Pyrimidinone compounds and their use

Abstract

The present invention provides compounds of formula (1) and pharmaceutically acceptable salts thereof, wherein R.sub.1, R.sub.2, Y and Z are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. ##STR00001##

Claims

1. A compound of formula (1): ##STR00095## wherein: R.sub.1 is chosen from H, halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl, and C.sub.1-6 alkoxy; R.sub.2 is chosen from H and C.sub.1-6 alkyl; Y is chosen from .sup.a-A.sub.1-S(O).sub.p-A.sub.2-, .sup.a-A.sub.1-C(O)-A.sub.2-, and .sup.a-A.sub.5-O-A.sub.6-, wherein .sup.a indicates the point of attachment to the pyrimidinyl ring; p is chosen from 0, 1, and 2; A.sub.1 is a covalent bond and A.sub.2 is C.sub.1-3 alkylene unsubstituted or substituted with at least one R.sub.8, wherein each R.sub.8 may be the same or different; A.sub.5 is a covalent bond; A.sub.6 is C.sub.1-3 alkylene unsubstituted or substituted with at least one R.sub.8, wherein each R.sub.8 may be the same or different; R.sub.8 represents C.sub.1-6 alkyl; Z is chosen from aryl, heteroaryl, C.sub.3-8 cycloalkyl, and heterocyclyl; wherein the aryl, heteroaryl, C.sub.3-8 cycloalkyl and heterocyclyl groups are unsubstituted or substituted by at least one R.sub.10; wherein each R.sub.10 may be the same or different; R.sub.10 is chosen from -halogen, C.sub.1-6 alkyl, -haloC.sub.1-6 alkyl, C.sub.0-6alkylCN, NO.sub.2, C.sub.0-6 alkyl-CO.sub.2R.sub.11, C.sub.0-6 alkyl-COR.sub.11, C.sub.0-6 alkyl-NR.sub.11R.sub.14, C.sub.0-6 alkyl-CONR.sub.11R.sub.12, C.sub.0-6 alkyl-NR.sub.11COR.sub.12, C.sub.0-6alkyl-NR.sub.11SO.sub.2R.sub.12, C.sub.0-6alkyl-SO.sub.2NR.sub.11R.sub.12, C.sub.0-6alkyl-OCONR.sub.11R.sub.12, C.sub.0-6 alkyl-NR.sub.11CO.sub.2R.sub.12, C.sub.0-6alkyl-NR.sub.11CONR.sub.11R.sub.12, C.sub.0-6alkyl-OR.sub.13, C.sub.0-6alkyl-SR.sub.14, C.sub.0-6alkyl-SOR.sub.14, C.sub.0-6alkyl-SO.sub.2R.sub.14, C.sub.0-6alkyl-OSO.sub.2R.sub.14, C.sub.0-6alkyl-C.sub.3-6cycloalkyl, C.sub.0-6alkyl-aryl, C.sub.0-6alkyl-heteroaryl, and C.sub.0-6alkyl-heterocyclyl, wherein the C.sub.1-6 alkyl, C.sub.0-6alkyl-C.sub.3-6cycloalkyl, C.sub.0-6alkyl-aryl, C.sub.0-6alkyl-heteroaryl, and C.sub.0-6alkyl-heterocyclyl groups are unsubstituted or substituted with at least one R.sub.15, wherein each R.sub.15 may be the same or different; R.sub.11 and R.sub.12 independently are chosen from H and C.sub.1-6alkyl; R.sub.13 is chosen from H, C.sub.1-6alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl-OR.sub.18, and haloC.sub.1-6 alkyl; R.sub.14 represents C.sub.1-6alkyl; R.sub.15 is chosen from halogen, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl, C.sub.0-6 alkylCN, NO.sub.2, O, C.sub.0-6 alkyl-C.sub.02R.sub.16, C.sub.0-6 alkyl-COR.sub.16, C.sub.0-6 alkyl-NR.sub.16R.sub.17, C.sub.0-6 alkyl-CONR.sub.16R.sub.17, C.sub.0-6 alkyl-NR.sub.16COR.sub.17, C.sub.0-6 alkyl-NR.sub.16SO.sub.2R.sub.17, C.sub.0-6 alkyl-SO.sub.2NR.sub.16R.sub.17, C.sub.0-6 alkyl-OCONR.sub.16R.sub.17, C.sub.0-6 alkyl-NR.sub.16CO.sub.2R.sub.17, C.sub.0-6 alkyl-NR.sub.16CONR.sub.16R.sub.17, C.sub.0-6 alkyl-OR.sub.18, C.sub.0-6 alkyl-SR.sub.19, C.sub.0-6 alkyl-SOR.sub.19, C.sub.0-6 alkyl-SO.sub.2R.sub.19, and C.sub.0-6 alkyl-OSO.sub.2R.sub.19; R.sub.16 and R.sub.17 independently are chosen from H and C.sub.1-6 alkyl; R.sub.18 is chosen from H, C.sub.1-6 alkyl, and -haloC.sub.1-6 alkyl; and R.sub.19 represents C.sub.1-6alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R.sub.1 represents a hydrogen atom.

3. The compound according to claim 1, wherein R.sub.2 represents a hydrogen atom.

4. The compound according to claim 1, wherein Y is chosen from .sup.a-A.sub.1-S(O).sub.p-A.sub.2- and .sup.a-A.sub.5-O-A.sub.6-.

5. The compound according to claim 1, wherein Y is chosen from .sup.aSCH.sub.2 and .sup.aSCH(CH.sub.3).

6. The compound according to claim 1, wherein Z is chosen from aryl, heteroaryl, and C.sub.3-8 cycloalkyl, wherein the aryl, heteroaryl and C.sub.3-8 cycloalkyl groups are unsubstituted or substituted with at least one R.sub.10.

7. The compound according to claim 1, wherein Z is chosen from phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxin-5-yl, 2,3-dihydro-1-benzofuran-5-yl, pyrazolyl, pyridinyl, isoquinolinyl, imidazopyridinyl and cyclopropyl, each of which may be unsubstituted or substituted with at least one R.sub.10.

8. The compound according to claim 1, wherein R.sub.10 is chosen from -halogen, C.sub.1-6 alkyl, -haloC.sub.1-6 alkyl, C.sub.0-6 alkyl-OR.sub.13, and C.sub.0-6alkyl-heteroaryl, and wherein the C.sub.1-6 alkyl and C.sub.0-6alkyl-heteroaryl groups are unsubstituted or substituted with at least one R.sub.15.

9. The compound according to claim 1, chosen from: 2-(3-chlorobenzylthio)-5-hydroxypyrimidin-4(3H)-one; 2-(benzylsulfanyl)-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-[(3-methylbenzyl)sulfanyl]pyrimidin-4(3H)-one; 2-[(4-chlorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-[(naphthalen-2-ylmethyl)sulfanyl]pyrimidin-4(3H)-one; 2-[(3-fluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-[(4-methoxybenzyl)sulfanyl]pyrimidin-4(3H)-one; 2-[(3,4-difluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-[(3-methoxybenzyl)sulfanyl]pyrimidin-4(3H)-one; 5-hydroxy-2-{[3-(trifluoromethyl)benzyl]sulfanyl}pyrimidin-4(3H)-one; 2-[(3-chloro-5-fluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-sulfanyl}-pyrimidin-4(3H)-one; 2-[(2-chlorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-[(1-phenylethyl)sulfanyl]pyrimidin-4(3H)-one; 2-(cyclopropylmethylthio)-5-hydroxypyrimidin-4(3H)-one; 2-[(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-(pyridin-2-ylmethylthio)pyrimidin-4(3H)-one; 2-(3-(difluoromethoxy)benzylthio)-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-((4-methylpyridin-2-yl)methylthio)pyrimidin-4(3H)-one; 5-hydroxy-2-(pyridin-3-ylmethylthio)pyrimidin-4(3H)-one; 2-((1,3-dimethyl-1H-pyrazol-5-yl)methylthio)-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-(pyridin-4-ylmethylthio)pyrimidin-4(3H)-one; 2-(4-fluoro-3-(trifluoromethoxy)benzylthio)-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-[(isoquinolin-1-ylmethyl)sulfanyl]pyrimidin-4(3H)-one; 5-hydroxy-2-{[2-(2,2,2-trifluoroethoxy)benzyl]sulfanyl}-pyrimidin-4(3H)-one; 5-hydroxy-2-[(imidazo[1,2-a]pyridin-6-ylmethyl)sulfanyl]-pyrimidin-4(3H)-one; 2-[(2,3-dihydro-1-benzofuran-5-ylmethyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one; 5-hydroxy-2-[(naphthalen-1-ylmethyl)sulfanyl]pyrimidin-4(3H)-one; 5-hydroxy-2-[(imidazo[1,2-a]pyridin-2-ylmethyl)sulfanyl]-pyrimidin-4(3H)-one; 2-(benzylsulfanyl)-5-hydroxy-6-(trifluoromethyl)pyrimidin-4(3H)-one; 5-methoxy-2-(4-methoxybenzylthio)pyrimidin-4(3H)-one; and a pharmaceutically acceptable salt thereof.

10. The compound according to claim 2, wherein R.sub.2 represents a hydrogen atom.

11. The compound according to claim 2, wherein Y is chosen from .sup.a-A.sub.1-S(O).sub.p-A.sub.2- and .sup.a-A.sub.5-O-A.sub.6-.

12. The compound according to claim 3, wherein Y is chosen from .sup.a-A.sub.1-S(O).sub.p-A.sub.2- and .sup.a-A.sub.5-O-A.sub.6-.

Description

1. SYNTHETIC METHODOLOGIES

(1) The methods used for synthesis of the compounds of the invention are illustrated by the general schemes below and the preparative examples that follow. The starting materials and reagents used in preparing these compounds are available from commercial suppliers. These general schemes are merely illustrative of methods by which the compounds of this invention can be synthesised, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.

(2) Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz; the chemical shifts () are reported in parts per million. Spectra were recorded using a Bruker 400 Avance instrument fitted with a 5 mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2.1 software, unless stated otherwise.

(3) Purity was assessed using UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 nm, using a Waters Acquity UPLC system equipped with Acquity UPLC BEH or HSS C18 columns (2.1 mm id50 mm long) operated at 50 or 60 C. Mobile phases typically consisted of acetonitrile or MeOH mixed with water containing either 0.05% formic acid or 0.025% ammonia. Mass spectra were recorded with a Waters SQD single quadrupole mass spectrometer using atmospheric pressure ionisation, unless stated otherwise.

(4) Compounds were purified using normal phase chromatography on silica or alumina, or by reverse phase chromatographic methods, using Biotage or Isolute KPNH Cartridge, SCX cartridge and SCX-2 solid phase extraction cartridges.

(5) Preparative HPLC was performed using an Agilent Technologies 1100 Series system typically using Waters 19 mm id100 mm long C18 columns such as XBridge or SunFire 5 m materials at 20 mL/min. Mobile phases typically consisted of acetonitrile or MeOH mixed with water containing either 0.1% formic acid or 0.1% ammonia, unless stated otherwise.

(6) In the following descriptions room temperature ranges from 20 C. to 25 C.

Abbreviations

(7) AIBN Azobisisobutyronitrile

(8) AlMe.sub.3 Trimethylaluminium

(9) DCM Dichloromethane

(10) DMF Dimethyl formamide

(11) DMSO Dimethyl sulfoxide

(12) d.sub.6-DMSO Deuterated dimethyl sulfoxide

(13) Et Ethyl

(14) EtOAc Ethyl acetate

(15) EtOH Ethanol

(16) Et.sub.2O Diethyl ether

(17) Et.sub.3N Triethylamine

(18) LCMS Liquid chromatography mass spectrum

(19) LDA Lithium diisopropylamide

(20) MS Mass spectrum

(21) Me Methyl

(22) MeOD Deuterated MeOH

(23) MeOH Methanol

(24) MTBE tert-butylmethyl ether

(25) NaOEt Sodium ethoxide

(26) NBS N-bromosuccinimide

(27) NMR Nuclear magnetic resonance

(28) Ph Phenyl

(29) PTSA para-Toluene sulfonic acid

(30) Rt room temperature

(31) THF Tetrahydrofuran

(32) Schemes 1-5 (shown in 1.1 to 1.5 below) serve to illustrate the methodologies that may be used to synthesize the exemplified compounds of formula (1) and intermediates used in the synthesis of the exemplified compounds of formula (1).

(33) ##STR00018##

(34) Compounds according to formula (1), wherein Y represents SC.sub.1-3alkylene-, may be prepared according to Scheme 1:

(35) Wherein Hal represents a halide e.g. chloro or bromo, A.sub.2 represents optionally substituted C.sub.1-3alkylene and Z is as defined herein and R.sub.1 and R.sub.2 represent H.

(36) ##STR00019##

(37) Alternatively compounds according to Formula (1), wherein Y represents SC.sub.1-3alkylene-, may be prepared according to Scheme 2:

(38) Wherein Hal represents a halide e.g. chloro or bromo, A.sub.2 represents optionally substituted C.sub.1-3alkylene and Z is as defined herein and R.sub.1 and R.sub.2 represent H.

(39) ##STR00020##

(40) Alternatively compounds according to Formula (1), wherein Y represents SC.sub.1-3alkylene-, may be prepared according to Scheme 3:

(41) Wherein Hal represents a halide e.g. chloro or bromo, A.sub.2 represents optionally substituted C.sub.1-3alkylene and Z is as defined herein and R.sub.1 and R.sub.2 represent H.

(42) ##STR00021##

(43) Compounds according to formula (1), wherein Y represents C.sub.1-3alkylene-S, C.sub.1-3alkylene-S or optionally substituted C.sub.2-6alkylene may be prepared according to Scheme 4:

(44) Wherein Y represents C.sub.1-3alkylene-S, C.sub.1-3alkylene-S or optionally substituted C.sub.2-6alkylene, Z is as defined herein and R.sub.1 and R.sub.2 represent H.

(45) ##STR00022##

(46) Compounds according to Formula (1), wherein Y represents SC.sub.1-3alkylene- and R.sub.1 represents haloC.sub.1-6alkyl, may be prepared according to Scheme 5:

(47) wherein A.sub.2 and Z are as defined herein and R.sub.2 represents H.

1.1.1 Intermediate 1 (Prepared According to Scheme 1 Step (a))

(48) ##STR00023##

3-(5-Methyl-1,2,4-oxadiazol-3-yl)benzyl carbamidothioate hydrobromide

(49) To a solution of 1-(bromomethyl)-3-chlorobenzene (2.7 g, 13.1 mmol) in EtOH (Volume: 100 ml) was added thiourea (1 g, 13.1 mmol) and the reaction stirred at reflux overnight. The reaction mixture was concentrated to yield 3-chlorobenzyl carbamimidothioate, HBr in quauntitative yield.

(50) MS ES.sup.+: 201

1.1.2 Intermediate 2 (Prepared According to Scheme 1 Step (b)

(51) ##STR00024##

2-[(3-Chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(52) To a suspension of sodium hydride (0.26 g, 6.39 mmol) in Et.sub.2O (10 ml) was added ethyl formate (0.40 g, 5.33 mmol) and then ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (1.00 g, 5.33 mmol) drop-wise and the mixture stirred at reflux for 2 hours. 3-Chlorobenzyl carbamimidothioate HBr salt (Int 1) (1.5 g, 5.33 mmol) was then added followed by EtOH (10 ml). The ether was removed in vacuo and then the resulting ethanolic solution heated at reflux for 4 hours. The reaction mixture was evaporated and the resulting solid purified by column chromatography (SiO.sub.2: 0-10% MeOH in DCM) to yield 2-[(3-chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (524 mg, 28%).

(53) .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2): 7.79 (s, 1H), 7.45 (s, 1H), 7.18-7.39 (m, 3H), 5.41-5.51 (m, 1H), 4.42 (s, 2H), 3.83-4.02 (m, 1H), 3.56-3.69 (m, 1H), 1.44-2.18 (m, 6H).

(54) MS ES.sup.: 351.

(55) The compounds according to Intermediates 3 to 15 were prepared in a similar manner to the methodology described for Intermediate 3 and according to Scheme 1 step (a) and step (b) using commercially available reagents unless otherwise stated.

1.1.3 Intermediate 3

(56) ##STR00025##

2-[(4-Chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(57) Prepared from 1-(bromomethyl)-4-chlorobenzene.

1.1.4 Intermediate 4

(58) ##STR00026##

2-(Benzylsulfanyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(59) Prepared from 1-(bromomethyl)benzene.

(60) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.70 (s, 1H), 7.11-7.50 (m, 5H), 5.44 (m, 1H), 4.37 (s, 2H), 3.76-3.86 (m, 1H) 3.48-3.58 (m, 1H), 1.35-1.98 (m, 6H).

(61) MS ES.sup.+: 319.

(62) Alternatively Intermediate 4 may be prepared according to the methodology described in Scheme 2 step (a):

(63) To a solution of 2-sulfanyl-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (315 mg, 1.38 mmol) in DMF (15 ml) at 0 C. was added triethylamine (0.20 ml, 1.38 mmol) and then (bromomethyl)benzene (236 mg, 1.38 mmol) drop-wise. The reaction mixture was allowed to stir at this temperature for 2 hours before being quenched with water and extracted with EtOAc. The organics were isolated and evaporated. The residue was purified by column chromatography ((SiO.sub.2: 0-5% MeOH in DCM) to yield 2-(benzylsulfanyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (55 mg, 13%).

1.1.5 Intermediate 5

(64) ##STR00027##

2-[(3-Methylbenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(65) Prepared from 1-(bromomethyl)-3-methylbenzene.

(66) MS ES.sup.+: 333.

1.1.6 Intermediate 6

(67) ##STR00028##

2-[(Naphthalen-2-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(68) Prepared from 2-(bromomethyl)naphthalene.

(69) MS ES.sup.+: 369.

1.1.7 Intermediate 7

(70) ##STR00029##

2-[(3-Fluorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(71) Prepared from 1-(bromomethyl)-3-fluorobenzene.

(72) MS ES.sup.+: 337.

1.1.8 Intermediate 8

(73) ##STR00030##

2-[(4-Methoxybenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(74) Prepared from 1-(bromomethyl)-4-methoxybenzene.

(75) MS ES.sup.+: 349.

1.1.9 Intermediate 9

(76) ##STR00031##

2-[(3,4-Difluorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(77) Prepared from 1-(bromomethyl)-3,4-difluorobenzene.

(78) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.68 (s, 1H), 7.49 (m, 1H), 7.31-7.43 (m, 1H), 7.28 (m, 1H), 5.43 (m, 1H), 4.35 (s, 2H), 3.72-3.93 (m, 1H), 3.45-3.60 (m, 1H), 1.66-1.92 (m, 3H), 1.43-1.66 (m, 3H).

(79) MS ES.sup.+: 355.

1.1.10 Intermediate 10

(80) ##STR00032##

2-[(3-Methoxybenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(81) Prepared from 1-(bromomethyl)-3-methoxybenzene.

(82) MS ES.sup.+: 349.

1.1.11 Intermediate 11

(83) ##STR00033##

5-(Tetrahydro-2H-pyran-2-yloxy)-2-{[3-(trifluoromethyl)benzyl]sulfanyl}pyridin-4(3H)-one

(84) Prepared from 1-(bromomethyl)-3-trifluoromethylbenzene.

(85) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.69 (s, 1H), 7.16-7.45 (m, 3H), 5.44 (m, 1H), 4.37 (s, 2H), 3.73-3.89 (m, 1H), 3.44-3.58 (m, 1H), 1.66-1.96 (m, 3H), 1.44-1.65 (m, 3H).

(86) MS ES.sup.: 385.

1.1.12 Intermediate 12

(87) ##STR00034##

2-[(3-Chloro-5-fluorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(88) Prepared from 1-(bromomethyl)-3-chloro-5-fluorobenzene.

(89) MS ES.sup.: 369.

1.1.13 Intermediate 13

(90) ##STR00035##

2-{[3-(5-Methyl-1,2,4-oxadiazol-3-yl)benzyl]sulfanyl}-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(91) Prepared from 3-(3-(bromomethyl)phenyl)-5-methyl-1,2,4-oxadiazole.

(92) MS ES.sup.+: 401.

1.1.14 Intermediate 14

(93) ##STR00036##

(94) 2-[(2-Chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(95) Prepared from 1-(bromomethyl)-2-chlorobenzene.

(96) MS ES.sup.+: 353.

1.1.15 Intermediate 15

(97) ##STR00037##

2-[(1-Phenylethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(98) Prepared from (1-bromoethyl)benzene.

(99) MS ES.sup.+: 333.

1.3.1 Intermediate 16 (Prepared According to Scheme 3 Step a)

(100) ##STR00038##

Sodium-6-oxo-5-(tetrahydro-2H-pyran-2-yloxy)-1,6-dihydropyrimidine-2-thiolate

(101) A 100 ml round-bottomed flask was charged with diced sodium (2.30 g, 0.1 mol), in toluene (30 ml) to give a colourless suspension. A mixture of ethyl formate (8.14 ml, 0.10 mol) and ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (9.9 ml, 0.10 mol) were added drop-wise, taking care to make sure the temperature did not exceed 30 C. The reaction was stirred at room temperature overnight by which point a brown viscous oil had settled out with some sodium remaining. The toluene was decanted off and ethanol (15 ml) was added and the reaction was stirred until remaining sodium had dissolved. Carbamimidothioic acid (7.61 g, 0.10 mol) was added and the reaction was stirred at room temperature for 1 hour and then heated to reflux for 4 hours. The reaction was cooled and diluted with water (50 ml) and diisopropyl ether and the aqueous layer separated. The diisopropyl ether layer was washed with water and the combined aqueous layers were washed with diisopropyl ether and then made up to 100 ml and used crude in the next step.

1.3.2 Intermediate 17 (Prepared According to Scheme 3 Step (b))

(102) ##STR00039##

2-[(Cyclopropylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(103) To a crude aqueous solution of sodium 6-oxo-5-(tetrahydro-2H-pyran-2-yloxy)-1,6-dihydropyrimidine-2-thiolate (Intermediate 16) (2.50 g, 10 mmol) in water (10.0 ml) was added dioxane (10 ml) and (bromomethyl)cyclopropane (945 mg, 7.00 mmol) the reaction was stirred for one hour after which solid had precipitated. This was filtered off, washed with water and ether and dried to yield pure 2-[(cyclopropylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (452 mg, 16% yield).

(104) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.63 (br, s, 1H), 7.40 (br, s, 1H), 5.18 (br, s, 1H), 3.46-3.66 (m, 1H), 3.19-3.34 (m, 1H), 2.80 (m, 2H), 1.42-1.73 (m, 3H), 1.15-1.43 (m, 3H), 0.86 (m, 1H), 0.20-0.41 (m, 2H), 0.04 (m, 2H).

(105) MS ES.sup.+: 283.

(106) The compounds according to Intermediates 18 to 31 were prepared in a similar manner to the methodology described for Intermediate 17 and according to Scheme 3 step (b) using commercially available alkylating reagents unless otherwise stated.

1.3.3 Intermediate 18

(107) ##STR00040##

2-[(2,3-Dihydro-1,4-benzodioxin-5-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(108) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.68 (s, 1H), 6.91 (m, 1H), 6.59-6.87 (m, 2H), 5.43 (m, 1H), 4.05-4.48 (m, 6H), 3.75-3.91 (m, 1H), 3.47-3.55 (m, 1H), 1.65-1.95 (m, 3H), 1.35-1.67 (m, 3H).

(109) MS ES.sup.+: 377.

1.3.4 Intermediate 19

(110) ##STR00041##

2-(Pyridin-2-ylmethylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(111) MS ES.sup.+: 320.

1.3.5 Intermediate 20

(112) ##STR00042##

2-(3-(Difluoromethoxy)benzylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(113) MS ES.sup.+: 385.

1.3.6 Intermediate 21

(114) ##STR00043##

2-((4-Methylpyridin-2-yl)methylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(115) MS ES.sup.+: 334.

1.3.7 Intermediate 22

(116) ##STR00044##

2-(Pyridin-3-ylmethylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(117) MS ES.sup.+: 320.

1.3.8 Intermediate 23

(118) ##STR00045##

2-((1,3-Dimethyl-1H-pyrazol-5-yl)methylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(119) MS ES.sup.+: 337.

1.3.9 Intermediate 24

(120) ##STR00046##

2-(Pyridin-4-ylmethylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(121) MS ES.sup.+: 320.

1.3.10 Intermediate 25

(122) ##STR00047##

2-(4-Fluoro-3-(trifluoromethoxy)benzylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(123) MS ES.sup.+: 421.

1.3.11 Intermediate 26

(124) ##STR00048##

2-[(Isoquinolin-1-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(125) MS ES.sup.+370,

1.3.12 Intermediate 27

(126) ##STR00049##

5-(Tetrahydro-2H-pyran-2-yloxy)-2-{[2-(2,2,2-trifluoroethoxy)benzyl]sulfanyl}pyrimidin-4(3H)-one

(127) MS ES.sup.+417.

(128) Prepared from 1-(bromomethyl)-2-(2,2,2-trifluoroethoxy)benzene:

(129) To a solution of 1-methyl-2-(2,2,2-trifluoroethoxy)benzene (0.8 g, 4.2 mmol, CAS RN 80054-83-7) in carbon tetrachloride (25 ml) was added AIBN (0.07 g, 0.4 mmol) and N-bromo succinimide (0.82 g, 4.6 mmol) at room temperature and the reaction was stirred at reflux temperature for 3 hours. The reaction mixture was washed with saturated sodium bicarbonate solution (25 ml) followed by brine solution (25 ml). The organic layer was dried and evaporated to give crude product which was purified by column chromatography (SiO.sub.2: 0-3% EtOAc in petrol) and product fractions concentrated to yield 1-(bromomethyl)-2-(2,2,2-trifluoroethoxy)benzene (0.6 g, 53%).

(130) .sup.1H NMR (400 MHz, DMSO-d6): 7.47-7.45 (d, 1H), 7.41-7.35 (t, 1H), 7.16-7.14 (d, 1H), 7.06-7.02 (t, 1H), 4.91-4.82 (m, 2H), 4.64 (s, 2H).

1.3.13 Intermediate 28

(131) ##STR00050##

2-[(Imidazo[1,2-a]pyridin-6-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(132) MS ES.sup.+359.

1.3.14 Intermediate 29

(133) ##STR00051##

2-[(2,3-Dihydro-1-benzofuran-5-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

1.3.15 Intermediate 30

(134) ##STR00052##

2-[(Naphthalen-1-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(135) MS ES.sup.+ 284 (M-pyran).

1.3.16 Intermediate 31

(136) ##STR00053##

2-[(Imidazo[1,2-a]pyridin-2-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(137) MS ES.sup.+359.

1.4.1 Intermediate 32 (Prepared According to Scheme 4 Step (a))

(138) ##STR00054##

2-(Phenylsulfanyl)ethanimidamide

(139) To a suspension of ammonium chloride (1.33 g, 24.8 mmol) in toluene (10 ml) under N.sub.2 at 0 C. was added trimethyl aluminium (12.1 ml, 24.1 mmol). The reaction mixture was stirred at RT for 2 hours. To this flask was then added a solution of 2-(phenylthio)acetonitrile (1 g, 6.70 mmol) in toluene (10 ml). The reaction was then stirred at 110 C. overnight. The reaction mixture was allowed to cool and then poured onto a slurry of silica in DCM. The slurry was stirred for 15 minutes and then filtered. The resulting filtrate was concentrated under vacuum and taken up in DCM. The organic mixture was washed with 1M HCl. The aqueous layer was concentrated under vacuum, taken up in water and then basified with 2M NaOH. The aqueous mixture was extracted with DCM. The organic layer was concentrated to yield 2-(phenylsulfanyl)ethanimidamide (850 mg, 5.11 mmol, 76% yield).

(140) .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2): 7.31-7.51 (m, 4H), 7.18-7.31 (m, 1H), 5.13 (br. s., 3H) and 3.67 (s, 2H).

(141) MS ES.sup.+: 167.

1.4.2 Intermediate 33 (Prepared According to Scheme 4 Step (b))

(142) ##STR00055##

2-[(Phenylsulfanyl)methyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(143) To a suspension of sodium hydride (182 mg, 4.55 mmol) in diethyl ether (10 ml) was added ethyl formate (281 mg, 3.79 mmol) followed by ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (713 mg, 3.79 mmol). The resulting mixture was stirred under reflux for 1.5 hours. To this mixture was then added a pre-mixed solution of 2-(phenylsulfanyl)ethanimidamide (Intermediate 32) (630 mg, 3.79 mmol) and sodium ethoxide (1.23 g, 3.79 mmol) in EtOH (10 ml). The ether was removed under vacuum and the resulting suspension stirred at reflux for 3 hours. The reaction mixture was concentrated and purified by column chromatography (SiO.sub.2: 0-10% MeOH in DCM) to yield 2-[(phenylsulfanyl)methyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (275 mg, 23% yield).

(144) MS ES.sup.: 317.

(145) The compounds according to Intermediates 34 to 35 were prepared in a similar manner to the methodology described for Intermediate 32 and 33 and according to Scheme 4 steps (a) and (b) using commercially available reagents unless otherwise stated.

1.4.3 Intermediate 34

(146) ##STR00056##

2-(Phenoxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(147) Prepared from phenoxyacetonitrile.

(148) MS ES.sup.+: 303.

1.4.4 Intermediate 35

(149) ##STR00057##

2-[2-(3-Chlorophenyl)ethyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(150) Prepared from 3-(3-chlorophenyl)propanenitrile

(151) .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2): 7.79 (s, 1H), 7.45 (s, 1H), 7.19-7.37 (m, 4H), 5.44 (m, 1H), 4.42 (s, 2H), 3.87-3.98 (m, 2H), 3.57-3.72 (m, 2H), 1.44-2.14 (m, 6H).

1.4.5 Intermediate 36 (Prepared According to Scheme 4 Step (b))

(152) ##STR00058##

2-(2-Phenylethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one

(153) To a suspension of sodium hydride (29.0 mg, 0.74 mmol) in diethyl ether (2 ml), ethyl formate (45.0 mg, 0.61 mmol) was added. Ethyl-2-(tetrahydro-2H-pyran-2-yloxy)acetate (115 mg, 0.61 mmol) was then added dropwise and the mixture stirred under reflux for 2 hours. To the reaction was then added a pre-stirred solution of trimethylaluminium (0.34 ml, 0.68 mmol) and 3-phenylpropanimidamide (100 mg, 0.68 mmol, CAS RN 24442-03-3) in THF (1 ml). The ether was taken off under vacuum and then the reaction stirred under reflux for 4 hours. The reaction mixture was poured onto a slurry of silica in DCM. The resulting slurry was stirred for 15 minutes and then concentrated in vacuo. The resulting solid (dry loaded crude product on silica) was then purified by column chromatography (SiO.sub.2: 0-10% MeOH in DCM) to yield 2-(2-phenylethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (65 mg, 35% yield).

(154) .sup.1H NMR (400 MHz, CD.sub.3OD): 7.70 (br. s., 1H), 6.98-7.37 (m, 5H), 5.45 (br. s., 1H), 3.79-3.96 (m, 1H), 3.58-3.68 (m, 1H), 2.97-3.12 (m, 2H), 2.75-2.95 (m, 2H), 1.13-2.18 (m, 6H).

(155) MS ES.sup.+: 301.

1.5.1 Intermediate 37 (Prepared According to Scheme 5 Step (a))

(156) ##STR00059##

2-(Benzylsulfanyl)-5-methoxy-6-(trifluoromethyl)-pyrimidin-4(3H)-one

(157) To a solution of diisopropylamine (283 mg, 2.79 mmol) in THF (15 ml) at 0 C. was added n-butyl lithium (1.80 ml, 2.80 mmol). The mixture was stirred for 15 minutes and then cooled to 78 C. before ethyl 2-methoxyacetate (300 mg, 2.54 mmol) was added drop-wise and the whole mixture was allowed to stir for 30 minutes. Ethyl 2,2,2-trifluoroacetate (361 mg, 2.54 mmol) was then added and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. A solution of benzyl carbamimidothioate (422 mg, 2.54 mmol) in ethanol (15 ml) was then added and the resulting mixture was stirred at reflux for 4 hours and then allowed to cool and stirred at room temperature for 72 hours. The reaction mixture was then evaporated and diluted with DCM and the organic extracts was washed with water. The organic layer was isolated and evaporated and the resulting residue purified by column chromatography (SiO.sub.2: 0-10% MeOH in DCM) to yield 2-(benzylsulfanyl)-5-methoxy-6-(trifluoromethyl)pyrimidin-4(3H)-one (319 mg, 40%).

(158) .sup.1H NMR (400 MHz, CD.sub.3OD): 7.43 (m, 2H), 7.10-7.36 (m, 3H), 4.43 (s, 2H), 3.92 (s, 3H).

(159) MS ES.sup.+: 317.

2. EXAMPLES

2.1. Example 1 (Prepared According to Scheme 1)

(160) ##STR00060##

2-(3-Chlorobenzylthio)-5-hydroxypyrimidin-4(3H)-one

(161) To a solution of 2-[(3-chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (0.60 g, 1.71 mmol) (Intermediate 2) in dioxane (5 ml) was added HCl, 4M in dioxane (0.43 ml, 1.71 mmol). The reaction mixture was stirred at RT overnight before being filtered. The resulting mass was triturated with diethyl ether and then isolated and dried to give a yellow solid. This was recrystallised from methanol (4 ml) and ethyl acetate (15 ml) to yield 2-(3-chlorobenzylthio)-5-hydroxypyrimidin-4(3H)-one (137 mg, 30%).

(162) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.50-13.10 (s, br, 1H), 8.90-9.10 (s, br, 1H), 7.25-7.53 (m, 5H) and 4.34 (s, 2H).

(163) MS ES.sup.+: 269.

(164) The compounds according to Examples 2 to 14 were prepared in a similar manner to the methodology described for Example 1 and according to Scheme 1 step (c).

2.2. Example 2

(165) ##STR00061##

2-(Benzylsulfanyl)-5-hydroxypyrimidin-4(3H)-one

(166) Prepared from 2-(benzylsulfanyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 4).

(167) Alternatively, to a solution of 2-(benzylsulfanyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 4) (70 mg, 0.22 mmol) in methanol (1.5 ml) was added PTSA (42 mg, 0.22 mmol). The reaction mixture was stirred at RT overnight before being was evaporated and taken up in DCM. The organics were washed with water, concentrated and purified by column chromatography (SiO.sub.2: 0-10% MeOH in DCM) to yield 2-(benzylsulfanyl)-5-hydroxypyrimidin-4(3H)-one.

(168) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.35-12.50 (s, br, 1H), 9.10-9.60 (s, br, 1H), 7.21-7.49 (m, 6H) and 4.34 (s, 2H).

(169) MS ES.sup.+: 235.

2.3 Example 3

(170) ##STR00062##

5-Hydroxy-2-[(3-methylbenzyl)sulfanyl]pyrimidin-4(3H)-one

(171) Prepared from 2-[(3-methylbenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy) pyrimidin-4(3H)-one (Intermediate 5).

(172) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.27-9.40 (s, br, 1H), 7.39-7.51 (m, 1H), 7.15-7.24 (m, 4H), 7.03-7.10 (m, 1H), 7.32 (s, 2H) and 2.28 (s, 3H).

(173) MS ES.sup.+: 249.

2.4 Example 4

(174) ##STR00063##

2-[(4-Chlorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one

(175) Prepared from 2-[(4-chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 3).

(176) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.28-7.56 (m, 5H) and 4.33 (s, 2H).

(177) MS ES.sup.+: 269.

2.5 Example 5

(178) ##STR00064##

5-Hydroxy-2-[(naphthalen-2-ylmethyl)sulfanyl]pyrimidin-4(3H)-one

(179) Prepared from 2-[(naphthalen-2-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 6).

(180) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.80-7.97 (m, 4H), 7.45-7.58 (m, 4H) and 4.61 (s, 2H).

(181) MS ES.sup.+: 285.

2.6 Example 6

(182) ##STR00065##

2-[(3-Fluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one

(183) Prepared from 2-[(3-fluorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one. (Intermediate 7).

(184) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.80-13.00 (s, br, 1H), 9.25-9.40 (s, br, 1H), 7.32-7.48 (m, 2H), 7.20-7.25 (m, 2H), 7.04-7.12 (m, 1H) and 4.36 (s, 2H).

(185) MS ES.sup.+: 253.

2.7 Example 7

(186) ##STR00066##

5-Hydroxy-2-[(4-methoxybenzyl)sulfanyl]pyrimidin-4(3H)-one

(187) Prepared from 2-[(4-methoxybenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one. (Intermediate 8).

(188) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.48 (s, 1H), 7.28-7.36 (m, 2H), 6.85-6.91 (m, 2H), 4.35 (s, 2H) and 3.79 (s, 3H).

(189) MS ES.sup.+: 264.

2.8 Example 8

(190) ##STR00067##

2-[(3,4-Difluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one

(191) Prepared from 2-[(3,4-difluorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 9).

(192) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.46 (s, 1H), 7.32-7.40 (m, 1H), 7.15-7.25 (m, 2H) and 4.41 (s, 2H).

(193) MS ES.sup.+: 271.

2.9 Example 9

(194) ##STR00068##

5-Hydroxy-2-[(3-methoxybenzyl)sulfanyl]pyrimidin-4(3H)-one

(195) Prepared from 2-[(3-methoxybenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one. (Intermediate 10).

(196) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.48 (s, 1H), 7.19-7.26 (m, 1H), 6.95-7.05 (m, 2H), 6.80-6.88 (m, 1H), 4.40 (s, 2H) and 3.33 (s, 3H).

(197) MS ES.sup.+: 265.

2.10 Example 10

(198) ##STR00069##

5-Hydroxy-2-{[3-(trifluoromethyl)benzyl]sulfanyl}pyrimidin-4(3H)-one

(199) Prepared from 5-(tetrahydro-2H-pyran-2-yloxy)-2-{[3-(trifluoromethyl)benzyl]sulfanyl}pyridin-4(3H)-one (Intermediate 11).

(200) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.75-7.85 (m, 2H), 7.44-7.60 (m, 3H) and 4.48 (s, 2H).

(201) MS ES.sup.+: 303.

2.11 Example 11

(202) ##STR00070##

2-[(3-Chloro-5-fluorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one

(203) Prepared from 2-[(3-chloro-5-fluorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 12).

(204) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.48 (s, 1H), 7.29 (s, 1H), 7.05-7.20 (m, 2H) and 4.42 (s, 2H).

(205) MS ES.sup.+: 287.

2.12 Example 12

(206) ##STR00071##

5-Hydroxy-2-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-sulfanyl}-pyrimidin-4(3H)-one

(207) Prepared from 2-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]sulfanyl}-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 13).

(208) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.13 (s, 1H), 7.92-7.97 (m, 1H), 7.56-7.63 (m, 1H), 7.45-7.52 (s, 2H), 4.48 (s, 2H) and 2.68 (s, 3H).

(209) MS ES.sup.+: 317.

2.13 Example 13

(210) ##STR00072##

2-[(2-Chlorobenzyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one

(211) Prepared from 2-[(2-chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 14).

(212) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.10-9.60 (s, br, 1H), 7.53-7.60 (m, 1H), 7.48-7.57 (s, 2H), 7.27-7.37 (m, 2H) and 4.41 (s, 2H).

(213) MS ES.sup.+: 269.

2.14 Example 14

(214) ##STR00073##

5-Hydroxy-2-[(1-phenylethyl)sulfanyl]pyrimidin-4(3H)-one

(215) Prepared from 2-[(1-phenylethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 15).

(216) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.38-7.41 (m, 3H), 7.28-7.34 (s, 2H), 7.23-7.27 (m, 1H), 4.92-4.98 (m, 1H), 1.68 (s, 3H).

(217) MS ES.sup.+: 249.

2.15 Example 15 (Prepared According to Scheme 3)

(218) ##STR00074##

2-(Cyclopropylmethylthio)-5-hydroxypyrimidin-4(3H)-one

(219) 2-[(Cyclopropylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 17) (520 mg, 1.84 mmol) was dissolved in dioxane (5 ml) and HCl (0.9 ml, 3.70 mmol) 4M in dioxane was added. A white precipitate formed. The resulting mixture was stirred for 1 hour at RT before pouring into ether and filtering. The solid obtained was dissolved in boiling ethanol, filtered hot, and then water was added drop-wise to the refluxing solution. The ethanol was boiled off until an aliquot withdrawn into a small sample vial showed crystallisation on cooling. The solution was allowed to cool with stirring to RT. The crystals formed were filtered off washed with water and dried to yield 2-(cyclopropylmethylthio)-5-hydroxypyrimidin-4(3H)-one (342 mg, 94%)

(220) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.60-9.30 (s, br, 1H), 7.40 (s, 1H), 3.01-3.04 (m, 2H), 1.04-1.18 (m, 1H), 0.52-0.56 (m, 2H) and 0.26-0.29 (m, 2H).

(221) MS ES.sup.+: 199.

(222) The compounds according to Examples 16 to 29 were prepared in a similar manner to the methodology described for Example 15 and according to Scheme 3 step (c).

2.16 Example 16

(223) ##STR00075##

2-[(2,3-Dihydro-1,4-benzodioxin-5-ylmethyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one

(224) Prepared from 2-[(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 18).

(225) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.25-9.35 (s, br, 1H), 7.40-7.45 (m, 1H), 6.88-6.92 (m, 1H), 6.74-6.81 (m, 2H) and 4.21-4.35 (m, 6H).

(226) MS ES.sup.+: 293.

2.17 Example 17

(227) ##STR00076##

5-Hydroxy-2-(pyridin-2-ylmethylthio)pyrimidin-4(3H)-one

(228) Prepared from 2-(pyridin-2-ylmethylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 19).

(229) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.73-8.79 (m, 1H), 8.29-8.35 (m, 1H), 7.91-7.95 (m, 1H), 7.75-7.80 (m, 1H), 7.42 (s, 1H) and 4.65 (s, 2H).

(230) MS ES.sup.+: 236.

2.18 Example 18

(231) ##STR00077##

2-(3-(Difluoromethoxy)benzylthio)-5-hydroxypyrimidin-4(3H)-one

(232) Prepared from 2-(3-(difluoromethoxy)benzylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 20).

(233) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.70-13.00 (s, br, 1H), 9.25-9.50 (s, br, 1H), 7.37-7.48 (m, 2H), 7.20-7.28 (m, 2H), 7.01-7.08 (m, 1H) and 4.38 (s, 2H).

(234) MS ES.sup.+: 301.

2.19 Example 19

(235) ##STR00078##

5-Hydroxy-2-((4-methylpyridin-2-yl)methylthio)pyrimidin-4(3H)-one

(236) Prepared from 2-((4-methylpyridin-2-yl)methylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 21).

(237) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.69-8.73 (m, 1H), 7.92-7.95 (m, 1H), 7.72-7.78 (m, 1H), 7.43 (s, 1H), 4.63 (m, 2H) and 2.54 (s, 3H).

(238) MS ES.sup.+: 250.

2.20 Example 20

(239) ##STR00079##

5-Hydroxy-2-(pyridin-3-ylmethylthio)pyrimidin-4(3H)-one

(240) Prepared from 2-(pyridin-3-ylmethylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 22).

(241) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.65 (s, 1H), 8.39-8.42 (m, 1H), 7.72-7.78 (m, 1H), 7.23-7.36 (m, 1H), 7.16 (s, 1H) and 4.21 (m, 2H).

(242) MS ES.sup.+: 236.

2.21 Example 21

(243) ##STR00080##

2-((1,3-Dimethyl-1H-pyrazol-5-yl)methylthio)-5-hydroxypyrimidin-4(3H)-one

(244) Prepared from 2-((1,3-dimethyl-1H-pyrazol-5-yl)methylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 23).

(245) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.88-9.50 (s, br, 1H), 7.45 (s, 1H), 5.95 (s, 1H), 4.34 (s, 2H), 3.73 (s, 3H) and 2.08 (s, 3H).

(246) MS ES.sup.+: 253.

2.22 Example 22

(247) ##STR00081##

5-Hydroxy-2-(pyridin-4-ylmethylthio)pyrimidin-4(3H)-one

(248) Prepared from 2-(pyridin-4-ylmethylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 24).

(249) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.34-9.52 (s, br, 1H), 8.60-8.66 (m, 2H), 7.63-7.69 (m, 2H), 7.42 (s, 1H) and 4.44 (s, 2H).

(250) MS ES.sup.+: 236.

2.23 Example 23

(251) ##STR00082##

2-(4-Fluoro-3-(trifluoromethoxy)benzylthio)-5-hydroxypyrimidin-4(3H)-one

(252) Prepared from 2-(4-fluoro-3-(trifluoromethoxy)benzylthio)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 25).

(253) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.75-12.90 (s, br, 1H), 9.31-9.42 (s, br, 1H), 7.60-7.66 (m, 1H), 7.37-7.55 (m, 3H) and 4.44 (s, 2H).

(254) MS ES.sup.+: 337.

2.24 Example 24

(255) ##STR00083##

5-Hydroxy-2-[(isoquinolin-1-ylmethyl)sulfanyl]pyrimidin-4(3H)-one

(256) Prepared from 2-[(isoquinolin-1-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 26).

(257) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.41-8.47 (m, 1H), 8.29-8.35 (m, 1H), 8.00-8.06 (m, 1H), 7.79-7.85 (m, 2H), 7.70-7.78 (m, 1H), 7.44 (s, 1H) and 5.06 (s, 2H)

(258) MS ES.sup.+286.

2.25 Example 25

(259) ##STR00084##

5-Hydroxy-2-{[2-(2,2,2-trifluoroethoxy)benzyl]sulfanyl}-pyrimidin-4(3H)-one

(260) Prepared from 5-(tetrahydro-2H-pyran-2-yloxy)-2-{[2-(2,2,2-trifluoroethoxy)benzyl]sulfanyl}pyrimidin-4(3H)-one. (Intermediate 27).

(261) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.60-12.90 (s, br, 1H), 8.95-9.45 (s, br, 1H), 7.38-7.45 (m, 2H), 7.27-7.33 (m, 1H), 7.12-7.17 (m, 1H), 6.95-7.05 (m, 1H), 4.75-4.80 (m, 2H) and 4.30. (s, 2H)

(262) MS ES.sup.+333.

2.26 Example 26

(263) ##STR00085##

5-Hydroxy-2-[(imidazo[1,2-a]pyridin-6-ylmethyl)sulfanyl]-pyrimidin-4(3H)-one

(264) Prepared from 2-[(imidazo[1,2-a]pyridin-6-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 28).

(265) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.70-13.5 (s, br, 1H), 9.35-9.55 (s, br, 1H), 8.70 (s, 1H), 8.12 (s, 1H), 7.83 (s, 1H), 7.64-7.73 (m, 1H), 7.52-7.62 (m, 2H) and 4.47 (s, 2H)

(266) MS ES.sup.+275.

2.27 Example 27

(267) ##STR00086##

2-[(2,3-Dihydro-1-benzofuran-5-ylmethyl)sulfanyl]-5-hydroxypyrimidin-4(3H)-one

(268) Prepared from 2-[(2,3-dihydro-1-benzofuran-5-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 29).

(269) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.70-12.85 (s, br, 1H), 9.25-9.40 (s, br, 1H), 7.43 (s, 1H), 7.26 (s, 1H), 7.08-7.14 (m, 1H), 7.67-7.76 (m, 1H), 4.45-4.58 (m, 2H), 4.28 (s, 2H) and 3.10-3.18 (m, 2H)

(270) MS ES.sup.+299 (M+Na).

2.28 Example 28

(271) ##STR00087##

5-Hydroxy-2-[(naphthalen-1-ylmethyl)sulfanyl]pyrimidin-4(3H)-one

(272) Prepared from 2-[(naphthalen-1-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 30).

(273) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.20-13.25 (s, br, 1H), 8.80-9.60 (s, br, 1H), 8.10-8.18 (m, 1H), 7.97-8.05 (m, 1H), 7.84-7.92 (m, 1H), 7.55-7.71 (m, 3H), 7.45-7.51 (m, 2H) and 4.88 (s, 2H)

(274) MS ES.sup.+285.

2.29 Example 29

(275) ##STR00088##

5-Hydroxy-2-[(imidazo[1,2-a]pyridin-2-ylmethyl)sulfanyl]-pyrimidin-4(3H)-one

(276) Prepared from 2-[(imidazo[1,2-a]pyridin-2-ylmethyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 31).

(277) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.11-9.30 (s, br, 1H), 8.48-8.55 (m, 1H), 7.88 (s, 1H), 7.45-7.55 (m, 2H), 7.20-7.28 (m, 1H), 6.83-6.88 (m, 1H) and 4.45 (m, 2H).

(278) MS ES.sup.+275.

2.30 Example 30 (Prepared According to Scheme 4 Step (c))

(279) ##STR00089##

5-Hydroxy-2-[(phenylsulfanyl)methyl]pyrimidin-4(3H)-one

(280) To a solution of 2 2-[(phenylsulfanyl)methyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 33) (275 mg, 0.86 mmol) in dioxane (4 ml) was added HCl (4M in dioxane; 0.65 ml, 2.59 mmol) and the reaction stirred at RT overnight. The reaction mixture was concentrated under vacuum. The crude residue was purified by column chromatography (SiO.sub.2: 0-10% MeOH in DCM) and product fractions concentrated. The resulting solid was purified further by trituration with diethyl ether to yield 5-hydroxy-2-[(phenylsulfanyl)methyl]pyrimidin-4(3H)-one (11 mg, 5% yield).

(281) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.38-7.50 (m, 3H), 7.27-7.40 (m, 3H) and 3.98 (s, 2H).

(282) MS ES.sup.+: 235.

(283) The compounds according to Examples 31 to 32 were prepared in a similar manner to the methodology described for Example 14 and according to Scheme 4 step (c).

2.31 Example 31

(284) ##STR00090##

5-Hydroxy-2-(phenoxymethyl)pyrimidin-4(3H)-one

(285) Prepared from 2-(phenoxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 34).

(286) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.30-, 9.80 (s, br, 1H), 9.43-9.47 (m, 2H), 7.25-7.35 (m, 2H), 6.98-7.07 (m, 2H) and 4.86 (s, 2H).

(287) MS ES.sup.+: 219.

2.32 Example 32

(288) ##STR00091##

2-[2-(3-Chlorophenyl)ethyl]-5-hydroxypyrimidin-4(3H)-one

(289) Prepared from 2-[2-(3-Chlorophenyl)ethyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 35).

(290) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.44 (s, 1H), 7.26-7.46 (m, 2H), 7.15-7.19 (m, 1H), 3.35 (s, 2H, hidden under MeOD peak) and 3.08 (s, 2H).

(291) MS ES.sup.+: 251.

2.33 Example 33 (Prepared According to Scheme 4 Step (c))

(292) ##STR00092##

5-Hydroxy-2-(2-phenylethyl)pyrimidin-4(3H)-one

(293) To a solution of 2-(2-phenylethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (Intermediate 36) (65 mg, 0.216 mmol) in methyl alcohol (1.5 ml) was added pTSA (41.0 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 3 hours before being concentrated and then purified by column chromatography (SiO.sub.2:0-15% MeOH in DCM) to yield a mixture of desired product and sulphonic acid. This crude material was then taken up in dichloromethane and washed with water. The organics were separated and concentrated to yield 5-hydroxy-2-(2-phenylethyl)pyrimidin-4(3H)-one (5.1 mg, 11% yield).

(294) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.40-7.48 (m, 1H), 7.15-7.23 (m, 2H), 7.25-7.33 (s, 3H), 2.95-3.08 (m, 2H) and 2.78-2.88 (m, 2H).

(295) MS ES.sup.+: 217

2.34 Example 34 (Prepared According to Scheme 5 Step (b))

(296) ##STR00093##

2-(Benzylsulfanyl)-5-hydroxy-6-(trifluoromethyl)pyrimidin-4(3H)-one

(297) To a solution of 2-(benzylsulfanyl)-5-methoxy-6-(trifluoromethyl)pyrimidin-4(3H)-one (Intermediate 37, 319 mg, 1.00 mmol) in DCM (5 ml) at 78 C. was added boron tribromide (1 M in DCM, 2.00 ml, 2.00 mmol). The reaction mixture was allowed to warm to 0 C. and then stirred for 1 hour. The reaction had not proceeded to completion so it was cooled to 78 C. and a further portion of boron tribromide (1.00 ml, 1.00 mmol) was added. The reaction mixture was then allowed to warm to room temperature and stirred overnight. The whole was then added drop-wise to a solution of aqueous sodium hydroxide solution (2M). The resulting mixture was extracted into dichloromethane and the aqueous layer was acidified to pH 1 with 1M hydrochloric acid and then re-extracted. The combined organics were concentrated in vacuo. The resulting residue was purified by column chromatography (SiO.sub.2: 0-10% MeOH in DCM) to yield 2-(benzylsulfanyl)-5-hydroxy-6-(trifluoromethyl)pyrimidin-4(3H)-one (28 mg, 9 70).

(298) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.41-7.46 (m, 2H), 7.23-7.36 (m, 3H) and 4.34 (s, 2H).

(299) MS ES.sup.+: 303.

2.35 Example 35

(300) ##STR00094##

5-Methoxy-2-(4-methoxybenzylthio)pyrimidin-4(3H)-one

(301) To a solution of 5-hydroxy-2-(4-methoxybenzylthio)pyrimidin-4(3H)-one (Example 7, mg, 0.11 mmol) in DMF (2 ml) at 0 C. was added potassium carbonate (24.0 mg, 0.17 mmol) and then methyl iodide (7 l, 0.11 mmol). The reaction mixture was allowed to stir at 0 C. for 3 hours, before being quenched with water and extracted with ethyl acetate. The organics were dried (MgSO.sub.4) and evaporated to dryness and the resulting residue was purified by column chromatography (SiO.sub.2: 0-5% MeOH in DCM). Product fractions were evaporated. The resulting solid was recrystalised from MTBE to yield 5-methoxy-2-(4-methoxybenzylthio)pyrimidin-4(3H)-one (7 mg, 22%).

(302) .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2): 7.48 (s, 1H), 7.21-7.28 (m, 2H), 6.85-6.91 (m, .sup.2H), 4.31 (s, 2H), 3.68 (s, 3H) and 3.42 (s, 3H).

(303) MS ES.sup.+: 279,

3. BIOLOGICAL EFFICACY OF COMPOUNDS OF THE INVENTION

3.1 In Vitro DAAO Enzyme Assay

(304) The functional activity of compounds inhibiting the DAAO enzyme was determined by utilizing the co-product of the catalysis of D-Serine, H.sub.2O.sub.2 which can be quantitatively measured using the Amplex Red (Invitrogen) detection. Amplex Red reagent is a colorless substrate that reacts with hydrogen peroxide (H.sub.2O.sub.2) with a 1:1 stoichiometry in the presence of hydrogen peroxide to produce highly fluorescent resorufin (excitationemission maxima=570/585 nm). The changes in fluorescence were monitored by a fluorescence plate reader, Envision (Perkin Elmer) and increases in DAAO activity were readily detected upon addition of D-Serine and suppression of this response observed with the application of test compounds.

(305) Human DAAO Enzyme was supplied by the Takeda Pharmaceutical Company (Osaka) and each batch was tested and used at concentrations giving comparable levels of activity. The K.sub.m of D-Serine was measured for each enzyme batch to maintain consistency; this K.sub.m was used in subsequent assays.

(306) On the day of the assay compounds were serially diluted in DMSO before being diluted 1:20 with assay buffer (20 mM Tris ph 7.4). A 5 l portion of assay buffer was added to the wells of a 384 clear base black walled plate (Corning), 5 l of diluted compound was then added via automated plate to plate transfer using the Bravo liquid handler (Agilent technologies) followed by 5 l of human DAAO enzyme and then 5 l D-Serine 50 mM was added to all but the negative control wells (final concentration of 10 mM). Finally 5 l Amplex red reagent (Invitrogen) was added to all wells as per manufacturer's protocol. The plate was incubated for 60 minutes in the dark at 25 C. and the fluorescence in each well was measured in the Envision plate reader.

(307) The IC.sub.50 values for compounds were determined from ten point half log scale dose-response studies and represent the concentration of compound required to prevent 50% inhibition of DAAO activity in the presence of 10 mM D-Serine. Concentration response curves were generated using the average of duplicate wells for each data point and analyzed using nonlinear regression and four parameter curve fit.

3.2 Results

(308) TABLE-US-00001 Example No. Mean IC.sub.50 (nM) 1 120 2 230 4 220 5 120 6 170 9 160 10 150 11 150 12 500 14 1200 16 540 18 190 20 470 21 1600 26 740 30 2800 31 3200 33 1200 34 2700 35 1800

(309) These results indicate that compounds of the invention have potent inhibitory activity against the DAAO enzyme. The compounds tested above exhibit IC.sub.50 values significantly less than 5 M, with the most potent compounds showing activity at the DAAO enzyme with IC.sub.50 values <250 nM. Accordingly, the compounds of the invention are expected to have usefulness in the prevention or treatment of conditions; such as those discussed above, in which DAAO enzyme activity is implicated.