WO2004111057A1

WO2004111057A1 - Thienopyrimidine derivatives as potassium channel inhibitors

Info

Publication number: WO2004111057A1
Application number: PCT/GB2004/002454
Authority: WO
Inventors: John Ford; Nicholas John Palmer; John Frederick Atherall; David John Madge; Brad Sherborne; Mark Bushfield; Edward Benedict Stevens
Original assignee: Xention Discovery Limited
Priority date: 2003-06-11
Filing date: 2004-06-10
Publication date: 2004-12-23
Also published as: PL1641803T6; HK1093064A1; ES2324536T7; CN1823071B; KR101186678B1; CA2528848C; MXPA05013549A; SI1641803T1; DE602004020070D1; ZA200600225B; KR20060057539A; CA2528848A1; AU2004247470A1; PL1641803T3; EP1641803B3; AU2004247470B2; ES2324536T3; EP1641803B1; CN1823071A; BRPI0411239A

Abstract

The present invention provides thienopyrimidine compounds which are potasium channels inhibitors. Pharmaceutical compositions comprising the compounds and their use in the treatment of arrhythmia are also provided.

Description

THIENOPYRIMIDINE DERIVATIVES AS POTASSIUM CHANNEL INHIBITORS

The present invention relates, to thienopyrimidine compounds which are potassium channel inhibitors. Pharmaceutical compositions comprising the compounds and their use in the treatment of arrhythmia are also provided.

Ion channels are proteins that span the lipid bilayer of the cell membrane and provide an aqueous pathway through which specific ions such as Na⁺, K⁺, Ca²⁺ and Cl^" can pass (Herbert, 1998). Potassium channels represent the largest and most diverse sub-group of ion channels and they play a central role in regulating the membrane potential and controlling cellular excitability (Armstrong & Hille, 1998). Potassium channels have been categorized into gene families based on their amino acid sequence and their biophysical properties (for nomenclature see Gutman et ah, 2003).

Compounds which modulate potassium channels have multiple therapeutic applications in several disease areas including cardiovascular, neuronal, auditory, renal, metabolic and cell proliferation (Shieh et ah, 2000; Ford et ah, 2002). More specifically potassium channels such as Kv4.3, Kir2.1, hERG, KCNQl/minK, and Kvl.5 are involved in the repolarisation phase of the action potential in cardiac myocytes. These potassium channels subtypes have been associated with cardiovascular diseases and disorders including long QT syndrome, hypertrophy, ventricular fibrillation, and atrial fibrillation, all of which can cause cardiac failure and fatality (Marban, 2002).

The human delayed rectifier voltage gated potassium channel subunit, Kvl.5, is exclusively expressed in atrial myocytes and is believed to offer therapeutic opportunities for the management of atrial fibrillation for several different reasons (see review of

Brendel and Peukert, 2002): (i) There is evidence that Kvl.5 underlies the cardiac ultrarapid delayed rectifier (Kv(_Ur)) physiological current in humans due to similar biophysical and pharmacological properties (Wang et ah, 1993; and Fedida et ah, 1993). This has been supported with antisense oligonucleotides to Kvl.5 which have been shown to reduce Kv(_Ur) amplitude in human atrial myocytes (Feng et ah, 1997). (ii) electrophysiological recordings have demonstrated that Kv^) is selectively expressed in atrial myocytes, and therefore avoids inducing potentially fatal ventricular arrhythmia through interfering with ventricular repolarisation (Amos et al., 1996; Li et al, 1996; and Nattel, 2002). (iii) Inhibiting Kv_(ur) in atrial fibrillation-type human atrial myocytes prolonged the action potential duration compared to normal healthy human atrial myocytes (Courtemanche et al, 1999). (iv) Prolonging the action potential duration by selectively inhibiting Kv 1.5 could present safer pharmacological interventions for protecting against atrial re-entrant arrhythmias such as atrial fibrillation and atrial flutter compared to traditional class III antiarrythmics, by prolonging the atrial refractory period while leaving ventricular refractoriness unaltered (Nattel et al., 1999, Knobloch et al, 2002; and Wirth et al., 2003). Class III antiarrythmics have been widely reported as a preferred method for treating cardiac arrhythmias (Colatsky et al, 1990).

Traditional and novel class III antiarrythmic potassium channel blockers have been reported to have a mechanism of action by directly modulating KvI.5 or Kv(_ur>. The known class III antiarrythmics ambasilide (Feng et al. , 1997), quinidine (Wang et al, 1995), clofilium (Malayev et al, 1995) and bertosamil (Godreau et al, 2002) have all been reported as potassium channel blockers of Kv(_Ur) in human atrial myocytes. The novel benzopyran derivative, NIP-142, blocks KvI.5 channels, prolongs the atrial refractory period and terminates atrial fibrillation and flutter in in vivo canine models (Matsuda et al, 2001), and S9947 inhibited KvI.5 stably expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells and Kv_(ur) in native rat and human cardiac myocytes (Bachmann et al, 2001). Elsewhere, other novel potassium channel modulators which target KvI.5 or Kv_(ur) have been described for the treatment of cardiac arrhythmias, these include biphenyls (Peukert et al 2003), thiophene carboxylic acid amides (WO0248131), bisaryl derivatives (WO0244137, WO0246162), carbonamide derivatives (WO0100573, WO0125189) anthranillic acid amides (WO2002100825, WO02088073, WO02087568), dihydropyrimidines (WO0140231), cycloakyl derivatives (WO03063797), indane derivatives (WO0146155 WO9804521), tetralin benzocycloheptane derivatives (WO9937607), thiazolidone and metathiazanone derivatives (WO9962891), benzamide derivatives (WO0025774), isoquinoline derivatives (WO0224655), pyridazinone derivatives (WO9818475 WO9818476), chroman derivatives (WO9804542), benzopyran derivatives (WO0121610, WO03000675, WO0121609, WO0125224, WO02064581), benzoxazine derivatives (WO0012492), and the novel compound A1998 purified from Ocean material (Xu & Xu, 2000).

Thienopyrimidines have been reported to be useful as anti-inflammatory, anti-fungal, anti-osteoporosis and anti-microbial agents amongst others. Although also reported as cardiovascular agents (acting through modulation of the phosphodiesterase group of enzymes or through modulation of the sodium/proton exchange system), thienopyrimidines have not previously been reported as useful agents for modulating ion channels.

Thieno[2,3-</I-pyrimidines substituted in the 4-position with an optionally substituted benzylamine or phenethylamine moiety and in the 5-position with a methyl group may serve as anti-inflammatory or anti-osteoporosis agents (Katada et ah, 1999). Such compounds were shown to modulate the activity of several cell types including leukocytes, which originate from hematopoietic precursor cells in the bone marrow.

Increased activity in leukocytes can lead to various inflammatory diseases; therefore compounds cytotoxic to leukocytes could function as anti-inflammatory drugs. Such compounds are thought to suppress cellular activity by binding to integrins on the surface of leukocytes and preventing downstream cellular signalling events. Thieno[2,3-

JJpyrimidines substituted in the 4-position with heteroarylthiols, aryl thiols, arylmethyl thiols, heteroarylamines, benzylamine, hydroxyl and chloro groups may also be useful anti-inflammatory agents (Stewart et al., 2001). This series of compounds were shown to inhibit induced expression of cell adhesion molecules on the luminal surface of vascular endothelial thus preventing the adhesion of leukocytes at the site of inflammation.

Thieno[2,3-c2]pyrirnidines with a substituted hydrazine in the 4-position and a phenyl group in the 5 position (Hozien et ah, 1996), tetrahydrobenzo[b]thieno[2,3-^pyrimidines

(Ismail et α/., 1995), thieno[2,3-(f]pyrimidines which have a hydrogen, chloro, hydrazine, heterocyclyl, amino, methyl, ethyl or phenyl group in the 2-position, an alkylamino, alkylarylamino, amino, dialkylamino or hydrazino substituent in the 4-position, a hydrogen or methyl group in the 5-ρosition, a hydrogen, methyl acetamide or phenyl group in the 6-position or a tetramethylene in the 5,6-position (GB7549025), and the lead series of 5-phenyl- and 5,6-tetramethylenethieno[2,3-<tf]pyrimidines with methyl or phenyl in the 2-position and alkylamino or arylamino in the 4- position (Konno et al., 1989) have all been shown to have anti-microbial activity. Tetrahydrobenzothieno[2,3- όOpyrimidine with the 2-oxo-3-pyrrolidinylmethylene~hydrazino moiety in the 4-position showed some herbicidal activity against velvet leaf (Ram et ah, 1981). It has also been reported that 4-chlorotetrahydrobenzothieno[2,3-J]pyrimidine is herbicidal, tetrahydrobenzothieno-[2,3-<i]pyrimidines with a thiol, hydrazine, 2-fluoroanilino, 3- fluoroanilino or 4-diethylanilino substituent in the 4-position are bactericidal against Streptococcus fecales and tetrahyrobenzothieno[2,3-if]pyrimidines with a 2,4- dichlorobenzylamino or 2-fluoroanilino substituent in the 4-position are fungicidal against Pythium (Ram, 1979). Thieno[2,3-d]pyrimidines with a hydrogen, hydroxyl, thiol, halogen or cyano group in the 2-position, alkylamino, arylalkylamino or hydroxyalkyl amino groups in the 4-position, a hydrogen, alkyl or halogen in the 5- and/or 6- position or alkylene in the 5,6-position have been reported as tick-control agents (AU 521790).

Elsewhere, tetrahydrobenzo[b]thieno[2,3-J]pyrimidines exhibited anti-tumour activity

(Shehata et al., 1996) and analgesic activity half that of aspirin (Moneer et al., 1994), a series of thieno[2,3-<f|pyrimidines with 4-alkylamino or arylamino, 5-H or 5-methyl, 6- methyl or 5,6-tetramethylene were shown to have potential as anticytokinins (Jordis et al., 1986), a series of 5,6-dimethyl-thieno[2,3-J]pyrimidines and 5,6- tetramethylenethieno[2,3-d]pyrimidines, both substituted in the 2-position with arylamines or heterocyclic amines and in the 4-position with arylamines displayed blood platelet aggregation inhibiting properties (DD 226893), pyrano- and thiopyrano[3,4- b]thieno[5,4-d]pyrimidines with the 4-position substituted with amino, butylamine, aniline, cyclohexylamine, benzylamine, phenethylamine and 2-hydroxyethylamine have been reported to exhibit anticonvulsive activity (Noravyan et al., 1977), and 4-[(Benzo- 2,l,3-thiadiazolyl-4)amino]-5,6,7,8-tetrahydrobenzothieno-(2,3-J)"pyrimidine has been reported to possess anthelmintic activity in larval alveolar echinococcosis (RU 2116309).

Thieno[2,3-^0pyrimidines with a substituted amino group at the 4-position, hydrogen, alkyl or halo substitution at the 5 and 6-positions and an alkyl chain at the 2-position are claimed to be inhibitors of phosphodiesterase V and useful in the treatment of cardiovascular diseases and for disturbances in potency (DE10104802).

Elsewhere, 5-alkyl thieno[2,3-_f]pyrimidines with a piperazinyl substituent at the 4- position were found to be inhibitors of the sodium/proton exchanger and useful in the treatment of various cardiovascular disorders, including angina pectoris and arrhythmia (WO 01/27107).

4-[(Phenyl)amino]-thieno[2,3-(i]pyrimidines bearing a 5-thiophenyl substituent and a 2- methyl substituent were found to have molluscicidal activity (Hosni et al, Acta Poloniae Pharmaceutica, 1999, 56(1), 49-56).

Recently thienopyrimidines have also been reported as potent VEGFR inhibitors (Munchhof, 2004).

Several publications disclose compounds which are indicated as acting on potassium channels. Thus, US6531495 discloses 2'-aminomethylbiphenyl-2-carboxamides, WO2002/100825 discloses anthranillic acid amides as antiarrhythmics and WO2002/036556 discloses acylaminoalkylbenzenesulfonamides as cardiovascular agents.

This invention provides compounds that are potassium channel inhibitors. These compounds are particularly useful for inhibiting potassium channels KvI.5 or Kv_(ur), which are known targets for the treatment of cardiac arrhythmia in the atria such as atrial fibrillation (Nattel et al, 1999; Wang et al, 1993). This invention is not limited to treating cardiac arrhythmias, the compounds also being useful to treat diseases which require potassium channel inhibition (e.g. Shieh et ah, 2000; Ford et al., 2002). Thus, in a first aspect, the present invention provides a compound of formula (I)

Wherein

Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, C(O)NR4R5 or halo;

R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy;

R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S;

X is O, S or NR6;

R6 is H or alkyl; R7 is hydrogen, methyl or ethyl;

R8 is methyl or ethyl;

L is (CH₂)_n, where n is 1, 2 or 3; and

Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof;

with the proviso that when Y is phenyl, phenyl monosubstituted by Cl or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyl, then Rl is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl; and wherein the compound is not:

N-Butyl-5-phenylthieno[2,3-d]pyrimidin-4-amine; 5-Phenyl-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-[3-(lH-imidazol-l-yl)propyl]thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-(2-cyclohex- 1 -en- 1 -ylethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(2-furylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Fluorophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; N-Allyl-5-phenylthieno[2,3-d]pyrimidin-4-amine;

5-(4-Methylphenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]pyrimidin-4-amine;

N-(2-Furylmethyl)-5-phenylthieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Fluorophenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]ρyrimidin-4-amine; N-Allyl-5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-Phenyl-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Bromophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

N-[3-(lH-Imidazol-l-yl)propyl]-5-phenylthieno[2,3-d]pyrimidin-4-amine; l-(2-{[5-(4-Methylphenyl)thieno[2,3-d]ρyrimidin-4-yl]amino}ethyl)imidazolidin-2-one; or

N-(2-Furylmethyl)-5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-amine.

As used herein, an alkyl group or moiety is typically a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C₁-C₄ alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl and t-butyl. An alkyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, cyano, nitro,

NR9R10, alkoxy, hydroxyl, unsubstituted aryl, unsubstituted heteroaryl, CO₂R7, C(O)NRSRlO, NC(O)R8 and SO₂NR9R10.

As used herein, an aryl group is typically a C₆-C_1O aryl group such as phenyl or napthyl. A preferred aryl group is phenyl. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2, 3 or 4 substituents. Suitable substituents include cyano, halogen, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy, NR9R10, CO₂R7, C(O)NR9R10, NC(O)R8 and SO₂NR9R10 and hydroxyl. As used herein, a heterocyclic group is a heteroaryl group, typically a 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl and pyrazolyl groups. Preferred heteroaryl groups are furanyl, thienyl and pyridyl. Examples of polycyclic heterocycles include indolyl, benzofuranyl, benzothiophenyl and benzodioxolyl. Non-aryl heterocyclic groups are also included, such as tetrahydrofuranyl or pyrrolidinyl. A heterocyclic group may be unsubstituted or substituted at any position. Suitable substituents include cyano, nitro, halogen, alkyl, alkylthio, alkoxy, NR9R10, CO₂RJ, C(O)NR9R10, NC(O)R8 and SO₂NR9R10 and hydroxyl.

R9 and RlO can be the same or different, and may be selected from H, unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, hydroxyethyl, alkoxyethyl, or R9 and RlO may together form a saturated, unsaturated or partially saturated 4 to 7 member ring.

When R4 and R5 or R9 and RlO together form a saturated, unsaturated or partially saturated 4 to 7 member ring, the ring may optionally comprise one, two, or three further heteroatoms.

As used herein, alkoxy means C_1-3 alkoxy, cycloalkyl means C_3-6 cycloalkyl and halogen means Cl, F, Br, or I, preferably Cl, F or Br.

Preferred compounds of formula I are those wherein Rl is aryl or heteroaryl, R2 is H or alkyl, R3 is H, NR4R5, alkoxy or alkyl, X is O or NR6, R6 is H, n is 1 or 2 and Y is alkyl, cycloalkyl, aryl or heteroaryl.

More preferred compounds of formula I are those wherein Rl is aryl or heteroaryl, R2 is H or methyl, R3 is H, NR4R5, alkoxy or alkyl, X is NR6, R6 is H, n is 1 and Y is heteroaryl. Preferably Y is furanyl, thienyl or pyridyl. More preferably Y is optionally substituted furan-2-yl or optionally substituted pyridin-2-yl.

Preferred compounds include: 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-yl}-propane-l,3- diol;

2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2- ylamino }-ethanol;

Pyridin-2-ylmethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine; 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-ylamino}-ethanol;

2-{5-Phenyl-4-[(pyridin-2-ylmethyl)arnino]thieno[2,3--i]pyrimidin-2-yl}ethanol;

2-((2-Hydroxy-ethyl)-{5-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-

2-yl}-amino)-ethanol;

2-Methyl-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylarnine; 2- { 4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl } -ethanol;

[2-(2-Methoxy-ethoxy)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl- amine;

(2-Methoxy-5-phenyl-thieno[2,3-d]pyrirnidin-4-yl)-pyridin-2-ylmethyl-amine;

5-(4-Fluorophenyl)-N²-(2-methoxy-ethyl)-N⁴-pyridin-2-ylmethyl-thieno[2,3- d]pyrimidine-2,4-diamine;

[5-(4-Dimethylamino-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine;

5-(4-Fluorophenyl)-N²,N²-dimethyl-N⁴-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4- diamine;

Pyridin-2-ylmethyl-[5-(4-trifluoromethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-amine; [5-(lH-Indol-6-yl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine;

(5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine;

2-{ 5-Phenyl-4-[(pyridin-2-ylmethyl)-arnino]-thieno[2,3-d]pyrimidin-2-ylarnino } - propane-l,3-diol;

3-{5-Phenyl-4-[(pyridin-2-ylmethyl)-aπύno]-thieno[2,3-d]pyrirnidin-2-ylarnino}- propane-l,2-diol; N-Methyl-2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2- yl}acetamide; or 6-Methyl-N-[(6-methylpyridin-2-yl)methyl]-5-phenylthieno[2,3-d]pyrimidin-4-amine;

and pharmaceutically acceptable salts thereof.

Compounds of formula I wherein R3 is H, alkyl or trifluoroalkyl are synthesised from a compound of formula II by reaction with a suitable nucleophile X-L-Y, where X, Y and L are as defined herein, optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation. Preferably the solvent (if present) is an alcohol, preferably ethanol, and the base is a hindered nitrogen base such as triethylamine. If a solvent is present the reaction is carried out at the reflux temperature of the solvent, or under sealed conditions and with microwave irradiation at a temperature of 120-160⁰C.

A compound of formula II may be obtained from a compound of formula III by reaction with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride in a suitable solvent or no solvent, and with heating. Preferably the chlorinating reagent is phosphorous oxychloride and the reaction is carried out at reflux temperature and in the absence of additional solvent.

Compounds of formula IH may be obtained by the reaction of a compound of formula IV with a suitable substituted or unsubstituted amidine of formula V, or its salt equivalent. The reaction may be carried out in the presence of a suitable solvent at elevated temperature. Preferably the solvent is ethanol and the reaction is carried out under reflux conditions.

In an alternative synthesis of compounds of formula III, also applicable to those examples wherein R3 is an alkyl group, reaction of a compound of formula VI under basic conditions in a suitable solvent is performed. Suitable bases include alkali metal alkoxides such as sodium methoxide. Suitable solvents include alcohols such as methanol.

A compound of formula VI can be prepared by reaction of a compound of formula VII under acylating conditions, for example in the presence of an acid chloride and a base. Exemplified acid chlorides include acetyl chloride. Suitable bases include the nitrogenous bases such as triethylamine and pyridine.

I l

Compounds of formula VII are widely available from standard commercial sources or may be obtained from compounds of formula IV by simple functional group intercon versions.

Compounds of formula V are widely available from standard commercial sources or can be synthesised by routine organic chemistry procedures.

A compound of formula IV can be prepared by reaction of a compound of formula VIII, under basic conditions and in a suitable solvent, with powdered sulphur. Preferably the base is diethylamine and the reaction is carried out at 25 to 65⁰C. The solvent may be an alcohol, preferably ethanol.

Compounds of formula VIII can be prepared by heating a compound of formula IX with ethylcyanoacetate (NCCHaCO₂Et) in the presence of an acid and ammonium acetate in a suitable solvent, optionally with azeotropic water removal. Preferably the acid is acetic acid.

Compounds of formula IX are widely available from commercial sources or can be readily synthesised using standard synthetic organic chemistry procedures.

Alternatively, compounds of formula I wherein R3 is other than H, alkyl or trifluoroalkyl, can be prepared from a compound of formula X by displacement of the 2-chloro substituent with a suitable nucleophilic species. Such a reaction may be carried out with heating or microwave irradiation.

Compounds of formula X are readily synthesised from compounds of formula XI by reaction with a suitable nucleophile X-L-Y, optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation. Preferably the solvent (if present) is an alcohol, preferably propan-2-ol, and the base is a hindered nitrogen base such as triethylamine. The reaction is carried out at ambient temperatures.

A compound of formula XI may be synthesised by reaction of a compound of formula XII with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride.

Compounds of formula XII are available by the reaction of a compound of formula IV with an alkali metal cyanate, preferably potassium cyanate.

Alternatively, compounds of formula I wherein R3 is an ester-substituted alkyl group, in particular an acetic acid ester, can be prepared by the reaction of a compound of formula XIII, by reaction with a suitable nucleophile X-L-Y optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation. Preferably the solvent (if present) is an alcohol, preferably ethanol, and the base is a hindered nitrogen base such as triethylamine. If a solvent is present the reaction is carried out at the reflux temperature of the solvent, or under sealed conditions and with microwave irradiation at a temperature of 120-160⁰C.

Compounds of formula XIII may be synthesized from compounds of formula XIV by reaction with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride.

Compounds of formula XIV are synthesized by reaction of compounds of formula IV with ethyl cyanoacetate, performed under acidic conditions with or without the presence of solvent. Suitable acids include gaseous hydrogen chloride.

It is understood that compounds of formula I wherein R3 is a carboethoxy group may undergo functional group transformation of the ester moiety using methods familiar to those skilled in the art. In a preferred instance such compounds may undergo amidation by reaction with an alkyl or dialkylamine. In another preferred instance compounds of formula I wherein R3 is a 1-hydroxyethyl group can be prepared by reaction with a reducing agent such as diisobutylaluminium hydride or lithium aluminium hydride. In a further instance compounds of formula I wherein R3 is a carboethoxy group may be reacted with a dialkyl carbonate under basic conditions to provide a compound of formula I wherein R3 is a dialkylmalonyl group. Such compounds may be reduced, preferably with a reducing agent such as diisobutylaluminium hydride or lithium aluminium hydride, to provide compounds of formula I wherein R3 is a propanediol group.

Compounds of formula I wherein R3 is a chloromethyl group may be synthesized from compounds of formula XV by reaction with a suitable nucleophile X-L-Y optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation. Preferably the solvent (if present) is an alcohol, preferably propan-2-ol, and the base is a hindered nitrogen base such as triethylamine. The reaction is carried out at ambient temperature.

Compounds of formula XV may be synthesized from compounds of formula XVI by reaction with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride.

Compounds of formula XVI may be synthesized by reaction of a compound of formula IV under acidic conditions in a suitable solvent with chloroacetonitrile. Suitable acids include gaseous hydrogen chloride. Suitable solvents include alkyl ethers such as 1,4- dioxane.

It is understood that compounds of formula I wherein R3 is a chloromethyl group may undergo standard functional group transformations of the chloromethyl moiety using methods familiar to those skilled in the art. In a preferred instance reaction with a nucleophile is carried out. Suitable nucleophiles may include an alkyl or dialkyl amine, an alcohol or a thiol, or anion derivatives thereof.

In an alternative synthesis of compounds of formula I, particularly applicable to those examples wherein Rl comprises an aryl or heteroaryl group, a compound of formula XVII is reacted with an aryl or heteroaryl boronic acid, preferably under coupling conditions such as in the presence of a palladium(0) catalyst, preferably tetrakis(triphenylphosphine) palladium(O) which may be generated in situ or attached to a polymer resin. Alternative coupling conditions will be familiar to those skilled in the art. If a solvent is present the reaction is carried out at the reflux temperature of the solvent, or under sealed conditions and with microwave irradiation at a temperature of 120-160⁰C.

A compound of formula XVII may be synthesised from a compound of formula XVIII by reaction with a suitable nucleophile X-L-Y optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation. Preferably the solvent (if present) is an alcohol, preferably ethanol, and the base is a hindered nitrogen base such as triethylamine. If a solvent is present the reaction is carried out at the reflux temperature of the solvent, or under sealed conditions and with microwave irradiation at a temperature of 120-160⁰C.

XVIII

Compounds of formula XVIII wherein R2 is H may be synthesized by reaction of a compound of formula XIX under basic conditions at reduced temperature in a suitable solvent. Preferably the base is an alkyllithium, in the most preferred instance lithium diisopropylamide and the solvent is an alkylether, in the most preferred instance tetrahydrofuran. The reaction may be carried out from -80⁰C to ambient temperature.

A compound of formula XIX may be obtained from a compound of formula XX by reaction with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride in a suitable solvent or no solvent, and with heating. Preferably the chlorinating reagent is phosphorous oxychloride and the reaction is carried out at reflux temperature and in the absence of additional solvent.

Compounds of formula XX may be synthesized by reactions of compounds of formula III wherein Rl is H and R2 is H with an electrophilic halogenating reagent preferably bromine in a suitable solvent preferably glacial acetic acid.

Alternatively, compounds of formula XVIII wherein R3 is other than H, alkyl or trifluoroalkyl and R2 is other than hydrogen may be synthesized from compounds of formula XXI by displacement of the 2-chloro substituent with a suitable nucleophilic species. Such a reaction may be carried out with heating or microwave irradiation.

Compounds of formula XXI are readily synthesised from compounds of formula XXII by reaction with a suitable nucleophile X-L-Y, optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation. Preferably the solvent (if present) is an alcohol, preferably ethanol, and the base is a hindered nitrogen base such as triethylamine.

A compound of formula XXII may be synthesised by reaction of a compound of formula XXIII with a chlorinating reagent such as phenylphosphonic dichloride or phosphorous oxychloride.

A compound of formula XXIII may be synthesized by reaction of a compound of formula XII wherein Rl is H and R2 is alkyl with an electrophilic halogenating reagent, preferably bromine, in a suitable solvent, preferably glacial acetic acid.

Many of the starting materials referred to in the reactions described above are available from commercial sources or can be made by methods cited in the literature references. Synthetic methods can also be found in reviews; thiophenes for example can be found in references cited in Comprehensive Heterocyclic Chemistry, Eds Katritzky, A. R., Rees, C. R., (4), 863-934, and Comprehensive Heterocyclic Chemistry (II), Eds Katritzky, A. R., Rees, C. W., Scriven, E. F. V., (2). 607-678.

Suitable starting materials include:

As discussed herein, the compounds of the invention are useful in the treatment of various conditions. Thus, in a second aspect, the present invention provides a pharmaceutical formulation comprising at least one compound and optionally one or more excipients, carriers or diluents; wherein said compound has the formula:

Wherein Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo;

R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy;

X is O, S or NR6;

R6 is H or alkyl;

R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl;

L is (CH₂)_n, where n is 1, 2 or 3; and

with the proviso that when Y is phenyl, phenyl monosubstituted by Cl or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyl, then Rl is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl.

Preferably the compound is a compound as described in the first aspect.

The compositions of the invention may be presented in unit dose forms containing a predetermined amount of each active ingredient per dose. Such a unit may be adapted to provide 5-100mg/day of the compound, preferably either 5-15mg/day, 10-30mg/day, 25-

50mg/day 40-80mg/day or 60-100mg/day. For compounds of formula I, doses in the range 100-lOOOmg/day are provided, preferably either 100-400mg/day, 300-600mg/day or 500-1000mg/day. Such doses can be provided in a single dose or as a number of discrete doses. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be at the doctor's discretion.

The compositions of the invention may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For applications to the eye or other external tissues, for example the mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. In a further aspect the present invention provides a compound, or a pharmaceutical composition comprising said compound for use in medicine, wherein said compound has the formula:

Wherein Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo;

R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy;

X is O, S or NR6;

R6 is H or alkyl;

R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl;

L is (CH₂)_n, where n is 1, 2 or 3; and

with the proviso that when Y is phenyl, phenyl monosubstituted by Cl or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyl, then Rl is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl. Preferably, the compound is a compound of the first aspect. The compositions of the invention can be used to treat conditions which require inhibition of potassium channels, for example in the treatment of arrhythmia. Thus, in further aspects, the present invention provides:

(i) a method of treating or preventing a disorder which requires potassium channel inhibition, eg arrhythmia, comprising administering to a subject an effective amount of at least one compound or of a pharmaceutical composition comprising said at least one compound and optionally one or more excipients, diluents and/or carriers wherein said compound has the formula:

Wherein

Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo;

R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S;

X is O, S or NR6; R6 is H or alkyl;

R7 is hydrogen, methyl or ethyl;

R8 is methyl or ethyl;

L is (CH₂)_n, where n is 1, 2 or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof; and

(ii) the use of a compound of the invention in the manufacture of a medicament for use in potassium channel inhibition; wherein the compound has the formula:

Wherein

Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo;

X is O, S or NR6; R6 is H or alkyl;

R7 is hydrogen, methyl or ethyl;

R8 is methyl or ethyl;

L is (CH₂)_n, where n is 1, 2 or 3; and

Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof.

In particular, the medicament is for use in the treatment or prevention of arrhythmia. Preferably the compounds are compounds of the first aspect. Examples

Using the information outlined herein the following compounds can be synthesised which are given by way of example only. The pharmacological profile of compounds of the present invention can readily be assessed by those skilled in the art using routine experimentation, such as procedures and techniques illustrated herein and described in detail in Ford et at, 2002.

Example 1.

2-Cyano-3-phenyl-but-2-enoic acid ethyl ester A stirred mixture of acetophenone (18Og, 1.5mol), ethyl cyanoacetate (17Og, 1.3mol), ammonium acetate (23.Ig), acetic acid (72g) and toluene (300ml) was heated under reflux for 18 hours while water was removed from the reaction by azeotropic distillation. The mixture was allowed to cool to ambient temperature, toluene (100ml) was added, then the mixture was washed with water (3 x 100ml). The combined aqueous washings were shaken with toluene (50ml), then the combined toluene solutions were dried (MgSO₄) and the solvent was removed in vacuo. The residual oil was distilled under reduced pressure to give 2-cyano-3-phenyl-but-2-enoic acid ethyl ester as an oil which was used without further purification.

Examples 2 to 18

The compounds set out below were prepared in the same way as in Example 1, using the appropriate starting materials.

Example Compound

2 2-Cyano-3-(5-methyl-pyridin-2-yl)-but-2-enoic acid ethyl ester

3 2-Cyano-3-(4-fluoro-phenyl)-but-2-enoic acid ethyl ester

4 2-Cyano-3-thiophen-2-yl-but-2-enoic acid ethyl ester

5 2-Cyano-3-methyl-but-2-enoic acid ethyl ester

6 2-Cyano-3-p-tolyl-but-2-enoic acid ethyl ester

7 3-(4-Chloro-phenyl)-2-cyano-but-2-enoic acid ethyl ester 8 2-Cyano-3-(4-methoxy-phenyl)-but-2-enoic acid ethyl ester

9 2-Cyano-3-phenyl-hex-2-enoic acid ethyl ester

10 2-Cyano-3-o-tolyl-but-2-enoic acid ethyl ester

11 2-Cyano-3-(3,4-dimethyl-phenyl)-but-2-enoic acid ethyl ester

12 3-(4-Bromo-phenyl)-2-cyano-but-2-enoic acid ethyl ester

13 2-Cyano-3-cyclohexyl-but-2-enoic acid ethyl ester

14 3-(4-tert-Butyl-phenyl)-2-cyano-but-2-enoic acid ethyl ester

15 2-Cyano-3-ρhenyl-ρent-2-enoic acid ethyl ester

16 3-Benzo[l,3]dioxol-5-yl-2-cyano-but-2-enoic acid ethyl ester

17 3-Benzo[l,3]dioxol-5-yl-2-cyano-pent-2-enoic acid ethyl ester

18 2-Cyano-3-(4-fluoro-phenyl)-pent-2-enoic acid ethyl ester

Example 19

2-Amino-4-phenyl-thiophene-3-carboxyIic acid ethyl ester

2-Cyano-3-phenyl-but-2-enoic acid ethyl ester (513.25g, 2.3mol) was added at ambient temperature to a vigorously-stirred suspension of powdered sulfur (76g, 2.3mols) in ethanol (500ml). Diethylamine (200ml) was added in portions over 20 minutes, during which time the temperature of the reaction rose to 62°C. The mixture was allowed to cool to 36°C, then it was heated to 50°C and stirring at that temperature was continued for 1 hour. After this time, stirring was discontinued, the hot solution was removed by decantation from unreacted sulfur, then it was allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol and dried in vacuo to give 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester as an orange solid which was used without further purification.

Examples 20 to 36

The compounds set out below were prepared in the same way as in Example 19, using the appropriate starting materials.

Example Compound 20 2-Amino-4-(5-methyl-pyridin-2-yl)-thiophene-3-carboxylic acid ethyl ester

21 2-Amino-4-(4-fluoro-phenyl)-thiophene-3-carboxylic acid ethyl ester

22 5'-Amino-[2,3']bithiophenyl-4'-carboxylic acid ethyl ester

23 2-Amino-4-methyl-thiophene-3-carboxylic acid ethyl ester

24 2-Amino-4-p-tolyl-thiophene-3-carboxylic acid ethyl ester

25 2-Amino-4-(4-chloro-phenyl)-thiophene-3-carboxylic acid ethyl ester

26 2-Amino-4-(4-bromo-phenyl)-thiophene-3-carboxylic acid ethyl ester

27 2-Amino-4-(4-methoxy-phenyl)-thiophene-3-carboxylic acid ethyl ester

28 2-Amino-4-(3,4-dimethyl-phenyl)-thiophene-3-carboxylic acid ethyl ester

29 2-Amino-4-o-tolyl-thioρhene-3-carboxylic acid ethyl ester

30 2-Amino-5-ethyl-4-phenyl-thiophene-3-carboxylic acid ethyl ester

31 2-Amino-4-(4-tert-butyl-phenyl)-thiophene-3-carboxylic acid ethyl ester

32 2-Amino-4-cyclohexyl-thiophene-3-carboxylic acid ethyl ester

33 2-Amino-5-methyl-4-phenyl-thiophene-3-carboxylic acid ethyl ester

34 2-Amino-4-benzo[l,3]dioxol-5-yl-thiophene-3~carboxylic acid ethyl ester

35 2-Amino-4-benzo[l,3]dioxol-5-yl-5-methyl-thiophene-3-carboxylic acid ethyl ester

36 2-Amino-4-(4-fluoro-phenyl)-5-methyl-thiophene-3-carboxylic acid ethyl ester

Example 37 5-PhenyI-3H-thieno[2,3-d]pyrimidin-4-one

A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43g, 1.535mol), formamidine acetate (799.13g, 7.7mol) and ethanol (1500ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 5-Phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification.

Examples 38 to 54 The compounds set out below were prepared in the same way as in Example 37, using the appropriate starting materials.

Example Compound

38 5-(5-Methyl-pyridin-2-yl)-3H-thieno[2,3-d]pyrimidin-4-one;

39 5-(4-Fluoro-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one;

40 5-Thiophen-2-yl-3H-thieno[2,3-d]pyrimidin-4-one;

41 5-Methyl-3H-thieno[2,3-d]pyrimidin-4-one;

42 5-p-Tolyl-3H-thieno[2,3-d]pyrimidin-4-one;

43 5-(4-ChIoro-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one;

44 5-(4-Bromo-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one;

45 5-(4-Methoxy-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one;

46 5-(3,4-Dimethyl-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one;

47 5-(4-tert-Butyl-phenyl)-3H-thieno[2,3-d]pyrimidin-4-one;

48 6-Ethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one;

49 5-Cyclohexyl-3H-thieno[2,3-d]pyrirnidin-4-one;

50 5-o-Tolyl-3H-thieno[2,3-d]pyrimidin-4-one;

51 6-Methyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one

52 5-Benzo[l,3]dioxol-5-yl-3H-thieno[2,3-d]pyrimidin-4-one

53 5-Benzo[l,3]dioxol-5-yl-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one

54 5-(4-Fluoro-phenyl)-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one

Example 55 2-Methyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one

A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43g, 1.54mol), acetamidine hydrochloride (725.13g, 7.676mol) and ethanol (1500ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 2-Methyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification. Example 56

The compound set out below was prepared in the same way as in Example 55, using the appropriate starting materials.

Example Compound

56 5-(4-Fluoro-phenyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-one

Example 57 4-phenyϊ-2-propionyIaminothiophene-3-carboxylic amide A mixture of 2-amino-4-phenylthiophene-3-carboxylic acid amide (3.Og, 13.8mmol) and anhydrous pyridine (12ml) was treated with propionyl chloride (1.32ml, 15.2mmol) and stirred at ambient temperature for 3 hours. The excess pyridine was removed in vacuo to give a residue, which was treated with ethanol (50ml) and sodium methoxide (2.24g, 41.4mmol) and the resultant mixture was heated under reflux for 18 hours. The cooled mixture was then diluted with water (300ml) and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 4-phenyl-2-propionylaminothiophene-3-carboxylic amide.

Example 58 2-ethyl-5-phenyl-3H-thieno[2,3-d^r]pyrimidin-4-one

The solid 4-phenyl-2-propionylaminothiophene-3-carboxylic amide was added to a mixture of ethanol (50ml) and sodium methoxide (2.24g) and the resultant mixture was heated under reflux with stirring for 18 hours. The cooled mixture was diluted with water (300ml) and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water followed by acetonitrile and dried in vacuo to give 2-ethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one (2.38g), which was used without further purification. Example 59 5-Phenyl-2-trifluoromethyl-3H-thieiio[2,3-d]pyrimidin-4-one

A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43g, 1.535mol), trifluoromethylacetamidine hydrochloride (1167.36g, 7.676mol) and ethanol (1500ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 5-Phenyl-2-trifluoromethyl-3H-thieno[2,3- d]pyrimidin-4-one as a yellow solid which was used without further purification.

Example 60

2-Isopropyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one

A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43 g,

1.54mol), isopropylacetamidine hydrochloride (958.75g, 7.7mol) and ethanol (1500ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 2-Isopropyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification.

Example 61

4-Chloro-5-phenyl-thieno[2,3-d]pyrimidine

5-Phenyl-3H-thieno[2,3-d]pyrimidin-4-one (294.6g, 1.29mol) was added in portions to stirred phosphoryl chloride (1000ml), then the stirred suspension was warmed gently to reflux temperature, heated under reflux for 4 hours, and allowed to stand at ambient temperature for 18 hours. The resulting dark solution was removed by decantation from a solid residue and concentrated in vacuo to give a gummy solid. The two solids were combined and added to crushed ice (1000ml). The product was extracted into dichloromethane (3 x 500ml), then the combined extracts were washed with water (2 x 300ml) and saturated aqueous sodium hydrogen carbonate solution (500ml) and dried and decolourised (MgSO₄ + charcoal). The solvent was removed in vacuo to give 4-Chloro- 5-phenyl-thieno[2,3-d]pyrimidine as a yellow/orange solid which was used without further purification.

Examples 62 to 82 The compounds set out below were prepared in the same way as in Example 61, using the appropriate starting materials.

Example Compound

62 4-Chloro-5-(5-methyl-pyridin-2-yl)-thieno[2,3-d]pyrimidine

63 4-Chloro-5-(4-fluoro-phenyl)-thieno[2,3-d]pyrimidine

64 4-Chloro-5-thiophen-2-yl-thieno[2,3-d]pyrimidine

65 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine

66 4-ChloiO-5-p-tolyl-thieno[2,3-d]pyrimidine

67 4-Chloro-5-(3,4-dimethyl-phenyl)-thieno[2,3-d]pyrimidine

68 4-Chloro-5-(4-chloro-phenyl)-thieno[2,3-d]pyrimidine

69 5-(4-Bromo-phenyl)-4-chloro-thieno[2,3-d]pyrimidine

70 4-Chloro-5-(4-memoxy-phenyl)-mieno[2,3-d]pyrimidine

71 4-Chloro-6-ethyl-5-phenyl-thieno[2,3-d]pyrimidine

72 4-Chloro-5-o-tolyl-thieno[2,3-d]pyrimidine

73 5-(4-tert-Butyl-phenyl)-4-chloro-thieno[2,3-d]pyrimidine

74 4-Chloro-5-cyclohexyl-thieno[2,3-d]pyrimidine

75 4-Chloro-2-methyl-5-phenyl-thieno[2,3-d]pyrimidine

76 4-Chloro-5-phenyl-2-trifluoromethyl-thieno[2,3-d]pyrimidine

77 4-Chloro-2-isopropyl-5-phenyl-thieno[2,3-d]pyrimidine

78 4-Chloro-2-ethyl-5-phenyl-thieno[2,3-d]pyrimidine

79 4-Chloro-6-methyl-5-phenyl-thieno[2,3-d]pyrimidine

80 4-Chloro-5-(4-fluoro-phenyl)-2-methyl-thieno[2,3-d]pyrimidine

81 5-(l,3-Benzodioxol-5-yl)-4-chloro-6-methylthieno[2,3-d]pyrimidine

82 4-Chloro-5-(4-fluorophenyl)-6-methylthieno[2,3-d]pyrimidine Example 83

Furan-2-yImethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

A stirred mixture of 4-chloro-5-phenylthieno[2,3-d]pyrimidine (2.2g, 0.009mol), furfurylamine (1.26g, 0.013mol), triethyl amine (1.3g) and ethanol (20ml) was heated under reflux for 2 hours then cooled to ambient temperature and poured into water (50ml). The resulting solid was collected by filtration, washed with water (30ml), dried in vacuo and crystallised from a mixture of hexane and toluene to give furan-2-ylmethyl- (5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine as a pale yellow solid, m.pt. 77-79⁰C.

Examples 84 to 100

The compounds set out below were prepared in the same way as in Example 83, using the appropriate starting materials.

Example Compound

84 Cyclopropylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

85 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-thiophen-2-ylmethyl-amine

86 Benzyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

87 Allyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

88 Furan-2-ylmethyl-methyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

89 Cyclohexylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

90 Phenethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

91 Cyclohexyl-(5-phenyl-thieno[2,3-d]ρyrimidin-4-yl)-amine

92 Furan-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

93 (4-Nitro-benzyl)-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

94 (5-Thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-(3,4,5-trimethoxy-benzyl)- amine

95 Cyclopropylmethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

96 Isobutyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine 97 Benzyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

98 Thiophen-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

99 Allyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

100 Furan-2-ylmethyl-methyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)- amine

Example 101

2-Methyl-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine

In a 10 ml glass tube were placed 2-methyl-4-chloro-5-phenylthieno[2,3-d]pyrimidm-4- ylamine (0.076g, 0.293 mmol), 2-(aminomethyl)pyridine (0.0364g, 0.03mmol) and ethanol (2.5ml). The vessel was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped from room temperature to 15O⁰C. Once 15O⁰C was reached, the reaction mixture was held at this temperature for 10 minutes. After cooling to ambient temperature, water (4ml) was added and the mixture stirred for 2.5 hours. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 2-methyl-N-(2-pyridyl)methyl-5- phenylthieno[2,3-d]pyrimidin-4-ylamine (0.084g) as an off white solid, m.pt. 110-112⁰C.

Examples 102 to 167

The compounds set out below were prepared in the same way as in Example 101, using the appropriate starting materials.

Example Compound

102 (l-Ethyl-pyrrolidin-2-ylmethyl)-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- amine

103 N,N-Dimethyl-2-(5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-acetamide

104 (34midazol-l-yl-propyl)-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-arnine

105 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine

106 5-Phenyl-4-(pyridin-2-ylmethoxy)-thieno[2,3-d]pyrimidine

107 Furan-3-ylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine 108 (5-Methyl-furan-2-ylmethyl)-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

109 4-(Furan-2-ylmethoxy)-5-phenyl-thieno[2,3-d]pyrimidine

110 (l-Methyl-lH-pyrrol-2-ylmethyl)-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- amine

111 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-pyridin-2-yl-ethyl)-amine

112 (5-Phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-acetic acid methyl ester

113 (2-Methoxy-ethyl)-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

114 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(tetrahydro-furan-2-ylmethyl)- amine

115 Thiophen-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

116 [l,3]Dioxolan-2-ylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

117 4-(Furan-2-ylmethylsulfanyl)-5-phenyl-thieno[2,3-d]pyrimidine

118 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-thiophen-2-yl-ethyl)-amine

119 4-B enzyloxy-5 -phenyl-thieno [2,3 -d]pyrimidine

120 5-Phenyl-4-(pyridin-2-ylmethylsulfanyl)-thieno[2,3-d]pyrimidine

121 [5-(5-Methyl-pyridin-2-yl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

122 Furan-2-ylmethyl-[5-(5-methyl-pyridin-2-yl)-thieno[2,3-d]pyrimidin-4-yl]- amine

123 [5-(4-Fluoro-phenyl)-thieno[2,3-d]pyrirnidin-4-yl]-pyridin-2-ylmethyl- amine

124 [5-(4-Fluoro-ρhenyl)-thieno[2,3-d]pyrimidin-4-yl]-furan-2-ylmethyl-amine

125 [2-(4-ChloiO-phenyl)-ethyl]-(5-methyl-thieno[2,3-d]pyrimidin-4-yl)-amine

126 Furan-2-ylmethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine

127 [2-(3,4-Dimethoxy-phenyl)-ethyl]-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)- amine

128 l-[2-(5-p-Tolyl-thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]-imidazolidin-2- one

129 4-(Naphthalen-2-yloxy)-5-p-tolyl-thieno[2,3-d]pyrimidine

130 Phenethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine 131 4-(5-p-Tolyl-thieno[2,3-d]pyrimidin-4-yloxy)-benzoic acid methyl ester

132 [2-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-[5-(3,4-dimethyl-phenyl)- thieno[2,3-d]pyrimidin-4-yl]-amine

133 [5-(3,4-Dimethyl-phenyl)-thieno[2,3-d]ρyiimidin-4-yl]-furan-2-ylmethyl- amine

134 4-(4-tert-Butyl-phenoxy)-5-(4-chloro-phenyl)-thieno[2,3-d]ρyrimidine

135 [5-(4-Chloro-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-furan-2-ylmethyl-amine

136 [5-(4-Chloro-phenyI)-thieno[2,3-d]pyrimidin-4-yl]-phenethyl-amine

137 [5-(4-Bromo-ρhenyl)-thieno[2,3-d]pyrimidin-4-yl]-[2-(2,3-dihydro- benzo[l,4]dioxin-6-yl)-ethyl]-amine

138 [5-(4-Methoxy-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl- amine

139 Furan-2-ylmethyl-[5-(4-methoxy-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- amine

140 (6-Ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2-ylinethyl-amine

141 (6-Ethyl-5-furan-3-yl-thieno[2,3-d]ρyrimidin-4-yl)-furan-2-ylmethyl-amine

142 Pyridin-2-ylmethyl-(5-o-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine

143 Furan-2-ylmethyl-(5-o-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine

144 [5-(4-tert-Butyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl- amine

145 [5-(4-tert-Butyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-furan-2-ylmethyl- amine

146 (5-Cyclohexyl-thieno[2,3-d]pyriniidin-4-yl)-pyridin-2-ylmethyl-amine

147 (5-Cyclohexyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2-ylmethyl-amine

148 (2-Isoproρyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl- amine

149 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(l-pyridin-2-yl-ethyl)-amine

150 Furan-2-ylmethyl-(2-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine

151 (5-Phenyl-2-trifluoromethyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- ylmethyl-amine 152 (2-Ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine

153 (2-Ethyl-5-ρhenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2-ylmethyl-amine

154 (6-Methylpyridin-2-ylmethyl)-(5-phenyl-thieno[2,3-d]pyriinidin-4-yl)- amine

155 [5-(4-Fluorophenyl)-2-methyl-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

156 (3-methyl-pyridin-2-ylmethyl)-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- amine

157 (6-Methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl- amine

158 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(l,2,3,4-tetrahydro-naphthalen-l- yl)-amine

159 6-Methyl-5-phenyl-4-piρeridin-l-yl-thieno[2,3-d]pyrimidine

160 2-[(5-Phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-methyl]-nicotinic acid ethyl ester

161 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-thiophen-2-yl-thiazol-4- ylmethyl)-amine

162 (2-Phenyl-thiazol-4-ylmethyl)-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- amine

163 Phenethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine

164 (6-Bromo-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine

165 (6-Bromo-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2-ylmethyl-amine

166 6-methyl-N-[(6-methylpyridin-2-yl)methyl]-5-phenylthieno[2,3- d]pyrimidin-4-amine

167 6-bromo-N-[(6-methylpyridin-2-yl)methyl]-5-phenylthieno[2,3- d]pyrimidin-4-amiive Example 168

5-Phenyl-l,3H-thieno[2,3-d]pyrimidine-2,4-dione

A mixture of ethyl 2-amino-4-phenyl-thiophene-3-carboxylate (2.Og, 8.1 mmol) and potassium cyanate (2.Og, 24.3 mmol) in glacial acetic acid (20ml) was stirred at ambient temperature for 72 hours. The resultant solid material was filtered off. The filtrate was diluted with water (50ml) and the precipitated solid was filtered off. The two solids were combined, suspended in water (100ml) and made alkaline by the addition of concentrated sodium hydroxide solution. The resultant suspension was heated at 100⁰C for 2 hours with stirring, then allowed to cool to ambient temperature and acidified by the addition of glacial acetic acid. The resulting solid was collected by filtration to give 5-phenyl-l,3H- thieno[2,3-J]pyrimidin-2,4-dione (1. Ig) as a white solid which was used without further purification.

Examples 169 to 174 The compounds set out below were prepared in the same way as in Example 168, using the appropriate starting materials.

Example Compound

169 5-(4-Fluorophenyl)-l,3Η-thieno[2,3-d]pyrimidine-2,4-dione

170 6-Methyl- 1 ,3H-thieno [2,3-d]pyrimidine-2,4-dione

171 5-Benzo[l,3]dioxol-5-yl-l,3H-thieno[2,3-d]pyrimidine-2,4-dione

172 5-(l,3~Benzodioxol-5-yl)-6-methyl-l,3H-thieno[2,3-d]pyrimidme-2,4- dione

173 5-(4-Fluorophenyl)-6-methyl-l,3H-thieno[2,3-d]pyrimidine-2,4-dione

174 6-Methyl-5-phenyl-l,3H-thieno[2,3-d]pyrimidine-2,4-dione

Example 175 2,4-DichIoro-5-phenyI-thieno[2,3-d]pyrimidine

A stirred mixture of 5-phenyl-l,3H-thieno[2,3-^]pyrimidin-2,4-dione (1.07g, 4.39 mmol) and phenylphosphonic dichloride (10ml) was heated at 15O⁰C for 7 hours then allowed to stand at ambient temperature for 18 hours. The resulting dark solution was poured into ice-water and extracted with dichloromethane (3 x 150ml). The combined extracts were washed with saturated sodium hydrogen carbonate solution (150ml) and dried (MgSO₄). The solvent was removed in vacuo and the oily residue triturated with 40-60⁰C petrol to give 2,4~dichloro-5-phenyl-thieno[2,3-d]pyrimidine (0.82g) as a pale yellow solid which was used without further purification.

Examples 176 to 180

The compounds set out below were prepared in the same way as in Example 175, using the appropriate starting materials.

Example Compound

176 2,4-Dichloro-5-(4-fluoro-phenyl)-thieno[2,3-d]pyrimidine

177 5-Benzo[l,3]dioxol-5-yl-2,4-dichloro-thieno[2,3-d]pyrimidine

178 2,4-Dichloro-6-methyl-5 -phenylthieno [2,3 -djpyrimidine

179 2,4-Dichloro-5-(4-fluorophenyl)-6-methylthieno[2,3-d]pyrimidine

180 5-(l,3-Benzodioxol-5-yl)-2,4-dichloro-6-methylthieno[2,3-d]ρyrimidine

Example 181 (2-ChIoro-5-phenyI-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine A mixture of 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (0.82g, 2.92 mmol), 2- (aminomethyl)pyridine (0.35g, 3.21 mmol), triethylamine (0.32g, 0.45ml, 3.21 mmol) and propan-2-ol (20 ml) was stirred at ambient temperature for 72 hours. Water (50ml) was added to the reaction mixture and the organic phase was extracted using dichloromethane (3 x 50ml). The combined extracts were washed with water and dried (MgSO₄). The solvent was removed in vacuo to give 2-chloro-iV-(2-pyridyl)methyl-5- phenylthieno[2,3-(i]pyrimidin-4-ylamine (1.Og) as a white solid which was used without further purification. Examples 182 to 187

The compounds set out below were prepared in the same way as in Example 181, using the appropriate starting materials.

Example Compound

182 (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2-ylmethyl-amine;

183 [2-Chloro-5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

184 (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-(6-methyl-pyridin-2-yl methyl)-amine

185 [2-Chloro-5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-(6-methyl-p yridin-2-ylmethyl)-amine

186 (5-Benzo[l,3]dioxol-5-yl-2-chloro-thieno[2,3-d]pyrimidin-4-yl)-(6-meth yl-pyridin-2-ylmethyl)-amine

187 (5-Benzo[l,3]dioxol-5-yl-2-chloro-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- ylmethyl-amine

Example 188

^-Cyclopropylmethyl-S-phenyl-^-pyridin-Z-ylmethyl-thienotZ^-dlpyrimidine-l^- diamine

In a 10 ml glass tube were placed 2-chloro-N-(2-pyridyl)methyl-5-phenylthieno[2,3- <2]pyrimidin~4-ylamine (0.03g, 0.0852 mmol) and cyclopropylmethylamine (0.5ml). The vessel was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 200⁰C. Once 200⁰C was reached, the reaction mixture was held at this temperature for 40 minutes. After cooling to ambient temperature, water (4ml) was added and the mixture stirred for 2.5 hours. The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give N²-Cyclopropylmethyl-5-phenyl-N⁴-pyridin-2- ylmethyl-thieno[2,3-d]pyrimidine-2,4-diamine (0.025g) as a yellow solid, m.p.t. 109- Hl⁰C. Examples 189 to 224

The compounds set out below were prepared in the same way as in Example 188, using the appropriate starting materials.

Example Compound

189 N²-(2-Methoxyethyl)-5-phenyl-N⁴-(pyridin-2-ylmethyl)thieno[2,3- d]pyrimidine-2,4-di amine

190 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2- ylamino } -ethanol

191 (2-Methoxy-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl- amine

192 5-Phenyl-N-4-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4-diamine

193 N,N'-Bis(2-furylmethyl)-5-ρhenylthieno[2,3-d]pyrimidine-2,4-di amine

194 5-(3,4-Dimethylphenyl)-N-(2-furylmethyl)thieno[2,3-d]pyrimidin-4- amine

195 (2-Benzyloxy-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2-ylmethyl- amine

196 N²-methyl-5-phenyl-N⁴-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidine-2,4- di amine

197 (2-Morpholin-4-yl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- ylmethyl-amine

198 N²,N²-Dimethyl-5-phenyl-N⁴-pyridin-2-ylmethyl-thieno[2,3- d]pyrimidine-2,4-di amine

199 5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidine-2- carbonitrile

200 5-(4-Fluoroρhenyl)-N²,N²-dimethyl-N⁴-ρyridin-2-ylmethyl-thieno[2,3- d]pyrimidine-2,4-diamine

201 1 - { 5-(4-Fluorophenyl)-4- [(pyridin-2-ylmethyl)-amino] -thieno[2,3- d]pyrimidin-2-yl}-piperidine-4-carboxylic acid methyl ester 202 3-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2- ylamino} -propionic acid ethyl ester

203 [2-(2-Methoxy-ethoxy)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

204 5-(4-Fluorophenyl)-N²-methyl-N⁴-pyridin-2-ylmethyl-thieno[2,3- d]pyrimidine-2,4-di amine

205 5-(4-Fluorophenyl)-N⁴-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4- di amine

206 2-(l-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin- 2-yl } -piperidin-4-yl)-ethanol

207 [5-(4-Fluorophenyl)-2-morpholin-4-yl-thieno[2,3-d]pyrimidin-4-yl]- pyridin-2-ylmethyl-amine

208 2-((2-Hydroxy-ethyl)- { 5-phenyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-amino)-ethanol

209 5-(4-Fluorophenyl)-N²-(2-methoxy-ethyl)-N⁴-pyridin-2-ylmethyl- thieno[2,3-d]pyrimidine-2,4-di amine

210 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2- ylamino } -prop ane- 1 ,3-diol

211 [2-(2-Dimethylamino-ethoxy)-5-phenyl~thieno[2,3-d]pyrimidin-4-yl]- pyridin-2-ylmethyl-amine

212 2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-ylamino } -ethanol

213 2-{4-[(6-Methyl-pyridin-2-ylmethyl)-amino]-5-ρhenyl-thieno[2,3- d]pyrimidin-2-ylamino } -ethanol

214 3-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2- ylamino } -propane- 1 ,2-diol

215 [2-(4-Methyl-piperazin-l-yl)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]- pyridin-2-ylmethyl-amine

216 2-{4-[(6-Methyl-pyridin-2-ylmethyl)-amino]-5-phenyl-thieno[2,3- d]pyrimidin-2-ylamino } -ethanol 217 2-((2-Hydroxy-ethyl)-{4-[(6-methyl-ρyridin-2-ylmethyl)-amino]-5- phenyl-thieno[2,3-d]pyrimidin-2-yl}-amino)-ethanol

218 2-{5-(4-Fluorophenyl)-4-[(6-methyl-pyridin-2-ylmethyl)-amino]- thieno [2,3-d]pyrimidin-2-ylamino } -ethanol

219 2-[{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl } -(2-hydroxy-ethyl)-amino]-ethanol

220 2-[ { 5-(4-Fluorophenyl)-4-[(6~methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrirnidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol

221 2-{5-Benzo[l,3]dioxol-5-yl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-ylamino } -ethanol

222 2-{5-Benzo[l,3]dioxol-5-yl-4-[(6~methyl-pyridin-2-ylmethyl)-amino]- thieno [2 ,3 ~d]pyrimidm-2-ylamino } -ethanol

223 2-[{5-Benzo[l,3]dioxol-5-yl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol

224 2-[{5-Benzo[l,3]dioxol-5-yl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol

Example 225

(4-Oxo-5-phenyl-3,4-dihydrothieno[2,3-J]pyrimidin-2-yl)acetic acid ethyl ester

Hydrogen chloride gas was bubbled through a stirred reaction mixture of 2-amino-4- phenylthiophene-3-carboxylic acid ethyl ester (4.94g, 0.02mol) in ethyl cyanoacetate (50ml) for 2 hours. A thick suspension formed initially which slowly dissolved on gentle warming. The mixture was allowed to stand at ambient temperature for 18 hours. Excess hydrogen chloride was removed by bubbling nitrogen through the reaction mixture and most of the excess ethyl cyanoacetate was distilled out at reduced pressure. The solid residue was recrystallised from ethanol to give (4-oxo-5-phenyl-3,4-dihydrothieno[2,3- d]pyrimidin-2-yl)acetic acid ethyl ester (3.64g), which was used without further purification. Examples 226 to 230

The compounds set out below were prepared in the same way as in Example 225, using the appropriate starting materials.

Example Compound

226 [5-(4-Fluorophenyl)-4-oxo-3,4-dihydro-thieno[2,3-d]ρyrimidin-2-yl]- acetic acid ethyl ester

227 (5-Benzo[l,3]dioxol-5-yl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2- yl)-acetic acid ethyl ester

228 (6-Methyl-4-oxo-5-phenyl-3,4-dihydro-thieno[2,3-d]pyrimidin-2-yl)- acetic acid ethyl ester

229 [5-(4-Fluorophenyl)-6-methyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin- 2-yl]-acetic acid ethyl ester

230 (5-Benzo[l,3]dioxol-5-yl-6-methyl-4-oxo-3,4-dihydro-thieno[2,3~ d]pyrimidin-2-yl)-acetic acid ethyl ester

Example 231

(4-Chloro-5-phenylthieno[2,3-rf]pyrimidin-2-yl)acetic acid ethyl ester

A stirred solution of (4-oxo-5-phenyl-3,4-dihydrothieno[2,3-£f]pyrimidin-2-yl)acetic acid ethyl ester (1.Og, 3.185mmol), phosphoryl chloride (15ml) and iV,Λf-dimethylaniline (4.8ml) was heated under reflux for 6 hours and then left to stand at ambient temperature for 18 hours. The excess phosphoryl chloride was removed in vacuo to give a dark residue, which was dissolved in dichloromethane (100ml) and then washed with water (2x50ml) followed by saturated sodium hydrogen carbonate solution (50ml). The organic layer was dried (MgSO₄) and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane and 40°-60° petroleum ether (3:1) gave (4-chloro-5-phenylthieno[2,3-<i]pyrimidin-2-yl)acetic acid ethyl ester as a pale-yellow solid (0.86g). Examples 232 to 236

The compounds set out below were prepared in the same way as in Example 231, using the appropriate starting materials.

Example Compound

232 [4-Chloro-5-(4-Fluorophenyl)-thieno[2,3-d]pyrimidin-2-yl]-acetic acid ethyl ester

233 (4-Chloro-5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-2-yl)-acetic acid ethyl ester

234 (4-Chloro-6-methyl-5-ρhenyl-thieno[2,3-d]pyrimidin-2-yl)-acetic acid ethyl ester

235 [4-Chloro-5-(4-fluorophenyl)-6-methyl-thieno[2,3-d]pyrimidin-2-yl]- acetic acid ethyl ester

236 (5-Benzo[l,3]dioxol-5-yl-4-chloro-6-methyl-thieno[2,3-d]pyrimidin-2- yl)-acetic acid ethyl ester

Example 237

{5-Phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-J]pyrimidin-2-yl} acetic acid ethyl ester

A stirred mixture of (4-chloro-5-phenylthieno[2,3-J]pyrimidin-2-yl)acetic acid ethyl ester (0.36g, 1.08mmol), 2-aminomethylρyridine (0.12ml, 1.19mmol), triethylamine (0.17ml, 1.19mmol) and ethanol (8ml) was heated under reflux for 4 hours. The solution was then cooled to ambient temperature, poured into water (100ml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:2) gave { 5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-£f]pyrimidin-2-yl } acetic acid ethyl ester as a colourless gum (0.4Ig). Examples 238 to 249

The compounds set out below were prepared in the same way as in Example 237, using the appropriate starting materials.

Example Compound

238 {4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl}- acetic acid ethyl ester

239 {5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrim idin-2-yl} -acetic acid ethyl ester

240 {5-Benzo[l,3]dioxol-5-yl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]p yrimidin-2-yl} -acetic acid ethyl ester

241 {5-(4-Fluorophenyl)-4-[(6-memyl-pyridin-2-ylmethyl)-amino]~ thieno[2,3-d] pyrimidin-2-yl} -acetic acid ethyl ester

242 {5-Benzo[l,3]dioxol-5-yl-4-[(6-methyl-ρyridin-2-ylmethyl)-amino]-thien o[2,3-d]pyrimidin-2-yl}-acetic acidethyl ester

243 {6-Methyl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]-5-phenyl- thieno[2,3-d]pyrimidin-2-yl} -acetic acid ethyl ester

244 {5-(4-Fluorophenyl)-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl} -acetic acid ethyl ester

245 {5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-yl} -acetic acid ethyl ester

246 {6-Methyl-5-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl} -acetic acid ethyl ester

247 {5-(4-Fluorophenyl)-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-acetic acid ethyl ester

248 {5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(pyridin-2-ylmethyl)-amino]-thien o[2,3-d]pyrimidin-2-yl}-acetic acid ethyl ester

249 4-[(6-Methyl-pyridin-2-ylmethyl)-amino]-5-phenyl-thieno[2,3- d]ρyrimidine-2-carboxylic acid ethyl ester Example 250 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-rf]pyrimidin-2-yl}ethanol A stirred solution of {5-phenyl-4-[(pyridin-2-ylmethyl)aimno]thieno[2,3-(i]pyrimidin-2- yl}acetic acid ethyl ester (O.lOg, 0.248mmol) in anhydrous tetrahydrofuran (ImI) was cooled in an ice-bath and treated, under a nitrogen atmosphere, with diisobutylaluminium hydride (IM solution in hexane, 1.04ml, 1.04mmol) over about 15 minutes. The reaction mixture was allowed to warm up and left to stir at ambient temperature for 3 hours. The resultant mixture was then cooled in an ice-bath and quenched by the slow addition of methanol (0.5ml) followed by water (ImI). The mixture was then diluted with 2M sodium hydroxide solution (10ml) and extracted with ethyl acetate (3x20ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (4:1) gave 2-{5-phenyl-4-[(pyridin-2- ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}ethanol as an off-white solid (0.05g), m.p. 90°-92°C.

Examples 251 to 262 The compounds set out below were prepared in the same way as in Example 250, using the appropriate starting materials.

Example Compound

251 2- { 4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl } - ethanol

252 2-{4-[(6-Methyl-pyridin-2-ylmethyl)-amino]-5-phenyl-thieno[2,3- d]pyrimidin-2-yl } -ethanol

253 2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl } -ethanol

254 2-{5-(4-Fluorophenyl)-4-[(6-methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-ethanol 255 2-{5-Benzo[l,3]dioxol-5-yl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]ρyrimidin-2-yl } -ethanol

256 2-{5-Benzo[l,3]dioxol-5-yl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-ethanol

25 2-{6-Methyl-5-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl }-ethanol

258 2- { 6-Methyl-4-[(6-methyl-pyridin-2~ylmethyl)-amino]-5-phenyl- thieno[2,3-d]pyrimidin-2-yl}-ethanol

259 2- { 5-(4-Fluorophenyl)-6-methyl-4- [(pyridin-2-ylmethyl)-amino] - thieno[2,3-d]pyrimidin-2-yl}-ethanol

260 2-{5-(4-Fluorophenyl)-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-yl}-ethanol

261 2-{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-ethanol

262 2- { 5-Benzo [ 1 ,3]dioxol-5-yl-6-methyl-4- [(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-yl } -ethanol

Example 263

2-{5-Phenyl-4-[(pyridin-2-yImethyl)amino]thieno[2,3-J]pyrimidin-2-yl}malonic acid diethyl ester

Sodium hydride (60% dispersion in oil, 64mg, 1.59mmol) was treated with a solution of

{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-rf]pyrimidin-2-yl}acetic acid ethyl ester (0.43g, 1.06mmol) in diethyl carbonate (2.5ml). The resulting suspension was stirred at ambient temperature for 5 hours and left to stand for 18 hours. The mixture was then quenched with aqueous ammonium chloride solution (50ml) and extracted with diethyl ether (3x50ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane followed by dichloromethane and ethyl acetate (5:1) gave 2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3- d]pyrimidin-2-yl}malonic acid diethyl ester as a colourless gum (0.32g). Examples 264 to 274

The compounds set out below were prepared in the same way as in Example 263, using the appropriate starting materials.

Example Compound

264 2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyr imidin-2-yl}-malonic acid diethyl ester

265 2-{5-Benzo[l,3]dioxol-5-yl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d ]pyrimidin-2-yl}-malonic acid diethyl ester

266 2-{5-(4-Fluorophenyl)-4-[(6-methyl-pyridin-2-ylmethyl)-amino]-thieno[ 2,3-d]pyrimidin-2-yl}-rnalonic acid diethyl ester

267 2-{4-[(6-Methyl-pyridin-2-ylmethyl)-amino]-5-phenyl-thieno[2,3d]pyrim idin-2-yl}-malonic acid diethyl ester

268 2-{5-Benzo[l,3]dioxol-5-yl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]-thi eno[2,3-d]pyrimidin-2-yl}-malonic acid diethyl ester

269 2- { 6-Methyl-5-phenyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3d]pyrimidin-2-yl}-malonic acid diethyl ester

270 2-{5-(4-Fluorophenyl)-6-methyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[ 2,3-d]pyrimidin-2-yl}-malonic acid diethyl ester

271 2-{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-malonic acid diethyl ester

272 2- { 6-Methyl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]-5- phenylthieno[2,3-d]pyrimidin-2-yl}-malonic acid diethyl ester

273 2-{5-(4-Fluorophenyl)-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-yl}-malonic acid diethyl ester

274 2- { 5-Benzo[l ,3]dioxol-5-yl-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)-a mino]-thieno[2,3-d]pyrimidin-2-yl}-malonic acid diethyl ester Example 275

2-{5-PhenyI-4-[(pyridin-2-yImethyl)-amino]-thieno[2,3-d]pyrimidin-2-yl}-propane- 1,3-dioI

A stirred solution of 2-{5-phenyl-4-[(pyiidin-2-ylmethyl)amino]thieno[2,3-J]pyriinidin- 2-yl}malonic acid diethyl ester (0.32g, 0.672mmol) in anhydrous tetrahydrofuran (10ml) was cooled in an ice-bath and treated, under a nitrogen atmosphere, with diisobutylaluminium hydride (IM solution in hexane, 5.52ml, 5.52mmol) over 15 minutes. The reaction mixture was allowed to warm up and left to stir at ambient temperature for 3 hours. The resultant mixture was then cooled in an ice-bath and quenched by the slow addition of methanol (5ml) followed by water (10ml). The mixture was then diluted with 2M sodium hydroxide solution (50ml) and extracted with ethyl acetate (3x50ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with 5% methanol in dichloromethane gave 2-{5-ρhenyl-4-[(pyridin-2- ylmethyl)amino]thieno[2,3-cf]pyrimidin-2-yl}propane-l,3-diol as a pale yellow solid (0.08g), m.p. 137°-139°C.

Examples 276 to 286

The compounds set out below were prepared in the same way as in Example 275, using the appropriate starting materials.

Example Compound

276 2-{4-[(6-Methyl-pyridin-2-ylmethyl)-amino]-5-phenyl-thieno[2,3- d]pyrimidin-2-yl } -propane- 1 ,3-diol

277 2-{5-(4-Fluoroρhenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl } -propane- 1 ,3-diol

278 2- { 5-(4-Fluorophenyl)-4- [(6-methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl } -propane-1 ,3-diol

279 2-{5-Benzo[l,3]dioxol-5-yl-4-[(ρyridin-2-ylmethyl)-amino]-thieno[2,3- d]ρyrimidin-2-yl}-propane-l,3-diol

280 2- { 5-B enzo [ 1 ,3 ] dioxol-5-yl-4- [(6-methyl-pyridin-2-ylmethyl)-amino] - thieno[2,3-d]pyrimidin-2-yl}-propane-l,3-diol 281 2- { 6-Methyl-5-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl } -propane- 1 ,3-diol

282 2-{6-Methyl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]-5-phenyl- thieno [2,3-d]pyrimidin-2-yl } -propane- 1 ,3-diol

283 2-{5-(4-Fluorophenyl)-6-methyl-4-[(pyridin-2-ylniethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-propane-l,3-diol

284 2-{5-(4-Fluorophenyl)-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]thieno[2,3-d]pyrimidin-2-yl}-propane-l,3-diol

285 2-{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(pyridm-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-propane-l,3-diol

286 2-{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino] -thieno[2,3-d]pyrimidin-2-yl } -propane- 1 ,3-diol

Example 287

N-Methyl-2-{5-phenyl-4-[{pyridin-2-ylmethyl)amino]thieno[2,3-</]pyrimidin-2- yljacetamide In a 10ml glass tube were placed {5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3- <f]pyrimidin-2-yl} acetic acid ethyl ester (35mg, 0.088mmol) and a saturated solution of methylamine in ethanol (2.0ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped from room temperature to 100°C. Once 100⁰C was reached, the reaction mixture was held at this temperature for 30 minutes. The temperature was then ramped up to 15O⁰C and the reaction mixture was held at this temperature for a further 30 minutes. The resultant mixture was diluted with water (50ml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 5% methanol in dichloromethane to give N-methyl-2-{5-phenyl-4-[{pyridin-2- ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl }acetamide (2mg). Examples 288 to 298

The compounds set out below were prepared in the same way as in Example 287, using the appropriate starting materials.

Example Compound

288 N-Methyl-2-{4~[(6-methyl-pyridin-2-ylmethyl)-amino]-5-phenyl- thieno[2,3-d]pyrimidin-2-yl}-acetamide

289 2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl } -N-methyl-acetamide

290 2-{5-(4-Fluorophenyl)-4-[(6-methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-N-methyl-acetamide

291 2-{5-Benzo[l,3]dioxol-5-yl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-yl } -N-methyl-acetamide

292 2-{5-Benzo[l,3]dioxol-5-yl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-N-methyl-acetamide

293 N-Methyl-2-{6-methyl-5-phenyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl } -acetamide

294 N-Methyl-2-{6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]-5- phenyl-thieno[2,3-d]pyrimidin-2-yl } -acetamide

295 2-{5-(4-Fluorophenyl)-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl}-N-methyl-acetamide

296 2-{5-(4-Fluorophenyl)-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-yl } -N-methyl-acetamide

297 2-{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-yl } -N-methyl-acetamide

298 2-{5-Benzo[l,3]dioxol-5-yl-6-methyl-4~[(6-methyl-pyridin-2~ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-yl } -N-methyl-acetamide Example 299 2-Chloromethyl-5-phenyl-3H-thieno[2,3-rf]pyrimidin-4-one

Hydrogen chloride gas was bubbled through a stirred solution of 2-amino-4- phenylthiophene-3-carboxylic acid ethyl ester (4.94g, 0.02mol) and chloroacetonitrile (1.4ml, 0.022mol) in anhydrous 1,4-dioxane (60ml) for about 4 hours. A thick suspension formed initially which slowly dissolved. The mixture was stirred at ambient temperature for 18 hours before being poured into water (250ml) and basified (pH 8) by the addition of sodium hydrogen carbonate. The supernatant was then decanted to leave a gummy solid which was triturated with aqueous ethanol to give 2-chloromethyl-5- phenyl-3H-thieno[2,3-<f]pyrirnidin-4-one as a yellow solid (3.7Og), which was used without further purification.

Example 300 4-Chloro-2-chloromethyl-5-phenylthieno[2,3-rf]pyrimidine A stirred suspension of 2-chloromemyl-5-phenyl-3H-thieno[2,3-d]pyrirnidin-4-one (1.5g, 5.42mmol) and phosphoryl chloride (23ml) was heated under reflux for 7 hours and then left to stand at ambient temperature for 18 hours. The excess phosphoryl chloride was removed in vacuo to give a dark residue, which was dissolved in dichloromethane (100ml) and then washed with water (2xl00ml) followed by saturated sodium hydrogen carbonate solution (100ml). The organic extract was dried (MgSO₄) and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane gave 4-chloro-2-chloromethyl-5-phenylthieno[2,3- <f]pyrimidine as a pale-yellow solid (1.42g).

Example 301

(2-ChIoromethyl-5-phenylthieno[2,3-έflpyriinidin-4-yl)pyridin-2-yImethylamine

A reaction mixture of 4-chloro-2-chloromethyl-5-phenylthieno[2,3-cf]pyrimidine (0.50g,

1.69mmol), 2-aminomethyrpyridine (0.17ml, 1.69mmol), triethylamine (0.26ml,

1.86mmol) and propan-2-ol (15ml) was stirred at ambient temperature for 4 days. The solution was then poured into water (150ml) and extracted with ethyl acetate (3x75ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:4) gave (2-chloromethyl-5-phenylthieno[2,3- c0pyrimidin-4-yl)pyridin-2-ylmethylamine as a yellow solid (0.17g), m.p. 97°-99°C.

Example 302

(2-Dimethylaminomethyl-5-phenylthieno[2,3-rf]pyrimidin-4-yl)pyridin-2- ylmethylamine In a 10ml glass tube were placed (2-chloromethyl-5-phenylthieno[2,3-<i]pyrirnidin-4- yl)pyridin-2-ylmethylamine (50mg, 0.136mmol) and a saturated solution of dimethylamine in ethanol (2.0ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped from room temperature to 150⁰C. Once 150⁰C was reached, the reaction mixture was held at this temperature for 10 minutes. The resultant mixture was diluted with water (50ml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with 4% triethylamine in ethyl acetate gave (2-dimethylaminomethyl-5-phenylthieno[2,3-rf]pyrimidin-4-yl)pyridin-2- ylmethylamine as a yellow gum (36mg).

Examples 303 to 304

The compounds set out below were prepared in the same way as in Example 302, using the appropriate starting materials.

Example Compound

303 (2-Morpholin-4-ylmethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin- 2-ylmethyl-amine

304 (2-Methylaminomethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- ylmethyl-amine Example 305 (2-Methoxymethyl-5-phenylthien[2,3-fi]primidin-4-yl)pyridin-2-yImethylamine

In a 10ml glass tube was placed anhydrous methanol (ImI). This was cooled in an ice- bath and treated with sodium hydride (60% dispersion in oil, 6mg, 0.147mmol). After stirring for about 10 minutes, (2-chloromethyl-5-phenylthieno[2,3-<f]pyrimidin-4- yl)pyridin-2-ylmethylamine (36mg, 0.098mmol) was added. The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped from room temperature to 15O⁰C. Once 150⁰C was reached, the reaction mixture was held at this temperature for 10 minutes. The resultant mixture was diluted with water (50ml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (3:2) gave (2-methoxymethyl-5-phenylthien[2,3- rf]primidin-4-yl)pyridin-2-ylmethylamine as a pale brown gum (lmg).

Example 306 6-Bromo-3iϊ-thieno[2,3w/]pyrimidin-4-one

A suspension of 3H-thieno[2,3-<i]pyrimidin-4-one (7.68g, 0.056mol) in glacial acetic acid (75ml) was treated with bromine (7.5ml) and stirred at ambient temperature for 4 hours. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 6-biOmo-3H-thieno[2,3-d]pyrimidin-4~one as a light brown solid (11.64g), which was used without further purification.

Example 307

The compound set out below was prepared in the same way as in Example 306 , using the appropriate starting materials.

Example Compound

307 6-Bromo-5-phenylthieno[2,3-d]pyrimidin-4(3Η)-one Example 308 6-Bromo-4-chlorothieno[2,3-£θpyrimidine

6-Bromo-3H-thieno[2,3-J]pyrimidin-4-one (11.64g, 0.05mol) was added portion-wise to phosphoryl chloride (220ml) and the resulting mixture was heated under reflux for 6 hours. The excess phosphoryl chloride was then removed in vacuo. The resulting residue was dissolved in dichloromethane (250ml) and washed with water (2xl00ml), followed by saturated sodium hydrogen carbonate solution (100ml). The organic layer was then dried (MgSO₄) and the solvent was removed in vacuo to give 6-bromo-4- chlorothieno[2,3-d]pyrimidine (9.06g) as a yellow solid, which was used without further purification.

Example 309

The compound set out below was prepared in the same way as in Example 308, using the appropriate starting materials.

Example Compound

309 6-Bromo-4-chloro-5-phenylthieno[2,3-d]pyrimidin-4(3Η)-one

Example 310 5-Bromo-4-chlorothieno[2,3-</]pyrimidine

A stirred solution of 6-bromo-4-chlorothieno[2,3-<i]pyrimidine (4.Og, O.Olβmol) in anhydrous tetrahydrofuran (100ml) was cooled in a dry-ice/acetone bath and treated, under a nitrogen atmosphere, with lithium diisopropylamide (1.8M solution in tetrahydrofuran, 9.0ml, O.Olόmol) over about 20 minutes. The resultant dark solution was stirred in the cold for 1 hour and then treated with a mixture of water (5ml) and tetrahydrofuran (20ml) over about 20 minutes. The mixture was then allowed to warm up to about 0⁰C before being poured into water (250ml) and extracted with dichloromethane (3xl00ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane gave 5-bromo-4-chlorothieno[2,3- cQpyrimidine as a pale brown solid (3.8g).

Example 311

(5-Bromothieno[2,3-df]pyrimidin-4-yl)pyridin-2-ylmethylamine

A stirred mixture of 5-bromo-4-chlorothieno[2,3-d]pyrimidine (3.8g, 15.2mmol), ethanol (250ml), triethylamine (2.32ml, 16.7mmol) and 2-aminomethylpyridine (1.72ml, 16.7mmol) was heated under reflux for 2.5 hours. The solution was then cooled to ambient temperature, poured into water (300ml) and extracted with dichloromethane (3xl50ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (1:1) gave (5-bromothieno[2,3- <i]ρyrimidin-4-yl)pyridin-2-ylmethylamine as a yellow solid (3.12g), m.pt. 127°-129°C.

Example 312

[5-(l-Methyl-lJΪ-indol-5-yl)thieno[2,3-d]pyrimidin-4-yl]pyridin-2-yImethylamine In a 10ml glass tube were placed 5-bromothieno[2,3-d]pyrimidin-4-yl)pyridin-2- ylmethylamine (47mg, 0.146mmol), iV-methylindole-5-boronic acid (51mg, 0.294mmol), polymer-bound triphenylphosphine-Pd(0) (Argonaut PS-PPh₃-Pd, 0.13mmol/g,146mg, 0.0146mmol), sodium carbonate (46mg, 0.440mmol), dimethoxyethane (0.75ml), ethanol (0.75ml) and water (0.5ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped from room temperature to 15O⁰C. Once 15O⁰C was reached, the reaction mixture was held at this temperature for 1 hour. The resultant mixture was filtered through Kieselguhr, the filtered solid being washed through with water and dichloromethane. The filtrate was then extracted with dichloromethane (3x50ml) and the organic extracts dried (MgSO₄). The solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with ethyl acetate and 40°-60° petroleum ether (2:1) gave [5-(l-methyl-lH-indol-5-yl)thieno[2,3-£f]pyrimidin-4-yl]pyridin-2-ylmethylamine as a yellow solid (25mg), m.pt. 184-185⁰C. Examples 313 to 333

The compounds set out below were prepared in the same way as in Example 312, using the appropriate starting materials.

Example Compound

313 Pyridin-2-ylmethyl-[5-(4-trifluoromethyl-phenyl)-thieno[2,3- d]pyrimidin-4-yl]-amine

314 (5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmeth yl-amine

315 [5-(4-Dimethylamino-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

316 [5-(3,4-Dimethyl-phenyl)-thieno[2,3-d]ρyrimidin-4-yl]-pyridin-2- ylmethyl-amine

317 Pyridin-2-ylmethyl-[5-(4-trifluoromethoxy-phenyl)-tm^'eno[2,3- d]pyrimidin-4-yl]-amine

318 Pyridin-2-ylmethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine

319 (5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- ylmethyl-amine

320 [5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-thieno[2,3-d]pyrimidin-4-yl]- pyridin-2-ylmethyl-amine

321 [5-(3-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl- amine

322 [5-(3-Methoxyphenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl- amine

323 [5-(lH-Indol-6-yl)-thieno[2,3-d]pyrimidin-4-yl]-ρyridin-2-ylmethyl- amine

324 [5-(4-Methoxymethoxy-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

325 [5-(4-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl- amine 326 [5-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-thieno[2,3-d]pyrimidin-4-yl]- pyridin-2-ylmethyl-amine

327 4-{4-[(Pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-5-yl}-benzoic acid methyl ester

328 [5-(6-Methoxy-pyridin-3-yl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

329 [5-(2,4-Dichloro-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

330 [5-(4-Chloro-3-trifluoromethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- pyridin-2-ylmethyl-amine

331 [5-(3-Fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl- amine

332 [5-(4-Morpholin-4-yl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

333 [5-(3,4-Difluoro-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- ylmethyl-amine

Example 334 5-Bromo-6-methyl-l£T-thieno[2,3-flf]pyrimidine-2,4-dione

A brown glass round-bottom flask was charged with 6-methyl-lH-thieno[2,3- d]pyrimidine-2,4-dione (2.7Og, 14.8mmol) and glacial acetic acid (30ml). Bromine (2.70ml) was added and the mixture stirred at ambient temperature for 4 hours. The resultant mixture was diluted with water (30ml) and the solid was collected by filtration, washed thoroughly with water and then dried in vacuo to give 5-bromo-6-methyl-lH- thieno[2,3-^pyrimidine-2,4-dione as a brown solid (2.43g), which was used without further purification. Example 335 5-Bromo-2,4-dichloro-6-methylthieno[2,3-/flpyriinidine A stirred mixture of 5-bromo-6-methyl-lH-thieno[2,3-cflpyrimidine-2,4~dione (2.43g, 9.3mmol) and phenylphosphonic dichloride (15ml) was heated at a temperature of 15O⁰C for 6 hours in a vessel protected by a calcium chloride drying tube. The reaction mixture was allowed to cool to ambient temperature and poured into ice-water (250ml). After stirring for 45 minutes, the resulting mixture was extracted with dichloromethane (3xl00ml). The combined organic extracts were washed with water (100ml) followed by saturated sodium hydrogen carbonate solution (100ml) and dried (MgSO₄). The solvent was removed in vacuo to give the crude product which was purified by flash chromatography (silica) eluting with dichloromethane giving 2.02g of 5-bromo-2,4- dichloro-6-methylthieno[2,3-<f|pyrimidine as a yellow solid.

Example 336

5-Bromo-2-chloro-6-methylthieno[2,3-rf]pyrimidin-4-yl)pyridin-2-ylmethyIamine A stirred mixture of 5-bromo-2,4~dichloro-6-methylthieno[2,3-^pyrimidine (1.Og, 3.35mmol), ethanol (40ml), 2-aminomethylpyridine (0.40ml, 3.69mmol) and triethylamine (0.50ml, 3.69mmol) was heated at a temperature of 60⁰C for 1 hour. The reaction mixture was then cooled to ambient temperature, diluted with water (100ml) and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give a residue. Purification by flash chromatography (silica) eluting with dichloromethane followed by 5% ethyl acetate in dichloromethane gave (5-bromo-2-chloro-6-methylthieno[2,3-J]pyrimidin-4-yl)pyridin- 2-ylmethylamine as a white solid (0.99g).

Example 337

The compound set out below was prepared in the same way as in Example 336, using the appropriate starting materials. Example Compound

337 5-Bromo-2-chloro-6-methyl-thieno[2,3-d]pyrimidin-4-yl)-(6-methyl-pyri din-2-ylmethyl)-amine

Example 338

2-[{5-Bromo-6-methyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-J]pyrimidin-2-yl}-

(2-hydroxyethyI)amino]ethanol

In a 10ml glass tube were placed 5-bromo-2-chloro-6-methylthieno[2,3-rf]pyrimidin-4- yl)pyridin-2-ylmethylamine (O.lOg, 0.27mmol) and diethanolamine (0.80ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped from room temperature to 200⁰C. Once 200⁰C was reached, the reaction mixture was held at this temperature for 30 minutes. After cooling to ambient temperature, water (50 ml) was added and the mixture extracted with dichloromethane (3x50 ml). The combined organic extracts were dried (MgSO₄) and the solvent removed in vacuo to give the crude product which was recrystallised from dichloromethane to give 2-[{5-bromo-6-methyl-4-[(pyridin-2-ylmethyl)amino]thieno [2,3-J]pyrimidin-2-yl}-(2-hydroxyethyl)amino]ethanol as a white solid (0.7Ig), m.pt. 152°C.

Examples 339 to 341

The compounds set out below were prepared in the same way as in Example 338, using the appropriate starting materials.

Example Compound

339 2- { 5-Bromo-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-ylamino}-ethanol

340 2-[{5-Bromo-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]thieno[2,3-d]pyrimidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol

341 2-({5-Bromo-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3d]pyrimidin-2-yl } amino)-ethanol Example 342

2-((2-hydroxyethyl)-{6-methyI-5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3- d]pyrimidin-2-yl}amino)ethanol

In a 10ml glass tube were placed 2-[{5-bromo-6-methyl-4-[(pyridin-2- ylmethyl)amino]thieno[2,3-^pyrirrndin-2-yl}-(2-hydroxyethyl)amino]ethanol (32mg, 0.073mmol), phenylboronic acid (20mg, 0.166mmol), sodium carbonate (26mg, 0.249mmol), triphenylphosphine (7mg, 0.025mmol), palladium(II)acetate (2mg, 0.008mmol), dimethoxyethane (0.75ml) and water (0.25ml). The tube was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200W was used, the temperature being ramped from room temperature to 150⁰C. Once 150⁰C was reached, the reaction mixture was held at this temperature for 1 hour. The resultant mixture was diluted with water (50ml), extracted into dichloromethane (3x50ml) and the combined organic extracts were dried (MgSO₄). The solvent was removed in vacuo to give the crude product which was purified by flash chromatography (silica) eluting with ethyl acetate followed by 5% methanol in ethyl acetate to give 2-((2-hydroxyethyl)-{6- methl-5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-(i]pyrimidin-2- yl}amino)ethanol as a brown gum (7mg).

Examples 343 to 353

The compounds set out below were prepared in the same way as in Example 342, using the appropriate starting materials.

Example Compound

343 2-[{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-^pyrimidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol

344 2-[{5-(4-Fluorophenyl)-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-cT]pyrimidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol

345 2-{6-Methyl-5-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- d]pyrimidin-2-ylamino } -ethanol 346 2-{6-Methyl-4-[(6-methyl-pyridin-2-ylmethyl)-arnino]-5-phenyl- thieno[2,3-d]pyrimidin-2-ylamino}-ethanol

347 2-((2-Hydroxy-ethyl)-{6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl}-amino)-ethanol

348 2- { 5-(4-Fluorophenyl)-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-ylamino}-ethanol

349 2-{5-(4-Fluorophenyl)-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-ylamino } -ethanol

350 2-[{5-(4-Fluorophenyl)-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-yl}-(2-hydroxy-ethyl)-amino]-ethanol

351 2-{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(pyridin-2-ylmethyl)-amino]- thieno[2,3-d]pyrimidin-2-ylamino}-ethanol

352 2-{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-ylamino}-ethanol

353 2-[{5-Benzo[l,3]dioxol-5-yl-6-methyl-4-[(6-methyl-pyridin-2-ylmethyl)- amino]-thieno[2,3-d]pyrimidin-2-yl } -(2-hydroxy-ethyl)-amino]-ethanol

Example 354

Analytical Data for compounds representative of the above examples are shown in the table below.

Example 355

Bioassays-Kvl.5 Rb⁺ Efflux Assay

The pore of a potassium channel is permeable to other monovalent cations such as Rb⁺ and Tl⁺. Analysis of cellular efflux of potassium channel permeable ions enables potassium channel activity to be monitored directly. Cells stably transfected with cDNA for human Kvl.5 (in pEF6::VA-His-TOPO) were grown in Dulbecco's Modified Eagle media (DMEM) alpha supplemented with 10% Fetal Calf Serum (FCS), 20 μl/ml penicillin (5000U/ml) streptomycin (5000μg/ml), lOμl/ml [10Ox] glutamine, and blasticidin (7.5μg/ml). Cells were dispensed into 96 well cellstar TC plates and allowed to grow until a confluent monolayer was visible. On the morning of the assay run, cold media was aspirated using the TECAN plate washer, and a 50μl media spike containing 2μCi/ml (37kBq/ml) ⁸⁶Rb⁺ added to each well containing cells using the Shallow-Well Matrix Platemate. Plates were placed in a incubator at 37⁰C for a minimum of 3 hours. Unloaded ⁸⁶Rb⁺ in the "hot" media was aspirated and each well washed 4x250μl with Earls Balanced Salt Solution (EBSS) which contained 5mM KCl, 14OmM NaCl, 2mM CaCl₂, ImM MgSO₄, 1OmM HEPES, and 5mM glucose, pH 7.4, 290-300 mOsm. These cells were then pre-incubated with 50/xl of EBSS +/- test compounds for 10 minutes at room temperature. After the 10 minute incubation, 50μl of modified EBSS which contained 145mM KCl, 2mM CaCl₂, ImM MgSO₄, 1OmM HEPES, 5mM glucose, pH 7.4, 290-300 mOsm, was added, and the cells were incubated for a further 10 minutes at room temperature. The high KCl EBSS was used to depolarise cells to a membrane potential that would activate Kvl.5 channels. After the final incubation 80μl/100μl of the reaction from each well was transferred to equivalent wells in a Packard "Optiplate" white 96 well plate and counted in a Packard TopCount liquid scintillation counter by Cerenkov emission. Percentage inhibition ⁸⁶Rb⁺ efflux through Kvl.5 was calculated by normalisation to, 2.5mM 4 amino-pyridine control block of Kvl.5. Alternatively cells were loaded with ⁸⁵Rb⁺ and quantified by atomic absorption spectroscopy. IC₅₀ determinations were derived from 10 point concentration response curves n=2 using the method described above. Data was fitted as variable slope sigmoidal fit using Graphpad Prism (V3.02) software.

Example Compound IC₅₀ (μM)

83 Furan-2-ylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 0.07 amine

102 (l-Ethyl-pyrrolidin-2-ylmethyl)-(5-phenyl-thieno[2,3- >30 d]pyrimidin-4-yl)-amine

103 N,N-Dimethyl-2-(5-phenyl-thieno[2,3-d]pyrimidin-4- >30 ylamino)-acetamide

104 (3-Imidazol-l-yl-propyl)-(5-phenyl-thieno[2,3-d]pyrimidin- >30 4-yl)-amine

105 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-ρyridin-2-ylmethyl~ 0.28 amine

106 5-Phenyl-4-(pyridin-2-ylmethoxy)-thieno[2,3-d]pyrimidine 0.33

84 Cyclopropylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 0.80 amine

107 Furan-3-ylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 1.05 amine

108 (5-Methyl-furan-2-ylmethyl)-(5-phenyl-thieno[2,3- 0.41 d]pyrimidin-4-yl)-amine

109 4-(Furan-2-ylmethoxy)-5-phenyl-thieno[2,3-d]pyrimidine 0.8

110 (l-Methyl-lH-pyrrol-2-ylmethyl)-(5-phenyl-thieno[2,3- 3.90 d]pyrimidin~4-yl)-amine

85 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-thiophen-2- 4.21 ylmethyl-amine

86 Benzyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine 4.36

111 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-pyridin-2-yl- 4.49 ethyl)-amine

112 (5-Phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-acetic acid 5.03 methyl ester 87 Allyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine 5.14

113 (2-Methoxy-ethyl)-(5-phenyl-thieno[2,3-d]ρyrimidin-4-yl)- 5.27 amine

114 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(tetrahydro-furan-2- 5.18 ylmethyl)-amine

88 Furan-2-ylmethyl-methyl-(5-ρhenyl~thieno[2,3- 6.82 d] pyrimidin~4-yl)-amine

115 Thiophen-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3- 7.07 d]pyrimidin-4-yl)-amine

116 [l,3]Dioxolan-2-ylmethyl-(5-phenyl-thieno[2,3- 6.16 d]pyrimidin-4-yl)-amine

89 Cyclohexylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 8.10 amine

117 4-(Furan-2-ylmethylsulfanyl)-5-phenyl-thieno[2,3- 9.37 d]pyrimidine

118 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-thiophen-2-yl- 8.56 ethyl)-amine

90 Phenethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine 10.09

91 Cyclohexyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine >30

119 4-Benzyloxy-5-phenyl-thieno[2,3-d]pyrimidine 5.79

120 5-Phenyl-4-(pyridin-2-ylmethylsulfanyl)-thieno[2,3- 12.73 d]pyrimidine

121 [5-(5-Methyl-pyridin-2-yl)-thieno[2,3-d]pyrimidin-4-yl]- 2.09 pyridin-2-ylmethyl-amine

122 Furan-2-ylmethyl-[5-(5-methyl-pyridin-2-yl)-thieno[2,3- 3.53 d]pyrimidin-4-yl] -amine

123 [5-(4-Fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin- 0.05 2-ylmethyl-amine

124 [5-(4-Fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-furan-2- 1.16 ylmethyl-amine 92 Furan-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin- 1.91 4-yl)-amine

93 (4-Nitrobenzyl)-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4- >30 yl)-amine

94 (5-Thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-(3,4,5- >30 trimethoxy-benzyl)-amine

95 Cyclopropylmethyl-(5~thiophen-2-yl-thieno[2,3- 4.51 d]pyrimidin-4-yl)-amine

96 Isobutyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)- 6.32 amine

97 Benzyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)- 6.53 amine

98 Thiophen-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3- 6.95 d]pyrimidin-4-yl)-amine

99 AUyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine 7.53

100 Furan-2-ylmethyl-methyl-(5-thiophen-2-yl-thieno[2,3- 9.71 d]pyrimidin-4-yl)-amine

125 [2-(4-Chloro-phenyl)-ethyl]-(5-methyl-thieno[2,3- 6.91 d]pyrimidin-4-yl)-amine

126 Furan-2-ylmethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)- 0.47 amine

127 [2-(3,4-Dimethoxy-phenyl)-ethyl]-(5-p-tolyl-thieno[2,3- 5.3 d]pyrimidin-4-yl)-amine

128 l-[2-(5-p-Tolyl-thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]- >30 imidazolidin-2-one

129 4-(Naphthalen-2-yloxy)-5-p-tolyl-thieno[2,3-d]pyrimidine >30

130 Phenethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine 8.05

131 4-(5-p-Tolyl-thieno[2,3-d]pyrimidin-4-yloxy)-benzoic acid >30 methyl ester 132 [2-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-[5-(3,4- 4.58 dimethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-amine

133 [5-(3 ,4-Dimethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl] - 0.67 furan-2-ylmethyl-amine

135 [5-(4-Chloroρhenyl)-thieno[2,3-d]pyrimidin-4-yl]-furan-2- 0.93 ylmethyl-amine

136 [5-(4-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]- 16.8 phenethyl-amine

137 [5-(4-Bromophenyl)-thieno[2,3-d]ρyrimidin-4-yl]-[2-(2,3- 10.68 dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-amine

138 [5-(4-Methoxy-phenyl)-thieno[2,3-d]pyrimidin-4~yl]- 0.22 pyridin-2-ylmethyl-amine

139 Furan-2~ylmethyl-[5-(4-methoxy-phenyl)-thieno[2,3- 1.68 d]pyrimidin-4-yl]-amine

140 (6-Ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 2.71 ylmethyl-amine

141 (6-Ethyl-5-furan-3-yl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 2.15 ylmethyl-amine

142 Pyridin-2-ylmethyl-(5-o-tolyl-thieno[2,3-d]pyrimidin-4-yl)- 1.28 amine

143 Furan-2-ylmethyl-(5-o-tolyl-thieno[2,3-d]pyrimidm-4-yl)- 1.32 amine

144 [5-(4-tert-Butyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- 1.32 pyridin-2-ylmethyl-amine

145 [5-(4-tert-Butyl-phenyl)-thieno[2,3-d]ρyrimidin-4-yl]- 3.05 furan-2-ylmethyl-amine

146 (5-Cyclohexyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 1.68 ylmethyl-amine

147 (5-Cyclohexyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 2.52 ylmethyl-amine 148 (2-Isopropyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 1.51 pyridin-2-ylmethyl-amine

149 (5-Phenyl-thieno[2,3-d]pyrimidm~4-yl)-(l-pyridin-2-yl- 0.37 ethyl)-amine

150 Furan-2-ylmethyl-(2-methyl-5-phenyl-thieno[2,3- 0.14 d]pyrimidin-4-yl)-amine

151 (5-Phenyl-2-trifluoromethyl-thieno[2,3-d]pyrimidin-4-yl)- 1.68 pyridin-2-ylmethyl-amine

181 (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 4.13 ylmethyl-amine

182 (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 1.04 ylmethyl-amine

188 N²-Cyclopropylmethyl-5-phenyl-N⁴-pyridin-2-ylniethyl- 2.52 thieno[2,3'-d]pyrimidine-2,4-di amine

189 N²-(2-Methoxy-ethyl)-5-phenyl-N⁴-pyridin-2-ylmethyl- 0.28 thieno[2,3-d]pyrimidine-2,4-diamine

190 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 0.26 d]pyrimidin-2-ylamino } -ethanol

191 (2-Methoxy-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin- 0.47 2-ylmethyl-amine

192 5-Phenyl-N⁴-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine- 2.18 2,4-di amine

193 N²,N⁴-Bis-furan-2-ylmethyl-5-ρhenyl-thieno[2,3- 2.5 d]pyrimidine-2,4-diamine

194 N⁴-Furan-2-ylmethyl-5-phenyl-N²-pyridin-2-ylmethyl- 4.16 thieno[2,3-d]pyrimidine-2,4-di amine

195 (2-Benzyloxy-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan- 6.39 2-ylmethyl-amine

196 N²-Methyl-5-phenyl-N⁴-pyridin-2-ylmethyl-thieno[2,3- 0.04 d]pyrimidine-2,4-diamine 197 (2-Morpholin-4-yl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 0.15 pyridin-2-ylmethyl-amine

198 N²,Nⁱ-Dimethyl-5-phenyl-N⁴-ρyridin-2-ylmethyl- 0.57 thieno[2,3-d]pyrimidine-2,4-diamine

152 (2-Ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 0.39 ylmethyl-amine

153 (2-Ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 3.63 ylmethyl-amine

154 [5-(4-Fluorophenyl)-2-methyl-thieno[2,3-d]pyrimidin-4-yl]- 1.62 pyridin-2-ylmethyl-amine

157 (6-Methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 0.24 ylmethyl-amine

158 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(l,2,3,4-tetrahydro- 17.70 naphthalen- 1 -yl)-amine

159 6-Methyl-5-ρhenyl-4-piperidin-l-yl-thieno[2,3- 13.36 d]pyrimidine

161 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-thiophen-2-yl- 25.46 thiazol-4-ylmethyl)-amine

162 (2-Phenyl-thiazol-4-ylmethyl)-(5-phenyl-thieno[2,3- 19.72 d]pyrimidin-4-yl)-aniine

163 Phenethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)- 14.32 amine

164 (6-Bromo-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 0.53 ylmethyl-amine

165 (6-Bromo-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 1.6 ylmethyl-amine

199 5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 6.61 d]pyrimidine-2-carbonitrile

200 5-(4-Fluorophenyl)-N²,N²-dimethyl-N⁴-pyridin-2-ylmethyl- 71.77 thieno[2,3-d]pyrimidine-2,4-di amine 201 l-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]- 15.87 thieno [2,3-d]pyrimidin-2-yl}-piperidine-4-carboxylic acid methyl ester

202 3-{5-Phenyl-4-[(pyridin-2-ylmethyl)-arnino]-thieno[2,3~ 2.7 d]pyrimidin-2-ylamino} -propionic acid ethyl ester

203 [2~(2-Methoxy-ethoxy)-5-phenyl-thieno[2,3-d]pyrimidin-4- 0.48 yl] -pyridin-2-ylmethyl-amine

204 5-(4-Fluorophenyl)-N²-methyl-N⁴-pyridin-2-ylmethyl- 4.7 thieno[2,3-d]pyrimidine-2,4-di amine

205 5-(4-Fluorophenyl)-N⁴-pyridin-2-ylmethyl-thieno[2,3- 11.87 d]pyrimidine-2,4-diamine

206 2-( 1 - { 5-Phenyl-4- [(pyridin-2-ylmethyl)-amino] -thieno [2,3- 3.41 d]pyrimidin-2-yl } -piperidin-4-yl)-ethanol

207 [5~(4-Fluorophenyl)-2-morpholin-4-yl-thieno[2,3- 42.5 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

208 2-((2-Hydroxy-ethyl)-{5-phenyl-4-[(pyridin-2-ylmethyl)- 0.33 amino] -thieno [2,3-d]pyrimidin-2-yl } -amino)-ethanol

209 5-(4-Fluorophenyl)-N²-(2-methoxy-ethyl)-N⁴-pyridin-2- 1.83 ylmethyl-thieno[2,3-d]pyrimidine-2,4-di amine

210 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 0.74 d]pyrimidin-2-ylamino } -propane- 1 ,3-diol

211 [2-(2-Dimethylamino~ethoxy)-5-phenyl-thieno[2,3- 5.37 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

212 2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]- 7.63 thieno[2,3-d]pyrimidin-2-ylamino}-ethanol

237 {5-Phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3- 0.54 J]pyrimidin-2-yl} acetic acid ethyl ester

238 {4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3- 3.33 d]pyrimidin-2-yl} -acetic acid ethyl ester 250 2- { 5-Phenyl-4- [(pyridin-2-ylmethyl)amino]thieno [2,3- 0.33 ύ(jpyrimidin-2-yl } ethanol

251 2-{4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3- 0.08 d]pyrimidin-2-yl } -ethanol

275 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 1.53 d]pyrimidin-2-yl } -propane- 1 ,3 -diol

313 Pyridin-2-ylmethyl-[5-(4~trifluoromethyl-phenyl)- 2.90 thieno[2,3-d]pyrimidin-4-yl]-amine

314 (5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-4-yl)- 0.01 pyridin-2-ylmethyl-amine

320 [5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-thieno[2,3- 0.37 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

321 [5-(3-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin- 1.52 2-ylmethyl-amine

322 [5-(3-Methoxyphenyl)-thieno[2,3-d]pyrimidin-4-yl]- 0.26 pyridin-2-ylmethyl-amine

323 [5-(lH-Indol-6-yl)-thieno[2,3-d]ρyrimidin-4-yl]-pyridin-2- 0.04 ylmethyl-amine

325 [5-(4-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin- 2.54 2-ylmethyl-amine

326 [5-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-thieno[2,3- 10.43 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

331 [5-(3-Fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin- 0.03 2-ylmethyl-amine

332 [5-(4-Morpholin-4-yl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- 47.43 pyridin-2-ylmethyl-amine

333 [5-(3,4-Difluoroρhenyl)-thieno[2,3-d]pyrimidin-4-yl]- 10.36 pyridin-2-ylmethyl-amine Example 356

Kvl.5 Autopatch Electrophysiology Method

The external bathing solution contained (in mM): 150 NaCl, 10 KCl, 100 Potassium Gluconate, 3 MgCl₂, 1 CaCl₂, 10 HEPES, pH 7.4. Patch pipettes were filled with an electrode solution of composition (in mM): 160 KCl, 0.5 MgCl₂, 10 HEPES, 1 EGTA, pH 7.4 with KOH.

Compounds were dissolved in DMSO (100 %) and made up in the external bather at a concentration of lμM. All experiments were conducted at room temperature (22-24⁰C).

A cell suspension (10 ml), with a density of 100,000 cells/ml, was aliquoted into a 15ml centrifuge tube and transferred to an incubator (37°C, 5% CO₂) for approximately one hour before use. Following 60 min incubation, a tube was taken and centrifuged at 1000 rpm for 4 mins at room temperature. 9.5 ml supernatant was thence discarded, leaving a cell pellet at the bottom of the tube. The pellet was then resuspended using 100 μl of cold (4 ⁰C), filtered (0.22 μm), 0.2 % BSA/bather solution (0.02g BSA/lOml bather). The bottom of the tube was manually agitated gently until the solution became cloudy with cells. The 100 μl cell resuspension solution was then stored on the bench at 4 ⁰C (using a Peltier-based temperature control device) until used.

A length of capillary glass (1B150F-4, WPI) was dipped into the cell suspension solution, such that ~ 3 cm column of fluid was taken up by capillary action. A Ag/AgCl wire was dropped into the non-dipped end of the capillary also. The outside of the solution-filled end of the capillary was then dried and the capillary was loaded into the AutoPatch™. Borosilicate glass patch pipettes (from 1.5mm OD, thin-walled filamented, GC150-TF capillary glass, Harvard) were pulled using a DMZ pipette puller (Zeitz Instruments), and were back-filled using the internal pipette solution, being careful that no bubbles remain at the tip or in the body of the pipette. Patch pipettes typically had resistances of 2.3-3.5 MΩ. Once filled, the pipette tip and a proportion of the shaft (~ 15 mm) were dipped into Sigmacote (Sigma). The recording pipette was then loaded into the AutoPatch™. Automated patch-clamping was initiated by the operator, but thereafter AutoPatch.exe continued the experiment providing that pre-set conditions and criteria were satisfied.

Whole cell patch-clamp recordings were made using the AutoPatch™ rig, which incorporated an EPC9 amplifier (HEKA, Germany) under control of Pulse software

(v8.54, HEKA, Germany), a motion controller with 2 translators (Newport, UK), valve controller (VFl) and a c-level suction device all at room temperature (22-24⁰C). This equipment was completely under the control of AutoPatch.exe and operator intervention was only made when there was a requirement to refill the drug reservoirs or to prevent the loss of a cell due to a technical error. Cells with an R_serie_S greater than 18 MΩ were discounted from the experiment.

Qualification stages prior to perfusion and drug application ensured that the observed current met the criteria for the experiment. Only those cells with an /K > 500 pA were used for experiments. Cells were continuously perfused with external solution at a flow rate of 1.8-2 ml/minute. The perfusion chamber had a working volume of 80-85μl and allowed for rapid exchange of drug solutions. Online analysis of the hK_v1.5 current during the application of compounds was performed by the AutoPatch™ software. Voltage-step protocols and analysis of data was performed as described for conventional electrophysiology.

Electrophysiology voltage-step protocols and analysis of data was performed as follows.

Data was sampled at 5kHz, and filtered with a -3 dB bandwidth of 2.5kHz. Cells were held at a voltage of -8OmV. Currents were evoked to a voltage step for 1000ms in duration at OmV every 5s. Currents were analysed using Pulsefit software (v8.54, HEKA, Germany), with the total charge measured during the whole of the voltage step. AU other plots were produced using Igor Pro (WaveMetrics). Example Compound % Inhibition at lμM

83 Furan-2-ylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 21.9 amine

103 N,N-Dimethyl-2-(5-phenyl-thieno[2,3-d]pyrimidin-4- 13.6 ylamino)-acetamide

105 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl- 63.0 amine

106 5-Phenyl-4-(pyridin-2-ylmethoxy)-thieno[2,3-d]pyrimidine 21.9

84 Cyclopropylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 15.3 amine

107 Furan-3-ylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 25.3 amine

108 (5-Methyl-furan-2-ylmethyl)-(5-phenyl-thieno[2,3- 37.2 d]pyrimidin-4-yl)-amine

109 4-(Furan-2-ylmethoxy)-5-phenyl-thieno[2,3-d]pyrimidine 52.3

110 (l-Methyl-lH-pyrrol-2-ylmethyl)-(5-phenyl-thieno[2,3- 14.2 d]pyrimidin-4-yl)-amine

85 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-thiophen-2- 24.2 ylmethyl-amine

86 Benzyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine 46.0

111 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-pyridin-2-yl- 40.0 ethyl)-amine

112 (5-Phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-acetic acid 43.5 methyl ester

87 Allyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine 3.4

111 (2-Methoxy-ethyl)-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 22.2 amine

88 Furan-2-ylmethyl-methyl-(5-phenyl-thieno[2,3- 26.4 d]pyrimidin-4-yl)-amine 115 Thiophen-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3- 45.9 d]pyrimidin-4-yl)-amine

89 Cyclohexylmethyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 73.4 amine

117 4-(Furan-2-ylmethylsulfanyl)-5-phenyl-thieno[2,3- 43.6 djpyrimidine

118 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-thiophen-2-yl- 15.8 ethyl)-amine

89 Cyclohexyl-(5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-amine 42.2

117 4~Benzyloxy-5-phenyl~thieno[2,3-d]pyrirnidine 57.2

119 [5-(5-Methyl-pyridin-2-yl)-thieno[2,3-d]pyrimidin-4-yl]- 44.1 pyridin-2-ylmethyl-amine

120 Furan-2-ylmethyl-[5-(5-methyl-pyridin-2-yl)-thieno[2,3- 25.0 d]pyrimidin-4-yl]-amine

121 [5-(4-Fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin- 82.6 2-ylmethyl-amine

122 [5-(4-Fluorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-furan-2- 36.3 ylmethyl-amine

92 Furan-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin- 27.6 4-yl)-amine

93 (4-Nitrobenzyl)-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4- 44.0 yl)-amine

94 (5-Thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-(3,4,5- 19.4 trimethoxy-benzyl)-amine

95 Cyclopropylmethyl-(5-thiophen-2-yl-thieno[2,3- 32.6 d]pyrimidin-4-yl)-amine

96 Isobutyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)- 22.9 amine

97 Benzyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)- 43.3 amine 98 Thiophen-2-ylmethyl-(5-thiophen-2-yl-thieno[2,3- 21.0 d]pyrimidin-4-yl)-amine

99 Allyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)-amine 17.5

100 Furan-2-ylmethyl-methyl-(5-thiophen-2-yl-thieno[2,3- 19.9 d]pyrimidin-4-yl)-amine

126 Furan-2-ylmethyI-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)- 83.4 amine

127 [2-(3 ,4-Dimethoxyρhenyl)-ethyl]-(5-p-tolyl-thieno [2,3- 20.7 d]pyrimidin-4-yl)-amine

128 l-[2-(5-p-Tolyl-thieno[2,3-d]pyrimidin-4-ylamino)-ethyl]- 25.0 imidazolidin-2-one

129 4-(Naphthalen-2-yloxy)-5-p-tolyl-thieno[2,3-d]pyrimidine 47.4

131 4-(5-p-Tolyl-thieno[2,3-d]pyrimidin-4-yloxy)-benzoic acid 29.8 methyl ester

132 [2-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-ethyl]-[5-(3,4- 92.0 dimethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-amine

133 [5-(3,4-Dimethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- 77.0 furan-2-ylmethyl-amine

135 [5-(4-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-furan-2- 84.8 ylmethyl-amine

136 [5-(4-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]- 27.2 phenethyl-amine

137 [5-(4-Bromophenyl)-thieno[2,3-d]pyrimidin-4-yl]-[2-(2,3- 96.0 dihydro-benzo [ 1 ,4] dioxin-6-yl)-ethyl] -amine

138 [5-(4-Methoxyphenyl)-thieno[2,3-d]pyrimidin-4-yl]- 92.6 pyridin-2-ylmethyl-amine

139 Furan-2-ylmethyl-[5-(4-methoxy-phenyl)-thieno[2,3- 46.9 d]pyrimidin-4-yl] -amine

140 (6-Ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 74.2 ylmethyl-amine 141 (6-Ethyl-5-furan-3-yl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 81.3 ylmethyl-amine

142 Pyridin-2-ylmethyl-(5-o-tolyl-thieno[2,3-d]pyrimidin-4-yl)- 49.7 amine

143 Furan-2-ylmethyl-(5-o-tolyl-thieno[2,3-d]pyrimidin-4~yl)- 63.0 amine

144 [5-(4-tert-Butyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- 81.0 pyridin-2-ylmethyl-amine

145 [5-(4-tert-Butyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- 68.0 furan-2-ylmethyl-amine

146 (5-Cyclohexyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 81.0 ylmethyl-amine

147 (5-Cyclohexyl-mieno[2,3-d]pyrimidin-4-yl)-furan-2- 71.0 ylmethyl-amine

148 (2-Isopropyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 88.0 pyridin-2-ylmethyl-amine

149 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(l-pyridin-2-yl- 78.0 ethyl)-amine

150 Furan-2-ylmethyl-(2-methyl-5-phenyl-thieno[2,3- 96.8 d]pyrimidin-4-yl)-amine

151 (5-Phenyl-2-trifluoromethyl-thieno[2,3-d]pyrimidin-4-yl)- 95.0 pyridin-2-ylmethyl-amine

181 (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 96.0 ylmethyl-amine

182 (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 75.8 ylmethyl-amine

188 N²-Cyclopropylmethyl-5-phenyl-N⁴-ρyridin-2-ylmethyl- 98.0 thieno[2,3-d]pyrimidine-2,4-di amine

189 N^z-(2-Methoxy-ethyl)-5-phenyl-N⁴-pyridin-2-ylmethyl- 97.4 thieno[2,3-d]pyrimidine-2,4-di amine 190 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 97.1 d]pyrimidin-2-ylamino } -ethanol

191 (2-Methoxy-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-ρyridin- 91.8 2-ylmethyl-amine

192 5-Phenyl-N⁴-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine- 90.0 2,4-di amine

193 N²,N⁴-Bis-furan-2-ylmethyl-5-phenyl-thieno[2,3- 89.2 d]pyrimidine-2,4-diamine

194 N⁴-Furan-2-ylmethyl-5-phenyl-N²-pyridin-2-ylmethyl- 81.0 thieno[2,3-d]pyrimidine-2,4-di amine

195 (2-Benzyloxy-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan- 90.0 2-ylmethyl-amine

196 N²-Methyl-5-phenyl-N⁴-pyridin-2-ylmethyl-thieno[2,3- 97.0 d]pyrimidine-2,4-diamine

197 (2-Morpholin-4-yl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)- 98.0 pyridin-2-ylmethyl-amine

198 N²,N²-Dimethyl-5-phenyl-N⁴-pyridin-2-ylmethyl- 98.1 thieno[2,3-d]pyrimidine-2,4-diamine

152 (2-Ethyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 98.7 ylmethyl-amine

153 (2-Ethyl-5-phenyl-thieno[2,3-d]ρyrimidin-4-yl)-furan-2- 96.8 ylmethyl-amine

154 (6-Methylpyridin-2-ylmethyl)-(5-phenyl-thieno[2,3- 93.0 d]pyrimidin-4-yl)-amine

155 [5-(4-Fluorophenyl)-2-methyl-thieno[2,3-d]pyrimidin-4-yl]- 92.2 pyridin-2-ylmethyl-amine

156 (6-Methyl-pyridin-2-ylmethyl)-(5-phenyl-thieno[2,3- 92.0 d]pyrimidin-4-yl)-amine

157 (6-Methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 88.0 ylmethyl-amine 158 (5-Phenyl-thieno[2,3-d]ρyrimidin-4-yl)-(l,2,3,4-tetrahydro- 83.4 naphthalen- 1 -yl)-amine

159 6-Methyl-5-phenyl-4-piperidin-l-yl-thieno[2,3- 83.0 djpyrimidine

160 2-[(5-Phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-methyl]- 80.0 nicotinic acid ethyl ester

161 (5-Phenyl-thieno[2,3-d]pyrimidin-4-yl)-(2-thiophen-2-yl- 79.4 thiazol-4-ylmethyl)-amine

162 (2-Phenyl-thiazol-4-ylmethyl)-(5-phenyl-thieno[2,3- 74.5 d]pyrimidin-4-yl)-amine

163 Phenethyl-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-yl)- 70.8 amine

164 (6-Bromo-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2- 92.8 ylmethyl-amine

165 (6-Bromo-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-furan-2- 91.0 ylmethyl-amine

199 5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 99.5 d]pyrimidine-2-carbonitrile

200 5-(4-Fluorophenyl)-N²,Nⁱ-dimethyl-N⁴-pyridin-2-ylmethyl- 99.3 thieno[2,3-d]pyrimidine-2,4-di amine

201 1- { 5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]- 98.2 thieno[2,3-d]pyrimidin-2-yl } -piperidine-4-carboxylicacid methyl ester

202 3-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 98.0 d]pyrimidin-2-ylammo} -propionic acid ethyl ester

203 [2-(2-Methoxy-ethoxy)-5-phenyl-thieno[2,3-d]pyrimidin-4- 98.0 yl]-pyridin-2-ylmethyl-amine

204 5-(4-Fluorophenyl)-N^z-methyl-N⁴-pyridin-2-ylmethyl- 97.9 thieno[2,3-d]ρyrimidine-2,4-di amine 205 5-(4-Fluorophenyl)-N⁴-pyridin-2-ylmethyl-thieno[2,3- 97.5 d]pyrimidine-2,4-diamine

206 2-(l-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 97.5 d]pyrimidin-2-yl } -piperidin-4-yl)-ethanol

207 [5-(4-Fluorophenyl)-2-morpholin-4-yl-thieno[2,3- 97.2 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

208 2-((2-Hydroxy-ethyl)-{5-phenyl-4-[(pyridm-2-ylmethyl)- 96.6 amino]-thieno[2,3-d]pyrimidin-2-yl}-amino)-ethanol

209 5-(4-Fluorophenyl)-N^z-(2-methoxy-ethyl)-N⁴-pyridin-2- 96.0 ylmethyl-thieno[2,3-d]pyrimidine-2,4-diamine

210 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 95.6 d]pyrimidin-2-ylamino } -propane- 1 ,3 -diol

211 [2-(2-Dimethylamino-ethoxy)-5-phenyl-thieno[2,3- 89.0 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

212 2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-arnino]- 87.0 thieno[2,3-d]pyrimidin-2-ylamino}-ethanol

214 3-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 87.0 d]pyrimidin-2-ylamino } -propane- 1 ,2-diol

215 [2-(4-Methyl-piperazin-l-yl)-5-phenyl-thieno[2,3- 82.0 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

237 {5-Phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3- 95.0 d]pyrimidin-2-yl} acetic acid ethyl ester

238 {4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3- 96.0 d]pyrimidin-2-yl} -acetic acid ethyl ester

250 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3- 98.0 d]pyrimidin-2-yl } ethanol

251 2-{4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3- 98.0 d] pyrimidin-2-yl } -ethanol

275 2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3- 93.0 d]pyrimidin-2-yl}-propane-l,3-diol 287 iV-Methyl-2- { 5-phenyl-4-[ { pyridin-2-ylmethyl) 91.0 amino]thieno[2,3-</jpyrimidin-2-yl } acetamide

302 (2-Dimethylaminomethyl-5-phenylthieno[2,3-d]pyrimidin- 76.0 4-yl)pyridin-2-ylmethylamine

303 (2-Morpholin-4-ylmethyl-5-phenyl-thieno[2,3-d]pyrimidin- 63.0 4-yl)-pyridin-2-ylmethyl-amine

304 (2-Methylaminomethyl-5-phenyl-thieno[2,3-d]pyrimidin-4- 58.0 yl)-pyridin-2-ylmethyl-amine

305 (2-Methoxymethyl-5-phenylthien[2,3-d]primidin-4- 94.0 yl)pyridin-2-ylmethylamine

313 Pyridin-2-ylmethyl-[5-(4-trifluoromethyl-phenyl)- 98.3 thieno[2,3-d]pyrimidin-4-yl]-amine

314 (5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-4-yl)- 97.3 pyridin-2-ylmethyl-amine

315 [5-(4-Dimethylammo-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- 98.0 pyridin-2-ylmethyl-amine

316 [5-(3 ,4-Dimethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl] - 98.0 pyridin-2-ylmethyl-amine

317 Pyridin-2-ylmethyl-[5-(4-trifluoromethoxy-phenyl)- 98.0 thieno[2,3-d]pyrimidin-4-yl]-amine

318 Pyridin-2-ylmethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)- 98.0 amine

319 (5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-4-yl)- 97.3 pyridin-2-ylmethyl-amine

320 [5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-thieno[2,3- 97.0 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

321 [5-(3-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin- 95.0 2-ylmethyl-amine

322 [5-(3-Methoxyphenyl)-thieno[2,3-d]pyrimidin-4-yl]~ 94.0 pyridin-2-ylmethyl-amine 323 [5-(lH-Indol-6-yl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2- 94.0 ylmethyl-amine

324 [5-(4-Methoxymethoxy-phenyl)-thieno[2,3-d]pyrimidin-4- 93.0 yl] -pyridin-2-ylmethyl-amine

325 [5-(4-Chlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin- 90.8 2-ylmethyl-amine

326 [5-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-thieno[2,3- 89.0 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

327 4-{4-[(Pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin- 83.0 5-yl} -benzoic acid methyl ester

328 [5-(6-Methoxy-pyridin-3-yl)-thieno[2,3-d]pyrimidin-4-yl]- 83.0 pyridin-2-ylmethyl-amine

329 [5-(2,4-Dichlorophenyl)-thieno[2,3-d]pyrimidin-4-yl]- 81.0 pyridin-2-ylmethyl-amine

330 [5-(4-Chloro-3-trifluoromethyl-phenyl)-thieno[2,3- 79.0 d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine

331 [5-(3-Fluorophenyl)-thieno[2,3-d]pyrimidin-4~yl]-pyridin- 76.0 2-ylmethyl-amine

332 [5-(4-Morpholin-4-yl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- 73.0 pyridin-2-ylmethyl-amine

333 [5-(3,4-Difluoro-phenyl)-thieno[2,3-d]pyrimidin-4-yl]- 63.0 pyridin-2-ylmethyl-amine

166 6-Methyl-N-[(6-methylpyridin-2-yl)methyl]-5- 97 phenylthieno[2,3-d]pyrimidin-4-amine

167 6-Bromo-N-[(6-methylpyridin-2-yl)methyl]-5- 99 phenylthieno[2,3-d]pyrimidin-4-amine Abbreviations

KV(ur) Cardiac Ultrarapid Delayed Rectifier

CHO Chinese Hamster Ovary Cells

DMEM Dulbecco's Modified Eagle media

FCS Fetal Calf Serum

EBSS Earls Balanced Salt Solution

WCPC Whole-Cell Patch-Clamp

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Claims

CLAIMS:

1. A compound of formula (I)

Wherein Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo;

R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy;

X is O, S or NR6;

R6 is H or alkyl;

R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl;

L is (CH₂)_n, where n is 1, 2 or 3; and

Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof; with the proviso that when Y is phenyl, phenyl monosubstituted by Cl or methoxy, furanyl, tetrahydrofurayl, pyrimidinyl, pyrrolidinyl or 1,3-benzodioxolyl, then Rl is not phenyl, phenyl monosubstituted by halogen or phenyl substituted by methyl; and wherein the compound is not:

N-Butyl-5-phenylthieno[2,3-d]pyrimidin-4-amine; 5-Phenyl-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-[3-(lH-imidazol-l-yl)propyl]thieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(pyridin-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(2-cyclohex-l-en-l-ylethyl)thieno[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(2-furylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Fluorophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

N-Allyl-5-phenylthieno[2,3-d]pyrimidin-4-amine;

5-(4-Methylphenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]pyrimidin-4-amine; N-(2-Furylmethyl)-5-ρhenylthieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Fluorophenyl)-N-(2-thien-2-ylethyl)thieno[2,3-d]pyrimidin-4-amine;

N-Allyl-5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Chlorophenyl)-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine; 5-Phenyl-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

5-(4-Bromophenyl)-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine;

N-[3-(lH-Imidazol-l-yl)propyl]-5-phenylthieno[2,3-d]pyrimidin-4-amine; l-(2-{[5-(4-Methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}ethyl)imidazolidin-2-one; or N-(2-Furylmethyl)-5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-amine.

2. A compound as claimed in claim 1 wherein Rl is aryl or heteroaryl, R2 is H or alkyl, R3 is H, NR4R5, alkoxy or alkyl, X is O or NR6, R6 is H, n is 1 or 2 and Y is alkyl, cycloalkyl, aryl or heteroaryl.

3. A compound as claimed in claim 2 wherein Rl is aryl or heteroaryl, R2 is H or methyl, R3 is H, NR4R5, alkoxy or alkyl, X is NR6, R6 is H, n is 1 and Y is heteroaryl.

4. A compound as claimed in any one of claims 1 to 3 wherein Y is furanyl, thienyl or pyridyl.

5. A compound as claimed in any one of claims 1 to 4 wherein Y is optionally substituted furan-2-yl or optionally substituted pyridin-2-yl.

6. A compound as claimed in claim 1 which is:

2- { 5-Phenyl-4-[(pyridin-2-ylmethyl)-amino] -thieno[2,3-d]pyrimidin-2-yl } -propane- 1,3- diol;

2-{5-(4-Fluorophenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2- ylamino } -ethanol; Pyridin-2-ylmethyl-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-yl)-amine;

2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-ylamino}-ethanol;

2-{5-Phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-rf]pyrimidin-2-yl}ethanol;

2-yl}-amino)-ethanol; 2-Methyl-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine;

2-{4-[(Furan-2-ylmethyl)-amino]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl}-ethanol;

(2-Methoxy-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine; 5-(4-Fluorophenyl)-N²-(2-methoxy-ethyl)-N⁴-pyridin-2-ylmethyl-thieno[2,3- d]pyrimidine-2,4-diamine;

5-(4-Fluorophenyl)-N²,N²-dimethyl-N⁴-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4- diamine; Pyridin-2-ylmethyl-[5-(4-trifluoromethyl-phenyl)-thieno[2,3-d]pyrimidin-4-yl]-amine; [5-(lH-Indol-6-yl)-thieno[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethyl-amine;

(5-Benzo[l,3]dioxol-5-yl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine;

2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-ylamino}- propane-l,3-diol; 3-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-ylamino}- propane-l,2-diol;

N-Methyl-2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2- yl}acetamide; or 6-Methyl-N-[(6-methylpyridin-2-yl)methyl]-5-phenylthieno[2,3-d]pyrimidin-4-amine;

and pharmaceutically acceptable salts thereof.

7. A process for preparing a compound as claimed in any one of claims 1 to 6 comprising:

(i) reacting a compound of formula II with a suitable nucleophile X-L-Y, optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation; or

(ii) reacting a compound of formula X by displacement of the 2-chloro substituent with a suitable nucleophilic species; or

(iii) reacting a compound of formula XVII with an aryl or heteroaryl boronic acid, optionally in the presence of a palladium catalyst, and optionally at elevated temperature or with microwave irradiation.

8. A pharmaceutical composition comprising at least one compound and optionally one or more excipients, diluents and/or carriers, wherein said compound has the formula

Wherein

Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo;

R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy;

X is O, S or NR6;

R6 is H or alkyl;

R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl;

L is (CHz)_n, where n is 1, 2 or 3; and

9. A pharmaceutical composition as claimed in claim 8 wherein said compound is a compound as claimed in any one of claims 1 to 6.

10. A compound, or a pharmaceutical composition comprising said compound for use in medicine, wherein said compound has the formula:

Wherein

Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo; R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy;

R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S; X is O, S or NRό; R6 is H or alkyl; R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl; L is (CHa)_n, where n is 1, 2 or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof;

11. A compound or pharmaceutical composition as claimed in claim 10, wherein said compound is a compound as claimed in any one of claims 1 to 6.

12. A method of treating or preventing a disorder which requires potassium channel inhibition, comprising administering to a subject an effective amount of at least one compound or a pharmaceutical composition comprising said at least one compound and optionally one or more excipients, diluents and/or carriers wherein said compound has the formula:

Wherein

Rl is aryl, heteroaryl, cycloalkyl or alkyl;

R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo;

R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy; R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S; X is O, S or NR6;

R6 is H or alkyl;

R7 is hydrogen, methyl or ethyl;

R8 is methyl or ethyl;

L is (CEb)_n, where n is 1, 2 or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof;

13. A method as claimed in claim 12, wherein the disorder is arrhythmia.

14. The use of a compound having the formula:

Wherein

Rl is aryl, heteroaryl, cycloalkyl or alkyl; R2 is H, alkyl, nitro, CO₂R7, CONR4R5 or halo; R3 is H, NR4R5, NC(O)R8, halo, trifluoromethyl, alkyl, nitrile or alkoxy;

R4 and R5 may be the same or different, and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R4 and R5 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S; X is O, S or NR6; R6 is H or alkyl; R7 is hydrogen, methyl or ethyl; R8 is methyl or ethyl; L is (CH₂)_n, where n is 1, 2 or 3; and

Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; or pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in potassium channel inhibition.

15. The use as claimed in claim 14 wherein the medicament is for use in the treatment or prevention of arrhythmia.