352 (M-r, 100%)
1H ΝMR (D6-DMSO) δ 8.16 (IH, dd), 7.78 (IH, br s), 7.68 (IH, t), 7.62 (IH, br s), 3.9
(3H, s)
MP 192-194 °C
Example 208 2,3-Dichloro-Ν-{5-chloro-3-[l-(cyclopropyl)ethoxy]-2- pyrazinyljbenzenesulphonamide
Figure imgf000148_0002
Prepared by the method of Example 31b using l-(cyclopropyl)ethanol (O.lg) and 2,3- dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (O.lg). Yield
0.04g. m/e 422 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 11.70-11.50 (lH, br s), 8.07 (IH, dd), 7.94 (IH, dd), 7.77 (IH, s),
7.59 (IH, t), 4.60-4.50 (IH, m), 1.33 (3H, d), 1.1-1.0 (IH, m), 0.6-0.3 (4H, m)
MP 161-162°C Example 209
2,3-Dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2- py r azinyl] b enzenesulphonamide
a) [5-(l,3-Dimethyl-2-imidazolidinyl)-2-furanyl]methanol
Figure imgf000149_0001
5-hydroxymethylfuran-2-carbaldehyde (5.0g) and N,N'-dimethylethane-l,2-diamine (3.8g) in toluene (lOOmL) was heated under reflux using a Dean and Stark apparatus. After 12h, the toluene was evaporated to give an oil. Yield 8.3g. Used directly.
b) 2,3-Dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide
Figure imgf000149_0002
Prepared by the method of Example 31b (reaction heated at 60°C for 4h) using [5-(l,3- dimethyl-2-imidazolidinyl)-2-furanyl]methanol (2.3g) and 2,3-dichloro-N-(3,5-dichloro-2- pyrazinyl)benzenesulphonamide (Example 74) (3.0g). The reaction was quenched with 2M hydrochloric acid and left for 16h. The solid product was collected. Purified by silica gel chromatography eluting with ethyl acetate/z'so-hexane mixtures to give the title compound.
Yield 2.5g. m/e 460 (M+l+, 100%)
1H ΝMR (D6-DMSO) δ 9.64 (IH, s), 8.06 (IH, dd), 7.94 (IH, dd), 7.87 (IH, s), 7.57 (2H, d+t), 6.93 (IH, d), 5.47 (2H, d)
Example 210 2,3-Dichloro-N-[5-chloro-3-(5-cyclopropylaminomethyl-2-furanylmethoxy)-2- pyrazinylj-benzenesulphonamide
Figure imgf000150_0001
Prepared by the method of Example 107b using 2,3-dichloro-N-[5-chloro-3-(5-formyl-2- furanylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 209) (0.3g) and cyclopropylamine (O.lg). Yield O.lg. m/e 503 (M-l+, 100%)
1H ΝMR (D6-DMSO) δ 7.93 (IH, dd), 7.63 (IH, dd), 7.36 (IH, t), 7.30 (IH, s), 6.66 (IH, d), 6.63 (IH, d), 5.21 (2H, s) , 4.34 (2H, s) , 2.71 (IH, m) , 0.76 (4H, m) MP 175-176°C
Example 211
N-[5,6-b/s-(HydroxymethyI)-3-methoxy-2-pyrazinyI]-2,3- dichlorobenzenesulphonamide
a) 2,3-Dichloro-N-(5,6-dicyano-3-methoxy-2-pyrazinyl)benzenesulphonamide
Figure imgf000150_0002
Prepared by the method outlined in Example 1 using 5-amino-6-chloro-2,3- dicyanopyrazine (1.8g) and 2,3-dichlorobenzenesulfonyl chloride (2.7g). The adduct was reacted by the method outlined in example 31b using sodium methoxide to afford the subtitled compound that was used directly. m/e 382, 383 (M-l+, 100%)
b) 5-{[(2,3-Dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2,3-dicarboxylic acid, dimethyl ester
Figure imgf000151_0001
The crude product from above (Example 211a) was dissolved in 10% aqueous sodium hydroxide solution and heated under reflux for 10 hours. The reaction mixture was cooled, concentrated and the residue was treated with thionyl chloride (3 OmL) and refluxed for 1 s hour, cooled and concentrated, azeotroping with dry toluene. The resulting residue was dissolved in methanol (3 OmL) and allowed to stand for 10 hours and concentrated to afford the sub-titled compound that was used directly, m/e 448, 450 (M-l+, 100%)
o c) N-[5,6-b/i,-(Hydroxymethyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
Figure imgf000151_0002
To a solution of 5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2,3- dicarboxylic acid, dimethyl ester (Example 21 lb, 0.5g) dissolved in anhydrous tetrahydrofuran (20 mL) at 0°C was added a solution of lithium triethylborohydride (Super s hydride®) (5.55 mL of a IM solution in tetrahydrofuran) and the resulting solution was stirred for 1 hour. The reaction was quenched by the addition of IN hydrochloric acid (10 mL) and extracted into ethyl acetate (2x20mL). The combined extracts were dried (MgSO4), filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with ethyl acetate/dichloromethane mixtures to afford the titled 0 compound (0.201 g) as a foam, m/e 392, 394 (M-l+, 100%)
1H ΝMR (CDC13) δ 8.30 (IH, d); 7.91 (IH, br s), 7.71 (IH, d), 7.46 (IH, t), 4.59 (2H, s), 4.50 (2H, s), 4.0 (3H, s)
5 Example 212
N-[3-[(2-amino-4-oxazolyl)methoxy]-5-chloro-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
a) (4-Hydroxymethyl-2-oxazolyl)carbamic acid tez-t-butyl ester
Figure imgf000152_0001
Prepared by the method of Example 120 using 2-{bis[(l,l- dimethylethoxy)carbonyl]amino}-4-oxazolcarboxylic acid, ethyl ester (0.65g) and sodium triethylborohydride (5.5mL of a IM solution in tetrahydrofuran). Yield 0.24g. Used directly.
b) N-[3-[(2-amino-4-oxazolyl)methoxy]-5-chloro-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
Figure imgf000152_0002
Prepared by the method of Example 112 using (4-hydroxymethyl-2-oxazolyl)carbamic acid te/ -butyl ester (Example 212a) (0.12g) and 2,3-dichloro-N-(3,5-dichIoro-2- pyrazinyl)benzenesulphonamide (Example 74) (0.2 lg). Purification was by silica gel chromatography eluting with ethyl acetate/wo-hexane mixtures to give the title compound with the BOC (tert-butyl carbonyl) attached (0.1 lg). This compound was dissolved in trifluoroacetic acid (1.5mL) and dichloromethane (1.5mL). After 2h, the solution was evaporated. Purification was by silica gel chromatography eluting with ethyl acetate/tsø- hexane mixtures to give the title compound. Yield 0.08g. m/e 450 (M+l+, 100%) 1H ΝMR (D6-DMSO) δ 8.04 (IH, dd), 7.91 (IH, dd), 7.80 (lH,s), 7.55 (IH, t), 7.49 (IH, s), 6.71 (2H, br s), 5.10(2H, s). MP 137°C Pharmacological Analysis
FMAT Whole cell binding assay
Cells
CHO-K1 cells stably expressing the human recombinant CCR4 receptor (Euroscreen; Brussels, Belgium) were cultured in NUT.MIX.F_12(HAM) medium with glutamax-1, containing 10% (v/v) foetal bovine serum and 400 μgml"1 geneticin.
Cells were harvested at approximately 70%> confluence by treatment with a cell dissociation buffer, and seeded at 5xl03 cells/lOOμl culture medium into wells of a black Costar clear-bottomed 96-well microtitre plates. Plates were incubated overnight at 37°C in 5% CO2 and used the following day.
ASSAY
Before use, the cell plates were washed twice with 100 μl Hanks balanced salt solution (HBSS). To each well was then added 65μl of HBSS, 10 μL of 10% DMSO in HBSS ± test compound and then 25 μL of 2.8 nM FB-MDC (Applied Biosystems). This fluorescent probe was prepared from a lOμM stock in 0.08%> (v/v) TFA/16% (v/v) acetonitrile, diluted into HBSS.
After two hours incubation in the dark at room temperature, the plates were analysed in an FMAT8100 reader (Applied Biosystems) to measure fluorescence that was associated with binding of FB-MDC to the cells. Compound activity was detennined as an pIC5o [log(concentration of compound that results in 50%> inhibition)], comparing fluorescence in control and background wells.
Typical Data
Fluorescence (ctrl) = 1200 Fluorescence (bkg) = 0
The compounds of the examples all have a pIC5o of greater than 5.0. Data for specific compounds is given below.
Mean
Example 112 pIC5o 9.5 Example 119 pIC50 7.2
Example 186 pICso 6.2

Claims

1. A compound of fonnula (I) or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000155_0001
(I) in which:
R1, R2 and R3 are independently hydrogen, halogen, cyano, CF3, OCF3, OC1-6 alkyl or C1-6 all yl;
R4 is halogen, CO2R12,
C1-6 alkoxy where the alkyl group may fonn a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
C3-6 alkenyloxy or C3-6 alkynyloxy where either may be optionally substituted with hydroxy or NR14R15;
OC1-6 alkyl-X-d-ό alkyl where the alkyl groups may fonn a 3-6 membered saturated ring;
OC1-6 alkylR11, or OC2-6 alkyl-X-R11 where the alkyl group may foπn a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)2R13, S(O)R13 or COR13;
OC1-6 alkylR16; R5 and R6 are independently hydrogen, cyano, halogen, CO2R12, CONR1 R15;
Cι-6 alkyl optionally substituted by hydroxy, NR1 R15, or 1-3 fluorines;
Cι-6 alkylR11 or XCH(Rn)C1-6 alkyl or XCH(R16)C1-6 alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NR14R15;
NR1 R15; N(RH)R1]; X-(CH2)qNR1 R15; (CH2)nNR14R15; NHC(O)C1-6 alkyl optionally substituted by one or more hydroxy groups,
C3-6 alkynyl or C3-6 alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O;
R11; X-R11; X-R12; X-C1-6alkylR16; X-R16; X-(CH2)nCO2R12; X-(CH2)nCONR14R15; X-^H^nR11 ; X-(CH2)nCN; X-(CH2)qOR12; (CH2)nOR12;
(CH2)n-X-Rπ; X-(CH2)qNHC(O)NHR12; X-(CH2)qNHC(O)R12; X-(CH2)qNHS(O)2R12; X-(CH2)qNHS(O)2Rπ; X-C3-6alkenyl; X-C3-6alkynyl;
n is 1 ,2, 3, 4 or 5;
q is 2, 3, 4, 5 or 6;
X is R13, O, S, S(O), S(O)2;
R11 is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR14R15, C(O)OR12, hydroxy, =O, =S, CN, NO2, COR13, NR14R15, X(CH2)qNR14R15, (CH2)nNR14R15, (CH2)nOH, SR13, S(O)R13, S(O)2R13 C1-6 alkyl-X-C1-6 alkyl, C1-6 alkyl or C1-6 alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR1 R15, SR13, S(O)R13, S(O)2R13;
R12 and R13 are independently hydrogen or C1-6 alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may fonn a saturated 3-6 membered ring;
R14 and R15 are independently hydrogen, Cι-6 alkyl, C3-6 cycloalkyl or (CH2)qOH, or R14 and R15 together with the nitrogen atom to which they are attached fonn a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C1-6 alkyl, C1-6 alkyl-OH, or hydroxy; and
5
R is a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O,
lo provided that:
• when R4 is halogen or C1- alkoxy and R5 is hydrogen, halogen, C1- alkyl, C1-2alkoxy, C1-2alkylthio, trifluoromethyl or ethynyl and when one of R1, R2 or R3 is C1-6alkyl or C1-6alkoxy and is meta to the sulphonamide group then the group ortho to both the sulphonamide group and the C1-6alkyl or C1-6alkoxy group is not is hydrogen,
• when R4 is halogen or C1-4alkoxy and R5 is hydrogen, halogen, C1-4alkyl, C1-2alkoxy, C1-2alkylthio, trifluoromethyl or ethynyl and when one of R , R or R is C1-6alkyl or C1-6alkoxy and is ortho to the sulphonamide group then the group ortho to the C1-6Alkyl or C1-6alkoxy and also meta to the sulphonamide group is not
• 20 hydrogen,
• when two of R , R , R are hydrogen and the other is a methyl group para to the sulphonamide and R4 is methoxy then R5 is not hydrogen or bromo, and
• when R5 is methyl and R6 is methoxy and one of R1, R2 or R3 is bromo or iodo and the other two are both hydrogen, then the bromo or iodo group is not ortho to the
25 sulphonamide group..
2. A compound according to claim 1 in which one of R1, R2 and R3 is hydrogen and the other is chloro, bromo or methyl.
30 3. A compound according to claim 1 or 2 in which R4 is C1-6 alkoxy such as methoxy, 2- furanylmethoxy, bromo, chloro, 2-methoxyethoxy, (5-methyl-3-isoxazolyl)methoxy, pyridylmethoxy, 3-pyridazinylmethoxy, methoxy, 2-(l-imidazolyl)ethoxy, (2-methyl-4- oxazolyl)methoxy and 4-methoxyphenylmethoxy.
35 4. A compound according to any one of claims 1 to 3 in which R5 is hydrogen, halogen such as bromo and chloro, phenyl,-Cι_6 alkyl such as methyl, CH2OH, cyano and 2-aminothanethiol
5. A compound according to any one of claims 1 to 3 in which R is hydrogen, C1-6 alkyl, CH2OH and halogen.
6. A compound according to claim 1 in which is: 2,3-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-benzenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,3,4-tifluorobenzenesulphonamide 3-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide 2,3-Dichloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,5-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,5-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,4-dichlorobenzenesulphonamide Ν-(5-Bromo-3-methoxy-2-pyrazinyl)-4-chlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3-chlorobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-fluorobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)-3-fluorobenzenesulphonamide 2- [ [(3 -Methoxy-5 -methyl-2-pyrazinyl)amino] sulphonyl]benzonitrile N-(5-Bromo-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)2-iodobenzenesulphonamide
2,3-Dichloro-N-[3-(2-furanylmethoxy)-5-methyl-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(5-methyl-3-isoxazolylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(6-methyl-2-pyridinylmethoxy)-2- pyrazinyljbenzenesulphonamide
2,3-Dichloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(4-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(3-methyl-2-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-methyl-3-(3-pyridazinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide N-[5-Bromo-3-(2-pyrazinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(l-methyl-6-oxo-l,6-dihydro-3-pyridinylmethoxy)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
N-[5-Bromo-3-(3-pyridazinyllmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Chloro-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide 4-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenezenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-3,4-dichlorobenezenesulphonamide
3-Chloro-Ν-(3-methoxy-5-methyl-2-pyrazinyl)-2-methylbenezenesulphonamide 2-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 4-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 2,4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 3,4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2-trifluoromethoxybenezenesulphonamide 3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide 2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 4-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(4-morpholinyl)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3,5-dimethoxy-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(l-pynolinyl)-2-pyrazinyl]benzenesulphonamide 3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide 2,3-Dichloro-N-(5,6-dichloiO-3-methoxy-2-pyrazinyl)benzenesulphonamide 2-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 4-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 2,4-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 3,4-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-(3-methoxy-5,6-dimethyl-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-(6-chloro-3,5-dimethoxy-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(4-morpholinyl)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[6-chloro-5-(2-hydroxyethylamino)-3-methoxy-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[6-chloro-5-dimethylamino-3-methoxy-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(2-methoxyethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[6-chToro-5-hydroxy-3-methoxy-2-pyrazinyl]benzenesulphonamide
2,3-DichloiO-N-[6-methoxy-5-([2,2']bipyrazinylyl)]benzenesulphonamide
4-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyloxy]benzoic acid
2,3-Dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-{6-chloro-3-methoxy-5-([2-methoxyethyl)amino]-2- pyrazinyl}benzenesulphonamide
N-{2-[3-Chloro-5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-2- pyrazinylamino] ethyl } acetamide
2,3-Dichloro-N-[5-(4-hydroxymethyl- 1 -piperidinyl)-3-methoxy-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-cyano-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-(6-chloro-3-methoxy-5-methylamino-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-(3-methoxy-5-methylsulphanyl-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-[5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide [5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid methyl ester [5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid
2,3-Dichloro-N-[5-(2-chlorobenzylsulphanyl)-3-methoxy-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[6-chloro-5-(3-hydroxy-l-azetidinyl)-3-methoxy-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-methyl-3-(l-oxy-3-pyrazinylmethoxy)-2- pyι-azinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(4-pyridinylmethoxy)-2-ρyrazinyl]benzenesulphonamide 2,3-DichloiO-N-[5-chloro-3-(l-oxy-4-pyridinylmethoxy)-2- pyrazinyl]b enzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(2-methylsulphanylethoxy)-2-pyrazinyl]benzenesulphonamide
N-(3-Butoxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(2-methyl-3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(6-methyl-2-pyridinylmethoxy)-2- pyrazinyl]benzenesulρhonamide
2,3-Dichloro-N-[5-chloro-3-(l-oxy-2-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide 3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-methylbenzenesulphonamide
3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-fluorobenzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(4-methoxyphenylmethoxy)-2- pyrazinyl]benzenesulphonamide
N-[5-Bromo-6-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[6-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
N-[5-(2-Aminoethylsulphanyl)-3-(2-pyridinylmethoxy)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(6-methoxy-3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide
N-[3-(3-Bromophenylmethoxy)-5-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]benzoic acid methyl ester
3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]benzoic acid 2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(3-methylaminomethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-{3-([2 -hydroxy ethylamino]methyl)phenylmethoxy}-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(4-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-{4-([2-hydroxyethylamino]methyl)phenylmethoxy}-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(4-hydroxymethylphenylmethoxy)-2-pyrazinyl]benzenesulρhonamide 2,3-DichloiO-N-[5-chloro-3-(2-hydroxymethylphenyhnethoxy)-2- pyrazinyl]benzenesulphonamide
5-(2,3-Dichlorobenzenesuphonylamino)-6-methoxypyrazine-2-caι-boxylic acid, methyl ester 2,3-Dichloro-N-[5-(l-hydroxy-l-methylethyl)-3-methoxy-2- pyrazinyl]benzenesulphonamide
N-[5-(2-Aminoethoxy)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
N-{5-[(2-Aminoethyl)thio]-6-chloro-3-methoxy-2-pyrazinyl}-2,3- dichlorobenzenesulfonamide 3-[(5-{[(2,3-Dichlorophenyl)sulphonyl]amino}-6-methoxy-2-pyrazinyl)thio]propanoic acid, methyl ester
2,3-Dichloro-N-[5-bromo-3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide
5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-3-methylpyrazine-2-carboxylic aicd, methyl ester 2,3-Dichloro-N-[5-(hydroxymethyl)-3-methoxy-6-methyl-2- pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-[5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
3-Chloro-N-(5-chIoro-3-methoxy-2-pyrazinyl)-2-fluorobenzenesulphonamide
3-Chloro-2-fluoro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 3-{[(2,3-Dichlorophenyl)sulphonyl]amino}pyrazine-2-carboxylic acid, methyl ester
N-(5-Bromo-6-chloro-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
3-Chloro-5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2-carboxylic acid, methyl ester
2,3-Dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxypyrazin-2- yl]benzenesulphonamide
2 ,3 -Dichloro-N- { 3 - [(6-methoxy-3 -pyridinyl)methoxy] -2-pyrazinyl } benzenesulphonamide
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(methoxymethyl)-2- pyrazinyl]benzenesulphonamide
2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide 2-Chloro-3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
2-Chloro-3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
N-[5-Bromo-3-[(2S)-2-pynolidinylmethoxy]-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-carboxylic acid, methyl ester 5-{[(2,3-Dichlorophenyl)sulphonyl]amino}-6-(3-pyridinylmethoxy)-2- pyrazinecarboxamide
2,3-Dichloro-N-[5-(4-pyridinyl)-3-(3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-(hydroxymethyl)-3-(3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-(hydroxymethyl)-3-methoxy)-2-pyrazinyl]benzenesulphonamide
N-(5-Allyloxy-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
2,3-Dichloro-N-[5-(3-hydroxy-l-propynyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide N-{3-[(5-Bromo-3-pyridinyl)methoxy]-5-chloro-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-{[6-(hydroxymethyl)-2-pyridinyl]methoxy}-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-{5-chloro-3-[(2-methyl-4-oxazolyl)methoxy]-2- pyrazinyl}benzenesulphonamide
2,3-Dichloro-N-{3-[(2-methyl-4-oxazolyl)methoxy]-2-pyrazinyl}benzenesulphonamide
N-[5-Bromo-3-(phenylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
N-[5-Bromo-3-(2-cycIopropylethoxy)pyrazinyl]-2,3-dichlorobenzenesulphonamide
N- [5 -Bromo-3 -(3 -thienylmethoxy)pyrazinyl] -2 ,3 -dichlorobenzenesulphonamide N-{5-Bromo-3-[(2-methyl-3-furanyl)methoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
N-{5-Bromo-3-[(3-furanyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenzenesulphonamide
N-{5-Bromo-3-[(4-fluorophenyl)methoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide N-{5-Bromo-3-[(3-fluorophenyl)methoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
N-{5-Bromo-3-[3-(2-pyridinyl)propoxy]-2-pyrazinyl}-2,3-dichlorobenzenesulphonamide
N-[5-Bromo-3-(pentyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
N-[5-Bromo-3-(propyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(2-methoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
N-[5-Bromo-3-(2-ethoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
N-[5-Bromo-3-(2-fluoroethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
N-{5-Bromo-3-[2-(lH-imidazol-l-yl)ethoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide N-{5-Bromo-3-[3-(3-pyridinyl)propoxy]-2-pyrazinyl}-2,3-dichlorobenzenesulphonamide
N-[5-BiOmo-3-[2-(methylamino)ethoxy]-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[3-(4-hydroxyphenyl)propoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide
N-[5-Bromo-3-(2-phenoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
N-[5-Bromo-3-(cyclopropylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N- [5 -Bromo-3 -(3 -phenoxypropoxy)-2-pyrazinyl] -2,3 -dichlorobenzenesulphonamide
2,3-Dichloro-N-(5-ethoxy-3-methoxy-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-[3-methoxy-5-([l,2,4]-l-triazolyl)-2-pyrazinyl]benzenesulphonamide
2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]-N- methylacetamide 2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetamide
2,3-Dichloro-N-[5-(4-fluorobenzylsulphanyl)-3-methoxy-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-cyanomethylsulphanyl-3-methoxy-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[3-methoxy-5-([l,2,4]-3-oxadiazolylmethylsulphanyl)-2- pyrazinyl]benzenesulphonamide
N-[5-(2-Aminoethylsulphanyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
2,3-Dichloro-N-[3-methoxy-5-(5-methyl-3-isoxazolylmethoxy))-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-(5-dimethylaminomethyl-2-furanylmethoxy)-3-methoxy-2- pyrazinyl]benzenesulphonamide
N-[5-Bromo-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]-2,3-dichloro- benzenesulphonamide
2,3-Dichloro-N-[5-(2-hydroxyethylsulphanyl)-3-methoxy-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-{5-[2-(ethylureido)ethylsulphanyl]-3-methoxy-2- pyrazinyl } b enzenesulphonamide
2,3-Dichloro-N-[3-(5-dimethylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[6-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[6-chloro-3-(5-methylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(5-dimethylaminomethyl-2-furanyhnethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(5-methylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide N-(5-Bromo-3-methoxypyrazinyl)-2-cyanobenzenesulphonamide
N-(5-Bromo-3-methoxypyrazinyl)-2,3-dichloro-4-fluorobenzenesulphonamide
2,3-Dichloro-N-[3-methoxy-5-(4-morpholinylmethyl)-2-pyrazinyl]benzenesulphonamide
N-(3-Allyloxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(2-propynyloxy)-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[3-(2-propynyloxy)-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-(5-cyano-3-methoxy-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-{3-ιhethoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-2- pyrazinyl}benzenesulfonamide hydrochloride 2,3-Dichloro-N-{6-chloro-3-methoxy-5-[(2R)-2-pynolidinylmethoxy]-2- pyrazinyl}benzenesulphonamide Hydrochloride
2,3-Dichloro-N-[3-methoxy-5-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
Hydrochloride
2,3-Dichloro-N-(3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(lH-l,2,4-triazol-l-ylmethyl)-2- pyrazinyl]benzenesulphonamide
N-(3-(5-Aminomethyl-2-furanylmethoxy)-5-chloro-2-pyrazinyl)-2,3-dichloro- benzenesulphonamide
N-(3-(5-Aminomethyl-2-furanylmethoxy)-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(2-propyn-l-yloxy)-2-pyrazinyl]benzenesulphonamide
{[5-(2,3-Dichlorophenylsulfonylamino)-6-methoxy-2-pyrazinyl]oxy} acetic acid, methyl ester
N-[5-(2,3-Dichlorophenylsulphonylamino)-6-methoxy-2-pyrazinyl]-2-hydroxyacetamide
6-(2,3-Dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxylic acid, methyl ester
2,3-Dichloro-N-[6-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-(5-methanesulphonyl-3-methoxy-2-pyrazinyl)benzenesulphonamide
2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyloxy]-N,N-diethyl- acetamide 2,3-Dichloro-N-{5-[2-(dimethylamino)ethylsulphanyl]-3-methoxy-2- pyrazinyljbenzenesulphonamide
2,3-Dichloro-N-(5-difluoromethyl-3-methoxy-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-4-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-Ν-{5-chloro-3-[l-(cyclopropyl)ethoxy]-2-pyrazinyl}benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(5-fonnyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(5-cyclopropylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]- benzenesulphonamide
N-[5,6-bz*i,-(Hydroxymethyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
N-[3-[(2-amino-4-oxazolyl)methoxy]-5-chloro-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide and phannaceutically acceptable salts and solvates thereof.
7. A process for the preparation of compound (I) which comprises: (a) reaction of a compound of formula (II):
Figure imgf000166_0001
(II)
where R4, R5 and R6 are as defined in formula (I) or are protected derivatives thereof with a compound of fonnula (III):
Figure imgf000166_0002
(HI) where R1, R2 and R3 are as defined in formula (I) or are protected derivatives thereof and
LG is a leaving group, or
(b) for compounds where R4 is C1-6 alkoxy where the alkyl group may fonn a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
C3-6 alkenyloxy or C3.6 alkynyloxy where either may be optionally substituted with hydroxy or NR14R15;
OCι-6 alkyl-X-C1-6 alkyl where the alkyl groups may fonn a 3-6 membered saturated ring;
OC1-6 alkylR11, or OC2-6 alkyl-X-R11 where the alkyl group may fonn a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)2R13, S(O)R13; or OCι-6 alkylR , 1160;. treating a compound of the foπnula (NI), where LG is a leaving group:
Figure imgf000167_0001
(VI)
with a compound of formula (V) in the presence of a suitable base, or
(c) for compounds of structure (1), where R5 is an optionally substituted aryl or heteroaryl ring as defined above, reacting a compound of foπnula (XI) or (Nil) where LG is a leaving group with an aryl or heteroaryl boronic acid in the presence of a palladium catalyst and a suitable base at elevated temperature:
Figure imgf000167_0002
(Nil) Q
and optionally thereafter process (a), (b) or (c)
• removing any protecting groups,
• converting a compound of fonnula (I) to a further compound of fonnula (I)
• fonning a phannaceutically acceptable salt.
8. A phannaceutical composition comprising a compound of fonnula (I), or a phannaceutically acceptable salt or solvate thereof, as claimed in claim 1 in association with a phannaceutically acceptable adjuvant, diluent or carrier.
9. A process for the preparation of a phannaceutical composition as claimed in claim 2 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 with a phannaceutically acceptable adjuvant, diluent or carrier.
10. A compound of foπnula (I), or a pharmaceutically acceptable salt or solvate thereof for use in therapy.
11. A method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine receptors, which comprises administering to a patient a therapeutically effective amount of a compound of fonnula (IB), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000168_0001
(IB) in which:
1 9 ^
R , R and R are independently hydrogen, halogen, cyano, CF3, or C1-6 alkyl;
R4 is halogen, CO2R12,
Cι_6 alkoxy where the alkyl group may foπn a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
C3-6 alkenyloxy or C3-6 alkynyloxy where either may be optionally substituted with hydroxy or NR1 R15; OC1-6 alkyl-X-C1-6 alkyl where the alkyl groups may form a 3-6 membered saturated ring;
OC1-6 alkylR11, or OC2-6 alkyl-X-R11 where the alkyl group may fonn a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)2Ri3, S(O)R13;
OCι.6 alkylR16;
R5 and R6 are independently hydrogen, cyano, halogen, CO2R12, CONR14R15;
C1-6 alkyl optionally substituted by hydroxy, NR14R15, or 1-3 fluorines;
Cι-6 alkylR11 or XCH(Rπ)C1-6 alkyl or XCH(R16)C1-6 alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NR14R15;
NR14R15; N(Ru)Rn; X-(CH2)qNR14R15; (CH2)nNR14R15;
C3-6 alkynyl or C3-6 alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O;
R11; X-R11; X-R12; X-C1-6alkylR16; X-R16; X-(CH2)nCO2R12; X-(CH2)nCONR14R15; X-(CH2)nRπ; X-(CH2)nCN; X-(CH2)qOR12; (CH2)nOR12; (CH2)n-X-Rn; X-(CH2)qNHC(O)NHR12; X-(CH2)qNHC(O)R12; X-(CH2)qNHS(O)2R12; X-(CH2)qNHS(O)2Ru; X-C3-6alkenyl; X-C3-6alkynyl;
n is 1 ,2, 3, 4 or 5;
q is 2, 3, 4, 5 or 6;
X is NR13, O, S, S(O), S(O)2;
R . 11 is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR14R15, C(O)OR12, hydroxy, =O, =S, CN, NO2 NR,4R15, X(CH2)qNR14R15, (CH2)nNRI4R15, (CH2)nOH, SR13, S(O)R13, S(O)2R13 Q.6 alkyl-X-Ci-6 alkyl, C1-6 alkyl or C1-6 alkoxy where the alkyl group may foπn a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR14R15, SR13, S(O)R13, S(O)2R13;
R12 and R13 are independently hydrogen or Cι-6 alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered ring;
R14 and R15 are independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)qOH,
or R14 and R15 together with the nitrogen atom to which they are attached fonn a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C1-6 alkyl, C1-6 alkyl-OH, or hydroxy; and
R16 is a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O,
12. A method according to claim 11 in which the chemokine receptor belongs to the CCR chemokine receptor subfamily.
13. A method according to claim 11 or 12 in which the chemokine receptor is the CCR4 receptor.
14 A method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (IB), or a phannaceutically acceptable salt or solvate thereof, as defined in claim 11.
15. A method according to claim 14, wherein the disease is asthma.
PCT/SE2003/000041 2002-01-16 2003-01-14 N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases WO2003059893A1 (en)

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