OA16813A - 2-Thiopyrimidinones. - Google Patents

Abstract

Myeloperoxidase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, cardiovascular conditions.

Description

2-THIOPYRIMIDINONES

BACKGROUND OF THE INVENTION

This invention relates to compounds that are myeloperoxidase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat for example, cardiovascular conditions including acute coronary syndrome. Myeloperoxidase (MPO) is a heme-containing enzyme belonging to the peroxidase superfamily. Examples of animal peroxidases are lactoperoxidase, thyroid peroxidase, éosinophile peroxidase and myeloperoxidase. Myeloperoxidase is présent 10 in primary granules of neutrophils and to a lesser extent in monocytes. It catalyzes the synthesis of hypochlorous acid from chloride and hydrogen peroxide. The hypochlorous acid formed is a powerful oxidant that reacts with a variety of cellular substrates including heme proteins, porphyrins, thiols, iron sulfur centers, nucléotides, DNA, unsaturated lipids, amines and amino acids.

In addition, MPO-catalyzed reactions and their products hâve been found to exhibit pro-atherogenic biological activity during the development of atherosclerosis and cardiovascular disease. For example, the myeloperoxidase plasma content is correlated with the appearance of cardiovascular disorders in patients suffering unstable angina pectoris. Myeloperoxidase has been reported to contribute to the development of 20 atherosclerosis by the oxidation of lipid and protein in LDL and HDL.

Furthermore, it has been observed that MPO-generated oxidants reduce the bioavailability of nitric oxide, an important vasodilator. Accordingly, high MPO plasma levels are inversely correlated with the success of therapy to establish reperfusion of occluded arteries. High MPO levels are also associated with decreased survival from 25 congestive heart failure. Additionally, it has been shown that MPO plays a rôle in plaque destabilization which leads to plaque rupture and myocardial infarction.

Therefore, MPO is thought to play a rôle in several processes that lead to cardiovascular disease including 1) impaired cholestérol trafficking and progession of the athe rose le rôtie plaque towards an unstable state , 2) destabilization of the atherosclerotic plaque and plaque rupture, 3) consumption of nitric oxide leading to impaired endothélial function and flow, and 4) pathological tissue damage post ischemia contributing to atrial fibrillation and adverse cardiac remodeling with left ventricular hypertrophy leading to congestive heart failure. As such inhibitors of MPO activity are proposed to offer significant therapeutic benefit in the prévention and treatment of cardiovascular disease.

Nevertheless, although MPO has been implicated extensively in the etiology and progression of cardiovascular disease, a biologically safe and non-toxic inhibitor of MPO has yet to be developed, Accordingiy, there remains a need for pharmaceutical agents that hâve myeloperoxidase inhibiting activity and are useful in the treatment, prévention or diminution of the manifestations of the maladies described herein.

SUMMARY OF THE INVENTION

The présent invention is directed to a compound of the Formula I, o

R²

Formula I or a pharmaceutically acceptable sait or prodrug thereof wherein

R¹ is a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said R¹ is optionally mono-, di-, or tri-substituted independently with cyano, halo, hydroxyl, amino, (CrC₄)alkyl, (CrC₄)alkoxy, (Ci-C₄)alkoxy(CrC₄)alkyl, hydroxy(C₂C4)alkoxy, carbamoyl(CrC4)alkoxy, amino(C2-C4)alkoxy, cyano(Ci-C₄)alkyl, mono-N- or di-N,N-(Ci-C4)alkylamino, aminocarbonyl, mono-N- or di-N,N(Ci-C4)alkylaminocarbonyl, (CrC₄)alkylthio, aminosulfonyl, (Ci-C₄)alkylsulfinyl, (Ci-C₄)alkyIsulfonyl, or mono-N- or di-N,N(Ci-C₄)alkylaminosulfonyl, wherein any of the (Ci-C₄)alkyl or (Ci-C₄)alkoxy may be optionally mono-, di- or tri-substituted with fluoro; or wherein R¹ is optionally substituted with a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen;

R² is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the carbons, other than the connecting carbon,

a. may be branched

b. may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur is optionally mono- or di-substîtuted with oxo,

c. may optionally be mono-, di- or tri-substituted independently with halo,

d. may optionally be mono-substituted with hydroxy, and

e. may optionally be mono-substituted with oxo, and wherein the carbon chain is optionally mono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;

wherein said Z is optionally mono-, di- or tri-substituted independently with halo, (CrC₆)alkyl, (CrC₆)alkylcarbonyl, aminothioxo, amino(CrCe)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or (C_rCe)alkoxy and wherein said (C_r Ce)alkyl or (Ci-Ce)alkoxy substituent is also optionally substituted with one to three halo, and wherein said (CrCeJalkyl or (C₂-Ce)alkoxy substituent is also optionally substituted with one to three hydroxy;

with the proviso that R¹ is not phenyl, and R² is not (CrCe)alkyl.

Yet another aspect of this invention is directed to a method for treating cardiovascular conditions in a mammal (including a human being either male or female) by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a phannaceutically acceptable sait of said compound or of said prodrug.

Also provided herein are compositions comprising a phannaceutically effective amount of one or more of the compounds described herein and a pharmaceutically acceptable carrier, vehicle, or diluent.

This invention is also directed to pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable sait of said compound or of said prodrug;

a second compound, said second compound being an angiotensin converting enzyme inhibitor, a HMG-CoA reductase inhibitor, a non-steroidal anti-inflammatory agent, a Factor Xa inhibitor or warfarin; and/or optionaliy a pharmaceutical carrier, vehicle, or diluent.

The présent invention is directed to a compound of the Formula IA,

Formula IA or a pharmaceutically acceptable sait or prodrug thereof wherein

R¹ is a five to six membered aromatic ring optionaliy having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionaliy having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said R¹ is optionaliy mono-, di-, or tri-substituted independently with cyano, halo, hydroxyl, amino, (Ci-C₄)alkyl, (CrC^alkoxy, (Ci-C4)alkoxy(Ci-C₄)alkyl, hydroxy(C2C4)alkoxy, carbamoyl(C_rC4)alkoxy, amino(C2-C4)alkoxy, cyano(Ci-C4)alkyl, (CiC4)alkylcarbonyloxy(Ci-C4)alkyl, amino(Ci-C4)alkylcarbonyloxy(Ci-C4)alkyl, (CiC4)alkylcarbonyloxy(Ci-C4)alkoxy, amino(Ci-C4)alkylcarbonyloxy(Ci-C4)alkoxy, monoN- or di-N,N-(Ci-C4)alkylamino, aminocarbonyl, mono-N- or di-N,N(CiC4)alkylaminocarbonyl, (Ci-C₄)alkylthio, aminosulfonyl, (Ci-C₄)alkylsulfinyl, (C_r C4)alkylsulfonyl, or mono-N- or di-N,N(Ci-C4)alkylaminosulfonyl, wherein any of the (CiC₄) alkyl or (C₁-C₄)alkoxy may be optionaliy mono-, di- or tri-substituted with fluoro; or wherein R¹ is optionaliy substituted with a five to six membered aromatic ring optionaliy having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen;

R² is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the carbons, other than the connecting carbon, a, may be branched

b. may optionally be replaced with one or two heteroatoms selected independently from oxygen and sulfur and may optionally be replaced with one to four nitrogens, wherein said sulfur is optionally mono- or di-substituted with oxo,

c. may optionally be mono-, di- or tri-substituted independently with halo,

d. may optionally be mono-substituted with hydroxy, and

e. may optionally be mono-substituted with oxo, and wherein the carbon chain is optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;

wherein said Z is optionally mono-, di- or tri-substituted independently with amino, halo, (Ci-Cejalkyl, (CrC₆)alkylcarbonyl, aminothioxo, amino(Cr

C_e)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or (Ci-Ce)alkoxy and wherein said (CrC₆)alkyl or (Ci-Ce)alkoxy substituent is also optionally substituted with one to three halo, and wherein said (Ci-Ce)alkyl or (C2-Ce)alkoxy substituent is also optionally substituted with one to three hydroxy;

with the proviso that R¹ is not unsubstituted phenyi, and R² is not unsubstituted(Ci25 Cejalkyl.

This invention is also directed to a method for treating cardiovascular events and conditions comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula IA or a prodrug thereof or a pharmaceutically acceptable sait of said compound or of said prodrug wherein the cardiovascular condition or event is heart failure, congestive heart failure, peripheral arterial disease, pulmonary hypertension, vasculitis, a primary or secondary myocardial infarction, ischemia, ischemia reperfusion injury, atrial fibrillation or coronary artery bypass graft surgery (CABG).

This invention is also directed to a method for treating a condition comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula IA or a prodrug thereof or a pharmaceutically acceptable sait of said compound or of said prodrug wherein the condition is diabètes, rénal insufficiency, dialysis, delayed graft fonction, transplant organ rejection or nephropathy caused by contrasting agents.

Also provided herein are compositions comprising a pharmaceutically effective amount of one or more of the Formula IA compounds described herein and a pharmaceutically acceptable carrier, vehicle, or diluent.

This invention is also directed to pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a Formula IA compound, a prodrug thereof, or a pharmaceutically acceptable sait of said compound or of said prodrug;

a second compound, said second compound being an angiotensin converting enzyme inhibitor, a HMG-CoA reductase inhibitor, a non-steroidal anti-inflammatory agent, a Factor Xa inhibitor or warfarin; and/or optionally a pharmaceutical carrier, vehicle, or diluent.

Ail patents and patent applications referred to herein are hereby incorporated by référencé.

Other features and advantages of this invention will be apparent from this spécification and the appendant ciaims which describe the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic x-ray powder diffraction pattern showing a crystalline form of Example 1 (Vertical Axis: Intensity (CPS); Horizontal Axis: Two thêta (degrees)).

FIG. 2 is a characteristic x-ray powder diffraction pattern showing a crystalline form of Example 2(Vertical Axis: Intensity (CPS); Horizontal Axis: Two thêta (degrees)).

DETAILED DESCRIPTION OF THE INVENTION

A preferred group of compounds, designated the A Group, contains those compounds having the Formula I as shown above wherein R¹ is phenyl, naphthyl, foranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolinyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; and wherein said R¹ is mono-, di-, or triΊ

substituted independently with cyano, (Ci-C₄)alkyl, (Ci-C₄)alkoxy, hydroxy(C₂C₄)alkoxy, trifluoro(Ci-C₄)alkyl, trifluoro(Ci-C₄)alkoxy or halo.

A group of compounds which is preferred among the A Group of compounds designated the B Group, contains those compounds wherein R^z is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the carbons, other than the connecting carbon,

a. may be branched

b. may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur is optionally mono- or di-substituted with oxo,

c. may optionally be mono-, di- or tri-substituted independently with halo,

d. may optionally be mono-substituted with hydroxy, and

e. may optionally be mono-substituted with oxo; or

R^z is furanyl(CrC4)alkyl, triazolyl(CrC4)alkyl, pyridînyl(Ci-C4)alkyl, pyrizinyl(Ci-C4)alkyl, pyridazinyl(Ci-C4)alkyl, pyrimidinyl(Ci-C4)alkyl, imidazolyl(Ci-C4)alkyl or pyrrolidinyi(CiC4)alkyl, said R² rings optionally mono-, di- or tri-substituted independently with (Cr C₄)alkyI, (Ci-C₄)alkoxy or halo.

A group of compounds which is preferred among the B Group of compounds designated the C Group, contains those compounds wherein R¹ is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; wherein said R¹ is mono-, di-, or trisubstituted independently with (CrC₄)alkyl, (CrC₄)alkoxy, hydroxy(C₂-C₄)alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and

R² is (CrC4)alkoxy(CrC4)alkyl, carboxy(Ci-C₄)alkyl, mono-or di-hydroxy(C2-C6)alkyl, amino(C₂-C₄)alkyl, diaminomethyleneamino(C2-C₄)alkyl, mono-N- or di-N,N(CiC₄)alkylamino(C₂-C₄)alkyl, (CrC₄)alkylcarbonyloxy(Ci-C₄)alkyl,, (Cr C₄)alkoxycarbonyl(Ci-C₄)alkyl, carbamoyl(Ci-C₄)alkyl, carbamoylamino(C₂-C₄)alkyl, mono-N- or di-N,N(Ci-C₄)alkylcarbamoyl(Ci-C₄)alkyl, amino(C₂-C₄)alkylcarbamoyl(CiC₄)alkyl, (Ci-C₄)alkylcarbonylamino(C₂-C₄)alkyl, amino(Ci-C₄)alkylcarbonylamino(C₂C₄)alkyl, (Ci-C₄)alkoxycarbonylamino(C2-C₄)alkyl, (CrC₄)alkylsulfonylamino(C₂C₄)alkyl, (Ci-C₄)alkylaminosulfonyl(Ci-C₄)alkyl, aminosulfonyl(Ci-C₄)alkyl, amino(C₃C₄)hydroxyalkyl or (C₁-C₄)alkylthioalkyl(C₁-C₄).

A group of compounds which is preferred among the C Group of compounds designated the D Group, contains those compounds wherein R¹ is phenyl and said R¹ is mono-, di-, or tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro; and

R² is diaminomethyleneamino(C2-C4)alkyl, carbamoyl(Ci-C4)alkyl, hydroxy(C₂-C4)alkyl, amino(C2-C4)alkylcarbamoyl(CrC4)alkyl, (Ci-C4)alkylcarbonylamino(C₂-C4)alkyl, amino(Ci-C4)alkylcarbonylamino(C2-C4)alkyl, amino(C3-C4)hydroxyalkyl or amino(C2C₄)alkyl.

A group of compounds which is preferred among the B Group of compounds 10 designated the E Group, contains those compounds wherein R¹ is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo(b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; wherein said R¹ is mono-, di-, or trisubstituted independently with (CrC^alkyl, (Ci-C4)alkoxy, hydroxy(C₂-C4)alkoxy, 15 cyano, trifluoromethyl, trifluoromethoxy or halo; and

R² is triazolyl(CrC4)alkyl, pyridinyl(Ci-C₄)alkyI, pyrizinyl(Ci-C4)alkyl, pyridazinyl(Cr

C4)alkyl, pyrimidinyl(Ci-C4)alkyl, imidazolyl(Ci-C4)alkyl or pyrrolidinyl(Ci-C4)alkyl, said R² rings optionally mono-, di- or tri-substituted independently with (Ci-C4)alkyl, (C_r

C4)alkoxy or halo.

A preferred group of compounds, designated the F Group, contains those compounds having the Formula I as shown above wherein wherein R¹ is phenyl and said R¹ is mono-, di-, tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro.

A preferred group of compounds, designated the G Group, contains those compounds having the Formula I as shown above wherein R² is hydroxy(C₂-C4)alkyl, diaminomethyleneamino(C₂-C4)alkyl, carbamoyl(C₁-C₄)alkyl, amino(C3-C4)hydroxyalkyl, amino(C₂-C4)alkylcarbamoyl(Ci-C4)alkyl, (Ci-C4)alkylcarbonylamino(C2-C4)alkyl, amino(Ci-C₄)alkylcarbonylamino(C2-C4)alkyl or amino(C2-C4)alkyl.

A preferred group of compounds, designated the H Group, contains those compounds having the Formula I as shown above wherein R² is (Ci-C4)alkyl mono- or di-substituted independently with amino, carbamoyl, hydroxyl, (C₄-C4)alkoxy, amino(CiC4)alkylcarbonylamino, amino(C2-C4)alkylcarbamoyl, (Ci-C4)alkylcarbonylamino or diaminomethyleneamino.

A preferred group of compounds, designated the I Group, contains those compounds wherein the compound is

6-(2,4-dimethoxyphenyl)-1 -(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1 H)-one;

1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;

2-[6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3_l4-dihydropyrimidin-1(2H)-yl]acetamide;

2-[6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl]acetamîde;

1-(2-aminoethyl)-2-thioxo-6-(2,4,5-trimethoxyphenyl)-2_l3-dihydropyrimidin-4(1 H)-one;

1- (3-aminopropyl)-6-(2-methoxy-5-methylphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)one;

N-{2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl]ethyl}glycinamide;

2- {3-[6-(2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl]propyl}guanidine;

1-[(2S)-3-amino-2-hydroxypropyl]-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3dihydropyrimidin-4(1 H)-one;

1-[(2R)-3-amino-2-hydroxypropyl]-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3dihydropyrimidin-4(1 H)-one;

N-(2-aminoethyl)-2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yljacetamide; or

1- (2-aminoethyl)-6-[2-(2-hydroxyethoxy)phenyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one or a pharmaceutically acceptable sait thereof.

An especially preferred compound is

2- (6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)-yl)acetamide or a pharmaceutically acceptable sait thereof.

It is especially preferred that the compound is

Another especially preferred compound is

2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl)acetamide or a pharmaceutically acceptable sait thereof.

It is especially preferred that the compound is

A group of compounds which is preferred among the C Group of compounds designated the J Group contains those compounds wherein R¹ is naphthyl, quinolinyl, isoquinolinyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl and said R¹ is mono-, di-, or tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro; and R² is diaminomethyleneamino(C2-C4)alkyl, carbamoyl(CrC4)alkyl, hydroxy(C₂-C4)alkyl, amino(C2-C₄)alkylcarbamoyl(C₁-C4)alkyl, (Ci-C4)alkylcarbonylamino(C2-C4)alkyl, amino(Ci-C4)alkylcarbonylamino(C2-C4)alkyl, amino(C₃-C4)hydroxyalkyl or amino(C₂15 C₄)alkyl.

A preferred group of compounds, designated the K Group, contains those compounds wherein the compound is 2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide; 2-[6-(2-methoxy-5-methylphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)20 yljacetamide;

1- [(2R)-2-aminopropyl]-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)one;

2- [6-(3-methoxy-2-naphthyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide; or 2-[6-( 1 H-indol-4-yl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)-yl]acetamide or a pharmaceutically acceptable sait thereof.

A preferred group of compounds, designated the L Group, contains those compounds wherein the compound is

2-{6-[2-(2-hydroxyethoxy)-5-methoxyphenyl]-4-oxo-2-thioxo-3,4-dihydropynmidin-1(2H)yl}acetamide;

N-(2-aminoethyl)-2-{6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-4-oxo-2-thioxo-3,4dihydropyrimidin-1 (2H)-yl)acetamide;

6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-1-(2-hydroxyethyl)-2-thioxo-2,3dihydropyrimidin-4(1 H)-one;

6-[5-fluoro-2-(2-hydroxyethoxy)phenyl]-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin4(1H)-one; or

2-{6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yljacetamide or a pharmaceutically acceptable sait thereof.

An especially preferred compound is N-(2-aminoethyl)-2-[6-(2,4dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)-yl]acetamide or a pharmaceutically acceptable sait thereof.

It is especially preferred that the compound is

Preferred cardiovascular conditions include heart failure, congestive heart failure, peripheral arterial disease, pulmonary hypertension or vasculitis.

Other preferred cardiovascular conditions include unstable angina or a patient that has experienced a myocardial infarction.

Pharmaceutically acceptable salts of the compounds of Formula I or IA include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stéarate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples inciude the aluminium, arginine, calcium, choline, diethylamine, glycine, lysine, magnésium, meglumine, olamme, potassium, sodium, trimethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties. Sélection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

The compounds of the invention may exist in both unsolvated and solvated . forms. The term 'solvaté' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molécules, for example, éthanol. Such solvent molécules are those commonly used in the pharmaceutical art, which are known to be innocuous to the récipient, e.g., water, éthanol, and the like. Other solvents may be used as intemnediate solvatés in the préparation of more désirable solvatés, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and the like. The term ‘hydrate’ is employed when said solvent is water. Pharmaceutically acceptable solvatés inciude hydrates and other solvatés wherein the solvent of crystallization may be isotopîcally substituted, e.g. D₂O, d₆-acetone, d₆-DMSO. The term “hydrate refers to the complex where the solvent molécule is water. The solvatés and/or hydrates preferably exist in crystalline form.

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvatés, the drug and host are présent in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

The compounds of the invention inciude compounds of Formula I or IA as hereinbefore defined, polymorphs, and isomers thereof (including optical, géométrie and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of Formula I or IA.

The compounds of the présent invention may be administered as prodrugs. Thus certain dérivatives of compounds of Formula I or IA which may hâve little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I or IA having the desired activity, for example, by hydrolytic cleavage. Such dérivatives are referred to as ‘prodrugs’. [Further information

on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T Higuchi and W Stella) and ‘Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical

Association).]

Prodrugs can, for example, be produced by replacing appropriate functionalities présent in the compounds of Formula I or IA with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985).

Some examples of such prodrugs include:

(i) where the compound of Formula I or IA contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (CrCa)alkyl;

(ii) where the compound of Formula I or IA contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (CrCe) alkanoyloxymethyl; and (iii) where the compound of Formula I or IA contains a primary or secondary amino functionality (-NH₂or -NHR where R # H), an amide thereof, for example, replacement of one or both hydrogens with (Ci-C-io)alkanoyl.

In addition, certain compounds of Formula I or IA may themselves act as prodrugs 20 of other compounds of Formula I or IA.

Compounds of Formula I or IA containing an asymmetric carbon atom can exist as two or more stereoisomers. Where a compound of Formula I or IA contains an alkenyl or alkenylene group or a cycioalkyl group, géométrie cisHrans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an 25 aromatic moiety, tautomeric isomerism (‘tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism. For example, the following is illustrative of tautomers of the compounds of Formula I or IA.

most prédominant tautomer

OH

Additional example of tautomerism within the scope of the claimed compounds is the following illustration of guanidine tautomers of the compounds.

Example of guanidine tautomers and géométrie tsomers

Included within the scope of the claimed compounds of the présent invention are ail stereoisomers, géométrie isomers and tautomeric forms of the compounds of Formula (l), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racémie, for example, DL-tartrate or DL-arginine.

The présent invention includes ail pharmaceutically acceptable isotopicallylabelled compounds of Formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹ C, ¹³C and ¹⁴C, chlorine, such as ³®CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0,¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of Formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue

distribution studies. The radioactive isotopes tritium, /.e. ³H, and carbon-14, /.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of détection.

Substitution with heavier isotopes such as deuterium, /.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁰F, ¹⁵O and ¹³N, can be useful in Positron Emission Tomography (PET) studies forexamining substrate receptor 10 occupancy.

Isotopically-labelled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Préparations using an appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

References herein to treat, “treating, “treatment and the like include curative, palliative and prophylactic treatment.

As used herein, the expressions reaction-inert solvent and inert solvent refer to a solvent or a mixture thereof which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the 20 desired product.

By pharmaceutically acceptable is meant the carrier, vehicle, or diluent and/or sait must be compatible with the other ingrédients of the formulation, and not deleterious to the récipient thereof.

The term “pharmaceutically effective amount, as used herein, refers to an amount of the compound of Formula I or IA (or a combination agent or a Formula I or IA compound in combination with a combination agent) sufficient to treat, prevent onset of or delay or diminish the symptoms and physiological manifestations of the indications described herein.

The term “room température or ambient température means a température between 18 to 25 ^QC, “HPLC refers to high pressure liquid chromatography, “MPLC” refers to medium pressure liquid chromatography, “TLC refers to thin layer chromatography, “MS refers to mass spectrum or mass spectroscopy or mass spectrometry, NMR” refers to nuclear magnetic résonance spectroscopy, “DCM” refers to dichloromethane, “DMSO refers to dimethyl sulfoxide, DME refers to dimethoxyethane, EtOAc” refers to ethyl acetate, “MeOH refers to methanol, “Ph” ) refers to the phenyl group, Pr refers to propyl, trityl” refers to the triphenylmethyl group, “ACN refers to acetonitrile, “DEAD” refers to diethylazodicarboxylate, and DIAD” refers to diisopropylazodicarboxylate.

It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a spécifie point of attachment, then ail possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridyl means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or 3-thienyl, and so forth. In general the compounds of this invention can be made by processes which include processes analogous to those known in the chemical arts, partîcularly in light of the description contained herein.

As used herein the term mono-N- or di-N,N-(Ci-C_x)alkyl... refers to the (C_r C_x)alkyl moiety taken independently when it is di-N,N-(C₁-C_x)alkyl...(x refers to integers).

By halo is meant chloro, bromo, iodo, or fluoro.

By alkyl is meant straight chain saturated hydrocarbon or branched chain saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

By alkoxy is meant straight chain saturated alkyl or branched chain saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.

The following paragraphe describe exemplary ring(s) for the generic ring descriptions contained herein.

Exemplary five to six membered aromatic rings optionally having one to three heteroatoms selected independently from oxygen, nitrogen and sulfur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl.

Exemplary six membered rings include 2H-pyranyl, 4H-pyranyl, pyridinyl, pîperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1.335 oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5 oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazînyl,

Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen include indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1 H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 11-1-2,3-benzoxazinyl, 4H-3,1benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.

Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes may be described in the experimental section. Spécifie synthetic schemes for préparation of the compounds of Formula I or IA are outlined below.

As an initial note, in the préparation of the Formula I or IA compounds it is noted that some of the préparation methods useful for the préparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Formula I or IA precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the préparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991,

For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfère with reactions at other sites of the molécule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subséquent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction

conditions described and can typically be removed without chemically altering other functionality in the Formula I or IA compound.

O^R¹

SCHEME I

XVII

R¹

XXV

RO₂C ==- R¹

XXX

OH

O^R¹

XV

EtO₂C ‘R

XX

(HO)₂B-R¹ XXXV

XXII +

XXXII

Those skilled in the art will recognize that there exists a variety of methods for preparing thiouracils, including the condensation of a thiourea with various carbonyl containing compounds, or by reaction of a uracil with a thiating agent such as phosphorous pentasulfide or Lawesson’s reagent. In forming the thiouracils of the 10 présent invention it is useful to consider the method of construction in order to enhance the desired compounds over the variety of possible isomers in a regiospecific manner.

The Formula I or IA thiouracil compounds wherein R¹ and R² are as described above may be prepared from the Formula III enamine by a cyclization reaction. The Formula III enamine is cyclized to the corresponding Formula I or IA thiouracil, for 15 example, by reaction with an isothiocyanate such as benzoyl, carboxyethyl or preferably (trimethylsilyl)isothiocyanate (TMSNCS). The reaction proceeds under reaction conditions such as a polar aprotic solvent (e.g., methyl tetrahydrofuran, tetrahydrofuran, dioxane, isobutylnitrile or neat in the isothiocyanate) at a température of about 20 °C to about 150 °C, typically about 85 °C (via microwave or thermal heating), for about three hours to about forty-eight hours.

The Formula III enamine may be conveniently prepared from the Formula VI βketoester by reaction with an appropriate R²-NH₂ amine (wherein R² is as described above or wherein reactive functionality in R², such as a primary amine, is in a suitably a protected form, such as an O-tert-butyl carbamate). For example, the Formula VI βketoester is reacted with the R²-NH₂ amine in the presence of a weak acid such as acetic acid in a polar solvent (e.g., methanol, éthanol, isopropanol, toluene or neat in the amine) at a température of about 20 °C to about 120 °C, for about four hours to about seventy-two hours, typically about 80 °C for about 12 hours.

As described above, the Formula VI β-ketoester may be prepared, for example, from a Formula X methyl ketone, a Formula XV carboxylic acid, a Formula XX aryl halide or other precursors known to those skilled in the art.

The Formula VI β-ketoester is prepared from the Formula X methyl ketone by carboalkoxylation. For example, the Formula X methyl ketone is reacted with a dialkylcarbonate, preferably dimethyi carbonate, in the presence of an alkoxide base such as potassium tert-butoxide, in a polar solvent such as methyl tert-butyl ether or the corresponding alcohol for the dialkylcarbonate, at a température of about 15°C to about 100 °C, typically ambient température, for about four hours to about forty-eight hours, typically twelve hours.

The Formula VI β-ketoester may also be prepared for example from a carboxylic acid. For example, the Formula VI β-ketoester may be prepared from an activated carboxylic acid. The Formula XV acid is conveniently converted to a corresponding XVII acyl imidazole by reaction with 1,1‘-carbonyldiimidazole in a polar solvent, typically tetrahydrofuran at a température between 0 °C and 100 °C, preferably ambient température, for between 1 hour and twenty-four hours, preferably three hours. A solution of the resulting acyl imidazole XVII in a polar aprotic solvent such as tetrahydrofuran is converted to the corresponding Formula VI β-ketoester by reaction with a solution of an activated acetate species, such as the enolate of an acetate ester or preferably ethyl magnésium malonate in a polar aprotic solvent such as tetrahydrofuran, at a température between -80 °C and 100 °C, preferably ambient température, for between one and fourty-eight hours, preferably twelve hours to prépare the corresponding Formula VI β-ketoester.

Those skilled in the art will recognize that a variety of other methods can be used to prépare the β-ketoester from an acid.

Those skilled in the art will recognize that the Formula VI β-ketoesters may also be prepared from esters of Formula XV carboxylic acids, such as methyl, ethyl,

isopropyl, or tert-butyl, preferably the isopropyl ester of Formula XV carboxylic acid by a condensation reaction with an activated acetate species, such as the enolate of an acetate ester, preferably the enolate of isopropyl acetate, in a polar aprotic solvent such as tetrahydrofuran, dioxane, or toluene, preferably tetrahydrofuran, at a température between -80 ’C and 40 °C, preferably ambient température, for between one and twenty-four hours, preferably twelve hours to prépare the corresponding Formula VI βketoester.

In addition, those skilled in the art will recognize that there are a variety of methods for converting an aryl halide into a β-ketoester including the following exemplary procedures. A Formula XX aryl halide (e.g., an aryl bromide) is combined via a palladium-mediated coupling with a Formula XXII β-alkoxyacrylate, such as ethyl 3-ethoxyacrylate employing a palladium catalyst, typically bis(tri-tert-butylphosphine) palladium (optionally with lithium chloride), in the presence of an amine such as N,N-dicyclohexylmethylamine under an inert atmosphère such as nitrogen at a température of about 90 °C to about 140 °C, typically at about 110 °C, for about four hours to about forty-eight hours, typically 12 hours. The resulting XXV enolether is converted to the corresponding Formula VI β-ketoester by treatment with an acid such as aqueous HCl in a polar solvent (e.g.,dichloromethane, methanol, acetic acid) at a température of about 15 °C to about 40 °C, typically at about ambient, for about thirty minutes to about 20 six hours.

Alternatively, the Formula III enamine may be prepared from the Formula XXX propiolate via the following two-step réaction.

A Formula XXXII alkyne is coupled with a Formula XXXV boronic acid wherein R¹ is as described above, to prépare the Formula XXX propiolate via a transition métal mediated coupling. For example, the appropriate R¹-boronic acid in a polar aprotic solvent such as dichloromethane is reacted with césium carbonate, copper iodide, silver (I) oxide and tert-butyl propiolate at a température of about 60 °C to about 100°C, typically about 80 °C, for about 30 minutes to about six hours.

The resulting Formula XXX propiolate is transformed to the corresponding

Formula III enamine by amination with the appropriate R²-NH₂ amine (wherein R² is as defined above) in the presence of a weak acid such as acetic acid. The reaction proceeds in a polar solvent such as éthanol or isopropanol at a température of about 60 °C to about 100 °C typically, about 80 °C for about 24 hours to about 72 hours.

(NH₄)₂S, pyr

LVII

Ο R¹B(OH)₂ PddppfCI₂

Na₂CO₃

R²

R¹

I

LVIII

The Formula I or IA thiouracil may also be prepared from a Formula LVI 6halothiouracil as shown in Scheme II.

The thiocarbonyl of a Formula LVI halothiouracil is protected, for example, by reaction with iodomethane in the presence of a base such as diisopropylethylamine in a polar solvent (e.g., acetonitrile) at a température of about 15°C to about 40 °C, typically 10 ambient température, for about eight hours to about twenty-four hours. The resulting Formula LVII halide undergoes a transition métal mediated coupling with the appropriate R¹-metal species (wherein R¹ is as defined above) by for example reaction with [1,T-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) and R¹boronic acid (wherein R¹ is as described above) with 1,4 dioxane and aqueous sodium carbonate.

The mixture is heated at a température of about 90 °C to about 150 °C, typically by subjecting to microwave irradiation at 120°C for about fifteen minutes to about one hour. The resulting Formula LVIII compound is deprotected by reaction with a nucleophile, typically by reaction with ammonium sulfide in a polar solvent such as pyridine at a température of about 60 °C to about 150 °C, typically by microwave irradiation at 75 °C for about fifteen minutes to about one hour to prépare the Formula I or IA thiouracil.

The Formula LVI halothiouracils may be prepared from the corresponding Formula LV thiouracils by for example, a two-step deprotonation/lithium-halogenexchange with iodine. Typically the thiouracil is treated with a base such as lithium 25 diisopropylamide in a polar aprotic solvent such as tetrahydrofuran at a température of about -20 °C to about -100 °C, typicaliy -78 °C. Then the solution is allowed to warm to a température of about 0°C to about-25 °C, typicaliy-10 °C for about fifteen minutes to about one hour to préparé the corresponding lithium intermediate followed by cooling to a température of about -60 °C to about -80 °C, typicaliy -78 °C whereupon the lithium intermediate is reacted with iodine in an appropriate polar aprotic solvent for about 5 minutes to about forty-eight hours, typicaliy eight hours.

SCHEME III

LX LXI IB

The Formula IB and LXI thiouracil compounds (wherein R¹ is described above, and while R³ and R⁴ are not specifically denoted above, refer to substituents that are generally described above) may be prepared from the Formula LX enamines as shown in Scheme III.Formula LXI thiouracils,wherein R is an alkyl group such as methyl, ethyl, isopropyl or tert-butyl, preferentially methyl or ethyl, may be converted into the corresponding carboxylic acid, wherein R = H, by a variety of methods known to those skilled in the art such as acid or base hydrolysis, preferably treatment with 5 équivalents of sodium or lithium hydroxide, in a polar solvent such as water, methanol, éthanol, tetrahydrofuran, or a mixture of such solvents, preferably water and éthanol, at a température between 0 °C to about 100 °C, preferably ambient température, for a period between one hour and twenty-four hours, preferably four hours. The resulting Formula LXI carboxylic acid may be converted into the Formula IB amide by use of amide coupling reagents known to those skilled in the art, such as propane phosphonic acid anhydride (T3P) or (CDI), preferably propane phosphonic acid anhydride, in the presence of an organic base, such as pyridine, triethylamine, imidazole or diisopropylethylamine, preferably diisopropylethylamine, in a polar solvent, such as N.N'-dimethylformamide, methylene chloride or ethyl acetate, preferably methylene chloride, at a température between 0 °C and solvent reflux, preferably ambient température, for a period between 15 minutes and forty-eight hours, preferably eighteen hours.

The Formula LXI thiouracil compounds may be prepared from Formula LX enamines by reaction with an isothiocyanate, such as N-benzoyl-, N-carboxyethyl- or preferably (trimethylsilyl)isothiocyanate (TMSNCS) optionally in the presence ofa polar aprotic solvent, such as., methyl tetrahydrofuran, tetrahydrofuran, dioxane, isobutylnitrile, n-butylacetate, Ν,Ν’-dimethylformamide, preferably neat in the isothiocyanate at a température between 20 °C and 150 °C, typically about 85 °C, heating with amicrowave reactor or a conventional heat source, for between 15 minutes and forty-eight hours, preferably three hours.

SCHEME IV

The Formula IC, LXXI and LXXII thiouracils may be prepared from the Formula

LXX thiouracils as shown in Scheme IV.

The Formula IC (thiouracils (wherein R¹ is described above, and while R³ -R⁹ are not specifically denoted above, refer to substituents that are generally described above and wherein at least one of R⁶ through R⁹ is bonded to the corresponding guanidine nitrogen through a carbonyl moiety) may be prepared from Formula LXXII thiouracils, which may exist in a variety of tautomeric forms such as these shown., by reaction of LXXII guanidines with an acylating reagent known to those skilled in the art such as an acyl chloride or alkyl chloroformate in the presence of an aqueous base such as sodium carbonate or sodium bicarbonate in polar aprotic solvent, such as tetrahydrofuran, at a température between 0 °C and solvent reflux, preferably ambient température, to provide the corresponding Formula ICguanidines. Alternatively, reaction of LXXII

thiouracils with a dialkyl carbonate, in the presence of an alkoxide base such as sodium ethoxide, in a polar solvent such as the corresponding alcohol for the dialkylcarbonate, at a température of between 15 °C to about 100 ^eC, preferably at 50 °C, for between four hours and forty-eight hours, preferably fifteen hours provides the corresponding Formula IC thiouracils.

The Formula LXXII thiouracils may be prepared from the corresponding Formula LXX thiouracils by reaction with R⁷R⁸NCN-containing guanylating reagent, such as benzotriazole-R⁷R⁸N-methanimine, imidazole-R⁷R⁸N-methanimine, or pyrazole-R⁷R⁸Nmethanimine in a polar aprotic solvent,preferably Ν,Ν'-dimethylformamide, in the presence of a base, preferably diisopropylethylamine, at a température between 15 °C to 60 °C, preferably ambient température, for between four to seventy-two hours, preferably eighteen hours. Alternative^, Formula LXX amines may be converted to an activated thiouracil LXXI wherein X is a leaving group, such as benzotriazole, imidazole, pyrrazole, by reaction with a methanimine reagent, such as 1,1-di(1H-benzotriazol-115 yl)methanimine, 1,1-di(1H-imidazol-1-yl)methanimine or 1,1-di(1 H-pyrazol-1yl)methanimine, in the presence of a base, such as diisopropylamine, in a polar aprotic solvent, such as Ν,Ν’-dimethylformamide, at a température between 15 °C and 100 °C, preferably ambient température, for between four hours and forty-eight hours, preferably eighteen hours. The resulting Formula LXXI activated thiouracils can then be treated with R⁷R⁸NH in the presence of a base, such as diisopropylethylamine, in a polar aprotic solvent, such as Ν,Ν’-dimethylformamide, at a température between 20 °C and 120 ’C, preferably 60 °C, for between one hour and 24 hours, preferably three hours to obtain Formula LXXII guanidine thiouracils.

The starting materials and reagents for the above described Formula I or IA compounds, are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein, are related to, or are derived from compounds in which there is a large scientifîc interest and commercial need, and accordingly many such compounds are commerclally available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.

Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, “Stereochemistry of Organic Compounds by E L Eliel (Wiley, New York, 1994).]

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor.

Altematively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

Pharmaceutically acceptable salts of compounds of Formula I or IA may be prepared by one or more of three exemplary methods:

(i) by reacting the compound of Formula I or IA with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or IA or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one sait of the compound of Formula I or IA to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. Ail three reactions are typically carried out in solution. The resulting sait may precipitate out and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionization in the resulting sait may vary from completely ionized to almost non-ionized.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents (e.g., antiatherosclerotic and antithrombotic agents) for the treatment of the disease/conditions described herein.

COMBINATION AGENTS

The compounds of the présent invention can be administered alone or in combination with one or more additional therapeutic agents. By administered in 5 combination or combination therapy it is meant that a compound of the présent invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time 10 so as to provide the desired therapeutic effect. Thus, the methods of prévention and treatment described herein inciude use of combination agents.

The combination agents are administered to a mammal in a therapeutically effective amount. By therapeutically effective amount it is meant an amount of a compound of the présent invention that, when administered alone or in combination with 15 an additional therapeutic agent to a mammal, is effective to treat the desired disease/condition e.g., cardiovascular condition such as acute coronary syndrome.

Additional therapeutic agents inciude anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents, anti-arrythmic agents, anti-hypertensive agents, calcium channel 20 blockers (L-type and T-type), cardiac glycosides, diruetics, mineralocorticoid receptor antagonists, NO donating agents such as organonitrates, NO promoting agents such as phosphodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile thérapies, anti-diabetic agents, anti-depressants, anti-inflammatory agents (stéroïdal and non-steroidal), anti-osteoporosis agents, hormone replacement thérapies, oral 25 contraceptives, anti-obesity agents, anti-anxiety agents, anti-proliferative agents, antîtumor agents, anti-ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid hormone receptor antagonist), anti-infective agents, anti-viral agents, anti-bacterial agents, and anti-fungal agents.

Agents used in an ICU setting are included, for example, dobutamine, dopamine, dpinephrine, nitroglycerin, nitroprusside etc.

Combination agents useful for treating vasculitis are included, for example, azathioprine, cyclophosphamide, mycophenolate, mofetil, rituximab etc.

In another embodiment, the présent invention provides a combination wherein 35 the second agent is at least one agent selected from a factor Xa inhibitor, an anti coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent.

Exemplary factor Xa inhibitors include apixaban and rivaroxaban.

Examples of suitable anti-coagulants for use in combination with the compounds of the présent invention include heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin).

In another preferred embodiment the second agent is at least one agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, Indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase.

A preferred second agent is is at least one anti-platelet agent. Especially preferred anti-platelet agents are aspirin and clopidogrel.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, dénotés agents that inhibit platelet function, for example by inhibiting the aggregation, adhesion or granular sécrétion of platelets. Agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA) and COX-2 inhibitors such as CELEBREX or piroxicam are preferred. Other suitable platelet inhibitory agents include llb/llla antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, PDE-III inhibitors (e.g., Pletal, dipyridamole), and pharmaceutically acceptable salts or prodrugs thereof.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P2Y1 and P2Y12· with P2Y12 being even more preferred. Preferred P2Y12 receptor antagonists include ticagrelor, prasugrel, ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are

also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use.

The term thrombin inhibitors (or anti-thrombin agents), as used herein, dénotés inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular sécrétion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrîn formation are disrupted, A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the présent compounds. Such inhibitors include, but are not limited to, boroarginine dérivatives, boropeptides, heparins, hirudin, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine dérivatives and boropeptides include N-acetyl and peptide dérivatives of boronic acid, such as C-terminal alpha-aminoboronic acid dérivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable dérivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. The term thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, dénoté agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor Vlla inhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha2antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in EP 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to dénoté both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Examples of suitable anti-arrythmic agents include: Class I agents (such as propafenone); Class II agents (such as metoprolol, atenolol, carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K⁺ channel openers such as lA_Ch inhibitors, and IKur inhibitors (e.g., compounds such as those disclosed in

W001/40231).

The compounds of the présent invention may be used in combination with antihypertensive agents and such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of suitable anti-hypertensive agents include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cîlazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, îrbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary antianginal agent is ivabradine.

Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine and mybefradil.

Examples of suitable cardiac glycosides include digitalis and ouabain.

In one embodiment, a Formulae I or IA compound may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (such as LASIX™), torsemide (such as DEMADEX™), bemetanide (such as BUMEX™), and ethacrynic acid (such as EDECRIN™); (b) thiazide-type diuretics such as chlorothiazide (such as DIURIL™, ESIDRIX™ or HYDRODIURIL™), hydrochlorothiazide (such as MICROZIDE™ or ORETIC™), benzthiazide, hydroflumethiazide (such as SALURON™), bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, and indapamide (such as LOZOL™); (c) phthalimidinetype diuretics such as chlorthalidone (such as HYGROTON™), and metolazone (such as ZAROXOLYN™); (d) quinazoline-type diuretics such as quinethazone; and (e) potassium-sparing diuretics such as triamterene (such as DYRENIUM™), and amiloride (such as MIDAMOR™ or MODURETIC™).

In another embodiment, a compound of Formula I or IA may be co-administered with a loop diuretic. In still another embodiment, the loop diuretic is selected from furosemide and torsemide. In still another embodiment, one or more compounds of

Formulae I or IA may be co-administered with furosemide. In still another embodiment, one or more compounds of Formulae I or IA may be co-administered with torsemide which may optionally be a controlled or modified release form of torsemide.

In another embodiment, a compound of Formulae I or IA may be co-administered with a thiazide-type diuretic. In still another embodiment, the thiazide-type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In still another embodiment, one or more compounds of Formulae I or IA may be coadministered with chlorothiazide. In still another embodiment, one or more compounds of Formulae I or IA may be co-administered with hydrochlorothiazide.

In another embodiment, one or more compounds of Formulae I or IA may be coadministered with a phthalimidine-type diuretic. In still another embodiment, the phthalimidine-type diuretic is chlorthalidone.

Examples of suitable combination mineralocorticoid receptor antagoniste înclude sprionolactone and eplerenone.

I5 Examples of suitable combination phosphodiesterase inhibitors înclude: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

The compounds of the présent invention may be used in combination with cholestérol modulating agents (including cholestérol lowering agents) such as a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG20 CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B sécrétion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholestérol absorption inhibitor, a cholestérol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase/squalene cyclase inhibitor, a fibrate, niacin, an ion25 exchange resin, an antioxidant, an ACAT inhibitor or a bile acid séquestrant or an agent such as mipomersen..

Examples of suitable cholesterol/lipid lowering agents and lipid profile thérapies înclude: HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and

ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid séquestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors; and cholesteryl ester transfer protein inhibitors.

Anti-inflammatory agents also include sPLA2 and lpPLA2 inhibitors (such as darapladib), 5 LO inhibitors (such as atrelueton) and IL-1 and IL-1 r antagonists (such as canakinumab).

Other atherosclerotic agents include agents that modulate the action of PCSK9.

Cardiovascular complications of type 2 diabètes are associated with deleterious levels of MPO, accordingly, the compounds of the présent invention may be used in combination with anti-diabetic agents, particularly type 2 anti-diabetic agents. Examples of suitable anti-diabetic agents include (e.g. insulins, metfomin, DPPIV inhibitors, GLP1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors) Suitable anti10 diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in WO2009144554, W02003072197, WO2009144555 and W02008065508, a diacylglycérol O-acyitransferase 1 (DGAT-1) inhibitor, such as those described in W009016462 or WO2010086820, AZD7687 or LCQ908, diacylglycérol 0acyltransferase 2 (DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an aglucoside hydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such as an agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Byetta®), albiglutide, lixisenatide, dulaglutide, semaglutide, NN-9924,TTP-054, a protein tyrosine phosphatase-1B (PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug Discovery Todav. 12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor (e.g., those in W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor,. glucokinase activators (GKa) such as those described in WO2010103437, WO2010103438, W02010013161, W02007122482, TTP-399, TTP-355, TTP-547,

AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, an insulin

mimetic, a glycogen phosphorylase inhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors, such as those described in E.C. Ghao étal. Nature Reviews Drug Discovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin (CSG452), ASP-1941, THR1474, TS-071, ISIS388626 and 5 LX4211 as well as those in WO2010023594, a glucagon receptor modulator such as those described in Demong, D.E. et al. Annual Reports in Médicinal Chemistry 2008, 43, 119-137, GPR119 modulators, particularly agonists, such as those described in

W02010140092, WO2010128425, W02010128414, W02010106457, Jones, R.M. et al. in Médicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821), FGF21 dérivatives or analogs such as those described in Kharitonenkov,

A. et al. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topîcs in Médicinal Chemistry, 2010, 10(4), 386-396 and INT777,

GPR40 agonists, such as those described in Médina, J.C., Annual Reports in Médicinal

Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further représentative listing of anti-diabetic agents that can be combined with the compounds of the présent invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO2011005611. Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g,, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCa, PKCp, PKCy), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including IL1 beta, modulators of

RXRalpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

Those skilled in the art will recognize that the compounds of this invention may also be used in conjunction with other cardiovascular or cerebrovascular treatments

including PCI, stenting, drug eluting stents, stem cell therapy and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.

Myeloperoxidase activity has been demonstrated in neuroinflammatory conditions, accordingly, the compounds of the présent invention may be used in combination with neuroinflammatory and neurodegenerative agents in mammals. Examples of additional neuroinflammatory and neurodegenerative agents include antidepressants, antipsychotics, anti-pain agents, anti-Alzheimer’s agents, and antianxiety agents. Examples of particular classes of antidepressants that can be used in combination with the compounds of the invention include norepinephrine reuptake inhibitors, sélective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), réversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagoniste, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Examples of suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butriptyline, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Examples of suitable SSRIs include fluoxetine, fluvoxamine, paroxetine, and sertraline. Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine. Examples of suitable réversible inhibitors of monoamine oxidase include moclobemide. Examples of suitable SNRIs of use in the présent invention include venlafaxine. Examples of suitable atypical anti-depressants include bupropion, lithium, trazodone and viloxazine. Examples of anti-Alzheimer's agents include NMDA receptor antagonists such as memantine; and cholinestérase inhibitors such as donepezil and galantamine. Examples of suitable classes of anti-anxiety agents that can be used in combination with the compounds of the invention include benzodiazépines and serotonin 1A receptor (5-HT1A) agonists, and CRF antagonists. Suitable benzodiazépines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazépam, oxazepam, and prazepam. Suitable 5-HT1A receptor agonists include buspirone and ipsapirone. Suitable CRF antagonists include verucerfont. Suitable atypical antipsychotics include paliperidone, ziprasidone, rispéridone, aripiprazole, olanzapine, and quetiapine. Suitable nicotine acétylcholine agonists include CP-601927 and varenicline. Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and ziconotide.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingrédients. For this reason, when a Formula I or IA compound and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingrédients are combined in a single dosage unit, the physical contact between the active ingrédients is minimized (that is, reduced). For example, one active ingrédient may be enteric coated. By enteric coating one of the active ingrédients, it is possible not only to minimize the contact between the combined active ingrédients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these 10 components is not released in the stomach but rather is released in the intestines. One of the active ingrédients may also be coated with a material that affects a sustainedrelease throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingrédients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the présent invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the présent disclosure. In combination therapy treatment, both the compounds of this invention and the other drug thérapies are administered to mammals (e.g., humans, maie or female) by conventional methods.

The Formula I or IA compounds of this invention, their prodrugs and the salts of such compounds and prodrugs are ail adapted to therapeutic use as agents that inhibit myeloperoxidase in mammals, particularly humans and thus are useful for the treatment of the various conditions (e.g., those described herein) in which such action is implicated.

It is believed that myeloperoxidase is involved in the pathologie oxidation of proteins, lipids and nucleic acids and contributes to dysfunctional cholestérol metabolism, tissue damage, and organ dysfonction and can induce or contribute to the development of cardiovascular diseases and associated adverse outcomes.

The disease/conditions that can be treated in accordance with the présent invention include, but are not limited to, cardiovascular conditions, diabètes (e.g., type II) and diabetic complications, vascular conditions, neuroinflammatory conditions, neurodegenerative conditions, pain, cancer, sepsis, NASH (non-alcoholic steatatohepatitis), pulmonary injury and hypertension, rénal diseases, and vasculitis syndromes especially those related to ANCA (anti-neutrophil cytoplasmic antibodies) and the like.

Given the positive corrélation between activation of the myeloperoxidase with the development of cardiovascular and associated disease/conditions, Formula I or IA compounds of this invention, their prodrugs and the salts of such compounds and prodrugs, by virtue of their pharmacologie action, are useful for the prévention, arrestment and/or régression of atherosclerosis and its associated disease states.

It is believed that MPO exhibits pro-atherogenic biological activity during the évolution of cardiovascular disease. Furthermore, it has been observed that MPOgenerated oxidants reduce the bioavailability of nitric oxide, an important vasodilator. Additionally, it has been shown that MPO plays a rôle in plaque destabilization by causing the activation of metalloproteinases, leading to a weakening of the fibrous cap of the plaques and subséquent plaque destabilization and rupture. Given these wideranging effects of MPO, MPO has thus been implicated in a wide variety of cardiovascular diseases.

Cardiovascular conditions include, but are not limited to coronary heart disease, acute coronary syndrome, ischaemic heart disease, first or récurrent myocardial infarction, secondary myocardial infarction, non-ST segment élévation myocardial infarction, or ST segment élévation myocardial infarction, ischémie sudden death, transient ischémie attack, peripheral occlusive arterial disease, angina, atherosclerosis, hypertension, heart failure (such as congestive heart failure), diastolic dysfonction (such as left ventricular diastolic dysfonction, diastolic heart failure, and impaired diastolic filling), systolic dysfonction (such as systolic heart failure with reduced éjection fraction), atrial fibrillation, arrhythmia (ventricular), ischemia, hypertrophie cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial necrotic lésions, vascular damage, left ventricular hypertrophy, decreased éjection fraction, cardiac lésions, vascular wall hypertrophy, endothélial thickening, fîbrinoid necrosis of coronary arteries, adverse remodeling, stroke, and the like. Also, included are venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cérébral arterial thrombosis, cérébral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling cathéters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promûtes thrombosis. It is noted that thrombosis includes occlusion (e.g., after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty).

Cardiovascular complications of type 2 diabètes are associated with deleterious levels of MPO, accordingly, the compounds of the présent invention may be used to treat diabètes and diabetic complications such as macrovascular disease, hyperglycemia, metabolic syndrome, tmpaired glucose tolérance, hyperuricemia, glucosuria, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesîty, dyslididemîa, hypertension, hyperinsulînemia, and insulin résistance syndrome.

In addition, linkage of myeloperoxidase activity to disease has been demonstrated in neuroinflammatory and neurodegenerative conditions. Therefore, the compounds of the présent invention are particularly indicated for use in the treatment of neuroinflammatory and neurodegenerative conditions (i.e.,disorders or diseases) in mammals including humans such as multiple sclerosis, migraine; epilepsy; Alzheirïier’s disease; Parkinson’s disease; brain injury; stroke; cerebrovascular diseases (including cérébral arteriosclerosis, cérébral amyloid angiopathy, hereditary cérébral hemorrhage, and brain hypoxia-ischemia); cognitive disorders (including amnesia, senile dementia, HIV associated dementia, Alzheimer's associated dementia, Huntington’s associated dementia, Lewy body dementia, vascular dementia, drug related dementia, delirium, and mild cognitive impairment); mental deficiency (including Down syndrome and fragile X syndrome); sleep disorders (including hypersomnia, circadian rhythm sleep disorder, insomnia, parasomnia, and sleep deprivation) and psychiatrie disorders (such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder); factitious disorder (including acute hallucinatory mania); impulse control disorders (including compulsive gambling and intermittent explosive disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, major dépréssion, chronic dépréssion, seasonal dépréssion, psychotic dépréssion, and postpartum dépréssion); psychomotor disorder; psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform, and delusional disorder);

drug dependence (including narcotic dependence, alcoholism, amphétamine dependence, cocaïne addiction, nicotine dependence, and drug withdrawal syndrome);

eating disorders (including anorexia, bulimia, binge eating disorder, hyperphagia, and pagophagia); and pédiatrie psychiatrie disorders (including attention déficit disorder, attention deficit/hyperactive disorder, conduct disorder, and autism) in a mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or IA or pharmaceutically acceptable sait thereof.

Other inflammatory diseases or disorders such as asthma, chronic obstructive pulmonary disease, cystic fîbrosis, idiopathic pulmonaryfibrosis, acute respiratory distress syndrome, sinusitis, rhinitis, psoriasis, dermatîtis, uveitis, gingivitis, atherosclerosis, inflammatory bowel disease, rénal glomerular damage, liver fîbrosis, sepsis, proctitis, rheumatoid arthritis, and inflammation associated with reperfusion injury, spinal cord injury and tissue damage/scaming/adhesion/rejection.

The term nephropathy caused by contrasting agents includes contrasting induced nephropathy following procedures that utilize imaging agents including cardiac surgery, non-cardiac surgery and transplant surgery. Nephropathy caused by contrasting agents also includes nephropathy caused by the use of enhanced imaging contrasting agents in patients including those at risk of a primary Ml or secondary Ml.

The utility of the Formula I or IA compounds of the invention, their prodrugs and the salts of such compounds and prodrugs as medical agents in the treatment of the above described disease/conditions in mammals (e.g. humans, male or female) is demonstrated by the activity of the compounds of this invention in conventional in vitro and in vivo assays described below. The in vivo assays (with appropriate modifications within the skill in the art) may be used to détermine the activity of other agents as well as the compounds of this invention. Such assays also provide a means whereby the activities of the Formula I or IA compounds of this invention, their prodrugs and the salts of such compounds and prodrugs (or the other agents described herein) can be compared to each other and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.

The following protocols may of course be varied by those skilled in the art.

MPO Amplex Red Activity Assay.

MPO peroxidase activity was measured by monitoring the formation of resorufin generated from the oxidation of Amplex Red (10-Acetyl-3,7-dihydroxyphenoxazine) (Invitrogen, Carlsbad, CA) by MPO (Gomes, Fernandes et al. 2005). Assay mixtures (100 μι. total volume) contained 50 mM NaPi pH 7.4, 150 mM NaCI, 1 mM DTPA (diethylenetriaminepentaacetic acid), 2% DMSO, 2 μΜ H₂O₂, 30 μΜ Amplex Red and the reaction was initiated by the addition of 100 pM MPO (purified from human polynuclear leukocytes and purchased from Calbiochem/EMD Biosciences, Gibbstown, NJ). Ail assays were performed in 96-well, half-area, black, nonbinding surface, polystyrène plates (Corning) and the production of resorufin (excitation 530 nm, émission 580 nm) was monitored every 20 sec on a Spectramax M2 Microplate Spectrophotometer (Molecular Devices, Palo Alto, CA) equipped with Softmax Pro software (Molecular Devices, Palo Alto, CA). Reactions to détermine the background reaction rate consisted of ail assay components and 4 μΙ_ of 500 unit/mL bovine catalase (Sigma) in 50 mM KPi pH 7.0. The background rate was subtracted from each reaction progress curve. Ail data was analyzed using non-linear régression analysis in Microsoft Excel and Kaleidagraph (Synergy Software).

To détermine inhibitor potency (kinact/Ki) against MPO, the first 600 sec of the reaction progress curves were fit to équation 1, where is the initial rate in RFU/sec and t is time in seconds, to obtain the first order rate constant for enzyme inactivation (k_oba) at each inhibitor concentration.

*

Prcdüct-— Ll-ffitfGW)! (D

4*»

Equation 1 is a variation of the standard équation for slow binding inhibition where the steady state velocity (V_a) is set to zéro. Each fc_ob8 value was corrected for autoinactivation of the enzyme by subtracting the k_ob9 value for the uninhibited reaction. The corrected k_obs values were then plotted versus inhibitor concentration ([I]) and fit to équation 2 ^+[1] (2) where k_inact is the maximal rate of inactivation and Ki is the inhibitor concentration that yields half the rate of maximal inactivation (Copeland 2005),

Table 1 and (1 A) below provides the myeloperoxidase inhibitory activity for the Examples below in accordance with the above-described assay.

Table 1. MPO k_lnact/Ki for Examples

Example #	MPO k|nact/K| (1/s per M)
1	11600
2	12500
3	29300
4	8790
5	1280
6	12900
7	10900
8	12100
9	15000
10	619
11	6880
12	5010
13	745
14	5310
15	5420
16	6510
17	4460
18	8280
19	1960
20	1330
21	4530
22	6340
23	991
24	7640
25	9210
26	3180
27	15800
28	13700
29	14900
30	5870
31	7680
32	2120
33	4520
34	13100
35	4110
36	5980
37	6460
38	5240
39	4520
40	6430
41	5000

Example #	ΜΡΟ kïnact/K (1/s per M)
42	6070
43	34600
44	3440
45	4000
46	1110
47	2340
48	6570
49	2230
50	2610
51	6180
52	33.4
53	3290
54	7070
55	7740
56	4770
57	13100
58	11700
59	8480
60	3470
61	3530
62	6930
63	12200
64	22500
65	7940
66	1580
67	7520
68	1160
69	4250
70	1590
71	3570
72	3580
73	9870
74	14400
75	2040
76	4190
77	6660
78	9730
79	1580
80	4130
81	24300
82	3390
83	3510
84	6630
85	10700
86	3960
87	15400

Example #	MPO klnac/K| (1/s per M)
88	898
89	276
90	11600
91	9360
92	22100
93	5120
94	6930
95	15400
96	2200
97	6310
98	1870
99	2920
100	16100
101	4140
102	4200
103	41600
104	1210
105	27300
106	10500
107	1280
108	5800
109	914
110	864
111	10300
112	14900
113	25900
114	9770
115	4380
116	9920
117	11400
118	5500
119	25600
120	9720
121	15800
122	9310
123	3780
124	4610
125	10600
126	18200
127	5810
128	7680
129	18700
130	4830
131	14500
132	3840
133	15300

Example #	MPO klnacf/K| (1/s per M)
134	5350
135	6750
136	1920
137	701
138	4530
139	2890
140	10400
141	10500
142	4210
143	8110
144	6010
145	5080
146	8950
147	6500
148	6690
149	9770
150	8970
151	3740
152	4770
153	2200
154	1070
155	8090
156	16800
157	7320
158	1750
159	11400
160	7540
161	29600
162	8950
163	8090
164	14900
165	1280
166	8920
167	20300
168	8890
169	17800
170	4030
171	8590
172	2950
173	2910
174	10500
175	459
176	2160
177	5130
178	11100
179	2790

Example #	MPO k|nact/K| (1/s per M)
180	6960
181	7160
182	8200
183	4830
184	5970
185	9740
186	3930
187	5640
188	2180
189	2210
190	4090
191	14100
192	10800
193	458
194	2560
195	5350
196	5640
197	5650
198	8460
199	9080
200	4930
201	4350
202	8280
203	3450
204	3900
205	4900
206	7690
207	2400
208	3760
209	4360
210	968
211	6090
212	7590
213	4690
214	10700
215	1920
216	3260
217	3940
218	14100
219	1970
220	2420
221	6230
222	9820
223	3000
224	3280
225	5490

Example #	MPO kjnact/K| (1/s per M)
226	6280
227	745
226	615
229	5900
230	1740
231	1910
232	4520
233	2510
234	3060
235	2690
236	5740
237	2360
238	8740
239	1850
240	7070
241	7060
242	142
243	952
244	8970
245	1520
246	246
247	3060
248	3590
249	1050
250	7510
251	68
252	2480
253	12700
254	5630
255	3550
256	6520
257	3700
258	1460
259	4000
260	19700
261	2280
262	1730
263	4340
264	3620
265	3730
266	604
267	3840
268	6640
269	9510
270	20500
271	2010

Example #	MPO ^ïnact/K| (1/s per M)
272	3160
273	8180
274	22800
275	4730
276	6710
277	767
27Θ	1560
279	386
280	430
281	1060
282	1180
283	2790
284	1470
285	1750
286	1500
287	2130
288	4230
289	1580
290	1890
291	2450
292	1070
293	1810
294	1910
295	793
296	1570
297	762
298	1080
299	2060
300	2460
301	3330
302	3630
303	5270
304	6290
305	6370
306	6740
307	14400
308	5340
309	3160
310	3110
311	2080
312	17100
313	973
314	429
315	1420
316	3060
317	7380

Example #	MPO Mnac(/K| (1/s per M)
318	5240
319	7810
320	2390
321	2480
322	2800
323	10200
324	11300
325	1160
326	7480
327	1880
328	4370
329	963
330	5210
331	6330
332	3270
333	6100
334	6840
335	9820
336	589
337	13200
338	1280
339	10400
340	1450
341	14300
342	817
343	3570
344	8480
345	946
346	5890
347	378
348	1400

Table 1A below provides the myeloperoxidase inhibitory activity for the Examples below in accordance with the above-described assay.

Table 1A. MPO kmact/Ki for Examples

Example #	MPO kjnact/Kj (1/s per M)
349	3630
350	8740
351	7870
352	6720

Example #	MPO k|nact/K| (1/s per M)
353	11000
354	1830
355	1540
356	2910
357	2940
358	1710
359	2660
360	2280
361	2060
362	2690
363	9680
364	6580
365	9290
366	13600
367	1340
368	3270
369	8040
370	9060
371	4570
372	6250
373	12800
374	4600
375	11300
376	7870
377	8770
378	5040
379	7370
380	4470
381	1970
382	2310
383	5230
384	2930
385	3530
386	4960
387	4720
388	8690
389	4910
390	6250
391	3480
392	5830
393	13600
394	4020

Example #	MPO k|nact/K| (1/s per M)
395	6980
396	10900
397	4050
398	4780
399	4860
400	2650
401	4060
402	4810
403	13300
404	6200
405	5970
406	4480
407	18700
408	9890
409	18000
410	3150
411	15000
412	3980
413	6560
414	1680
415	3910
416	4480
417	9280
418	11500
419	1200
420	5210
421	4950
422	4460
423	3290
424	6870
425	13400
426	4410
427	5360
428	5890
429	6620
430	9440
431	3440
432	1410
433	3490
434	4070
435	2420
436	3710

Example #	MPO k|nact/K| (1/s per M)
437	3400
438	7550
439	9200
440	3310
441	3260
442	12300
443	7330
444	17400
445	7350
446	14200
447	17200
448	6490
449	12000
450	7730
451	16000
452	11600
453	27800

TPO Amplex Red activity assay.

TPO activity was measured using the same assay as MPO with 2 μΜ H2O2, 30 μΜ Amplex Red and the reactions were initiated with 1.3pg of protein from HEK293 cell membranes expressing human TPO. The cDNA encoding 933 amino acids of the full length human TPO was cloned into the inducible expression vector pcDNA5/frt/to (InVitrogen), stable 293 clones were selected using 100 ug/ml of hygromycin and 15 ug/ml blasticidine in DM EM w/10% FBS. When cells reached 50-60% confluence, TPO expression was induced in medium containing ail of above plus 10 ug/ml doxicycline and 5 ug/ml hemin (Sigma). Membranes were isolated from HEK293hTPO by harvesting the cells in PBS. The cells were pelleted at 1000 x g for 5 minutes at 4°C, resuspended in homogenization buffer (1 mM sodium bicarbonate, pH 7.4) containing EDTA-Free protease inhibitor (Roche), and incubated on ice for 10 minutes followed by Dounce homogenization. Nuclei and unlysed cells were removed by pelleting at 1000 x g for 10 minutes at 4°C. The supernatent was then centrifuged at 25,000 x g for 20 minutes at 4°C. The pellet was resuspended in homogenization buffer and centrifuged again at 25,000 x g for 20 minutes at 4°C. The final pellet was resuspended in storage buffer (50 mM Tris pH 7, 150 mM NaCI) containing protease inhibitors as described above. Membrane concentration was determined using the BCA Protein Assay

(Pierce), TPO activity was measured using the Amplex Red assay as described above. Aliquots were made based on the activity accordingly and stored at -80°C.

The IC₅o values were determined by plotting the initial rates (from the first 200 sec of each reaction progress curve) as percentage of inhibition relative to the uninhibited (DMSO) reaction as a function of inhibitor concentration. The data were fit to équation 3

100

I + (λ/IC^ where IC₅₀ is the inhibitor concentration at 50% inhibition and z is the Hill slope (the slope of the curve at its inflection point).

REFERENCES

Copeland, R. A. (2005). Evaluation of Enzyme Inhibitors in Drug Discoverv A Guide for

Médicinal Chemists and Pharmacoloqists. Hoboken, Wiley.

Gomes, A., E. Fernandes, et al. (2005). Fluorescence probes used for détection of reactive oxygen species. J Biochem Biophys Methods 65(2-3): 45-80.

Human Whole Blood Assay for Irréversible Inhibition of MPQ

To measure the inhibition of MPO activity in a biological System in the présent invention, bioassays are performed with human whole blood that is collected from 20 medication-free, human volunteers in heparin treated tubes (APP Pharmaceuticals, LLC, cat # NDC#63323-047-10, #4710). Blood is aliquoted and treated with different concentrations of the MPO inhibitor or vehicle control and co-treated with or without bacterial lipopolysaccharide (LPS, InVivogen, cat# tlrl-pelps) to stimulate blood leukocytes to simultaneously generate H₂0₂ (a required MPO substrate) and the release of MPO. After 4 hour incubation at room température the plasma fraction is collected following a 2000Xg centrifugation at 4 °C.

The plasma fraction is divided into two for analysis of total MPO and active MPO. The total MPO content is determined using a standard sandwich ELISA (capture and détection antibodies: Cell Sciences, Cat# HP9048, and Cell Sciences, Cat# HM2164, 30 clone 266-6K1) and calculated relative to a standard curve of purified MPO (myeloperoxidase, Calbiochem, cat# 475911) that is prepared by dilution in the autologous donor plasma. The MPO activity is determined by capturing the total MPO from plasma using the capture step as described for the ELISA method. After washing unbound plasma material including unreacted MPO inhibitor, MPO reaction substrates are added [H2O2 (2uM) and Amplex Red (Invitrogen, Cat# A12222)] and the Vmax of the MPO-catalyzed conversion of the Amplex Red substrate to resorufin is determined by measuring the increase in fluorescence (excitation 530 nM, émission 580 nm) using a fluorescent plate reader in a kinetic analysis. The MPO activity of the captured material is compared to that obtained with a standard curve of purified MPO (myeloperoxidase, Calbiochem, cat# 475911) that was prepared in autologous donor plasma. The percent of ‘active’ myeloperoxidase for each sample is calculated from the ratio of the active myeloperoxidase in the Amplex Red assay and the total myeloperoxidase from the ELISA for each sample. A dose response curve of the MPOi concentration versus MPO activity is then plotted to détermine the IC50 value.

Administration of the compounds of this invention can be via any method which delivers a compound of this invention systemically and/or locally. These methods inciude oral routes, parentéral, intraduodenal routes, buccal, intranasal etc. Generally, the compounds of this invention are administered orally, but parentéral administration (e.g., intravenous, intramuscular, subcutaneous or intramedullary) may be utilized, for example, where oral administration is inappropriate for the target or where the patient is unable to ingest the drug.

For administration to human patients, an oral daily dose of the compounds herein may be in the range 1 mg to 5000 mg depending, of course, on the mode of and frequency of administration, the disease state, and the âge and condition of the patient, etc. An oral daily dose is in the range of 3 mg to 2000 mg may be used. A further oral daily dose is in the range of 5 mg to 1000 mg. For convenience, the compounds of the présent invention can be administered in a unit dosage form. If desired, multiple doses per day of the unit dosage form can be used to increase the total daily dose. The unit dosage form, for example, may be a tablet or capsule containing about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 500, or 1000 mg of the compound of the présent invention. The total daily dose may be administered in single or divided doses and may, at the physician’s discrétion, fall outside of the typical ranges given herein.

For administration to human patients, an infusion daily dose of the compounds herein may be in the range 1 mg to 2000 mg depending, of course, on the mode of and frequency of administration, the disease state, and the âge and condition of the patient, etc. A further infusion daily dose is in the range of 5 mg to 1000 mg. The total daily

dose may be administered in single or divided doses and may, at the physician’s discrétion, fall outside of the typical ranges given herein.

These compounds may also be administered to animais other than humans, for example, for the indications detailed above. The précisé dosage administered of each 5 active ingrédient will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the âge of the animal, and the route(s) of administration.

A dosage of the combination pharmaceutical agents to be used in conjuction with the Formula l or IA compounds is used that is effective for the indication being treated.

Such dosages can be determined by standard assays such as those referenced above and provided herein. The combination agents may be administered simultaneously or sequentially in any order.

These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to détermine doses for subjects 15 whose weight falls outside this range, such as infants and the elderly.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parentéral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrète units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The spécification for the dosage unit forms of the invention are dictated by and directly dépendent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inhérent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods wellknown in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a détectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering

each agent to provide a détectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way llmit the dose and administration regimen that may be provided to a patient in practicing the présent invention.

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, spécifie dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage 10 ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on phamnacokinetic or pharmacodynamie parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the présent invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and régiments for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

The présent invention further comprises use of a compound of Formula I or IA for use as a médicament (such as a unit dosage tablet or unit dosage capsule). In another 20 embodiment, the présent invention comprises the use of a compound of Formula I or IA for the manufacture of a médicament (such as a unit dosage tablet or unit dosage capsule) to treat one or more of the conditions prevrously identified in the above sections discussing methods of treatment.

A pharmaceutîcal composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a unit dose is discrète amount of the pharmaceutîcal composition comprising a predetermined amount of the active ingrédient. The amount of the active ingrédient is generally equal to the dosage of the active ingrédient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one· third of such a dosage.

The compounds described herein may be administered as a formulation comprising a pharmaceutically effective amount of a compound of Formula I or IA, in association with one or more pharmaceutically acceptable excipients including carriers, vehicles and diluents. The term “excipient herein means any substance, not itself a

therapeutic agent, used as a diluent, adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a solid dosage form such as a tablet, capsule, or a solution or suspension suitable for oral, parentéral, intradermal, subcutaneous, or topical application. Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, stabilizers, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Acceptable excipients include (but are not limited to)

I0 stearic acid, magnésium stéarate, magnésium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnésium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches, gelatin, cellulosic materials, such as cellulose esters of alkanoic acids and cellulose alkyl esters, low meltïng wax, cocoa butter or powder, polymers such as polyvinyl-pyrrolidone, polyvinyI 15 alcohol, and polyethylene glycols, and other pharmaceutically acceptable materials.

Examples of excipients and their use may be found in Reminqton's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000).The choice of excipient will to a large extent dépend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, 20 The compounds herein may be formulated for oral, buccal, intranasal, parentéral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation. The compounds of the invention may also be formulated for sustained delivery.

Methods of preparing various pharmaceutical compositions with a certain amount of active ingrédient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions see Reminqton’s Pharmaceutical Sciences. 20th Edition (Lippincott Williams & Wilkins, 2000).

Pharmaceutical compositions according to the invention may contain 0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In any event, the composition to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the disease/condition of the subject being treated.

Since the présent invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingrédients which may 35 be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I or IA a prodrug thereof or a sait of such compound or prodrug and a second compound as described above. The kit comprises a means for containing the separate compositions such as a container, a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parentéral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses hâve the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a resuit, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be désirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows First Week, Monday, Tuesday.etc.... Second Week, Monday, Tuesday,... etc. Other variations of memory aids will be readily apparent. A daily dose can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I or IA compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

In another spécifie embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

Also, as the présent invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingrédients which may be administered jointly, the invention also relates to combining separate pharmaceutical compositions in a single dosage form, such as (but not limited to) a single tablet or capsule, a bilayer or multilayer tablet or capsule, or through the use of segregated components or compartments within a tablet or capsule.

The active ingrédient may be delivered as a solution in an aqueous or nonaqueous vehicle, with or without additional solvents, co-solvents, excipients, or complexation agents selected from pharmaceutically acceptable diluents, excipients, vehicles, or carriers.

An exemplary intravenous formulation is prepared as follows:

Formulation : Intravenous Solution

Ingrédient	Quantity
Active ingrédient dissolved in 5% Dextrose	150 mg
Injection, USP
5% Dextrose Injection, USP	1.0 mL

The solution of the above ingrédients is intravenously administered to a patient at a rate of about 1 mL per minute.

The active ingrédient may be formulated as a solid dispersion or as a self emulsified drug delivery system (SEDDS) with pharmaceutically acceptable excipients.

The active ingrédient may be formulated as an immédiate release or modified release tablet or capsule. Alternatively, the active ingrédient may be delivered as the active ingrédient alone within a capsule shell, without additional excipients.

GENERAL EXPERIMENTAI PROCEDURES

Ail chemicals, reagents and solvents were purchased from commercial sources when available and used without further purification. Proton nuclear magnetic spectroscopy 5 (¹H NMR) was recorded with 400 and 500 MHz Varian spectrometers. Chemical shifts are expressed in parts per million downfield from tetramethylsîlane, The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI) or électron scatter (ES) ionization sources. Observed mass 10 (Obs Mass) reported in the Tables correspond to the exact mass of the parent molécule plus one, unless otherwise noted. Silica gel chromatography was performed primarily using a medium pressure Biotage or ISCO Systems using columns pre-packaged by various commercial vendors including Biotage and ISCO. Microanalyses were performed by Quantitative Technologies Inc. and were within 0.4% of the calculated 15 values. The terms “concentrated and “evaporated” refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath température less than 60 °C. The abbreviation min and “h stand for minutes and “hours respectively.

Powder X-rav Diffraction

Powder diffraction analysis was conducted using a Bruker D8 diffractometer equipped with a Cu radiation source, fixed slits (divergence=1.0 mm, anti-scatter=0.6 mm, and receiving=0.6 mm) and a scintillation counter detector. Data was collected in the Theta-Theta goniometer at the Cu wavelength Ko! =1.54056 Â from 3.0 to 40.0 degrees 2-Theta using a step size of 0.040 degrees and a step time of 2.0 second. X25 ray tube voltage and amperage were set at 40 kV and 40 mA respectively. Samples were prepared by placement in a Nickel Disk (Gasser & Sons, Inc. Commack, NY) and rotated during data collection. Data were collected and analyzed using Bruker DIFFRAC Plus software (Version 2.6).

I. Beta Keto Ester Route Section

A. Carboxvlic Acid Route Section

Préparation 1

Eto₂c.

^z A OMe

Cl

Ethyl 3-(5-chloro-2-methoxyphanyl)-3-oxopropanoate

A 3000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with magnésium ethoxide (67.46 g, 589.51 mmoles) and THF (1100 mL), and the resulting mixture was stirred as ethyl hydrogen malonate (162.26 g, 1.18 moles; 145.00 mL diluted in 100 ml of THF) was added and the mixture was heated at 45 °C for 4 hours. Meanwhile, a 2000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with 5-chloro-2-methoxybenzoic acid (100 g, 536 mmoles) and THF (600 mL). To this mixture stirring at room température was added Ι,Γ-carbonyldiimidazole (95.59 g, 589.5 mmoles) in portions to avoid excess foaming. After stirring for 3 hours at room température the second solution was added gradually to the first solution. After addition the reaction mixture was heated to 45 °C. After 20 hours, the reaction mixture was concentrated under reduced pressure before adding ethyl acetate (1 L) followed by 2 N HCl (500 mL). After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCl (500 mL), saturated sodium bicarbonate (500 mL), and water (500 mL). The organic phase was concentrated under reduced pressure, the residue taken up in ethyl acetate (1000 mL) and concentrated again to afford the title compound (104.94 g).

MS (ES+) 257.2 [M+1]⁺. ¹H NMR showed product as a 7.5:1 keto:enol mixture. For the keto tautomer: ¹H NMR (500 MHz, CDCI₃) δ ppm 7.85 (d, J=2.93 Hz, 1 H) 7.45 (dd, J=8.90, 2.81 Hz, 1 H) 6.92 (d, J=8.78 Hz, 1 H) 4.18 (q, J=7.16 Hz, 2 H) 3.95 (s, 2 H) 3.90 (s, 3 H) 1.24 (t, J=7.07 Hz, 3 H).

Préparation 2

nh₂ ci (Z)-Ethyl 3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate A 5-L reaction vessel was charged with methanol (3.3 L), sodium methoxide (102.4 g,

1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65 °C for 1 hour before cooling to 50 °C and adding acetic acid (514.25 mmoles,

30.88 g, 29.47 mL) and ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). After heating to reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10 °C. After 30 min the resulting solid was collected by vacuum filtration, 10 pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65 °C) for 14 hours to afford the title compound (339.4 g).

MS (ES+) 313.2 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d_e) δ ppm 8.80 (t, J=5.00 Hz, 1 H) 7.47 (dd, J=8.90, 2.81 Hz, 1 H) 7.27 (br. s., 1 H) 7.22 (d, J=2.68 Hz, 1 H) 7.14 (d, J=8.78 Hz, 1 H) 7.09 (br. s., 1 H) 4.30 (s, 1 H) 4.03 (q, J=7.07 Hz, 2 H) 3.80 (s, 3 H) 15 3.56 (br. s., 1 H) 3.45 (br. s„ 1 H) 1.18 (t, J=7.07 Hz, 3 H).

2-(6~(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimîdin-1(2H)-yl) acetamide

A reaction vessel equipped with an efficient stirrer was charged with (Z)-ethyl 3-((2amino-2-oxoethyl)amino)-3-(5-chloro-2-methoxyphenyl)acrylate (15 g, 50.2 mmol), butyl acetate (150 mL) and trimethylsilyl isothiocyanate (160.7 mmole, 21.1 g, 22.7 mL) and the mixture was heated to reflux. After 15 hours, the mixture was cooled to 30 °C and treated with 1 N aqueous sodium hydroxide (112.5 mL, 112.5 mmoles). After 30 min, the organic layer was separated and extracted with another portion of 1 N sodium hydroxide (37.5 mL, 37.5 mmoles). The combined aqueous phases were extracted twice with dichloromethane (2 x 45 mL), filtered, and treated with 6N HCl until a pH of

2.5 was achieved. After stirring for 1 hour, the resulting solid was isolated by vacuum filtration, resuspended in 100 mL of a 1:1 methanol-water solution, heated with stirring at 50 °C for 2 hours, and cooled to room température before collecting the solid by vacuum filtration, pulling dry and drying in a vacuum oven (20 mm Hg, 50 °C) for 12 hours to afford 8.7 g of the desired product as a tan solid.

MS (ES+) 326.0 [M+1 ]⁺. ¹H NMR (500 MHz, DMSO-cfe) δ ppm 12.85 (s, 1 H) 7.57 (dd, J=9.03, 2.68 Hz, 1 H) 7.33 (s, 1 H) 7.17 - 7.23 (m, 2 H) 7.10 (s, 1 H) 5.89 (d, J=1.7,1 Hz, 1 H) 5.41 (br. s, 1 H) 3.89 (br. s, 1 H) 3.84 (s, 3 H).

Alternative Préparation of Example 1

2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropynmidin-1(2H)-yl) acetamide

A slurry of (Z)-ethyl 3-((2-amino-2-oxoethyl)amino)-3-(5-chloro-2methoxyphenyl)acrylate (20 g, 63 mmol) in a mixture of butyl acetate (140 mL) and DMF (38 mL) was treated with trimethylsilyl isothiocyanate (16.8 g, 125 mmol) and the mixture was heated at 115-120 °C for 5-6 hours. The mixture was cooled to 0-5 °C, butyl acetate (100 mL) was added and the mixture was slurried for 8 hours. The formed solids were filtered, and the filter cake was washed with butyl acetate (2 x 100 mL). The solid was dried in a vacuum oven at 50 °C for 12 hours to a tan solid. The solid was dissolved in a 5:1 mixture of DMF and water at room température and additional water was added slowly to crystallize the material. The slurry was cooled to 10 °C and stirred for 8 hours, followed by filtration and washing with water. The filter cake was dried in a vacuum oven at 50 °C for 8 hours. The solid was dissolved in a 1:1 mixture of methanol and water and the slurry was heated to 50 °C and held at this température for 2 hours. After cooling to 10 °C over 30 minutes, the slurry was held at this température for 1 hour, filtered and washed with water and dried in a vacuum oven at 50 °C for 8 hours to give the title compound as a white solid.

φ MS (ES+) 326.0 [M+1]⁺. ¹H NMR (500 MHz, DMSO-cfe) δ ppm 12.85 (s, 1 H) 7.57 (dd, J=9.03, 2.68 Hz, 1 H) 7.33 (s, 1 H) 7.17 - 7.23 (m, 2 H) 7.10 (s, 1 H) 5.89 (d, J=1.71 Hz, 1 H) 5.41 (br. s, 1 H) 3.89 (br. s, 1 H) 3.84 (s, 3 H).

Préparation 3

Eto₂c

NaO

OMe

Sodium 1-(2,5-dimethoxyphenyl)-3-ethoxy-3-oxoprop-1-en-1-olate

A 20-L reaction vessel was charged with magnésium ethoxide (3.61 moles; 413.52 g) and THF (6.6 L), and the resulting mixture was stirred as ethyl hydrogen malonate (7.23 moles; 888.89 mL; 994.67 g; diluted with 20 mL of THF) was added and the mixture was heated at 45 °C for 4 hours. Meanwhile, a 20 L reactor was charged with 2,5dimethoxybenzoic acid (3.29 moles; 600.00 g) and THF (3.6 L). To this mixture stirring at room température was added 1,T-carbonyldiimidazole (3.61 moles; 585.98 g) in portions to avoid excess foaming. After stirring for 3 hours at room température the second solution was added gradually to the first solution. After addition the reaction mixture was heated to 45 °C. After 20 hours, the reaction mixture was concentrated under reduced pressure before adding ethyl acetate (6 L) followed by 2 N HCl (3 L). After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCl (3 L), saturated sodium bicarbonate (3 L), and water (3 L). The organic phase was concentrated under reduced pressure, the residue taken up in ethyl acetate (6 L) and concentrated again to afford an oil, which was transferred to a 20 L reaction vessel with 5 L of ethyl acetate and treated with sodium methoxide (3.45 moles; 793.00 mL of a 4.35 M solution in methanol). After stirring at room température for 3 hours, an additional 6 L of ethyl acetate was added and the solid collected by vacuum filtration and dried ovemight in a vacuum oven at 40 °C to give 661 grams of the title product. MS (ES+) 253.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₀) δ ppm 6.92 (d, J=3.0 Hz, 1 H) 6.84 (d, J=8.8 Hz, 1 H) 6.73 (dd, J=8.8, 3.0 Hz, 1 H) 4.67 (s, 1 H) 3.88 (q, J=7.0 Hz, 2 H) 3.67 (s, 6 H) 1.12 (t, J=7.0 Hz, 3 H).

Préparation 4

(Z)-Ethyl 3-((2-amino-2-oxoethyl)amino)-3-(2,5-dimethoxyphenyl)acrylate

A 5-L reaction vessel was charged with methanol (3.3 L), sodium methoxide (102.4 g, 1.Θ moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65 °C for 1 hour before cooling to 50 °C and adding acetic acid (514.25 mmoles,

30.88 g, 29.47 mL) and ethyl 3-(2,5-dimethoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). After heating at reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10 °C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65 °C) for 14 hours to afford the title compound (339.4 g).

MS (ES+) 309.1[M+1]⁺. ¹H NMR (400 MHz, DMSO-d₀) δ ppm 8.84 (t, J=4.7 Hz, 1 H) 7.36 (s, 1 H) 7.09 (s, 1 H) 7.02 (d, J=8.9 Hz, 1 H) 6.97 (dd, J=8.9, 2.8 Hz, 1 H) 6.74 (d,

J=2.8 Hz, 1 H) 4.31 (s, 1 H) 4.03 (q, J=7.1 Hz, 2 H) 3.74 (s, 6 H) 3.58 (br. s., 1 H) 3.47 (br. s., 1 H) 1.18 (t, J=7.1 Hz, 3 H).

Example 2

NH₂ OMe

2-(6-(2,5-Dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin- 1(2H)-yl)acetamide

A 5-L reaction vessel equipped with an efficient stirrer was charged with (Z)-ethyl 3-((2amino-2-oxoethyl)amino)-3-(2,5-dimethoxyphenyl)acrylate (1.30 moles; 400.00 g), butyl acetate (3.4 L) and trimethylsilyl isothiocyanate (4.15 moles; 585.67 mL; 544.96 g) and 25 the mixture was heated to reflux. After 16 hours, the mixture was cooled to 40 °C and treated with 2 N aqueous sodium hydroxide (1.95 L). The organic layer was separated and extracted with another portion of 2 N sodium hydroxide (0.325 L). The combined aqueous phases were filtered, extracted twice with dichloromethane (2 x 1.6 L), and added slowly to a well-stirred 3N aqueous HCl solution (1.3 L) at room température. After stirring for 30 min, the resulting solid was isolated by vacuum filtration, rinsing with water, and pulled dry to afford a water wet cake (640 g). The cake was dissolved in dimethylformamide (2.4 L) at 90 °C and stirred as water (2 L) was added slowly to the solution. The mixture was cooled gradually to room température and the resulting solid isolated by vacuum filtration, rinsing with water and pulling dry to afford 245 g of solid. This solid was then suspended in 1.25 L of methanol and stirred as 1.25 L of water was added. The mixture was heated with stirring at 50 °C for 2 hours, and then cooled to 10 °C for 2 hours before collecting the solid by vacuum filtration, pulling dry before drying in a vacuum oven (20 mm Hg, 60 C) to afford the desired product.

MS (ES+) 322.2[M+1]⁺. ¹H NMR (500 MHz, DMSO-d6) δ ppm 12.80 (s, 1 H) 7.32 (br. s„ 1 H) 7.06 - 7.11 (m, 2 H) 7.06 (br. s., 1 H) 6.74 - 6.77 (m, 1 H) 5.82 (d, J=2.20 Hz, 1 H) 5.37 (br. s., 1 H) 3.88 (br. s., 1 H) 3.78 (s, 3 H) 3.70 (s, 3 H).

B. Methyl Ketone Route Section

Préparation 5

OMe

Methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate

To a three-necked round-bottomed flask equipped with a mechanical stirrer under N₂ was added potassium tert-butoxide (1M in THF, 108.77 mL, 108.77 mmol), followed by a solution of 2,4-dimethoxyacetophenone (10.00 g, 54.38 mmol) and dimethyl carbonate (13.93 mL, 163.15 mmol) in methyl fert-butyl ether (50 mL) dropwise via an addition funnel over 1.5 hours. During addition, reaction tumed from a initial cloudy yellow mixture to a thick red-orange slurry. Reaction mixture was stirred at room température overnight. Aqueous citric acid solution (0.5 N, 110.95 mL, 54.39 mmol) was added via addition funnel to quench the reaction. Exotherm was observed during quenching and solids dissolved to give an orange mixture. The layers were separated and the aqueous layer was extracted with methyl fert-butyl ether (2 x 25 mL). The combined organic extracts were concentrated to low volume. Heptane (50 mL) was added and brown solids precipîtated. The resulting slurry was stirred under N₂ overnight at room température. Solids were filtered and dried under N₂ to give the title compound (11,05 g, 85% yield) as a beige colored powder.

MS (ES+) 239.1 [M+1]⁺. Ή NMR (500 MHz, CDCI₃) δ 7.95 (d, 7=8.78 Hz, 1 H) 6.57 (dd, 7=8.78, 2.20 Hz, 1 H) 6.45 (d, 7=2.20 Hz, 1 H) 3.94 (s, 2 H) 3.88 (s, 3 H) 3.87 (s, 3 H) 3.73 (s, 3 H).

Préparation 6

OH (Z)-Methyl 3-(2,4-dimethoxyphenyl)-3-((2-hydroxyethyl)amino)acrylate

To a mixture of methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (3.50 g, 14.69 mmol) and acetic acid (0.17 mL, 2.94 mmol) in /-PrOH (70 mL) was added ethanolamine (0.88 mL, 14.69 mmol) and the réaction mixture was heated to 83 °C. Additional ethanolamine (0.88 mL, 14.69 mmol) was added to the reaction mixture at two, four and six hours. After stirring at 80 °C for 48 hours, the reaction mixture was cooled and concentrated under reduced pressure before the residue was suspended in equal parts of a saturated sodium bicarbonate solution and water under N₂. After stirring overnight, the solids were collected by vacuum filtration and dried in a vacuum oven at 30 °C overnight to afford the title compound (2.72 g, 63%) as a beige colored power.

¹H NMR (400 MHz, CDCIg) δ 8.77 (t, 7=5.37 Hz, 1 H) 7.13 (d, 7=8.29 Hz, 1 H) 6.47-6.52 (m, 2H) 4.53 (s, 1 H) 3.84 (s, 3 H) 3.82 (s, 3 H) 3.66 (s, 3H) 3.61 (td, J=5.45, 5.45 Hz, 2 H) 3.15 (td, 7=5.53, 5.53 Hz, 2 H).

6-(2,4-Dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

To a solution of (Z)-methyl 3-(2,4-dimethoxyphenyl)-3-((2-hydroxyethyl)amino)acrylate (9.50 g, 33.77 mmol) in 2-MeTHF (100 mL) was added (trimethylsilyl)isothiocyanate (23.80 mL, 168.79 mmol), and the reaction mixture was heated at 85 °C. After stirring ovemight, the réaction mixture was cooled, extracted with an aqueous 1N NaOH solution (1 x 250 mL, then 1 x 50 mL), the combined aqueous layers were washed with CH2CI2 (2 x 50 mL) and the aqueous phase acidified to pH 4 with concentrated HCl. The resulting solids were filtered, washed with water (2 x 50 mL) and dried under N₂ ovemight to give a light yellow powder. The product was dissolved in DMF (70 mL) at 90 °C, and then water (80 mL) was added to this hot solution. After allowing to cool to room température and stirring ovemight, the solids were collected by vacuum filtration, washed with water and dried under high vacuum to provide the title compound (6.7 g,

61%) as an off-white powder.

MS (ES+) 309.1 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.68 (s, 1 H) 7.24 (d, J=8.29 Hz, 1 H) 6.69 (d, J=2.44 Hz, 1 H) 6.65 (dd, J=8.42, 2.32 Hz, 1 H) 5.70 (d, J=2.20 Hz, 1 H) 4.69 (t, J=4.88 Hz, 1 H) 4.50 (ddd, J=13.42, 7.07, 4.15 Hz, 1 H) 3.83 (s, 3 H) 3.82 (s, 3 H) 3.59 (dt, J=13.42, 7.32 Hz, 1 H) 3.46 - 3.55 (m, 1 H) 3.38 - 3.46 (m, 1 H).

C. Aryi Halide Route Section

Préparation 7

(Z,E)-Ethyl 3-(2,6-dimethoxypyhdin-3-yl)-3-ethoxyacrylate

Bis(tri-f-butylphosphine)palladium (47 mg, 0.092 mmol)) and lithium chloride (292 mg, 0.27 mmol) were added to a flask equipped with reflux condenser, and the apparatus was evacuated under vacuum and refilled with N₂ several times. To this flask was added via cannula a degassed solution of anhydrous 1,4-dioxane (8 mL) under N₂, followed by 3-bromo-2,6-dimethoxypyridine (500 mg, 2.29 mmol), N.N25 dicyclohexylmethylamine (540 uL, 2.52 mmol) and ethyl 3-ethoxyacrylate (1.0 mL, 6.88 mmol), and the resulting orange solution was heated to 110 °C. After 20 hours, the reaction mixture was cooled to room température, quenched with water and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-50% EtOAc/heptane to yield the title compound (604 mg, 94%) as an amber oil. ¹H NMR showed the product to be composed of a 2.5:1 mixture of E/Z isomers.

Préparation 8

Ethyl 3-(2,6-dimethoxypyridin~3-yl)-3-oxopropanoate

To a solution of ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-ethoxyacrylate (600 mg, 2.13 mmol) in CH2CI2 (18 mL) was gradually added 3N aqueous HCl (3.5 mL). The reaction mixture was stirred at room température for 2 hours, then carefully added to a saturated sodium bicarbonate solution (30 mL). The layers were separated and the aqueous layer 10 was extracted with CH2CI2. The combined organic extracts were passed though a plug of cotton to dry and concentrated in vacuo. The resulting oil was purified by flash chromatography (0-60% EtOAc/heptanes) to provide the title compound (515 mg, 95% yield) as a white solid.

¹H NMR (400 MHz, CDCI3) δ ppm 8.22 (d, J=8.59 Hz, 1 H) 6.40 (d, J=8.39 Hz, 1 H) 15 4.20 (q, J=7.03 Hz, 2 H) 4.03 (s, 3 H) 3.99 (s, 3 H) 3.94 (s, 2 H) 1.26 (t, J=7.13 Hz, 3 H).

D. Amine Deprotection Route and Derivativation

Préparation 9

(Z)-Ethyl 3-(2,6-dimethoxypyndin-3-yl)-3~((2-hydroxyethyl)amino)acrylate

To a solution of ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-oxopropanoate (500 mg, 1.97 mmol) in EtOH (4 mL) was added 2-aminoethanol (0.60 mL, 9.9 mmol) followed by acetic acid (0.63 mL, 9.9 mmol). The reaction mixture was heated to 90 °C for 16 hours, cooled to room température and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was concentrated in vacuo and the crude material was purified by chromatography on silica eluting with 20-80% EtOAc/heptane to provide the title compound (573 mg, 98%) as a clear gum.

MS (ES+) 297.3 [M+1]⁺. ¹H NMR (500 MHz, CDCI₃) δ 8.75 (br. s„ 1 H) 7.44 (d, J=8.05

Hz, 1 H) 6.34 (d, J=8.05 Hz, 1 H) 4.51 (s, 1 H) 4.14 (q, J=7.16 Hz, 2 H) 3.97 (s, 3 H)

3.95 (s, 3 H) 3.64 (td, J=5.53, 5.53 Hz, 2 H) 3.17 (td, J=5.53, 5.53 Hz, 2 H) 1.96 (br. s„

H) 1.27 (t, J=7.07 Hz, 3 H).

Example 4

6-(2_l6~Dimethoxypyhdin-3-yl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropynmidin-4(1H)one

To a solution of (Z)-ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-((2hydroxyethyl)amino)acrylate (100 mg, 0.34 mmol) in 2-MeTHF (1.0 mL) was added (trimethylsilyl)isothiocyanate (0.30 mL, 2.0 mmol) and the reaction mixture was heated 15 at 80 °C for 4 hours. The cooled reaction mixture was diluted with EtOAc and washed with a saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was concentrated in vacuo. The residue was triturated with MeOH and the resulting solids were collected by vacuum filtration to give the title compound (16 mg, 16%) as a white solid.

MS (ES+) 310.2 [M+1]⁺. ¹H NMR (500 MHz, CD₃OD) δ 7.60 (d, J=8.29 Hz, 1 H) 6.47 (d, J=8.05 Hz, 1 H) 5.76 (s, 1 H) 4.66 - 4.75 (m, 1 H) 4.01 (s, 3 H) 3.98 (s, 3 H) 3.77 - 3.85 (m, 2 H) 3.57 - 3.63 (m, 1 H)

Préparation 10

(Z)-ethyl 3-(2-(tert-butoxycarbonylamino)ethylamino)-3-(2,4-dimethoxyphenyl)acrylate

A solution of ethyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (41.91 g, 166 mmol), tertbutyl 2-aminoethylcarbamate (54.7 g, 342 mmol), and acetic acid (16.14 g, 269 mmol) in éthanol (180 mL) was heated at reflux for 5.3 h. After removal of most of the solvent by rotary évaporation, the resulting oil was partitioned between EtOAc (ca. 300 mL) and 10% (w/v) aq. ammonium chloride. The EtOAc layer was separated and then washed with water, 10% (w/v) aq. ammonium chloride (3 mL), and brine (10 mL). The EtOAc layer was washed with sat. aq. sodium bicarbonate, brine (6 mL) was added, and the émulsion was allowed to settle. The EtOAc layer was finally washed with brine and dried over sodium sulfate. Evaporation of the EtOAc layer's volatile components afforded a viscous, amber taffy (62.3 g, 95%). This crude product was used without further purification.

LCMS (ESI) m/z: 395.4 [M+H] (100 %). ¹H NMR (500 MHz, CDCI₃) δ 1.27 (t, J=7,1 Hz, 3 H), 1.43 (s, 9 H), 3.03-3.21 (m, 4 H), 3.83 (s, 6 H), 4.14 (q, J=7.1 Hz, 2 H), 4.51 (s, 1 H), 4.88 (br. s., 1 H), 6.47 (d, J=1,7 Hz, 1 H), 6.50 (dd, J=8.4, 1.8 Hz, 1 H), 7.12 (d, J=8.3 Hz, 1 H), 8.65 (br. s., 1 H).

Example 5 O

OMe tert-butyl 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropynmidin-1(2H)yl)ethylcarbamate (Trimethylsilyl)isothocyanate (66 mL, 470 mmol) was added to a solution of (Z)-ethyl 3(2-(tert-butoxycarbonylamino)ethylamino)-3-(2,4-dimethoxyphenyl)acrylate (62.3 g, 158 mmol) in 2-MeTHF (160 mL). After heating at reflux under nitrogen for 15 h, the reaction mixture was cooled to ambient température and quenched by cautious addition of sat. aq. sodium bicarbonate (470 mL). The rxn. mixture was extracted with dichloromethane, and the aq. layer was twice more extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to afford a yellow-amber foam, which was purified by chromatography on silica eluting with 0-80%

I ethyl acetate in heptanes to afford 49.2 g of solid. These solids were re-suspended in 1:1 EtOAc/heptane at 70 °C for 1 h and then at r.t. for another 1 h. The resulting solids were isolated by vacuum filtration, rinsing with additional 1:1 EtOAc/heptane, and pulled dry on the filter. The title compound was obtained as a white, microcrystalline solid (38.3 g, 59.5 % yield).

LCMS (ESI) m/z: 408.3 [M+H] (100 %). ¹H NMR (500 MHz, CDCI₃, major rotamer) δ 1.40 (s, 9 H), 3.23-3.45 (m, 2 H), 3.74 (dt, J=14.4, 5.4 Hz, 1 H), 3.84 (s, 3 H), 3.87 (s, 3 H), 4.68-4.81 (m, 2 H), 5.81 (d, J=2.2 Hz, 1 H), 6.51 (d, J=2.2 Hz, 1 H), 6.59 (dd. J=8.4, 2.1 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 9.58 (br. s., 1 H).

1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropynmidin-4(1H)-one hydrochloride

To a solution of EtOH (50 mL, 860 mmol) in EtOAc (390 mL), cooled in an ice/water bath, was slowly added acetyl chloride (55 mL, 770 mmol) over 3 minutes. After 5 minutes the cooling bath was removed, and after stirring for 45 min, the solution was added to tert-butyl 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin1(2H)-yl)ethylcarbamate (31.7 g, 77.8 mmol). A suspension formed over time, and after stirring for 5 h, the solid was collected by vacuum filtration, rinsing with EtOAc. The solid was pulled dry and dried further under vacuum to afford 26.6 g (99.3 %) of thé desired product as a colorless solid.

LCMS (ESI) m/z: 291.3 [M-NH3+H] (100 %), 308.3 [M+H] (33 %), 615.5 [2M+H] (2.3 %). ¹H NMR (500 MHz, CD3OD) δ 3.06 (ddd, J=12.9, 7.8, 5.9 Hz, 1 H), 3.12 (ddd,

J=12.9, 7.7, 6.4 Hz, 1 H), 3.87 (s, 3 H), 3,89 (s, 3 H), 4,14 (ddd, J=14.0, 7.8, 5.9 Hz, 1

H), 4.82 (ddd, J=14.0, 7.7, 6.4 Hz, 1 H), 5.80 (s, 1 H), 6.70 (dd, J=8.3, 2.2 Hz, 1 H), 6.73 (d, J=2.2 Hz, 1 H), 7.27 (d, J=8.3 Hz. 1 H).

Example 7

2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl) ethyl)guanidine

Düsopropylethylamine (0.22 mL, 1.3 mmol) was added to a suspension of 1-(2aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one hydrochloride (181.6 mg, 0.528 mmol) (the product of Example 6) and 1H-pyrazole-1carboxamtdine hydrochloride (90.6 mg, 0.618 mmol) in DMF (0.55 mL). After heating for 1 h at 55 °C, the reaction mixture was cooled to ambient température, diluted with EtOH (1.6 mL), and the solid product collected by vacuum filtration, rinsing with additional EtOH. The isolated solid was re-suspended in EtOH (2.1 mL) for 3 h at r.t. before being collected again by vacuum filtration and rinsing with additional EtOH. The desired product was obtained, after drying, as a colorless solid. Solubility data for this product is consistent with it being in its zwitterionic form.

1H NMR (500 MHz, CD3OD+2 drops 20. % DCI in D2O) δ 3.31-3.37 (m, 1 H), 3.67 (ddd, J=14.8, 8.6, 5.9 Hz, 1 H), 3.88-3.99 (m, 1 H), 3.90 (s, 6 H), 4.66-4.77 (m, 1 H), 5.80 (s, 1 H), 6.69 (d, J=2.2 Hz, 1 H), 6.71 (dd, J=8.3, 2.2 Hz, 1 H), 7.28 (d, J=8.3 Hz, 1 H).

2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)yl)ethyl)guanidine hydrochloride

The product from the above reaction (116.3 mg, 0.333 mmol) was suspended in dioxane and treated with a 4.0 M HCI/dioxane solution (0.30 mL, 1.2 mmol). After thorough vortexing, the volatile components of the mixture were removed to afford a white solid (130.6 mg, 0.338 mmol). LCMS (ESI) m/z: 350.1 [M+H] (100 %).

tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl)ethylamino)-2-oxoethylcarbamate

To a solution of 1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3dihydropyrimidin-4(1H)-one hydrochloride (123 mg, 0.4 mmol)(the product of Example 6) in dry methylene chloride (4 mL) was added 0-(7-azabenzotriazol-1-yl)-N,N_lN’,N'tetramethyluronium hexafluorophosphate (182 mg, 0.48mmol) and tertio butoxycarbonylamino-acetic acid (70 mg, 0.4 mmol) and diisoproplyethylamine (336 mg, 1.6 mmol). After stirring ovemight at RT the reaction mixture was concentrated under reduced pressure and the residue purified by préparative thin layer chromatography (1:1 petroleum ether : ethyl acetate) to provide tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)-4oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)-yl)ethylamino)-2-oxoethylcarbamate (120 mg,

65%).

2-amino-N-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl)ethyl)acetamide hydrochloride

To a solution of tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4dihydropyrimidin-1(2H)-yl)ethylamino)-2-oxoethylcarbamate (70 mg, 0.15 mmol) in ethyl acetate (2 mL) was added a solution of HCl in ethyl acetate (2 mL). After stirring at room température for 4 hours, the reaction mixture was concentrated under reduced pressure to afford the desired 2-amino-N-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4dihydropyrimidin-1(2H)-yl)ethyl)acetamide hydrochloride as a solid (65 mg, 100%).

II. 6-lodo-Thiouracil Route Section

Préparation 12

H H

N-((2-Methoxyethyl)carbamothioyl)benzamide

2-Methoxyethylamine (17.7 mL, 202.2 mmol) was added dropwise over 30 minutes to a 10 stirring solution of benzoylisothiocyanate (30.00 g, 183.8 mmol) in CH₂CI₂ (300 mL) at room température under argon and the mixture was stirred at room température for 16 hours. The mixture was washed sequentially with 10% aqueous citric acid (75 mL), water (75 mL) and brine (75 mL), dried over MgSO₄ and concentrated in vacuo. The resulting yellow oil solidîfied on standing to give the title compound (41,85 g, 96%). The 15 material was used directly in the next step without further purification.

Préparation 13 NH, nh

OMe

1-(2-Methoxyethyl)thiourea

A solution of N-((2-methoxyethyl)carbamothioyl)benzamide (41.82 g, 175.5 mmol), potassium carbonate (24.25 g, 175.5 mmol) in MeOH (200 mL) and water (200 mL) was stirred at room température for 16 hours. The mixture was concentrated in vacuo and the aqueous layer was extracted with EtOAc (5 x 100 mL), The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The resulting yellow oil solidîfied on standing to provide the title compound (21.38 g, 91%). The material was used directly in the next step without further purification.

MS (ES+) 135.1 (M+1 )⁺. ¹H NMR (500 MHz, CDCI₃) δ 6.66 (br. s„ 1 H) 6.46 (br. s., 1 H) 5.81 (br. s., 1 H) 3.80 (br. s., 2 H) 3.48 - 3.65 (m, 2 H) 3.40 (s, 3 H).

Préparation 14 ο

OMe

-(2-Methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3 mmol) and ethyl 3,3diethoxypropanoate (46.5 mL, 239,0 mmol) in MeOH (300 mL) was added a freshly prepared solution of 0.96N sodium methoxide in MeOH (250 mL, 239.0 mmol) dropwise over 30 minutes at room température under argon. The reaction mixture was heated to 60 °C for 45 minutes and cooled to room température. Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue. The mixture was stirred at reflux for an additional 3 hours and then cooled to room température. Water (200 mL) was added and the layers were separated. The aqueous layer was washed with CH₂C1₂ (50 mL), neutralized with 2N aqueous HCl and extracted with CH₂CI₂ (3 x 200 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was recrystallized from /-PrOH (200 mL) to give the title compound (13.3 g, 45%) as a light yellow crystalline solid.

MS (ES+) 187.1 (M+1)⁺. ¹H NMR (400 MHz, CDCI₃) δ 9.81 (br. s„ 1 H) 7.39 (d, J=7.81 Hz, 1 H) 5.94 (d, J=8.00 Hz, 1 H) 4.39 (dd, J=5.27, 4.49 Hz, 2 H) 3.73 (dd, J=5.07, 4.29 Hz, 2 H) 3.36 (s, 3 H).

Préparation 15

O

OMe

6-lodo-1 -(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

To a stirring solution of diisopropylamine (8.3 mL, 59.10 mmol) in THF (50 mL) was added n-butyl lithium (2N in hexanes, 30.0 mL, 60.0 mmol) dropwise at -78 ’C under argon. The reaction mixture was slowly warmed to -20 °C and then cooled to -78 °C. A solution of 1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (5.0 g, 26.85 mmol) in THF (50 mL) was added dropwise at -78 °C. The reaction mixture was slowly warmed to -10 C over 1 hour and then cooled to -78 C. A solution of iodine (15.0 g, 59.07 mmol) in THF (50 mL) was added at -78 °C and the reaction mixture was stirred at room température for 20 hours. Reaction was diluted with saturated aqueous ammonium chloride (200 mL) and the organic solvents were removed under reduced pressure. The aqueous residue was acidified to pH 4 with 1N aqueous HCl and extracted with CH₂CI₂ (3 x 300 mL, 1 x 200 mL). The combined organic layers were washed with 10% aqueous sodium thiosulfate solution (400 mL), brine (300 mL), dried over MgSO₄ and concentrated in vacuo. The resulting residue was stirred in CH₂CI₂ at room température and solids were collected by filtration to give the title compound (9.05 g, 54%) as a pale brown solid. The filtrate was concentrated and purified by flash chromatography (0-25% CH₂CI₂/EtOAc) to afford a second batch of the title compound (3.10 g, 18%) as a cream colored solid (72% combined yield).

MS (ES+) 313.0 [M+1f. ¹H NMR (400 MHz, CDCI₃) δ 9.88 (br. s., 1 H) 6.70 (s, 1 H)

4.88 (br. s., 2 H) 3.78 (t, J=6.05 Hz, 2 H) 3.40 (s, 3 H).

Préparation 16

O

OMe

6-lodo-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one

To a stirring solution of 6-iodo-1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)one (9.00 g, 28.83 mmol) in MeCN (200 mL) was added diisopropylethylamine (5.0 mL, 28.83 mmol) and iodomethane (9.0 mL, 144.17 mmol). The reaction mixture was stirred at room température for 18 hours, and concentrated in vacuo. The residue was partitioned ortioned between CH₂CI₂ (200 mL) and 1N aqueous HCl (100 mL). The layers were separated and the organic layer was washed with brine (100 mL), dried over MgSO₄ and concentrated in vacuo. The resulting residue was purified by hot trituration with CH₂CI₂/heptane to give the title compound (4.05 g, 43%) as a cream colored solid.

MS(ES+) 327.0 [M+1 ]⁺. ¹H NMR (500 MHz, CDCI₃) δ 6.77 (s, 1 H) 4.42 (t, J=6.34 Hz, 2

H) 3.69 (t, J=6.34 Hz, 2 H) 3.40 (s, 3 H) 2.58 (s, 3 H).

IIA. Suzuki Route Section

Préparation 17

OMe OMe

6-(2,5-dimethoxyphenyl)-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one

To a mixture of 6-iodo-1-(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1H)-one (100 mg, 0.31 mmol), (2,5-dimethoxyphenyl)boronic acid (0.37 mmol, 1.2 equiv.) and [1,Tbis(diphenylphosphino)ferrocene] dichloropalladium(ll) (14 mg, 0.017 mmol, 0.05 equiv) was added degassed 1,4-dioxane (2 mL), followed by a degassed solution of sodium carbonate (65 mg, 0.61 mmol) in water (0.7 mL). This reaction mixture was subjected to microwave irradiation at 120 °C for 30 minutes and the crude reaction mixture was used directly in the next step.

Example 9

6-(2,5-dimethoxyphenyl)- 1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one Ammonium sulfide (1 mL, 14.63 mmol) and pyridine (1 mL, 12.41 mmol) were added to the crude reaction mixture obtained from the previous Suzuki coupling reaction (0.31 mmol theoretical yield), and the mixture was subjected to microwave irradiation at 75°C for 30 minutes. The reaction mixture was cooled to room température, taken up in CH2CI2 (10 mL) and water (10 mL), then basified with 2N NaOH. The layers were separated and the aqueous layer was washed with CH₂CI₂ (2x10 mL). The aqueous layer was then acidified to pH 6 with 2N aqueous HCl and extracted with EtOAc (3x10 mL). The combined organic extracts were dried over MgSO₄ and concentrated in vacuo.

The crude reaction mixture was purified by flash chromatography to give the desired product (38 mg, 38% over two steps) as solid.

MS (ES+) 323.1 [M+1]⁺. ¹H NMR (400 MHz, CDCI₃) δ 10.14 (br. s„ 1 H), 7.01 (dd,

J=8.90, 3.10 Hz, 1 H), 6.89 (d, J=9.16 Hz, 1 H), 6.80 (d, J=3.21 Hz, 1 H), 5.84 (d,

J=1.83 Hz, 1 H), 4.70 (dt, J=13.74, 4.35 Hz, 1 H), 3.83 - 3.92 (m, 1 H), 3.78 - 3.82 (m, 6

H), 3.73 - 3.79 (m, 1 H), 3.44 (ddd, J=9.96, 5.84, 3.89 Hz, 1 H), 3.16 (s, 3 H)

Il B. Negishi Route Section

1-(2-Methoxyethyl)-2-(methylthio)-6-(pyridin-2-yl)pyrimidin-4(1H)-one η-Butyl lithium (2.0 M, 0.32 mL, 0.64 mmol) was slowly added to 2-bromopyridine (0.058 mL, 0.61 mmol) in dry THF (2 mL) at -78 °C. After 30 minutes, anhydrous zinc chloride (92 mg, 0.67 mmol) was added and the reaction mixture was stirred for an additional 30 minutes as it warmed to room température. To the reaction mixture was added 6-iodo-1(2-methoxyethyl)-2-(methylthio)pyrimidin-4(1 H)-one (200 mg, 0.61 mmol), followed by tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol), 2-dicyclohexylphosphino2',6'-dimethoxybiphenyl (26 mg, 0.06 mmol) and DMF (2 mL), and the reaction mixture was then heated to 80 °C. After stirring overnight, the product was extracted with EtOAc (3x10 mL) and washed with water (3 x 10 mL). The aqueous was then acidified with 2M HCl to pH 4 and the product was extracted with DCM (3x10 mL) and dried over MgSO₄, The solvent was removed in vacuo to give an orange oil (100 mg) as a mixture of 1-(2-methoxyethyl)-2-(methylthio)-6-(pyridin-2-yl)pyrimidin-4(1H)-one (37%) and 1-(2methoxyethyl)-2-(methylthio)pyrimidin-4(1 H)-one (32%).

Example 10

1-(2-Methoxyethyl)-6-(pyndin-2-yl)-2-thioxo-2,3-dihydropynmidin-4(1H)-one

A mixture of crude 1-(2-methoxyethyl)-2-(methylthio)-6-(pyridin-2-yl)pyrimidin-4(1H)-one (100 mg, 0.36 mmol), ammonium sulfide solution (0.2 mL, 0.64 mmol) and pyridine (0.2 mL) was stirred in dioxane (2 mL) at 70 °C for 4 hours. The reaction mixture was diluted with water (10 mL), basified with 2M NaOH and washed with dichloromethane (3x10 mL). The aqueous layer was acidified to pH 6 with 2M HCl and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with water (3x10 mL), brine (3x10 mL), dried over MgSO₄ and concentrated in vacuo. The crude material was purified by mass directed automatic purification using an acidic method to give the product as a brown solid (3 mg, 3%).

MS(ES+) 264.07 [M+H]⁺. 1H NMR (400 MHz, CDCI3) 6 8,76 (br s, 1H), 7.92 (br s, 1H), 7,48-7.54 (m, 2H), 7.32 (br d, 1H), 5.95 (br d, 1H), 4.65 (br s, 2H), 3.64 (br s, 2H).

The following Examples of Table 2 were prepared from the corresponding carboxylic acid to afford the intermediate beta-keto-ester as described for the Préparations in the Carboxylic Acid Route Section above followed by employing other methods described above in the I. Beta-Keto Ester Route Section as well as standard methods and techniques known to those skilled in the art.

Table 2. Examples from Carboxylic Acid Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
11	0	1-(2aminoethyl)-6(2methoxyphenyl) ~2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	278.1	1H NMR (400 MHz, DMSO-d6) δ ppm 7.58 - 7.98 (m, 3 H), 7.54 (td, J=8.20, 1.60 Hz, 1 H), 7.35 (dd, J=7.56, 1.60 Hz, 1 H), 7.19 (d, J=8.24 Hz, 1 H), 7.08 (t, J=7.44 Hz, 1 H), 5.77 (s, 1 H), 4.60 (ddd, J=13.51, 7.79, 6.41 Hz, 1 H), 3.82 - 3.87 (m, 1 H), 3.81 (s, 3 H), 2.76 - 2.91 (m, 2 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
12	0 OH^ I	1-(2hydroxyethyl)-6(4methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one	279.0	1H NMR (500 MHz, METHANOL-d4) δ ppm 7.38 (d, J=8.54 Hz, 2 H) 7.05 (d, J=8.54 Hz, 2 H) 5.77 (s, 1 H) 4.37 (t, J=6.22 Hz, 2 H) 3.86 (s, 3 H) 3.74 (t, J=6.34 Hz, 2 H)
13	-¼.	4-(3-(2methoxyethyl)6-oxo-2-thioxo- 1,2,3,6tetrahydropyrimi din-4yllbenzonitrile	268.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.53 (br. s, 1 H), 7.80 (d, J=8.70 Hz, 2 H), 7.50 (d, J=8.70 Hz, 2 H), 5.80 (s, 1 H), 4.30 (br. s., 2 H), 3.65 (t, J=5.04 Hz, 2 H), 3.21 (s. 3 H)
14	0	1-(2- aminoethyl)-6(2,3-dihydro-1benzofuran-5yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	290.0	1H NMR (300 MHz, DMSO-d6) δ ppm 12.82 (br. s., 1 H), 7.79 (br. s„ 3 H), 7.38 (s, 1 H), 7.24 (dd, J=8.01, 1.74 Hz, 1 H), 6.90 (d, J=8.36 Hz, 1 H), 5.76 (d. J=2.09 Hz, 1 H), 4.61 (t, J=8.71 Hz, 2 H), 4.34 (t, J=8.01 Hz, 2 H), 3.24 (t, J=8.71 Hz, 2 H), 2.89 - 3.02 (m, 2 H)
15		6-(2,3-dihydro1-benzofuran-5yl)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	291.0	1H NMR (300 MHz, DMSO-d6) δ ppm 12.68 (br. s., 1 H), 7.34 (s, 1 H), 7.20 (d, J=8.36 Hz, 1 H), 6.86 (d, J=8.36 Hz, 1 H), 5.70 (d, J=2.09 Hz, 1 H), 4.75 (t, J=5.57 Hz, 1 H), 4.60 (t, J=9.06 Hz, 2 H), 4.19 (t, J=6.62 Hz, 2 H), 3.53 (td, J=5.60 Hz, 2 H), 3.23 (t, J=8.71 Hz, 2 H)
16	OH	6-(2,3-dihydro1-benzofuran-7yl)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	291.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.50 (br. s., 1 H), 7.33 (d, J=7.10 Hz, 1 H), 7.04 (d, J=7.56 Hz, 1 H), 6.95 (t, J=7.56 Hz, 1 H), 5,86 (s, 1 H), 4.70-4.81 (m, 1 H), 4.64 (t, J=8.70 Hz, 2 H), 3.98 4.10 (m, 1 H), 3.81 -3.90(m, 1 H), 3.65 - 3.78 (m, 2 H), 3.30 (t, J=8.70 Hz, 1 H), 1.86 (t, J=5.95 Hz, 1 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
17	0 hfJL cri' °γ^ LJ NH,	2-(6-(2methoxyphenyl) -4-oxo-2-thioxo- 3.4dihydropyrimidin -1(2H)yl]acetamide	292.0	1H NMR (400 MHz, DMSO-d6) ôppm 12.78 (br. s., 1 H), 7.48 (td, J=7.90, 1.60 Hz, 1 H), 7.26 (br. s., 1 H), 7.08-7.17 (m, 2 H), 7.00 (t, J=7.44 Hz, 1 H), 6.96 (br. s., 1 H), 5.76 (d, J=2.06 Hz, 1 H), 5.22 - 5.48 (m, 2 H), 3.80 (s, 3 H)
18	O H|l ri6	1-(3aminopropyl)-6(2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	292.0	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (ddd, J=8.00, 8.00, 1.30 Hz, 1 H), 7.33 (dd, J=7.42, 1.37 Hz, 1 H), 7.17 (d, J=8.39 Hz, 1 H), 7.10 (dd, J=7.40, 7.40 Hz, 1 H), 5.78 (s, 1 H), 4.58 (dt, J=15.13, 7.66 Hz, 1 H), 3.88 (s, 3 H), 3.72 - 3.83 (m, 1 H), 2.73 (t, J=7.81 Hz, 2 H), 1.94-2.07 (m, 1 H), 1.75- 1.88 (m, 1 H) .
19	0 H™|1 cri' Jv NH, I	1-(2aminoethyl)-6(2-methoxy-5methylpyridin-3yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one trifluoroacetate	292.9	1H NMR (400 MHz, DMSO-d6): δ 12.99 (br, 1H), 8.27 (s, 1H), 7.81 (br, 3H), 7.74 (s, 1H), 5.96 (s, 1H), 3.96-4.02 (m, 5H), 3.00 (m, 2H), 2.38 (s, 3H).
20	X3 L	1-(2methoxyethyl)- 6-(3methoxypyridin2-yl)-2-thioxo2,3dihydropyrimidin -4(1H)-one	294.0	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.30 (dd, J=4.81, 1.14 Hz, 1 H). 7.43 (dd, J=8.70, 4.58 Hz, 1 H), 7.35 (dd, J=8.70, 1.37 Hz, 1 H), 5.92 (s, 1 H), 4.33 (br. s„ 2 H), 3.88 (s, 3 H), 3.55 (t, J=6.41 Hz, 2 H), 3.13 (s, 3 H)
21	O	1-(2hydroxyethyl)-6(2-methoxy-6methylpyridin-3yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	294.1	1H NMR (400 MHz, DMSO-d6) ôppm 12.73 (br. s., 1 H), 7.62 (d, J=7.56 Hz, 1 H), 6.97 (d, J=7.33 Hz, 1 H), 5.76 (s, 1 H), 4.69 (t, J=5.38 Hz, 1 H), 4.43 4.55 (m, 1 H), 3.86 (s, 3 H), 3.44 - 3.60 (m, 3 H), 2.43 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
22	O	1-(2hydroxyethyl)-6(3-methoxy-6methylpyridin-2yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	294.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.33 (d, J=8.47 Hz, 1 H), 7.29 (d, J=8.47 Hz, 1 H), 5.93 (s, 1 H), 4.18-4.35 (m, 2 H), 3.91 -3.98 (m, 2 H), 3.84 (s, 3 H), 2.54 (s, 3 H)
23	O f6	1-(2methoxyethyl)- 6-(2methoxypyridin3-yl)-2-thioxo- 2,3dihydropyrimidin -4(1H)-one	294.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.76 (br. s, 1 H), 8.32 (dd, J=5.04, 1.83 Hz, 1 H), 7.56 (dd, J=7.33, 1.83 Hz, 1 H), 7.03 (dd, J=7.33, 5.04 Hz, 1 H), 5.80 (s, 1 H), 4.76 (dt, J=13.74, 3.43 Hz, 1 H), 3.99 (s, 3 H), 3.69 - 3.86 (m, 2 H), 3.40 (dt, J=10.00, 4.20 Hz, 1 H), 3.15 (s, 3 H)
24	0 OH^	1-(2hydroxyethyl)-6[2(methylthio)phe nyl]-2-thioxo2,3dihydropyrimidin -4(1H)-one	295.0	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.54 (br. s, 1 H), 7.44 - 7.52 (m, 1 H), 7.30 (d, J=8.01 Hz, 1 H), 7.25 - 7.27 (m, 2 H), 5.85 (s, 1 H), 4.71 (dt, J=13.74, 5.38 Hz, 1 H), 3,88 (td, J=11,28, 5.38 Hz, 1 H), 3.80 (dt, J=13.74, 5.95 Hz, 1 H), 3.70 (td, J=11.05, 5.15 Hz, 1 H), 2.49 (s, 3 H), 1.87 (t, J=5.72 Hz, 1 H)
25	0 ^NH,	1(2aminoethyl)-6(4-fluoro-2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	296.0	3H NMR (400 MHz, DMSO-d6) δ ppm 12.89 (s, 1 H), 7.80 (br. s., 3 H), 7.44 (dd, J=8.39, 6.64 Hz, 1 H), 7.18 (dd, J=11.22, 2.24 Hz, 1 H), 6.97 (ddd, J=8.40, 8.40, 2.20 Hz, 1 H), 5.82 (s, 1 H), 4.54 - 4.66 (m, 1 H), 3.86 (s, 3 H), 3.79 - 3.85 (m, 1 H), 2.88 (br. s, 2 H)
26	S —o TrSjH AAA0 F	1-(2aminoethyl)-6(5-fluoro-2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	296.2	1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (s, 1 H), 7.88 (br. s., 3 H), 7.42 (td, J=8.78, 3.12 Hz, 1 H), 7.34 (dd, J=8.20, 3.12 Hz, 1 H), 7.23 (dd, J=9.27, 4.20 Hz, 1 H), 5.88 (d, J=1.95 Hz, 1 H), 4.53-4.63 (m, 1 H), 3.853.93 (m, 1 H), 3.83 (s, 3 H), 2.85 - 2.99 (m, 2 H)

ai

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
27	O OH	6-(4-fluoro-2methoxyphenyl) -1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	297.0	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.33 (dd, J=8.39, 6.44 Hz, 1 H), 6.95 (dd, J=10.83, 2.24 Hz, 1 H), 6.82 (ddd, J=8.40, 8.40, 2.30 Hz, 1 H), 5.73 (s, 1 H), 4.57 4.69 (m, 1 H), 3.87 (s, 3 H), 3,67 - 3.83 (m, 2 H), 3.55 - 3.62 (m, 1 H)
2Θ	Ju F	6-(5-fluoro-2methoxyphenyl) -1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(lH)-one	297.3	1H NMR (500 MHz, DMSO-d6) ôppm 12.77 (br. s., 1 H), 7.37 (ddd, J=8.70, 8.70, 2.90 Hz, 1 H), 7.26 (dd, J=8.42, 3.05 Hz, 1 H). 7.18 (dd, J=9.03, 4.15 Hz, 1 H), 5.82 (d, J=1.71 Hz, 1 H), 4.45-4.54 (m, 1 H), 3.82 (s, 3 H), 3.50 - 3.64 (m, 2 H), 3.40 3.47 (m, 1 H)
29	-ÿk JL T*1 oÇju NH,	2-(6-(1 H-indol-4yl)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	301.0	1H NMR (400 MHz, DMSO-d6) ôppm 12.81 (br. s., 1 H), 11.49 (br. s, 1 H), 7.54 (d, J=8.31 Hz, 1 H), 7.49 (br. s., 1 H), 7.27 (br. s., 1 H), 7.17 (t, J=7.83 Hz, 1 H), 6.99 (d, J=7.34 Hz, 1 H), 6.96 (br. s., 1 H), 6.36 (br. s., 1 H), 5.84 (s, 1 H), 5.16-5.34 (m, 1 H), 3.77 - 3.96 (m, 1 H)
30	0	1-(3- aminopropyl)-6(1H-indol-4-yl)2-thioxo-2,3dihydropyrimidin -4(1H)-one trifluoroacetate	301.1	1HNMR (300 MHz, METHANOL-d4) δ ppm 7.60 (d, J=8.36 Hz, 1 H), 7.43 (d, J=3.14 Hz, 1 H), 7.28 (t, J=7.66 Hz, 1 H), 7.12 (d, J=6.97 Hz, 1 H), 6.37 (d, J=2.09 Hz, 1 H). 5.92 (s, 1 H), 4.49-4.63 (m, 1 H), 3.94-4.09 (m, 1 H), 2.63 (t, J=7.84 Hz, 2 H), 1.79-2.05 (m, 2 H)
31	O	2-(6-(1benzofuran-7yl)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	301.9	1H NMR (300 MHz, METHANOL-d4) δ ppm 7.88 (d, J=2.09 Hz, 1 H), 7.80-7.84 (m, 1 H), 7.34 - 7.38 (m, 2 H), 6.99 (d, J=2.26 Hz, 1 H), 5.98 (s, 1 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
32	H	1-(3- amînopropyl)-6(1H-indazol-3yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one formate	302.1	1.36 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
33	0	6-(1 H-indol-3yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	302.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.63 (s, 1 H), 7.45 (t, J=8.01 Hz, 2 H), 7.22 (t, J=7.79 Hz, 1 H), 7J6 (t, J=7.33 Hz, 1 H), 5.92 (s, 1 H), 4.64 (br. s., 2 H), 3.60 (t, J=5.72 Hz, 2 H), 3.03 (s, 3 H)
34	0 A	1-(3aminopropyl)-6(1-benzofuran7-yl)-2-thioxo2,3dihydropyrimidin -4(1H)-one hydrochloride	302.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.91 (d, J=1.96 Hz, 1 H), 7.88 (dd, J=6.85, 2.45 Hz, 1 H), 7.41 7.46 (m,2H), 7.03 (d, J=1.96 Hz, 1 H), 5.98 (s, 1 H), 4.48 4.60 (m, 1 H), 3.87-4.00 (m, 1 H), 2.67 (t, J=7.83 Hz, 2 H), 1.83-1.98 (m, 2H)
35	0	1-(2methoxyethyl)6-(1Hpyrrolo[2,3b]pyridin-3-yl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	303.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (br. s„ 1 H), 8.30 (dd, J=4.81, 1.60 Hz, 1 H), 7.94 (dd, J=8.01, 1.60 Hz, 1 H), 7.89 (s, 1 H), 7.17 (dd, J=7.79, 4.58 Hz, 1 H), 5.87 (s, 1 H), 4.44 (br. s„ 2 H), 3.45 (t, J=5.95 Hz, 2 H), 2.92 (s, 3 H)
36	0 Nl^	1-(2aminoethyl)-6(1-benzothien-3yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	304.0	1H NMR (400 MHz, D2O) δ ppm 7.92-7.94 (m, 1 H), 7.82 (s, 1H), 7.51-7.48 (m, 1H), 7.397.37 (m, 2H), 5.99 (s, 1H), 4.724.71 (m, 1 H), 4.05-3.99 (m, 1H), 3.01-2.94 (m, 2H)
37	0	2-(6-(2,3dîhydro-1benzofuran-5yl)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yllacetamide	304.0	1H NMR (300 MHz, DMSO-d6) δ ppm 12.74 (br. s., 1 H), 7.45 (br. s., 1 H), 7.29 (br. s, 1 H), 7.09 - 7.17 (m, 2 H), 6.85 (d, J=8.36 Hz, 1 H), 5.75 (s, 1 H), 4.59 (t, J=8.62 Hz, 1 H), 3.20 (t, J=8.88 Hz, 2 H)

Θ3

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
38	0 7¾	1-(3aminopropyl)-6(2,3-dihydro-1benzofuran-5yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	304.1	1H NMR (300 MHz, DMSO-d6) δ ppm 12.74 (s, 1 H), 7.81 (br. s., 3 H), 7.37 (s, 1 H), 7.23 (dd, J=8.36, 2.09 Hz, 1 H), 6.88 (d, J=8.36 Hz, 1 H), 5.76 (d, J=2.79 Hz, 1 H), 4.61 (t, J=8.71 Hz, 2 H), 4.10 (t, J=6.97 Hz, 2 H), 3.25 (t, J=8.71 Hz, 2 H), 2.53-2.61 (m, 2 H), 1.79-1.93 (m, 2 H)
39	0	6-(1-benzothien3-yl)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	305.0	1H NMR (400MHz, METHANOL-d4) 7.97 (d, 1 H), 7.92 (s, 1H), 7.61 (dd, 1 H), 7.46-7.45 (m, 2H), 5.92 (s, 1H), 4.65-4.63 (m, 1H), 3.90-3.85 (m, 1H), 3.84-3.80 (m, 1H), 3.62-3.61 (m, 1H)
40	0	6-(1-benzothien- 2-yl)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	305.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.82 (br. s., 1 H), 8.02 8.06 (m, 1 H), 7.89-7.94 (m, 1 H), 7.74 (s, 1 H), 7.41 - 7.47 (m, 2 H), 6.06 (d, J=2.29 Hz, 1 H), 4.86 (t, J=6.18 Hz, 1 H), 4.31 (t, J=6.18 Hz, 2 H), 3.63 (td, J=6.40, 6.40 Hz, 2 H)
41		6-(2,3-dihydro1-benzofuran-7yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	305.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.89 (br. s., 1 H), 7.31 (d, J=7.33 Hz, 1 H), 7.03 (d, J=7.56 Hz, 1 H), 6.93 (t, J=7.56 Hz, 1 H), 5.84 (s, 1 H), 4.68-4.81 (m, 1 H), 4.63 (t, J=8.70 Hz. 2 H), 3.95 4.05 (m, 1 H), 3.67 (br. s., 1 H), 3.48 (br. s, 1 H), 3.28 (t, J=8.70 Hz, 2 H), 3.14 (s, 3 H)
42		6-(1,3benzothiazol-7yl)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	305.9	1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (s, 1 H) 9.50 (s, 1 H) 8.24 (d, J=7.34 Hz, 1 H) 7.71 (dd, J=7.83, 7.34 Hz, 1 H) 7.65 (d, J=7.83 Hz, 1 H) 6.03 (s, 1 H) 4.72 (t, J=5.62 Hz, 1 H) 4.22 - 4.31 (m, 1 H) 3.86 - 3.96 (m, 1 H) 3,43 - 3.56 (m, 2 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
43	NK ά -O V>JH AfkA.	1-(3aminopropyl)-6(2-methoxy-5methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	306.1	nH NMR (500 MHz, DMSO-d6) δ ppm 12.79 (s, 1 H), 7.92 (br. s., 3 H), 7.34 (dd, J=8.29, 1.22 Hz, 1 H), 7.19 (d, J=1.46 Hz, 1 H), 7.08 (d, J=8.54 Hz, 1 H), 5.78 (d, J=1.46 Hz, 1 H), 4.38 (br. s., 1 H), 3.62 (br. s., 1 H), 3.34 (s, 3 H), 2.47 - 2.56 (m, 2 H), 2.30 (s, 3 H), 1.84 (s, 1 H), 1.69- 1.79 (m, 1 H)
44	0 H™|l o''' OyJ NH, I	2-(6-(2methoxy-5methylpyridin-3yl)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	306.7	1H NMR (400 MHz, DMSO-d6): δ 12.82 (br.s., 1H), 8.14 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 7.02 (s, 1H), 5.86 (s, 1H), 5.50 (br.s., 1H), 3.87 (s, 4H), 2.20 (s, 3H).
45	□ Ax ►vA a	1-(3aminopropyl)-6(2-methoxy-5methylpyridin-3yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one trifluoroacetate	306.9	1H NMR (400 MHz, DMSO-d6): δ 12.82 (S, 1H), 8.20 (s, 1H), 7.71 (s, 1H), 7.60 (br.s., 2H), 5.90 (s, 1H), 4.35-4.45 (m, 1H), 3.97 (s, 3H), 3.58-3.65 (m, 1 H), 2.50-2.65 (m, 2H), 2.30 (s, 3H), 1.90-1.65 (m, 2H).
46	0 OH A	6-(2-(2hydroxyethyl)ph enyl]-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	307.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.44 (br. s., 1 H), 7.44-7.52 (m, 1 H), 7.41 (d, J=7,10Hz, 1 H), 7.34 (dd, J=7.79, 6.87 Hz, 1 H), 7.23-7.25 (m, 1 H), 5.84 (s, 1 H), 4.48 (dt, J=13.68, 5.07 Hz, 1 H), 3.81 - 3.99 (m, 3 H), 3.65 (ddd, J=10.25, 6.93, 5.27 Hz, 1 H), 3.58 (dt, J=10.36, 5.24 Hz, 1 H), 3.16 (s, 3 H), 2.83 (dt, J=14.25, 6.96 Hz, 1 H), 2.72 (dt, J=14.20, 7.00 Hz, 1 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
47	OH	6-(2,3-dîhydro- 1.4benzodioxin-5yl)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	307.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.57 (br. s, 1 H), 7.02 (dd, J=8.24, 1.37 Hz, 1 H), 6.94 (dd, J=7.90, 7.90 Hz. 1 H), 6.80 (dd, J=7.56, 1.37 Hz, 1 H), 5.87 (s, 1 H), 4.73 (dt, J=14.14, 5.52 Hz, 1 H), 4.30 (s, 4 H), 3.97 (dt, J=14.31, 5.78 Hz, 1 H), 3.833.92 (m, 1 H), 3.67 - 3.78 (m, 1 H)
48	0	1-(2aminoethyl)-6- (3,5dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	308.0	3.442 min Column: XBRIDGEC18 4.6X75mm 3.5pm; Mobile phase- A=0.1% TFA IN ACN, B=0.1% TFA IN WATER; Time(min)/% B= 0/90, 0.8/90 , 1.8/55, 3/5, 6.5/5 ,7/90; Flow :0.8mL/min, Column Temp=40°C; Diluent: CAN
49	0	1-(2methoxyethyl)6-(3-methoxy-6methylpyridin-2yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	308.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.41 (br. s., 1 H), 7.25 - 7.27 (m, 2 H), 5.90 (s, 1 H), 4.22 - 4.38 (m, 2 H), 3.84 (s, 3 H), 3.57 (t, J=6.41 Hz, 2 H), 3.15 (s, 3 H), 2.53 (s, 3 H)
50	0 o'' çna /°	1-(2methoxyethyl)6-(2-methoxy-6methylpyridin-3yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	308.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.56 (d, J=7.56 Hz, 1 H), 6.94 (d, J=7.33 Hz, 1 H), 5.74 (s, 1 H), 4.72 (dt, J=13.57, 3.86 Hz, 1 H), 3.95 (s, 3 H), 3.67 - 3.83 (m, 2 H), 3.35-3.43 (m, 1 H), 3.11 (s, 3 H), 2.49 (s, 3 H)
51	O Hhr% cr^	1-(2methoxyethyl)6-(2-methoxy-5methylpyridin-3yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	308.1	1H NMR (400 MHz, METHANOL-d3) ôppm 8.11 (s, 1 H), 7.56 (d, J=2.06 Hz, 1 H), 5.76 (s, 1 H), 4.64 - 4.76 (m, 1 H), 3.94 (s, 3 H), 3.68 - 3.82 (m, 2 H), 3.35-3.44 (m, 1 H), 3.10 (s, 3 H), 2.30 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
52		6-[2-(2aminoethoxy)ph enyl]-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one formate	308.2	2.14 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
53	.OH Λ / NH^	1-(2aminoethyl)-6[2-(2hydroxyethoxy)p henyl]-2-thioxo- 2.3dihydropyrimidin -4(1H)-one hydrochloride	308.2	1H NMR (400 MHz, CD3OD) δ 3.09 (ddd, J=12.9, 7.6, 6.1 Hz, 1 H), 3.19 (ddd, J=12.9, 7.6, 6.5 Hz, 1 H), 3.81-3.91 (m, 2 H), 4.16 (ddd, J=10.6, 4.7, 3.5 Hz, 1 H), 4.22 (ddd, J=10.8, 6.1, 3.9 Hz, 1 H), 4.26-4.37 (m, 1 H), 4.60-4.74 (m, 1 H), 5.84 (s, 1 H), 7.15 (td, J=7.5, 1.0 Hz, 1 H), 7.23 (dd, J=8.4, 0.6 Hz, 1 H), 7.36 (dd, J-7.4, 1.6 Hz, 1 H), 7.57 (ddd, J=8.5, 7.5, 1.8 Hz, 1 H)
54	0 a	6-(3,5dimethoxypheny 1)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	309.1	1H NMR (300 MHz, DMSO-d6) δ ppm 12.72 (br. s, 1 H), 6.67 (d, J=2.26 Hz, 2 H), 6.62 (t, J=2.30 Hz, 1 H), 5.76 (d, J=2.26 Hz, 1 H), 4.77 (t, J=5.57 Hz, 1 H), 4.14 (t, J=6.45 Hz, 2 H), 3.78 (s, 6 H), 3.57 (td, J=5.90 Hz, 2 H)
55	0	1-(2methoxyethyl)- 6-[2(methylthio)phe nyl]-2-thioxo2.3dihydropyrimidin -4(1H)-one	309.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.66 (br. s, 1 H), 7.40 - 7.50 (m, 1 H), 7.28 (d, J=8.01 Hz, 1 H), 7.24 (d, J=6.64 Hz, 2 H), 5.82 (s, 1 H), 4.59-4.71 (m, 1 H), 3.68-3.81 (m, 2 H), 3.41 -3.51 (m, 1 H), 3.15 (s, 3 H), 2.48 (s, 3 H)
56	0 NH,	2-[6-(4-fluoro-2methoxyphenyl) -4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]acetamide	310.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.78 (s, 1 H), 7.27 (br. S., 1 H), 7.17 (dd, J=8.30, 6.93 Hz, 1 H), 7.08 (dd, J=11.13, 2.15 Hz, 1 H), 6.97 (br. s„ 1 H), 6.86 (td, J=8.44, 2.24 Hz, 1 H), 5.78 (d, J=2.15Hz, 1 H), 5.36 (br. s., 2 H), 3.28 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
57	0	1-(3amînopropyl)-6(4-fluoro-2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1 H)-one hydrochloride	310.0	1H NMR (400 MHz, METHANOL-d4) ôppm 7.36 (dd, J=8.39, 6.44 Hz, 1 H), 7.01 (dd, J=10.83, 2.24 Hz, 1 H), 6.85 (td, J=8.30, 2.34 Hz, 1 H), 5.79 (s, 1 H), 4.51 -4.63 (m, 1 H), 3.89 (s, 3 H), 3.69 - 3.81 (m, 1 H), 2.76 (t, J=7.81 Hz, 2 H), 1.93-2.07 (m, 1 H), 1.74-1.88 (m, 1 H)
58	0 Ax yv	1-(3- aminopropyl)-6(5-fluoro-2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	310.0	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.31 (td, J=8.59, 3.12 Hz, 1 H), 7.14 - 7.23 (m, 2 H), 5.81 (s, 1 H), 4.51 -4.64(m, 1 H), 3.87 (s, 3 H), 3.73 - 3.83 (m, 1 H), 2.77 (t, J=7.71 Hz, 2 H), 1.95-2.09 (m, 1 H), 1.77-1.91 (m, 1 H)
59	Ύι ~~-o rr	2-[6-(5-fluoro-2methoxyphenyl) -4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yljacetamîde	310.0	1H NMR (500 MHz, DMSO-d6) δ ppm 3.35 (br. s., 2 H) 3.83 (s, 3 H) 5.85 - 5.90 (m, 1 H) 7.03 (d, J=7.56 Hz, 1 H) 7.07 (br. s., 1 H) 7.19 (dd, J=9.15,4.27 Hz, 1 H) 7.33 (br. s., 1 H) 7.38 (td, J=8.72, 3.05 Hz, 1 H) 12.85 (br. s., 1 H)
60	O HN-Xj] cA A6	6-(2-fluoro-6methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	311.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.08 (br. s., 1 H), 7.44 (ddd, J=8,30, 8.30, 6.80 Hz, 1 H), 6.82 (t, J=8.47 Hz, 1 H), 6.77 (d, J=8.47 Hz, 1 H), 5.88 (s, 1 H), 4.49-4.65 (m, 1 H), 3.883.97 (m, 1 H), 3.85 (s, 3 H), 3.56 - 3.66 (m, 1 H), 3.45 - 3.54 (m, 1 H), 3.16 (s, 3 H)
61	0 NH^ I	1-(2aminoethyl)-6(2-chloro-4methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	311.9	1H NMR (300 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1 H), 7.74 (br. s., 3 H), 7,55 (d, J=8.36 Hz, 1 H), 7.30 (d, J=2.09 Hz, 1 H), 7.12 (dd, J=8.36, 2.09 Hz. 1 H), 5.91 (d, J=2.09 Hz, 1 H), 4.53 4.71 (m. 1 H), 3.85 (s, 3 H), 3.73 - 3.84 (m, 1 H), 2.92 - 3.08 (m, 1 H), 2.77 - 2.90 (m, 1 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
62	0 Al NH,	1-(2aminoethyl)-6(4-chloro-2methoxypheny!) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	312.0	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.34 (d, J=8.24 Hz, 1 H), 7.27 (d, J=1.60 Hz, 1 H), 7.16 (dd, J=8.13, 1.72 Hz, 1 H), 5.83 (s, 1 H), 4.68-4.81 (m, 1 H), 4.01 -4.12(m, 1 H), 3.91 (s, 3 H), 2.97-3.16 (m, 2 H)
63	O NH, Cl	1-(2amînoethyl)-6(5-chloro-2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	312.2	1.67 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
64	0 HtrS (T^ aAa /V	6-(5-chloro-2methoxyphenyl) -1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	313.2	1H NMR (500 MHz, DMSO-d6) δ ppm 12.76 (br. s., 1 H) 7.57 (dd, J=8.78, 2.68 Hz, 1 H) 7.42 (d, J=2.68 Hz, 1 H) 7.19 (d, J=9.03 Hz, 1 H) 5.83 (d, J=2.20 Hz, 1 H) 5.18 (br. s., 1 H) 4.444.52 (m, 1 H) 3.83 (s, 3 H) 3.56 - 3.62 (m, 1 H) 3.53 (dt, J=13.66, 6.83 Hz, 1 H) 3.42 (ddd, J=10.12, 6.46, 3.90 Hz, 1 H)
65	H^jl 0^ /9 OH Cl	6-(5-chloro-2methoxypyridin3-yl)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	314.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.80 (br.s., 1 H), 8.38 (d, J=2.75 Hz, 1 H), 7.89 (d, J=2.75 Hz, 1 H), 5.93 (d, J=2.06 Hz, 1 H), 4.45-4.54 (m, 1 H), 3.89 (s, 3 H), 3.55 - 3.65 (m, 1 H), 3.36-3.51 (m, 2 H)
66	0 ,A>	1-(2methoxyethyl)6-(1-methyl-1Hindol-2-yl)-2thioxo-2,3dihydropyrimidin -4(1H)-°ne	316.0	1H NMR (400 MHz, CHLOROFORM-d) d ppm 9.90 (br. s, 1 H), 7.67 (d, J=7.79 Hz, 1 H), 7.31-7.42 (m, 2 H), 7.21 (dd, J=7.10, 7.10 Hz, 1 H), 6.65 (s, 1 H), 5.98 (s, 1 H), 4.71 (br. s, 1 H), 4.34 (br. s, 1 H). 3.723.84 (m, 1 H), 3.69 (s, 3 H), 3.43-3.58 (m, 1 H), 3.11 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
67	O X	1-(2methoxyethyl)6-(1-methyl-1Hîndol-3-yl)-2thîoxo-2,3dihydropyrimidin -4(1H)-one	316.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.70 (br. s., 1 H), 7.50 (d, J=7.79 Hz, 1 H), 7.36 - 7.43 (m, 2 H), 7.33 (t, J=7.44 Hz, 1 H), 7.19-7.26 (m, 1 H), 5.99 (s, 1 H), 4.61 (br. s., 2 H), 3.88 (s, 3 H), 3.68 (t, J=5.50 Hz, 2 H), 3.18 (s, 3 H)
66	O X1	2-(6-(1benzothien-3yl)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	318.0	1H NMR (400 MHz, METHANOL-d3) ôppm 7.99 8.12 (m, 1 H), 7.92 (s, 1 H), 7.77 (d, J=6.18Hz, 1 H), 7.427.57 (m, 2 H), 6.02 (s, 1 H), 5.17-5.68 (m, 1 H), 3.77-4,25 (m, 1 H)
69	0 Zu V *~o lin,	2-(6-(1- benzothien-2yl)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yllacetamide	318.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.63 (br. s, 1 H), 7,97 8.04 (m, 1 H), 7.86 - 7.93 (m, 1 H), 7.61 (s, 1 H), 7.40 - 7.48 (m, 2 H), 7.34 (br. s, 1 H), 6.97 (br. s., 1 H), 6.03-6.11 (m, 1 H), 4.53 - 5.06 (m, 2 H)
70	0 yi,.	3-methoxy-4-[3(2methoxyethyl)6-oxo-2-thioxo1,2,3,6tetrahydropyrimi din-4yljbenzonitrile	318.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.46 (br. s, 1 H), 7.32 - 7.42 (m, 2 H), 7.20 (s, 1 H), 5.75 (s, 1 H), 4.71 (dt, J=14.20, 3.43 Hz, 1 H), 3.90 (s, 3 H), 3.80 (td, J=9.79, 3.78 Hz, 1 H), 3.64 (ddd, J=14.20, 9.39, 4.35 Hz, 1 H), 3.36 (ddd, J=10.30, 4.35, 3.21 Hz, 1 H). 3.14 (s, 3 H)
71	0 Z5	1-(3- aminopropyl)-6(1-benzothien-2yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	318.1	1H NMR (300 MHz, DMSO-d6) ôppm 12.90 (br. s., 1 H), 8.068.11 (m, 1 H), 7.95-8.01 (m, 1 H), 7.80 (s, 1 H), 7.73 (br. s„ 3 H), 7.47 - 7.54 (m, 2 H), 6.16 (s, 1 H), 4.22-4.33 (m, 2 H), 2.60 -2.70 (m, 2 H), 1.94-2.06 (m, 2 H)
72		1-(3aminopropyl)-6(1,3benzothiazol-7yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one trifluoroacetate	319.2	1H NMR (400 MHz, DMSO-d6) ôppm 12.98(5. 1 H), 9.54 (s, 1 H), 8.29 (d, J=7.34 Hz, 1 H), 7.72 (m, J=9.78 Hz, 2 H), 7.52 (br. s., 3 H), 6.10 (d, J=1.96 Hz, 1 H), 4.21-4.31 (m, 1 H). .3.49 -3.82 (m, 3 H), 1.68-1.87 (m, 2 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
73	0	6-(1-benzothien7-yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	319.4	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.72 (br. s, 1 H), 7.94 (dd, J=8.01, 0.69 Hz, 1 H), 7.53 (d, J=5.50 Hz, 1 H), 7.49 (t, J=7.67 Hz, 1 H), 7.42 (d, J=5.50 Hz, 1 H), 7.33 (d, J=7.33 Hz, 1 H), 6.02 (s, 1 H), 4.55 (dt, J=14.03, 4.89 Hz, 1 H), 4.06 (dt, J=13.40, 6.58 Hz, 1 H), 3.65 (ddd, J=10.42, 6.98, 5.04 Hz, 1 H), 3.47 (dt, J=10.42, 5.09 Hz, 1 H), 3.07 (s, 3 H)
74	0	6-(1-benzothien4-yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimîdin -4(1H)-one	319.4	1H NMR (301 MHz, DMSO-d6) δ ppm 12.85 (br. s., 1 H), 8.16 (t, J=4.48 Hz, 1 H), 7.90 (d, J=5.51 Hz, 1 H), 7.47 (d, J=4.36 Hz, 2 H), 7.37 (d, J=5.51 Hz, 1 H), 5.87 (s, 1 H), 4.31 (ddd, J=13.31, 7.57, 5.74 Hz, 1 H), 3.84 (dt, J=13.37, 6.74 Hz, 1 H), 3.32 - 3.45 (m, 2 H), 2.82 (s, 3 H)
75		6-(1,3benzothiazol-2yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	320.0	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.91 (br. s., 1 H), 8.14 (d, J=8.01 Hz, 1 H), 7.98 (d, J=7.79 Hz, 1 H), 7.61 (ddd, J=8.01, 7.10, 1.15 Hz, 1 H), 7.54 (ddd, J=7.80, 7.80, 0.90 Hz, 1 H), 6.27 (s, 1 H), 5.04 (t, J=5.27 Hz, 2 H), 3.63 (t. J=5.27 Hz, 2 H), 3.09 (s, 3 H)
76	0	1-(3aminopropyl)-6(2,3-dihydro- 1,4benzodioxin-6yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	320.0	1H NMR (300 MHz, DMSO-d6) δ ppm 12.76 (br. s., 1 H), 7.71 (br. s., 3 H), 7.07 (s, 1 H), 6.93 7.02 (m, 2 H), 5.77 (d, J=2.09 Hz, 1 H), 4.30 (s, 4 H), 4.03 4.18 (m, 2 H), 2.53-2.66 (m, 2 H), 1.76-1.93 (m, 2H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
77	O KH,	2-{2-[6-(2methoxyphenyl) -4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]ethyl}guanidîn e hydrochloride	320.0	1H NMR (500 MHz, DMSO-d6) δ ppm 12.85 (s, 1 H), 7.65 (br. t, J=6.10, 6.10 Hz, 1 H), 7.53 (td, J=7.93, 1.46 Hz, 1 H), 7.32 (dd, J=7.56, 1.46 Hz, 1 H), 7.17 (d, J=8.29 Hz, 1 H), 7.07 (t, J=7.44 Hz, 2 H), 6.97 (br. s., 4 H), 5.80 (d, J=2.20 Hz, 1 H), 4.54 (br. d, J=13.70 Hz, 1 H), 3.84 (s, 3 H), 3.63 (m, J=9.03 Hz, 1 H), 3.53 (td, J=9.33,4.51 Hz, 1 H), 3.17-3.22 (m, TH)
78	0 Ï1 P	6-(1,3benzothiazol-7yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	320.4	1H NMR (301 MHz, CHLOROFORM-d) δ ppm 9.97 (br. s„ 1 H), 9.10 (s, 1 H), 8.27 (d, J=8.26 Hz, 1 H), 7.66 (t, J=7.80 Hz, 1 H), 7.44 (d, J=7.34 Hz, 1 H), 6.01 (s, 1 H), 4.48 (dt, J=14.00, 4.82 Hz, 1 H), 4.11 -4.32 (m, 1 H), 3.453.69 (m, 2 H), 3.06 (s, 3 H)
79		1-(2aminoethyl)-6[2-(3aminopropoxy)p henyl]-2-thioxo- 2,3dihydropyrimidin -4(1H)-one hydrochloride	321.0	1H NMR (400 MHz, METHANOL-d4) ôppm 7.57 (t, J=7.42 Hz, 1 H), 7.40 (d, J=6.83 Hz, 1 H), 7.22 (d, J=8.59 Hz, 1 H), 7.15 (t, J=7.03 Hz, 1 H), 5.83 (s, 1 H), 4.90 5.00 (m, 1 H), 4.26-4.35 (m, 1 H), 4.17-4.25 (m, 1 H), 4.024.13 (m, 1 H), 2.97-3.18 (m, 4 H), 2.08 - 2.20 (m, 2 H)
80	0 Λ P1 jAy	6-(2,3-dihydro- 1.4benzodioxin-5yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	321.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.79 (br. s., 1 H), 7.00 (dd, J=8.24, 1.60 Hz, 1 H), 6.92 (t, J=7.90 Hz, 1 H), 6.79 (dd, J=7.56, 1.60 Hz, 1 H), 5.84 (s, 1 H), 4.70 (dt, J=13.91,4.84 Hz, 1 H), 4.29 (s, 4 H), 3.94 (dt, J=14.08, 6.93 Hz, 1 H), 3.70 (ddd, J=10.19, 7.67, 5.95 Hz, 1 H), 3.48 (ddd, J=10.25, 6.13,4.24 Hz, 1 H), 3.16 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Tlme and Conditions
81	0 ηΎ|1 HH, Il	1-(2aminoethyl)-6(2,4-dimethoxy5methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	321.8	1H NMR (400 MHz, DMSO-d6): δ 12.85 (s, 1 H), 7.80 (br.s., 3 H), 7.11 (s, 1 H), 6.76 (s, 1 H), 5.75 (s, 1 H), 4.58-4.69 (m, 1 H), 3.88-3.95 (m, 1H), 3.89 (s, 4 H), 3.86 (s, 3 H), 2.82-2.95 (m, 2 H), 2.10 (s, 3 H):
82	χ.	1-(3aminopropyl)-6(3,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	322.0	1H NMR (400 MHz. DMSO-d6) Ôppm12.76 (br. s., 1 H), 7.71 (br. s., 3 H), 7.13 (d, J=1.96 Hz, 1 H), 7.05 (d, J=5.38 Hz, 2 H), 5.81 (d, J=1.96 Hz, 1 H), 4.094.20 (m, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H), 2.53 - 2.62 (m, 2 H), 1.79-1.90 (m, 2 H)
83	0 ό\χ NH, I	2-(6-(3,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]acetamide	322.0	1H NMR (300 MHz, DMSO-d6) ôppm12.75 (br. s., 1 H), 7.46 (br. s„ 1 H), 7.16 (br. s., 1 H), 7.00-7.09 (m, 2 H), 6.91 -6.99 (m, 1 H), 5.81 (s, 1 H), 4.98 5.44 (m, 1 H), 3.94-4.29 (m. 1 H), 3.80 (s, 3 H), 3.74 (s, 3 H)
84	0	1-(2aminoethyl)-6(2,5-dimethoxy4methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	322.0	1H NMR (400 MHz, METHANOL-d4); δ 6.95 (s, 1H), 6.81 (s, 1H), 5.75 (s, 1H), 4.58-4.47 (m, 1H), 4.11-4.20 (m, 1H), 3.75 (s, 3H), 3.30 (s, 3H), 2.95-3.08 (m, 2H), 2.18 (s, 3H).
85	ο	1-(3aminopropyl)-6- (3,5dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	322.0	3.567 min (Column: XBRIDGEC18 4.6X75mm 3.5pm; Mobile phase- A=0.1% TFA IN ACN, B=0.1% TFA IN WATER; Time(min)/% B= 0/90, 0.8/90 , 1.8/55, 3/5, 6.5/5 ,7/90 Flow :0.8mL/min, Column Temp=40°C; Diluent: CAN)
86	0 b Y	2-(6-(3,5dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	322.1	1H NMR (300 MHz, DMSO-d6) δρριη 12.79(br. s., 1 H), 7.46 (br. s., 1 H), 7.17 (br. s„ 1 H), 6.62 (d, J=1.74 Hz, 1 H), 6.60 (s, 2 H), 5.83 (d, J=1.92 Hz, 1 H), 5.17 (br. s, 1 H), 4.08 (br. s, 1 H), 3.75 (s, 6 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
87	0 σ''' Λ	1-(3aminopropyl)-6- (2,5dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	322.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.08 7.12 (m. 2 H), 6.93 (s, 1 H), 5.79 (s, 1 H), 4.47 - 4.62 (m. 1 H), 3.84 - 3.87 (m, 1 H), 3.83 (s, 3 H), 3.78 (s, 3 H), 2.76 (t, J=7.71 Hz, 2 H), 1.95-2.09 (m. 1 H), 1.78- 1.93 (m, 1 H)
88	H/r	1-(3aminopropyl)-6[2-(2hydroxyethoxy)p henyl]-2-thioxo- 2,3dihydropyrimidin -4(1H)-one hydrochloride	322.2	1H NMR (500 MHz, CD3OD) δ 1.81-1.92 (m, 1 H), 2.05 (dqd, J=13.4, 8.1, 5.6 Hz, 1 H). 2.76 (t, J=7.8 Hz. 2 H). 3.82-3.90 (m, 2 H), 3.90-4.02 (m, 1 H). 4.16 (ddd, J=11.0, 4.6, 3.7 Hz, 1 H), 4.20 (ddd, J=10.7, 5.9, 4.1 Hz, 1 H). 4.45-4.59 (m, 1 H). 5.82 (s. 1 H). 7.13 (t, J=7.4 Hz, 1 H), 7.21 (d, J=8.5 Hz, 1 H), 7.35 (dd, J=7.4, 1.6 Hz, 1 H). 7.55 (ddd, J=8.4, 7.6, 1.3 Hz, 1 H)
89	0 HbrS cr^	[6-(2.4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1 (2H)-yl]acetic acid	323.1	2.09 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
90	0 NH, F I	1-(2aminoethyl)-6(5-fluoro-2.4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	325.9	1H NMR (400 MHz, DMSO-d6): δ 12.88 (s, 1 H). 7.87 (br.s., 3 H), 7.32 (d, 1 H), 6.97 (d, 1 H), 5.82 (s, 1 H), 4.55-4.66 (m, 1 H), 3.95 (s, 3 H), 3.87 (s, 3 H), 3.83-3.92 (m, 1H), 2.87-2.98 (m, 2 H).
91	0 yÂ	1-(3aminopropyl)-6(2-chloro-4methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	326.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (s, 1 H), 7.66 (br. s, 3 H), 7.55 (d, J=8.80 Hz, 1 H), 7.27 (d, J=2.45 Hz, 1 H), 7.09 (dd, J=8.80, 2.45 Hz, 1 H), 5.89 (d, J=1.96 Hz, 1 H), 4.364.46 (m, 1 H), 3.85 (s, 3 H), 3.57-3.63 (m, 1 H), 2.53-2.64 (m, 2H), 1.86-1.95 (m, 1 H), 1.67-1.76 (m, 1 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
92	0 y^	1-(3aminopropyl)-6(5-chloro-2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	326.3	'H NMR (500 MHz, METHANOL-d4) δ ppm 7.57 (dd, J=9.03, 2.68 Hz, 1 H), 7.44 (d, J=2.44 Hz, 1 H), 7.19 (d, J=9.03 Hz, 1 H), 5.83 (s, 1 H), 4.53 - 4.63 (m, 1 H), 3.91 (s, 3 H), 3.75 - 3.84 (m, 1 H), 2.80 (t, J=7.81 Hz, 2 H), 1.98-2.08 (m, 1 H), 1.80- 1.90 (m, 1 H)
93	0 (Z' y i	1-(3- aminopropyl)-6(5-chloro-2methoxypyridin3-y|)-2-thioxo- 2,3dihydropyrimidin -4(1H)-one hydrochloride	326.9	1H NMR (400 MHz, METHANOL-d4) δ ppm 8.37 (d, J=2.45 Hz, 1 H), 7.92 (d, J=2.45 Hz, 1 H), 5.90 (s, 1 H), 4.52-4.62 (m, 1 H), 4.02 (s, 3 H), 3.74 - 3.85 (m, 1 H), 2.84 (t, J=7,83 Hz. 2 H), 1.98 - 2.09 (m, 1 H), 1.81 -1.94 (m, 1 H)
94	0 y^	6-(5-chloro-2methoxyphenyl) -1-(3hydroxypropyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	327.0	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.51 (dd, J=8.93, 2.52 Hz, 1 H), 7.39 (d, J=2.29 Hz, 1 H), 7.14 (d, J=8.93 Hz, 1 H), 5.77 (s, 1 H), 4.52 (ddd, J=13.91, 9.79, 4.69 Hz, 1 H), 3.88 (s, 3 H), 3.78 (ddd, J=14.43, 10.08, 5.27 Hz, 1 H), 3.36 (t, J=6.18 Hz, 2 H), 1.82-1.96 (m, 1 H), 1.62-1.76 (m, 1 H)
95	0 Hrr\ σ'''	1-(2aminoethyl)-6(3-methoxy-2naphthyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	327.9	1H NMR (400 MHz, DMSO-d6) δ ppm 12.92 (d, J=1.83 Hz, 1 H), 7.97 (s, 1 H), 7.90 (t, J=7.33 Hz, 2 H), 7.73 (br. s„ 3 H), 7.53 - 7.59 (m, 2 H), 7.40 - 7.46 (m, 1 H), 5.92 (d, J=2.29 Hz, 1 H), 4.58-4.69 (m, 1 H), 3.92 (s, 3 H), 3.77 - 3.87 (m, 1 H), 2.79 2.99 (m, 2 H)
96	0 HW^j> O'' ^,0 et	6-(5-chloro-2methoxypyridin3-yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	328.0	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 9.79 (br. s., 1 H), 8.24 (d, J=2.52 Hz, 1 H), 7.54 (d, J=2.52 Hz, 1 H), 5.78 (d, J=2.29 Hz, 1 H), 4.76 (dt, J=14.37, 2.89 Hz, 1 H), 3.96 (S, 3 H), 3.86 (td, J=9.96, 3.43 Hz, 1 H), 3.65 (ddd, J=14.20, 9.85, 3.89 Hz, 1 H), 3.36 (dt, J=10.36, 3.52 Hz, 1 H), 3.17 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
97	0 LA	1-(2aminoethyl)-6(2methoxyquinolin -3-yl)-2-thioxo- 2,3dihydropyrimidin -4(1H)-one trifluoroacetate	328.8	1H NMR (400 MHz, DMSO-d6): 0 12.92 (br.s., 1 H), 8.20 (s, 1 H), 7.83-7.65 (m, 6 H), 7.38 (t, 1 H), 6.01 (s, 1 H), 4.52-4.61 (m, 1 H), 3.70-3.80 (m, 1H), 3.68 (s, 3 H), 2.98-3.18 (m, 2 H).
98	Aa h/A M	1-(3- aminopropyl)-2thioxo-6-[2-(2H1,2,3-triazol-2yl)phenyl]-2,3dihydropyrimidin -4(1H)-one hydrochloride	328.9	0.893 min Column: LCMS-Q Supelco 3x30 mm; Mobile phase: from 0% CH3CN (0.1%TFA) in water (0.1%TFA) to 60% CH3CN (0.1%TFA) in water (0.1 %TFA)
99	8 o hA v o^jÔ NH,	2-{4-oxo-2thioxo-6-[2-(2H1,2,3-triazol-2yl)phenyl]-3,4dihydropyrimidin -1(2H)yljacetamide	329.0	1H NMR (400 MHz, DMSO-d6): 612.76 (s, 1H), 8.11 (s, 2H), 7.98 (d, 1H), 7.72 (t, 1H), 7.55 (t, 1H), 7.45 (d, 1H). 7.35 (s, 1 H), 7.04 (s, 1H), 5.68 (s, 1H), 5.22 (d, 1H), 3.79 (d, 1H).:
100	0 Hj|| OH	1-(2hydroxyethyl)-6(3-methoxy-2naphthyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	329.4	1H NMR (400 MHz, DMSO-d6) δ ppm 12.80 (d, J=1.37 Hz, 1 H), 7.92 (s, 1 H), 7.88 (d, J=9.16 Hz, 2 H), 7.54 (ddd, J=8.13, 6.98, 0.92 Hz, 1 H), 7.49 (s, 1 H), 7.41 (ddd, J=8.24, 6.87, 0.92 Hz, 1 H), 5.87 (d, J=2.29 Hz, 1 H), 4.68 (br. s., 1 H), 4.47-4.58 (m, 1 H), 3.91 (s, 3 H), 3.44 - 3.54 (m, 2 H)
101	? F^ JL Ά ηγγ > AÂA /Ό /°	1-(2methoxyethyl)2-thioxo-6-[2(2H-1.2.3triazol-2yl)phenyl]-2,3dihydropyrimidin -4(1H)-one	330.1	1H NMR (300 MHz, DMSO-d6) δ ppm 12.77 (br. s., 1 H), 8.14 (s, 2 H), 8.05 (d. J=7.67 Hz, 1 H), 7.77 (td, J=7.67, 2.09 Hz, 1 H), 7.60-7.71 (m, 2 H), 5.79 (s, 1 H), 4.32 - 4.44 (m, 1 H), 3.47 - 3.62 (m, 1 H), 3.36 - 3.46 (m, 1 H), 2.99 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
102	Λ -J	6-(2ethoxyphenyl)1(tetrahydrofuran -2-ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	333.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.25-10.39 (m, 1 H) 7.397.50 (m, 1 H) 7.30 - 7.36 (m, 1 H) 7.00-7.07 (m, 1 H) 6.88 6.99 (m, 1 H) 5.81 - 5.88 (m, 1 H) 4.68-4.77 (m, 1 H) 4.564.65 (m, 1 H) 4.05-4.14 (m, 2 H) 3.49-3.57 (m, 1 H) 3.343.44 (m, 1 H) 3.05-3.13 (m, 1 H) 1.90-2.01 (m, 1 H) 1.631.78 (m, 1 H) 1.40-1.49 (m, 1 H) 1.32- 1.38 (m, 3 H) 1.231.32 (m, 1 H)
103	jf	2-{3-[6-(2methoxyphenyl) -4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]propyl}guanidi ne	334.1	1.31 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
104	Λ J Ÿ0	6-(2ethoxyphenyl)- 1-(2isopropoxyethyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one	335.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.15 (br, s., 1 H) 7.45 (ddd, J=8.29, 7.51, 1.76 Hz, 1 H) 7.24 (dd, J=7.51, 1.66 Hz, 1 H) 7.03 (ddd, J=7.41,0.78 Hz, 1 H) 6.94 (d, J=8.39 Hz, 1 H) 5.83 (d, J=2.34 Hz, 1 H) 4.69 (ddd, J=13.46, 5.66, 4.10 Hz, 1 H) 4.10 (q, J=6.89 Hz, 2 H) 3.68-3.85 (m, 2H) 3.50 (ddd, J=9.71,6.19, 3.61 Hz, 1 H) 3.43 (spt, J=6.05 Hz, 1 H) 1.37 (t, J=7.02 Hz, 3 H) 1.02 (dd, J=6.05, 1.76 Hz, 6 H)
105	H/r	1-(3aminopropyl)-6(2,4-dimethoxy5methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	335.9	1H NMR (400 MHz, DMSO-d6): δ 12.76 (s, 1H), 7.68 (br.s., 3H), 7.11 (s, 1H), 6.74 (s, 1 H). 5.73 (s, 1H), 4.35-4.45 (m, 1 H), 3.88 (s, 3H), 3.85 (s, 3H), 3.59-3.68 (m, 1 H), 2.52-2.51 (m, 2H), 2.09 (s, 3H), 1.81-1.71 (m, 2H).:

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
106	0 hnA yL	1-(3aminopropyl)-6(2,5-dimethoxy4methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	336.0	1H NMR (400 MHz, METHANOL-d4): δ 6.91 (s, 1H), 6.79 (s, 1H), 5.72 (s, 1H), 4.40-4.50 (m, 1H), 3.78-3.88 (m, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 2.68 (t, 2H), 2.17 (s, 3H), 1.89-1.94 (m, 1H), 1.76-1.86 (m. 1H).
107	0 φΦφ NH, F 1	2-[6-(5-fluoro2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	339.9	1H NMR (400 MHz, DMSO-d6): δ 7.11 (br.s., 1 H), 6.94 (d, 1 H), 6.87 (d, 1 H), 6.83 (br.s., 1 H), 5.72 (br.s., 1 H), 5.41 (s, 1 H), 3.91 (s, 3 H), 3.83 (s, 3 H), 3.72-3.82 (m, 1 H).
108	0	1-(3aminopropyl)-6(5-fluoro-2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	339.9	1H NMR (400 MHz, DMSO-d6): δ 7.36 (d, 1H), 6.95 (d, 1H), 5.80 (s, 1 H), 4.38-4.48 (m, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.593.67 (m, 1H), 2.45-2.61 (m, 2H), 1.67-1.78 (m, 2H).:
109	0 H|l 0 rcr	1-(2methoxyethyl)- 6-[3(methylsulfonyl) phenyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one	341.0	1H NMR (400 MHz, CHLOROFORM-d) d ppm 10.70 (br.s., 1 H), 8.08 (d, J=7.79 Hz, 1 H), 8.03 (s, 1 H), 7.72 (dd, J=7.80, 7.80 Hz, 1 H), 7.65 (d, J=7.33 Hz, 1 H), 5.87 (s, 1 H), 4.30 (br. s., 2 H), 3.67 (br. s., 2 H), 3.22 (s, 3 H), 3.12 (s, 3 H)
110	0 J	1-(2methoxyethyl)- 6-[4(methylsulfonyl) phenyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one	341.1	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.08 (d, J=8.24 Hz, 2 H), 7.59 (d, J=8.24 Hz, 2 H), 5.81 (S, 1 H), 4.31 (br. s., 2 H), 3.66 (t, J=5.04 Hz, 2 H), 3.21 (s, 3 H), 3.14 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
111	0	1-(2aminoethyl)-6(5-chloro-2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	342.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.87 (br. s, 1 H), 7.80 (br. s, 3 H), 7.48 (s, 1 H), 6.94 (s, 1 H), 5.84 (d, J=1.96 Hz, 1 H), 4.55-4.65 (m, 1 H), 3.97 (S, 3 H), 3.90 (s, 3 H), 3.71 - 3.80 (m, 1 H), 2.86 - 2.99 (m, 2 H)
112	0 Hir-j] σ'' NK,	2-[6-(3methoxy-2naphthyl)-4-oxo2-thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	342.0	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.84 (d, J=8.24 Hz. 1 H), 7.81 (d, J=7.79 Hz, 1 H), 7.79 (s, 1 H), 7.52 (ddd, J=8.24, 7.10, 1.14 Hz, 1 H), 7.35 - 7.44 (m, 2 H), 5.89 (s, 1 H), 5.42 - 5.70 (m, 1 H), 4.05-4.26 (m, 1 H), 3.98 (s, 3 H)
113	ABS M^r	1-[(2S)-3-amino2hydroxypropyl]6-(5-chloro-2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one trifluoroacetate	342.1	1H NMR (300 MHz, DMSO-d6) δ ppm 12.84 (s, 1 H), 7.69 (br. s, 3 H), 7.56 (dd, J=9.06, 2.79 Hz, 1 H), 7.29 (d, J=2.79 Hz, 1 H), 7.18 (d, J=9.06 Hz, 1 H), 5.87 (d, J=2.09 Hz, 1 H), 5.74 (d, J=5.57 Hz, 1 H), 4.55-4.65 (m, 1 H), 4.21-4.34 (m, 1 H), 3.83 (s, 3 H), 3.13-3.23 (m, 1 H), 2.75-2.88 (m, 2 H)
114	ABS	1-[(2R)-3amino-2hydroxypropyl]6-(5-chloro-2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one trifluoroacetate	342.2	1H NMR (300 MHz, DMSO-d6) δ ppm 12.84 (s, 1 H), 7.69 (br. s, 3 H), 7.56 (dd, J=9.06, 2.79 Hz, 1 H), 7.29 (d, J=2.79 Hz, 1 H), 7.18 (d, J=9.06 Hz, 1 H), 5.87 (d, J=2.09 Hz, 1 H), 5.74 (d, J=5.57 Hz, 1 H), 4.55-4.65 (m, 1 H), 4.21 -4.34(m, 1 H), 3.83 (s, 3 H), 3.13-3.23 (m, 1 H), 2.75 - 2.88 (m, 2 H)
115	0 Htr-'ji o<	1-(2- methoxyethyl)6-(1-methoxy-2naphthyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	343.0	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.54 (br. s., 1 H), 8.11 -8.19 (m, 1 H), 7.86 - 7.95 (m, 1 H), 7.71 (d, J=8.47 Hz, 1 H), 7.61 (dd, J=6.30, 3.09 Hz, 2 H), 7.28 (d, J=8.47 Hz, 1 H), 5.96 (s, 1 H), 4.67-4.81 (m, 1 H), 4.02 (ddd, J=14.03, 8.30,5.38 Hz, 1 H), 3.90 (s, 3 H), 3.68 - 3.78 (m, 1 H), 3.36 (dt, J=9.90, 4.78 Hz, 1 H), 3.06 (s, 3 H)

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
116	ABS 0	6-(5-chloro-2methoxyphenyl) -1-[(2R)-2,3dihydroxypropyl] -2-thioxo-2,3dihydropyrimidin -4(1H)-one	343.0	1.942 min (Column:AQUITY BEH C-18,2.1x50mm,1.7pm; Mobile Phase:A-0.1%FA IN ACN, B-0.1%FA IN WATER; T/%B(min):0/90, 0.7/90, 2/55, 3/55, 3.8/5, 5.8/5, 6/90; Flow:0.5mL/min, DiluentCAN)
117	0	1-(2methoxyethyl)6-(3-methoxy-2naphthyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	343.4	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.76 (br. s, 1 H), 7.80 (t, J=8.36 Hz, 2 H), 7.74 (s, 1 H), 7.55 (ddd, J=8.13, 7.10, 1.03 Hz, 1 H), 7.43 (ddd, J=8.07, 6.93, 1.03 Hz, 1 H), 7.21 (s, 1 H), 5.90 (d, J=2.06 Hz, 1 H), 4.67 - 4.77 (m, 1 H), 3.95 (s, 3 H), 3.70 - 3.86 (m, 2 H), 3.34 - 3.44 (m, 1 H), 3.07 (s, 3 H)
118	0 F	1-(2methoxyethyl)2-thioxo-6-[2(trifluoromethox y)phenyl]-2,3dihydropyrimidin -4(1H)-one	347.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.79 (br. s., 1 H), 7.54 - 7.63 (m, 1 H), 7.35 - 7.48 (m, 3 H), 5.86 (s, 1 H), 4.57-4.73 (m, 1 H), 3.71 -3.94 (m, 2 H), 3.38-3.49 (m, 1 H), 3.17 (s, 3 H)
119	0 hît^ïi er^ aAa fy Η/r''^''NH,	2-{3-[6-(2methoxy-5methylphenyl)4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]propyl}guanidi ne	348.2	1.37 min Waters XBridge C18 4.6x50mm, 5um 95%H20 ! 5%MeCN linear to 5%H201 95%MeCN over 4.0min, HOLD at 5%H20 / 95%MeCN to 5.0min. Flow: 2.0ml_/min.NH4OH 0.03%. Flow rate: 2 mL/min
120	o H/r	N-{2-[6-(2methoxy-5methylphenyl)4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]ethyl}glycina mide hydrochloride	349.2	1H NMR (500 MHz, CD3OD) d ppm 7.37 (d, 1 H), 7.22 (s, 1 H), 7.06 (d, 1 H), 5.78 (s, 1 H), 4.81 (m, 1 H), 3.88 (s, 3 H), 3.86 (br. s„ 0 H), 3.55 (m, 2 H), 3.45 (m, 2 H), 2.36 (s, 3 H)

100

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
121	0 *<.	2-{2-[6-(2,5dimethoxypheny IJ-4-OXO-2thîoxo-3,4dihydropyrimidin -1(2H)yl]ethyl)guanidin e hydrochloride	350.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (s, 1 H), 7.61 (br. t, J=6.10, 6.10 Hz, 1 H), 7.07 7.12 (m, 2 H), 6.98 (br. s.t 3 H), 6.93 (d, J=1.56 Hz, 1 H), 5.85 (d, J=2.15 Hz, 1 H), 4.54 (br. d, J=14.30 Hz, 1 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.66 - 3.75 (m, 1 H), 3.47-3.60 (m, 1 H), 3.153.26 (m, 1 H)
122	ABS 0 As <y t	6-(5-chloro-2methoxyphenyl) -1-[(2R)pyrrolidin-2ylmethyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	352	3.641 min Column: XBRIDGEC16 4.6X75mm 3.5pm; Mobile phase- A=0.1% FA IN ACN, B=0.1% FA IN WATER; Time(min)/% B= 0/90, 0.8/90 . 1.Θ/55, 3/5, 6.5/5 ,7/90; Flow :0.8mL/min, Column Temp=40°C; Diluent: CAN
123	ABS O X?	6-(5-chloro-2methoxyphenyl) -1-[(2S)pyrrolîdin-2ylmethyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	352.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1 H), 9.08 (br. s., 1 H), 8.14-8.52 (m, 1 H), 7,61 -7.67(m, 1 H), 7.507.58 (m, 1 H), 7.23 - 7.28 (m, 1 H), 5.92-6.00 (m, 1 H), 4.905.04 (m, 1 H), 3.83-3.88 (m, 3 H), 3.63 - 3.77 (m, 1 H), 2.98 3.20 (m, 3H), 1.76-1.89 (m, 2 H), 1.62-1.75 (m, 2 H)
124	0 s-\ Jj νζΡ	2-[4-oxo-2thioxo-6-(2,4,5trimethoxypheny 1)-3,4dihydropyrimidin -1(2H)yljacetamide	352.1	1.23 min Waters Atlantîs dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
125		1-(3- aminopropyl)-2thîoxo-6-(2,4,5trimethoxypheny 1)-2,3dihydropyrimidin -4(1H)-one hydrochloride	352.1	1H NMR (500 MHz, DMSO-d6) ôppm 1.70-1.91 (m, 2 H) 2.53 - 2.60 (m, 2 H) 3.57 (s, 2 H) 3.69 (d, J=7.07 Hz, 1 H) 3.75 (s, 3 H) 3.83 (s, 3 H) 3.87 (s, 3 H) 4.42 (br. s., 1 H) 5.79 (d, J=1.95 Hz, 1 H) 6.62 (s, 1 H) 7.00 (s, 1 H) 7.86 (br. s„ 2 H) 12.76 (s, 1 H)

101

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
126		2-{3-[6-(5-fluoro2methoxyphenyl) -4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]propyl}guanidi ne	352.2	1.22 min Waters XBridge C18 4.6x50mm, 5um; 95%H20 / 5%MeCN linear to 5%H20 ! 95%MeCN over 4.0min, HOLD at 5%H20 / 95%MeCN to 5.0min. Flow: 2.0mL/min.NH4OH 0.03% Flow rate: 2 mL/min
127	O Hhr|l	N-{2-[6-(5fluoro-2methoxyphenyl) -4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]ethyl}glycina mide hydrochloride	353.2	1H NMR (500 MHz, CD3OD) d ppm 7.30 (td, 1 H), 7.25 (dd, 1 H), 7.16 (dd, 1 H), 5.81 (s, 1 H), 4.79 (m, 1 H), 3.89 (s, 3 H), 3.82 (m, 1 H), 3.54 (m, 2 H), 3.45 (m, 2 H)
128	0 NH,	2-{2-[6-(5chloro-2methoxyphenyl) -4-oxo-2-thioxo- 3,4dihydropyrimidin -1(2H)yl]ethyl}guanidin e hydrochloride	354.0	1H NMR (500 MHz, DMSO-d6) δ ppm 12.88(5, 1 H), 7.63 (br. s., 1 H), 7.58 (dd, J=9.03, 2.68 Hz, 1 H), 7.39-7.41 (m, 1 H), 7.20 (d, J=9.03 Hz, 1 H), 7.00 (br. s., 4 H), 5.91 (d, J=2.20 Hz, 1 H), 4.54 (br. d, J=13.40 Hz, 1 H), 3.84 (s, 3 H), 3.59 - 3.67 (m, 1 H), 3,55 (dt, J=9.33, 4.97 Hz, 1 H), 3.17-3.25 (m, 1 H)
129	O viy^ *	1-(3aminopropyl)-6(5-chloro-2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	356.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.78 (s, 1 H), 7.75 (br. s., 3 H), 7.49 (s, 1 H), 6.92 (s, 1 H), 5.83 (d, J=2.45 Hz, 1 H), 4.32-4,45 (m, 1 H), 3.97 (S, 3 H). 3.90 (s, 3 H), 3.59 - 3.70 (m, 1 H), 2.53 - 2.65 (m, 2 H), 1.66 -1.88 (m,2H)
130	âq % Ην<Ί£'ΝΗ	1-(2-{4-oxo-2thioxo-6-[2-(2H1,2,3-triazol-2yl)phenyl]-3,4dihydropyrimidin -1(2H)yl}ethyl)guanidin e hydrochloride	357.1	1H NMR (400 MHz, METHANOL-d4): δ 8.12 (d, 1H), 7.91 (s, 2H), 7.75 (t, 1 H), 7.55-7.59 (m, 2H), 5.74 (s, 1 H), 4.40 (m, 1H), 3.75 (m, 1H), 3.55 (m, 1H), 3.35 (m, 1H).

102

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
131	0	2-{3-[6-(2,5dimethoxypheny l)-4-oxo-2thîoxo-3,4dihydropyrimidin -1(2H)yl]propyl)guantdi ne trifluoroacetate	364.1	2.44 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
132	0 H”|l σ'' iÿv	6-(5-chloro-2methoxyphenyl) -1-(piperidin-4ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	366.0	3.639 min Column: XBRIDGEC18 4.6X75mm 3.5pm Mobile phase- A=0.1% FA IN ACN, B=0.1% FA IN WATER Time(min)/% B= 0/90, 0.8/90 , 1.8/55, 3/5, 6.5/5 ,7/90 Flow :0.8mL/min, Column Temp=40°C; Diluent: MEOH
133	0	2-{3-[6-(5chloro-2methoxyphenyl) -4-oxo-2-thioxo- 3,4dihydropyrimidin -1(2H)yl]propyl}guanidi ne	368.1	1.38 min Waters XBridge C18 4.6x50mm, 5um 95%H20 / 5%MeCN linear to 5%H20 / 95%MeCN over 4.0min, HOLD at 5%H20 / 95%MeCN to 5.0min. Flow: 2.0mL/min.NH4OH 0.03% Flow rate: 2 mL/min
134	0 O'' y	N-{3-[6-(5chloro-2methoxyphenyl) -4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]propyl}acetam ide	368.1	1H NMR (400 MHz, DMSO-d6) dppm 12.73 (s, 1 H), 7.62 (t, J=6.0 Hz, 1 H), 7.58 (dd, J=9.0, 2.7 Hz, 1 H), 7.50 (d, J=2.7 Hz, 1 H), 7,21 (s, 0 H), 5.83 (d, J=2.1 Hz, 1 H), 4.12-4.27 (m, 1 H), 3.85 (s, 3 H), 3.58 - 3.70 (m, 1 H), 2.78 (q, J=6.2 Hz, 2 H), 1.65-1.75 (m, 0 H), 1.61 (s, 3 H), 1.46-1.58 (m, 1 H)
135	0	N-{2-[6-(5chloro-2methoxyphenyl) -4-oxo-2-thioxo3.4dihydropyrimidin -1(2H)yl]ethyl}glycina mide hydrochloride	369.2	1H NMR (400 MHz, CD3OD) d ppm 7.54 (dd, 1 H), 7.46 (d, 1 H), 7.17 (d, 1 H), 5.81 (s, 1 H), 4.78 (m, 1 H), 3.91 (s, 3 H), 3.80 (m, 1 H), 3.55 (m, 2 H), 3.46 (t, 2 H)

103

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
136	Xx NH i	1-cyano-3-{2-[6(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidîn -1(2H)yl]ethyl)guanidin e	375.0	1H NMR (400 MHz, DMSO-d6): 5 7.17 (d, 1 H), 6.70-6.88 (br, 1 H), 6.55-6.65 (m, 4 H), 5.69 (s, 1 H), 4.43-4.45 (m, 1 H), 3.88 (s, 3 H), 3.84 (s, 3 H), 3.59-3.68 (m, 1 H), 3.30-3.40 (m, 1H), 3.16-3.17 (m, 1 H).
137	0 λΛα A	tert-butyl [6(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetate	379.1	2.59 min Waters XBridge C18 4.6x50mm, 5um 95%H20 / 5%MeCN linear to 5%H20 / 95%MeCN over 4.0min, HOLD at 5%H20 / 95%MeCN to 5.0min. Flow: 2.0mL/min.NH4OH 0.03% Flow rate: 2 mL/min
138	0 W,	2-{2-[4-oxo-2thioxo-6-(2,4,5trimethoxypheny 1)-3,4dîhydropyrimidin -1(2H)yl]ethyl}guanidin e hydrochloride	380.1	1H NMR (500 MHz, DMSO-d6) δ ppm 12.80 (d, J=1.71 Hz, 1 H), 7.59 (t, J=6.10 Hz, 1 H), 6.98 (br. s„ 4 H), 6.89 (s, 1 H), 6.80 (s, 1 H), 5.81 (d, J=2.20 Hz, 1 H), 4.54 (br. d, J=14.15 Hz, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.77 - 3.81 (m, 1 H), 3.75 (s, 3 H), 3.53 (ddt, J=14.45, 8.72, 5.49, 5.49 Hz, 1 H), 3.153.25 (m, 1 H)
139		ethyl [4-ΟΧΟ-2thioxo-6-(2,4,5trimethoxypheny 1)-3,4dihydropyrimidin -1(2H)yljacetate	381.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.60 (br. s., 1 H), 6.71 (s, 1 H), 6.52 (s, 1 H), 5.86 (s, 1 H), 5.39 (br. d, J=17.40 Hz, 1 H), 4.24 (br. d, J=17.80 Hz, 1 H), 4.02-4.18 (m, 2 H), 3.93 (s, 3 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 1.18 (t, J=7.13 Hz, 3 H)
140	M X H/tXm	1-(2-(2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]ethoxy}ethyl)g uanidine formate	393.8	1H NMR (400 MHz, METHANOL-d4): δ 8.38 (br.s., 1 H), 7.21 (d, 1 H), 6.66-6.62 (m, 2H), 5.73 (s, 1 H), 4.82-4.76 (m, 1H), 3.93-3.81 (m, 7H), 3.773.71 (m, 1H), 3.57-3.51 (m, 1H), 3.44-3.40 (m, 2H), 3.273.22 (m, 2H).

104

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
141	:¾	2-{3-[4-oxo-2thioxo-6-(2,4,5trimethoxypheny 1)-3,4dihydropyrimidin -1(2H)yl]propyl)guanidi ne trifluoroacetate	394.1	1.60 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
142	0	1-(2aminoethyl)-6(1 H-indol-4-yl)2-thioxo-2,3dihydropyrimidin -4(1H)-one trifluoroacetate	270.1 [M- NH3+ 1]+	1H NMR (300 MHz, METHANOL-d4) δ ppm 11.13 (br. s., 1 H), 7.62 (d, J=8.01 Hz, 1 H), 7.44 (d, J=3.14 Hz, 1 H), 7.29 (t, J=7.66 Hz, 1 H), 7.13 (d, J=7.32 Hz, 1 H), 6.40 (d, J=2.44 Hz, 1 H), 5.93 (s, 1 H), 4.70 - 4.81 (m, 1 H), 4.32 (dt, J=14.28, 7.14 Hz, 1 H), 2.91 3.11 (m, 2H)
143	0 NH^	1-(2- aminoethyl)-6(1-benzofuran7-yl)-2-thioxo2,3dihydropyrimidin -4(1H)-one hydrochloride	270.9 [M- NH3+ 1]+	1H NMR (400 MHz, DMSO-d6) δ ppm 13.01 (br. s, 1 H), 8.13 (d, J=1.96 Hz, 1 H), 7.90 (dd, J=7.34, 1.96 Hz. 1 H), 7.67 (br. s, 3 H), 7.42 - 7.49 (m, 2 H), 7.14 (d, J=2.45 Hz, 1 H), 6.04 (s, 1 H), 4.57 - 4.73 (m, 1 H), 3.85 - 4.02 (m, 1 H), 3.03 - 3.09 (m, 1 H), 2.83-2.91 (m, 1 H)
144	S ηΛ v NH^	1-(2aminoethyl)-2thioxo-6-[2-(2H1,2,3-triazol-2yl)phenyl]-2,3dihydropyrimidin -4(1H)-one hydrochloride	297.9 [MNH3+ Ψ	1H NMR (400 MHz, METHANOL-d4): δ 8.11 (d, 1H), 7.90 (s, 2H), 7.74 (t, 1H), 7.60 (d, 2H), 5.62 (s, 1 H), 4.67 (m, 1H), 4.10 (m, 1H), 3.28 (m, 1H), 3.05 (s, 1H).:
145	0 Hrr> d' NH, Cl	2-[6-(5-chloro-2methoxypyridin3-yl)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]acetamide	325.0 [M-H]-	1H NMR (400 MHz, METHANOL-d4) δ ppm 8.31 (s, 1 H), 7.72 (s, 1 H), 5.88 (s, 1 H), 5.56-5.72 (m, 1 H), 4.064,21 (m, 1 H), 3.95 (s, 3 H)

105

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
146	0 Hir^i <A ΨΑ NH, 1 1	2-(6-(2,4dimethoxy-5methylphenyl)4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]acetamide	358.0 [M+N a]+	1H NMR (400 MHz, DMSO-d6): δ 12.55 (br, 1 H), 7.31 (s, 1 H), 7.02 (s, 1 H), 6.92 (s, 1 H), 6.72 (s, 1 H), 5.72 (s, 1 H), 5.35 (br.s., 1 H), 3.93 (br.s., 1 H), 3.88 (s. 3 H), 3.85 (s, 3 H), 2.05 (s, 3 H).
147	0 Hbr\ <A NFÇ	2-(6-(2,5dimethoxy-4methylphenyl)4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]acetamide	358.0 (M+N a]+	1H NMR (400 MHz, METHANOL-d4): δ 6.86 (s, 1H), 6.69 (s, 1H), 5.72 (s, 1H), 4.57 (m, 1H), 4.10 (m, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 2.16 (s, 3H).
148	0 cAh,	1-(3-(6-(5chloro-2methoxyphenyl) -4-oxo-2-thioxo- 3,4dihydropyrimidin -1(2H)yljpropyljurea	367.2 [M-1]-	1H NMR (500 MHz, DMSO-d6) d ppm 12.72 (br. s, 1 H), 7.57 (dd, J=9.0, 2.7 Hz, 1 H), 7.52 (d, J=2.7 Hz, 1 H), 7.19 (d, J=9.0 Hz, 1 H), 5.84 (s, 1 H), 5.75 (m, 1 H), 5.26 (s, 2 H), 4.26 (m, 1 H), 3.84 (s, 3 H), 3.61 (m, J-10.0 Hz, 1 H), 2.72 (m,2H), 1.65 (m, 1 H), 1.49 (dd, J=11.6, 5.7 Hz, 1 H)
149	A A	N-{3-[6-(5chloro-2methoxyphenyl) -4-oxo-2-thioxo3.4dihydropyrimidin -1(2H)yl]propyl}glycina mide hydrochloride	381.2 [Μ-1Γ	1H NMR (500 MHz, DMSO-d6) d ppm 8.29 (t, J=5.6 Hz, 1 H), 7.87 - 8.16 (m, 2 H), 7.60 (dd, J=9.0, 2.7 Hz, 1 H), 7.53 (d, J=2.7 Hz, 1 H), 7.23 (d, J=9.0 Hz, 1 H), 5.87 (s, 1 H), 4.174.32 (m, 1 H), 3.84 (s, 3 H), 3.56 - 3.73 (m, 1 H), 3.34 - 3.42 (m, 2 H), 2.80-3.00 (m, 2 H), 1.74 (d, J=6.6 Hz, 1 H), 1.551.64 (m, 1 H)
150	0 hî/S cA OH^	1-(2hydroxyethyl)-6(2-methoxy-5methylpyridin-3yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	293.8	1H NMR (400 MHz, CD3OD) d ppm 8.14 (m, 1 H), 7.59 (d, 1 H), 5.78 (d, 1 H), 4.71 (m, 1 H), 3.96 (d, 3 H), 3.85 (dt, 1 H), 3.70 (dt, 1 H), 3.59 (m, 1 H), 2.32 (s, 3 H)

106

The following Examples of Table 3 were prepared from the corresponding methyl ketone to afford the intermediate beta-keto-ester as described above for the

Préparations in the Methyl Ketone Route section followed by employing other methods described in the I, Beta Ketone Ester Route Section as well as standard methods and techniques known to those skilled in the art.

Table 3. Examples from Methyl Ketone Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
151	ABS 0 H	6-(2,4dimethoxypheny |)-1-[(3R)piperidin-3ylmethyl]-2thioxo-2,3dihydropyrimidin -4(1 H)-one hydrochloride	362.0	3.653 min Column: XBRIDGEC18 4.6X75mm 3.5pm Mobile phase- A=0.1% FA IN ACN, B=0.1% FA IN WATER Time(min)/% B= 0/90, 0.8/90 , 1.8/55, 3/5, 6.5/5 ,7/90 Flow :0.8mL/min, Column Temp=40°C; Diluent: CAN
152	0	6-(2,4dimethoxypheny l)-1 -(2-piperidin4-ylethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	376.1	1HNMR(400 MHz, METHANOL-d4): δ 7.26 (d, 1H), 6.70 (d, 1H), 6.67 (dd, 1H), 5.76 (s, 1H), 4.56-4.67 (m, 1H), 3.88 (s, 3H), 3.8 (s, 3H), 3.723.80 (m, 1H), 3.22-3.25 (m, 2H), 2.82-2.89 (t, 2H), 1.631.75 (m, 3H), 1.341.48 (m, 2H), 1.08-1.29 (m, 2H).
153	A>	1-(2-(1acetylpiperidin4-yl)ethyl]-6(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	440.1 [M+N a]+	1HNMR(400 MHz, METHANOL-d4): δ 7.25 (d, 1H), 6.71 (d, 1 H), 6.68 (dd, 1H), 5.75 (s, 1H), 4.52-4.65 (m, 1H), 4.27-4.35 (m, 1H), 3.88 (s, 6H), 3.70-3.80 (m, 2H), 2.92-3.03 (m, 1H), 2.49-2.56 (m, 1H), 2.05 (s, 3H), 1.71-1.74 (m, 1H), 1.33-1.57 (m, 4H), 0.68-1.10 (m, 2H).
154	J»	6-(1H-imidazol2-yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	253.1	1HNMR (400 MHz, METHANOL-d3) δ ppm 7.26 (br. s., 2 H), 6.04 (s, 1 H), 4.84 (br. s., 2 H), 3.63 (t, J=5.27 Hz, 2 H), 3.13 (s, 3 H)

107

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
155	0 çœr	1-(2hydroxyethyl)-6(3methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one	279.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.43 (dd, J=7.80, 7.80 Hz, 1 H), 7.08 (ddd, J=8.47, 2.52, 0.92 Hz, 1 H), 7.04 (dd, J=2.29, 2.29 Hz, 1 H), 7.00 (ddd, J=7.80, 2.30, 0.92 Hz, 1 H), 5.79 (s, 1 H), 4.26 - 4.39 (m, 2 H), 3.84 (s, 3 H), 3.77 (t, J=6.18 Hz, 2 H)
156	0 ΗΙ'Γ-'Τι Cf'' aAa fO OH	1-(2hydroxyethyl)-6(2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one	279,1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51 (ddd, J=8.24, 7.30, 1.80 Hz, 1 H), 7.25 (dd, J=7.56,1.60 Hz, 1 H), 7.08 (ddd, J=7.60, 7.60, 0.90 Hz, 1 H), 7.00 (d, J=8.24 Hz, 1 H), 5.86 (s, 1 H), 4.70 4.79 (m, 1 H), 3.83 - 3.91 (m, 5 H), 3.64 - 3.72 (m, 1 H)
157	O	6-(2,6dimethoxypheny l)-1-methyl-2thioxo-2,3dihydropyrimidin -4(1H)-one	279.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.00 (br. s., 1 H), 7.40 (t, J=7.79 Hz, 1 H), 6.62 (d, J=8.24 Hz, 2 H), 5.85 (s, 1 H), 3.80 (s, 6 H), 3.45 (s, 3 H)
158	0	6-(2fluorophenyl)-1(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	281.1	1HNMR (400 MHz, METHANOL-d3) δ ppm 7.54 7.63 (m, 1 H), 7.47 (ddd, J=7.60, 7.60, 1.80 Hz, 1 H), 7.35 (ddd, J=7.80, 7.80, 1.40 Hz, 1 H), 7.29 (ddd, J=9.85, 8.47, 0.92 Hz, 1 H), 5.86 (s, 1 H), 4.64 (dt, J=14.08, 4.64 Hz, 1 H), 3.99-4.12 (m, 1 H), 3.70 (ddd, J=10.53, 7.33, 5.04 Hz, 1 H), 3.48 (dt, J=10.42, 5.09 Hz, 1 H), 3.11 (s, 3 H)
159	0 Hhr-’ji σ''	1-(2aminoethyl)-6(2-methoxy-5methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	292	1H NMR (500 MHz, DMSO-d6) δ ppm 12.80-12.90 (m, 1 H) 7.95 (br. s., 3 H) 7.36 (dd, J=8.42, 1.83 Hz, 1 H) 7.18 (d, J=1.95 Hz, 1 H) 7.10 (d, J=8.54 Hz, 1 H) 5.78 (d, J=2.20 Hz, 1 H) 4.54 - 4.65 (m, 1 H) 3.86 - 3.96 (m, 1 H) 3.81 (s, 3 H) 2.82 -2.95 (m, 2H) 2.29 (s, 3 H)

108

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
160	o HtrSi aAa	1-(2methoxyethyl)- 6-(2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one	293.1	1H NMR (400 MHz, METHANOL-d3) d ppm 7.53 (ddd, J=8.00, 8.00, 1.80 Hz, 1 H), 7.32 (dd, J=7.33, 1.83 Hz, 1 H), 7.14 (d, J=8.70 Hz, 1 H), 7.09 (ddd, J=7.60, 7.60, 0.90 Hz, 1 H), 5.75 (s, 1 H), 4.71 (ddd, J=13.74, 5.95, 4.12 Hz, 1 H), 3.89 (s, 3 H), 3.80 - 3.88 (m, 1 H), 3.68 (ddd, J=10.53, 7.79, 5.95 Hz, 1 H), 3.43 (ddd, J=10.42, 6.53,4.12 Hz, 1 H), 3.08 (s, 3 H)
161	0 HhrA cA aAa OH I	1-(2hydroxyethyl)-6(2-methoxy-5methylphenyl)2-thîoxo-2,3dihydropyrimidin -4(1H)-one	293.2	1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (br. s, 1 H) 7.32 (ddd, J=8.39, 2.15, 0.59 Hz, 1 H) 7.14 (d, J=2.15 Hz, 1 H) 7.06 (d, J=8.39 Hz, 1 H) 5.72 (d, J=2.15Hz, 1 H) 4.70 (t, J=5.56 Hz, 1 H) 4.43 - 4.51 (m, 1 H) 3.79 (s, 3 H) 3.55 - 3.64 (m, 1 H) 3.47 - 3.55 (m, 1 H) 3.38 - 3.46 (m, 1 H) 2.28 (s, 3 H)
162	O OH	1-(2hydroxyethyl)-6(1-naphthyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	299.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.82 (br. s„ 1 H), 7.998.13 (m, 2 H), 7.67-7.73 (m, 1 H), 7.52-7.66 (m, 4 H), 5.87 (d, J=1.76 Hz, 1 H), 4.61 (br. s., 1 H), 4.23 - 4.37 (m, 1 H), 3.34 - 3.51 (m, 3 H)
163	Χλ aaa y	3-(3-(2hydroxyethyl)-6oxo-2-thioxo- 1,2,3,6tetrahydropyrimi din-4-yl]-4methoxybenzoni trile	304.2	1H NMR (500 MHz, DMSO-d6) δ ppm 12.80 (s, 1 H) 8.03 (dd, J=8.78, 1.95 Hz, 1 H) 7.82 (d, J=2.20 Hz, 1 H) 7.36 (d, J=8.78 Hz. 1 H) 5.87 (d, J=2.20 Hz, 1 H) 4,46 - 4.54 (m, 1 H) 3.92 (s, 3 H) 3.57 - 3.64 (m, 1 H) 3.38 3.49 (m, 2 H)
164	0 hitA cA ούφ NH, I	2-(6-(2methoxy-5methylphenyl)4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yl]acetamide	306.0	1.44 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linearto 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min

109

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
165	□	6-[6(dimethylamino) pyridin-3-yl]-1(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	307.2	1HNMR (400 MHz, METHANOL-d3) δ ppm 8.07 (d, J=1.83Hz, 1 H), 7.99 (dd, J=9.62, 2.29 Hz, 1 H), 7.28 (d, J=9.62 Hz, 1 H), 5.90 (s, 1 H), 4.40 (br. s., 2 H), 3.71 (t, J=5.04 Hz, 2 H), 3.33 (s, 6 H), 3.26 (s, 3 H)
166	0	1-(2aminoethyl)-6- (2,5dîmethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1 H)-one hydrochloride	308.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.87 (s, 1 H) 7.93 (br. s., 3 H) 7.09-7.16 (m, 2 H) 7.03 (d, J=2.73 Hz, 1 H) 5.82 (d, J=1,95 Hz, 1 H) 4.54-4.64 (m, 1 H) 3.86 - 3.98 (m, 1 H) 3.79 (s, 3 H) 3.75 (s, 3 H) 2.85 2.97 (m, 2 H)
167	0 aAa	6-(2,6dimethoxypheny 1)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1 H)-one	309.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.72 (br. s., 1 H), 7.45 (t, J=8.36 Hz, 1 H), 6.79 (d, J=8.47 Hz, 2 H), 5.71 (d, J=2.06 Hz, 1 H), 3.94 (t, J=7.21 Hz, 2 H), 3.76 (s, 6 H), 3.35 (t, J=7.56 Hz, 2 H)
168	A X •yô OH	6-(2-(2hydroxyethoxy)p henyl]-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	309.1	1.57 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
169	0 OH	6-(2,5dimethoxypheny 1)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	309.2	1H NMR (500 MHz, DMSO-d6) δ ppm 12.72 (s, 1 H) 7.06-7.11 (m, 2 H) 6.95 (d, J=2.44 Hz, 1 H) 5.77 (d, J=2.20 Hz, 1 H) 4.72 (t, J—5.61 Hz, 1 H) 4.44 - 4.50 (m, 1 H) 3.77 (s, 3 H) 3.74 (s, 3 H) 3.51 - 3.64 (m, 2 H) 3.40 - 3.46 (m, 1 H)
170	Ύλ —o >r 6^° N	2-[6-(5-cyano-2methoxyphenyl) -4-oxo-2-thioxo3,4dihydropyrimidin -1(2H)yljacetamide	317.2	1H NMR (500 MHz, DMSO-d6) Ô ppm 3.76 - 3.94 (m, 2 H), 3.93 (S, 3 H), 5.92 (d, J=1.7 Hz. 1 H), 7.10 (br. s., 1 H), 7.31 (br. s., 1 H), 7.37 (d, J=8.8 Hz, 1 H), 7.61 (s, 1 H), 8.03 (dd, J=8.7, 1.6 Hz, 1 H), 12.88 (br. s„ 1 H)

110

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
171	OvL	4-methoxy-3-[3(2methoxyethyl)6-oxo-2-thioxo1,2,3,6tetrahydropyrimi din-4yl]benzonitrile	318.1	2.34 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
172	0	1-(2isopropoxyethyl) -6-(4methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one	321.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.19 (br. s., 1 H) 7.29 (d, J=8.78 Hz, 2 H) 6.97 (d, J=8.97 Hz, 2 H) 5.84 (d, J=2.15 Hz, 1 H) 4.37 (t, J=5.46 Hz, 2 H) 3.87 (s, 3 H) 3.68 (t, J=5.66 Hz, 2 H) 3.47 (spt, J=6.08 Hz, 1 H) 1.06 (d, J=6.05 Hz, 6 H)
173	0 70	1-(2isopropoxyethyl) -6-(2methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one	321.5	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.53 (ddd, J=8.39, 7.61, 1.76 Hz, 1 H) 7.33 (dd, J=7.41, 1.76 Hz, 1 H) 7.13 (d, J=8.58 Hz, 1 H) 7.08 (ddd, J=7.51, 7.51, 0.98 Hz, 1 H) 5.75 (s, 1 H) 4.69 (ddd, J=13.51,6.58, 3.90 Hz, 1 H) 3.88 (s, 3 H) 3.78 (dt, J=13.61, 7.34 Hz, 1 H) 3.643.72 (m, 1 H) 3.50 (ddd, J=9.80, 7.07, 4.00 Hz, 1 H) 3.38 (spt, J=6.11 Hz, 1 H) 0.99 (dd, J=6.15, 2.44 Hz, 6 H)
174	0 XjlT X I	2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	322.2	1H NMR (500 MHz, DMSO-d6) δ ppm 12.75 (s, 1 H) 7.31 (br. s., 1 H) 7.08 (d, J=8.54 Hz, 1 H) 6,98 (br. s., 1 H) 6.69 (d, J=2.20 Hz, 1 H) 6.61 (dd, J=8.54, 2.20 Hz, 1 H) 5.74 (s, 1 H) 5.38 (br. s„ 1 H) 3.87 (br. s„ 1 H) 3.82 (s, 3 H) 3.81 (s, 3 H)
175	ABS 0 7½ NH, 1	1-[(2R)-2aminopropyl]-6(2,4dîmethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	322.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.21 7.31 (m, 1 H), 6.71 (d, J=1.83 Hz, 1 H), 6.68 (dd, J=8.24, 2.29 Hz, 1 H), 5.77 - 5.85 (m, 1 H), 5.10-5.24 (m, 1 H), 3.87-3.90 (m, 3 H), 3.83 - 3.86 (m, 3 H), 3.61 - 3.73 (m, 1 H), 3,47 - 3.59 (m, 1 H), 0.90 -1.15 (m, 3 H)

111

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
176	ABS 0 NH, 1	1-[(2S)-2aminopropyl]-6(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	322.1	1H NMR (400 MHz,· METHANOL-d3) δ ppm 7.24 7.33 (m, 1 H), 6.67 - 6.76 (m, 2 H), 5.80-5.85 (m, 1 H), 5.13 5.25 (m, 1 H), 3.87 - 3.92 (m, 6 H), 3.51-3.76 (m, 2 H), 0.951.16 (m, 3 H)
177	0 1	6-(2,4dimethoxypheny 1)-1-(2(methylamino)et hyl]-2-thioxo2,3dihydropyrimidin -4(1H)-one formate	322.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.27 (d, J=8.24 Hz, 1 H), 6.73 (d, J=2.29 Hz, 1 H), 6.70 (dd, J=8.47, 2.52 Hz, 1 H), 5.81 (s, 1 H), 4.06 - 4.17 (m, 2 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 2.99 3.16 (m, 2 H), 2.55 (s, 3 H)
178	0	1-(3aminopropyl)-6- (2.4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one formate	322.1	1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 (s, 1 H), 7.25 (d, J=8.70 Hz, 1 H), 6.68 (d, J=2.29 Hz, 1 H), 6.62 (dd, J=8.24, 2.29 Hz, 1 H), 5.72 (s, 1 H), 4.31 -4.45 (m, 2 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.16- 3.62 (m, 3 H), 2.39 - 2.44 (m, 2 H), 1.52-1.81 (m, 2H)
179	0 ''oi/ 1	6-(2,4dimethoxypheny 1)-1-(2hydroxypropyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	323.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.57 -9.72 (m, 1 H), 7.11-7.21 (m, 1 H), 6.45 - 6.60 (m, 2 H), 5.82 (dd, J=13.05, 2.52 Hz, 1 H), 4.41 -4.93 (m, 1 H), 4.27-4.41 (m, 1 H), 3.86 (s, 3 H), 3.82 (m, 3 H), 3.53-3.69 (m, 1 H), 0.94 -1.05 (m, 3 H)
180	,(X (iC- 1	6-(2,6dimethoxypheny 1)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimîdin -4(1H)-one	323.1	2.50 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min

112

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
181	0 HirX σ''' TA	6-(2,4dimethoxypheny 1)-1-(3hydroxypropyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	323.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.46 (br. s., 1 H), 7.11 (d, J=8.24 Hz, 1 H), 6.56 (dd, J=8.24, 2.29 Hz, 1 H), 6.52 (d, J=2.29 Hz, 1 H), 5.82 (d, J=2 75 Hz, 1 H), 4.64 4.75 (m, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.80-3.89 (m, 2H), 3.49 (t, J=5.72 Hz, 1 H), 1.56- 1.83 (m, 2H)
182	0	6-(2,4dimethoxypheny 1)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	323.2	1HNMR (300MHz, CDCI3) 9.80 (bs, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.50 (s, 1H), 5.80 (d, J=2.1Hz, 1H), 4.70 (dt, J=13.5, 4.5 Hz, 1H), 3.86 (s, 3H), 3.83-3.91 (m, 1H) 3.82 (s, 3H), 3.66-3.74 (m, 1H), 3.41-3.47 (m, 1H), 3.16 (s, 3H)
183	0 NH,	1-(2aminoethyl)-6(3bromophenyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	M+1 (NH2) 311.0	1H NMR (500 MHz, DMSO-d6) d ppm 12.88 (br. s., 1 H), 7.86 (br. s„ 2 H), 7.82 (s, 1 H), 7.77 (d, J=7.8 Hz, 1 H), 7.56 (m. 1 H), 7.51 (m, 1 H), 5.87 (s, 1 H), 4.26 (br. s., 2 H), 2.94 (m, 2 H)
184	0 hZ\ σ'' ζ» F I	6-(5-fluoro-2,4dimethoxypheny 1)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	326.8	1H NMR (400 MHz, CD3OD) d ppm 7.12 (dd, 1 H), 6.85 (d, 1 H), 5.75 (d, 1 H), 4.60-4.73 (m, 1 H), 3.97 (s, 3 H), 3.90 (s, 3 H), 3.76 - 3.86 (m, 2 H), 3.56 - 3.65 (m, 1 H)
185	0 NH, I	1-(2- aminoethyl)-6(4-methoxy-1naphthyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	327.9	1H NMR (400 MHz, DMSO-d6) δ ppm 12.92 (br. s, 1 H), 8.24 (dd, J=7.44, 1.95 Hz, 1 H), 7.73 (d, J=7.33 Hz, 1 H), 7.49 - 7.65 (m, 6 H), 7.08 (d, J=8.01 Hz, 1 H), 5.89 (s, 1 H), 4.47 (ddd, J=13.91, 8.87, 5.15 Hz, 1 H), 4.01 (s, 3 H), 3.66 - 3.77 (m, 1 H), 2.82-2.91 (m, 1 H), 2.77 (ddd, J=12.31, 8.87, 6.30 Hz, 1 H)

113

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
186	O F A T0	1-(2hydroxyethyl)-2thioxo-6-[2(trifluoromethox y)phenyl]-2,3dihydropyrimidin -4(1H)-one	333.0	1H NMR (400 MHz, CDCI3): δ 9.89 (br.s., 1H), 7.63-7.58 (m, 1 H), 7.45-7.40 (m, 3H), 5.89 (d, 1H), 4.74-4.67 (m, 1 H), 4.013.95 (m, 1H), 3.82-3.75 (m, 1H), 3.71-3.66 (m, 1H), 1.83 (s, 1H).
187	0 hi<^| cr'’ Z-	3-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljpropanimidam ide trifluoroacetate	335.1	1HNMR (400 MHz, METHANOL-d4) δ ppm 7.23 (d, J=8.22 Hz, 1 H), 6.71 (d, J=2.15Hz, 1 H), 6.68 (dd, J=8.41, 2.15 Hz, 1 H), 5.78 (s, 1 H), 4.97 (dt, J=14.57, 5.72 Hz, 1 H), 3.99-4.07 (m, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 2.87 (ddd, J=14.48, 8.22, 5.50 Hz, 1 H), 2.62 - 2.72 (m, 1 H)
188	O O	2-(6-(2,4dimethoxypheny l)-4-oxo-2thîoxo-3,4dihydropyrimidin -1(2H)yl]propanamide	336.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.79 (br. s., 1 H), 7.11 -7.25 (m, 1 H), 6.48 - 6,64 (m, 2 H), 5.85 5.91 (m, 1 H), 5.42 - 5.75 (m, 2 H), 4.35-4.76 (m, 1 H), 3.853.90 (m, 3 H), 3.81 - 3.85 (m, 3 H), 1.85 (m, J=6.87 Hz, 3 H)
189	0 Hlf\ oX Z®	3-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]propanamide	336.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.66 (br. s, 1 H), 7.23 (d, J=8.70 Hz, 1 H), 7.21 (br. s„ 1 H), 6.72 (br. s., 1 H), 6.67 (d, J=2.29 Hz, 1 H), 6.60 (dd, J=8.24, 2.29 Hz, 1 H), 5.69 (s, 1 H), 4.31 - 4.44 (m, 2 H), 3.79 (s, 3 H), 3.78 (s, 3 H)
190	0 ίχΐΧίΧο Λ 1	2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)-yl]-Nmethylacetamid e	336.2	1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (br. s., 1 H), 7.75 (d, J=4.58 Hz, 1 H), 7.07 (d, J=8.24 Hz, 1 H), 6.67 (d, J=2.29 Hz, 1 H), 6.60 (dd, J=8.47, 2.06 Hz, 1 H), 5.75 (s, 1 H), 5.24 - 5.43 (m, 1 H), 3.87 -3.99 (m, 1 H), 3.81 (s, 3 H), 3.78-3.81 (m, 3H), 2.45 (d, J=4.58 Hz, 3 H)

114

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
191	0	1-(4amînobutyl)-6- (2.4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	335.9	1H NMR (300 MHz, DMSO-d6) δ ppm 12.73 (br. s., 1 H), 7.85 (br. s., 3 H), 7.31 (d, J=8.36 Hz, 1 H), 6.72 (d, J=2.09 Hz, 1 H), 6.66 (dd, J=8.36, 2.79 Hz, 1 H), 5.75 (d, J=2.09 Hz, 1 H), 4.29- 4.48 (m, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.45 - 3.50 (m, 1 H), 2.53-2.62 (m, 2 H), 1.38- 1.66 (m, 2 H), 1.21 -1.37 (m, 2 H)
192	0 Hrr I	6-(2,4dimethoxypheny 1)-1-(3(methylamino)pr opyl]-2-thioxo2,3dihydropyrimidin -4(1H)-one hydrochloride	336.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.75 (br. s., 1 H), 8.38 (br. s., 2 H), 7.28 (d, J=8.24 Hz, 1 H), 6.69 (d, J=2.06 Hz, 1 H), 6.63 (dd, J=8.47, 2.29 Hz, 1 H), 5.73 (d, J=2.06 Hz, 1 H), 4.32 - 4.44 (m, 1 H), 3.80 (s, 6 H), 3.52 - 3.63 (m, 1 H), 3.28 (s, 3 H), 2.39 (t, J=4.92 Hz, 2 H), 1.63- 1.92 (m, 2 H)
193	0 0<î!^oh	3-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljpropanoic acid	337.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.76 (br. s., 1 H), 7.30 (d, J=8.70 Hz, 1 H), 6.70 (d, J=2.29 Hz, 1 H), 6.65 (dd, J=8.70, 2.29 Hz, 1 H), 5.74 (s, 1 H), 4.38-4,51 (m, 1 H), 3.82 (s, 3 H), 3,82 - 3.87 (m, 1 H), 3.82 (s, 3 H), 2.53-2.63 (m, 1 H), 2.40 - 2.48 (m, 1 H)
194	0	6-(2,4dimethoxypheny l)-1-(2-hydroxy2-methylpropyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	337.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.89 (br. s, 1 H), 7.21 (d, J=8.24 Hz, 1 H), 6.58 (dd, J=8.70, 1.83 Hz, 1 H), 6.51 (d, J=1.83 Hz, 1 H), 5.87 (s, 1 H), 5.11 -5.30 (m, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.46-3.64 (m, 1 H), 1.11 (br. S., 3 H), 0.96 (br. s., 3 H)

115

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
195	0	6-(2,4dimethoxypheny l)-1-(3-hydroxy2-methylpropyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	337.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.07 (br. s., 1 H), 7.13 (d, J=8.70 Hz, 1 H), 6.57 (dd, J=8.70, 2.29 Hz, 1 H), 6.52 (d, J=2.29 Hz, 1 H), 5.87 (s, 1 H), 4.95 (br. s., 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.54 (dd, J=11.91, 3.21 Hz, 1 H), 3.34 - 3.41 (m, 1 H), 1.83 (br. s„ 1 H), 0.62 (d, J=6.87 Hz, 3 H)
196	0 A OH	6-(2,4dimethoxypheny 1)-1-(4hydroxybutyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	337.1	H NMR (400 MHz, METHANOL-d4) δ ppm 7.20 (d, J=8.20 Hz, 1 H), 6.66 (d, J=2.15 Hz, 1 H), 6.64 (dd, J=8.20, 2.34 Hz, 1 H), 5.71 (s, 1 H), 4.44 - 4.56 (m, 1 H), 3.85 (S, 6 H), 3.62 - 3.75 (m, 1 H), 3.32 (t, J=6.64 Hz, 2 H), 1.661.81 (m, 1 H), 1.40-1.56 (m, 1 H), 1.16-1.32 (m, 2H)
197	AÔÔ O sAXvA	1-[(2R)-3amino-2hydroxypropyl]6-(2,4dîmethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one trifluoroacetate	336.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.72- 12.82 (m, 1 H), 7.61 - 7.74 (m, 3 H), 7.16-7.28 (m, 1 H), 6.59-6.75 (m, 2 H), 5.70 - 5.79 (m, 1 H), 5.60 - 5.65 (m, 1 H), 4.53 - 4.63 (m, 1 H), 4.21-4.31 (m, 1 H), 3.77-3.86 (m, 6 H), 2.72 - 2.85 (m, 2 H)
196	3a	1-(2aminoethyl)-2thioxo-6-(2,4,5trimethoxypheny 1)-2,3dihydropyrimidin -4(1H)-one hydrochloride	338.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.79 (s, 1 H), 7.92 (br. S., 3 H), 6.99 (s, 1 H), 6.80 (s, 1 H), 5.76 (d, J=1.76 Hz. 1 H), 4.55 (dt, J=13.96, 6.88 Hz, 1 H), 3.93 (dt, J=14.06, 7.03 Hz, 1 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.70 (s, 3 H), 2.80 - 2.97 (m, 2 H)
199	0 yA	1-(3-amino-2hydroxypropyl)6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	338.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.69- 12.76 (m, 1 H), 7.61 -8.08 (m, 3H), 7.13-7.26 (m, 1 H), 6.56 - 6.71 (m, 2 H), 5.65 - 5.76 (m, 1 H), 5.60 (m, J=4.90 Hz, 1 H), 4.55 (s, 1 H), 4.15-4.30 (m, 1 H), 3.74-3.84 (m, 6 H), 3.54 - 3.63 (m, 1 H), 2.61 - 2.95 (m, 2 H)

116

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
200	AB8 0 hyA o’ A-	1-[(2S)-3-amino2hydroxypropyl]6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1 H)-one trifluoroacetate	338.2	1H NMR (300 MHz, DMSO-d6) δ ppm 12.78 (m, 1 H), 7.63 (br. s, 3 H), 7.18-7.28 (m, 1 H), 6.60-6.75 (m, 2 H), 5.715.80(m, 1H), 5.58-5.66 (m, 1 H), 4.54-4.62 (m, 1 H), 4.084.23 (m, 1H), 3.78-3.85 (m, 6H), 3.23-3.41 (m, 1H), 2.712.83 (m, 1H), 2.38-2.45 (m, 1H)
201	OH A -~-o Yr'NH	1-(2,3dihydroxypropyl) -6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	339.2	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 10.33 (br. s., 1 H) 7.17 (br. s., 1 H) 6.58 (br. s., 1 H) 6.52 (d, J=7.22 Hz, 1 H) 5.88 (d, J=7.22 Hz, 1 H) 4.80 - 4.95 (m, 1 H) 4.60-4.73 (m, 1 H) 3.99-4.14 (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H) 3.23 - 3.68 (m, 4 H)
202	Aa yO' 1 A0	1-(2hydroxyethyl)-2thioxo-6-(2,4,5trimethoxypheny 1)-2,3dihydropyrimidin -4(1H)-one	339.2	1H NMR (500 MHz, DMSO-d6) δ ppm 12.68 (s, 1 H), 6.95 (s, 1 H), 6.80 (s, 1 H), 5.74 (s, 1 H), 4.43 - 4.51 (m, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.71 (s, 3 H), 3.64 - 3.70 (m, 1 H), 3.49 - 3.56 (m, 1 H), 3.40 - 3.46 (m, 1 H)
203	ABS OH υίΥ0	1-[(2S)-2,3dihydroxypropyl] -6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	339.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.33 (br. s., 1 H) 7.17 (br. s., 1 H) 6.58 (br. s„ 1 H) 6.52 (d, J=7.22 Hz, 1 H) 5.88 (d, J=7.22 Hz, 1 H) 4.80 - 4.95 (m, 1 H) 4.60-4.73 (m, 1 H) 3.99-4.14 (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H) 3.23 - 3.68 (m, 4 H)
204	ABS OH rf. o vSh	1-[(2R)-2,3dihydroxypropyl] -6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidîn -4(1H)-one	339.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.33 (br. s„ 1 H) 7,17 (br. s., 1 H) 6.58 (br. s., 1 H) 6.52 (d, J=7.22 Hz, 1 H) 5.88 (d, J=7.22 Hz, 1 H) 4.80-4.95 (m, 1 H) 4.60-4.73 (m, 1 H) 3.99-4.14 (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H) 3.23 - 3.68 (m, 4 H)

117

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
205	0 NH, 1	2-(6-(4methoxy-1naphthyl)-4-oxo2-thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	342.2	1H NMR (400 MHz, DMSO-d6) δ ppm 12.90 (br. s, 1 H), 8.25 (d, J=7.33 Hz, 1 H), 7.69 - 7.77 (m, 1 H), 7,56-7.68 (m, 2 H), 7.38 - 7.47 (m, 1 H), 7.23 (s, 1 H), 7.06 (d, J=8.24 Hz, 1 H), 6.98 (br. s., 1 H), 5.92 (d, J=1.83 Hz, 1 H), 5.10-5.35 (m, 2 H), 4.02 (s, 3 H)
206	0 HW^ji C< oh	6-(4-chloro-2,5dimethoxypheny 1)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	343	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.88 (br. s., 1 H), 7.03 (s, 1 H), 6.85 (s, 1 H), 5.84 (s, 1 H), 4.73 (dt, J=14.20, 5.15 Hz, 1 H), 3.91 4.00 (m, 1 H), 3.87-3.90 (m, 1 H), 3.86 (s, 3 H), 3.81 (s, 3 H), 3.59-3.73 (m, 1 H), 1.95 (br. s., 1 H)
207	0	6-(2,4dimethoxypheny l)-1-(1H-pyrazol5-ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	345.1	1HNMR (500 MHz, METHANOL-d4) δ ppm 7.48 (br. s., 1 H), 6.90 (d, J=8,05 Hz, 1 H), 6.62 (d, J=2.20 Hz, 1 H), 6.46 (d, J=5.12 Hz, 1 H), 5.95- 6.13 (m, 2 H), 5.77 (s, 1 H), 4.88-5.01 (m, 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H)
208	0 F Ax oÇjÔ NH,	2-{4-oxo-2thioxo-6-[2(trifluoromethox y)phenyl]-3,4dihydropyrimidin -1(2H)yljacetamide	345.9	1H NMR (400 MHz, Methoanold3) d ppm 7.67 (ddd, J=7.7, 7.6, 2.0 Hz, 1 H), 7.46-7.52 (m, 3 H), 5.89 (s, 1 H), 5.50 (br.s., 1 H), 4.01 (br.s., 1H)
209	Ai. V™ 1	6-(2,4dimethoxypheny l)-2-thioxo-1(1H-1.2.4triazol-5ylmethyl)-2,3dihydropyrimidin -4(1H)-one	346.0	1.84 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min

118

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
210	ÿW:	1-(2methoxyethyl)2-thioxo-6-[4(trifluoromethox y)phenyl]-2,3dihydropyrimidin -4(1H)-one	347.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.53 (br. s., 1 H), 7.42 (d, J=8.70 Hz, 2 H), 7.34 (d, J=8.24 Hz, 2 H), 5.82 (d, J=2.29 Hz, 1 H), 4.34 (br. s„ 2 H), 3.67 (t, J=5.27 Hz, 2 H), 3.20 (s, 3 H)
211	A	6-(2.4dimethoxypheny l)-1-(pyrrolîdin2-ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	348.4	1H NMR (400 MHz, DMSO-d6) δ ppm 12.89 (s, 1 H), 9.25 (br. s, 1 H), 8.08 - 8.71 (br. m.t 1 H), 7.24 - 7.42 (m, 1 H), 6.74 (d, J=2.33 Hz, 1 H), 6.69 (dd, J=8.61,2.09 Hz, 1 H), 5.80 (m, 1 H), 4.97-5.07 (m, 1 H), 3.81 - 3.88 (m, 6 H), 3.61 - 3.78 (m, 2 H), 2.96-3.17 (m, 2 H), 1.73 -1.90(m, 1 H), 1.65 (m, 2 H), 1.13-1.26 (m, 1 H)
212	0 M H	6-(2,4dimethoxypheny l)-1-(pyrrolidin3-ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	348.4	1H NMR (300 MHz, DMSO-d6) δ ppm 12.80 (s, 1 H), 8.77 (br. s., 2 H), 7.27-7.38 (m, 1 H), 6.73 (d, J=2.09 Hz, 1 H), 6.67 (dd, J=8.36, 2.09 Hz, 1 H), 5.76 -5.79 (m, 1 H), 4.60-4.75 (m, 1 H), 3.84 (br. s., 4 H), 3.57 (s, 3 H), 3.13-3.24 (m, 1 H), 3.01 -3.13(m, 1 H), 2.85-2.97 (m, 1 H), 2.70 - 2.83 (m, 1 H), 2.55 -2.69 (m, 1 H), 1.81 -1.95 (m, 1 H), 1.62-1.79 (m, 1 H)
213	ABS 0 H^|j AA	6-(2.4dimethoxypheny l)-1-[(2S)tetrahydrofuran2-ylmethyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one	349.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.59 (br. s, 1 H), 7.12-7.24 (m, 1 H), 6.56 (dd, J=8.24, 1.83 Hz, 1 H), 6.43 - 6.51 (m, 1 H), 5.75 5.82 (m, 1 H), 4.67 (dd, J=13.74, 2.29 Hz, 1 H), 4.534.62 (m. 1 H), 3.85 (s, 3 H), 3.79 - 3.83 (m, 3 H), 3.54 (q, J=7.20 Hz, 1 H), 3.39 (dd, J=13.28, 10.08 Hz, 1 H), 3.15 (q, J=7.17 Hz, 1 H), 1.89-2.02 (m, 1 H), 1.64-1.80 (m, 1 H), 1.45- 1.54 (m, 1 H), 1.23-1.35 (m, 1 H)

119

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
214	ASS 0	6-(2,4dimethoxypheny l)-1-[(2R)tetrahydrofuran2-ylmethyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one	349.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.20 7.26 (m, 1 H) 6.63 - 6.68 (m, 2 H) 5.70 - 5.74 (m, 1 H) 4.71 (dd, J=14.07, 2.74 Hz, 1 H) 4.56-4.65 (m, 1 H) 3.84-3.88 (m, 6 H) 3.50 - 3.57 (m, 1 H) 3.43-3.50 (m, 1 H) 3.22 (dt, J=8.26, 6.72 Hz, 1 H) 1.93 (m, J=12.46, 7.89, 7.89, 6.16 Hz, 1 H) 1.64-1.77 (m, 1 H) 1.431.55 (m, 1 H) 1.31 -1.40 (m, 1 H)
215	0	N-{2-[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]ethyl}acetami de	350.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (br.s., 1 H), 7.77 (t, J=5.95 Hz, 1 H), 7.20 (d, J=8.24 Hz, 1 H), 6.61 - 6.70 (m, 2 H), 5.70 (s, 1 H), 4.50 (dt, J=13.40, 5.21 Hz, 1 H), 3.82 (s, 3 H), 3.79 (S, 3 H), 3.59 (dt, J=13.62, 6.70 Hz, 1 H), 3.153.28 (m, 2H), 1.67 (s, 3 H)
216	0 HrrSi cA aAa ? A oAh 1	3-(6-(2,4dîmethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)-yl]-Nmethylpropana mide	350.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.63 (br. s., 1 H), 7.71 (br. s., 1 H), 7.25 (d, J=7.79 Hz, 1 H), 6.70 (s, 1 H), 6.64 (d, J=8.70 Hz, 1 H), 5.72 (s, 1 H), 4.37-4.53 (m, 2H), 3.83 (s, 3 H), 3.82 (s, 3 H), 3.35 - 3.44 (m, 2 H), 2.45 (d, J=4,58 Hz, 3 H)
217	0 Hj| V'' OïÿPX,^NHr	3-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1 (2H)-yl]-2methylpropana mide	350.2	1H NMR (500 MHz, DMSO-d6) δ ppm 12.50-12.85 (m, 1 H) 7.15-7.34 (m, 2H) 6.55-6.83 (m, 3 H) 5.64 - 5.77 (m, 1 H) 4.34-4.67 (m, 1 H) 3.75-3.89 (m, 6 H) 3.46 - 3.71 (m, 1 H) 2.75-3.13 (m, 1 H) 0.66-0.90 (m, 3 H)
216	Xs, h/t	1-(5amînopentyl)-6- (2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	349.9	ΊΗ NMR (400 MHz, METHANOL-d4) δ ppm 7.24 (d, J=7.81 Hz, 1 H), 6.69 (s, 1 H), 6.66 (d, J=8.00 Hz, 1 H), 5.75 (s, 1 H), 4.46 - 4.60 (m, 1 H), 3.87 (s, 6 H), 3.62 - 3.75 (m, 1 H), 2.83 (br. s, 2 H), 1.69-1.83 (m, 1 H), 1.41-1.57 (m, 3 H), 1.05-1.24 (m, 2 H)

120

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
219	X	1-(3-amino-3methylbutyl)-6(2.4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	350.1	1H NMR (400 MHz, DMSO-d6): δ 7.28 (d, 1 H), 6.71 (s, 1 H), 6.65 (d, 1 H), 5.76 (s, 1 H), 4.49 (br.s., 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.50-3.60 (br.s., 1H), 1.82-1.95 (m, 1 H), 1.42-1.55 (m, 1 H), 0.89 (s, 3 H), 0.80 (s, 3 H):
220	0 I	6-(2,4dimethoxypheny 1)-1-(3(dimethylamino) propyl]-2-thioxo2,3dihydropyrimidin -4(1H)-one	350.2	1H NMR (400 MHz. DMSO-d6) δ ppm 12.76 (br. s., 1 H), 7.29 (d, J=8.47 Hz, 1 H). 6.70 (d. J=2.06 Hz, 1 H). 6.64 (dd, J=8.47, 2.06 Hz. 1 H), 5.74 (s, 1 H), 4.29-4.47 (m, 1 H), 3.80 (s, 6 H). 3.50 - 3.68 (m, 1 H), 3.41 - 3.51 (m, 1 H). 2.74 (br. s., 1 H), 2.55 (br. s„ 6 H), 1.791.94 (m, 1 H), 1.63- 1.78 (m, 1 H)
221		ethyl [6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]acetate	351.2	1H NMR (400 MHz, DMSO-d6) δ ppm 12,94(5, 1 H), 7.11 (d, J=8.70 Hz, 1 H), 6.70 (d, J=2.29 Hz. 1 H), 6.63 (dd. J=8.24, 2.29 Hz, 1 H), 5.83 (s, 1 H), 5.18-5.40 (m, 1 H), 4.16 -4.31 (m, 1 H), 4.02 (dit, J=10.88, 7.16, 7.16, 3.66, 3.66 Hz, 2 H), 3.82 (s, 6 H), 1.08 (t, J=7.10 Hz, 3 H)
222	0	2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)-yl]ethyl acetate	351.2	1H NMR (500 MHz, DMSO-d6) δ ppm 12.78 (br. s., 1 H) 7.28 (d. J=8.54 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 6.67 (dd, J=8.29, 2.20 Hz. 1 H) 5.75 (s, 1 H) 4.70 (dt, J=14.70, 4.36 Hz. 1 H) 4.29 (ddd, J=11.95, 7.81, 4.39 Hz, 1 H) 4.02 (dt, J=11.71, 4.64 Hz, 1 H) 3.83 (s, 3 H) 3.82 (s, 3 H) 3.77 - 3.81 (m, 1 H) 1.91 (s, 3 H)
223	0 Hrr'ji cr'’ 1 NH,	1-(2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]ethyl}urea	351.2	1.80 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min

121

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
224	0 HFTTi cri /A	6-(2,4dimethoxypheny l)-1-(3-hydroxy2,2dimethylpropyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	351.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.31 (d, J=8.24 Hz, 1 H), 6.63 - 6.69 (m, 2 H), 5.76 (s, 1 H), 5.19 (d, J=15.11 Hz, 1 H), 3.87 (s, 3 H), 3.87 (s, 3 H), 3.50 (d, J=14.66 Hz, 1 H), 3.29 (d, J=10.53 Hz, 1 H), 3.05 (d, J=10.99Hz, 1 H), 0.83 (s, 3 H), 0.66 (s, 3 H)
225	O •fri J '	6-(2,4dimethoxypheny 1)-1-(5hydroxypentyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	351.1	ΊΗ NMR (500 MHz, METHANOL-d4) δ ppm 7.22 (d, J=8.29 Hz, 1 H), 6.68 (d, J=1.95 Hz, 1 H), 6.66 (dd, J=8.29, 2.20 Hz, 1 H), 5.73 (s, 1 H), 4.44 - 4.57 (m, 1 H), 3.87 (s, 6 H), 3.61 - 3.71 (m, 1 H), 3.40 (t, J=6.46 Hz. 2 H), 1.681.79 (m, 1 H), 1.39-1.51 (m, 1 H), 1.25-1.36 (m, 2 H), 1.031.20 (m, 2H)
226	0 L1	6-(2,4dimethoxypheny 1)-1-(2isopropoxyethyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one	351.1	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 9.58 (br. s., 1 H) 7.15 (d, J=8.40 Hz, 1 H) 6.55 (dd, J=8.40, 2.35 Hz, 1 H) 6.50 (d, J=2.35 Hz, 1 H) 5.79 (d, J=2.35 Hz, 1 H) 4.64 4.71 (m, 1 H) 3.87 (s, 3 H) 3.82 (s, 3 H) 3.69 - 3.61 (m, 2 H) 3.49 (ddd, J=9.58, 5.86, 3.13 Hz, 1 H) 3.46 (dt, J=12.31,6.25 Hz, 1 H) 1.04 (dd, J=6.06, 1.37 Hz, 6 H)
227	O cri /A I	6-(2,4dimethoxypheny l)-1-[3(methylthio)prop yl]-2-thioxo-2,3dihydropyrimidin -4(1H)-one	353.1	1H NMR (400 MHz, DMSO-d6) d ppm 7.32 (d, J=8.4 Hz, 1 H), 6.73 (d, J=2.0 Hz, 1 H), 6.68 (dd, J=8.4, 2.0 Hz, 1 H), 5.76 (d, J=2.0 Hz, 1 H), 4.45 (br.s., 1 H), 3.84 (s, 6H), 3.70 (br.s., 1 H), 2.22 (tt, d=6.4, 6.4 Hz, 2 H), 1.85-1.91 (m, 1 H), 1.83 (s, 3 H), 1.59-1.65 (m, 1 H)

122

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
228	0	1-benzyl-6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	355.2	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 9.84 (br. S., 1 H), 7.14-7.22 (m, 3 H), 6.84 - 6.93 (m, 2 H), 6.72 (d, J=8.24 Hz, 1 H), 6.44 (d, J=1.83 Hz, 1 H), 6.34 (dd, J=8.47, 2.06 Hz, 1 H), 5.96 (d, J=16.03 Hz, 1 H), 5.84 (s, 1 H), 4.94 (d, J=15.11 Hz, 1 H), 3.82 (s, 3 H), 3,70 (s, 3 H)
229	0 NH,	2-[6-(4-chloro2,5dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide	356.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.20 (s, 1 H), 6.96 (s, 1 H), 5.84 (s, 1 H), 4.65 (br. s, 2 H), 3.83 (s, 3 H), 3.81 (s, 3 H)
230	0	6-(2,4dimethoxypheny l)-1-(pyridin-2ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	356.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.57 (br. s., 1 H), 8.43 (dd, J=4.58, 0.90 Hz, 1 H), 7.57 (ddd, J=7.60, 7.60, 1.80 Hz, 1 H), 7.11 (ddd, J=7.79, 5.04, 0.92 Hz, 1 H), 7.00 (d, J=7.79 Hz, 1 H), 6.88 (d, J=8.24 Hz, 1 H), 6.43 (d, J=2.29 Hz, 1 H), 6.32 (dd, J=8.24, 2.29 Hz, 1 H), 6.02 (d, J=16.03 Hz, 1 H), 5.87 (s, 1 H), 4.95 (d, J=16.49 Hz, 1 H), 3.79 (s, 3 H), 3.75 (s, 3 H)
231	0	6-(2,4dîmethoxypheny l)-1-(pyridin-3ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	356.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.56 (br. s., 1 H), 8.46 (dd, J=4.81, 1.60 Hz, 1 H), 7.97 (d, J=1.83 Hz, 1 H), 7.51 (ddd, J=8.00, 1.80, 1.80 Hz, 1 H), 7.18 (ddd, J=8.01, 4.81, 0.92 Hz, 1 H), 6.79 (d, J=8.24 Hz, 1 H), 6.46 (d, J=2.29 Hz, 1 H), 6.42 (dd, J=8.24, 2.29 Hz, 1 H), 5.88 (d, J=15.11 Hz, 1 H), 5.84 (s, 1 H), 5.06 (d, J=15.57 Hz, 1 H), 3.84 (s, 3 H), 3.68 (s, 3 H)

123

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
232	0	6-(2,4dimethoxypheny l)-1-(pyridin-4ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1 H)-one	356.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.02 (br. s, 1 H), 8.48 (d, J=5.95 Hz, 2 H), 6.87 (d, J=5.95 Hz, 2 H), 6.77 (d, J=8.24 Hz, 1 H), 6.42 (d, J=2.29 Hz, 1 H), 6.36 (dd, J=8.24, 2.29 Hz, 1 H), 5.88 5.90 (m, 1 H), 5.87 (s, 1 H), 4.93-5.08 (m, 1 H), 3.81 (s, 3 H), 3.66 (s, 3 H)
233	0	6-(4-chloro-2,5dimethoxypheny 1)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	357.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.81 (br. s., 1 H), 7.27 (s, 1 H), 7.16 (s, 1 H), 5.83 (s, 1 H), 4.50 (dt, J=14.14, 5.41 Hz, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.66 - 3.75 (m, 1 H), 3.52 (dt, J=9.96, 6.93 Hz, 1 H), 3.33 - 3.39 (m, 1 H), 3.01 (s, 3 H)
234	0 μτΊ] σ'	6-(2,4dimethoxypheny l)-1 -(pyrimidin-2ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	357.0	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 9.81 (br. s., 1 H), 8.59 (d, J=4.81 Hz, 2 H), 7.12 (t, J=4.81 Hz, 1 H), 6.91 (d, J=8.47 Hz, 1 H), 6.44 (d, J=1.83 Hz, 1 H), 6.28 (dd, J=8.36, 1.95 Hz, 1 H), 6.21 (d, J=17.40 Hz, 1 H), 5.87 (s, 1 H), 4.94 (d, J=17.17 Hz, 1 H), 3.81 (s, 3 H), 3.76 (s, 3 H)
235	As,	6-(2,4dimethoxypheny l)-1-(piperidin-4ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	362.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (d, J=1.86 Hz, 1 H), 8.66-8.77 (m, 1 H), 8.178.31 (m, 1 H), 7.32 (d, J=8.37 Hz, 1 H), 6.71 (d, J=2.33 Hz, 1 H), 6.67 (dd, J=8.37, 2.33 Hz, 1 H), 5.76 (d, J=2.33 Hz, 1 H), 4.51 - 4.77 (m, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.67 - 3.79 (m, 1 H), 3.03 - 3.20 (m, 2 H), 2.57 -2.80 (m, 2H), 1.98-2.16 (m, 1 H), 1.56-1.71 (m, 1 H), 1.38 -1.52 (m, 1 H), 1.11 -1.27 (m, 1 H), 0.78 - 0.99 (m, 1 H)

124

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
236	X, I NH,	N- [amino(imino)m ethyl]-2-[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljacetamide trifluoroacetate	364.0	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.19 (d, J=8.41 Hz, 1 H), 6.68 (d, J=2.15Hz, 1 H), 6.63 (dd, J=8.41,2.35 Hz, 1 H), 5.84 (s, 1 H), 5.44 (br. d, J=15.10Hz, 1 H), 4.55 (br. d, J=17.40 Hz, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H)
237	0 I	3-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)-yl]-N,Ndimethylpropan amide	364.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (br. s, 1 H), 7.30 (d, J=8.24 Hz, 1 H), 6.70 (d, J=1.83 Hz, 1 H), 6.65 (dd, J=8.24, 2.29 Hz, 1 H), 5.74 (s, 1 H), 4.39-4.55 (m, 2 H), 3.82 (s, 6 H), 2.81 (s, 3 H), 2.69 (s, 3 H)
238	O	6-(2,4dimethoxypheny l)-1-(morpholin2-ylmethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	364.2	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.19 (d, J=8.39 Hz, 1 H), 6.57 - 6.69 (m, 2 H), 5.73 (s, 1 H), 4.74 (dd, J=14.45, 2.15 Hz, 1 H), 4.33 (ddt, J=11.18, 8.44, 2.39 Hz, 1 H), 3.93 (dd, J=12.98, 3.61 Hz, 1 H), 3.84 (d, J=1.17 Hz, 6 H), 3.54-3.68 (m,3H), 3.13 (d, J=12.69 Hz, 1 H), 2.95 (td, J=12.69, 3.90 Hz, 1 H), 2.67 (t, J-11.91 Hz, 1 H)
239	BÆx aÇOX	ethyl 2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljpropanoate	365.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.69-12.78 (m, 1 H), 7.09-7.31 (m, 1 H), 6.61 -6.73 (m, 2 H), 5.75 - 5.83 (m, 1 H), 4.44-4.57 (m, 1 H), 3.91-4.18 (m, 2 H), 3.75 - 3.85 (m, 6 H), 1.67 (d, J=6.90 Hz, 3 H), 1.09- 1.24 (m, 3H)
240		ethyl 3-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yljpropanoate	365.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.78 (s, 1 H), 7.29 (d, J=8.24 Hz, 1 H), 6.71 (d, J=1.83 Hz, 1 H), 6.66 (dd, J=8.24, 2.29 Hz, 1 H), 5.75 (d, J=2.29 Hz, 1 H), 4.43 - 4.58 (m, 1 H), 3.94 (q, J=6.87 Hz, 2 H), 3.83 - 3.89 (m, 1 H), 3.82 (s, 3 H), 3.82 (s, 3 H), 2.59 (td, J=10.19, 6.18 Hz, 2 H), 1.08 (t, J=7.10 Hz, 3 H)

125

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
241	O 1 i Η/Γ	N-(2aminoethyl)-2[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]acetamide hydrochloride	364.8	1HNMR(400 MHz, METHANOL-d4): δ 8.28 (m, 1H), 7.15 (d, 1H), 6.66 (d, 1H), 6.62 (dd, 1H), 5.79 (s, ÎH), 5.42-5.40 (m, 1 H), 4.37-4.23 (m, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.20-3.15 (m, 1H), 3.05- 3.12 (m, 1H), 2.95-2.85 (m, 2H).
242	Ά A 1	N~2—-(2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]ethyl}glycina mide	365.1	1HNMR (400 MHz, METHANOL-d4): δ 7.14 (d, 1H), 6.55-6.60 (m, 2H), 5.65 (s, 1H), 4.55-4.62 (m, 1 H), 4.51 (s, 1H), 3.77 (s, 6H), 3.00 (s, 2H), 2.64-2.79 (m, 2H).
243	0 1 cAoh	14-(2-(6-(2,4dimethoxypheny l)-4-oxo-2thîoxo-3,4dihydropyrimidin -1(2H)yl]ethyl}glycine hydrochloride	365.9	1H NMR (400MHz, DMSO-d6): δ 12.88 (br, 1H), 7.26 (d, 1H), 6.66-6.74 (m, 2H), 5.78 (s,1H), 4.76 (m,1H) ,3.92 (m, 1H), 3.83 (s, 6H), 3.70 (s, 2H), 3.02 (m, 2H).
244	y '	2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimîdin -1(2H)-yl]ethyl glycinate tosylate	366.2	1H NMR (400 MHz, CD3OD) δ 2.37 (s, 3 H), 3.71 (d, J=17.2 Hz, 1 H), 3.79 (d, J=17.2 Hz, 1 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 4.04 (ddd, J=14.8, 6.8, 5.5 Hz, 1 H), 4.28 (dt, J=11.7, 5.3 Hz, 1 H), 4.51 (ddd, J=11.6, 6.7, 5.1 Hz, 1 H), 4.97 (dt, J=14.5, 5.0 Hz, 1 H), 5.78 (s, 1 H), 6.656.72 (m, 2 H), 7.23 (d, J=8.0 Hz, 2 H), 7.27 (d, J=8.0 Hz, 1 H), 7.71 (d, J=8.2 Hz, 2 H)
245	A	6-(2,4dimethoxypheny 1)-1-(3-((2hydroxyethyl)am ino]propyl}-2thioxo-2,3dihydropyrimidin -4(1H)-one	365.9	1.58 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min

126

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
246	O / 1 O*%H	{2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]ethoxy}acetic acid	388.9 [M+N a]+	1HNMR (400 MHz, METHANOL-d4): δ 7.25 (d, 1H), 6.64 (m, 2H), 5.73 (s, 1H), 4.74 (m, 1H), 3.92 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.75 (m, 3H), 3.61 (m, 1H).
247	0 ΑΛΑ	6-(2,4dimethoxypheny l)-1-[(5methylpyrazin2-yl)methyt]-2thioxo-2,3dihydropyrimidin -4(1H)-one	371.1	1H NMR (400 MHz, DMSO-d6) δ ppm 12.81 (br. s., 1 H), 8.34 (s, 1 H), 8.19 (s, 1 H), 6.98 (d, J=8.24 Hz, 1 H), 6.58 (d, J=2.06 Hz, 1 H), 6.42 (dd, J=8.36, 2.18 Hz, 1 H), 5.81 (d, J=16.26 Hz, 1 H), 5.78 (s, 1 H), 4.88 (d, J=16.72 Hz, 1 H), 3.72 (s, 3 H), 3.71 (br. s., 3 H), 2.39 (s, 3 H)
248	O HtrA A CAÎPNHr 0	2-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]ethanesulfona mide	372.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.76 (br. s., 1 H), 7.26 (d, J=8.24 Hz, 1 H), 6.92 (s, 2 H), 6.66 (d, J=2.06 Hz, 1 H), 6.61 (dd, J=8.47, 2.06 Hz, 1 H), 5.72 (d, J=1.60 Hz, 1 H), 4.57 (br. s., 1 H), 3.92-4.06 (m. 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.08 - 3.29 (m, 2 H)
249	O ër	6-(2,4dimethoxypheny l)-1-[2-(1Himidazol-2ylaminojethylj2-thioxo-2,3dihydropyrimidin -4(1H)-one	374.0	1H NMR (500 MHz, METHANOL-d4) δ ppm 7.05 (d, J=8.29 Hz, 1 H) 6.71 (s, 2 H) 6.62 (d, J=2.20 Hz, 1 H) 6.43 (dd, J=8.42, 2.07 Hz, 1 H) 5.77 (s, 1 H) 4.84 (br. s., 1 H) 3.903.93 (m, 1 H) 3.88 (s, 3 H) 3.84 (s, 3 H) 3.26-3.33 (m, 2 H)
250	0 G '	1 -(2-(4,5dihydro-1Himidazol-2ylamino)ethyl]6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimîdin -4(1H)-one	376.1	1HNMR (400 MHz, METHANOL-d4) δ ppm 7.21 (d, J=8.00 Hz, 1 H), 6.68 - 6.73 (m, 2 H), 5.79 (s, 1 H), 4.72 - 4.84 (m, 2H), 3.89 (s, 6 H), 3.69- 3.81 (m, 1 H), 3.57-3.67 (m, 2 H), 3.43-3.57 (m, 2 H), 3.23 (d, J=15.23 Hz, 1 H)

127

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
251	0 0	6-(2,4dimethoxypheny 1)-1-(2morpholin-4ylethyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	377.8	1HNMR(400 MHz, CDCI3): 6 9.89 (br.s., 1H), 7.13 (d, 1H), 6.56 (dd, 1H), 6.53 (s, 1H), 5.80 (s, 1H), 4.68 (br.s., 1H), 3.813.85 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.58-3.65 (m, 4H), 2.52-2.66 (m, 2H), 2.28-2.38 (m, 4H).
252		6-(2,4dimethoxypheny 1)-1-((4hydroxypiperidin -4-yl)methyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	378.1	1H NMR (500 MHz, DMSO-d6) δ ppm 12.73 (br. s., 1 H), 8.63 (d, J=8.78 Hz, 1 H), 8.26 (d, J=10.00 Hz, 1 H), 7.25 (d, J=8.29 Hz, 1 H), 6.66 (s, 1 H), 6.63 (d, J=8.29 Hz, 1 H), 5.74 (d, J=1.46 Hz, 1 H), 5.24 (d, J=14.64 Hz, 1 H), 4.82 (br. s., 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.47 - 3.53 (m, 1 H), 3.05 (d, J=11.95 Hz, 1 H), 2.97 (d, J=11.22 Hz, 1 H), 2.86 (q, J=11.63 Hz, 2 H), 1.88 (td, J=13.54, 3.90 Hz, 1 H), 1.55 (d, J=13.91 Hz, 1 H), 1.48 (td, J=13.42, 4.15 Hz, 1 H), 1.29 (d, J=13.42 Hz, 1 H)
253		1-(4-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]butyl}guanidin e	378.0	1HNMR (400 MHz, METHANOL-d4): δ 8.57 (br, 1H), 7.25 (d, 1H), 6.71 (d, 1H), 6.68 (dd, 1H), 5.77 (s, 1H), 4.58-4.61 (m, 1H), 3.70-3.72 (m, 1H), 3.02-3.06 (t, 2H), 1.761.78 (m, 1H), 1.52-1.55 (m, 1H), 1.33-1.40 (m, 2H).
254	J4H I	N~2~-{[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]acetyl}glycina mide	305.1 [MNHC H2CO NH2] +	1H NMR (400 MHz, CD3OD) δ 3.69 (d, J=17.0Hz, 1 H), 3.79 (d, J=17.0 Hz, 1 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 4.34 (br. d, J=16.2 Hz, 1 H), 5.33 (br.d, J=14.9 Hz, 1 H), 5.81 (s, 1 H), 6.61 (dd, J=8.5, 2.2 Hz, 1 H), 6.66 (d, J=2.3 Hz, 1 H), 7.18 (d, J=8.4 Hz, 1 H)

128

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
255	ABS il η/<Ά	N-{2-[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)-yl]ethyl}D-alaninamide trifluoroacetate	379.2	7.51 min Chiralcel OD-H 4.6mmx25cm, 75%CO2/25%MeOH (0.2% iPrNH2). Fiow rate: 2.5 mL/min
256	Afl8 ii 1	N-{2-[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1 (2H)-yl]ethyl}L-alaninamide trifluoroacetate	379.2	6.32 min Chiralcel OD-H 4.6mmx25cm, 75%CO2/25%Me0H (0.2% iPrNH2). Flow rate: 2.5 mL/min
257	1 0	N-{2-[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]ethyl}methane sulfonamide	386.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.48 (br. s„ 1 H), 7.21 (d, J=8.70 Hz, 1 H), 6.61 (dd, J=8.24, 2.29 Hz, 1 H), 6.54 (d, J=2.29 Hz, 1 H), 5.85 (d, J=2.29 Hz, 1 H), 4.62 (t, J=6.64 Hz, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.27 - 3.47 (m, 2 H), 2.86 (s, 3 H)
258	$5.	2-{[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dîhydropyrimidin -1(2H)yl]methyl}pyrroli dine-1carboximidamid e trifluoroacetate	390.1	1.72 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min
259	Âi h/A. w	3-((6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidîn -1(2H)yl]methyl}pyrroli dine-1carboximidamid e trifluoroacetate	390.1	1.69 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min

129

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
260		6-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidîn -1(2H)yl]norleucinamid e hydrochloride	393.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.23 (d, J=8.20 Hz, 1 H), 6.68 (d, J=2.15Hz, 1 H), 6.66 (dd, J=8.39, 2.54 Hz, 1 H), 5.75 (s, 1 H), 4.48 - 4.59 (m, 1 H), 3.87 (s, 6 H), 3.75-3.81 (m, 1 H), 3.65-3.74 (m, 1 H), 1.73-1.83 (m, 1 H), 1.63- 1.73 (m, 2 H), 1.45- 1.57 (m, 1 H), 1.14-1.25 (m, 2 H)
261	Μ V* 1	34(6-(2.4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]methyl}-1Hpyrazole-1carbothioamide	404.2	1H NMR (500 MHz, DMSO-d6) δ ppm 12.81 (d, J=1.71 Hz, 1 H). 9.86 (s, 1 H), 9.11 (s, 1 H), 8.47 (d, J=2.93 Hz, 1 H), 7.20 (d, J=8.54 Hz, 1 H), 6.63 (d, J=2.20 Hz, 1 H), 6.51 (dd, J=8.29, 2.20 Hz, 1 H), 6.32 (d, J=2.93 Hz, 1 H), 5.80 (d, J=2.20 Hz, 1 H), 5,77 (d, J=17.08 Hz, 1 H), 4.78 (d, J=16.34 Hz, 1 H), 3.77 (s, 3 H), 3.75 (s, 3 H)
262		6-(2,4dimethoxypheny 1)-1-((1glycylpyrrolidin2-yl)methyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	405.1	0.83 min Column: Xtimate C18, 2.1x30mm, 3pm; Mobile phase: from 10% MeCN (0.06% TFA) in water (0.06% TFA) to 80% MeCN (0.06% TFA) in water (0.06% TFA); wavelength; 220 nm
263	Αβί Ογ»Η 1	N-{2-[6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)-yl]ethyl}L-valinamide trifluoroacetate	407.3	5.74 min Column: XBRIDGE- C18 4.6mmX150mm 5pm Mobile phase- A=0.1% TFA IN MeCN, B=0.1%TFAIN WATER: Phase A = 5% to 1.5 min, linear to 100% to 10 min. Flow rate = 1.5 mL/min.
264	0 ΝΙΛ	1-(2aminoethyl)-6(3methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	278.1	1H NMR (300 MHz, DMSO-d6) δ ppm 12.87 (br. s., 1 H), 7.81 (br. s„ 3 H), 7.46 (t, J=7.67 Hz, 1 H), 7.10 - 7.17 (m, 2 H), 7.07 (d, J=7.67 Hz, 1 H), 5.82 (s, 1 H), 4.31 (t, J=6.62 Hz, 2 H), 3.81 (s, 3 H), 2.90-3.01 (m, 2 H)

130

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
265	ÿv	1-(3aminopropyl)-6(3methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	292.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.80 (s, 1 H), 7.73 (br. S, 3 H), 7.45 (dd, J=9.05, 7.58 Hz, 1 H), 7.09-7.13 (m, 2 H), 7.07 (d, J=7.83 Hz, 1 H), 5.82 (d, J=1.96 Hz, 1 H), 4.02-4.14 (m, 2 H), 3.81 (s, 3 H), 2.53 - 2.59 (m, 2 H), 1.79- 1.90 (m, 2 H)
266	O HN-K V	1-allyl-6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	305.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.35 (br. s„ 1 H), 7.04 (d, J=8.19 Hz, 1 H), 6.52 (d, J=2.34 Hz, 1 H), 6.47 - 6.50 (m, 1 H), 5.82 (d, J=2.15Hz, 1 H), 5.72 (ddt, J=16.78, 10.93, 5.46, 5.46 Hz, 1 H), 5.21 (dd, J=15.80, 5.07 Hz, 1 H), 5.04 (dd, J=10.34, 0.98 Hz, 1 H), 4.77 (dd, J=17.27, 0.88 Hz, 1 H), 4.24 (dd, J=15.80, 6.05 Hz, 1 H), 3.84 (s, 3 H), 3.79 (s, 3 H)
267	ABS % ~-O V^NH	6-(2,4dimethoxypheny |)-1-[(2R)pyrrolidin-2ylmethylJ-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	348.1	1H NMR (500 MHz, DMSO-d6) δ ppm 12.89 (br. s., 1 H), 9.259.43 (m, 1 H), 8.74 (br. s., 1 H), 7.25 - 7.43 (m, 1 H), 6.73 (d, J=1,46 Hz, 1 H), 6.68 (dd, J=8.42, 1.83 Hz, 1 H), 5.73- 5.85 (m, 1 H), 4.96 - 5.08 (m, 1 H), 3.80 - 3.88 (m, 6 H), 3.61 - 3.77 (m, 1 H), 3.42 - 3.53 (m, 1 H), 2.93 - 3.15 (m, 2 H), 1.73- 1.90 (m, 1 H), 1.50 -1.73 (m, 2 H), 1.14-1.25 (m, 1 H)
268	ABS y8 ~O	6-(2,4dimethoxypheny l)-1-[(2S)pyrrolidin-2ylmethyl]-2thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride hydrochloride hydrochloride	348.1	1H NMR (500 MHz, DMSO-d6) δ ppm 12.89 (br. s., 1 H), 9.259.43 (m, 1 H), 8.74 (br. s., 1 H), 7.25-7.43 (m, 1 H), 6.73 (d, J=1.46Hz, 1 H), 6.68 (dd, J=8.42,1.83 Hz, 1 H), 5.73- 5.85 (m, 1 H), 4.96 - 5.08 (m, 1 H), 3.80 - 3.88 (m, 6 H), 3.61 3.77 (m, 1 H), 3.42 - 3.53 (m, 1 H), 2.93 - 3.15 (m, 2 H), 1.731.90 (m, 1 H), 1.50-1.73 (m, 2 H), 1.14-1.25 (m, 1 H)

ΙΟ I

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
269	M J	1-(2-(2aminoethoxy)et hyl]-6-(2,4dimethoxypheny l)-2-thioxo-2,3dihydropyrimidin -4(1H)-one hydrochloride	352.3	1H NMR (300 MHz, DMSO-d6) δ ppm 12.78 (br. s, 1 H), 7.73 (br. s, 3 H), 7.29 (d, J=8.36 Hz, 1 H), 6.72 (s, 1 H), 6.66 (dd, J=8.36, 2.09 Hz, 1 H), 5.76 (d, J=2.09 Hz, 1 H), 4.55 - 4.68 (m, 1 H), 3.83 (s, 6 H), 3.70 - 3.79 (m, 1 H), 3.47 - 3.56 (m, 2 H), 3.34-3.41 (m, 2 H), 2.80-2.90 (m. 2 H)
270		2-(3-(6-(2,4dimethoxypheny l)-4-oxo-2thioxo-3,4dihydropyrimidin -1(2H)yl]propyl}guanidi ne trifluoroacetate	364.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.22 (d, J=8.41 Hz, 1 H), 6.68 (d, J=1.96 Hz, 1 H), 6.65 (dd, J=8.41, 2.15 Hz, 1 H), 5.76 (s, 1 H), 4.51 -4.63 (m, 1 H), 3.86 (s, 6 H), 3.75 - 3.83 (m, 1 H), 2.98-3.09 (m, 2H), 1.86-2.00 (m, 1 H), 1.67- 1.79 (m, 1 H)

The following Examples of Table 4 were prepared from the corresponding aryl halide to afford the intermediate beta-keto-ester as described above for the Préparations in the Aryl Halide Route section followed by employing the methods described in the I. Beta 5 Keto Ester Route Section as well as standard methods and techniques known to those skilled in the art.

132

Table 4. Examples from Aryl Halide Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
271		1-(2-hydroxyethyl)-6[2-(2methoxyethyl)phenyl] -2-thioxo-2,3dihydropyrimidin4(1H)-one	306.9	1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.31 (br. s., 1 H), 7.48 (dd, J=7.80, 7.80 Hz, 1 H), 7.42 (d, J=7.81 Hz, 1 H), 7.35 (dd, J=7.60 Hz, 1 H), 7.25 (d, J=7.81 Hz, 1 H), 5.88 (s, 1 H), 4.57 (dt, J=13.80, 5.80 Hz, 1 H), 3.92 (dt, J=14.00, 5.90 Hz, 1 H), 3.75 - 3.85 (m, 2 H), 3.61 (t, J=6.46 Hz, 2 H), 3.31 (s, 3 H), 2.88 (dt, J=14.45, 7.04 Hz, 1 H), 2.73 (dt, J=14.45, 5.95 Hz, 1 H)
272		2-{2-[3-(2aminoethyl)-6-oxo-2thioxo-1,2,3,6tetrahydropyrimidin4yl]phenoxy}acetamid e trifluoroacetate	320.9	1H NMR (500 MHz, METHANOL-d4) δ ppm 3.11 - 3.20 (m, 1 H) 3.26- 3.33 (m, 1 H) 4.46 (dt, J=13.72, 6.92 Hz, 1 H) 4.65 (d, J=6.10Hz, 1 H) 4.70-4.81 (m, 2 H) 5.89 (s, 1 H) 7.08 (d, J=8.54 Hz, 1 H) 7.19 (t, J=7.56 Hz, 1 H) 7.40 (dd, J=7.32, 1.22 Hz, 1 H) 7.54-7.60 (m, 1 H)
273	Zx XkA.	6-(2,5-dimethoxy-4methylphenyl)-1-(2hydroxyethyl)-2thioxo-2,3dihydropyrimidin4(1H)-one	323.2	1H NMR (500 MHz, METHANOL-d4) δ ppm 6.97 (s, 1 H), 6.88 (s, 1 H), 5.78 (s, 1 H), 4.61 4.71 (m, 1 H), 3.85-3.91 (m, 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.79 - 3.81 (m, 1 H), 3.59-3.67 (m, 1 H), 2.28 (s, 3 H)
274	O OH^ I	1-(2-hydroxyethyl)-6(4-methoxy-1naphthyl)-2-thioxo2,3-dihydropyrimidin4(1H)-one	329.0	2.53 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min

133

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
275	Oa	6-(2,5-dimethoxy-4methylphenyl)-1-(2methoxyethyl)-2thioxo-2,3dihydropyrimidin4(1H)-one	337.1	2.79 min Waters Atlantis dC18 5um 4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 mL/min

The following Examples of Table 5 were prepared from 6-iodo-1-(2-methoxyethyl)-2(methylthio)pyrimidin-4(1H)-one and the appropriate aryl boronate as described above for the Préparations and procedures in the Suzuki Route section as well as standard 5 methods and techniques known to those skilled in the art.

Table 5. Examples from Suzuki Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
276	0 Z03	1-(2methoxyethyl)6-(2-naphthyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	313.1	1HNMR (400 MHz, METHANOL-d3) δ ppm 7.93 8.05 (m, 4 H), 7.58 - 7.65 (m, 2 H), 7.52 (dd, J=8.24, 1.83 Hz, 1 H), 5.90 (s, 1 H), 4.40 - 4.52 (m, 2 H), 3.59 - 3.68 (m, 2 H), 3.07 (s, 3 H)
277		6-(2-furyl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	253.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.80 (dd, J=1.83, 0.92 Hz, 1 H), 7.06 (dd, J=3.66, 0.92 Hz, 1 H), 6.66 (dd, J=3.21, 1.83 Hz, 1 H), 6.10 (s, 1 H), 4.66 (t, J=5.04 Hz, 2 H), 3.73 (t, J=6.18 Hz, 2 H), 3.25 (s, 3 H)
278	0 HirS jl 1 s A'	1-(2methoxyethyl)6-(1H-pyrazol-5yl)-2-thioxo-2,3dihydropyrimidin -4(1H)-one	253.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.81 (br. s., 1 H), 6.66 (d, J=2.29 Hz. 1 H), 5.99 (s, 1 H), 4.76 (br. s., 2 H), 3.66 (t, J=6.18 Hz, 2 H), 3.17 (s, 3 H)

134

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
279	0	1-(2- methoxyethyl)6-pyridin-3-yl-2thioxo-2,3dihydropyrimidin -4(1H)-one	264.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.76 (br. s., 1 H), 8.76 (dd, J=4.81, 1.60 Hz, 1 H), 8.64 (d, J=1.83 Hz, 1 H), 7.72 (ddd, J=7.80, 2.10, 2.10 Hz, 1 H), 7.45 (ddd, J=7.79, 4.58, 0.92 Hz, 1 H), 5.85 (s, 1 H), 4.34 (br. s„ 2 H), 3.67 (t, J=5.04 Hz, 2 H), 3.21 (s, 3 H)
280	A γυ	3-(2methoxyethyl)2-thioxo-2,3dihydro-4,5’bipyrimidin6(1H)-one	265.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 9.26 (s, 1 H), 8.90 (s, 2 H). 5.94 (s, 1 H), 4.35 (br. s„ 2 H), 3.67 (t, J=4.81 Hz, 2 H), 3.20 (s, 3 H)
281	A	1-(2- methoxyethyl)6-(1-methyl-1Hpyrrol-2-yl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	266.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 6.87 (dd, J=2.70, 1.80 Hz, 1 H), 6.32 (dd, J=3.66, 1.83 Hz, 1 H), 6.19 (dd, J=3.66, 2.75 Hz, 1 H), 5.86 (s, 1 H), 4.50 (br. s., 2 H), 3.62 (t, J=5.27 Hz, 2 H), 3.58 (s, 3 H), 3.12 (s, 3 H)
282	A At>	1-(2- methoxyethyl)6-(2-thienyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	269.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.54 (br. s., 1 H), 7.53 (dd, J=5.04, 1.37 Hz, 1 H), 7.33 (dd, J=3.66, 0.92 Hz, 1 H), 7.13 (dd, J=5.04, 3.66 Hz, 1 H), 6.02 (d, J=2.29 Hz, 1 H), 4.53 (t, J=5.72 Hz, 2 H), 3.74 (t, J=5.72 Hz, 2 H), 3.28 (s, 3 H)
283	•A' A	1-(2methoxyethyl)- 6-(3methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	277.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.55 (br.s., 1 H), 7.29-7.41 (m, 2 H), 7.12 - 7.16 (m, 2 H), 5.83 (d, J=2.75 Hz, 1 H), 4.38 (t, J=5.27 Hz, 2 H), 3.63 (t, J=5.50 Hz, 2 H), 3.18 (s, 3 H), 2.42 (s, 3 H)

135

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Tlme and Conditions
284	/°	1-(2methoxyethyl)- 6-(2methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	277.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.65 (br. s., 1 H), 7.41 (ddd, J=7.80, 7.80, 1.80 Hz, 1 H), 7.28-7.34 (m, 2H), 7.23 (dd, J=6.87, 1.83 Hz, 1 H), 5.82 (d, J=2.29 Hz, 1 H), 4.57 (dt, J=13.74, 5.04 Hz, 1 H), 3.89 (dt, J=13.28, 6.87 Hz, 1 H), 3.67 (ddd, J=10.53, 7.33, 5.04 Hz, 1 H), 3.56 (dt, J=10.53, 5.04 Hz, 1 H), 3.16 (s, 3 H), 2.25 (s, 3 H)
285	O	1-(2methoxyethyl)- 6-(4methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	277.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.71 (br. s., 1 H), 7.29 (d, J=7.79 Hz, 2 H), 7.23 (d, J=8.24 Hz, 2 H), 5.83 (s, 1 H), 4.39 (t, J=5.04 Hz, 2 H), 3.63 (t, J=5.72 Hz, 2 H), 3,19 (S, 3 H), 2.43 (s, 3 H)
286	0 A	6-(4hydroxyphenyl)- 1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	279.1	1H NMR (400 MHz, DMSO-d6) dppm 12.73 (br. s., 1 H), 9.97 (s, 1 H), 7.29 (d, J=8.24 Hz, 2 H), 6.85 (d, J=8.24 Hz, 2 H), 5.72 (s, 1 H), 4.29 (t, J=5.95 Hz, 2 H), 3.46 (t, J=6.41 Hz, 2 H), 3.02 (s, 3 H)
287	Ά’	6-(3hydroxyphenyl)- 1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	279.1	1H NMR (301 MHz, DMSO-d6) δ ppm 12.75 (br. s.t 1 H), 9.85 (s, 1 H), 7.27 (dd, J=7.80, 7.80 Hz, 1 H), 6.82 - 6.90 (m, 2 H), 6.79 (br. s„ 1 H), 5.72 (s, 1 H), 4.20 (t, J=6.54 Hz, 1 H), 3.45 (t, J=6.08 Hz, 2 H), 3.00 (s, 3 H)
288	O	6-(2hydroxyphenyl)- 1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidîn -4(1H)-one	279.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.34 (td, J=7.90, 1.60 Hz, 1 H), 7.23 (dd, J=7.67, 1.49 Hz, 1 H), 6.94 (t, J=7.44 Hz, 1 H), 6.90 (d, J=8.24 Hz, 1 H), 5.73 (s, 1 H), 4.76 (ddd, J=13.51, 5.72, 4.58 Hz. 1 H), 3.97 (dt, J=13.91, 7.13 Hz, 1 H), 3.65 (ddd, J=10.25, 7.38, 6.64 Hz, 1 H), 3.45 (ddd, J=10.42, 6.41,4.24 Hz, 1 H), 3.06 (s, 3 H)

136

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
289	Λ yv	6-(3fluorophenyl)-1(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	281.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.00 (br. s„ 1 H), 7.47 (ddd, J=8.10, 8.10, 5.70 Hz, 1 H), 7.22 (ddd, J=8.10, 8.10, 2.10 Hz, 1 H), 7.07 - 7.16 (m, 2 H), 5.85 (d, J=1.37 Hz, 1 H), 4.36 (br. s„ 2 H), 3.66 (br. s., 2 H), 3.21 (s, 3 H)
290	O	6-(4fluorophenyl)-1(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	281.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.57 (br. s, 1 H), 7.35 (dd, J=8.93, 5.27 Hz, 2 H), 7.18 (dd, J=8.20 Hz, 2 H), 5.82 (s, 1 H), 4.35 (t, J=5.04 Hz, 2 H), 3.65 (t, J=5.50 Hz, 2 H), 3.20 (s. 3 H)
291	0 fer'	3-(3-(2methoxyethyl)6-oxo-2-thioxo- 1.2,3,6tetrahydropyrimi din-4yljbenzonitrile	288.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.70 (br. s., 1 H), 7.81 (d, J=7.33 Hz, 1 H), 7.71 (s, 1 H), 7.55 - 7.66 (m, 2H), 5.82 (d, J=1.83 Hz, 1 H), 4.29 (br. s., 2 H), 3.67 (br. s., 2 H), 3.23 (s, 3 H)
292	O JL ..OH γύ	6-[2(hydroxymethyl) phenyl]-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	293.0	1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (br. s., 1 H), 7.437.56 (m, 2 H), 7.30 - 7.41 (m, 2 H), 5.76 (s, 1 H), 5.27 (t, J=5.38 Hz, 1 H), 4.38 (d, J=5.27 Hz, 2 H), 4.26-4.35 (m, 1 H), 3.693.82 (m, 1 H), 3.45 - 3.55 (m, 1 H), 3.39 (dt, J=9.85, 6.75 Hz, 1 H), 2.97 (s, 3 H)
293		1-(2methoxyethyl)- 6-(3methoxyphenyl) -2-thîoxo-2,3dihydropyrimidin -4(1H)-one	293.2	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.42 (t, J=8.24, 8.24 Hz, 1 H), 7.08 (ddd, J=8.24, 2.75, 0.92 Hz, 1 H), 7.03 (dd, J=2.75, 1.37 Hz, 1 H), 6.99 (ddd, J=7.79, 1.83, 0,92 Hz, 2 H), 5.79 (s, 1 H), 4.39 (t, J=5.50 Hz, 2 H), 3.84 (s, 3 H), 3.64 (t, J=5.72 Hz, 2 H), 3.15 (s, 3 H)

137

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
			1-(2methoxyethyl)- 6-(4methoxyphenyl) -2-thioxo-2,3dihydropyrimidin -4(1H)-one		1H NMR (400 MHz,
294	0 hftX I		293.2	CHLOROFORM-d) δ ppm 9.62 (br. s., 1 H), 7.28 (d, J=8.70 Hz, 2 H), 6.99 (d, J=8.70 Hz, 2 H), 5.83 (d, J=1.37 Hz, 1 H), 4.41
	S	1		(t, J=5.50 Hz, 2 H), 3.87 (s, 3 H), 3.64 (t, J=5.72 Hz, 2 H), 3.20 (s, 3 H)
			1-(2- methoxyethyl)- 6-(6-		1H NMR (400 MHz,
	0			CHLOROFORM-d) δ ppm 9.53 (br. s., 1 H), 8.16 (d, J=1.83 Hz, 1 H), 7.58 (dd, J=8.70, 2.29 Hz,
295	T	Cv	methoxypyridin3-yl)-2-thîoxo2,3dihydropyrimidin -4(1H)-one	294.1	1 H), 6.85 (dd, J=8.70, 0.92 Hz, 1 H), 5.84 (d, J=2.29 Hz, 1 H), 4.37 (br. s., 2 H), 4.01 (s, 3 H), 3.68 (t, J=5.27 Hz, 3 H), 3.23 (s, 3 H)
					1H NMR (400 MHz,
					CHLOROFORM-d) δ ppm 9.61
			1-(2-		(br. s., 1 H), 8.42 (s, 1 H), 8.40
	0		methoxyethyl)-		(d, J=4.81 Hz, 1 H), 7.18 (d,
			6-(3-		J=4.81 Hz, 1 H), 5.77 (d,
296	JL J		methoxypyridin-	294.1	J=2.29 Hz, 1 H), 4.73 (dt,
I	H	4-yl)-2-thioxo-	J=13.97, 3.43 Hz, 1 H), 3.97 (s,
	y		2,3-		3 H), 3.80 (td, J-9.62, 3.89 Hz,
			dihydropyrimidin		1 H), 3.68 (ddd, J=13.80, 9.33,
			-4(1H)-one		4.58 Hz, 1 H), 3.36 (dt, J=10.08, 3.89 Hz, 1 H), 3.14 (s,
					3 H)
			1-(2methoxyethyl)- 6-(2methoxypyridin4-yl)-2-thioxo2,3dihydropyrimidin -4(1H)-one		1HNMR (400 MHz,
	0			CHLOROFORM-d) δ ppm 9.59 (br. s., 1 H), 8.29 (dd, J=5.04,
297	JJ JJ	'O	294.2	0.92 Hz, 1 H), 6.85 (dd, J=5.27, 1.60 Hz, 1 H), 6.74 (d, J=1.37 Hz, 1 H), 5.81 (d, J=2.29 Hz, 1
	I /°	°x.		H), 4.35 (br. s., 2 H), 4.00 (s, 3 H), 3.66 (t, J=5.27 Hz, 2 H), 3.22 (s, 3 H)
	0		6-(4-		1H NMR (400 MHz,
			chlorophenyl)-1(2methoxyethyl)2-thioxo-2,3-		METHANOL-d3) δ ppm 7.53 (d,
298			297.1	J=7.79 Hz, 2 H), 7.45 (d, J=8.24 Hz, 2 H), 5.79 (s, 1 H), 4.38 (t, J=5.04 Hz, 2 H), 3.62 (t,
			dihydropyrimidin -4(1H)-one		J=5.72 Hz, 2 H), 3.16 (s, 3 H)

138

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
299	0 Hhr-ji ci /Ό	6-(2chlorophenyl)-1(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	297.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.57 (br. s., 1 H), 7.44 - 7.52 (m, 2 H), 7.39 - 7.44 (m, 1 H), 7.34 7.39 (m, 1 H), 5.83 (d, J=1.37 Hz, 1 H), 4.66-4.76 (m, 1 H), 3.73-3.86 (m, 2H), 3.41 -3.47 (m, 1 H), 3.17 (s, 3 H)
300	ÿV	6-(3chlorophenyl)-1(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	297.1	1HNMR (400 MHz, METHANOL-d3) δ ppm 7.47 - 7.57 (m, 3 H), 7.39 (ddd, J=7.30, 1.40 Hz, 1 H), 5.80 (s, 1 H), 4.36 (br. s., 2 H), 3.64 (t, J=5.50 Hz, 2 H), 3.16(s, 3 H)
301	0	6-(1 H-indol-6yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	302.1	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 9.55 (br. s., 1 H), 8.44 (br. s., 1 H), 7.73 (d, J=8.24 Hz, 1 H), 7.41 (s, 1 H), 7,38 (dd, J=3,43, 2.52 Hz, 1 H), 7.05 (dd, J=8.24, 1.37 Hz, 1 H), 6.65 (ddd, J=3.09, 1.95, 0.92 Hz, 1 H), 5.91 (s, 1 H), 4.46 (br. s., 2 H), 3.63 (br. s., 2 H), 3.15(5, 3 H)
302	0	6-(1H-indol-2yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	302.1	1H NMR (400 MHz, DMSO-d6) d ppm 12.81 (s, 1 H), 11.66 (br. s., 1 H), 7.59 (d, J=7.79 Hz, 1 H), 7.41 (d, J=8.24 Hz, 1 H), 7.18 (t, J=7.67 Hz, 1 H), 7.05 (t, J=7.44 Hz, 1 H), 6.84 (s, 1 H), 6.03 (s, 1 H), 4.55 (t, J=5.84 Hz, 2 H), 3.52 (t, J=5.84 Hz, 2 H), 3.01 (s, 3 H)
303	0	6-(1 H-indol-5yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	302.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.54 (br. s„ 1 H), 8.39 (br. s., 1 H), 7,61 (s, 1 H), 7.48 (d, J=8.24 Hz, 1 H), 7.34 (t, J=2.75 Hz, 1 H), 7.12 (dd, J=8.36, 1.49 Hz, 1 H), 6.63 (d, J=2.06 Hz, 1 H), 5.90 (d, J=2.52 Hz, 1 H), 4.45 (br. s., 2 H). 3.60 (t, J=5.84 Hz, 2H), 3.08-3.18 (m, 3 H)

139

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
304	0 À I J 'NH A	6-(1H-indol-4yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	302.1	1H NMR (400 MHz, METHANOL-d3) ôppm 7.55 (d, J=8.01 Hz, 1 H), 7.39 (d, J=3.21 Hz, 1 H), 7.23 (t, J=7.79 Hz, 1 H), 7.09 (d, J=7.10 Hz, 1 H), 6.31 (d, J=2.98 Hz, 1 H), 5.86 (s, 1 H), 4.57-4.70 (m, 1 H), 4.15 (dt, J=13.34, 6.50 Hz, 1 H), 3.56 (dt, J=10.19, 6.58 Hz, 1 H), 3.42 (ddd, J=10.76, 6.18, 5.04 Hz, 1 H), 2.93 (s, 3 H)
305	o	6-(1benzofuran-3yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	303.0	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.69 (br. s, 1 H), 7.94 (s, 1 H), 7.59 (d, J=8.24 Hz, 1 H), 7.47 (d, J=7.79 Hz, 1 H), 7,42 (td, J=7.67, 1.14 Hz, 1 H), 7.36 (t, J=6.87 Hz, 1 H), 6.02 (d, J=2.52 Hz, 1 H), 4.49 (br. s„ 2 H), 3.63-3.72 (m, 2 H), 3.19 (s. 3 H)
306	0	6-(1benzofuran-2yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	303.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.54 (br. s., 1 H), 7.68 (d, J=7.56 Hz, 1 H), 7.55 (d, J=8.24 Hz, 1 H), 7.44 (t, J=7.67 Hz, 1 H), 7.34 (t, J=7.44 Hz, 1 H), 7.23 (s, 1 H), 6.25 (d, J=2.29 Hz, 1 H), 4.66 (br. s., 2 H), 3.78 (t, J=5.84 Hz, 2 H), 3.25 (s, 3 H)
307	0	6-(1benzofuran-7yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	303.4	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.48 (br. s., 1 H), 7.75 (dd, J=7.79, 1.37 Hz, 1 H), 7.67 (d, J=2.29 Hz, 1 H), 7.35 (dd, J=7.30, 7.30 Hz, 1 H), 7.27 (dd, J=7.56, 1.15 Hz, 1 H), 6.87 (d, J=2.29 Hz, 1 H), 5.98 (s, 1 H), 4.57-4.76 (m, 1 H), 3.93-4.10 (m, 1 H), 3.59-3.75 (m, 1 H), 3.33-3.50 (m, 1 H), 3.03 (s, 3 H)

140

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Tlme and Conditions
308	0	6-(2,3-dihydro1-benzofuran-5yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	305.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.97 (br. s., 1 H), 7.15 (d, J=1.37 Hz, 1 H), 7.08 (dd, J=8.01, 2.06 Hz, 1 H), 6.85 (d, J=8.24 Hz, 1 H), 5.84 (d, J=2.75 Hz, 1 H), 4.67 (t, J=8.70 Hz, 2 H), 4.43 (t, J=5.50 Hz, 1 H), 3.64 (t, J=5.50 Hz, 2 H), 3.28 (t, J=8.93 Hz, 2 H), 3.20 (s, 3 H)
309		6-(1,3benzodioxol-5yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	307.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 6.96 (d, J=1.83 Hz, 1 H), 6.94 (s, 1 H), 6.92 (d, J=1.83 Hz, 1 H), 6.05 (s. 2 H), 5.76 (s, 1 H), 4.43 (t, J=5.72 Hz, 2 H), 3.63 (t, J=5.72 Hz, 2 H), 3.17 (s, 3 H)
310	A J Hhr A cri A0	6-(2ethoxyphenyl)- 1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	307.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.51 (ddd, J=8.36, 7.44, 1.60 Hz, 1 H), 7.32 (dd, J=7.56, 1.60 Hz, 1 H), 7.11 (d, J=8.70 Hz, 1 H), 7.08 (t, J=7.30 Hz, 1 H), 5.75 (s, 1 H), 4.70-4.79 (m, 1 H), 4.15 (q, J=7.20 Hz, 2 H), 3.82- 3.92 (m, 1 H), 3.69 (ddd, J=10.08, 7.79, 5.95 Hz, 1 H), 3.43 (ddd, J=10.19, 6.30, 4.12 Hz, 1 H), 3.08 (s, 3 H), 1.36 (t, J=7.10 Hz, 3 H)
311	Ü	6-(4ethoxyphenyl)- 1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	307.2	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.36 (d, J=8.70 Hz, 2 H), 7.03 (d, J=8.70 Hz, 2 H), 5.76 (s, 1 H), 4.44 (t, J=5.50 Hz, 2 H), 4.10 (q, J=6.87 Hz, 2 H), 3.61 (t, J=5.95 Hz, 2 H), 3.14 (s, 3 H), 1.42 (t, J=7.10 Hz, 3 H)

141

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
312	0 HfrA 0^ ,/v	1-(2- methoxyethyl)6-(2-methoxy-5methylphenyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	307.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.46 (br. s, 1 H), 7.27-7.31 (m, 1 H), 7.03 (d, J=1.83 Hz, 1 H), 6.86 (d, J=8.20 Hz. 1 H), 5.81 (d, J=2.29 Hz, 1 H), 4.62 - 4.72 (m. 1 H). 3.84 - 3.93 (m, 1 H), 3.82 (s, 3 H), 3.72 (ddd, J=10.19, 7.90, 5.72 Hz, 1 H), 3.44 (ddd, J=10.19, 6.30, 4.12 Hz, 1H), 3.14 (s, 3 H), 2.34 (s, 3 H)
313	0	6-(6ethoxypyridin-3yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimïdin -4(1H)-one	308.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.60 (br. s., 1 H), 8.13 (d, J=2.29 Hz, 1 H), 7.57 (dd, J=8.47, 2.06 Hz, 1 H), 6.82 (d, J=8.70 Hz, 1 H), 5.84 (s, 1 H), 4.42 (q, J=7.02 Hz, 2 H), 4.37 (br. s, 2 H), 3.68 (t, J=5.04 Hz, 2 H), 3.23 (s, 3 H), 1.43 (t, J=6.87 Hz. 3 H)
314	0	2'(dimethylamino) -3-(2methoxyethyl)2-thioxo-2,3dihydro-4,5'bipyrimidrn6(1H)-one	308.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.83 (br. s., 1 H), 8.30 (s, 2 H), 5.83 (d, J=2.75 Hz, 1 H), 4.43 (br. s., 2 H), 3.72 (t, J=5.04 Hz, 2 H), 3.26 (s, 3 H), 3.26 (S, 6 H)
315		6-(3-fluoro-4methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1 H)-one	311.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.58 (br. s., 1 H), 7.13 (dd, J=11.22, 2.06 Hz, 1 H), 7.07 (dd, J=8.70, 1.83 Hz, 1 H), 7.03 (dd, J=7.80, 7.80 Hz, 1 H), 5.81 (d, J=2.29 Hz, 1 H), 4.37 (br. s., 2 H), 3.95 (s, 3 H), 3.65 (t, J=5.27 Hz, 1 H), 3.21 (s, 3 H)
316	0	6-(2-fluoro-4methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrlmidin -4(1H)-one	311.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.49 (br. s., 1 H), 7.22 (t, J=8.47 Hz, 1 H), 6.81 (dd, J=8.24, 2.29 Hz, 1 H), 6.72 (dd, J=11.68, 2.06 Hz, 1 H), 5.86 (d, J=2.75 Hz, 1 H), 4.60-4.70 (m, 1 H), 4.02- 4.12 (m, 1 H), 3.87 (s, 3 H), 3.71 - 3.81 (m, 1 H), 3.48 (dd, J=9.85, 4.81 Hz, 1 H), 3.18 (s, 3 H)

142

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
317	0 HrrSi ν' aAa F	6-(5-fluoro-2methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	311.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.58 (br.s, 1 H), 7.17 (ddd, J=9.05, 7.90, 3.21 Hz, 1 H), 6.98 (dd, J=7.79, 3.21 Hz, 1 H), 6.89 (dd, J=9.16, 4.12 Hz, 1 H), 5.79 (d, J=2.29 Hz, 1 H), 4.65 - 4.75 (m, 1 H), 3.82 (s, 3 H), 3.72 - 3.80 (m, 2 H), 3.37 - 3.43 (m, 1 H), 3.16 (s, 3 H)
318	O hnA ν'	6-(4-fluoro-2methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	311.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.58 (br. s„ 1 H), 7.21 (dd, J=8.24, 6.41 Hz, 1 H), 6.78 (ddd, J=8.20, 8.20, 2.30 Hz, 1 H), 6.71 (dd, J=10.53, 2.29 Hz, 1 H), 5.79 (s, 1 H), 4.65 - 4.75 (m, 1 H), 3.85 (s, 3 H), 3.69 3.83 (m, 2 H), 3.38 - 3.47 (m, 1 H), 3.16 (s, 2 H)
319	0 J*	1-(2methoxyethyl)6-(1-naphthyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	313.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 8.07 (dd, J=6.87, 2.75 Hz, 1 H), 7.98 - 8.04 (m, 1 H), 7.66 - 7.71 (m, 1 H), 7.58-7.66 (m, 4 H), 5.92 (s, 1 H), 4.50-4.60 (m, 1 H), 3.70-3.80 (m, 1 H), 3.59-3.67 (m, 1 H), 3.43 (ddd, J=10.42, 6.07, 4.58 Hz, 1 H), 2.98 (s, 3 . H) ...
320	0	1-(2methoxyethyl)6-quinolin-3-yl2-thioxo-2,3dihydropyrimidin -4(1H)-one	314.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.99 (br. s., 1 H), 8.89 (d, J=2.29 Hz, 1 H), 8.17-8.23 (m, 2 H), 7.91 (dd, J=8.01, 1.14 Hz, 1 H), 7.87 (ddd, J=8.59, 6.98, 1.37 Hz, 1 H), 7.69 (ddd, J=8.24, 6.87, 1.37 Hz, 1 H), 5.95 (d, J=0.92 Hz, 1 H), 4.36-4.46 (m, 2 H), 3.68 (t, J=4.81 Hz, 2 H), 3.21 (s, 3 H)

143

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
321	0 /ù	1-(2methoxyethyl)6-quinolin-5-yl2-thioxo-2,3dihydropyrimidin -4(1H)-one	314.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.50 (br. s„ 1 H), 9.02 (dd, J=4.12, 1.60 Hz, 1 H), 8.28 (d, J=8.47 Hz, 1 H), 8.02 (d, J=8.47 Hz, 1 H), 7.81 (dd, J=8.47, 7.33 Hz, 1 H), 7.56 (dd, J=7.10, 0.69 Hz, 1 H), 7.51 (dd, J=8.59, 4.24 Hz, 1 H), 5.96 (d, J=1.37 Hz, 1 H), 4.45 (dt, J=14.14, 4.84 Hz, 1 H), 3.833.98 (m, 1 H), 3.60 (ddd, J=10.48, 6.35, 4.69 Hz, 1 H), 3.49 (dt, J=10.30, 4.92 Hz, 1 H), 3.02 (s, 3 H)
322	0 J*	1-(2methoxyethyl)6-quinolin-8-yl2-thioxo-2,3dihydropyrimidin -4(1H)-one	314.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.82 (br. s., 1 H), 8.95 (dd, J=4.12, 1.83 Hz, 1 H), 8.25 (dd, J=8.47, 1.60 Hz, 1 H), 8.01 (dd, J=8.24, 1.37 Hz, 1 H), 7.74 (dd, J=6.87, 1.37 Hz, 1 H), 7.66 (dd, J=8.24, 6.87 Hz, 1 H), 7.52 (dd, J=8.24, 4.12 Hz, 1 H), 5.93 (d, J=2.29 Hz, 1 H), 4.65 (ddd, J=13.74, 5.04, 3.66 Hz, 1 H), 3.75 (ddd, J=10.30, 8.24, 5.50 Hz, 1 H), 3.65 (ddd, J=13.97, 8.24, 5.72 Hz, 1 H), 3.36 (ddd, J=10.30, 5.50, 3.66 Hz, 1 H), 3.07 (s, 3 H)
323	0	6-(1-benzothien2-yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	319.4	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.81 (br. s., 1 H), 7.80-7.92 (m, 2 H), 7.51 (s, 1 H), 7.42 - 7.48 (m, 2H), 6.10 (d, J=2.29 Hz, 1 H), 4.57 (t, J=5.50 Hz, 2 H), 3.74 (t, J=5.50 Hz, 2 H), 3.26 (s, 3 H)
324	0	6-(1-benzothien3-yl)-1-(2methoxyethyl)2-thioxo-2,3dïhydropyrimidin -4(1H)-one	319.4	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.88 (br. s., 1 H), 7.87-7.98 (m, 1 H), 7.67 (s, 1 H), 7.52 - 7.60 (m, 1 H), 7.41-7.51 (m, 2 H), 5,98 (d, J=2.29 Hz, 1 H), 4.66 (dt, J=13.97, 4,10 Hz, 1 H), 3.92-4.07 (m, 1 H), 3.69-3.82 (m, 1 H), 3.41 - 3.50 (m, 1 H), 3.11 (s, 3 H)

144

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
325	O	3-(3-(2methoxyethyl)6-oxo-2-thioxo- 1,2,3,6tetrahydropyrimi din-4-yl]-Nmethylbenzamid e	320.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.89 7.99 (m, 1 H), 7.86 (s, 1 H), 7.54 - 7.65 (m, 2 H), 5.81 (s, 1 H), 4.36 (br. s„ 2 H), 3.60 (t, J=5.50 Hz, 2 H), 3.11 (s, 3 H), 2.92 (s, 3 H)
326		6-(2,3-dihydro1,4benzodioxîn-6yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	321.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.49 (br. s., 1 H), 6.94 (d, J=8.24 Hz, 1 H), 6.87 (d, J=2.29 Hz, 1 H), 6.80 (dd, J=8.24, 2.29 Hz, 1 H), 5.82 (d, J=2.29 Hz, 1 H), 4.42 (t, J=5.27 Hz, 2 H), 4.27 - 4.35 (m, 4 H), 3.65 (t, J=5.72 Hz, 2 H), 3.22 (s, 3 H)
327	O	6-(4isopropoxyphen yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	321.2	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 9,59 (br. s., 1 H), 7.25 (d, J=9.16Hz, 2 H), 6.95 (d, J=8.70 Hz, 2 H), 5.83 (d, J=2.29 Hz, 1 H), 4.62 (spt, J=6.00 Hz, 1 H), 4.42 (t, J=5.50 Hz, 2 H), 3.64 (t, J=5.72 Hz, 2 H), 3.18-3.21 (m, 3 H), 1.38 (d, J=6.41 Hz, 6 H)
328	0 I Vô J·	6-(2isopropoxyphen yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	321.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.13 (br. s., 1 H), 7.45 (ddd, J=8.00, 7.80, 1.60 Hz, 1 H), 7.23 (dd, J=7.56,1.60 Hz, 1 H), 7.02 (ddd, J=7.80, 7.70, 0.92 Hz, 1 H), 6.95 (d, J=8.24 Hz, 1 H), 5.82 (s, 1 H), 4.74 (ddd, J=13.74, 5.04, 3.66 Hz, 1 H), 4.62 (spt, J=6.00 Hz, 1 H), 3.86 (ddd, J=13.85, 7.90, 6.18 Hz, 1 H), 3.71 (ddd, J=10.08, 8.24, 5.50 Hz, 1 H), 3.45 (ddd, J=10.08, 6.18, 3.89 Hz, 1 H), 3.13 (s, 3 H), 1.35 (d, J=5.95 Hz, 3 H), 1.28 (d, J=5.95 Hz, 3 H)

145

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Tlme and Conditions
329	0 HW|| A	6-(2,3dimethoxypheny 1)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	323.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.48 (br. s., 1 H), 7.15 (dd, J=8.20 Hz, 1 H), 7.06 (dd, J=8.24, 1.37 Hz, 1 H), 6.83 (dd, J=7.79, 1.37 Hz. 1 H), 5.85 (d, J=2.75 Hz, 1 H), 4.67 (dt, J=13.74, 4.58 Hz, 1 H), 3.92 (S, 3 H), 3.86-4.00 (m, 1 H), 3.82 (s, 3 H), 3.72 (ddd, J=10.30, 8.01, 5.95 Hz, 1 H), 3.44 (ddd, J=10.30, 6.18, 4.12 Hz, 1 H), 3.14 (s, 3 H)
330		6-(3,5dimethoxypheny 1)-1-(2methoxyethyl)2-thîoxo-2,3dihydropyrimidin -4(1H)-one	323.1	1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.17 (br. s., 1 H), 6.55 (t, J=2.30 Hz, 1 H), 6.48 (d, J=2.30 Hz, 2 H), 5.88 (d, J=1.84 Hz, 1 H), 4.39 (t, J=5.51 Hz, 2 H), 3.82 (s, 6 H), 3.68 (t, J=5.51 Hz, 2 H), 3.22 (s, 3 H)
331	O J* 1	6-(3,4dîmethoxypheny 1)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	323.1	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 10.27 (br. s„ 1 H), 6.85-6.98 (m, 3 H), 5.88 (s, 1 H), 4.33 4.49 (m, 2 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 3.63-3.75 (m, 2 H), 3.22 (s, 3 H)
332	0 Ηΐχη] A fA	6-(2,6dîmethoxypyridi n-3-yl)-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	324.1	1H NMR (400 MHz, CHLOROFORM-d) d ppm 9.77 (br. s„ 1 H), 7.43 (d, J=7.79 Hz, 1 H), 6.42 (d, J=8.24 Hz, 1 H), 5.79 (s, 1 H), 4.75 (ddd, J=13.60, 3.50, 3.50 Hz, 1 H), 3.98 (s, 3 H), 3.97 (s, 3 H), 3.85 (ddd, J=13.74, 8.70, 5.50 Hz, 1 H), 3.77 (ddd, J=9.20, 9.20, 4.10 Hz, 1 H), 3.43 (ddd, J=9.60, 4.60, 4.60 Hz, 1 H), 3.18 (s, 3 H)
333	0 Cl	6-(5-chloro-2methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	327.1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.51 (dd, J=8.70, 2.75 Hz, 1 H), 7.35 (d, J=2.75 Hz, 1 H), 7.13 (d, J=9.16Hz, 1 H), 5.77 (s, 1 H), 4.67-4.76 (m, 1 H), 3.89 (s, 3 H), 3.73 - 3.81 (m, 2 H), 3.38 3.45 (m, 1 H), 3.12 (s, 3 H)

146

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
334	0 A	6-(2-chloro-4methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	327.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.18 (br. s., 1 H), 7.26 (d, J=8.70 Hz, 1 H), 7.00 (d, J=2.29 Hz, 1 H), 6.92 (dd, J=8.93, 2.06 Hz, 1 H), 5.84 (s, 1 H), 4.64-4.78 (m, 1 H), 3.87 (s, 3 H), 3.76 - 3.85 (m, 2 H), 3.39-3.52 (m, 1 H), 3.19 (s, 3 H)
335	0 HFT|j t/	6-(4-chloro-2methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	327.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.96 (br. s., 1 H), 7.17 (d, J=7.79 Hz, 1 H), 7.06 (dd, J=8.24, 1.83 Hz, 1 H), 6.97 (d, J=1.37 Hz. 1 H), 5.79 (s, 1 H), 4.64-4.77 (m, 1 H), 3.86 (s, 1 H), 3.72 - 3.82 (m, 2 H), 3.36 - 3.47 (m, 1 H), 3.16 (s, 3 H)
336		4-(3-(2methoxyethyl)6-oxo-2-thioxo- 1,2,3,6tetrahydropyrimi din-4-yl]-N,Ndimethylbenzam ide	334.2	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.53 7.60 (m, 4 H), 5.82 (s, 1 H), 4.40 (t, J=5.27 Hz, 2 H), 3.62 (t, J=5.50 Hz, 2 H), 3.14 (s, 3 H), 3.13 (s, 3 H), 3.03 (s, 3 H)
337	0 HN''^ C/'' χ-° xA	6-(5-isopropyl-2methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	335.2	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.37 (dd, J=8.59, 2.18 Hz, 1 H), 7.16 (d, J=2.29 Hz, 1 H), 7.03 (d, J=8.70 Hz, 1 H), 5.72 (s, 1 H), 4.69 (dt, J=13.80, 4.89 Hz, 1 H), 3.83 (s, 3 H), 3.76 - 3.82 (m, 1 H), 3.66 (ddd, J=10.19, 7.79, 6.07 Hz, 1 H), 3.41 (ddd, J=10.25, 6.24, 4.12 Hz, 1 H), 3.06 (s, 3 H), 2.90 (spt, J=7.10 Hz, 1 H), 1.24 (dd, J=6.87, 2.98 Hz, 6 H)
338	0 HhrXi cA yÙz	6-[6(dimethylamîno) -4methoxypyridin3-yl]-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	337.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.61 (br. s., 1 H), 7.90 (s, 1 H), 7.27 (s, 1 H), 5.91 (s, 1 H), 4.78 (dt, J=14.08, 3.72 Hz, 1 H), 3.87 (s, 3 H), 3.82 (dt, J=13.74, 6.41 Hz, 1 H), 3.67 - 3.76 (m, 1 H), 3.42 - 3.51 (m, 1 H), 3.21 (s, 3 H), 3.16 (s, 6 H)

147

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
339	O	1-(2methoxyethyl)6-(2-methoxy-1naphthyl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	343.4	1H NMR (400 MHz, CHLOROFORM-d) 9.58 (S, 1H), 8.02 (d, 1H), 7.82 (d, 1H), 7.50- 7.58 (m, 2H), 7.39-7.43 (dd, 1H), 7.31 (d, 1H), 5.89 (s, 1H), 4.26-4.33 (m, 1H), 4.02- 4.11 (m, 1H), 3.97 (s, 3H), 3.51- 3.57 (m, 1 H). 3.31-3.39 (m, 1H), 2.88 (s, 3H)
340	jï’O'V	1-(2methoxyethyl)2-thioxo-6-[3(trifluoromethox y)phenyl]-2,3dihydropyrimidin -4(1H)-one	347.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.56 (br. s„ 0 H), 7.53 (dd, J=7.80, 7.80 Hz, 1 H), 7.37 (d, J=9.16 Hz, 1 H), 7.25-7.31 (m, 2 H), 5.84 (d, J=2.29 Hz, 1 H), 4.34 (br. s, 2 H), 3.66 (br. s, 2 H), 3.20 (s, 3 H)
341	0	1-(2methoxyethyl)6-(3-methoxy5,6,7,8tetrahydronapht halen-2-yl)-2thioxo-2,3dihydropyrimidin -4(1H)-one	347.5	1H NMR (400 MHz, METHANOL-d3) δ ppm 6.96 (s, 1 H), 6.78 (s, 1 H), 5.70 (s, 1 H), 4.60-4.72 (m, 1 H), 3.86 (dt, J=14.03, 7.30 Hz, 1 H), 3.81 (s, 3 H), 3.67 (ddd, J=10.30, 7.56, 6.41 Hz, 1 H), 3.41 (ddd, J=10.36, 6.35, 4.12 Hz, 1 H), 3.07 (s, 3 H), 2.82 (br. s.,2H), 2.72 (br. s., 2 H),.1.75 -1.86 (m, 4H)
342	0	1-(2methoxyethyl)2-thioxo-6(3.4,5trimethoxypheny 1)-2,3dihydropyrimidin -4(1H)-one	353.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.91 (br. s„ 1 H), 6.59 (s, 2 H), 5.88 (d, J=2.29 Hz, 1 H), 4.39 (t, J=5.50 Hz, 2 H), 3.92 (s, 3 H), 3.88 (s, 6 H), 3.73 (t, J=5.27 Hz, 2 H), 3.24 (s, 3 H)
343	0 AA	1-(2methoxyethyl)2-thioxo-6(2,3,4trimethoxypheny 1)-2,3dihydropyrimidin -4(1H)-one	353.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.49 (br. s., 1 H), 6.92 (d, J=8.70 Hz, 1 H), 6.73 (d, J=8.70 Hz, 1 H), 5.83 (d, J=2.29 Hz, 1 H), 4.62 4.71 (m, 1 H), 3.93 - 3.98 (m, 1 H), 3.92 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.73 (ddd, J=10.08, 8.01, 5.72 Hz, 1 H), 3.46 (ddd, J=10.08, 6.18, 3.89 Hz, 1 H), 3.17 (s, 3 H)

148

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
344	0 ην'Ά, σ''' λαλ	6-(4-fluoro-5isopropyl-2methoxyphenyl) -1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	353,1	1H NMR (400 MHz, METHANOL-d3) δ ppm 7.23 (d, J=8.24 Hz, 1 H), 6.87 (d, J=12.14 Hz, 1 H), 5.72 (s, 1 H), 4.69 (dt, J=13.45, 4.15 Hz, 1 H), 3.84 (S, 3 H), 3.64 - 3.81 (m, 2 H), 3.40 (ddd, J=9.79, 5.55, 3.66 Hz, 1 H), 3.19 (spt, J=7.10 Hz, 1 H), 3.10 (s, 3 H), 1.24 (d, J=6.87 Hz, 6 H)
345	0 Μ	1-(2methoxyethyl)6-(8-methoxy-2methylquinolin5-yl)-2-thioxo- 2,3dihydropyrimidin -4(1H)-one	358.2	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.86 (br. s., 1 H), 7.84 (d, J=8.70 Hz, 1 H), 7.42 (d, J=8.70 Hz, 2 H), 7.10 (d, J=8.24 Hz, 1 H), 5.95 (d, J=2.29 Hz, 1 H), 4.49 (dt. J=14.08, 5.09 Hz, 1 H), 4.15 (s, 3 H), 3.85-4.00 (m, 1 H), 3.61 (ddd, J=10.99, 6.87,4.58 Hz, 1 H), 3.49 (dt, J=10.30, 5.38 Hz, 1 H), 3.04 (s, 3 H), 2.84 (s, 3 H)
346	0 F „Λ X ΑΛΑ /° F	6-[5-fluoro-2(trifluoromethox y)phenyl]-1-(2methoxyethyl)2-thioxo-2,3dihydropyrimidin -4(1H)-one	365.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.58 (br. s., 1 H), 7.31 - 7.39 (m, 1 H), 7.26-7.29 (m, 1 H), 7.15 (dd, J=7.90, 3.09 Hz, 1 H), 5.83 (d, J=2.52 Hz, 1 H), 4.68 (dt, J=14.20, 3.32 Hz, 1 H), 3.88 (td, J=9.85, 3.66 Hz, 1 H), 3.72 (ddd, J=13.91, 9.45, 3.89 Hz, 1 H), 3.39 (dt, J=10.36, 3.75 Hz, 1 H), 3.19 (s, 3 H)
347	Q	4-(3-(2methoxyethyl)6-oxo-2-thioxo- 1,2,3,6tetrahydropyrimi din-4-yl]-N,Ndimethylbenzen esulfonamide	370.1	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.84 (br. s„ 1 H), 7.90 (d, J=6.87 Hz, 2 H), 7.56 (d, J=6.87 Hz, 2 H), 5.84 (s, 1 H), 4.32 (br. s„ 2 H), 3.66 (t, A4.35 Hz, 2 H), 3.20 (s, 3 H), 2.81 (s, 6 H)

150

Préparation 20

Ethyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate te/t-Butyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate (2.0 g, 7.14 mmol) in éthanol (20 mL) was heated in a microwave reactor at 120 °C for 90 min. The mixture was cooled to room température and the solvent was concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography (30-40% EtOAc: petroleum ether) to give the title compound as a yellow solid.

(Z)-Ethyl 3-((2-amino-2-oxoethyl)amino)-3-(2-(2-hydroxyethoxy)phenyl)acrylate

To a solution of ethyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate (2 g, 7.94 mmol) and glycinamide hydrochloride (3.5 g, 31.7 mmol) in methanol (20 mL) was added triethylamine (3.21 g, 31.7 mmol) at room température. The mixture was stirred at 40 °C for 20 min. Acetic acid (1.9 g, 31.7 mmol) was added, and the mixture was stirred at 80 °C for 18 hours. The reaction mixture was cooled to room température and saturated sodium bicarbonate (200mL) was added. The organic layer was separated, dried (Na₂SO₄) and concentrated to give a yellow solid. The solid was washed with EtOAc (20 mL), and the residue was dried under reduced pressure to give the title compound as a white solid. This material was used without further purification.

151

Example 349

2-( 6-(2-(2-Hydroxyethoxy)phenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)yl)acetamide

To a solution of (Z)-ethyI 3-((2-amino-2-oxoethyl)amino)-3-(2-(2hydroxyethoxy)phenyl)acrylate (1.0 g, 3.25 mmol) in tetrahydrofuran (15 mL) was added trimethylsilyl isothiocyanate (1.7 g, 12.9 mmol), and the mixture was stirred at 80 °C for 18 hours. The reaction mixture was cooled to room température, poured into a flask containing water and extracted with CH2CI2 (3 x 100 mL). The combined organic layers were dried and concentrated under reduced pressure to give a yellow solid, which was purified by flash chromatography (2-5% MeOH:CH₂CI₂) to give the title compound (330 mg, 31,7%) as a yellow solid.

MS (ES+) 343.9 [M+Na]. ¹H NMR (DMSO-d6) d: 12.77 (s, 1H), 7.44-7.53 (m, 1H), 7.31 (s, 1H), 7.14-7.22 (m, 2H), 7.02 (t, J=7.5 Hz, 1H), 6.98 (br. s., 1H), 5.74-5.82 (m, 1 H), 5.34 (br. s.. 1H), 4.84 (br. s., 1H), 4.00-4.16 (m, 2H), 3.93 (br. s„ 1H), 3.65 (q, J=4.4 Hz, 2H)

III, Amide Couplinq Route Section

Préparation 22

(Z)-Methyl 3-(2,4-dimethoxyphenyl)-3-((2-ethoxy-2-oxoethyl)amino)acrylate

152

To a solution of methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (5.0 g, 21 mmol) in

EtOH (30 mL) was added glycine methyl ester hydrochloride (10.5 g, 83.9 mmol) followed by acetic acid (1.20 mL, 21 mmol) and triethylamine (8.5 g, 83.9 mmol) and the reaction mixture was heated at 100 °C for 18 hours. After cooling to room température, the residue was partitioned between EtOAc and saturated aqueous ammonium chloride. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was dissolved in CH₂CI₂ (10 mL) filtered through a plug of silica gel, elutîng with 15-35% EtOAc in heptanes and dried under vacuum to give the title compound (4.7 g, 69%) as a yellow solid. This matériel was used in the next step without further purification.

MS (ES+) 324,3 (M+1f. ¹H NMR (500 MHz, CDCI₃) δ 8.95 (br. s., 1 H) 7.14 (d, J=10.57 Hz, 1 H) 6.49 (dd, J=8.28, 2.07 Hz, 1 H) 6.46 (d, J=2.07, 1 H) 4.60 (s, 1 H) 4.16 (q, J=7.80 Hz, 2 H) 3.83 (s, 3 H) 3.80 (s, 3 H), 3.69 (s, 3 H), 1.24 (t, J=7.80 Hz, 3 H).

Préparation 23

OMe

OEt

Ethyl 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropynmidin-1(2H)-yl)acetate

To a solution of (Z)-methyl 3-(2,4-dimethoxyphenyl)-3-((2-ethoxy-2oxoethyl)amino)acrylate (4.68 g, 15.1 mmol) in 2-methyltetrahydrofuran (38 mL) was added (trimethylsilyl)isothiocyanate (12.9 mL, 90.8 mmol). The resulting solution was purged with nitrogen gas for 3 times, and the mixture was heated at 110 °C for 18 hours. The mixture was cooled down to room température and the solvent was removed under reduced pressure to give a red solid. This residue was suspended in a mixture of 3:1 heptane/EtOAc (200 mL), and it was stirred at room température for 1 hour. The solid was filtered, and triturated with CH₂CI₂ (100 mL), concentrated under reduced pressure and dried under vacuum the title compound (4.42 g, 87%) as a pink solid. This material was used without further purification in the next step.

MS (ES+) 351.5 [M+1J*. ¹H NMR (500 MHz, CDCI₃) δ 9.91 (br s, 1 H) 7.13 (d, J=6.12 Hz, 1 H) 6.54 (s, 1 H) 6.51 (d, J=6.12 Hz, 1 H) 5.86 (s, 1 H) 5.44-5.40 (m, 1 H) 4.254.20 (m, 1 H) 4.16-4.06 (m, 2 H), 3.86 (s, 3 H) 3.83 (s, 3 H), 1.20 (t, J=6.12 Hz, 3 H).

153

Préparation 24

2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)-yl)acetic acid

To a solution of ethyl 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin1(2H)-yl)acetate (6.8 g, 20.3 mmol) in methanol (34 mL) was added 6N aqueous NaOH (16.9 mL), and the solution was stirred at 35 °C for 3 hours. The mixture was concentrated under reduced pressure, and water (100 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 200 mL), and acidified with concentrated HCl to pH - 2. The résultant acidic aqueous solution was extracted with EtOAc (3 x 200 mL), and the combined organic layers were dried with sodium sulfate, and concentrated under reduced pressure to give the title compound 6.53 g (99%) as a white solid.

MS (ES+) 323.2 [M+1f. ¹H NMR (500 MHz, CD₃OD) δ 7.16 (d, J=8.86 Hz, 1 H) 6.67 (s, 1 H) 6.64 (d, J=8.86 Hz, 1 H) 5.79 (s, 1 H) 5.52-5.40 (m, 1 H) 4.34-4.19 (m, 1 H) 3.87 (s, 3 H) 3.86 (s, 3 H).

Préparation 25

tert-Butyl (2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl)acetamido)ethyl)carbamata

To a solution of 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)yl)acetic acid (40 g, 124 mmol) in DMF (300 mL) was added tert-butyl (2aminoethyl)carbamate (40 g, 250 mmol) and pyridine (30 mL), and the mixture was stirred at room température for 15 minutes. The solution was cooled to 0 ’C and it was purged with nitrogen gas for 3 times. After 10 minutes, a 50% solution of T3P in DMF

154 (109 mL) was added drop-wise at 0 °C, and stirring was continued for 1 hour, whereupon the water/ice bath was removed and stirring was continued for 4 hours; The reaction solution was slowly poured into a stirring solution of aqueous HCl solution (2500 mL, 0.5 M), and the suspension was stirred at room température for 1 hour. The formed solid was filtered, and the filter cake was washed with 0.5M HCl solution (500 mL) foilowed by water (500 mL). The solid was dried in the vacuum oven at 50 °C for 20 hours to give 54.6 g of light beige powder. This solid was suspended in EtOAc (500 mL), heated to 70 °C under a stream of nitrogen gas with stirring for 1 hour, and then at room température for 18 h. The suspension was cooled down to 0 °C, and the solid was filtered, the filter cake washed with cold (0 °C) EtOAc (100 mL) and dried in the vacuum oven at 50 °C for 9 hours to give 49.0 g of off-white solid. This solid was suspended in acetonitrile (300 mL), and stirred at 70 °C under a stream of nitrogen for 18 h. The mixture was cooled to 0 °C, and the résultant solid was filtered, washed with cold acetonitrile (50 mL) and dried in the vacuum oven at 50 ^eC for 8 hours to give 46.5 g of off-white solid. This solid was suspended in EtOAc (350 mL), heated to 70 °C under a stream of nitrogen gas with stirring for 1 hour, and then at room température for 18 h. The suspension was cooled down to 0 °C, and the solid was filtered, the filter cake washed with cold (0 ’C) EtOAc (50 mL) and dried in the vacuum oven at 50 °C for 9 hours to give the title compound (45.4 g, 78.8%) as an off-white powder.

MS (ES+) 465.3 [M+1]*. ¹H NMR (500 MHz, CD₃OD) δ 8.99 (br. s., 1 H) 7.16 (d, J=7.65 Hz, 1 H) 6.65 (s, 1 H) 6.62 (d, J=7.65 Hz, 1 H) 5.78 (s, 1 H) 5.51-5.41 (m, 1 H) 4.224.14 (m, 1 H) 3,87 (s, 3 H) 3.85 (s, 3 H) 3.19-3.11 (m, 2 H) 3.06-3.00 (m, 2 H) 1.42 (s, 9 H).

Example 241

N-(2-aminoethyl)-2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin1 (2H)-yl)acetamide hydrochloride

155

To cold (0 °C) éthanol (21.5 mL) under nitrogen was added acetyl chloride (1.55 mL) dropwise over 5 minutes, and the reaction mixture was then heated at 50 °C for 30 minutes. The reaction mixture was cooled to room température and tert-butyl (2-(2-(6(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl)acetamido)ethyl)carbamate was added (1.0 g, 2.15 mmol), followed by heating to 50 °C for 1 hour. The mixture was cooled to room température and concentrated under reduced pressure. The residue was suspended in éthanol (10 mL), heated to 75 °C for 20 minutes, and EtOAc (20 mL) was added and heating was continued for another 20 minutes. The mixture was allowed to slowly cool to down to room température with stirring during 18 hours. The résultant precipitate was filtered and dried in a vacuum oven at 70 °C for 20 hours to give the title compound (751 mg, 87%) as a white solid. MS (ES+) 365.2 [M+1]*. ¹H NMR (500 MHz, DMSO-D₆) δ 12.81 (br. s„ 1 H) 8.26 (br. s„ 1 H) 8.01 (br. s., 2 H) 7.08 (d, J=7.91 Hz, 1 H) 6.70 (s, 1 H) 6.62 (d, J=7.91 Hz, 1 H) 5.78 (s, 1 H) 5.41-5.35 (m, 1 H) 4.07-4.02 (m, 1 H) 3.84 (s, 3 H) 3.83 (s, 3 H) 3.20-3.16 (m, 2 H) 2.74-2.64 (m, 2 H).

IV, Guanidine Route Section

Methyl [amino({3-[6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin1(2H)-yl]propyl}amino)methylidene]carbamate

To a solution of 1-(3-aminopropyl)-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3dihydropyrimidin-4(1H)-one (prepared in an analogous mannerto Example 6; 50 mg, 0.14 mmol) and methyl [amino(1H-pyrazol-1-yl)methylidene]carbamate (28 mg, 0.16 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine (0,024 mL, 0.14 mmol) at room température, and the mixture was stirred for 72 hours. The solvent was removed under reduced pressure, the residue was dissolved in DMSO (0.9 mL) and purified using mass-triggered automatic purification to give the title compound (4.9 mg)

MS (ES+) 425.9 [M+H]*. Rétention time: 1.54 min; Method: XBridge C18 5um

156

4.6x50mm, 95%H2O/5%MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at

5%H2O/95%MeCN to 5.0min. (0.03% NH₄OH). Flow rate: 2 mL/min.

Préparation 26

3,3-Difluoroazetidine-1-carbonitrile

A suspension of 3,3-difluoroazetidine hydrochloride (600 mg, 4.63 mmol) in DCM (15.4 mL) was treated with triethylamine (1.48 mL). The reaction mixture was cooled to 0 °C, treated with cyanogen bromide (3M in DCM, 2.01 mL, 6.02 mmol) and the reaction mixture was stirred at 0 ’C for 2 hours. The reaction mixture was diluted with water (10 mL) and saturated sodium bicarbonate (5 mL), and extracted with ethyl acetate (3 x 50 mL) and DCM (2 x 50 mL). The combined organîcs were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in dichlormethane (30 mL) and washed with saturated aqueous ammonium chloride (2x15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a light brown solid (490 mg, 89%).

¹H NMR (500 MHz, CDCI3) 5 4.52 (t, 4H).

Préparation 27

N NH

F

1-(1H-Benzotriazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)methanimine

A mixture of 3,3-difluoroazetidine-1-carbonitrile (135 mg, 1.14 mmol) and benzotriazole (136 mg, 1.14 mmol) in 1,2-dichloroethane (0.2 mL) was heated to 80 °C under nitrogen for 30 min. A needle was inserted to facilitate évaporation of the solvent and the mixture was heated at 80 °C for 45 min. The resulting solids were washed with ether (2 x 3 mL) and dried under reduced pressure to give the title compound as an off-white solid (160 mg, 51%).

¹H NMR (500 MHz, DMSO-d6) 5 8.35 (d, 1H, J = 8.4 Hz), 8.15 (d, 1 H, J = 8.4 Hz), 7.92 (s, 1H), 7.67 (t, 1H, J - 8.4 Hz), 7.52 (t, 1H, J = 8.4 Hz), 4.64 (t, 4H, J = 12.8 Hz).

157

Example 351

3,3-Difluoro-N-{3-[6-(5-fluoro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidÎn1 (2H)-yi]propyl}azetidine-1 -carboximidamide

To a mixture of 1-(3-aminopropyl)-6-(5-fluoro-2-methoxyphenyl)-2-thioxo-2,3dihydropyrimidin-4(1 H)-one (prepared in an analogous mannerto Example 6; 50 mg, 0.14 mmol) and 1-(1H-benzotriazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)methanimine (47.5 mg, 0.174 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) under nitrogen and heated at 60 °C under nitrogen for 1 h. The reaction mixture was cooled to room température, and treated with 4N HCl in dioxane (0.25 mL). The mixture was stirred at room température for 10 min, then concentrated in vacuo and azeotroped with heptanes (3 x 10 mL). The residue was dissolved in water (1 mL) and purified using medium pressure reverse-phase (C18) chromatography (100:0 to 70:30 water/acetonitrile) to give the title compound as a white solid (22 mg, 33%). MS(ES+) 428.2 [M+Hf. ¹H NMR (500 MHz, CD3OD) δ 7.36 (ddd, 1H, J = 9.1, 8.2, 3.2 Hz), 7.21-7.24 (m, 2H), 5.85 (s, 1H), 4.6 (brs, 1 H), 4.45 (td, 4H, J = 11.4, 4.7 Hz), 3.92 (s, 3H), 3.80 (brs, 1H), 3.12 (td, 2H, J = 6.0, 2.4 Hz), 2.00-2.05 (m, 1H), 1.72-1.82 (m, 1H).

The following Examples of Table 6 (additions to Table 2) were prepared from the corresponding carboxylic acid to afford the intermediate beta-keto-ester as described above for the Préparations in the Carboxylic Acid Route section followed by employing other the methods described in the I. Beta Keto Ester Route Section as well as standard methods and techniques known to those skilled in the art.

158

Table 6. Examples from Carboxylic Acid Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
352	Η/Γ	N-{2-[6-(2,5dimethoxyph enyl)-4-oxo2-thioxo-3,4dihydropyrim idin-1(2H)yl]ethyl}glyci namide	365.2	0.32 min Waters Acqity HSS T3, 2.1x50mm, C18, 1.7pm; A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in MeCN A: 0.1% ammonia in water; Mobile phase B: 0.1% ammonia in MeCN Flow 1.25ml/min
353	-v T	N-{3-[6-(5chloro-2methoxyphe nyl)-4-oxo-2thioxo-3,4-di hydropyrimid in-1(2H)yl]propyl} methanesulf onamide	404.0	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (dd, J=8.8, 2.7 Hz, 1H) 7.54 (d, J=2.7 Hz, 1H) 7.22 (d, J=9.0 Hz, 1 H) 6.86 (t, J = 6.2 Hz, 1H), 5.86 (d, J=2.2 Hz, 1H) 4.28 (br. s., 1H) 3.84 (s, 3H) 3.65 (br. s., 1H) 2.752.78 (m, 3H) 2.71 (tt, J=12.7, 6.3 Hz, 2H) 1.71-1.81 (m, 1H) 1.56-1.66 (m, 1H)
354	NH,	1-(2-amino ethyl)-6-(1benzothioph en-2-yl)-2thioxo-2,3dihydro pyrimidin4(1H)-one	305.0	1H NMR (400 MHz, DMSOd6) δ ppm 8.09 (br. s., 1 H), 8.01 (br. s., 3H), 7.98 (br. s., 1H), 7.79 (s, 1H), 7.49 (br. s., 2H), 6.12 (s, 1H), 4.50 (br. s., 2H), 3.12 (br. s„ 2H)
355		6-(3,4-di methoxy phenyl)-1-(2hydroxyethyl )-2-thioxo2,3dihydropyrim idin-4(1 H)one	309.1	1H NMR (400 MHz, DMSOd6) δ ppm 7.12 (d, J=1.8 Hz, 1H), 7.05 (d, J=8.3 Hz, 1 H), 7.01 (dd, J=8.1, 1.9 Hz, 1H), 5.74 (s, 1H), 4.72 (t, J=5.7 Hz, 1H), 4.19 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.57 (q, J=6.1 Hz, 2H)
356		6-(2,3dihydro-1,4benzo dioxin-6-yl)1-(2-hydroxy ethyl)-2thioxo-2,3dihydro pyrimidin4(1H)-one	307.1	1HNMR (400 MHz, DMSOd6) δ ppm 7.02 (d, J=1.8 Hz, 1H), 6.94-6.97 (m, 1H), 6.92 (dd, J=8.3, 1.8 Hz, 1H), 5.70 (s, 1H), 4.72 (t, J=5.7 Hz, 1H), 4.25-4.33 (m, 4H),4.17 (t, J=6.4 Hz, 2H), 3.55 (q, J-6.1 Hz, 2H)

159

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
357		1-(2aminoethyl)6-(2,3dihydro-1,4benzo dîoxin-6-yl)2-thioxo-2,3dihydropyrim idin-4(1H)one	306.0	1H NMR (400 MHz, DMSOd6) δ ppm 7.89-8.01 (m, 3H), 7.07 (d, J=1.8 Hz, 1H), 6.927.02 (m, 2H), 5.75 (s, 1H), 4.34 (br. s., 2H), 4.30 (br. s., 4H), 2.91-2.98 (m, 2H)
35Θ	nh, yy	2-(6-(2,3dihydro-1,4benzodioxin6-yl)-4-oxo2-thioxo-3,4dihydropyrim idin-1(2H)yljacetamide	320.0	2.039 min Symmetry-C18 2.1X50mm 3,5pm Mobile phase- A= 0.1 % FA in MeCN , B=0.1%FA IN water; Time(min)/% B=0/90,0.5/90, 2/55,3/55,3.5/10,6.5/10,7/90; Flow :0.5mL/min, Column Temp=40°C; Diluent: ACN
359	ABS HO^J XJ HCf	6-(5-chloro2methoxyphe nyl)-1-[(2S)2,3dihydroxypro pyl]-2-thioxo2,3dihydropyrim idin-4(1H)one	343.0	2.018 min AQUITY BEH C18,2.1x50mm,1.7pm Mobile Phase:A-0.1%FA IN MeCN,B-0.1%FA IN water T/%B(min):0/90,0.7/90,2/55, 3/55,3.8/5,5.8/5,6/90 Flow:0.5ml_/min, Diluent:ACN, Temp - 40°C
360		1-(2-amino ethyl)-6-(3,4dimethoxy phenyl)-2thioxo-2,3dihydropyrim idin-4(1H)- one	308.1	1H NMR (600MHz, DMSOd6) δ ppm 8.44 (br. s., 4H), 7.17 (d, J=1.3 Hz, 1H), 7.09 7.05 (m, 1H), 7.05-6.96 (m, 1H), 5.78 (s, 1H), 4.36 (br. s., 2H), 3.81 (S, 3H), 3.79 (s, 3H), 2.97 (t, J=7.2 Hz, 2H)
361	ABS Cl	1-[(2S)-2aminopropyl] -6-(5-chloro2methoxyphe nyl)-2-thioxo2,3dihydropyrim idin-4(1 H)one	326.1	4.82 min XBridge C-18 4.6x150mm, 3.5um M phase: A=MeCN; B = 5mM ammonium acetate in water; TIME (min) %OF B: 0/95 , 1/95,3/5,10/5 , 10.05/95 flow: 0.8ml/min, Diluent: ACN

160

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
362	NHj	1-(2- aminoethyl)6-(1,3-benzo thiazol-7-yl)2-thioxo-2,3dihydropyrim idin-4(1H)one	305.1	1H NMR (DMSO-d6) δ ppm 9.53 (s, 1H), 8.28 (dd, J=7.5, 1.3 Hz, 1H), 7.80-8.10 (m, 3H), 7.68-7.77 (m, 2H), 6.07 (s, 1H), 4.44-4.54 (m, 1H), 4.02 (br. s., 1H), 2.92-2.98 (m, 1H), 2.83-2.91 (m, 1H)
363	NHj	2-(6-(2,3dihydro-1,4benzodioxin5-yl)-4-oxo2-thioxo-3,4dihydropyrim idin-1 (2H)-yl] acetamide	319.8	1H NMR (400 MHz, DMSOd6) δ ppm 12.84 (br. s., 1H), 7.32 (s, 1H), 7.02 (dd, J=8.5, 1.5 Hz, 2H), 6.91 (t, J=7.8 Hz, 1H), 6.70-6.76 (m, J=1.5 Hz, 1H), 5.83 (s. 1H), 5.42 (br. s, 1 H), 4.26-4.38 (m, 4H), 3.93-4.07 (m, J=7.0 Hz, 1H)
364	NH,	2-(6-(2,3dihydro-1benzofuran7-yl)-4-oxo2-thioxo-3,4dihydropyrim idin-1 (2H)-yl] acetamide	304.1	1H NMR (400 MHz, DMSOd6) δ ppm 12.80 (br. s., 1H), 7,38 (d, J=7.5 Hz, 2H), 7,00 (d, J=8.5 Hz, 2H), 6.87-6.95 (m, 1H), 5.81 (s, 1H), 5.385.53 (m, 1H), 4.61 (t, J=8.8 Hz, 2H), 3.98-4.11 (m, 1H), 3.24 (t, J=9.0 Hz, 3H)
365	aji NH,	2-(6-(2(methyl sulfanyl)phe nyl]-4-oxo-2thioxo -3,4- dihydro pyrimidin1(2H) yl}acetamide	307.8	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.487.55 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.22-7.32 (m, 2H), 5.81 (s, 1H), 5.54 (d. J=17.1 Hz, 1H), 3.97 (d, J=18.1 Hz, 1H), 2.54 (s, 3H)
366	hA γύ	1-(2-hydroxy ethyl)-6-(2hydroxyphen yl)-2-thioxo2,3dihydropyrim idin-4(1H)one	264.7	1H NMR (400 MHz, DMSOd6) δ ppm 12.71 (br. s., 1H), 10.25 (s, 1H), 7.30-7.42 (m, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.86-7.00 (m, 2H), 5.71 (s, 1H), 4.72 (t, J=5.5 Hz, 1H), 4.51-4.63 (m, 1H), 3.60-3.74 (m, 1H), 3.43-3.55 (m, J=6.0 Hz, 2H)

161

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
367	ÿx? NH,	2-[4-oxo-6(quinolin-5yl)-2-thioxo3,4dihydropyrim idin-1(2H)yl]acetamide	313.1	1H NMR (400 MHz, DMSOd6) δ ppm 12.75-13.08 (m, 1H), 9.00 (d, J=2.5 Hz, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.82-7.91 (m,1H), 7.62 (br. s., 2H), 7.22 (s, 1H), 6.96 (br. s., 1 H), 6.00 (s, 1H)
368	Hr*|l QH QU NH,	2-(6-(2hydroxyphen yl)-4-oxo-2thioxo-3,4dihydropyrim idin-1(2H)yl]acetamide	277.8	1H NMR (400 MHz, DMSOd6) δ ppm 10.37 (br. s., 1H), 7.37 (br. s., 1H), 7.30-7.36 (m, J=7.8, 7.8 Hz, 1H), 7.09 (dd, J=7.8, 1.8 Hz, 1 H), 6.98 (br. s., 1H), 6.96 (d, J=8.5 Hz, 1H), 6.84-6.90 (m, 1H), 5.76 (s, 1H), 5.43 (br. s., 1H), 3.94 (br. s„ 1H), 3.16 (d, J=5.0 Hz, 1H)
369	HjbT	N-(2aminoethyl)2-(6-(5chloro-2methoxyphe nyl)-4-oxo-2thioxo-3,4dihydropyrim idin-1(2H)yljacetamide	369.2	1H NMR (400MHz, DMSOd6)5ppm 12.93 (br. s., 1H), 8.24 (br. s., 1H), 7.88 (br. s., 3H), 7.57 (d, J=9.0 Hz, 1H), 7.28-7.10 (m, 2H), 5.93 (s, 1H), 5.43 (d, J=14.1 Hz, 1H), 4.05-3.92 (m, 1H), 3.85 (s, 3H), 3.16 (d, J=4.5 Hz, 2H), 2.76 - 2.61 (m, 2H)
370	.NH	N-(2aminoethyl)2-(6-(2,5dimethoxyph enyl)-4-oxo2-thioxo-3,4dihydropyrim idin-1 (2H)yljacetamide	365.2	1H NMR (400 MHz, DMSOd6)5ppm 12.89 (s, 1H). 8.18 (t, J=5.5 Hz, 1H), 7.82 (br. s.,3H), 7.01-7.16 (m, 2H), 6.75 (s, 1 H), 5.86 (d, J=2.0 Hz, 1H), 5.25-5.53 (m, 1H), 4.02 (d, J=17.1 Hz, 1H), 3.78 (s, 3H), 3.73 (br. s., 3H), 3.10-3.20 (m, 2H), 2.59-2.75 (m, 2H)
371	A JlH F Hjtr	N-(2-amino ethyl)-2-[6(5-fluoro-2metho xyphenyl)-4oxo-2-thioxo- 3,4-dihydro pyrimidinK2H) yllacetamide	353.1	0.849 min LCMS-C(4#-302) Ultimate XB-C18 2.1x30mm Mobile phase: from 0 MeCN (0.1%TFA) in water (0.1%TFA) to 60 %MeCN (0.1%TFA) in water (0.1%TFA)

162

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
372	YjLf Çj C JIH HjlT	N-(2-amino ethyl)-2-[6(2methoxyphe nyl)-4-oxo-2thioxo-3,4dihydropyrim idin-1(2H)yljacetamide	335.1	nH NMR (400 MHz, METHANOL-d<) δ ppm 8.28 (t, J=5.5 Hz, 1H), 7.51-7.59 (m, 1H), 7.27 (dd, J=7.5, 1.5 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.01-7.10 (m, 1H), 5.84 (s, 1H), 5.45 (d, J=15.1 Hz, 1H), 4.23 (d, J=16.1 Hz, 1H), 3.90 (s, 3H), 3.35-3.45 (m, 1H), 3.23-3.29 (m, 1H), 2.873.00 (m, 2H)
373	HjhT	N-(2aminoethyl)2-(6-(2methoxy-5methyl phenyl)-4oxo-2-thioxo- 3,4dihydropyrim idin-1(2H)yl] a cet amide	349.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.34 (dd, J=8.5, 1.5 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 5.81 (s, 1H), 5.44 (d, J=14.1 Hz, 1H), 4.26 (d, J=17.1 Hz, 1H), 3.86 (s, 3H). 3.33-3.43 (m, 1H), 3.243.29 (m, 1H), 2.85-3.00 (m, 2H), 2.30 (s, 3H)
374	y T	6-(5-fluoro-2methoxyphe nyl)-1-[3(methyl amino)propyl ]-2-thioxo2,3dihydropyrim idin-4(1H)one	324.1	1H NMR (400 MHz, methanol-d3): δ ppm 7.33 (td, J=8.03, 3.01 Hz, 1H), 7.26-7.17 (m, 2H), 5.84 (s, 1H). 4.66-4.50 (brs, 1H), 3.89 (s, 3H), 3.85-3.73 (brm, 1H), 2.86 (t, J=7.53 Hz, 2H), 2.62 (S, 3H), 2.15-2.00 (m, 1H), 1.96-1.81 (m, 1H)
375	Si	1-(3-(6-(5fluoro-2meth oxyphenyl)4-oxo-2thioxo-3,4dihydro pyrimidinK2H) yl]propyl}-1methyl guanidine	366.1	1H NMR (400 MHz, DMSOd6): δ ppm 12.82 (s, 1H), 7.43-7.35 (m,2H), 7.23-7.17 (m, 1H), 7.17-7.06 (brm, 4H), 5.86 (d, J=2.01 Hz, 1H), 4.45-4.31 (brs, 1H), 3.82 (s, 3H), 3.67-3.54 (br m, 1H), 3.19-3.12 (br m, 2H), 2.752.65 (m 3H), 1.91-1.73 (m, 1H), 1.72-1.56 (m, 1H)

163

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
376	A Cl NH,	N-carbam imidoyl-2-[6(5-chloro-2methoxy phenyl)-4oxo-2-thioxo3.4dihydropyrim idin-1 (2H)-yl) acetamide	367.9	1H NMR (400 MHz, DMSOd6) δ ppm 13.08 (s, 1 H), 11.64 (br s, 1 H), 8.19 (br s, 4 H), 7.61 (dd, J=9.03, 2.51 Hz, 1 H), 7.34-7.30 (m, 1 H). 7.22 (d, J=9.03 Hz, 1H), 6.00 (s, 1 H), 5.15 (br s, 1 H), 4.45 (brs, 1 H), 3.83 (s, 3 H)
377	Hj|| ÇTu NHa Cl	2-(6-(5chloro-2hydroxy phenyl)-4oxo-2-thioxo3,4dihydropyrim idin-1 (2H)yl]acetamide	312.0	1H NMR (400 MHz, DMSOd6) δ ppm 12.80 (br. s., 1H), 10.64 (br. s., 1H), 7.34-7.42 (m, 2H), 7.10 (d, J=9.5 Hz, 2H), 6.95 (d, J=8.5 Hz, 1H), 5.86 (s, 1H), 5.47 (br. s., 1 H), 3.92 (br. s., 1H)

The following Exemples of Table 7 (additions to Table 3) were prepared from the corresponding methyl ketone to afford the intermediate beta-keto-ester as described above for the Préparations in the Methyl Ketone Route section followed by employing 5 other methods described in the I. Beta Ketone Ester Route Section as well as standard methods and techniques known to those skilled in the art.

Table 7. Examples from Methyl Ketone Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
378		N-(2-amino ethyl)-2-{6-[2(2-hydroxy ethoxy)-5methoxyphenyl ]-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	395.1	1.10min Xtimate C18, 2.1*30mm Mobile phase: from 0% MeCN in water (0.1 % TFA in water) to 30% MeCN in water (0.1% TFA in water)

164

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
379		6-(2-(2hydroxyethoxy) -5-methoxy phenyl]-1-(2hydroxyethyl)2-thîoxo-2,3dihydropyrimidi n-4(1H)-one	339.2	1H NMR (400 MHz, methanol-d4): δ ppm 7.117.04 (m, 2H), 6.94-6.91 (m, 1H), 5.79 (s, 1 H), 4.74-4.59 (m, 2H), 4.12-4.06 (m, 2H), 3.95-3.83 (m, 1H), 3.83-3.76 (m, 6H), 3.68-3.60 (m, 1H)
380		2-(6-(2-(2hydroxyethoxy) -5-methoxy phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	374.1	1H NMR (400 MHz, DMSOd6)ôppm 12.79 (s, 1H), 7.35 (br. s., 1H), 6.99-7.15 (m, 3H), 6.76 (br. s., 1H), 5.81 (s, 1H), 5.24-5.43 (m, 1 H), 4.73-4.92 (m, 1H), 4.01 (d, J=5.5 Hz, 2H), 3.84-3.95 (m, 1H), 3.70 (s, 3H), 3.62 (t, J=5.0 Hz, 2H)
381 I l“Z	1-(2-((2aminoethyl)ami no]ethyl}-6(2,4-dimethoxy phenyl)-2thioxo-2,3dihydropyrimidi n-4(1H)-one	351.1	0.77 min Waters Acqity HSS T3, 2.1x50mm, C18, 1.7pm; A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in MeCN A: 0.1% ammonia in water; Mobile phase B: 0.1% ammonia in MeCN Flow 1.25ml/min
382	Nt%	1-(2-amino ethyl)-2-thioxo6-[2-(trifluoro methoxyjpheny l]-2,3-dihydro pyrimidin4(1H)-one	331.9	3.41 min Waters symmetry 2.1x50 mm 5 um Mobile phase: from 0% MeCN in water (0.1% TFA) to 30% MeCN in water (0.1% TFA)
383		6-(2,4dimethoxyphen î yl)-1 -(2-((2hydroxyethyl)a mino]ethyl}-2thioxo-2,3dihydropyrimidi n-4(1H)-one	351.9	Ή NMR (400 MHz, DMSOd6) δ ppm 8.68 (br. s., 2H), 7.30 (d, J=8.8 Hz, 1H), 7.107.21 (m, 1H), 6.70-6.75 (m, 1H), 6.63-6.69 (m, 1H), 5.76 (s, 1H), 5.18 (br. s., 1H),4.69 (br. s., 1H), 3.99 (br. s., 1H), 3.85-3.81 (m, 6H), 3.70-3.78 (m, 1H), 3.55 (t, J=5.0 Hz, 1H), 3.06 (br. s., 1H), 2.973.01 (m, 1H) 2.84 (br. s„ 2H)

165

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
3Θ4	NHj	2-(6-(3methoxyphenyl )-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	292.0	3.661 min XBRIDGE-C18 4.6X75mm 3.5pm Mobile phase-A= 0.1% FA IN MeCN, B=0.1% FA IN water Time(min)/% B= 0/90, 0.8/90, 1.8/55, 3/5, 6.5/5 ,7/90 Flow: 0.8mL/min, Column Temp=40C; Diluent: ACN
385	y	2-(6-(2,4dimethoxyphen yl)-4-oxo-2□ thioxo-3,4dihydropyrimidi n-1(2H)-yl]-N(2hydroxyethyl)a cetamîde	365.4	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.98 (br. s., 1H) 7.15 (d, J=8.5 Hz, 1H) 6.65 (d, J=2.0 Hz, 1H) 6.60 (dd, J=8.5, 2.0 Hz, 1H) 5.77 (s, 1H) 5.50 (br. s., 1H) 4.20 (d, J=15.1 Hz, 1H) 3.87 (s, 3H) 3.85 (s, 3H) 3.41-3.53 (m, 2H) 3.14-3.22 (m, 2H)
386	ΝΗ, '	2-(6-(2,6dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	321.8	1H NMR (400 MHz, DMSOd6) δ ppm 12.75 (br. s„ 1H) 7.45 (t, J=8.5 Hz, 1H) 7.13 (br. s., 1H) 6.92 (s, 1 H) 6.77 (d, J=8.0 Hz, 2H) 5.76 (s,1 H) 4.33-4.80 (m, 2H) 3.74(s,1H)
387	NH,	2-{6-[4-(2hydroxyethoxy) * methoxyphenyl ]-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yl}acetamide	352.1	'H NMR (400 MHz, DMSOd0) δ ppm 12.76 (s, 1H), 7.31 (br. s., 1H), 7.06 (d, J=8.5 Hz, 1H), 6.98 (s, 1H), 6.68 (d, J=2.0 Hz, 1H), 6.60 (dd. J=8.5, 2.0 Hz, 1H), 5.74 (d, J=2.5 Hz, 1H), 5.37 (br. s., 1 H), 4.04 (t, J=5.0 Hz, 2H), 3.89 (br. s., 1H), 3.82 (s, 3H), 3.72 (t, J=4.8 Hz, 2H)
388 AM 2-(6-(2,4- Jt . dimethoxyphen Λί yl)-4-oxo-2- ζΤ XX thioxo-3,4- T dihydropyrimidi ÇT n-1(2H)-yl]-N- H [(3R)-pyrrolidin- | | 3-yl]acetamide	391.2	0.965 min LCMS-AI(4#-302) Ultimate XB-C18 2.1x30mm Mobile phase: from 0 MeCN (0.1%TFA) in water (0.1 %TFA) to 60 %MeCN (0.1%TFA) in water (0.1%TFA)

166

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
389 «s 1-{2-[(3R)-3- Jl - aminopyrrolidin XXX -1-yl]-2-oxoet ÇjXX hyl}-6-(2,41 ’ dimethoxyphen P yl)-2-thioxo-2,3 H,N -dihydropyrimi I | din-4(1H)-one	413.2	0.972 min LCMS-AI(4#-302) Ultimate XB-C18 2.1x30mm Mobile phase: from 0 MeCN (0.1%TFA) in water (0.1%TFA) to 60 % MeCN (0.1%TFA) in water (0.1%TFA)
390	Y	N-(2aminoethyl)-2[6-(2,4-dimeth oxyphenyl)-4oxo-2-thioxo3,4-dihydropyr imidin-1 (2H)yl]-N-methyl acetamide	379.0	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.17 (d, J=8.5 Hz, 1H), 6.68 (s, 1 H), 6.60 (d, J=7.5 Hz, 1H), 5.80 (s, 1H), 5.65 (d, J=17.1 Hz, 1H), 4.33 (d, J=16.6 Hz, 1 H), 3.88 (s, 3H), 3.85 (s, 3H), 3.59-3.70 (m, 1H), 3.363.49 (m, 1H), 3,02 (br. s., 2H), 2.97 (s, 3H)
391	Y Y	2-(6-(2.4dimethoxyphen > yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)-yl]-N[2(methylamino)e thyl]acetamide	379.2	'H NMR (400 MHz, METHANOL-d4) δ ppm 8.34 (t, J=5.8 Hz, 1H), 7.17 (d, J=8.5 Hz, 1 H), 6.67 (d, J=2.0 Hz, 1H), 6.62 (dd, J=8.5, 2.0 Hz. 1H), 5.81 (s, 1H), 5.42 (d, J=16.6 Hz, 1H), 4.28 (d, J=16.6 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.40-3.48 (m, 1H), 3.33-3.38 (m, 1H), 3.003.07 (m, 2H), 2.69 (s, 3H)
392	Y y	2-(6-(2,4dimethoxyphen yl)-4-oxo-2? thioxo-3,4dihydropyrimidi n-1 (2H)-yl]-N[2(dimethylamino )ethyl]acetamid e	393.2	ΊΗ NMR (400 MHz, DMSOde) δ ppm 12.82 (s, 1H), 10,19 (br. s., 1H), 8.28 (br. s., 1H), 7.09 (d, J=8.0 Hz, 1 H), 6.69 (d, J=2.0 Hz, 1H), 6.62 (dd, J=8.5, 2.0 Hz, 1H), 5.79 (d, J=2.0 Hz, 1H), 5.37 (d, J=12.5 Hz, 1 H), 4.02 (d, J=16.6 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.95 (d, J=18.1 Hz, 2H), 2.70 (br. s., 6H)

167

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
393	ABS Λ r	2-(6-(2,4dimethoxyphen î yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)-yl]-N[(3S)-pyrrolidin3-yljacetamide		H NMR (400 MHz, METHANOL-d4) δ ppm 7.16
	yÙ Y	391.2	(dd, J=8.3, 5.3 Hz, 1 H). 6.67 (s, 1H), 6.61 (dt, J=8.5, 2.3 Hz, 1H), 5.79 (s, 1H), 5.395.62 (m, 1H), 4.16-4.34 (m, 2H), 3.88 (d, J=3.5 Hz, 3H), 3.85 (sJ 3H), 3.49-3.37 (m, 2H), 3.09-3.17 (m, 1H), 2.953.02 (m, 1H), 2.14-2.32 (m, 1H), 1.80-1.98 (m, 1H)
394	ABS A, Htrr	N-[(2S)-1-		ΊΗ NMR (400MHz, METHANOL-d4, rotameric mixture) δ ppm 7.20 (d, J=8.0 Hz, 0.4H) 7,14 (d, J=8.5 Hz, 0.6H) 6.67 (d,
	aminopropan-		J=2.0 Hz, 1H) 6.61 (td,
	2-yl]-2-[6-(2,4-		J=2.3, 8.5 Hz, 1H) 5.81 (s,
		dimethoxyphen	379.2	0.6H), 5.79 (s, 0.4H) 5.63 (d,
		yl)-4-oxo-2-	J=15.6 Hz, 1H) 5.35-5.27 (m,
		thioxo-3,4-		1H) 4.35-4.27 (m, 0.4H)
		dihydropyrimidi		4.20 (d, J=16.6 Hz, 0.6H)
		n-1(2H)-		4.05-3.94 (m, 1H) 3.89 (s,
		yl]acetamide		2H), 3.87 (s, 1H) 3.85 (d, J=1.5 Hz, 3H) 3.04-2.92 (m, 0.7H) 2.89-2,77 (m, 1.3H) 1.19 (d, J=6.5 Hz, 1 H) 1.05 (d, J=7.0 Hz, 2H)
395	ABB	N-((2R)-2-		1H NMR (400 MHz,
		aminopropyl]-2-		METHANOL-d4) δ ppm 7.22
	ΑΛΛ	[6-(2,4-		(t, J=8.3 Hz, 1H), 6.72 (s,
	oÇjXX JlH I H.rA*	dimethoxyphen	379.2	1H), 6,66 (d, J=8.5 Hz, 1H),
	yl)-4-oxo-2-	5.86 (s, 1H), 5.37-5.64 (m,
	thioxo-3,4-		1H), 4.35 (d, J=15.1 Hz, 1H),
	dihydropyrimidi		3.93 (d, J=2.5 Hz, 3H), 3.90
		n-1(2H)-		(s, 3H), 3.34-3.47 (m, 3H),
		yljacetamide		1.25 (dd, J=13.3, 5.8 Hz, 3H)

it>a

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
396	A0S K/A	N-[(2S)-2aminopropyl]-2? [6-(2,4- dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	379.2	nH NMR (400 MHz, DMSOde) δ ppm 12.81 (br. s., 1H), 8.24 (d, J=3.0 Hz, 1H), 7.97 (br. s., 3H), 7.07 (dd, J=11.8, 8.3 Hz, 1 H), 6.65-6.73 (m, 1H), 6.59 (ddd, J=8.4,4.1, 2.0 Hz, 1H), 5.78 (d, J=2.0 Hz, 1H), 5.28-5.50 (m, 1H), 4.06 (d, J=15.6 Hz, 1H), 3.83 (d, J=2.5 Hz, 3H), 3.81 (s, 2H), 3.21 (d, J=6.5 Hz, 1H), 2.93-3.09 (m, 2H), 0.93-1.06 (m, 3H)
397	ÿô, Q	6-(2,4dimethoxyphen yl)-1-[2-oxo-2(piperazin-1yl)ethyl]-2thioxo-2,3dihydropyrimidi n-4(1H)-one	391.2	0.879 min Xtimate C18,2.1x30mm,3um Mobile phase: from 0% MeCN in water (0.0685% TFA in water) to 60% MeCN in water (0.0685% TFA in water)
398	ABS A	1-{2-[(3S)-3aminopyrrolidin -1-yl]-2oxoethyl}-6' (2,4- dimethoxyphen yl)-2-thioxo2,3dihydropyrimidi n-4(1H)-one	413.0	0.988 min LCMS-AI(4#-302) Xtimate C18,2.1x30mm,3um Mobile phase: from 0% MeCN (0.1%TFA) in water (0.1%TFA) to 60% MeCN (0.1%TFA) in water (0.1%TFA)
399	ABS y, Ά	N-[2-({[6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yl]acetyl}amino )ethyl]-Lalaninamide	436.0	H NMR (400 MHz, DMSOda) δ ppm 8.33 (s, 1 H) 8.12 (br. s., 1H) 8.06 (br. s., 1H) 7.07 (d, J=8.5 Hz, 1H) 6.68 (d, J=2.5 Hz, 1 H) 6.56-6.63 (m, 1H) 5.77 (s, 1H), 5.38 (br. s„ 1 H) 4.22 (br., 3H) 3.97 (d, J=13.6 Hz, 1H) 3.823.88 (m, 3H) 3.81 (s, 3H) 3.37-3.48 (m, 1H) 2.99 (br. s., 4H) 1.17 (d, J=7.0 Hz, 3H)

169

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
400	Z	r 2-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1 (2H)-yl]-Nmethyl-N-[2(methylamino)e thyljacetamide	393.2	Ή NMR (METHANOL-d4, rotameric mixture) δ ppm 7.18 (d, J=8.5 Hz, 0.6H)7.13 (d, J=8.5 Hz, 0.4H) 6.67 (d, J=2.0 Hz, 1 H) 6.56-6.63 (m, 1H) 5.74-5.81 (m, 1H) 5.66 (d, J=16.6 Hz, 1 H) 4.23-4.38 (m, 1H) 3.87-4.00 (m, 3H) 3.80 (s, 3H) 3.53 (dt, J=13.6, 6.8 Hz, 0.6H) 3.34-3.40 (m, 0.4H) 3.14-3.27 (m, 1H) 2.93 (s, 2H) 2.84 (s, 1H) 2.57-2.73 (m, 2H) 2.38 (s, 2H) 2.33 (s, 1H)
401	ABS	î N-[(2R)-1aminopropan2-yl]-2-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	379.1	ηΗ NMR (400MHz, METHANOL-d4, rotameric mixture) δ ppm 7.20 (d, J=8.0 Hz, 0.4H) 7.14 (d, J=8.5 Hz, 0.6H) 6.67 (d, J=2.0 Hz, 1H) 6.61 (td, >2.3, 8.5 Hz, 1 H) 5.81 (s, 0.6H) 5.79 (s, 0.4H) 5.63 (d, >15.6 Hz, 1H) 5.35-5.27 (m, 1H) 4.35-4.27 (m, 0.4H) 4.20 (d, >16.6 Hz, 0.6H) 4.053.94 (m, 1H) 3.89 (s, 2H) 3.87 (s, 1H) 3.85 (d, >1.5 Hz, 3H) 3.04 - 2.92 (m, 0.7H) 2.89-2.77 (m, 1.3H) 1.19 (d, >6.5 Hz, 1H) 1.05 (d, >7.0 Hz, 2H)
402	H |f»	1-(3aminopropyl)6-(2-(2hydroxyethoxy) -4methoxyphenyl ]-2-thioxo-2,3dihydropyrimidi n-4(1 H)-one	352.2	1H NMR (400 MHz, DMSOd6) δ ppm 12.75 (s, 1H), 7.73 (brs, 3H), 7.28 (d, J=8.03 Hz, 1H), 6.72 (d, J=2.51 Hz, 1H), 6.64 (dd, J=8.53, 2.51 Hz, 1H), 5.77- 5.73 (m, 1H), 4.40 (br s, 1H), 4.10 (t, J=5.02 Hz, 2H), 3.82 (s, 3H), 3.75-3.66 (br s, 1H), 3.64 (t, J=5.02 Hz, 2H), 2.50-2.51 (m, 2H), 1.90-1.78 (m, 1H), 1.78-1.66 (m, 1H)

170

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
403		1-(3-{6-[2-(2hydroxyethoxy) *4methoxyphenyl J-4-0X0-2thioxo-3,4dihydropyrimidi n-1(2H)yl}propyl)guani dîne	394.1	1HNMR (400 MHz, DMSOd6)ôppm 12.70 (s, 1H), 7.35 (t, J=6.02 Hz, 1H), 7.25 (d, J=8.53 Hz, 1H), 7.22-6.74 (brs, 4H), 6.71 (d, J=2.51 Hz, 1H), 6.62 (dd, J=8.03, 2.51 Hz, 1H>, 5.73 (d, J=2.01 Hz, 1H), 4.87 (br s, 1H),4.39 (brs. 1H),4.15-4.02 (m, 2H), 3.82 (s, 3H), 3.60-3.74 (m, 3H), 2.98-2.93 (m, 2H), 1.851.68 (m, 1H), 1.66-1.51 (m, 1H)
404	JM '	N-(2aminoethyl)-2{6-(2-(2hydroxyethoxy) -4methoxyphenyl H-oxo-2thioxo-3,4dihydropyrimîdi n-1(2H)yljacetamide	395.12	1H NMR (400 MHz, Methanol-d4) δ ppm 8.358.26 (m, 0.3H), 7.18 (d, J=8.53 Hz, 1H), 6.68 (d, J=2.01 Hz, 1H), 6.62 (dd, J=8.53, 2.01 Hz, 1H), 5.82 (s, 1H), 5.52-5.37 (br m, 1 H), 4.42-4.29 ( br m, 1H), 4.204.09 (m, 2H), 3.90-3.79 (m, 5H), 3.43-3.33 (m, 2H), 3.002.90 (m, 2H)
405	JiH F HJ*	N-(2aminoethyl)-2{6-[5-fluoro-2(2hydroxyethoxy) phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)yl}acetamide	383.1	1H NMR (400 MHz, Methanol-d4) δ ppm 7.27(td, J=9.03, 3.01 Hz, 1H), 7.16 (dd, J=9.03, 4.02 Hz, 1H), 7,08 (dd, J=8.03, 2.51 Hz, 1H), 5.88 (s, 1H), 5.50-5.38 (br m, 1 H), 4.36-4.26 (brm, 1 H), 4.20-4.10 (m, 2H), 3.84 (t, J=4.02 Hz, 2H), 3.44-3.33 (m, 2H), 3.00-2.93 (m, 2H)
406	Ay hA	1-(3aminopropyl)6-[5-fluoro-2(2hydroxyethoxy) phenyl]-2thioxo-2,3dihydropyrimidi n-4(1H)-one	340.1	1H NMR (400 MHz, Methanol-d4) δ ppm 7.31 (td, J=9.03, 3.01 Hz, 1 H), 7.257.18 (m, 2H>, 5.85 (s, 1 H), 4.57-4.44 (br s, 1 H), 4.033.90 ( br m, 2H), 3.97-3.96 (m, 1H), 3.84 (t, J=4.02 Hz, 2H), 2.79 (t, J=8.03 Hz, 2H), 2.13-2.00 (m, 1H), 1.95-1.82 (m, 1H)

171

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
407	A	1-(3-(6-(5- 1 fluoro-2-(2hydroxyethoxy) phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)yl}propyl)guani dîne	382.1	1H NMR (400 MHz, Methanol-d4) δ ppm 7.30 (td, J=9.03, 3.01 Hz, 1H), 7.257.15 (m, 2H), 5.84 (s, 1H), 4.60-4.46 (brm, 1 H), 4.194.10 (m, 2H), 3.96-3.79 (m, 3H), 3.10-3.01 (m, 2H), 2.061.93 (m, 1H), 1.83-1.68 (m, 1H)
408	A i	3-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljpropanenitrïl e	318.1	1H NMR (400 MHz, chloroform-d) δ ppm δ 9.57 (brs, 1H), 7.22 (d, J=8.53 Hz, 1H), 6.62 (dd, J= 8.53, 2.51 Hz, 1H), 6.55 (d, J=2.51 Hz, 1H), 5.85 (d, J= 2.51 Hz, 1H), 4.67-4.53 (brm, 1H), 4,19-4.05 (brm, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.19-3.06 (m, 1H), 2.71-2.63 (m, 1H)
409	K	6-(2-(2hydroxyethoxy) -4methoxyphenyl 1-1-(2hydroxyethyl)2-thioxo-2,3dihydropyrimidi n-4(1H)-one	338.9	1H NMR (400 MHz, DMSOd6) δ ppm 12.65 (s, 1 H), 7.22 (brs, 1 H), 6.78-6.53 (brm, 2 H), 5.68 (brs, 1H), 4.90-4.78 ( br m, 1 H), 4.724.62 (brm, 1 H), 4.59-4.42 (br m, 1H), 4.19-3.97 (brm, 2H), 3.81 (brs, 3H), 3.64 (brs, 3H)
410	ÇA NH,	2-(6-(4methoxyphenyl )-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	314.1	0.905 min LCMS-C (4#-302) Ultimate XB-C18 2.1x30mm Mobile phase: from 0 MeCN (0.1%TFA) in water (0.1%TFA) to 60 % MeCN (0.1%TFA) in water (0.1%TFA)
411	Ηΐ<η qX\x0H	6-[5-fluoro-2(2hydroxyethoxy) phenyl]-1-(2hydroxyethyl)2-thioxo-2,3dihydropyrimidi n-4(1H)-one	326.8	1HNMR (400 MHz, methanol-d4) δ ppm 7.25 (td, J=9.03, 3.01 Hz, 1H), 7.197.13 (m, 2H), 5.80 (s, 1H), 4.76-4.65 (m,1H), 4.61 (brs, 1 H), 4.16-4.09 (m, 2H), 3.883.78 (m, 3H), 3.66-3.60 (m, 1H)

172

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
412	φψ NHj F	2-{6-[5-fluoro2(2hydroxyethoxy) phenyl]-4-oxo2-thioxo-3,4dihydropyrimîdi n-1(2H)yljacetamide	362.1	1H NMR (400 MHz, methanol-d4) δ ppm 7.25 (td, J= 9.03, 3.01, 1H), 7.15 (dd, J=9.03, 4.02 Hz, 1H), 7.06 (dd, J=8.03, 3.01 Hz, 1H), 5.84 (s, 3H), 5.67-5.42 (br s, 1H), 4.37-4.18 (br s, 1H), 4.14 (t, J=4.52 Hz, 2H), 3.83 (t, J=4.02 Hz, 2H)
413	X OH	6-[4-fluoro-2(2hydroxyethoxy) phenyl]-1-(2hydroxyethyl)2-thioxo-2,3dihydropyrïmidi n-4(1H)-one	327.2	1H NMR (400 MHz, DMSOd6) δ ppm 12.71 (s, 1H), 7.39-7.33 (m, 1H), 7.12 (dd, J= 11.54, 2.01 Hz, 1H), 6.90 (td, J=8.53, 2.51 Hz, 1H), 5.75 (s, 1H), 5.73 (d, J=2.01 Hz, 1 H), 4.97-4.79 (brs, 1H), 4.77-4.62 (brs, 1H), 4.534,43 (m, 1H), 4.16-4.04 (m, 2H), 3.64 (br t, J=4.52 Hz, 2H), 3.61-3.49 (m, 2H)
414	K- NHj	2-{6-[4-fluoro2-(2hydroxyethoxy) phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	362.2	1H NMR (400 MHz, DMSOd6) δ ppm 12.80 (s, 1H), 7.33 (brs, 1 H), 7.24-7.17 (m, 1H), 7.12 (d, J=11.54 Hz, 1H), 7.01 (brs, 1H), 6.916.83 (m, 1H), 5.79 (s, 1H), 5.52-5.22 (brs, 1 H), 4.974.81 (brm, 1 H), 4.17-4.05 (br m, 2H), 4.02-3.85 (brs, 1H), 3.69-3.60 (br m, 2H)
415		N-(2aminoethyl)-2{6-[4-fluoro-2(2hydroxyethoxy) phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	383.2	1HNMR (400 MHz, methanol-d4) δ ppm 8.338.24 (m, 1H), 7.33-7.27 (m, 1H), 7.00 (dd, J= 10.90, 1.71 Hz, 1H), 6.81 (td, J=8.03, 2.01 Hz, 1H), 5.85 (s, 1H), 5.52-5.39 (br m, 1 H), 4.374.26 (br m, 1H), 4.23-4.12 (m, 2H), 3.85 (br t, J=4.02 Hz, 2H), 3.47-3.35 (m, 2H), 3.00-2.91 (m, 2H)

173

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
416	Xx NH,	2-(6-(2,3dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yl]acetamide	322.1	1H NMR (400 MHz, DMSOd6) δ ppm 12,77 (br. s., 1H), 7.26 (br. s„ 1H), 7.17-7.23 (m, 1H), 7.08-7.17 (m, 1H), 6.93 (br. s., 1H), 6.75 (d, J=7.5 Hz, 1H), 5.75 (br.s., 1H), 5.42 (br.s., 1 H), 4.11 (br. s., 1H), 3.85 (s, 3H), 3.72 (s, 3H)
417	NH,	2-(6-(4-chloro2methoxyphenyl )-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yllacetamide	326.2	1H NMR (400 MHz, DMSOd6) δ ppm 12.81 (br. s., 1H), 7.34 (br. s„ 1H), 7.28 (s, 1H), 7.15-7.20 (m, 1H>, 7.10-7.14 (m, 1H), 7.04 (br.s., 1H), 5.83 (s, 1H), 5.43 (br. s., 1H), 3.86 (s, 4H)
416	NH)	2-(6-(2methoxy-4methylphenyl)4-oxo-2-thioxo- 3,4dihydropyrimidi n-1(2H)yljacetamide	306.0	1H NMR (400 MHz, DMSOd6) δ ppm 12.78 (br. s., 1H), 7.04 (d, J=7.5 Hz, 1H), 7.00 (s, 2H), 6.85 (d, J=7.5 Hz, 1H), 5.75 (s, 1H), 5.35 (br. s., 1H), 3.86-3.94 (m, 1H), 3.82 (s, 3H), 2.36 (s, 3H)
419	h/tXnh	1-(2-(6-(5fluoro-2methoxyphenyl )-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljethoxyjguani dîne	354.2	1H NMR (400 MHz, METHANOL-d4) δ ppm 8.45 (br. s., 1H), 7.30 (td, J=8.5, 3.0 Hz, 1H), 7.10-7.24 (m, 2H), 5.83 (s, 1 H), 4.73-4.83 (m, 1H), 3.97-4.16 (m, 3H), 3.89 (s, 3H)
420	Χζ NH, '	H 2-(6-(2-(2hydroxyethoxy) -4methoxyphenyl ]-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	374.0	1H NMR (400 MHz, DMSOd6)5ppm 12.72 (br. s„ 1H), 7.32 (br. s„ 1H), 7.09 (d, J=8.0 Hz, 1H), 6.97 (br. s., 1H), 6.69 (br. s., 1H), 6.60 (d, J=9.0 Hz, 1H), 5.74 (d, J=11.0 Hz, 1H), 5.32 (br. s„ 1 H), 4.84 (br.s., 1H), 4.08 (d, J=4.0 Hz, 2H), 3.97 (br. s, 1H), 3.80 (s, 3H), 3.64 (br. s, 2H)

174

Example #	Structure	Compound Name	Obs Mass	1.H NMR Spectral Data or HPLC Rétention Time and Conditions
421	oÇTÇ) NHj F	' 2-{2-[3-(2- amino-2oxoethyl)-6oxo-2-thioxo1,2,3,6tetrahydropyrim idin-4-yl]-4fluorophenoxy} ethyl acetate	404.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 8.09 (s, 0.6H), 7.57 (br. s., 0.2H), 7.27 (td, J=8.5, 3.0 Hz, 1H), 7.14 (dd, J=9.0, 4.5 Hz, 1H), 7.07 (dd, J=8.3, 3.3 Hz, 1H), 6.99 (br. s„ 0.2H), 5.83 (s, 1H), 5.67 (d, J=14,1 Hz, 1H), 4.30-4.46 (m, 2H), 4.22-4.30 (m, 2H), 4.12 (d, J=17.1 Hz, 1H), 2.06 (s, 3H)

The following Examples of Table 8 (additions to Table 4) were prepared from the corresponding aryl halide to afford the intermediate beta-keto-ester as described above 5 for the Préparations in the Aryl Halide Route section followed by employing the methods described in the I. Beta Keto Ester Route Section as well as standard methods and techniques known to those skilled in the art.

Table 8. Examples from Aryl Halide Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
422	οόφ	2-{6-[5-(2hydroxyethoxy) -2-methoxy phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	352.0	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.097.18 (m, 1H), 7.03-7.09 (m, 1H), 6.88 (d, J=3.0 Hz, 1H), 5.81 (s, 1H), 5.46-5.63 (m, 1H), 4.17 (br. s., 1H), 4.00 (d, J=3.5 Hz, 2H), 3.84 (s, 5H)
423	Aa NU, O	2-{4-[3-(2aminoethyl)-6 oxo-2-thioxo1,2.3,6tetrahydropyrim idin-4-yl]-3methoxypheno xy}acetamide	351.2	1H NMR (400 MHz, DMSOd6) δ ppm 12.85 (s, 1H)8.06 (br s, 3H) 7.69 (s, 1H) 7.48 (s, 1H) 7.30 (d, J=8.53 Hz, 1H) 6.82 (d, J=2.01 Hz) 1H) 6.67 (dd, J=8.53, 2.01 Hz, 1H) 5.75 (s, 1H) 4.71-4.60 (br s, 1 H) 4.51 (s, 2H) 3.943.81 (m, 4H) 2.95-2.80 (m, 2H)

175

The following Examples of Table 9 were prepared from the corresponding aryl ester or lactone to afford the intermediate beta-keto-ester as described above for the

Préparations in the Ester Route section followed by employing the methods described in the I. Beta Keto Ester Route Section as well as standard methods and techniques known to those skilled in the art.

Table 9. Examples from Ester Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
424	A” Z “	„ N-(2- aminoethyl)-2{6-[5-chloro-2(2-hydroxy ethoxy)phenyl]4-oxo-2-thioxo3,4-dihydropyr imidin-1 (2H)yl}acetamide	398.9	1H NMR (400 MHz, Methanol-d4) δ ppm 7.50 (dd, J=9.03, 3.01 Hz, 1 H), 7.30 (d, J=2.51 Hz, 1 H), 7.17 (d, J=9.03 Hz, 1 H), 5.88 (s, 1H). 5.56-5.43 (brm, 1H), 4.31-4.06 (m, 4H), 3.84 (t, J= 4.52 Hz,2H), 3.44-3.33 (m, 2H), 3.03-2.89 (m, 2H)
425		6-[5-chloro-2(2hydroxyethoxy) phenyl]-1-(2hydroxyethyl)2-thioxo-2,3dihydropyrimidi n-4(1H)-one	342.7	1H NMR (400 MHz, DMSOd6) δ ppm 12.73 (brs, 1H), 7.52 (br s, 1H), 7.40 (br s, 1H), 7.28-7.15 (brm, 1 H), 5.88-5.72 (brm, 1 H), 4.92 (br s, 1H), 4.78 (brs, 1 H), 4.48 (brs, 1H), 4.08 (brs, 2H), 3.73-3.52 (br m, 4H)
426	NH, CI	2-{6-[5-chloro2-(2hydroxyethoxy) phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	378.1	1H NMR (400 MHz, DMSOd6) δ ppm 12.84 (br. s, 1H), 7.54 (dd, J=9.0, 3.0 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J=8.5 Hz, 2H), 7.09 (s, 1H), 5.87 (s, 1H), 5.37 (br. s., 1H), 4.86 (t, J-5.3 Hz, 1H), 4.04-4.13 (m, 2H), 3.95 (br. s., 1H), 3.58-3.70 (m, 2H)
427		1-(2aminoethyl)-6[5-chloro-2-(2hydroxyethoxy) phenyl]-2thioxo-2,3dihydropyrimidi n-4(1H)-one	341.9	1H NMR (400 MHz, METHANOL-d4) δ ppm 8.49 (br. s., 1H) 7.56 (dd, J=9.3, 2.3 Hz, 1H) 7.45 (d, J=2.5 Hz, 1H) 7.22 (d, J=9.0 Hz, 1H) 5.87 (s, 1 H) 4.62 (br. s., 2H) 4.12-4.30 (m, 3H) 3.85 (br. s.,2H) 3.14-3.25 (m, 1H) 3.04-3.13 (m, J=8.0 Hz, 1H)

176

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
428	X	N-(2aminoethyl)-2{6-[2-(2hydroxyethoxy) phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	365.1	]H NMR (400 MHz, METHANOL-d4) δ ppm 8.28 (t, J=5.8 Hz, 1H) 7.48-7.55 (m, 1H) 7.27 (dd, J=7.5, 1.5 Hz, 1H) 7.16 (d. J=8.0 Hz, 1 H) 7.06 (td, J=7.5, 1.0 Hz, 1H) 5.85 (s, 1H), 5.44 (br. s„ 1 H) 4.31 (d, J=15.1 Hz, 1H) 4.13-4.20 (m, 2H) 3.85 (ddd, J-5.4, 3.9, 2.3 Hz, 2H) 3.333.40 (m, 2H) 2.92 (t, J=5.8 Hz, 2H)

The following Examples of Table 10 were prepared from the corresponding thiouracil carboxylic acid as described above for the Préparations in the III, Amide Coupling Route section and by employing the methods described in the l. Beta Keto Ester Route

Section as well as standard methods and techniques known to those skilled in the art.

Table 10. Examples from Amide Coupling Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
429	X HXV	N-(2-amino-2methylpropyl)2-[6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	392.2	qH NMR (400 MHz, METHANOL-d4) δ ppm 8.42 (t, J=6.3 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 5.82 (s, 1H), 5.41 (d, J=13.6 Hz, 1H), 4.31 (d, J=15.6 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.34-3.40 (m, 1H), 3.09-3.17 (m, 1H), 1.221.29 (m, 5H), 1.26 (d, J=5.5 Hz, 6H)
430	.X	N-(cis-3aminocyclobuty V l)-2-[6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yl]acetamide	391.2	H NMR (400 MHz, METHANOL-di) δ ppm 8.31 (d, J=6.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1 H), 6.67 (d, J=2.0 Hz, 1H), 6.60 (dd, J=8.3, 2.3 Hz, 1H), 5.79 (s, 1H), 5.53 (br. s., 1H), 4.20 (br. s., 1H), 3.90-3.98 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.43-3.52 (m, 1H), 2.57-2.76 (m, 2H), 1.93-2.14 (m, 2H)

177

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
431	î	1-[2-(3aminoazetidin- 1-yl)-2oxoethyl]-6(2,4-dimethoxy phenyl)-2thioxo-2,3dihydropyrimidi n-4(1H)-one	377.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.21 (dd,J=14.05, 8.53 Hz, 1 H), 6.70-6.58 (m, 2 H), 5.80 (s, 1 H), 5.38-5.28 (brm, 1H), 5.18-5.09 (brm, 1H), 4.444.25 (m, 5H), 4.23-4.11 (m, 2H), 4.11-3.92 (m, 1H), 3.86 (s, 6H)
432	A	N-(1-amino-2methylpropan„ 2-yl)-2-[6-(2,4Tdimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yl]acetamide	392.9	1H NMR (400 MHz, DMSOd6)ôppm 12.81 (brs, 1H), 7.81 (s, 1 H),7.79-7.63 (brs, 3H), 7.08 (d, J=8.03 Hz, 1H), 6.70 (s, 1H), 6.61 (d, J= 8.50 Hz, 1H), 5.77 (s, 1H), 5.42 (brs, 1H), 4.05 (brs, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 2.94 (s, 2H), 1.13 (s, 3H), 1.09 (s, 3H)
433	ASft Xy-NH H/A	N-[(2R,3R)-3aminobutan-2yl]-2-[6-(2,4f dîmethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	393.1	0.931 min Xtimate C18 2.1x30mm 3um Mobile phase: from 0% MeCN (0.1% TFA) in water (0.1% TFA) to 60% MeCN (0.1% TFA) in water (0.1% TFA)
434	A ^NH I	2-[6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)-ylJ-Nethylacetamide	349.9	1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.75 (br, 1H), 7.20 (d, J=8.53 Hz, 1H), 6.55 (dd, J= 8.53, 2.51 Hz, 1H), 6.49 (d, J=2.51 Hz, 1 H),5.87 (s, 1H), 5.62 (br, 1H), 5.12 (br, 1 H). 4.25 (br, 1H), 3.85(s, 3 H),3.81 (s, 3H), 3.36-3.24 (m, 1 H), 3.24-3.14 (m, 1H), 1.10 (t, J=7.53 Hz, 3H)

178

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
435		2-(6-(2,4- > dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1 (2H)-yl]-Npropylacetamid e	364.1	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 9.61 (br, 1H), 7.21 (d,J=8.53 Hz, 1H). 6.54 (dd, J=8.53, 2.51 Hz, 1 H), 6.49 (d, J=2.51 Hz, 1H), 5.87 (s, 1H), 5.64 (br, 1H), 5.15 (br, 1H), 4.26 (br, 1H), 3.85 (s, 3 H),3.81 (s, 3H), 3.30-3.18 (m, 1 H),3.15-3.04 (m, 1H), 1.48 (q, J=7.03, 2 H), 0.88 (t, J=7.03 Hz, 3 H)
436		2-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)-yl]-N(2methoxyethyl)a cetamide	402.1	1HNMR (400 MHz, CHLOROFORM-d) δ ppm 9.59 (br, 1H), 7.22 (d, J=8.53 Hz, 1H), 6.54 (dd,J=8.53, 2.51, 1H), 6.49 (d, J=2.51 Hz, 1H), 5.99 (brs, 1H), 5.86 (s, 1H), 5.18 (brs, 1 H), 4.22 (brs, 1H), 3.85 (s, 3H), 3.82 (s, 3H) 3.51-3.38 (m, 3 H), 3.36-3.28 (m, 4H)
437	,cT H.N^	N-(trans-3aminocyclobuty 1)-2-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yl]acetamide	391.2	1HNMR (400 MHz, METHANOL-d4) δ ppm 7.13 (d, J=8.53 Hz, 1H), 6.67 (d, J=2.01 Hz, 1H), 6.59 (dd, J= 8.53, 2.01 Hz, 1H), 5.78 (s, 1H), 5.68-5.43 (brs, 1H), 4.38-4.27 (m, 1H), 4.27-4.13 (brm, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3,83-3.73 (m, 1H), 2.50-2.33 (m, 3H), 2.32-2.22 (m, 1H).
436		N-(azetidin-3yl)-2-[6-(2,4rjdimethoxyphen • yl)-4-oxo-2thioxo-3,4dihydropyrimïdi n-1(2H)yl]acetamide	377.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 8,71 (d, J=6.02 Hz, 1H), 7.15 (d, J=8.53 Hz, 1H), 6.69-6.65 (m, 1H), 6.60 (dd, J=8.53, 2.01 Hz, 1H), 5.80 (s, 1H), 5.54 (brs, 1H), 4.59-4.48 (m, 1 H), 4.27-4.15 (m, 3H), 4.133.98 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H).

179

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
439		N-[(1S,2S)-2aminocyclobuty l]-2-[6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidî n-1(2H)yl]acetamide	391.1	0.903 min Xtimate C18 2.1x30mm 3um Mobile phase: from 0% MeCN in water (0.0685% TFA in water) to 60% MeCN in water (0.0685% TFA in water)
440	X X	N-{2-[6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrîmidi n-1(2H)yl]ethyl}-Nmethylglycinam ide	378.9	1H NMR (400 MHz, DMSOd6) δ ppm 12.90 (s, 0.33H) ,12.75(3, 0.66H), 8.02 (br s, 3H), 7.33 (d, J=8.53 Hz, 0,33H),7.30 (d, J=8.53 Hz, 0.66H), 6.72-6.66 (m, 2H), 5.83 (s, 0.33H),5.73 (s, 0.66H), 4.66-4.44 (br m, 1H), 3.86-3.81 (m, 6H), 3.79-3.64 (m, 3H),3.62-3.51 (m, 1H), 2.62 (s, 2H), 2.40 (s, 1H)
441	AB8 NH,	N-[(1R,2R)-2aminocyclobuty l]-2-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yllacetamide	391.2	0.897 min Xtimate C18, 2.1x30mm 3um Mobile phase: from 0% MeCN (0.1% TFA) in water (0.1% TFA) to 60% MeCN (0.1% TFA) in water (0.1% TFA)
442	X NU,	N-(3aminopropyl)2-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yl]acetamide	379,1	1H NMR (400 MHz, METHANOL-d4) δ ppm 8.25 (t, 0.5H), 7.17 (d,J=8.53 Hz, 1 H), 6.66 (d, J=2.01 Hz, 1 H), 6.61 (dd,J=8.53, 2.01 Hz, 1H), 5.80 (s, 1H), 5.36 (brs, 1 H), 4.19-4.35 (m, 1H), 3.89 (s, 3H),3.87 (s, 3H), 3.213.05 (m, 2H), 2.98-2.90 (m, 2H), 1.85-1.75 (m, 2H).
443	X”	N-(3-amino2,2difluoropropyl)î 2-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	437.1	0.888 min Xtimate C18 2.1x30mm 3 um Mobile phase: from 0% MeCN in water (0.1% TFA in water) to 60% MeCN in water (0.1% TFA in water)

180

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
444	A NH,	N-(2aminoethyl)-3[6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yl]propanamide	379.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 7.23 (d, J=8.53 Hz, 1H), 6.68 (d, J=2.01 Hz, 1H), 6,65 (dd, J= 8.53, 2.01 Hz, 1H), 5.75 (s, 1 H), 4.81-4.70 (brs, 1H), 4.07-3.95 (brm, 1H), 3.88 (s, 3H), 3.87 (s, 1H), 3.93-3.32 (m, 2H), 3.01-2.95 (m, 2H), 2.70-2.48 (m, 2H), 1.40-1.35 (m, 2H).
445	JM H y	N-{2- * [(cyclopropylm ethyl)amino]eth y|}-2-[6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljacetamide	419.1	1H NMR (400 MHz, METHANOL-d4) δ ppm 8.428.35 (m, 1H), 7.52-7.45 (m, 0.5 H), 7.30-7.33 (m, 0.5H), 7.18 (d, J=8.53 Hz, 1 H), 6.69-6.66 (m, 1H), 6.64-6.60 (m, 1H), 5.82 (s, 1H), 5.49 (s, 1H), 5.44-5.28 (brs, 1H), 4.35-4.22 (brm, 1H), 3.88 (s, 3H), 3.85 (s, 1H), 3.54-3.42 (m, 1H), 3.15-2.99 (m, 2H), 2.95-2.86 (m, 2H), 1.12-1.01 (m, 1H), 0.73-0.66 (m, 2H), 0.43-0.37 (m, 2H).
446	A	Ncarbamimidoyl3-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljpropanamide	377.9	1H NMR (400 MHz, DMSOd6) δ ppm 12.81 (s, 1H), 11.82 (brs, 1H) 8.51-7.95 (br m, 4H) 7.27 (d, J=8.53 Hz. 1H) 6.69 (d, J=2.01 Hz, 1H) 6.63 (dd, J=8.53, 2.01 Hz, 1H) 5.76 (d, J=2.01 Hz, 1H) 4.57-4.41 (brm, 1H) 4.033.90 (brm ,1H) 3.86-3.78 (m, 6H) 2.82-2.71 (m, 2H).

The following Examples of Table 11 were prepared from the corresponding thiouracil amines as described above for the Préparations in the IV. Guanidine Route section and by employing the methods described in the I. Beta Keto Ester Route Section as well as 5 standard methods and techniques known to those skilled in the art.

181

Table 11. Examples from Guanidine Route

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
447	y V-	1-cyano-3-{3[6-(5-fluoro-2methoxyphenyl )-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)yljpropyljguani dîne	377.2	1H NMR (400 MHz, DMSOd6)ôppm 12.78 (s, 1H), 7.41-7.34 (m, 2H), 7.16 (dd, J=9.03,4.02 Hz, 1H), 6.946.31 (brs, 3H), 5.85 (s, 1H), 4.26 (brs, 1H), 3.82 (s, 3H), 3.72-3.58 (brm, 1H), 2.912.75 (m, 2H), 1.77-1.66 (br m, 1H), 1.61-1.46 (brm, 1H).
448		1-(2-(6-(5rt chloro-2-(2hydroxyethoxy) phenyl]-4-oxo2-thioxo-3,4dihydropyrimidi n-1(2H)-yl}ethyl )guanidine	383.9	1.31 min Atlantis dC18 5um 4.6x50mm, 95%H2O/5% MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% formic acid). Flow rate: 2 mL/min.
449	y „x	1-(3-(6-(5chloro-2-meth oxyphenyl)-4oxo-2-thioxo3,4-dihydropyr imidin-1 (2H)yl]propyl}-2ethylguanidine	395.9	1.62 min Atlantis dC18 5um 4.6x50mm, 95%H2O/5% MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% trifluoroacetic acid). Flow rate: 2 mL/min.
450		N-{3-(6-(5chloro-2-meth oxyphenyl)-4oxo-2-thioxo3,4-dihydropyr imidin-1 (2H)yl]propyl}pyrroli dine-1-carbox imidamide	422.0	2.02 min Atlantis dC18 5um 4.6x50mm, 95%H2O/5% MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5%H2O/95%MeCN to 5.0min. (0.05% trifluoroacetic acid). Flow rate: 2 mL/min.
451	y hfAnh	1-(3-(6-(5chloro-2-meth oxyphenyl)-4oxo-2-thioxo3,4-dihydropyr imidin-1 (2H)yl]propyl}-3(2,2-difluoro propyl) guanidine	446.2	1H NMR (500 MHz, METHANOL-d4) δ ppm 7.58 (m, 2H), 7.43 (m, 2H), 7.31 (brs, 1H), 7.20 (d, J = 8.8 Hz, 1H), 5.84 (s, 2H), 4.56 (brs, 1H), 3.92 (s, 3H), 3.81 (brs, 1H), 3.62 (td, J = 14.0, 6.4 Hz, 2H), 3.15 (q, J = 6.8 Hz, 2H), 1.95-2.03 (m, 1H), 1.75-1.85 (m, 1H), 1.67 (t, J = 18.2 Hz, 3H).

182

Example #	Structure	Compound Name	Obs Mass	1H NMR Spectral Data or HPLC Rétention Time and Conditions
452	A Η/γΐΗ	carbamimidoyl3-{2-[6-(2,4? dimethoxyphen yl)-4-oxo-2thioxo-3,4- dihydropyrimidi n-1(2H)yljethyljurea	393.1	1.002 min Xtimate C18 2.1x30mm,3um Mobile phase: from 0% MeCN (0.1% TFA) in water (0.1% TFA) to 60% MeCN (0.1% TFA) in water (0.1% TFA)
453	Η,Ν^ΝΗ,	2-(3-(6-(2,4dimethoxyphen yl)-4-oxo-2thioxo-3,4dihydropyrimidi n-1(2H)-yl]-2,2difluoropropyljg uanidine	400.1	1H NMR (400 MHz, DMSOd6) δ ppm 12.96 (s, 1 H), 7.81-7.72 (m, 1 H), 7.59-7.24 (brs, 4H), 7.23-7.16 (m, 2H), 6.70-6.67 (m, 1 H), 6.64 (dd, J=8.53,2.01 Hz, 1H), 5.82 (d, J=1.51 Hz, 1 H), 5.79-5.61 (m, 1 H), 3.89-3.80 (m, 6 H), 3.75-3.62 (m, 2 H)

Ail publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety.

Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the spécifie experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention.

Claims (9)

1. What Is claimed:

   1. A compound having Formula I

   O

   R²

   Formula I or a pharmaceutically acceptable sait or prodrug thereof wherein

   R¹ is a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said R¹ is optionally mono-, di-, or trl-substituted independently with cyano, halo, hydroxyl, amino, (Ci-C4)alkyl, (CrC4)alkoxy, (Ci-C4)alkoxy(C_rC4)alkyl, hydroxy(CîC4)alkoxy, carbamoyl(Ci-C4)alkoxy, amino(C2-C4)alkoxy, cyano(Ci-C4)alkyl, mono-N- or di-N,N-(CrC4)alkylamino, aminocarbonyl, mono-N- or di-N,N(C_rC4)alkylaminocarbonyl, (CrC4)alkylthio, aminosulfonyl, (Ci-C4)alkylsulfinyl, (Ci-C4)alkylsulfonyl, or mono-N- or di-N,N(Ci-C4)alkylamlnosulfonyl, wherein any of the (Ci-C4)alkyl or (CrC4)alkoxy may be optionally mono-, di- or tri-substituted with fluoro; or wherein R¹ is optionally substituted with a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen;

   R² Is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the carbons, other than the connecting carbon,

   a. may be branched b, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur Is optionally mono- or dl-substituted with oxo,

   184

   c. may optionally be mono-, di- or tri-substituted Independently with halo,

   d. may optionally be mono-substituted with hydroxy, and

   e. may optionally be mono-substituted with oxo, and wherein the carbon chaln is optionally mono-substituted with Z;

   wherein Z is a partially saturated, fully saturated orfully unsaturated three to seven membered ring optionally having one to three heteroatoms selected Independently from oxygen, sulfur and nltrogen, or a blcyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nltrogen, sulfur and oxygen;

   wherein said Z is optionally mono-, di- or tri-substituted independently with halo, (Ci-Ce)alkyl, (C_rC₆)alkylcarbonyl, aminothioxo, amlno(CrC_e)alkylcarbonyl, hydroxyl, dlamlnomethylene, carbamoyl or (Ci-Ce)alkoxy and wherein said (Cr C_e)alkyl or (C-i-C_a)alkoxy substituent Is also optionally substituted with one to three halo, and wherein said (Ci-Ce)alkyl or (Cî-Cejalkoxy substituent is also optionally substituted with one to three hydroxy;

   with the proviso that R¹ is not phenyl, and R² is not (CrCe)alkyl.
2. 2. The compound of claim 1 wherein R¹ Is phenyl, naphthyl, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoqulnolinyl, pyrazolyl, imldazolinyl, cyclopentyl, cyclohexyl, pyrrolyl, îndolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; and wherein said R¹ Is mono-, dl-, or tri-substituted independently with cyano, (Ci-C-Oalkyl, (C-i-C^alkoxy, hydroxy(C2-C4)alkoxy, trifluoro(Ci-C₄)alkyl, trifluoro(Ci-C4) alkoxy or halo.
3. 3. The compound of claim 2 wherein R² is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chaln wherein the carbons, other than the connecting carbon,

   a. may be branched

   b. may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur Is optionally mono- or di-substituted with oxo,

   c. may optionally be mono-, di- or tri-substituted independently with halo,

   184

   185

   d. may optionally be mono-substituted with hydroxy, and

   e. may optionally be mono-substituted with oxo; or

   R² is furanyl(Ci-C₄)alkyl, triazolyl(Ci-C₄)alkyl, pyridinyl(Ci-C₄)alkyl, pyrizinyl(C_rC₄)alkyl,

   5 pyridazinyl(Ci-C₄)alkyl, pyrimidinyl(Ci-C₄)alkyl, imidazolyl(CrC₄)alkyl or pyrrolidinyl(C₄C₄)alkyl, said R² rings optionally mono-, di- or tri-substituted Independently with (Cr C₄)alkyl, (Ci-C₄)alkoxy or halo.
4. 4. The compound of claim 3 wherein

   10 R¹ is phenyl, naphthyl, pyridinyl, quinollnyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolînyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothlazolyl, benzo[b]furanyl or thiophenyl; wherein said R¹ Is mono-, di-, or trl-substituted independently with (Ci-C₄)alkyl, (Ci-C₄)alkoxy, hydroxy(C₂C₄)alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and

   15 R² is (C₁-C₄)alkoxy(C₁-C₄)aikyl, carboxy(C₁-C₄)alkyl, mono-or di-hydroxy(C₂-C_e)alkyi, amino(C₂-C₄)alkyl, diamlnomethyleneamino(C₂-C₄)alkyl, mono-N- or dl-N,N(CiC₄)alkylamino(C₂-C₄)alkyl, (Ci-C₄)alkylcarbonyloxy(Ci-C₄)alkyl„ (CiC₄)alkoxycarbonyl(CrC₄)alkyl, carbamoyl(C-i-C₄)alkyl, carbamoylamlno(C₂-C₄)alkyl, mono-N- or dl-N,N(Ci-C₄)alkylcarbamoyl(Ci-C₄)alkyl, aminoiCrC^alkylcarbamoyltCr

   20 C₄)aikyl, (C₄-C₄)alkylcarbonylamino(C₂-C₄)alkyl, amino(C₁-C₄)alkylcarbonylamino(C₂C₄)alkyl, (CrC₄)alkoxycarbonylamino(C₂-C₄)alkyl, (Ci-C₄)alkylsulfonylamino(C₂C₄)alkyl, (Ci-C₄)alkylaminosulfonyl(Ci-C₄)alkyl, amlnosulfonyl(Ci-C₄)alkyl, amino(C3C₄)hydroxyalkyl or (Ci-C₄)alkylthioalkyl(C₁-C₄).

   25 5. The compound of claim 4 wherein

   R¹ is phenyl and said R¹ is mono-, di-, or tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro; and

   R² is diaminomethyleneamino(C₂-C₄)alkyl, carbamoyl(Ci-C₄)alkyl, hydroxy(C₂-C₄)alkyl, amino(C₂-C₄)alkylcarbamoyl(CrC₄)alkyl, (Ci-C^alkylcarbonylamlnotCz-C^alkyl,

   30 amino(Ci-C₄)alkylcarbonylamïno(C₂-C₄)alkyl, amino(C3-C₄)hydroxyalkyi or amlno(C₂C₄)alkyl.

   6. The compound of claim 3 wherein

   R¹ Is phenyl, naphthyl, pyridinyl, quinolinyI, isoquinolinyl, pyrazolyl, pyrimidinyl,

   35 pyridazinyl, pyrazinyl, imidazolînyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl,

   1Θ6 benzo[b]thiophenyl, benzothiazolyl, benzojbjfuranyl or thiophenyl; wherein said R¹ is mono-, di-, or trl-substltuted independently with (CrC₄)alkyl, (C₁-C₄)alkoxy, hydroxy(C₂C₄)alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and

   R² is triazolyl(Ci-C4)alkyl, pyrldinyl(Ci-C4)alkyl, pyrlzinyl(Ci-C4)alkyl, pyridazinyl(Ci5 C4)alkyl, pyrimidlnyl(Ci-C4)alkyl, Imidazolyl(Ci-C4)alkyl or pyrrolidinyl(Ci-C4)alkyl, said R² rings optionaily mono-, di- or tri-substîtuted Independently with (CrC₄)alkyl, (C_r C₄)alkoxy or halo.

   7. The compound of claim 1 wherein R¹ is phenyl and said R¹ Is mono-, dl-, trl-

   10 substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro.

   8. The compound of claim 1 wherein R² is hydroxy(C₂-C₄)alkyl, diamlnomethyleneamlno(C₂-C₄)alkyl, carbamoyl(Ci-C₄)alkyl, amlno(C3-C₄)hydroxyalkyl, amino(C2-C₄)alkylcarbamoyl(Ci-C₄)alkyl, (Ci-C₄)alkylcarbonylamlno(C₂-C₄)alkyl,

   15 amino(Ci-C₄)alkylcarbonylamino(C₂-C₄)alkyl or amino(C₂-C₄)alkyl.

   9. The compound of claim 1 wherein R² Is (Ci-C₄)alkyl mono- or dl-substituted independently with amino, carbamoyl, hydroxyl, (Ci-C₄)alkoxy, amino(CiC₄)alkylcarbonylamino, amino(C2-C₄)alkylcarbamoyl, (Ci-C₄)alkylcarbonylamino or

   20 diamlnomethyleneamlno.

   10. The compound or a pharmaceutically acceptable sait thereof wherein the compound Is

   6-(2_l4-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dlhydropyrlmldln-4(1H)-one;

   25 1-(2-aminoethyl)-6-(2,4-dlmethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one;

   2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimldin-1(2H)-yl]acetamlde;

   2-[6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thloxo-3,4-dlhydropyrimidln-1(2H)yljacetamide;

   1- (2-arninoethyl)-2-thloxo-6-(2,4,5-trimethoxyphenyl)-2,3-dihydropyrimldin-4(1H)-one; 30 1-(3-aminopropyl)-6-(2-methoxy-5-methylphenyl)-2-thioxo-2,3-dlhydropyrimidin-4(1H)- one;

   N-{2-[6-(2,4-dlmethoxyphenyl)-4-oxo-2-thloxo-3,4-dihydropyrimidln-1(2H)yl]ethyl}glyclnamide;

   2- {3-[6-(2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidîn-1(2H)-

   35 yl]propyl)guanidine;

   187

   Λ

   1-[(2S)-3-amino-2-hydroxypropyl]-6-(5-chloro-2-methoxyphenyl)-2-thioxo-2,3dihydropyrimidin-4(1H)-one;

   1-[(2R)-3-amino-2-hydroxypropyl]-6-(5-chloro-2-methoxyphenyl)-2-thloxo-2,3dihyd ropyrimidin-4(1 H)-one;
5. 5 N-(2-aminoethyl)-2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yl]acetamide; or

   1- (2-aminoethyl)-6-[2-(2-hydroxyethoxy)phenyl]-2-thloxo-2,3-dihydropyrimidin-4(1H)-one or a pharmaceutically acceptable sait thereof.

   10 11. The compound

   2- (6-(2,5-dimethoxyphenyl)-4-oxo-2-thloxo-3,4-dihydropyrimidln-1 (2H)-yl)acetamide or a pharmaceutically acceptable sait thereof.

   12. The compound

   15 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)yljacetamide or a pharmaceutically acceptable sait thereof.

   13. The compound having the Formula

   188

   14. The compound having the Formula

   5 15. Use of a compound of claim 1 or a prodrug thereof or a pharmaceutically acceptable sait of said compound or of said prodrug In the manufacture of a pharmaceutical composition for treating cardlovascular conditions In a mammal In need of such treatment.

   10 16. A use as reclted In claim 15 wherein the cardlovascular condition is heart * fallure, congestive heart fallure, peripheral artériel disease, pulmonary hypertension or vasculitis.

   17. A use as reclted In claim 15 wherein the mammal has unstable angina or has 15 experienced myocardlal Infarctlon.

   18. A pharmaceutical composition which comprises a therapeutlcally effective amount of a compound of claim 1 or a prodrug thereof or a pharmaceutically acceptable sait of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or

   20 diluent.

   19. A pharmaceutical combination composition comprising: a therapeutlcally effective amount of a composition comprising:

   a first compound, said first compound being a compound of claim 1, a prodrug

   25 thereof, or a pharmaceutically acceptable sait of said compound or of said prodrug;

   189 a second compound, said second compound being an angiotensin converting enzyme inhibitor, a HMG-CoA reductase inhibitor, a non-steroidal anti-lnflammatory agent, a Factor Xa inhibitor or warfarin; and a pharmaceutical carrier, vehicle ordiluents.

   20. The compound of claim 4 wherein

   R¹ is naphthyl, quinolinyl, isoquinolinyl, indolyl, benzo[b]thlophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl and said R¹ is mono-, di-, or tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro; and

   R² is diaminomethyleneamlnotCî-CxJalkyl, carbamoyl(Ci-C₄)alkyl, hydroxy(C₂-C₄)alkyl, amino(C2~C₄)alkylcarbamoyl(Ci-C₄)alkyl, (Ci-C₄)alkylcarbonylamlno(C₂-C₄)alkyl, amino(C₁-C₄)alkylcarbonylamino(C2-C₄)alkyl, amino(C₃-C₄)hydroxyalkyl or amino(C₂C₄)alkyl.

   21. The compound or a pharmaceutically acceptable sait thereof wherein the compound Is

   2-[6-(2,4-dlmethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrlmidln-1(2H)-yl]acetamlde;

   2-[6-(2-methoxy-5-methylphenyl)-4-oxo-2-thioxo-3,4-dihydropyrlmldln-1(2H)yljacetamide;

   1- [(2R)-2-amlnopropyl]-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dlhydropyrlmidin-4(1H)one;

   2- [6-(3-methoxy-2-naphthyl)-4-oxo-2-thloxo-3,4-dihydropyrlmidln-1(2H)-yl]acetamlde; or 2-(6-(1 H-indo1-4-yl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H)-yl]acetamlde,

   22. The compound or a pharmaceutically acceptable sait thereof wherein the compound is

   2-{6-[2-(2-hydroxyethoxy)-6-methoxyphenyl]-4-oxo-2-thioxo-3,4-dlhydropyrimldin-1(2H)yljacetamide;

   N-(2-amlnQethyl)-2-{6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-4-oxo-2-thioxo-3,4dihydropyrimidln-1(2H)-yl}acetamide;
6. 6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-1-(2-hydroxyethyl)-2-thioxo-2,3dihydropyrimidin-4(1 H)-one;

   6-[5-fluoro-2-(2-hydroxyethoxy)phenyl]-1-(2-hydroxyethyl)-2-thloxo-2,3-dihydropyrimidin4(1H)-one; or

   2-{6-[2-(2-hydroxyethoxy)-4-methoxyphenyl]-4-oxo-2-thioxo-3,4-dihydropyrimldin-1(2H)yljacetamide.

   190

   N-(2-aminoethyl)-2-[6-(2_l4-dimethoxyphenyl)-4-oxo-2-thioxo-3_I4-dihydropyrimldin-1(2H)yljacetamlde or a pharmaceutically acceptable sait thereof.

   24. The compound having the Formula

   23. The compound

   25. A compound having Formula IA

   R®

   Formula IA or a pharmaceutically acceptable sait or prodrug thereof wherein

   R¹ is a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen or a blcyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said R¹ is optionally mono-, di-, or tri-substituted independently wilh cyano, halo, hydroxyl, amino, (C_rC₄)alkyl, (Ci-C₄)alkoxy, (Ci-C₄)alkoxy(C_rC₄)alkyl, hydroxyfCr C₄)alkoxy, carbamoyl(CrC₄)alkoxy, amlno(C2-C₄)alkoxy, cyano(Ci-C₄)alkyl, (Cp C₄)alkylcarbonyloxy(Ci-C₄)alkyl, amino(CrC₄)alkylcarbonyloxy(Ci-C₄)alkyl, (CiC₄)alkylcarbonyloxy(Ci-C₄)alkoxy, amino(C₁-C₄)alkylcarbonyloxy(Ci-C₄)alkoxy, monoN- or dl-N,N-(Ci-C₄)alkylamino, aminocarbonyl, mono-N- or dl-N,N(Cr C₄)alkylaminocarbonyl, (C₁-C₄)alkylthlo, amlnosulfonyl, (CrC₄)alkylsulfinyl, (Ci16813

   191

   C^alkylsulfonyl, or mono-N- or dl-N.NfCrC^alkylamlnosulfonyl, wherein any of the (CiC₄)alkyl or (Ci-C4)alkoxy may be optionally mono-, dl- or trl-substituted with fluoro; or wherein R¹ Is optionally substituted with a flve to six membered aromatic ring optionally having one to three heteroatoms selected independently from nltrogen, sulfur and

   5 oxygen;

   R² is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered stralght carbon chain wherein the carbons, other than the connecting carbon,

   a. may be branched
7. 10 b. may optionally be replaced with one or two heteroatoms selected Independently from oxygen and sulfur and may optionally be replaced with one to four nitrogens, wherein said sulfur Is optionally mono- or dl-substituted with oxo,

   c. may optionally be mono-, dl- or tri-substltuted Independently with halo,

   d. may optionally be mono-substltuted with hydroxy, and -
8. 15 e. may optionally be mono-substltuted with oxo, and wherein the carbon chain Is optionally mono-substltuted with Z; wherein Z Is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected Independently from oxygen, sulfur and nltrogen, or a bicyclic ring consisting of 20 two fused partially saturated, fully saturated or fully unsaturated flve to six membered rings, taken Independently, optionally having one to four heteroatoms selected Independently from nltrogen, sulfur and oxygen;

   wherein said Z Is optionally mono-, dl- or trl-substltuted Independently with amino, halo, (Ci-C_e)alkyl, (CrCe)alkylcarbonyl, amlnothloxo, amlno(Ci25 Ce)alkylcarbonyl, hydroxyl, dlamlnomethylene, carbamoyl or (Ci-C_e)alkoxy and wherein said (Ci-C₀)alkyl or (CrC_e)alkoxy substituent is also optionally substituted with one to three halo, and wherein said (Ci-Ce)alkyl or (C2-Ce)alkoxy substituent Is also optionally substituted with one to three hydroxy;

   with the provlso that R¹ Is not unsubstltuted phenyl, and R² Is not unsubstltuted(Cr 30 C₀)alkyl.

   26. Use of a compound of claim 25 or a prodrug thereof or a pharmaceutically acceptable sait of said compound or of said prodrug in the manufacture of a pharmaceutîcal composition for treating cardlovascular events and conditions In a

   192 mammal ln need of such treatment wherein the cardlovascular condition or event

   Is heart fallure, congestive heart fallure, perlpheral arterlal disease, pulmonary hypertension, vasculltls, a primary or secondary myocardlal Infarctlon, Ischemla,

   Ischemia reperfusion Injury, atrial fibrillation or coronary artery bypass graft surgery.

   27. Use of a compound of clalm 25 or a prodrug thereof or a pharmaceutically acceptable sait of said compound ln said prodrug ln the manufacture of a pharmaceutical composition for treating a condition ln a mammal ln need of such treatment wherein the condition Is dlalysls, delayed graft function, transplant organ rejection or nephropathy caused by contrasting agents.

   28. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of clalm 25 or a prodrug thereof or a pharmaceutically acceptable sait of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehlcle or

   15 diluent.

   29. A'pharmacautical combination composition comprising: a therapeutically effective amount of a composition comprising:

   a first compound, said first compound being a compound of clalm 25, a prodrug
9. 20 thereof, or a pharmaceutically acceptable sait of said compound or of said prodrug;

   a second compound, said second compound being an anglotensln convertira enzyme Inhlbitor, a HMG-CoA reductase inhibltor, a non-steroldal anti-inflammatory agent, a Factor Xa Inhibltor or warfarin; and a pharmaceutical carrier, vehlcle or diluants.