HK1110859B - Novel pyrrolo [3, 2-d] pyrimidin-4-one derivatives and their use in therapy - Google Patents

Description

Novel pyrrolo [3,2-d ] pyrimidin-4-one derivatives and their therapeutic use

Technical Field

The present invention relates to novel pyrrolo [3,2-d ] pyrimidin-4-one derivatives, processes for their preparation, compositions containing them and their use in therapy.

Background

Myeloperoxidase (MPO) is a heme-containing enzyme found primarily in polymorphonuclear leukocytes (PMNs), and MPO is a member of a diverse protein family of mammalian peroxidases, including eosinophil peroxidase, thyroid peroxidase, salivary peroxidase, lactoperoxidase, prostaglandin H synthase, and the like. The mature enzyme is a dimer of identical moieties. Each half-molecule contains covalently bound heme, which exhibits unusual spectral properties related to the characteristic green color of MPO. The disulfide bridge linking the two halves of the MPO is cleaved, yielding a half-enzyme (hemi-enzyme) that exhibits spectral and catalytic properties indistinguishable from the intact enzyme. Enzymes use hydrogen peroxide to oxidize chloride to hypochlorous acid. Other halides and pseudohalides (e.g., thiocyanate) are also physiological substrates of MPO.

PMNs are particularly important for combating infections. These cells contain MPO and have a well documented bactericidal effect. PMNs act non-specifically by phagocytosis to engulf microorganisms, incorporating them into vacuoles, called phagosomes, which fuse with granules containing myeloperoxidase to form phagolysosomes. In phagolysosomes, the enzymatic activity of myeloperoxidase leads to the formation of hypochlorous acid, which is an effective bactericidal compound. Hypochlorous acid oxidizes itself and is most desirous of reacting with thiols and thioethers, but also converts amines to chloramines and chlorinates aromatic amino acids. Macrophages are large phagocytic cells that, like PMNs, are capable of phagocytosing microorganisms. Macrophages can produce hydrogen peroxide and, when activated, also produce myeloperoxidase. MPO and hydrogen peroxide can also be released to the outside of the cell where reaction with chloride can cause damage to adjacent tissues.

The link between myeloperoxidase activity and disease is implicated in neurological diseases with neuroinflammatory responses, including multiple sclerosis, alzheimer's disease, parkinson's disease and stroke, as well as other inflammatory diseases or disorders, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, atherosclerosis, inflammatory bowel disease (inflammatory bowel disease), glomerular lesions (renal glomular damage) and rheumatoid arthritis. Lung cancer is also thought to be associated with high MPO levels.

Multiple Sclerosis (MS)

MPO-positive cells are abundant in the circulation and in tissues undergoing inflammation. More specifically, MPO-containing macrophages and microglia were demonstrated in the CNS during disease; multiple sclerosis (Nagra RM, et al. journal of neuroimaging 1997; 78 (1-2): 97-107), Parkinson's disease (Choi D-K.et al. J. neurosci.2005; 25 (28): 6594-600), and Alzheimer's disease (Green PS.et al. journal of neuroimaging.2004; 90 (3): 724-33). It is speculated that certain aspects of chronic uninterrupted inflammation lead to overwhelming disruptions, where agents from the MPO response play an important role.

The enzyme is released extracellularly, as well as into phagolysosomes in neutrophils (Hampton MB, Kettle AJ, Winterbourn CC. blood 1998; 92 (9): 3007-17). The precondition for MPO activity is the presence of hydrogen peroxide, which is generated by NADPH oxidase and subsequent superoxide disproportionation. The oxidized enzyme is able to use a plethora of different substrates in which chloride is well validated. This reaction forms the strong non-free radical oxidant hypochlorous acid (HOCl). HOCl is very effective in oxidizing sulfur-containing amino acids such as cysteine and methionine (Peskin AV, Winterbourn CC. FreeRadical Biology and Medicine 2001; 30 (5): 572-9). It also forms chloramines with amino groups, which are present in both proteins and other biomolecules (Peskin AV. et al. free Radials biology and Medicine 2004; 37 (10): 1622-30). It chlorinates phenols (such as tyrosine) (Hazen SL. et al. Mass Free Biological and medical 1997; 23 (6): 909-16) and oxidizes unsaturated bonds in lipids (Albert CJ. et al. J. Biological. chem. 2001; 276 (26): 23733-41), iron oxide centers (Rosen H, Klebanoff SJ. journal of Biological Chemistry 1982; 257 (22): 13731) -354) and cross-links proteins (Fu X, Mueller DM, Heinecke JW. biochemistry 2002; 41 (4): 1293) -301).

The Proteolytic cascades are involved not only in cell infiltration across the BBB, but also in the destruction of the BBB, myelin and nerve cells (Cuzner ML, Opdenaker G. journal of neuroimaging 1999; 94 (1-2): 1-14; Yong VW. et al. Nature reviews neuroscience 2001; 2 (7): 502-11.). Activation of Matrix Metalloproteinases (MMPs) can be achieved by the action of upstream proteases in the cascade as well as by oxidation of disulfide bonds (Fu X.et al.J.biol.chem.2001; 276 (44): 41279-87; Gu Z.et al.science 2002; 297 (5584): 1186-90). This oxidation may be nitrosation or HOCl-mediated oxidation. Both reactions may be the result of MPO activity. Some reports suggest that MMP's in general, and MMP-9 in particular, in MS and EAE influence cell infiltration and the effects of tissue injury (BBB destruction and demyelination) (see Yong vw et al, supra). The importance of these particular classes of MS mechanisms stems from studies in which increased activity and the presence of proteases have been identified in MS brain tissue and CSF. Supporting data can also be generated by studies using mice lacking certain proteases involved in MS pathology, or by using pharmacological methods.

Demyelination is thought to be a toxic product that depends on cytotoxic T-cells and is produced by activated phagocytes (Lassmann H.J neural differentiation 2003; 74 (6): 695-7). Therefore, axonal loss is affected by proteases and reactive oxygen and nitrogen intermediates. When MPO is present, it apparently has the ability to activate proteases (directly and through inhibition release effects affecting protease inhibitors) and to generate active species.

Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease (COPD) is a disease state characterized by airflow limitation, which is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to non-toxic particles or gases. COPD is a serious public health problem. It is the fourth leading cause of chronic morbidity and mortality in the united states, and it is predicted to rank fifth in the world-grade disease burden of 2020. In the uk, the incidence of COPD is 1.7% in men and 1.4% in women. COPD ranges from mild to very severe in severity, with the cost of treatment rising rapidly as severity increases.

MPO levels of saliva and BAL are much higher in COPD patients compared to normal non-smoking controls (Keratings V.M., Barnes P.J.Am J Respir Crit Care Med 1997; 155: 449-. MPO levels further increase during exacerbations (Fiorini G.et al.biomedicine & Pharmacotherapy 2000; 54: 274-278; Crooks S.W.et al.European rapidatory journal.15 (2): 274-80, 2000). The role of MPO is likely to become more important in the exacerbation of COPD (Sharon S.D.et al.Am J Respir Crit Care Med.2001; 163: 349-355).

In addition to the destructive properties of MPO, there is a strong clinical link associated with vascular disease (Baldus S.et al circulation 2003; 108: 1440-5). The dysfunctional MPO polytype is associated with a reduced risk of coronary mortality (Nikporor B.et al.am Heart J2001; 142: 336), and patients with high MPO serum levels are at increased risk of developing acute coronary syndromes. The effects of MPO on vascular disease can be extended to COPD as there is strong evidence that the pulmonary vasculature is one of the earliest sites of involvement in smokers' lungs. Striking changes in the intima of pulmonary arteries have been described, indicating a dose relationship with smoking (Hale k.a., Niewoehner d.e., Cosio m.g., am RevResp Dis 1980; 122: 273-8).

The physiological functions of MPO are related to innate host defense. However, as in most cases with MPO deficient patients having relatively benign symptoms, this effect is not critical (Parry M.F. equivalent. Ann Int Med.1981; 95: 293-. In summary, there is a large body of evidence that increased MPO levels in COPD patients may contribute to the disease by several mechanisms. Therefore, selective inhibitors of MPO are expected to reduce the acute and chronic inflammatory aspects of COPD and may reduce the formation of emphysema.

Atherosclerosis of arteries

MPO inhibitors should reduce the atherosclerotic burden and/or vulnerability of existing atherosclerotic lesions and thus reduce the risk of acute myocardial infarction, unstable angina or stroke. A series of data supports the role of MPO in atherosclerosis. MPO is expressed in the shoulder region and necrotic core of human atherosclerotic lesions and the active enzyme has been isolated from autopsy samples of human lesions (Daugherty, A.et al (1994) J Clin Invest 94 (1): 437-44). In decayed and ruptured human lesions, an increase in the number of MPO expressing macrophages compared to fatty streaks has been demonstrated, suggesting a specific role for MPO in acute coronary syndromes (Sugiyama, S.et al (2001) Am JPathol 158 (3): 879-91). Patients diagnosed with coronary artery disease have higher plasma and leukocyte MPO levels than healthy controls (Zhang, r.et al (2001) Jama 286 (17): 2136-42). Furthermore, in two large prospective studies, plasma levels of MPO predict the risk of future coronary attacks or revascularization (Baldus, S.et al. (2003) Circulation 108 (12): 1440-5; Brennan, M.et al. (2003) N Engl J Med 349 (17): 1595-. The prevalence of total MPO deficiency in humans is: 2000-4000 individuals had one case. These individuals appeared to be generally healthy, but in a few cases severe Candida infections were reported. Interestingly, MPO-deficient patients are less affected by cardiovascular disease than controls with normal MPO levels (Kutter, d.et al. (2000) Acta Haematol 104 (1)). Polymorphism of the MPO promoter affects expression, leading to individuals with high and low MPO expression. In three different studies, the high expression genotype was associated with increased risk of cardiovascular disease (Nikporor, B.et al. (2001) Am HeartJ 142 (2): 336-9; Makela, R., P.J.Karhunen, et al (2003) Lab Invest 83 (7): 919-25; Aspergs, F.W., et al (2004) Am J Med 116 (6): 429-30). Cumulative data over the last decade indicate that proatherogenic actions of MPO include the oxidation of lipoproteins, the induction of endothelial dysfunction by nitric oxide depletion, and destabilization of atherosclerotic lesions by activation of proteases (Nichols, S.J. and S.L. Hazen (2005) Arterioscler Thromb Vasc Biol25 (6): 1102-11). Recently, some studies have focused on nitro-and chlorotyrosine modification of LDL and HDL lipoproteins. Since in vivo chlorotyrosine modifications can only be generated by hypochlorous acid produced by MPO, these modifications are considered specific markers for MPO activity (Hazen, S.L.and J.W.Heinecke (1997) J Clin Invest 99 (9): 2075-81). LDL particles exposed to MPO in vitro become aggregated, leading to promotion of uptake by macrophage scavenger receptors and foam cell formation (Hazell, L.J.and R.Stocker (1993) Biochem J290 (Pt 1): 165-72). Chlorotrityrosine modification of apoA1, the major apolipoprotein of HDL cholesterol, results in impaired cholesterol receptor function (Bergt, C., S.et. (2004) Proc Natl Acad Sci U S A; Zheng, L.et al. (2004) J Clin Invest 114 (4): 529-41). Systematic studies of these mechanisms have shown that MPO binds to and moves with apoA1 in plasma. In addition, MPO specifically targets those tyrosine residues of apoA1 that physically interact with the macrophage ABCA1 box transporter during cholesterol efflux from macrophages (Bergt, C.et al (2004) J Biol Chem 279 (9): 7856-66; Shao, B.et al (2005) J Biol Chem280 (7): 5983-93; Zheng et al (2005) J Biol Chem280 (1): 38-47). Thus, MPO appears to have a dual aggravating effect in atherosclerotic lesions, namely increasing lipid accumulation by aggregation of LDL particles, and reducing reverse cholesterol transport by attacking the HDL protein apoA 1.

1-beta-D-ribofuranosyl-2-oxopyrrolo [3,2-D ] pyrimidine-4 (3H, 5H) -thione and 1- (2, 3, 5-tri-O-benzoyl-1-beta-D-ribofuranosyl) -2-oxopyrrolo [3,2-D ] pyrimidine-4 (3H, 5H) -thione

Disclosed in j.heterocyclic Chemistry, 1992, 29, 343-. These compounds are believed to be pharmacologically inactive.

5, 7-dimercapto-1, 4, 6-triazaindene

Disclosed in chem. pharm. bull, 1964, 12, 1030-. The compound is believed to be pharmacologically inactive.

The present invention discloses novel pyrrolo [3,2-d ] pyrimidin-4-one derivatives which surprisingly exhibit useful properties as inhibitors of the enzyme MPO. These compounds may also exhibit selectivity for related enzymes such as Lactoperoxidase (LPO) and Thyroid Peroxidase (TPO).

Disclosure of Invention

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof

Wherein:

at least one of X and Y represents S, and the other represents O or S;

l represents a direct bond or C_1-7Alkylene, said alkylene optionally containing a member selected from the group consisting of O, S (O)_nAnd NR⁶Optionally containing one or two carbon-carbon double bonds, and optionally substituted with one or more substituents independently selected from OH, halogen, CN and NR⁴R⁵、C_1-6Alkyl and C_1-6Alkoxy optionally containing a carbonyl group adjacent to oxygen;

n represents an integer of 0, 1 or 2;

R¹represents hydrogen, or

i) A saturated or partially unsaturated 3-7 membered ring, optionally containing one or two heteroatoms independently selected from O, N and S, and optionally containing a carbonyl group, optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-7Alkyl radical, C_1-7Alkoxy, CN, CONR²R³、NR²COR³And COR³Said alkoxy group being optionally further substituted by C_1-6Alkoxy substituted, and the alkoxy optionally contains a carbonyl group adjacent to oxygen, and the alkyl is optionally further substituted with hydroxy or C_1-6Alkoxy substituted, and the alkyl or alkoxy optionally contains a carbonyl adjacent to oxygen or at any position of the alkyl; or

ii) an aromatic ring system (aromatic ring system) selected from phenyl, biphenyl, naphthyl or a monocyclic or bicyclic heteroaromatic ring structure containing 1-3 heteroatoms independently selected from O, N and S, said aromatic ring system being optionally substituted with one or more substituents independently selected from halogen, SO, and₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-7alkyl radical, C_1-7Alkoxy, CN, CONR²R³、NR²COR³And COR³(ii) a Said alkoxy group is optionally further substituted by C_1-6Alkoxy substituted, and the alkoxy optionally contains a carbonyl group adjacent to oxygen, and the alkyl is optionally further substituted with hydroxy or C_1-6Alkoxy substituted, and the alkyl or alkoxy optionally contains a carbonyl adjacent to oxygen or at any position of the alkyl;

R¹²represents hydrogen or halogen or carbon optionally substituted by one to three halogen atoms;

at each occurrence, R²、R³、R⁴、R⁵、R⁶、R⁹And R¹⁰Independently represent hydrogen, C_1-6Alkyl or C_1-6Alkoxy, said alkoxy optionally containingCarbonyl adjacent to oxygen, said alkyl being optionally further substituted by halogen, C_1-6Alkoxy, CHO, C_2-6Alkanoyl, OH, CONR⁷R⁸And NR⁷COR⁸Substitution;

or a group NR²R³、NR⁴R⁵And NR⁹R¹⁰Each independently represents a 5-7 membered saturated nitrogen heterocycle optionally containing one ring selected from O, S and NR¹¹And said ring is optionally further substituted by halogen, C_1-6Alkoxy, CHO, C_2-6Alkanoyl, OH, CONR⁷R⁸And NR⁷COR⁸Substitution;

at each occurrence, R⁷、R⁸And R¹¹Independently represent hydrogen or C_1-6Alkyl, or radicals NR⁷R⁸Represents a 5-to 7-membered saturated nitrogen heterocycle optionally containing one ring selected from O, S and NR¹¹The additional heteroatom of (a);

with the proviso that the compounds 1-beta-D-ribofuranosyl-2-oxopyrrolo [3,2-D ] pyrimidine-4 (3H, 5H) -thione, 1- (2, 3, 5-tri-O-benzoyl-1-beta-D-ribofuranosyl) -2-oxopyrrolo [3,2-D ] pyrimidine-4 (3H, 5H) -thione and 5, 7-dimercapto-1, 4, 6-triazaindene are excluded.

The compounds of formula (I) may exist in enantiomeric forms. It is understood that all enantiomers, diastereomers, racemates, tautomers and mixtures thereof are included within the scope of the present invention.

The compounds of formula (I) may exist in tautomeric forms. All such tautomers and mixtures of tautomers thereof are included within the scope of the present invention.

The term "C" as referred to herein, unless otherwise indicated_1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and hexyl. Operation of the artThe word "C_1-7Alkyl "is similarly explained.

The term "C" as referred to herein, unless otherwise indicated_1-7Alkylene "denotes a straight-chain or branched alkyl group having 1 to 7 carbon atoms and having two free valencies. Examples of such groups include, but are not limited to, methylene, ethylene, propylene, 1, 6-hexylene (hexamethylene), and ethylethylene (ethylethylene). The term "C_1-3Alkylene "is similarly explained.

The term "C" as referred to herein, unless otherwise indicated_1-6Alkoxy "denotes a straight or branched chain alkoxy group having 1 to 6 carbon atoms. Examples of such groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), t-butoxy, and pentoxy. The term "C_1-7Alkoxy "is similarly explained.

Unless otherwise indicated, reference herein to the term "C_2-6Alkanoyl "means a straight or branched alkyl group having 1 to 5 carbon atoms substituted at an optional position with a carbonyl group. Examples of such groups include acetyl, propionyl and pivaloyl.

The term "halogen" as referred to herein, unless otherwise indicated, denotes fluorine, chlorine, bromine and iodine.

Examples of saturated or partially unsaturated 3-to 7-membered rings optionally containing one or two heteroatoms independently selected from O, N and S, and optionally containing a carbonyl group include, but are not limited to, cyclopropane, cyclopentane, cyclohexane, cyclohexene, cyclopentanone, tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyridine, morpholine, piperazine, pyrrolidone, and piperidone.

Examples of monocyclic or bicyclic heteroaromatic ring structures containing 1-3 heteroatoms independently selected from O, N and S include, but are not limited to, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, indole, isoindole, and benzimidazole.

Optionally containing one selected from O, S and NR¹¹Examples of 5-to 7-membered saturated nitrogen heterocycles of (a) additional heteroatoms include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.

In the definition of L, "C_1-7An alkylene group; said alkylene group optionally containing a substituent selected from the group consisting of O, S (O)_nAnd NR⁶A heteroatom of (a); the alkylene group optionally containing one or two carbon-carbon double bonds "includes a linear or branched arrangement of saturated or unsaturated 1-7 carbon atoms having two free valencies, wherein any two singly-bound carbon atoms are optionally O, S or NR⁶And (4) separating. Thus, this definition includes, for example, methylene, ethylene, propylene, 1, 6-hexylene, ethylethylene, -CH₂＝CH₂-、-CH₂CH＝CH-CH₂-、-CH(CH₃)＝CH₂-、-CH₂＝CH₂-CH₂O-、-CH₂O-、-CH₂CH₂O-CH₂-、-CH₂CH₂O-CH₂-CH₂-、-CH₂CH₂S-and-CH₂CH₂NR⁶-。

In one embodiment, R¹Represents hydrogen.

In another embodiment, X represents S and Y represents O.

In another embodiment, Y represents S and X represents O.

In another embodiment, L is a direct bond or represents C_1-7Alkylene, said alkylene optionally containing a member selected from the group consisting of O, S (O)_nAnd NR⁶Optionally containing one or two carbon-carbon double bonds, and optionally substituted with one or more substituents independently selected from OH, C_1-6Alkoxy, halogen, CN and NR⁴R⁵。

In another embodiment, L is a direct bond or represents C_1-7An alkylene group; said alkylene is optionally substituted with one or more substituents independently selected from OH, C_1-6Alkoxy, halogen, CN and NR⁴R⁵。

In another embodiment, L is a direct bond or represents C_1-7An alkylene group; said alkylene group being optionally substituted by one or more C_1-6Alkoxy substitution.

In another embodiment, L is a direct bond or represents C_1-3An alkylene group; said alkylene is optionally substituted with one or more substituents independently selected from OH, C_1-6Alkoxy, halogen, CN and NR⁴R⁵。

In another embodiment, L represents C_1-3An alkylene group; said alkylene group being optionally substituted by one or more C_1-6Alkoxy substitution.

In another embodiment, L is a direct bond or represents an optionally substituted methylene group (-CH)₂-)。

In another embodiment, L is a direct bond or represents an optionally substituted ethylene (-CH)₂CH₂-)。

In another embodiment, R¹Represents a saturated or partially unsaturated 3-to 7-membered ring optionally containing one or two heteroatoms independently selected from O, N and S, and optionally containing a carbonyl group, said ring being optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-6Alkyl radical, C_1-6Alkoxy, CN, CONR²R³、NR²COR³And COR³Said alkoxy group being optionally further substituted by C_1-6Alkoxy substitution; and said alkyl is optionally further substituted by hydroxy or C_1-6Alkoxy substitution.

In another embodiment, R¹Represents a saturated or partially unsaturated 3-to 7-membered ring, optionally containing one or twoA heteroatom independently selected from O, N and S, and optionally containing a carbonyl group; said ring being optionally substituted with one or more substituents independently selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, said alkoxy being optionally further substituted by C_1-6Alkoxy substitution.

In another embodiment, R¹Represents an aromatic ring system selected from phenyl, biphenyl, naphthyl or a mono-or bicyclic heteroaromatic ring structure containing 1-3 heteroatoms independently selected from O, N and S, said aromatic ring being optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-6Alkyl radical, C_1-6Alkoxy, CN, CONR²R³、NR²COR³And COR³Said alkoxy group being optionally further substituted by C_1-6Alkoxy, and said alkyl is optionally further substituted by hydroxy or C_1-6Alkoxy substitution.

In another embodiment, R¹Represents an aromatic ring system selected from phenyl, biphenyl, naphthyl or a 5-or 6-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S, said aromatic ring being optionally substituted with one or more substituents independently selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, said alkoxy being optionally further substituted by C_1-6Alkoxy substitution.

In another embodiment, R¹Represents an optionally substituted phenyl group.

In another embodiment, R¹Represents an optionally substituted pyridyl group.

In another embodiment, L represents C_1-7Alkylene, and R¹Represents H.

In another embodiment, L represents optionally substituted C_1-3Alkylene, and R¹Represents a saturated or partially unsaturated 3-7-membered ring, which ring is substituted byOptionally containing one or two heteroatoms independently selected from O, N and S, and optionally containing a carbonyl group, said ring being optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-6Alkyl radical, C_1-6Alkoxy, CN, CONR²R³、NR²COR³And COR³Said alkoxy group being optionally further substituted by C_1-6Alkoxy, and said alkyl is optionally further substituted by hydroxy or C_1-6Alkoxy substitution.

In another embodiment, L represents optionally substituted C_1-3Alkylene, and R¹Represents a saturated or partially unsaturated 3-7-membered ring optionally containing one or two heteroatoms independently selected from O, N and S, and optionally containing a carbonyl group, said ring being optionally substituted with one or more substituents independently selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, said alkoxy being optionally further substituted by C_1-6Alkoxy substitution.

In another embodiment, L represents optionally substituted C_1-3Alkylene, and R¹Represents an aromatic ring system selected from phenyl, biphenyl, naphthyl or a 5-or 6-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S; the aromatic ring is optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-6Alkyl radical, C_1-6Alkoxy, CN, CONR²R³、NR²COR³And COR³Said alkoxy group being optionally further substituted by C_1-6Alkoxy, and said alkyl is optionally further substituted by hydroxy or C_1-6Alkoxy substitution.

In another embodiment, L represents optionally substituted C_1-3Alkylene, and R¹Represents an aromatic ring system selected from phenyl, biphenyl, naphthyl or containing 1-3 independently selected from O, NAnd S, said aromatic ring being optionally substituted with one or more substituents independently selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, said alkoxy being optionally further substituted by C_1-6Alkoxy substitution.

In another embodiment, X represents S, Y represents O, L represents optionally substituted C_1-3Alkylene, and R¹Represents an optionally substituted phenyl group.

In another embodiment, X represents S, Y represents O, L represents optionally substituted C_1-3Alkylene, and R¹Represents an optionally substituted pyridyl group.

In another embodiment, X represents S, Y represents O, L represents C_1-6Alkoxy-substituted C_1-3Alkylene, and R¹Represents hydrogen.

Specific compounds of the invention include:

1-butyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1-isobutyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (pyridin-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2-fluoro-benzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [2- (2-methoxyethoxy) -3-propoxybenzyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (6-ethoxy-pyridin-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1-piperidin-3-ylmethyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1-butyl-4-thioxo-1, 3, 4, 5-tetrahydro-2H-pyrrolo [3,2-d ] pyrimidin-2-one;

1- (2-isopropoxyethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2-methoxy-2-methylpropyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2-ethoxy-2-methylpropyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (piperidin-4-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (1-methylpiperidin-3-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ 2-hydroxy-2- (4-methoxyphenyl) ethyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2-methoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (3-methoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2, 4-dimethoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (3-chloropyridin-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- { [3- (2-ethoxyethoxy) pyridin-2-yl ] methyl } -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (6-oxo-1, 6-dihydropyridin-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-indol-3-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-benzoimidazol-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (5-chloro-1H-indol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (5-fluoro-1H-indol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-indol-6-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-indol-5-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (5-fluoro-1H-indol-3-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-imidazol-5-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-imidazol-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (5-chloro-1H-benzimidazol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (4, 5-dimethyl-1H-benzimidazol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

7-bromo-1-isobutyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one; and

1- (3-chlorophenyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one,

and pharmaceutically acceptable salts thereof.

Another aspect of the invention relates to the use of the novel compounds of formula (I) as medicaments.

Another aspect of the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition in which inhibition of the enzyme MPO is beneficial.

Another aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of neuroinflammatory disorders (neuro-and cerebellar atherogenic disorders), cardio-and cerebrovascular atherosclerotic disorders (cardiac-and peripheral arterial diseases) and respiratory disorders such as chronic obstructive pulmonary disease.

Another aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of multiple sclerosis. Treatment may include slowing the progression of the disease.

Another aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of atherosclerosis by preventing and/or reducing the formation of new atherosclerotic lesions or plaques and/or by preventing or slowing the progression of existing lesions and plaques.

Another aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of atherosclerosis by altering the composition of the plaque to reduce plaque rupture and atherosclerotic thrombotic events.

Another aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of a respiratory disease, such as chronic obstructive pulmonary disease. Treatment may include slowing the progression of the disease.

The invention also provides a method of treating, or reducing the risk of, a disease or condition in which inhibition of the enzyme MPO is beneficial which comprises administering to a patient suffering from, or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method of treating, or reducing the risk of, neuroinflammatory, cardiovascular or peripheral arterial disease or a respiratory disease, such as chronic obstructive pulmonary disease, in a patient suffering from, or at risk of, said disease, which comprises administering to said patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method of treating or reducing the risk of multiple sclerosis in a patient suffering from or at risk of multiple sclerosis comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating atherosclerosis or reducing the risk of atherosclerosis in a patient suffering from or at risk of atherosclerosis by preventing and/or reducing the formation of new atherosclerotic lesions or plaques and/or by preventing or slowing the progression of existing lesions and plaques, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating atherosclerosis or reducing the risk of atherosclerosis in a patient suffering from or at risk of atherosclerosis by altering the composition of said plaque to reduce the risk of plaque rupture and atherosclerotic thrombotic events, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the treatment or prevention of diseases or conditions in which inhibition of the enzyme MPO is beneficial.

In another aspect, the present invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the treatment or prevention of neuroinflammatory disorders.

In another aspect, the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier for use in the treatment or prophylaxis of multiple sclerosis, cardiovascular and cerebrovascular atherosclerotic diseases and peripheral arterial disease and respiratory diseases such as chronic obstructive pulmonary disease.

In another aspect, the present invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment or prevention of atherosclerosis by preventing and reducing the formation of new atherosclerotic lesions and/or plaques and/or by preventing or slowing the progression of existing lesions and plaques.

In another aspect, the invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for the treatment or prevention of atherosclerosis by altering the composition of the plaque to reduce the risk of plaque rupture and atherosclerotic thrombotic events.

The present invention also provides a process for preparing a novel compound of formula (I) or a pharmaceutically acceptable salt, tautomer, enantiomer, diastereomer or racemate thereof, which process comprises:

reacting a compound of formula (II) with C_1-6Alkoxycarbonyl isothiocyanate (C)_1-6alkoxycarbenylisothiocyanate) or phenylcarbonyl isothiocyanate (phenylcarbonyl isothiocyanate)isothiocyanate) is reacted,

wherein the compound of formula (II)

Wherein R is¹、R¹²And L is as defined for formula (I) and R represents C_1-6Alkoxy, where the oxygen in the direct bond is to the carbonyl in formula (II), where alkoxy is as defined above or NH₂；

And in phenylcarbonyl isothiocyanate, the phenyl group is optionally substituted with one or more groups independently selected from C_1-6Alkyl, halogen, C_1-6Alkoxy group, NO₂、OH、CN、C_1-6Alkylamino or NH₂(ii) a And if desired, converting the resulting compound of formula (I) or another salt thereof into a pharmaceutically acceptable salt thereof; or converting the resulting compound of formula (I) into another compound of formula (I); and, if desired, converting the resulting compound of formula (I) into its optical isomer.

In this process, the compound of formula (II) and the alkoxycarbonyl isothiocyanate or phenylcarbonyl isothiocyanate are dissolved or suspended in a suitable anhydrous organic solvent, such as dichloromethane, and stirred at 0 to 30 ℃ (e.g., ambient temperature) until the reaction is complete, typically between 5 and 60 minutes, but if necessary, overnight. Preferably, the alkoxycarbonyl isothiocyanate is ethoxycarbonyl isothiocyanate and the phenylcarbonyl isothiocyanate is preferably benzoyl isothiocyanate. After standard work-up, the intermediate product is optionally purified and then treated with a base such as sodium ethoxide in ethanol, aqueous sodium hydroxide or ammonia, methanolic ammonia to give the desired compound of formula (I). The cyclization reaction is carried out at elevated temperature or in an oil bath or in a microwave reactor. See, for example, Norman et al, J.Med.chem.2000, 43, 4288-. When ammonia in methanol is used, a pressure vessel is preferably used.

The compounds of formula (II) may be prepared by reaction of compounds of formula (III) (wherein R is¹²As defined in formula I, R is as defined in formula II) (see, for example, Furneaux et al, J.org.chem.1999, 64, 8411-

a) Reductive amination reaction. In this process, a compound of formula (III) can be combined with an aldehyde of formula (IV) in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, wherein R¹As defined in formula I. An acid, preferably acetic acid, may be added to catalyze the reaction. The reaction may be carried out in a solvent such as methanol at a temperature between ambient and 50 c, preferably ambient temperature. After standard work-up, the product is then optionally purified by flash column chromatography. See, for example, Suzuki et al, chem.pharm.Bull.2002, 50, 1163-.

b) And (4) alkylation. In this process, a mesylate of formula (V) (wherein R is¹As defined above) may be added to a stirred solution of the compound of formula (III), potassium iodide and a base, preferably potassium carbonate. The reaction can be carried out in a solvent such as N, N-dimethylformamide at a high reaction temperature (preferably 85 ℃). The reaction mixture can be worked up by extraction and then used in a flash columnAnd (5) carrying out chromatographic purification to obtain the compound of the formula (II).

c) A compound of formula (III) is reacted with a suitable aryl compound (VI) (wherein R is¹As defined above and halo as halogen, preferably bromo) to give a compound of formula (II). The reaction may be carried out using a suitable palladium catalyst (e.g., Pd)₂(dba)₃Or Pd (OAc)₂) Together with a suitable ligand (e.g. BINAP). A suitable base, such as cesium carbonate, may be used in the reaction, which is carried out in a suitable solvent, such as tetrahydrofuran, dioxane or toluene, at a temperature in the range of 80 ℃ to 100 ℃. See, e.g., J.P.Wolfe, S.L.Buchwald J.org.chem.2000, 65, 1144-.

The compounds of the formula (II) are either known from the literature or can be prepared using methods known to those skilled in the art. See, for example, Suzuki et al, chem.pharm.Bull.2002, 50, 1163-.

The compounds of formulae (IV), (V) and (VI) are either commercially available or can be prepared using methods well known in the literature.

The invention includes compounds of formula (I) in the form of salts. Suitable salts include those formed with organic or inorganic acids or with organic or inorganic bases. The salts will generally be pharmaceutically acceptable salts, although non-pharmaceutically acceptable acids or bases may be employed in the preparation and purification of the compounds. Thus, preferred acid addition salts include those formed with hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulfonic and benzenesulfonic acids. Preferred base addition salts include those wherein the cation is sodium, potassium, calcium, aluminum, lithium, magnesium, zinc, choline, ethanolamine, or diethylamine.

Salts of the compounds of formula (I) may be formed by reacting a compound or salt, enantiomer or racemate thereof with one or more equivalents of a suitable acid or base. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent (e.g. water, dioxane, ethanol, tetrahydrofuran or diethyl ether) or a mixture of solvents in which the salt is soluble, which may be removed in vacuo or by lyophilization. The reaction may also be a metathesis process or it may be carried out on an ion exchange resin.

The compounds of the present invention and intermediates thereof can be isolated from their reaction mixtures and, if desired, further purified by employing standard techniques.

The compounds of formula (I) may exist in enantiomeric forms. Accordingly, all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention. The various optical isomers can be separated from the racemic mixture of the compounds by employing conventional techniques, such as fractional crystallization or HPLC. Alternatively, the various optical isomers can be prepared directly from optically active starting materials.

The intermediate compounds may also exist in enantiomeric forms and may be used in the form of purified enantiomers, diastereomers, racemates or mixtures.

The compounds of formula (I) may exist in tautomeric forms. All such tautomers and mixtures of tautomers thereof are included within the scope of the present invention.

The intermediate compounds may also exist in tautomeric form and may be used in the form of purified tautomers or mixtures.

The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful because they have pharmacological activity as inhibitors of the enzyme MPO.

Compounds of formula (I) and pharmaceutically acceptable salts thereof are useful in the treatment or prevention of diseases or conditions in which modulation of the activity of the enzyme Myeloperoxidase (MPO) is desirable. In particular, the link of MPO activity to disease has been implicated in neuroinflammatory diseases. Accordingly, the compounds of the present invention are particularly useful in the treatment of neuroinflammatory disorders or diseases in mammals, including humans. The compounds may also be used in the treatment of cardiovascular and cerebrovascular atherosclerotic diseases or peripheral artery disease. The compounds are also useful in the treatment of respiratory diseases, such as respiratory diseases: an airway obstructive disease comprising: asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced asthma (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent, all of which are severe; and airway hyperreactivity for other reasons; chronic Obstructive Pulmonary Disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; pulmonary fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicated by anti-tumor therapy and chronic infection, including tuberculosis and pigeon-feeding disease and other fungal infections; complications of lung transplantation; pulmonary vasculitis and thrombotic disorders; and pulmonary hypertension; antitussive activity, including treatment of chronic and iatrogenic cough associated with airway inflammation and secretory events; acute and chronic rhinitis including rhinitis medicamentosa and vasomotor rhinitis; perennial rhinitis and seasonal allergic rhinitis, including rhinitis nervosa (hay fever); nasal polyposis; acute viral infections, including the common cold and infections caused by respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus. Such conditions or diseases will be apparent to those skilled in the art.

Symptoms or diseases that may be specifically mentioned include multiple sclerosis, alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis and stroke, as well as other inflammatory diseases or conditions, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, sinusitis, rhinitis, psoriasis, dermatitis, uveitis, gingivitis, myocardial infarction, stroke, coronary heart disease, hypoxic heart disease (ischeimic heart disease), restenosis, atherosclerosis, inflammatory bowel disease, glomerular damage, liver fibrosis, sepsis, proctitis, rheumatoid arthritis and inflammation associated with reperfusion injury, spinal cord injury and tissue injury/scar/adhesion/rejection. Lung cancer is also thought to be associated with high MPO levels. The compounds are also expected to be useful in the treatment of pain.

Prevention is considered to be particularly relevant in the treatment of persons suffering from the precursor signs of the disease or condition in question or who are considered to be at increased risk thereof. Persons at risk of developing a particular disease or condition generally include persons who have a family history of the disease or condition or who have been determined by genetic testing or screening to be significantly susceptible to developing the disease or condition.

For the above-mentioned therapeutic indications, the dosage administered will, of course, vary with the compound employed, the mode of administration and the desired treatment. However, satisfactory results are generally obtained when the compound is administered in a solid form dose of from 1mg to 2000mg per day.

The compounds of formula (I) and pharmaceutically acceptable derivatives thereof may be used alone or in the form of suitable pharmaceutical compositions. In the composition, the compound or derivative is mixed with a pharmaceutically acceptable adjuvant, excipient or carrier. Thus, another aspect of the present invention relates to a pharmaceutical composition comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Administration can be by, but is not limited to, enteral (including oral, sublingual, or rectal), intranasal, inhalation, intravenous, topical, or other parenteral routes. Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs", m.e. ulton, churchlill Livingstone, 1988. The pharmaceutical composition preferably contains less than 80%, more preferably less than 50% of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also provides a method for preparing the pharmaceutical composition, which comprises mixing the components.

Examples of pharmaceutical compositions

The following description of representative pharmaceutical dosage forms for prophylactic or therapeutic use in mammals contains a compound or salt, solvate, or solvated salt thereof of formula I (hereinafter referred to as compound X):

(a) the method comprises the following steps Tablet formulation	mg/tablet
		Compound X	100
Lactose	182.75
		Croscarmellose sodium	12.0
Corn starch paste (5% w/v paste)	2.25
		Magnesium stearate	3.0

(b) The method comprises the following steps Capsule preparation	mg/capsule
		Compound X	10
Lactose	488.5
		Magnesium stearate	1.5

(c) The method comprises the following steps Injection preparation	(50mg/ml)
		Compound X	5.0％w/v
1M sodium hydroxide solution	15.0％v/v

0.1M hydrochloric acid	(pH adjusted to 7.6)
		Polyethylene glycol 400	4.5％w/v
Water for injection	Make up to 100%

The above-mentioned composition can be obtained by a conventional method well known in the pharmaceutical field.

The invention also relates to a combination therapy wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition or formulation comprising a compound of formula (I) is administered simultaneously or sequentially with any one of the treatments and/or agents used in the treatment of cardiovascular and cerebrovascular atherosclerotic diseases and peripheral arterial disease.

In particular, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered with one or more compounds of the following group:

1) anti-inflammatory agents, e.g.

a) NSAIDs (e.g., acetylsalicylic acid, ibuprofen, naproxen, flurbiprofen, diclofenac, indomethacin);

b) leukotriene synthesis inhibitors (5-LO inhibitors such as AZD4407, jettison, licofelone, CJ13610, CJ 13454; FLAP inhibitors, such as BAY-Y-1015, DG-031, MK591, MK886, A81834; LTA4 hydrolase inhibitors, e.g., SC56938, SC 57461A);

c) leukotriene receptor antagonists (e.g., CP195543, amelubant, LY293111, ancrod, MK 571);

2) antihypertensive agents, e.g.

a) Beta-blockers (e.g., metoprolol, atenolol, sotalol);

b) angiotensin converting enzyme inhibitors (e.g., captopril, ramipril, quinapril, enalapril);

c) calcium channel blockers (e.g., verapamil, diltiazem, felodipine, amlodipine);

d) angiotensin II receptor antagonists (e.g., irbesartan, candesartan, telmisartan, losartan);

3) anticoagulants, e.g.

a) Thrombin inhibitors (e.g., ximelagatran), heparin, factor Xa inhibitors;

b) platelet aggregation inhibitors (e.g., clopidogrel, ticlopidine, prasugel, AZ 4160);

4) modulators of lipid metabolism, e.g.

a) Insulin sensitizers such as PPAR agonists (e.g., pioglitazone, rosiglitazone, Galida, muraglitazaar, gefemrozil, fenofibrate);

b) HMG-CoA reductase inhibitors, statins (e.g., simvastatin, pravastatin, atorvastatin, rosuvastatin, fluvastatin);

c) cholesterol absorption inhibitors (e.g., ezetimibe);

d) IBAT inhibitors (e.g., AZD-7806);

e) LXR agonists (e.g., GW-683965A, T-0901317);

f) FXR receptor modulators;

g) a phospholipase inhibitor;

5) anti-anginal drugs, e.g., nitrate and nitrite;

6) oxidative stress modulators, e.g., antioxidants (probucol).

General procedure

All solvents used were of analytical grade and the commercially available anhydrous solvents were those conventionally used for the reaction. The reaction is usually carried out in an inert atmosphere of nitrogen or argon.

¹H and¹³c NMR spectrum: 400MHz (protons) were recorded using a Varian Unity +400NMR spectrometer equipped with a Z-gradient 5mm BBO probe, a Bruker Avance 400NMR spectrometer equipped with a Z-gradient 60 μ l dual reflux probe, or a Bruker DPX400NMR spectrometer equipped with a Z-gradient 4-nuclear probe¹HNMR spectra and 100MHz (carbon-13)¹³C NMR spectrum. Unless specifically stated in the examples, 400MHz (proton) spectra and 100MHz (carbon-13) spectra were recorded. The following reference signals were used: DMSO-d₆Middle line delta 2.50: (¹H)，δ39.51(¹³C)；CD₃OD central line delta 3.31: (¹H) Or δ 49.15(¹³C) (ii) a Acetone-d₆2.04(¹H)，206.5(¹³C) (ii) a And CDCl₃δ7.26(¹H)，CDCl₃Center line δ 77.16(¹³C) (unless otherwise noted).

Mass spectrum: mass spectra were recorded on a Waters LCMS consisting of Alliance 2795(LC), Waters PDA 2996 and ELS detector (Sedex 75) and a ZMD single quadrupole mass spectrometer. The mass spectrometer is equipped with an electrospray ion source (ES) operating in positive or negative ion mode. The capillary voltage was 3kV and the cone voltage was 30V. The mass spectrometer was scanned between m/z 100-600 with a scan time of 0.7 s. The column temperature was set to 40 ℃. The diode array detector was scanned between 200 and 400 nm. The temperature of the ELS detector was adjusted to 40 ℃ and the pressure was set to 1.9 bar. For LC separation, a linear gradient was applied, starting from 100% A (A: 10mM NH)₄OAc/5% MeCN solution) and ends after four minutes at 100% B (B: MeCN). The column used was X-Terra MS C8, 3.0X 50; 3.5 μm (Waters), run at a flow rate of 1.0 mL/min.

Alternatively, mass spectrometry was performed on GC-MS (GC 6890, 5973N MSD) supplied by Agilent Technologies. The column used was VF-5MS, ID 0.25mm X30 m, 0.25 μm (Varian Inc.). A linear temperature gradient was applied, starting at 40 ℃ (hold for 1min) and ending at 300 ℃ (hold for 1min), 25 ℃/min. The MS was equipped with a CI ion source and the reaction gas was methane. The MS scans between m/z50-500 and the scan speed is set to 3.25 scans/second. The MS was equipped with an EI ion source. The MS scans between m/z50-500 and the scan speed is set to 3.25 scans/second. The electron voltage was set to 70 eV.

HPLC analysis: HPLC analysis was performed on an Agilent HP1000 system consisting of a G1379A Micro Vacuum Degasser, a G1312A Binary Pump, a G1367A Wellplate autosampler, a G1316A Thermostatted Column company and a G1315B diode array detector. Column: X-Terra MS, Waters, 3.0X 100mm, 3.5 μm. The column temperature was set at 40 ℃ and the flow rate was 1.0 mL/min. The diode array detector was scanned from 210-300nm with the step size and peak width set to 2nm and 0.05 min, respectively. A linear gradient was applied, starting from 100% A (A: 10mM NH)₄OAc/5% MeCN) was measured at 100% B (B: MeCN) ends for 6 minutes.

Microwave heating is carried out in an Initiator or Smith Synthesizer single-mode microwave resonant cavity, and continuous radiation is generated at 2450 MHz. Typical workup after the reaction (typical workup procedure) is extraction of the product with a solvent (e.g. ethyl acetate); washed with water, then MgSO₄Or Na₂SO₄The organic phase was filtered dried and the solution was concentrated in vacuo.

Thin Layer Chromatography (TLC): thin Layer Chromatography (TLC) was performed on Merck TLC-plates (silica gel 60F254) and spots were visualized by UV. In Combi FlashFlash column chromatography was performed on a company (TM) using a RediSepTM normal phase flash column. Typical solvents for flash column chromatography are mixtures of chloroform/methanol, dichloromethane/methanol and heptane/ethyl acetate.

Waters autopurification HP equipped with diode array detector for preparative chromatographyAnd (4) performing LC. Column: XTerra MS C8, 19X 300mm, 10 μm. Using a narrow gradient, MeCN/(95: 50.1 MNH)₄OAc: MeCN), flow rate 20 ml/min. Alternatively, another column is used; atlantis C1819X 100mm, 5 μm column. A gradient with acetonitrile/0.1M ammonium acetate in 5% acetonitrile in MilliQ Water was run from 0% to 35 to 50% acetonitrile over 15 min. Flow rate: 15 mL/min. Alternatively, purification was performed on a semi-preparative Shimadzu LC-8A HPLC equipped with a Waters SymmetryShimadzu SPD-10A UV-vis-detector of column (C18, 5 μm, 100 mm. times.19 mm). A narrow gradient was used, MeCN/0.1% trifluoroacetic acid in MilliQ Water, flow rate 10 ml/min.

Recrystallization is generally carried out in a solvent or solvent mixture, such as diethyl ether, ethyl acetate/heptane and methanol/water.

The following abbreviations are used:

aq. an aqueous solution;

BINAP 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl

equiv. equiv;

DMF N, N-dimethylformamide;

DMSO dimethyl sulfoxide;

DIBAL diisobutyl aluminum hydride;

Et₃n triethylamine;

HOAc acetic acid;

NaBH₄sodium borohydride;

NaCNBH₃sodium cyanoborohydride;

Pd₂(dba)₃tris (dibenzylideneacetone) dipalladium (0);

Pd(OAc)₂palladium diacetate;

r.t. room temperature;

TBDMSCl tert-butyldimethylsilyl chloride;

TEMPO 2, 2, 6, 6-tetramethyl-1-piperidinyloxy

THF tetrahydrofuran.

The starting materials used were obtained from commercial sources or prepared according to literature methods with reported experimental data. Examples of starting materials prepared are as follows:

3-amino-1H-pyrrole-2-carboxylate: furneaux, r.h., Tyler, p.c., j.org.chem.1999, 64, 8411-.

General method A

Aminopyrrole ester A1(1.0 equiv.), aldehyde A2(1.0-2.0 equiv.), and NaCNBH₃(1.0 equiv.) the reaction mixture in methanol was stirred at room temperature for 24 h. In some embodiments, acetic acid (1-2 equivalents) is added to catalyze the reaction. If the reaction is not complete after 24h (monitored by TLC or LC-MS), more aldehyde a2 is added and the mixture is stirred at room temperature until the reaction is complete. The mixture was then evaporated onto silica gel and purified by flash column chromatography.

General method B

Ethoxycarbonyl isothiocyanate B2(1.0-1.2 equivalents) was added to aminopyrrole B1(1.0 equivalent) in CH₂Cl₂To the solution, the mixture is then stirred at room temperature for 5-60 minutes, or overnight. Adding water, water phase with CH₂Cl₂And (4) extracting. The combined organic phases were dried (MgSO)₄) And concentrated. The crude ring-opened intermediate was purified by flash column chromatography. The intermediate product was dissolved in 1M NaOEt (1.1-1.5 equiv.) in EtOH and heated in a microwave reactor at 120 ℃ for 10 minutes. The pH was adjusted to neutral pH with 2M HCl and the solid was collected by filtration and washed with water. The crude product was purified by preparative HPLC, or by flash column chromatography or by recrystallization.

The present invention will be illustrated by the following examples, but the present invention is not limited to these examples. Unless otherwise indicated, the compounds of examples 1a-4a and 5c and 7B were prepared using the procedure of general procedure a, and the compounds of examples 1B-4B and 5d and 7c were prepared using the procedure of general procedure B.

Example 1

1-butyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- (butylamino) -1H-pyrrole-2-carboxylic acid ethyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.81g, 5.26mmol) and butyraldehyde (0.47+0.55mL, 11.4mmol), the title compound was obtained as an oil (60% yield).

¹H NMR(DMSO-d₆)δppm 10.71(1H，br s)，6.74(1H，t，J＝3.1Hz)，5.62(1H，t，J＝2.6Hz)5.19(1H，s)，4.17(2H，q，J＝7.0Hz)，3.04(2H，q，J＝6.6Hz)，1.50(2H，m)，1.34(2H，m)，1.25(3H，t，J＝7.0Hz)，0.90(3H，t，J＝7.3Hz)；

MS(ESI)m/z 211(M+1).

(b) 1-butyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Starting from ethyl 3- (butylamino) -1H-pyrrole-2-carboxylate (0.10g, 0.48mmol) and ethoxycarbonyl isothiocyanate (0.06mL, 0.58mmol), the title compound was obtained as a solid (44% yield).

¹H NMR(DMSO-d₆)δppm 12.38(1H，s)，12.10(1H，s)，7.37(1H，d，J＝2.9)，6.31(1H，d，J＝2.6Hz)，4.36(2H，m)，1.69(2H，m)，1.38(2H，m)，0.92(3H，t，J＝7.5Hz)；

MS(ESI)m/z 224(M+1).

Example 2

1-isobutyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- (isobutylamino) -1H-pyrrole-2-carboxylic acid ethyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.40g, 2.59mmol) and isobutyraldehyde (0.26+0.07mL, 3.61mmol), the title compound was obtained as an oil (71% yield).

¹H NMR(DMSO-d₆)δppm 10.68(1H，s)，6.74(1H，t，J＝3.0Hz)，5.62(1H.t，J＝2.4Hz)，5.30(1H，br s)，4.18(2H，q，J＝7.2Hz)，2.88(2H，t，J＝6.4Hz)，1.79(1H，m)，1.26(3H，t，J＝7.1Hz)，0.90(3H，s)，0.89(3H，s)；

¹³C NMR(DMSO-d₆)δppm 160.9，124.2，95.0，58.2，52.4，27.9，20.0，14.7；

MS(ESI)m/z 211(M+1).

(b) 1-isobutyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Starting from ethyl 3- (isobutylamino) -1H-pyrrole-2-carboxylate (0.38g, 1.79mmol) and ethoxycarbonyl isothiocyanate (0.24mL, 2.15mmol), the title compound was obtained as a solid (24% yield).

¹H NMR(DMSO-d₆)δppm 12.36(1H，br s)，12.13(1H，br s)，7.35(1H，d，J＝2.8Hz)，6.34(1H，d，J＝2.8Hz)，4.21(2H，d，＝7.33Hz)，2.44(1H，m)，0.91(3H，s)，0.90(3H，s)；

¹³C NMR(DMSO-d₆)δppm 172.8，152.4，137.3，127.7，113.6，97.1，56.2，26.4，19.7；

MS(ESI)m/z 224(M+1).

Example 3

1- (pyridin-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (pyridin-2-ylmethyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.40g, 2.59mmol) and 2-pyridinecarboxaldehyde (0.27+0.07mL, 3.55mmol), the title compound was obtained as an oil (54% yield).

¹H NMR(DMSO-d₆)δppm 10.77(1H，br s)，8.52(1H，d，J＝4.0Hz)，7.80-7.67(1H，m)，7.35(1H，d，J＝7.8Hz)，7.25(1H，dd，J＝7.3，5.0Hz)，6.71(1H，t，J＝3.0Hz)，6.10(1H，br s)，5.57(1H，t，J＝2.4Hz)，4.37(2H，d，J＝5.8Hz)，4.21(2H，q，J＝7.2Hz)，1.29(3H，t，J＝7.1Hz)；

MS(ESI)m/z 246(M+1).

(b)1- (pyridin-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Starting from ethyl 3- [ (pyridin-2-ylmethyl) amino ] -1H-pyrrole-2-carboxylate (0.34g, 1.39mmol) and ethoxycarbonyl isothiocyanate (0.19mL, 1.66mmol), the title compound was obtained as a solid (14% yield).

¹H NMR(DMSO-d₆)δppm 12.34(2H，br s)，8.49(1H，d，J＝4.5Hz)，7.73(1H，m)，7.29(1H，d，J＝2.8Hz)，7.27(1H，m)，7.21(1H，d，J＝7.8Hz)，6.09(1H，d，J＝2.8Hz)，5.75(2H，s)；

¹³C NMR(DMSO-d₆)δppm 173.4，155.2，152.6，149.1，137.1，136.8，127.9，122.4，121.2，113.6，96.9，54.2；

MS(ESI)m/z 259(M+1).

Example 4

1- (2-fluoro-benzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- (2-fluoro-benzylamino) -1H-pyrrole-2-carboxylic acid ethyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.50g, 3.2mmol) and 2-fluorobenzaldehyde (0.34mL, 3.2mmol), using general method a, the title compound was obtained as an oil (quantitative yield) but with the following changes. After 5h, more NaCNBH was added₃(100mg, 1.6mmol) followed by the addition of more 2-fluorobenzaldehyde (120mg, 1mmol) and the reaction was stirred overnight.

¹H NMR(DMSO-d₆)δppm 10.76(1H，br s)，7.47(1H，m)，7.38(1H，m)，7.28(2H，m)，6.70(1H，m)，5.74(1H，br s)，5.61(1H，m)，4.34(2H，m)，4.18(2H，q，J＝7.1Hz)，1.25(3H，t，J＝7.1Hz)；

MS(ES)m/z 263(M+1).

(b)1- (2-fluoro-benzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Starting from ethyl 3- (2-fluoro-benzylamino) -1H-pyrrole-2-carboxylate (0.85g, 3.2mmol) and ethoxycarbonyl isothiocyanate (0.44mL, 3.9mmol), the title compound was obtained as a solid (45% yield).

¹H NMR(DMSO-d₆)δppm 12.41(2H，br s.)，7.33(2H，m)，7.24(1H，m)，7.10(1H，m，J＝7.5，7.5Hz)，7.01(1H，m，J＝7.1Hz，7.1Hz)，6.12(1H，d，J＝2.8Hz)，5.72(2H，s)；

¹³C NMR(DMSO-d₆)δ173.9，161.4，159.0，152.9，137.1，129.6，129.5，128.5，128.1，128.1，125.0，124.9，123.2，123.0，115.8，115.6，114.1，96.9，47.1，47.1；

MS(ESI)m/z 276(M+1).

Example 5

1- [2- (2-methoxyethoxy) -3-propoxybenzyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a) 3-hydroxy-2- (2-methoxyethoxy) benzaldehyde

2-chloroethylmethyl ether (4.63mL, 50.7mmol) was added dropwise to a mixture of 2, 3-dihydroxybenzaldehyde (7.0g, 50.7mmol), potassium iodide (8.41g, 50.69mmol) and potassium carbonate (7.71g, 55.8mmol) in DMF (80 mL). The resulting mixture was stirred at room temperature under nitrogen for two days, followed by stirring at 70 ℃ for two days. The reaction mixture was washed with saturated ammonium chloride (aq.) and CH₂Cl₂Are allocated between them. Using CH as the aqueous phase₂Cl₂Re-extraction, combined organic phases washed with brine and dried (Na)₂SO₄) And evaporated onto silica. Purification by flash column chromatography (heptane/ethyl acetate gradient; 0-30% ethyl acetate) gave a crude oil which was further purified by flash column chromatography (heptane/ethyl acetate gradient; 0-40% ethyl acetate) to give the title compound as an oil (3.13g, 31%).

¹H NMR(DMSO-d₆)δppm 10.34(1H，br s)，9.88(1H，br s)，7.16(2H，m)，7.05(1H，m)，4.25(2H，m)，3.60(2H，m)，3.26(3H，m)；

¹³C NMR(DMSO-d₆)δppm 190.5，150.7，149.6，129.9，124.1，122.6，116.9，72.1，70.9，57.9；

MS(ESI)m/z 197(M+1).

(b)2- (2-methoxyethoxy) -3-propoxybenzaldehyde

1-iodopropane (3.09mL, 31.60mmol) was added to a solution of 3-hydroxy-2- (2-methoxyethoxy) benzaldehyde (3.1g, 15.8mmol) and potassium carbonate (4.37g, 31.60mmol) in DMF (80mL), and the mixture was stirred at 100 ℃ under nitrogen overnight. The reaction mixture was washed with saturated ammonium chloride (aq.) and CH₂Cl₂Are allocated between them. The organic phase was washed with brine and dried (Na)₂SO₄) And concentrated to give the title compound as an oil (quantitative yield, 3.8 g). This material was used in the next step without further purification.

¹H NMR(DMSO-d₆)δppm 10.37(1H，s)，7.36(1H，m，J＝8.0Hz)，7.26(1H，m)，7.17(1H.t，J＝7.8Hz)，4.28(2H，m)，4.02(2H，t，J＝6.3Hz)，3.62(2H，m)，3.26(3H，s)，1.80(2H，m)，1.02(3H，t，J＝7.3Hz)；

¹³C NMR(DMSO-d₆)ppm 190.3，152.1，150.9，129.6，124.4，119.4，117.8，72.5，70.9，70.0，57.9，22.1，10.4；

MS(ESI)m/z 239(M+1).

(c)3- { [2- (2-methoxyethoxy) -3-propoxybenzyl ] amino } -1H-pyrrole-2-carboxylic acid ethyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.35g, 2.27mmol) and 2- (2-methoxyethoxy) -3-propoxybenzaldehyde (0.47+0.08g, 3.06mmol), the title compound was obtained as an oil (quantitative yield).

¹H NMR(DMSO-d₆)δppm 10.69(1H，br s)，7.13(1H，s)，7.6.99(2H，m)，6.70(1H，m)，5.63(1H，m)，4.92(1H，t，J＝5.7Hz)，4.52(2H，d，J＝5.8Hz)，4.19(2H，m)，4.05(2H，m)，3.92(2H，t，J＝6.4Hz)，3.59(2H，m)，3.32(3H，s)，1.76(2H，m)，1.26(3H，t，J＝7.1Hz)，1.00(3H，m)；

MS(ESI)m/z 377(M+1).

(d)1- [2- (2-methoxyethoxy) -3-propoxybenzyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Starting from ethyl 3- { [2- (2-methoxyethoxy) -3-propoxybenzyl ] amino } -1H-pyrrole-2-carboxylate (0.87g, 2.31mmol) and ethoxycarbonyl isothiocyanate (0.26mL, 2.31mmol), the title compound was obtained as a solid (13% yield).

¹H NMR(DMSO-d₆)δppm 12.43(1H，br s)，12.31(1H，br s)，7.29(1H，d，J＝3.0Hz)，6.96-6.85(2H，m)，6.41(1H，dd，J＝7.3，1.5Hz)，6.02(1H，d，J＝2.8Hz)，5.71(2H，s)，4.23(2H，m)，3.95(2H，t，J＝6.3Hz)，3.65(2H，m)，3.33(3H，s)，1.82-1.72(2H，m)，1.02(3H，t，J＝7.4Hz)；

MS(ESI)m/z 390(M+1).

Example 6

1- (6-ethoxy-pyridin-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a) 6-ethoxy-pyridine-2-carboxylic acid ethyl ester

Ethyl iodide (2.3mL, 28.8mmol) was added to 6-hydroxy-pyridine-2-carboxylic acid (1.0g, 7.2mmol) and silver (I) carbonate (4.0g, 14.4mmol) in CHCl₃(70 mL). The suspension was stirred at ambient temperature for 3 days. Filtering to remove insoluble material, and adding CHCl to the solid₃And (6) washing. The filtrate was concentrated to give the title product as an oil (quantitative yield, 1.5 g). This material was used in the next step without further purification.

¹H NMR(CDCl₃)δppm 7.65(2H，m)，6.88(1H，m)，4.45(2H，q，J＝7.0Hz)，4.41(2H，q，J＝7.3Hz)，1.40(6H，m)；

MS(ESI)m/z 196(M+1).

(b) (6-ethoxy-pyridin-2-yl) -methanol

Over 35 minutes, NaBH is added₄(5.7g, 151mmol) was added portionwise to a solution of ethyl 6-ethoxy-pyridine-2-carboxylate (1.5g, 7.5mmol) in EtOH (75 mL). The resulting mixture was stirred at ambient temperature for two days. Adding water, mixing with CH₂Cl₂And (4) extracting. Organic phase drying (Na)₂SO₄) Filtration and concentration gave the title compound as an oil (0.85g, 74% yield). This material was used in the next step without further purification.

¹H NMR(CDCl₃)δppm 7.55(1H，m)，6.77(1H，d，J＝7.4Hz)，6.61(1H，d，J＝8.1Hz)，4.66(2H，d，J＝5.3Hz)，4.38(2H，q，J＝7.1Hz)，3.46(1H，t，J＝5.2Hz)，1.41(3H，t，J＝7.1Hz).

(c) 6-ethoxy-pyridine-2-carbaldehyde

DMSO (0.50mL, 6.4mmol) in CH at 60 deg.C₂Cl₂(10mL) solution was added dropwise to oxalyl chloride (2M CH)₂Cl₂Solution, 3.1mL, 6.1mmol) in CH₂Cl₂(20 mL). The resulting mixture was stirred at-60 ℃ for 10 minutes. (6-ethoxy-pyridin-2-yl) -methanol (0.85g, 5.6mmol) was added dropwise to CH₂Cl₂(5mL) and DMSO (4 mL). The mixture was stirred at-60 ℃ for 3h, then warmed to-20 ℃ and Et added₃N (6 mL). The resulting solution was stirred at ambient temperature for 40 minutes. Adding water, mixing with CH₂Cl₂And (4) extracting. The organic phase was washed with brine and dried (Na)₂SO₄) And then concentrated. Diethyl ether was added to the residue and the insoluble material was removed by filtration. The filtrate was concentrated to give the title product as a solid (0.60g, 70% yield). This crude product was used in the next step without further purification.

¹H NMR(CDCl₃)δppm 9.93(1H，s)，7.71(1H，m)，7.53(1H，d，J＝7.1Hz)，6.94(1H，d，J＝8.3Hz)，4.46(2H，d，J＝7.1Hz)，1.42(3H，t，J＝7.1Hz).

(d)3- [ (6-ethoxy-pyridin-2-ylmethyl) -amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Acetic acid (0.3mL) was added to a solution of 6-ethoxy-pyridine-2-carbaldehyde (0.59g, 3.9mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (0.30g, 1.9mmol) in ethanol (10 mL). After 1.5h, NaCNBH was added₃(0.24g, 3.9mmol) and the resulting mixture was stirred at ambient temperature for 19 h. The solvent was removed in vacuo and ethyl acetate was added to the residue, followed by filtration to remove insoluble material. The filtrate was concentrated and the crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0-35% ethyl acetate) to yield 0.25g (45%) of the title product as a solid.

¹H NMR(CDCl₃)δppm 8.16(1H，br s)，7.50(1H，m)，6.89(1H，d，J＝7.3Hz)，6.70(1H，br s)，6.57(1H，d，J＝8.1Hz)，4.45(2H，q，J＝7.0Hz)，5.71(1H，m)，4.38(5H，m)，1.37(6H，m)；

MS(ESI)m/z 290(M+1).

(e)1- (6-ethoxy-pyridin-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Ethoxycarbonyl isothiocyanate (0.12g, 0.90mmol) was added to 3- [ (6-ethoxy-pyridin-2-ylmethyl) -amino]-ethyl 1H-pyrrole-2-carboxylate (0.24g, 0.82mmol) in CH₂Cl₂(5mL) and the solution was then stirred at ambient temperature for 35 minutes. The solvent was evaporated, a 0.4M solution of NaOEt in ethanol (3mL, 1.2mmol) was added to the residue, and the mixture was refluxed for 1 h. More NaOEt (0.4M in ethanol, 1.5mL, 0.6mmol) was added, and the solution was refluxed for an additional 1.5 h. The solvent was evaporated off, the residue dissolved in water and the pH adjusted to neutral pH with 1M HCl. The resulting solid was collected, washed and dried to give the crude product. This material was purified by preparative HPLC to give the title compound (38mg, 15%) as a solid.

¹H NMR(DMSO-d₆)δppm 12.32(2H，br s)，7.62(1H，m)，7.29(1H，d，J＝3.0Hz)，6.78(1H，d，J＝7.3Hz)，6.64(1H，d，J＝8.3Hz)，6.13(1H，d，J＝2.8Hz)，5.65(2H，s)，4.17(2H，q，J＝7.1Hz)，1.19(3H，7，J＝7.0Hz)；

¹³C NMR(DMSO-d₆)δ173.5，162.7，152.8，152.5，139.6，137.2，127.8，113.9，113.6，109.0，97.0，61.0，53.8，14.3；

MS(ESI)m/z 303(M+1).

Example 7

1-piperidin-3-ylmethyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a) 3-formyl-piperidine-1-carboxylic acid tert-butyl ester

DMSO (0.18mL, 2.6mmol) in CH at-78 deg.C₂Cl₂(5mL) solution was added dropwise to oxalyl chloride (2M CH)₂Cl₂Solution, 0.65mL, 1.3mmol) in CH₂Cl₂(4 mL). The resulting mixture was stirred at-68 ℃ for 15 minutes. 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Dean A.Wacker et al.Bioorganic) was added dropwise&Medicinal Chemistry Letters 2002, 12, 1785-₂Cl₂(4mL) and stirred at-78 deg.C for 15min, Et was added₃N (6 mL). The resulting solution was stirred at ambient temperature for 16 h. Water was added, the mixture was extracted with diethyl ether and the organic layer was dried (Na)₂SO₄) And concentrated to give the product as a yellow oil (0.20g, 92% yield). This crude product was used in the next step without further purification.

MS(ESI)m/z 214(M+1).

(b)3- [ (2-ethoxycarbonyl-1H-pyrrol-3-ylamino) -methyl ] -piperidine-1-carboxylic acid tert-butyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.14g, 0.92mmol) and tert-butyl 3-formyl-piperidine-1-carboxylate (0.20g, 0.92mmol), the title compound was obtained as an oil (30% yield).

¹H NMR(CDCl₃)δppm 8.29(1H，br s)，6.70(1H，s)，5.67(1H，m)，4.27(2H，m)，3.93(1H，br s)，3.85(1H，d，J＝13.2Hz)，3.10-2.94(2H，m)，2.83(1H，m)，2.65(1H，br s)，1.85(1H，m)，1.76(1H，m)，1.64(1H，m)，1.42(9H，s)，1.31(3H，t，J＝6.8Hz)，1.22(1H，m)；

MS(ESI)m/z 352(M+1).

(c) 1-piperidin-3-ylmethyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Using this general method B, using 3- [ (2-ethoxycarbonyl-1H-pyrrol-3-ylamino) -methyl ] -piperidine-1-carboxylic acid tert-butyl ester (97mg, 0.27mmol) and ethoxycarbonyl isothiocyanate (36mg, 0.27mmol), the title compound was obtained as a solid (20% yield) with the following changes. After base-mediated cyclization, 6M HCl (0.3mL) was added to the reaction followed by heating at 100 ℃ for 4 minutes in a microwave reactor. The solvent was removed in vacuo and the residual solid was purified by preparative HPLC using an Atlantis C1819X 100mm, 5 μm column. Run from 0% to 50% acetonitrile in a gradient of acetonitrile/0.1M ammonium acetate in 5% acetonitrile in MilliQ Water over 15min, flow rate: 15 mL/min.

¹H NMR (methanol-d)₄)δppm 7.23(1H，d，J＝3.2Hz)，6.21(1H，d，J＝3.2Hz)，4.46(1H，m)，4.23(1H，m)，3.22(2H，m)，2.86(2H，m)，2.58(1H，m)，1.83(2H，m)，1.62(1H，m)，1.42(1H，m)；

¹³C NMR (methanol-d)₄)δ178.8，154.7，139.3，129.5，115.3，97.8，53.7，48.0，45.2，34.5，27.6，23.2；

MS(ESI)m/z 265(M+1).

Example 8

1-butyl-4-thioxo-1, 3, 4, 5-tetrahydro-2H-pyrrolo [3,2-d ] pyrimidin-2-one

Ethoxycarbonyl isothiocyanate (0.13mL, 1.1mmol) was added to a solution of ethyl 3- (butylamino) -1H-pyrrole-2-carboxylate (0.23g, 1.1mmol) in toluene (5mL), and the mixture was heated at 90 ℃ for 1H. The precipitate was filtered off and washed with hexane. The intermediate product was treated with a solution of potassium hydroxide (0.55g, 9.9mmol) in water (9mL) and heated at reflux for 15 h. After cooling to ambient temperature, the pH was adjusted to pH 5 with 12M HCl. The resulting precipitate was collected by filtration and washed with water. The crude product was purified by preparative HPLC to give the title compound (16mg, 6%) as a solid.

¹H NMR(DMSO-d₆)δppm 12.04(1H，br s)，11.95(1H，br s)，7.40(1H，s)，6.23(1H，d，J＝2.7Hz)，3.84(2H，t，J＝7.2Hz)，1.66-1.56(2H，m)，1.32(2H，m)，0.89(3H，t，J＝7.3Hz)；

MS(ESI)m/z 224(M+1).

Example 9

1- (2-Isopropoxyethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (2-Isopropoxyethyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Trichlorocyanuric acid (1.84g, 7.93mmol) was added to CH 2-isopropoxyethanol (0.75g, 7.21mmol)₂Cl₂(3mL) in solution. The reaction mixture was cooled to 0 ℃ and TEMPO (0.022g, 0.14mmol) was added carefully in small portions. The mixture was stirred at room temperature for 20 minutes, then filtered through celite and with CH₂Cl₂And (6) washing. During the filtration, the filtrate was kept ice-cold, 0 ℃. The aldehyde solution was added to a stirred mixture of ethyl 3-amino-1H-pyrrole-2-carboxylate (0.83g, 5.41mmol) and HOAc (0.62mL, 10.8mmol) in methanol (5mL) at 0 ℃. The mixture was stirred for 20 minutes, then NaCNBH was added₃(0.34g, 5.41 mmol). After stirring at room temperature for 2h, the solution was evaporated onto silica and flash evaporatedPurification by column chromatography (heptane/ethyl acetate gradient; 0-100% ethyl acetate) gave the title compound as an oil (0.75g, 58%).

¹H NMR(DMSO-d₆)δppm 10.72(1H，br s)，6.76-6.74(1H，m)，5.66-5.65(1H，m)，5.34(1H，br s)，4.17(2H，q，J＝7.0Hz)，3.59-3.49(3H，m)，3.15(2H，q，J＝5.6Hz)，1.26(3H，t，J＝7.0Hz)，1.10(3H，s)，1.08(3H，s)；

MS(ESI)m/z 241(M+1).

(b)1- (2-Isopropoxyethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Following general procedure B, using ethyl 3- [ (2-isopropoxyethyl) amino ] -1H-pyrrole-2-carboxylate (0.7g, 2.91mmol) and ethoxycarbonyl isothiocyanate (0.40mL, 3.50mmol), the title compound was prepared (0.17g, 23%).

¹H NMR(DMSO-d₆)δppm 12.74(2H，br s)，7.35(1H，d，J＝2.8Hz)，6.29(1H，d，J＝3.0Hz)，4.49(2H，t，J＝6.3Hz)，3.72(2H，t，J＝6.3Hz)，3.60-3.58(1H，m)，1.02(3H，s)，1.01(3H，s)；

MS(ESI)m/z 254(M+1).

Example 10

1- (2-methoxy-2-methylpropyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (2-methoxy-2-methylpropyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.250g, 1.62mmol) and 2-methoxy-2-methylpropionaldehyde (US 3,652, 579) (0.331g, 3.24mmol), using general method a, the title compound was obtained as an oil (75% yield), but with the following changes. After 6h, more 2-methoxy-2-methylpropionaldehyde (0.165g, 1, 62mmol) was added and the reaction mixture was stirred overnight.

¹H NMR(DMSO-d₆)δppm 10.69(1H，br s)，6.74(1H，t，J＝3.0Hz)，5.64(1H，t，J＝2.6Hz)，5.33(1H，br s)，4.17(2H，q，J＝7.1Hz)，3.11(3H，s)，3.03(2H，d，J＝5.8Hz)，1.26(3H，t，J＝7.1Hz，)，1.13(6H，s)；

MS(ESI)m/z 241(M+1).

(b)1- (2-methoxy-2-methylpropyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Starting from ethyl 3- [ (2-ethoxy-2-methylpropyl) amino ] -1H-pyrrole-2-carboxylate (0.283g, 1.18mmol) and ethoxycarbonyl isothiocyanate (0.13mL, 1.18mmol), using general method B, the title compound was obtained as a solid (3% yield), with the following changes. The reaction was run in a microwave reactor for a total of 35 minutes.

¹H NMR(DMSO-d₆)δppm 12.29(1H，br s)，12.17(1H，br s)，7.30(1H，d，J＝2.76)，6.29(1H，d，J＝2.76)，4.58(2H，br s)，3.12(3H，s)，1.21(6H，s)；

MS(ESI)m/z 254(M+1).

Example 11

1- (2-ethoxy-2-methylpropyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a) 2-bromo-1, 1-diethoxy-2-methylpropane

This product was synthesized according to the modified procedure described in US 3,652,579. Bromine water (2.95mL, 57.6mmol) was added dropwise to a solution of isobutyraldehyde (4.82g, 66.8mmol) in ethanol (22mL), and the resulting mixture was stirred at room temperature for 40 minutes. More bromine water (0.3mL, 5.86mmol) was added. The reaction mixture was neutralized by the addition of calcium carbonate (3.5g, 25.3 mmol). The remaining calcium carbonate was filtered off and the filtrate was poured onto an ice-water mixture. Using CH for the aqueous phase₂Cl₂Extracting and drying (Na)₂SO₄) Filtering, thenAnd (5) concentrating. After vacuum distillation, the title product was obtained (10.10g, 67%).

¹H NMR((DMSO-d₆)δppm 4.43(1H，s)，3.80-3.73(2H，m)，1.64(6H，s)，1.15(6H，t，J＝7.1Hz).

(b) 2-ethoxy-2-methylpropionaldehyde

This product was synthesized according to the method described in US 3,652,579. Over 50 minutes, 2-ethoxy-2-methylpropionaldehyde (5.63g, 25mmol) was added dropwise to potassium hydrogen tartrate (2.35g, 12.5mmol) in refluxing deionized water (22.5 mL). The resulting mixture was refluxed for 70 minutes. The solvent and the product were distilled off. Ammonium sulfate (8.5 g total) was added to the product-solvent mixture. The mixture was stirred, then the two phases were separated, and the upper phase was distilled with calcium chloride to obtain the title product (1.60g, 55%).

MS(CI)m/z 117(M+1).

(c)3- [ (2-ethoxy-2-methylpropyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.200g, 1.30mmol) and 2-ethoxy-2-methylpropionaldehyde (0.292g, 2.86mmol), using general method A, the title compound was obtained as an oil (63% yield), with the following changes. The reaction mixture was stirred at room temperature for 48 h.

¹H NMR(CDCl₃)δppm 6.74(1H，br s)，5.70(1H，br s)，4.32(2H，q，J＝7.4Hz)，3.54-3.47(2H，m)，3.44(2H，q，J＝7.6Hz)，3.12(2H，d，J＝4Hz)，1.25(6H，s)，1.20(3H，t，J＝7.4Hz)，1.19(3H，t，J＝7.6Hz)；

MS(ESI)m/z 255(M+1).

(d)1- (2-ethoxy-2-methylpropyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

3- (2-methoxy-2-methyl) -propylamino-1H-pyrrole-2 carboxylic acid ethyl ester (0.200g, 0.79mmol) was dissolved in CH at room temperature under nitrogen₂Cl₂(2 mL). Ethoxycarbonyl isothiocyanate (0.12mL, 1.02mmol) was added dropwise, followed by stirring the reaction mixture at room temperature overnight. The solvent was evaporated, sodium ethoxide (1M ethanol solution, 0.94mL, 0.94mmol) was added, and the reaction was heated to 40 ℃ for 48 h. Water (2mL) was added, followed by pH adjustment to neutral pH with 2M HCl. The precipitate was collected by filtration and purified by preparative HPLC to give the title compound (0.12g, 6% yield).

¹H NMR(DMSO-d₆)δppm 12.22(1H，br s)，7.30(1H，d，J＝2.8Hz)，6.35(1H，d，J＝3Hz)，4.60(2H，br s)，3.40-3.34(3H，m)，1.22(6H，s)，1.04(3H，t，J＝7.0Hz)；

MS(ESI)m/z 267(M+1).

Example 12

1- (piperidin-4-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)4- [ (2- (ethoxycarbonyl) -1H-pyrrol-3-ylamino) -methyl ] piperidine-1-carboxylic acid tert-butyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.68g, 4.4mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (P.C. Ting et al, Bioorganic & Medicinal Chemistry Letters, 2001, 11, 491-494) (0.98g, 4.6mmol), the title compound was prepared according to general procedure A (0.156g, 10%).

¹H NMR(DMSO-d₆)δppm 10.70(1H，br s)，6.74(1H，br s)，5.65(1H，br s)，4.19(2H，q，J＝7.2Hz)，3.95(2H，d，J＝12.0Hz)，2.97(2H，t，J＝6.0Hz)，2.65(2H，brs)，1.66(2H，d，J＝12.0Hz)，1.39(9H，s)，1.26(3H，t，J＝7.2Hz)，1.07-0.95(2H，m)；

MS(ESI)m/z 352(M+1).

(b)1- (piperidin-4-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Will ethoxyCarbonyl isothiocyanate (0.058g, 0.44mmol) was added to stirred 4- [ (2- (ethoxycarbonyl) -1H-pyrrol-3-ylamino) -methyl]Piperidine-1-carboxylic acid tert-butyl ester (0.156g, 0.44mmol) in CH₂Cl₂(2mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue taken up in ethanol (1mL) containing sodium (0.015g, 0.66 mmol). The resulting mixture was heated in a microwave reactor at 120 ℃ for 10 minutes. 6M HCl (0.5mL) was added and the reaction mixture was heated again in a microwave at 100 ℃ for 3 minutes. The pH was adjusted to neutral pH with 2M HCl, followed by vacuum concentration of the solution. The crude product was purified by preparative HPLC to give the title compound as a white solid (0.038g, 14%).

¹H NMR(DMSO-d₆)δppm 7.36(1H，d，J＝2.8Hz)，6.33(1H，d，J＝2.8Hz)，4.27(2H，br s)，2.95(2H，d，J＝12.0Hz)，2.40(2H，t，J＝10.4Hz)，2.25-2.15(1H，m)，1.50(2H，d，J＝10.8Hz)，1.37-1.20(2H，m)；

¹³C NMR(DMSO-d₆)ppm 173.2，152.9，137.6，128.1，114.0，97.5，55.2，45.5，34.7，30.0；

MS(ESI)m/z 265(M+1).

Example 13

1- [ (1-methylpiperidin-3-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

1-piperidin-3-ylmethyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ]]Pyrimidin-4-one (example 7) (0.092g, 0.35mmol) was dissolved in methanol (2mL) followed by addition of formic acid (37% aqueous solution, 0.059mL, 0.7 mmol). After stirring at room temperature for 5 minutes, a precipitate formed. Adding NaCNBH₃(0.026g, 0.42mmol), and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residual solid was purified by preparative HPLC to give the title compound as a white solid (0.022g, 22%).

¹H NMR(DMSO-d₆)δppm 12.22(1H，br s)，7.36(1H，d，J＝2.8Hz)，6.33(1H，s)，4.27(2H，br s)，2.61-2.5(1H，m)，2.36-2.30(1H，m)，2.09(3H，s)，1.93-1.82(3H，m)，1.65-1.52(2H，m)，1.44-1.32(1H，m)，1.16-1.07(1H，m)；

¹³C NMR(DMSO-d₆)δppm 173.2，152.9，137.6，128.1，114.0，97.3，59.2，56.0，53.3，46.7，34.9，27.7，24.7；

MS(ESI)m/z 279(M+1).

Example 14

1- [ 2-hydroxy-2- (4-methoxyphenyl) ethyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a) { [ tert-butyl (dimethyl) silyl ] oxy } (4-methoxyphenyl) acetic acid methyl ester

TBDMSCl (1.5g, 9.94mmol) and imidazole (1.0g, 14.6mmol) were added to a solution of methyl hydroxy- (4-methoxyphenyl) acetate (Teodozyj Kolasa et al, J.Org.chem., 1987, 22, 4978-4984) (1.3g, 6.62mmol) in DMF (8mL) and the mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried (MgSO)₄) Filtered and concentrated to give the title compound (2.0g, 97%).

¹H NMR(CDCl₃)δppm 7.39(2H，d，J＝8.8Hz)，6.88(2H，d，J＝8.8Hz)，5.19(1H，s)，3.81(3H，s)，3.69(3H，s)，0.92(9H，s)，0.11(3H，s)，0.03(3H，s).

(b) { [ tert-butyl (dimethyl) silyl ] oxy } (4-methoxyphenyl) acetaldehyde

Will { [ tert-butyl (dimethyl) silyl group { []Methyl oxy } (4-methoxyphenyl) acetate (0.5g, 1.61mmol) was dissolved in toluene (10mL) and then cooled to-78 ℃ under nitrogen. DIBAL (1.0M in toluene, 1.9mL, 1.93mmol) was added slowly and the mixture was stirred at-78 ℃ for 1 h. The reaction mixture was poured onto ice (20g) and CHCl₃(20 mL). The mixture was stirred at room temperature for 30 minutes. Separating the layers, using CHCl for the aqueous phase₃And (4) extracting. The organic phase was washed with brine and dried (MgSO)₄) Filtered and concentrated to give 99% (0.45g) of the title compound. The product was used directly in the next step without further purification.

¹H NMR(CDCl₃)δppm 7.40-7.38(2H，m)，6.89-6.87(2H，m)，5.19(1H，s)，3.81(3H，s)，0.92(9H，s)，0.11(3H，s)，0.03(3H，s).

(c)3- { [2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- (4-methoxyphenyl) ethyl ] amino } -1H-pyrrole-2-carboxylic acid ethyl ester

Using ethyl 3-amino-1H-pyrrole-2-carboxylate (0.16g, 1.07mmol) and { [ tert-butyl (dimethyl) silyl ] oxy } (4-methoxyphenyl) acetaldehyde (0.3g, 1.07mmol), the title compound was prepared according to general method A (0.13g, 19%).

MS(ESI)m/z 417(M-1).

(d)1- [2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- (4-methoxyphenyl) ethyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Using ethyl 3- { [2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- (4-methoxyphenyl) ethyl ] amino } -1H-pyrrole-2-carboxylate (0.13g, 0.31mmol) and ethoxycarbonyl isothiocyanate (0.042mL, 0.37mmol), the title compound (0.07g, 90%) was prepared according to general method B.

¹H NMR(DMSO-d₆)δppm 12.28-12.23(2H，m)，7.42(2H，d，J＝8.6Hz)，7.34-7.33(1H，m)，6.96(2H，d，J＝8.6Hz)，6.33(1H，br s)，5.53-5.50(1H，m)，4.57(1H，br s)，4.15(1H，br s)，3.76(3H，s)，0.61(9H，s)，0.31(3H，s)，0.39(3H，s)；

MS(ESI)m/z 432(M+1).

(e)1- [ 2-hydroxy-2- (4-methoxyphenyl) ethyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Tetra-n-butylammonium fluoride (1M in THF, 1.27mL, 1.27mmol) was added to the solution at 1- [2- { [ tert-butyl (dimethyl) silyl]Oxy } -2- (4-methoxyphenyl) ethyl]-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d]Pyrimidin-4-one (0.065g, 0.152mmol) in THF (8 mL). The mixture was stirred at 50 ℃ overnight. Ethyl acetate was added and the organic phase was washed with water and brine and dried (MgSO)₄) Filtered and concentrated. This crude material was purified by preparative HPLC to give the title compound as a solid (0.018g, 37%).

¹H NMR(DMSO-d₆)δppm 12.20(2H，br s)，7.40(2H，d，J＝8.5Hz)，7.29(1H，d，J＝2.8Hz)，6.91(2H，d，J＝8.8Hz)，6.27(1H，d，J＝2.8Hz)，5.42-5.41(1H，m)，5.28-5.24(1H，m)，4.62-4.58(1H，m)，4.19-4.16(1H，m)，3.74(3H，s)；

MS(ESI)m/z 316(M-1).

Example 15

1- (2-methoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (2-methoxybenzyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Starting from ethyl 3-amino-1H-pyrrole-2-carboxylate (0.350g, 2.27mmol) and o-anisaldehyde (0.34mL, 2.27mmol), the title compound was obtained as a white solid (quantitative yield) using general method a, but with the following changes. After stirring overnight, the reaction mixture was evaporated. Absorbing the crude solid into CHCl₃The crude product was used in the next step without further purification by filtration and evaporation of the solvent in vacuo.

MS(ESI)m/z 275(M+1).

(b)1- (2-methoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Starting from ethyl 3- [ (2-methoxybenzyl) amino ] -1H-pyrrole-2-carboxylate (0.622g, 2.27mmol) and ethoxycarbonyl isothiocyanate (0.26mL, 2.27mmol), using general method B, the title compound was obtained as a solid (16% yield), but with the following changes. The crude intermediate product was dissolved in 1M NaOEt (2.27mL, 2.27mmol) and stirred at 80 ℃ for 3 h.

¹H NMR(DMSO-d₆)δppm 12.36(2H，br s)，7.27(1H，d，J＝2.8Hz)，7.27-7.21(1H，m)，7.06(1H，d，J＝8.1Hz)，6.82(1H，t，J＝7.3Hz)，6.79-6.75(1H，m)，5.96(1H，d，J＝2.8Hz)，5.61(2H，s)，3.89(3H，s)；

MS(ESI)m/z 288(M+1).

Example 16

1- (3-methoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (3-methoxybenzyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Using ethyl 3-amino-1H-pyrrole-2-carboxylate (0.50g, 3.24mmol) and m-anisaldehyde (0.47mL, 3.89mmol), the title compound was obtained as an oil (57%, 0.508g) by general method A.

¹H NMR(DMSO-d₆)δppm 10.73(1H，br s)，7.24-7.20(1H，m)，6.90-6.86(1H，m)，6.80-6.77(1H，m)，6.71-6.69(1H，m)，5.75(1H，br s)，5.59-5.58(1H，m)，4.46(1H，d，J＝5.8Hz)，4.25(2H，d，J＝6.3Hz)，4.19(2H，q，J＝7.1Hz)，3.72(3H，s)，1.26(3H，t，J＝7.1Hz)；

MS(ESI)m/z 275(M+1).

(b)1- (3-methoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Using ethyl 3- [ (3-methoxybenzyl) amino ] -1H-pyrrole-2-carboxylate (0.494g, 1.80mmol) and ethoxycarbonyl isothiocyanate (0.20mL, 1.18mmol), the title compound was obtained as a solid (3% yield, 0.014g) according to general method B.

¹H NMR(DMSO-d₆)δppm 12.41-12.34(2H，m)，7.29(1H，d，J＝2.7Hz)，7.23(1H，t，J＝8.0Hz)，6.93-6.91(1H，m)，6.86(1H，d，J＝7.8Hz)，6.83(1H，dd，J＝8.2，2.4Hz)，6.14(1H，d，J＝2.8Hz)，5.67(2H，s)，3.71(3H，s)；

MS(ESI)m/z 288(M+1).

Example 17

1- (2, 4-dimethoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (2, 4-Dimethoxybenzyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Using ethyl 3-amino-1H-pyrrole-2-carboxylate (0.50g, 3.24mmol) and 2, 4-dimethoxybenzaldehyde (0.47mL, 3.89mmol), the title compound was obtained as an oil (85% yield, 0.838g) according to general procedure A.

¹H NMR(DMSO-d₆)δppm 10.69(1H，br s)，7.14(1H，d，J＝8.3Hz)，6.71(1H，t，J＝3.0Hz)，6.54(1H，d，J＝2.3Hz)，6.44(1H，dd，J＝8.3Hz)，5.66(1H，t，J＝2.5Hz)，5.59(1H，br s)，4.20-4.13(4H，m)，3.80(3H，s)，3.73(3H，s)，1.25(3H，t，J＝7.1Hz)；

¹³C NMR(DMSO-d₆)δppm 160.9，159.6，158.0，129.2，124.0，120.0，104.2，98.3，95.5，58.3，55.4，55.1，43.6，14.7；

MS(ESI)m/z 303(M-1).

(b)1- (2, 4-dimethoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Using ethyl 3- [ (2, 4-dimethoxybenzyl) amino ] -1H-pyrrole-2-carboxylate (0.828g, 2.72mmol) and ethoxycarbonyl isothiocyanate (0.31mL, 2.72mmol), following general method B, the title compound was obtained as a solid (14%, 0.118 g).

¹H NMR(DMSO-d₆)δppm 12.41(1H，br s)，12.27(1H，s)，7.27(1H，t，J＝2.9Hz)，6.77(1H，d，J＝8.3Hz)，6.61(1H，d，J＝2.3Hz)，6.41(1H，dd，J＝8.5，2.4Hz)，5.95(1H，t，J＝2.3Hz)，5.54(2H，s)，3.88(3H，s)，3.72(3H，s)；

MS(ESI)m/z 318(M+1).

Example 18

1- [ (3-Chloropyridin-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- { [ (3-Chloropyridin-2-yl) methyl ] amino } -1H-pyrrole-2-carboxylic acid ethyl ester

Using ethyl 3-amino-1H-pyrrole-2-carboxylate (0.231g, 1.50mmol) and 3-chloropyridine-2-carbaldehyde (Nadeem Iqbal et al, J.Med.chem.1998, 41, 1827-containing 1837) (0.212g, 1.50mmol), the title compound was obtained as a solid (91% yield, 0.225g) according to general procedure A.

¹H NMR(DMSO-d₆)δppm 10.81(1H，br s)，8.53-8.51(1H，m)，7.94-7.92(1H，m)，7.40-7.36(1H，m)，6.77-6.76(1H，m)，5.74-5.73(1H，m)，4.43(1H，d，J＝5.5Hz)，4.20-4.15(2H，m)，1.30-1.27(3H，m)；

MS(ESI)m/z 280(M+1).

(b)1- [ (3-Chloropyridin-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Using ethyl 3- { [ (3-chloropyridin-2-yl) methyl ] amino } -1H-pyrrole-2-carboxylate (0.215g, 0.77mmol) and ethoxycarbonyl isothiocyanate (0.09mL, 0.77mmol), following general procedure B, the title compound was obtained as a solid (5% yield, 0.011 g).

¹H NMR(DMSO-d₆)δppm 12.26(1H，br s)，8.32-8.30(1H，m)，7.96-7.93(1H，m)，7.34-7.30(1H，m)，7.28(1H，d，J＝3.0Hz)，6.16(1H，d，J＝2.8Hz)，5.80(2H，s)；

MS(ESI)m/z 293(M+1).

Example 19

1- { [3- (2-ethoxyethoxy) pyridin-2-yl ] methyl } -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- (2-ethoxyethoxy) -2-methylpyridine

Potassium carbonate (2.20g, 15.9mmol) was added to a stirred solution of 3-hydroxy-2-methylpyridine (1.45g, 13.3mmol) and 2-chloroethylethyl ether (1.75mL, 15.9mmol) in DMF (7mL) and the mixture was stirred at 70 ℃ overnight. The reaction was incomplete and additional 2-chloroethylether (1 eq) and potassium carbonate (1 eq) were added, followed by stirring the mixture at 85 ℃ for 8 h. Water and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (MgSO₄) Filtering, and concentrating. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 50% ethyl acetate) to yield 1.80g (75%) of the title compound.

¹H NMR(DMSO-d₆)δppm 8.03-7.99(1H，m)，7.33-7.31(1H，m)，7.18-7.14(1H，m)，4.13-4.11(2H，m)，3.73-3.71(2H，m)，3.52(2H，q，J＝7.0Hz)，2.35(3H，s)，1.12(3H，t，J＝6.9Hz)；

MS(ESI)m/z 182(M+1).

(b)3- (2-ethoxyethoxy) pyridine-2-carbaldehyde

A mixture of 3- (2-ethoxyethoxy) -2-methylpyridine (0.506g, 2.79mmol) and selenium dioxide (0.31g, 2.79mmol) in 1, 4-dioxane (10mL) was heated at 75 ℃ overnight. After cooling to room temperature, the mixture was filtered and the resulting solid was washed with ethyl acetate. The solvent was removed in vacuo. The reaction was not complete and the solid was dissolved in 1, 4-dioxane (15mL) and selenium dioxide (0.31g, 2.79mmol) was added. The mixture was heated at 110 ℃ overnight. Ethyl acetate (10mL) was added, and the mixture was filtered. The black solid was washed with ethyl acetate, and the filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate) to yield 0.21g (39%) of the title compound.

¹H NMR(DMSO-d₆)δppm 10.23(1H，s)，8.35(1H，d，J＝4.3Hz)，7.77(1H，d，J＝8.6Hz)，7.66-7.62(1H，m)，4.29(2H，m)，3.75(2H，m)，3.55-3.49(2H，m)，1.14-1.09(3H，m).

(c)3- ({ [3- (2-ethoxyethoxy) pyridin-2-yl ] methyl } amino) -1H-pyrrole-2-carboxylic acid ethyl ester

Following general procedure A, using 3- (2-ethoxyethoxy) pyridine-2-carbaldehyde (0.21g, 1.08mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (0.11g, 0.717mmol), the title compound was prepared (0.17g, 73%).

¹H NMR(DMSO-d₆)δppm 10.76(1H，s)，8.13-8.12(1H，m)，7.46-7.44(1H，m)，7.30-7.28(1H，m)，6.76-6.75(1H，m)，6.29(1H，br s)，5.71-5.70(1H，m)，4.32-4.31(2H，m)，4.22-4.17(4H，m)，3.77-3.74(2H，m)，3.57-3.51(2H，m)，1.30(3H，t，J＝7.0Hz)，1.15-1.12(3H，m)；

MS(ESI)m/z 334(M+1).

(d)1- { [3- (2-ethoxyethoxy) pyridin-2-yl ] methyl } -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Using ethyl 3- ({ [3- (2-ethoxyethoxy) pyridin-2-yl ] methyl } amino) -1H-pyrrole-2-carboxylate (0.17g, 0.52mmol) and ethoxycarbonyl isothiocyanate (0.07mL, 0.62mmol), the title compound (0.051g, 28%) was prepared according to general method B.

¹H NMR(DMSO-d₆)δppm 12.32-12.19(2H，m)，7.92(1H，d，J＝4.0Hz)，7.47(1H，d，J＝7.8Hz)，7.32-7.14(2H，m)，5.98(1H，d，J＝2.8Hz)，5.73(2H，s)，4.26-4.23(2H，m)，3.78-3.76(2H，m)，3.55(2H，q，J＝7.1Hz)，1.14(3H，t，J＝6.9Hz)；

¹³C NMR(DMSO-d₆)δ173.5，152.7，152.4，143.7，140.3，137.8，127.7，123.0，119.0，113.5，96.8，68.2，65.8，49.8，15.1；

MS(ESI)m/z 347(M+1).

Example 20

1- [ (6-oxo-1, 6-dihydropyridin-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- { [ (6-oxo-1, 6-dihydropyridin-2-yl) methyl ] amino } -1H-pyrrole-2-carboxylic acid ethyl ester

6-oxo-1, 6-dihydropyridine-2-carbaldehyde (WO 2002/006272) (0.31g, 2.5mmol) was dissolved in EtOH (10 mL). Ethyl 3-amino-1H-pyrrole-2-carboxylate (0.19g, 1.3mmol) was added followed by HOAc (0.14mL, 2.5 mmol). The mixture was stirred at room temperature for 75 minutes, then NaCNBH was added₃(0.16g, 2.5 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the crude product was purified by flash column Chromatography (CH)₂Cl₂A methanol gradient; 0 to 10% methanol) to yield 0.288g (85%) of the title product as an oil which crystallizes on standing.

¹H NMR(DMSO-d₆)δppm 11.57(1H，br s)，10.77(1H，br s)，7.34-7.30(1H，m)，6.71-6.70(1H，m)，6.16-6.13(2H，m)，5.98(1H，br s)，5.75(1H，s)，5.64-5.63(1H，m)，4.20(2H，q，J＝7.1Hz)，4.09-4.08(2H，m)，1.27(3H，t，J＝7.1Hz)；

MS(ESI)m/z 262(M+1).

(b)1- [ (6-oxo-1, 6-dihydropyridin-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Will dissolve in CH₂Cl₂Benzoyl isothiocyanate (0.27g, 1.6mmol) in (3mL) was added to 3- { [ (6-oxo-1, 6-dihydropyridin-2-yl) methyl]Amino } -1H-pyrrole-2-carboxylic acid ethyl ester (0.25g, 0.96mmol) in CH₂Cl₂(7mL) in solution. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo, the residue dissolved in methanol (15mL) and potassium carbonate (0.50g, 3.6mmol) added. The reaction mixture was stirred at 50 ℃ for 6.5 h. After cooling to room temperature, 1M HCl was added dropwise until a neutral pH was obtained. The resulting precipitate was collected, washed with methanol and purified by preparative HPLC to give the title compound (0.097g, 37%) as a solid.

¹H NMR(DMSO-d₆)δppm 12.46-12.38(2H，m)，11.69(1H，br s)，7.34-7.29(2H，m)，6.23(2H，s)，5.75(1H，br s)，5.49(2H，s)；

¹³C NMR(DMSO-d₆)δ173.6，162.7，152.5，140.6，136.7，128.0，113.6，96.6；

MS(ESI)m/z 275(M+1).

Example 21

1- (1H-indol-3-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (1H-indol-3-ylmethyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.075g, 0.49mmol), indole-3-carbaldehyde (0.085g, 0.58mmol), NaCNBH₃A reaction mixture of (0.031g, 0.49mmol) and HOAc (0.056mL, 0.97mmol) in methanol (3mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and the crude product-mixture was used in the next step without further purification.

MS(ESI)m/z 284(M+1).

(b)1- (1H-indol-3-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Reacting 3- [ (1H-indol-3-ylmethyl) amino](ii) A crude mixture of ethyl (max. 0.49mmol) of (E) -1H-pyrrole-2-carboxylate was added to CH₂Cl₂(5 mL). A few drops of methanol were added to increase dissolution. Benzoyl isothiocyanate (0.072g, 0.53mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. Ammonia (7N in methanol, 3mL) was added and the mixture was heated at 80 ℃ for 2 h. The mixture was concentrated and purified by preparative HPLC to give the title compound (0.030g, 21%) as a solid.

¹H NMR(DMSO-d₆)δppm 12.13(2H，br s)，11.08(1H，s)，7.87(1H，d，J＝8.1Hz)，7.54-747(1H，m)，7.38-7.30(1H，m)，7.29-7.25(1H，m)，7.10-7.03(1H，m)，7.01-6.93(1H，m)，6.33(1H，d，J＝2.8Hz)，5.88(2H，s)；

¹³C NMR(DMSO-d₆)δppm 173.14，152.86，136.71，136.42，128.02，126.45，125.83，121.61，119.67，119.16，114.36，111.95，109.51，97.74，46.31；

MS(ESI)m/z 295(M-1).

Example 22

1- (1H-benzimidazol-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (1H-Benzimidazol-2-ylmethyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Ethyl 3-amino-1H-pyrrole-2-carboxylate (0.77g, 4.99mmol), 1H-benzimidazole-2-carbaldehyde (0.88g, 5.99mmol) and NaCNBH₃A reaction mixture of (0.031g, 4.99mmol) and HOAc (0.57mL, 9.99mmol) in methanol (15mL) was stirred at room temperature overnight. The mixture was then heated at 50 ℃ for 5 h. Cooled to room temperature and evaporated in vacuo. The residue was dissolved in ethyl acetate, followed by washing with water. The aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried (MgSO)₄) And concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate (1: 0 to 0: 1) to yield 1.15g (81%) of the title compound.

¹H NMR(DMSO-d₆)δppm 12.27(1H，s)，10.85(1H，s)，7.63-7.37(2H，m)，7.17-7.08(2H，m)，6.71(1H，t，J＝3.0Hz)，5.99(1H，br s)，5.60(1H，t，J＝2.7Hz)，4.48(2H，d，J＝5.8Hz)，4.22(2H，q，J＝7.1Hz)，1.29(3H，t，J＝7.1Hz)；

MS(ESI)m/z 285(M+1).

(b)1- (1H-benzimidazol-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Reacting 3- [ (1H-benzimidazol-2-ylmethyl) amino group]-1H-pyrrole-2-carboxylic acid ethyl ester (0.33g, 1.16mmol) to CH₂Cl₂To (3mL), methanol was added until a clear solution was obtained. The solution was stirred at room temperature for 1 h. Benzoyl isothiocyanate (0.73mL, 0.46mmol) was added, and after stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was dissolved in ammonia (7N in methanol, 7mL) and the mixture was heated at 80 ℃ for 2h in a sealed steel vessel. After cooling to room temperature, the precipitated product is filtered off and washed with methanol, diethyl ether and ethyl acetate to yield 0.23g (66%) of the title compound in the form of a white solid.

¹H NMR(DMSO-d₆)δppm 12.27(3H，br s)，7.61-7.37(2H，m)，7.43-7.27(1H，m)，7.18-7.07(2H，m)，6.19(1H，d，J＝2.8Hz)，5.89(2H，s)；

MS(ESI)m/z 298(M+1).

Example 23

1- [ (5-chloro-1H-indol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Adding 5-chloro-1H-indole-2-carbaldehyde (0.15g, 0.76mmol) and NaCNBH₃(0.040g, 0.63mmol) and Et₃N (0.088mL, 0.63mmol) was added to a stirred solution of ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (0.12g, 0.63mmol) in methanol (3 mL). The resulting mixture was stirred at room temperature overnight. Mixing the reactionThe material was heated to 50 ℃. Adding additional NaCNBH₃(0.5 eq.) the mixture was then stirred at 50 ℃ for 3 h. A few drops of HOAc were added and after 1h the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH₂Cl₂(2mL) and methanol (2 mL). Benzoyl isothiocyanate (0.093mL, 0.69mmol) was added and after stirring at room temperature for 1h, the mixture was concentrated in vacuo. The residue was dissolved in ammonia (7N in methanol, 3mL) and heated at 80 ℃ for 2 h. The precipitated product was filtered and washed with methanol and diethyl ether, followed by purification by preparative HPLC to yield 0.063g (30%) of the title compound as a solid.

¹H NMR(DMSO-d₆)δppm 12.41(2H，br s)，11.51-11.04(1H，m)，7.51-7.46(1H，m)，7.40-7.33(1H，m)，7.33-7.30(1H，m)，7.07-6.99(1H，m)，6.34-6.27(2H，m)，5.87-5.80(2H，m)；

¹³C NMR(DMSO-d₆)δppm 173.65，153.05，136.84，135.98，134.74，129.28，128.27，123.97，121.26，119.19，114.24，113.25，100.33，97.17，47.31；

MS(ESI)m/z 331(M+1).

Example 24

1- [ (5-fluoro-1H-indol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.12g, 0.63mmol), 5-fluoro-1H-indole-2-carbaldehyde (0.12g, 0.76mmol), NaCNBH₃(0.040g, 0.63mmol, +0.5 eq.), Et₃N (0.088mL, 0.63mmol) and benzoyl isothiocyanate (0.093mL, 0.69mmol) were used in the general manner of example 23 to give 19% (0.038g) of the title compound as a solid.

¹H NMR(DMSO-d₆)δppm 12.38(2H，br s)，11.10(1H，s)，7.41-7.26(2H，m)，7.25-7.11(1H，m)，6.96-6.79(1H，m)，6.37-6.24(2H，m)，5.83(2H，s)；

¹³C NMR(DMSO-d₆)δppm 173.61，173.81，158.46，156.17，152.94，136.85，136.10，132.94，128.39，128.30，114.19，112.71，112.61，109.54，109.28，104.75，104.51，100.82，100.78，97.23，47.35；

MS(ESI)m/z 315(M+1).

Example 25

1- (1H-indol-6-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.12g, 0.63mmol), 6-formylindole (0.11g, 0.76mmol), NaCNBH₃(0.040g, 0.63mmol, +0.5 eq.), Et₃N (0.088mL, 0.63mmol) and benzoyl isothiocyanate (0.093mL, 0.69mmol) were used in the general manner of example 23 to give 19% (0.035g) of the title compound as a solid.

¹H NMR(DMSO-d₆)δppm 12.37(2H，br s)，11.01(1H，s)，7.53-7.43(1H，m)，7.33(1H，s)，7.32-7.25(2H，m)，7.09-7.03(1H，m)，6.41-6.34(1H，m)，6.17(1H，d，J＝2.8Hz)，5.79(2H，s)；

¹³C NMR(DMSO-d₆)δppm 173.76，152.91，137.06，136.21，128.88，128.27，127.31，125.99，120.35，118.91，114.16，110.24，101.28，97.63，53.32；

MS(ESI)m/z 297(M+1).

Example 26

1- (1H-indol-5-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.12g, 0.63mmol), 5-formylindole (0.11g, 0.76mmol), NaCNBH₃(0.040g, 0.63mmol, +0.5 eq.), Et₃N(0.088mL，0.63mmol) and benzoyl isothiocyanate (0.093mL, 0.69mmol) were prepared in the general manner of example 23 to give 39% (0.073g) of the title compound as a solid.

¹H NMR(DMSO-d₆)δppm 12.33(2H，br s)，11.07(1H，s)，7.52(1H，s)，7.36-7.29(2H，m)，7.29-7.25(1H，m)，7.21-7.12(1H，m)，6.39-6.34(1H，m)，6.21-6.16(1H，m)，5.77(2H，s)；

¹³C NMR(DMSO-d₆)δppm 173.32，152.51，136.63，135.20，127.83，127.50，126.15，125.81，120.54，118.81，113.82，111.40，101.00，97.28，52.99；

MS(ESI)m/z 297(M+1).

Example 27

1- [ (5-fluoro-1H-indol-3-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.10g, 0.52mmol) was dissolved in methanol (4mL) followed by the addition of 5-fluoro-1H-indole-3-carbaldehyde (0.10g, 0.63mmol), NaCNBH₃(0.033g, 0.52mmol) and Et₃N (0.073g, 0.52 mmol). The resulting mixture was stirred at room temperature overnight. Adding additional NaCNBH₃(0.01g), the mixture was then heated at 50 ℃ for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Dissolving the crude intermediate in CH₂Cl₂(3mL) and methanol (1 mL). Benzoyl isothiocyanate (0.078mL, 0.58mmol) was added and after stirring at room temperature for 1h, the mixture was concentrated in vacuo. The residue was dissolved in ammonia (7N in methanol, 3mL) and heated at 80 ℃ for 2 h. After removal of the solvent in vacuo and purification by preparative HPLC, the title compound was obtained as a solid (0.035g, 21%).

¹H NMR(DMSO-d₆)δppm 12.29(2H，s)，11.38-11.08(1H，m)，7.76-7.68(1H，m)，7.65-7.59(1H，m)，7.37-7.30(1H，m)，7.30-7.27(1H，m)，6.96-6.86(1H，m)，6.37(1H，d，J＝2.8Hz)，5.84(2H，s)；

¹³C NMR(DMSO-d₆)δppm 173.09，158.27，155.97，152.81，136.59，133.11，128.14，128.09，126.70，126.59，114.37，113.01，112.91，109.95，109.91，109.86，109.68，104.70，104.46，97.74，46.10；

MS(ESI)m/z 315(M+1).

Example 28

1- (1H-imidazol-5-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (0.10g, 0.52mmol) was dissolved in methanol (4mL) followed by the addition of 4-formylimidazole (0.060g, 0.63mmol), NaCNBH₃(0.033g, 0.52mmol) and Et₃N (0.073g, 0.52 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in CH₂Cl₂(3mL) and methanol (1 mL). Benzoyl isothiocyanate (0.078mL, 0.58mmol) was added and after stirring at room temperature for 30 minutes, the mixture was concentrated in vacuo. The residue was dissolved in ammonia (7N in methanol, 3mL) and heated at 80 ℃ for 1 h. The precipitated product was filtered and washed with methanol followed by ether. The crude product was purified by preparative HPLC to yield 0.017g (13%) of the title compound in solid form.

OC 710/07

¹H NMR(DMSO-d₆)δppm 12.49-11.78(3H，m)，7.53(1H，s)，7.30(1H，d，J＝2.8Hz)，7.05(1H，s)，6.36(1H，d，J＝3.0Hz)，5.54(2H，s)；

MS(ESI)m/z 335(M+1).

Example 29

1- (1H-imidazol-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (1H-imidazol-2-ylmethyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

Mixing ethyl 3-amino-1H-pyrrole-2-carboxylate (0.2g, 1.30mmol), 2-imidazolecarboxaldehyde (0.15g, 1.53mmol) and NaCNBH₃A reaction mixture of (0.082g, 1.30mmol) and OHA Ac (0.15mL, 2.60mmol) in methanol (5mL) was stirred at room temperature for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. Washed with water and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO)₄) Filtering, and concentrating. The crude product was purified by flash column Chromatography (CH)₂Cl₂A methanol gradient; 0 to 20% methanol) to yield 0.30g (99%) of the title compound.

¹H NMR(DMSO-d₆)δppm 10.84(1H，br s)，7.03(2H，s)，6.79-6.64(1H，m)，5.76(1H，br s)，5.68-5.57(1H，m)，4.29(2H，d，J＝5.8Hz)，4.19(2H，q，J＝7.1Hz)，3.16(1H，s)，1.26(3H，t，J＝7.1Hz)；

MS(ESI)m/z 235(M+1).

(b)1- (1H-imidazol-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Benzoyl isothiocyanate (0.19mL, 1.41mmol) was added to the stirred 3- [ (1H-imidazol-2-ylmethyl) amino group]-1H-pyrrole-2-carboxylic acid ethyl ester (0.3g, 1.28mmol) in CH₂Cl₂(4mL) and methanol (2mL), then the mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo and the residue was dissolved in ammonia (7N in methanol, 7mL) and heated at 80 ℃ for 1 h. The crude product was filtered and purified by preparative HPLC to yield 0.110 (35%) of the title compound as a white solid.

¹H NMR(DMSO-d₆)δppm 12.46-12.14(2H，m)，11.81(1H，br s)，7.28(1H，d，J＝2.5Hz)，6.99(1H，s)，6.79(1H，s)，6.13(1H，d，J＝2.8Hz)，5.67(2H，s)；

MS(ESI)m/z 248(M+1).

Example 30

1- [ (5-chloro-1H-benzimidazol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- { [ (5-chloro-1H-benzimidazol-2-yl) methyl ] amino } -1H-pyrrole-2-carboxylic acid ethyl ester

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.077g, 0.5mmol), NaCNBH₃The reaction mixture of (0.057g, 0.9mmol) and HOAc (0.030g, 0.5mmol) in methanol (4mL) was stirred at room temperature for 5 minutes, followed by addition of 5-chloro-1H-benzimidazole-2-carbaldehyde (0.144g, 0.8mmol) and further CH₂Cl₂(1mL) and DMF (0.4 mL). The resulting mixture was stirred at room temperature under nitrogen for 16 h. Additional 5-chloro-1H-benzimidazole-2-carbaldehyde (0.030g) and NaCNBH were added₃(0.015g), the reaction mixture was then stirred for 4 h. The reaction mixture was neutralized with 2M NaOH and diluted with ethyl acetate. Extraction with water and drying of the organic layer (Na)₂SO₄) And concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate) to yield 0.074g (46%) of the title product.

¹H NMR(CDCl₃)δppm 8.28(1H，br s)，7.52(1H，s)，7.44(1H，d，J＝2.0Hz)，7.22(1H，d，J＝2.0Hz)，6.66(1H，s)，5.61(1H，t，J＝2.4Hz)，4.67(2H，s)，4.27(2H，m)，1.33(3H，t，J＝6.8Hz)；

MS(ESI)m/z 319(M+1).

(b)1- [ (5-chloro-1H-benzimidazol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Coupling 3- { [ (5-chloro-1H-benzimidazol-2-yl) methyl]Amino } -1H-pyrrole-2-carboxylic acid ethyl ester (0.074g, 0.23mmol) in CH₂Cl₂The solution was stirred for 5 minutes. DMF (0.2mL) was added to increase dissolution. Benzoyl isothiocyanate (0.045g, 0.28mmol) was added and the mixture was stirred for 1h, then concentrated in vacuo. The crude intermediate was taken up in ammonia (7N in methanol, 2mL) and stirred in a sealed vessel at 70 ℃ for 1.5 h. After the mixture is cooled to the room temperature,the precipitated product was collected by vacuum filtration, washed with diethyl ether and dried to yield 0.033g (43%) of the title product as a white solid.

¹H NMR(DMSO-d₆)δppm 12.33(3H，br s)，7.48(2H，m)，7.32(1H，s)，7.17(1H，d，J＝8.0Hz)，6.21(1H，s)，5.88(2H，s)；

MS(ESI)m/z 332(M+1).

Example 31

1- [ (4, 5-dimethyl-1H-benzimidazol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)4, 5-dimethyl-1H-benzimidazole-2-carbaldehyde

3, 4-xylene-1, 2-diamine (0.409g, 3.0mmol) and dichloroacetic acid (0.768g, 6.0mmol) in 4N HCl (10mL) were heated at 100 ℃ for two days. After cooling to room temperature, the mixture was filtered and the mother liquor was extracted with chloroform (4 times). The pH was adjusted to 12 using 2M NaOH and the resulting white precipitate was collected by filtration. This crude product was used in the next step without further purification.

MS(ESI)m/z 175(M+1).

(b)3- { [ (4, 5-dimethyl-1H-benzimidazol-2-yl) methyl ] amino } -1H-pyrrole-2-carboxylic acid ethyl ester

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.077g, 0.5mmol), 4, 5-dimethyl-1H-benzimidazole-2-carbaldehyde (0.130g, 0.75mmol) and HOAc (0.045g, 0.75mmol) were stirred in methanol (4mL), followed by the addition of NaCNBH₃. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was neutralized with 2M NaOH and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, followed by extraction with water. The organic layer is (Na)₂SO₄) Drying and concentrating. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate) to yield 0.043g (27%) of the title compound as a white solid as a tautomeric mixture (1: 1).

¹H NMR(DMSO-d₆)δppm 12.15(1H，s)，12.04(1H，s)，10.81(2H，s)，7.26(1H，d，J＝8.4Hz)，7.12(1H，d＝8.0Hz)，6.94(2H，d，J＝8.4Hz)，6.72(2H，s)，5.93(2H，s)，5.70(1H，s)，5.61(1H，s)，4.44(4H，dd，J＝9.2，6.0Hz)，4.22(4H，m)，2.44(3H，s)，2.37(3H，s)，2.29(6H，s)，1.30(6H，m)；

MS(ESI)m/z 313(M+1).

(c)1- [ (4, 5-dimethyl-1H-benzimidazol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Coupling 3- { [ (4, 5-dimethyl-1H-benzimidazol-2-yl) methyl]Amino } -1H-pyrrole-2-carboxylic acid ethyl ester (0.043g, 0.14mmol) dissolved in CH₂Cl₂(1.5mL) and benzoyl isothiocyanate (0.026g, 0.16mmol) was added. After stirring at room temperature for 1h, the solvent was removed in vacuo. The residue was dissolved in ammonia (7N in methanol) and heated to 70 ℃ in a sealed vessel for 2 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC to yield 0.008g (18%) of the title compound as a tautomeric mixture (1: 1).

¹H NMR(DMSO-d₆)δppm 12.18(2H，s)，11.98(2H，s)，7.28(2H，t，J＝2.4Hz)，7.19(1H，d，J＝8.0Hz)，7.08(1H，d，J＝8.0Hz)，6.92(2H，t，J＝8.0Hz)，6.14(2H，dd，J＝8.0，2.8Hz)，5.89(2H，s)，5.86(2H，s)，2.41(3H，s)，2.37(3H，s)，2.29(3H，s)，2.28(3H，s)；

MS(ESI)m/z 326(M+1).

Example 32

7-bromo-1-isobutyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a) 3-amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester

Ethyl 3-amino-1H-pyrrole-2-carboxylate (0.92g, 0.6mmol) was dissolved in HOAc (1mL) and bromine water (0.96g, 0.6mmol) was added. The mixture was stirred at room temperature for 1h, and the resulting white precipitate was collected by filtration and washed with diethyl ether. The title compound was obtained as a white solid (0.136g, 97%) which was used in the next step without further purification.

¹H NMR(DMSO-d₆)δppm 11.67(1H，s)，7.05(1H，s)，6.02(2H，br s)，4.25(2H，q，J＝7.2Hz)，1.28(3H，t，J＝7.2Hz)；

MS(ESI)m/z 233(M+1).

(b) 4-bromo-3- (isobutylamino) -1H-pyrrole-2-carboxylic acid ethyl ester

3-amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (0.136g, 0.58mmol) and isobutyraldehyde (0.067g, 0.93mmol) in CH₂Cl₂The solution in/MeOH (1: 1, 3mL) was stirred at room temperature for 2 h. Adding NaCNBH₃(0.065g, 1.04mmol) and HOAc (0.035g, 0.58mmol), the mixture was stirred at room temperature for 2h, then at 50 ℃ for 16 h. Additional isobutyraldehyde (1 eq.) and NaCNBH were added₃(0.5 equiv.) the mixture was then stirred at 50 ℃ overnight. The reaction mixture was taken up in 2M NaOH and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and then extracted with water. The organic layer is (Na)₂SO₄) Drying and concentrating. The crude product was purified by flash chromatography (heptane/ethyl acetate gradient; 0 to 30% ethyl acetate) to yield (0.040g, 24%) of the title compound as a white solid.

¹H NMR(CDCl₃)δppm 6.75(1H，s)，4.32(2H，q，J＝7.2Hz)，3.28(2H，d，J＝6.8Hz)，1.85(1H，m)，1.35(3H，t，J＝7.2Hz)，0.97(3H，d，J＝6.8Hz)；

MS(ESI)m/z 289(M+1).

(c) 7-bromo-1-isobutyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Benzoyl isothiocyanate (0.034g, 0.2mmol) was added to 4-bromo-3- (isobutylamino) -1H-pyrrole-ethyl 2-carboxylate (0.050g, 0.17mmol) in CH₂Cl₂The solution was then stirred at room temperature for 1h, then concentrated in vacuo. The residue was dissolved in ammonia (7M in methanol, 1.5mL) and stirred at 70 ℃ for 4 h. Additional ammonia (7M in methanol, 1mL) was added and the mixture was stirred at 80 ℃ for 5 h. The mixture was cooled to room temperature and the precipitated product was filtered off, washed with diethyl ether. After recrystallization from methanol, the title compound was obtained as a white solid (0.028g, 55%).

¹H NMR(DMSO-d₆)δppm 1257(2H，br s)，7.58(1H，s)，4.92(1H，br s)，4.42(1H，br s)，2.39(1H，m)，0.94(6H，d，J＝6.4Hz)；

MS(ESI)m/z 303(M+1).

Example 33

1- (3-chlorophenyl) -2-thio-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

(a)3- [ (3-chlorophenyl) amino ] -1H-pyrrole-2-carboxylic acid ethyl ester

3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.20g, 1.3mmol), 3-bromochlorobenzene (0.30g, 1.6mmol), Pd₂(dba)₃A mixture of (0.048g, 0.052mmol), rac-BINAP (0.048g, 0.078mmol) and cesium carbonate (0.59g, 1.8mmol) was heated at 100 ℃ in a sealed microwave vial under nitrogen overnight. Adding additional Pd₂(dba)₃(0.10g, 0.11mmol) and R, S-BINAP (0.11g, 0.18mmol), followed by stirring the reaction at 100 ℃ overnight. Additional 3-bromochlorobenzene (0.15g), Pd was added₂(dba)₃(0.098g) and R, S-BINAP (0.098g), followed by stirring the reaction at 100 ℃ for an additional three days. The reaction mixture was poured into ethanol, and the resulting solution was filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (heptane/ethyl acetate gradient; 0-30% ethyl acetate) to yield 0.052g (45%) of the title product.

¹H NMR(CDCl₃)δppm 8.42(1H，br s)，7.17(1H，t，J＝8.0Hz)，7.14(1H，t，J＝2.0Hz)，6.96-6.94(1H，m)，6.87-6.84(1H，m)，6.82(1H，t，J＝3.0Hz)，6.32(1H，t，J＝3.0Hz)，4.35(2H，q，J＝7.2Hz)，1.38(3H，t，J＝7.1Hz)；

MS(ESI)m/z 263(M-1).

(b)1- (3-chlorophenyl) -2-thio-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one

Benzoyl isothiocyanate (0.035g, 0.22mmol) in CH₂Cl₂(0.5mL) solution was added to 3- [ (3-chlorophenyl) amino]-ethyl 1H-pyrrole-2-carboxylate (0.052g, 0.20mmol) in CH₂Cl₂(0.5mL) in solution. The mixture was stirred at room temperature overnight. Over 6h, additional benzoyl isothiocyanate (0.035g +0.035g +0.035g) was added, and the reaction was stirred at 50 ℃ for an additional 3 days. The solvent was removed in vacuo and the residue was dissolved in ammonia (7N in methanol, 4 mL). The reaction was heated at 50 ℃ for 2 h. The crude product was purified by preparative chromatography to yield 0.009g (15%) of the title compound as a solid.

¹H NMR(DMSO-d₆)δppm 12.41(2H，br s)，7.60-7.57(3H，m)，7.41-7.37(1H，m)，7.25(1H，d，J＝2.8Hz)，5.36(1H，d，J＝2.8Hz)；

¹³C NMR(DMSO-d₆)δppm 173.8，152.8，141.5，137.9，133.5，131.，3129.0，128.6，127.7，127.3，113.3，96.7；

MS(ESI)m/z 278(M+1).

Screening

A method for determining MPO inhibitory activity is disclosed in patent application WO 02/090575. The compounds of the invention were tested for pharmacological activity in a screen in which the compounds were tested alone or in the presence of added tyrosine.

Determination of buffer: 20mM sodium phosphate/potassium phosphate buffer, pH 6.5, containing 10mM taurine and 100mM NaCl.

Developing agent: 2mM 3, 3 ', 5, 5' -Tetramethylbenzidine (TMB), 200. mu.M KI, 200mM acetate buffer, pH 5.4, containing 20% DMF.

To 10. mu.l of diluted compound assay buffer, 40. mu.l of human MPO (final concentration 2.5nM) with or without 20. mu.M tyrosine (final concentration 8. mu.M if present) was added and the mixture incubated for 10 minutes at ambient temperature. Followed by 50. mu. l H₂O₂(final concentration 100. mu.M) or assay buffer alone as a control. After incubation at ambient temperature for 10 minutes, the reaction was stopped by adding 10. mu.l of 0.2mg/ml catalase (final concentration 18. mu.g/ml). After the reaction mixture was left for another 5 minutes, 100. mu.l of TMB developer was added. After about 5 minutes, the amount of oxidized 3, 3 ', 5, 5' -tetramethylbenzidine formed was measured by absorption spectroscopy at about 650 nM. Determination of IC by Standard methods₅₀The value is obtained.

The compounds of examples 1-32 gave IC's of less than 60. mu.M when tested in at least the same mode of the above-described screen₅₀Values indicating that they are expected to exhibit useful therapeutic activity. Representative results are shown in the table below.

Compound (I)	MPO inhibition (in the presence of tyrosine) IC50μM
		Example 2	0.26
Example 5	0.22
		Example 11	1.1

Claims (25)

1. Compounds of formula (I) and pharmaceutically acceptable salts thereof,

wherein:

at least one of X and Y represents S, and the other represents O or S;

l represents a direct bond or C_1-7Alkylene, said alkylene optionally containing a member selected from the group consisting of O, S (O)_nAnd NR⁶Optionally containing one or two carbon-carbon double bonds, and optionally substituted with one or more substituents independently selected from OH, halogen, CN and NR⁴R⁵、C_1-6Alkyl and C_1-6Alkoxy optionally containing a carbonyl group adjacent to oxygen;

n represents an integer of 0, 1 or 2;

R¹represents hydrogen, or

i) A saturated or partially unsaturated 3-7 membered ring, optionally containing one or two heteroatoms independently selected from O, N and S, and optionally containing a carbonyl group, optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-7Alkyl radical, C_1-7Alkoxy, CN, CONR²R³、NR²COR³And COR³Said alkoxy group being optionally further substituted by C_1-6Alkoxy substituted, and the alkoxy optionally contains a carbonyl group adjacent to oxygen, and the alkyl is optionally further substituted with hydroxy or C_1-6Alkoxy substituted, and the alkyl optionally contains a carbonyl group at any position of the alkyl, or the alkoxy optionally contains a carbonyl group adjacent to oxygen or at any position of the alkyl; or

ii) an aromatic ring system selected from phenyl, biphenyl, naphthyl or a monocyclic or bicyclic heteroaromatic ring structure containing 1-3 heteroatoms independently selected from O, N and S, said aromatic ring system being optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-7Alkyl radical, C_1-7Alkoxy, CN, CONR²R³、NR²COR³And COR³(ii) a Said alkoxy group is optionally further substituted by C_1-6Alkoxy substituted, and the alkoxy optionally contains a carbonyl group adjacent to oxygen, and the alkyl is optionally further substituted with hydroxy or C_1-6Alkoxy substituted, and the alkyl group optionally contains a carbonyl group at any position of the alkyl group, orSaid alkoxy group optionally containing a carbonyl group adjacent to oxygen or at any position of the alkyl group;

R¹²represents hydrogen or halogen or carbon optionally substituted by one to three halogen atoms;

at each occurrence, R²、R³、R⁴、R⁵、R⁶、R⁹And R¹⁰Independently represent hydrogen, C_1-6Alkyl or C_1-6Alkoxy optionally containing a carbonyl group adjacent to oxygen, said alkyl being optionally further substituted by halogen, C_1-6Alkoxy, CHO, C_2-6Alkanoyl, OH, CONR⁷R⁸And NR⁷COR⁸Substitution;

or a group NR²R³、NR⁴R⁵And NR⁹R¹⁰Each independently represents a 5-7 membered saturated nitrogen heterocycle optionally containing one ring selected from O, S and NR¹¹And said ring is optionally further substituted by halogen, C_1-6Alkoxy, CHO, C_2-6Alkanoyl, OH, CONR⁷R⁸And NR⁷COR⁸Substitution;

at each occurrence, R⁷、R⁸And R¹¹Independently represent hydrogen or C_1-6Alkyl, or radicals NR⁷R⁸Represents a 5-to 7-membered saturated nitrogen heterocycle optionally containing one ring selected from O, S and NR¹¹The additional heteroatom of (a);

with the proviso that the compounds 1-beta-D-ribofuranosyl-2-oxopyrrolo [3,2-D ] pyrimidine-4 (3H, 5H) -thione, 1- (2, 3, 5-tri-O-benzoyl-1-beta-D-ribofuranosyl) -2-oxopyrrolo [3,2-D ] pyrimidine-4 (3H, 5H) -thione and 5, 7-dimercapto-1, 4, 6-triazaindene are excluded.

2. The compound of claim 1, wherein R is¹Represents hydrogen.

3. A compound according to claim 1 or 2, wherein X represents S and Y represents O, and pharmaceutically acceptable salts thereof.

4. A compound according to claim 1 or 2, wherein Y represents S and X represents O, and pharmaceutically acceptable salts thereof.

5. A compound according to any one of claims 1 to 4, wherein L is a direct bond or represents C, and pharmaceutically acceptable salts thereof_1-7An alkylene group; said alkylene group being optionally substituted by one or more C_1-6Alkoxy substitution.

6. A compound according to any one of claims 1 to 4, wherein L represents C, and pharmaceutically acceptable salts thereof_1-3An alkylene group; said alkylene group being optionally substituted by one or more C_1-6Alkoxy substitution.

7. The compound of any one of claims 1-6, wherein R is¹Represents a saturated or partially unsaturated 3-to 7-membered ring, said ring optionally containing one or two heteroatoms independently selected from O, N and S, and optionally containing a carbonyl group; said ring being optionally substituted with one or more substituents independently selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, said alkoxy being optionally further substituted by C_1-6Alkoxy substitution.

8. The compound of any one of claims 1-6, wherein R is¹Represents an aromatic ring system selected from phenyl, biphenyl, naphthyl or a 5-or 6-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S, said aromatic ring being optionally substituted with one or more substituents independently selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, said alkoxy being optionally further substituted by C_1-6Alkoxy substitution.

9. A compound according to claim 1, wherein L represents optionally substituted C, and pharmaceutically acceptable salts thereof_1-3Alkylene and R¹Represents a saturated or partially unsaturated 3-7-membered ring, optionally containing one or two heteroatoms independently selected from O, N and S, and optionally containing a carbonyl group, said ring being optionally substituted with one or more substituents independently selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, said alkoxy being optionally further substituted by C_1-6Alkoxy substitution.

10. A compound according to claim 1, wherein L represents optionally substituted C, and pharmaceutically acceptable salts thereof_1-3Alkylene and R¹Represents an aromatic ring system selected from phenyl, biphenyl, naphthyl or a 5-or 6-membered heteroaromatic ring containing 1-3 heteroatoms independently selected from O, N and S, said aromatic ring being optionally substituted with one or more substituents independently selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, said alkoxy being optionally further substituted by C_1-6Alkoxy substitution.

11. The compound of claim 1 wherein X represents S, Y represents O, and L represents C, and pharmaceutically acceptable salts thereof_1-3Alkylene, and R¹Represents a phenyl group, and is represented by,

wherein said alkylene is optionally substituted with one or more substituents independently selected from OH, halogen, CN and NR⁴R⁵And C_1-6An alkoxy group;

said phenyl being optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-6Alkyl radical, C_1-6Alkoxy, CN, CONR²R³、NR²COR³And COR³(ii) a Said alkoxy group is optionally further substituted by C_1-6Alkoxy, and said alkyl is optionally further substituted withHydroxy or C_1-6Alkoxy substitution.

12. The compound of claim 1 wherein X represents S, Y represents O, and L represents optionally substituted C, and pharmaceutically acceptable salts thereof_1-3Alkylene, and R¹Represents an optionally substituted pyridyl group, wherein,

wherein said alkylene is optionally substituted with one or more substituents independently selected from OH, halogen, CN and NR⁴R⁵And C_1-6An alkoxy group;

the pyridyl is optionally substituted with one or more substituents independently selected from halogen, SO₂R⁹、SO₂NR⁹R¹⁰、OH、C_1-6Alkyl radical, C_1-6Alkoxy, CN, CONR²R³、NR²COR³And COR³(ii) a Said alkoxy group is optionally further substituted by C_1-6Alkoxy, and said alkyl is optionally further substituted by hydroxy or C_1-6Alkoxy substitution.

13. A compound of claim 1 wherein X represents S, Y represents O, L represents C, and pharmaceutically acceptable salts thereof_1-6Alkoxy-substituted C_1-3Alkylene, and R¹Represents hydrogen.

14. A compound, and pharmaceutically acceptable salts thereof, which compound is:

1-butyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1-isobutyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (pyridin-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2-fluoro-benzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [2- (2-methoxyethoxy) -3-propoxybenzyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (6-ethoxy-pyridin-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1-piperidin-3-ylmethyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1-butyl-4-thioxo-1, 3, 4, 5-tetrahydro-2H-pyrrolo [3,2-d ] pyrimidin-2-one;

1- (2-isopropoxyethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2-methoxy-2-methylpropyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2-ethoxy-2-methylpropyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (piperidin-4-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (1-methylpiperidin-3-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ 2-hydroxy-2- (4-methoxyphenyl) ethyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2-methoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (3-methoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (2, 4-dimethoxybenzyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (3-chloropyridin-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- { [3- (2-ethoxyethoxy) pyridin-2-yl ] methyl } -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (6-oxo-1, 6-dihydropyridin-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-indol-3-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-benzoimidazol-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (5-chloro-1H-indol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (5-fluoro-1H-indol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-indol-6-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-indol-5-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (5-fluoro-1H-indol-3-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-imidazol-5-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- (1H-imidazol-2-ylmethyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (5-chloro-1H-benzimidazol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

1- [ (4, 5-dimethyl-1H-benzimidazol-2-yl) methyl ] -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one;

7-bromo-1-isobutyl-2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one; and

1- (3-chlorophenyl) -2-thioxo-1, 2, 3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one.

15. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-14, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

16. Use of a compound of formula (I) as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition in which inhibition of the enzyme MPO is beneficial.

17. Use of a compound of formula (I) as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of neuroinflammatory disorders.

18. The use of claim 17, wherein the neuroinflammatory disorder is multiple sclerosis.

19. The use of claim 16, wherein the disease or condition is atherosclerosis.

20. The use according to claim 16, wherein the disease or disorder is COPD.

21. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the process comprises:

reacting compound (II) with compound C_1-6Alkoxycarbonyl isothiocyanate or reacting with phenylcarbonyl isothiocyanate,

(II) the compound is

Wherein R is¹、R¹²And L is as defined in claim 1, and R represents C_1-6Alkoxy or NH₂；

And

if desired, converting the resulting compound of formula (I) or another salt thereof into a pharmaceutically acceptable salt thereof; or converting the resulting compound of formula (I) into another compound of formula (I).

22. A compound of the formula or a pharmaceutically acceptable salt thereof,

23. a pharmaceutical composition comprising a compound of claim 22, or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

24. Use of a compound of claim 22, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a neuroinflammatory disorder.

25. Use of a compound of claim 22, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of parkinson's disease.