2-thiopyrimidinones as myeloperoxidase inhibitors

DESCRIPTIVE MEMORY 2-THIOPIRIMIDINONES

BACKGROUND OF THE INVENTION

The present invention relates to compounds that are myeloperoxidase inhibitors, to pharmaceutical compositions containing these inhibitors and to the use of these inhibitors for the treatment, for example, of cardiovascular conditions, which include acute coronary syndrome.

Myeloperoxidase (MPO) is an enzyme that contains a heme group, which belongs to the peroxidase superfamily. Examples of animal peroxidases are lactoperoxldasa, thyroid peroxidase, eosinophilic peroxidase and myeloperoxidase. Myeloperoxidase is present in the primary granules of neutrophils and, to a lesser extent, in monocytes. It catalyzes the synthesis of hypochlorous acid from hydrogen peroxide and chloride. The hypochlorous acid formed is a potent oxidant that reacts with various cell substrates, including hemoproteins, porphyrins, thiols, iron and sulfur centers, nucleotides, DNA, unsaturated lipids, amines and amino acids.

In addition, it was discovered that reactions catalyzed by MPO and its products exhibit proatrogenic biological activity during the development of atherosclerosis and cardiovascular diseases. For example, plasma myeloperoxidase content correlates with the appearance of cardiovascular disorders in patients suffering from unstable angina pectoris. Myeloperoxidase has been reported to contribute to the development of atherosclerosis through the oxidation of lipids and proteins in LDL and HDL.

Likewise, it was observed that the oxidants generated by MPO reduce the bioavailability of nitric oxide, an important vasodilator. Consequently, high plasma MPO levels are inversely correlated with the success of therapy to establish the revascularization of clogged arteries. High levels of MPO are also associated with a decreased survival of congestive heart failure. In addition, it was shown that MPO plays a role in plaque destabilization, which results in plaque rupture and myocardial infarction.

Therefore, the MPO is considered to play a role in several processes that lead to cardiovascular diseases, including 1) the decrease in cholesterol traffic and the progression of the atheroma plaque towards an unstable stage,

2) destabilization of the atheroma plaque and rupture of the plaque, 3) the consumption of nitric oxide resulting in decreased endothelial function and flow, and 4) damage to the pathological tissue after Ischemia, that contributes to atrial flbñlaclón and adverse cardiac restructuring; and left ventricular hypertrophy causes congestive heart failure. It is proposed that, as such, the MPO activity inhibitors offer important therapeutic benefits for the prevention and treatment of cardiovascular diseases.

However, while MPO was widely involved in the etiology and progression of cardiovascular diseases, it is still necessary to develop a non-toxic and biologically safe MPO inhibitor. Consequently, it is still necessary to find pharmaceutical agents that have mleloperoxldasa Inhibitory activity and are useful for the treatment, prevention or reduction of the manifestations of the diseases described herein.

SUMMARY OF THE INVENTION

The present invention relates to a compound of Formula I,

OR

<img file="CU20140049A7_D0001.tif" />

R²

Formula I or a pharmaceutically acceptable salt or prodrug thereof, where

R¹ it is an aromatic ring of 5 to 6 members which optionally has 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, or a bicyclic ring consisting of two fused 5 to 6 member rings, partially saturated, fully saturated or fully unsaturated , considered independently, which optionally have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen; and

R¹ it is optionally mono-, di- or t-substituted independently with cyano, halo, hydroxyl, amlno, (Ci-C₄) alqullo, (Ci-C₄) alcox¡, (Ci-C₄) alkoxy (Ci-C₄) alqullo, hldrox¡ (C₂-C₄) alcox¡, carbamoll (Ci-C₄) alcox¡, amlno (C₂-C₄) alkoxy, clano (Ci-C₄) alqullo, mono-N- od¡-N, N- (Ci-C₄) alkylamine, aminocarbonyl, mono-N- or dl-N, N (Ci2

C₄) alqullamlnocarbon¡lo, (Ci-C₄) alqulltlo, aminosulfonyl, (Ci-C₄) alkylsulfine, (CiC₄) alqullsulfon¡lo, or mono-N-od¡-N, N (Ci-C₄) alkylamulfonol, where any of (Ci-C₄) alqullo or (Ci-C₄) alkoxy can be opclonally mono-, di- or trisubstituted with fluoro; or where R¹ it is optionally substituted with a 5- to 6-membered aromatic ring that optionally has 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen;

R² it is a linear chain of 1 to 14 members fully saturated, partially saturated or completely saturated, where the carbons, except for the connecting carbon,

to. they can be branched,

b. they can be optionally replaced with 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, where sulfur is optionally mono- or disubstituted with oxo,

c. they can be, opclonally, mono-, di- or trisubstituted independently with halo,

d. they can be optionally monosubstituted with hydroxy, and

and. they can be, opclonally, monosubstituted with oxo, and wherein the carbon chain is opclonally monosubstituted with Z;

wherein Z is a partially saturated 3 to 7-membered ring, fully saturated or fully unsaturated, which has 1 to 3 hetero atoms independently selected from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two 5 to 6 rings fused, partially saturated, fully saturated or fully saturated members, considered independently, which have opclonally 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

where Z is opclonally mono-, di- or trisubstituted independently with halo, (Ci-C₆) alqullo, (Ci-C₆) alqullcarbon¡lo, amlnotloxo, amlno (CiC₆) alkullcarbonyl, hydroxyl, dlamlomethylene, carbamoyl or (Ci-C₆) alkoxy, where the substituent (Ci-C₆) alqullo or (Ci-C₆) alkoxy is also opclonally substituted with 1 to 3 halo, and wherein the substituent (Ci-C₆) alqullo or (C₂-C₆) alkoxy is also opclonally substituted with 1 to 3 hydroxy;

whenever R¹ don't be phenyl, and R² don't be (Ci-C₆) alqullo.

Even another aspect of the present invention relates to a method for treating cardiovascular conditions in a mammal (which includes humans, men or women) by administration to a mammal that needs the treatment of a therapeutically effective amount of a compound of the Formula I, a prodrug of this or a pharmaceutically acceptable salt of the compound or prodrug.

Compositions comprising a pharmaceutically effective amount of one or more of the compounds described herein and a pharmaceutically acceptable carrier, carrier or diluent are also provided herein.

The invention also relates to combined pharmaceutical compositions comprising a therapeutically effective amount of a composition comprising:

a first compound, wherein this first compound is a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug;

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

The present invention relates to a compound of Formula IA,

OR

<img file="CU20140049A7_D0002.tif" />

R²

Formula IA or a pharmaceutically acceptable salt or prodrug thereof, where

R¹ it is a 5 to 6-membered aromatic ring that optionally has 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, or a bicyclic ring consisting of two fused, partially saturated, fully saturated or fully saturated 5 to 6-membered rings. unsaturated, considered independently, which optionally have 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen; and

R¹ it is optionally mono-, di- or trisubstituted independently with cyano, halo, hydroxyl, amino, (Ci-C₄) rent it, (Ci-C₄) alcox¡, (Ci-C₄) alkoxy¡ (Ci-C₄) rent it, hydrox (C₂-C₄) alcox¡, carbamo¡l (Ci-C₄) alkoxy, amine (C₂-C₄) alkoxy, cano (Ci-C₄) rent it, (Ci-C₄) alcarboncarlox (Ci-C₄) Rent it, am (Ci-C₄) alcarboncarlox (Ci-C₄) rent it, (CiC₄) alkylcarbonyloxy (Ci-C₄) alkoxy, amino (Ci-C₄) alkylcarbonyloxy (Ci-C₄) alkoxy, mono-No d¡-N, N- (Ci-C₄) alkylamine, aminocarbonyl, mono-N- or dl-N, N (CiC₄) alkylaminocarbon, (Ci-C₄) alqulltlo, aminosulfonyl, (Ci-C₄) alqullsulf¡n¡lo, (CiC₄) alkylsulfonyl, or mono-N- or di-N, N (Ci-C₄) alkylaminosulfonyl, wherein any of (C₁-C₄) rent or (C₁-C₄) alkoxy can be optionally mono-, di- or trisubstituted with fluorine; or where F¡¹ it is optionally substituted with an aromatic ring of 5 to 6 members which optionally has 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen;

F² it is a linear chain of 1 to 14 members fully saturated, partially unsaturated or totally unsaturated, where the carbons, except for the connecting carbon,

to. they can be branched,

b. they can be optionally replaced with 1 or 2 heteroatoms independently selected from oxygen and sulfur, and optionally, they can be replaced with 1 to 4 nitrogen, where sulfur is opclonally mono- or dlsustltuldo with oxo,

c. they can be, opclonally, mono-, di- or trlsustltuldos independently with halo,

d. they can be, optionally, monosubstituted with hydroxy, and

and. they can be, opclonally, monosustltuldos with oxo, and where the carbon chain is opclonally monosustltulda with Z;

wherein Z is a partially saturated 3 to 7 member ring, fully saturated or fully saturated, which has 1 to 3 heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two 5 to 5 rings 6 members fused, partially saturated, fully saturated or fully saturated, considered independently, which have opclonally 1 to 4 heteroatoms independently selected from nitrogen, sulfur and oxygen;

where Z is opclonally mono-, di- or trisubstituted independently with amlno, halo, (Ci-C₆) alqullo, (Ci-C₆) alkylcarbonyl, amlnotloxo, amlno (CiC₆) alkullcarbonyl, hydroxyl, dlamlomethylene, carbamoyl or (Ci-C₆) alcox¡, where the substituent (Ci-C₆) alqullo or (Ci-C₆) alkoxy is also opclonally substituted with 1 to 3 halo, and wherein the substituent (Ci-C₆) rent or (C₂-C₆) alkoxy is also optionally substituted with 1 to 3 hydroxy;

whenever R¹ other than unsubstituted phenyl, and R² don't be (Ci-C₆) unsubstituted alkyl.

The present invention also relates to a method for treating cardiovascular conditions and events, which comprises administering to a mammal in need of treatment a therapeutically effective amount of a compound of Formula IA, a prodrug thereof or a salt acceptable from the point of pharmaceutical view of the compound or prodrug, where the condition or cardiovascular event is congestive heart failure, peripheral arterial disease, pulmonary hypertension, vasculitis, Primary or secondary myocardial infarction, ischemia, ischemia-revascularization injury, atrial fibrillation or coronary bypass graft surgery (CABG).

The present invention also relates to a method of treating a condition, which comprises administering to a mammal in need of treatment a therapeutically effective amount of a compound of Formula IA, a prodrug thereof or a pharmaceutically acceptable salt. of the compound or prodrug, where the condition is diabetes, kidney failure, dialysis, graft function delay, transplant organ rejection or nephropathy caused by contrast agents.

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

The invention also relates to combined pharmaceutical compositions comprising a therapeutically effective amount of a composition comprising:

a first compound, wherein this first compound is a compound of Formula IA, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug;

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

All patents or patent applications referred to herein are incorporated by reference herein.

Other features and advantages of the present invention will be apparent after analyzing this specification and the appended claims describing the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction pattern showing a crystalline form of Example 1 (vertical axis: intensity (CPS); horizontal axis: two zetas (degrees)).

Figure 2 is a characteristic powder X-ray diffraction pattern showing a crystalline form of Example 2 (vertical axis: intensity (CPS); horizontal axis: two zetas (degrees)).

DETAILED DESCRIPTION OF THE INVENTION

A preferred group of compounds, called Group A, contains the compounds having Formula I, as shown above, wherein F¡¹ it is phenyl, naphthyl, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrazolyl, imidazolinyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo [b] thiophenyl, benzothiazolyl, benzo [b] furanyl or thiophenyl; and where F¡¹ it is independently mono-, di- or trisubstituted with cyano, (C₁-C₄) alkyl, (C₁-C₄) alkoxy, hydroxy (C₂-C₄) alkoxy, trifluoro (C₁-C₄) alkyl, trifluoro (C₁-C₄) alkoxy or halo.

A preferred group of compounds of Group A of compounds, called Group B, contains the compounds in which F¡² it is a linear chain of 1 to 14 members fully saturated, partially unsaturated or totally unsaturated, where the carbons, except for the connecting carbon,

to. they can be branched,

b. they can optionally be replaced with 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, where sulfur is optionally mono- or disubstituted with oxo,

c. they can be optionally mono-, di- or trisubstituted independently with halo,

d. they can be optionally monosubstituted with hydroxy, and

and. they can be optionally monosubstituted with oxo, or

F² it is furanyl (Ci-C4) alkyl, triazolyl (Ci-C4) alkyl, pyrridyl (C1-C4) alkyl, pyrrhizin (Ci-C4) alkyl, p Ridaz¡n¡l (Ci-C4) alkylo, pırim¡d¡n¡l (Ci-C4) alkylo, midazol¡l (CiC4) alkyl or pyrroled (n) Ci-C4) rent, rings F¡² are optionally mono-, di- or trisubstituted independently with (Ci-C4) alkyl, (Ci-C₄) alkoxy or halo.

A preferred group of compounds of Group B of compounds, called Group C, contains the compounds in which F¡¹ it is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo [b] thiophenyl, benzothiazolyl, benzo [b] furanyl; where R¹ it is mono-, di- or trisubstituted independently with (Ci-C₄) rent it, (Ci-C₄) alcox¡, h¡drox¡ (C₂-C₄) alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and

R² is (Ci-C₄) alkoxy (Ci-C₄) alkyl, carboxy (Ci-C₄) alkyl, mono- od¡-h¡drox¡ (C₂C₆) alkyl, amino (C₂-C₄) alkyl, diamomethaneide (C₂-C₄) alkyl, mono-N-od¡N, N (Ci-C₄) alkylamino (C₂-C₄) alkyl, (Ci-C₄) alkylcarbonyloxy (Ci-C₄) alkyl, (CiC₄) alkoxycarbon¡l (C₁-C₄) rent, carbamoyl (C₁-C₄) alkyl, carbamoylamino (C₂-C₄) alkyl, mono-N- or di-N, N (C₁-C₄) alkylcarbamole (C₁-C₄) alkyl, amino (C₂-C₄) alkylcarbamole (C₁C₄) alkyl, (C₁-C₄) alkylcarbonylamino (C₂-C₄) alkyl, amine (C_r

C₄) alkylcarbon.lamino (C₂-C₄) rent it, (Ci-C₄) alkoxycarbonylamine (C₂-C₄) rent it, (CiC₄) alkylsulfonylamine (C₂-C₄) rent it, (Ci-C₄) alkylaminosulfon¡l (Ci-C₄) alkyl, aminosulfonyl (C₁-C₄) alkyl, amino (C₃-C₄) hydroxyalkyl or (C₁-C₄) alkylthioalkyl (C₁-C₄).

A preferred group of compounds of Group C of compounds, called Group D, contains the compounds in which R¹ it's phenyl and R¹ it is mono-, di- or trisubstituted independently with hydroxyethoxy, methyl, methoxy, fluorine or chlorine; and

R² It is diamometry! (C₂-C₄) alkyl, carbamoyl (Ci-C₄) alkyl, hydroxy (C₂C₄) alkyl, amino (C₂-C₄) alkylcarbamole (Ci-C₄) rent it, (Ci-C₄) alkylcarbonylamino (C₂C₄) alkyl, amino (C₁-C₄) alkylcarbonylamine (C₂-C₄) alkyl, amino (C₃-C₄) hydroxyalkyl or amino (C₂-C₄)I rent.

A preferred group of compounds of Group B of compounds, called Group E, contains the compounds in which R¹ it is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo [b] tofophenol, benzothiazolyl, benzo [b] furan! or thiophenyl; where R¹ it is mono-, di- or trisubstituted independently with (Ci-C₄) rent it, (Ci-C₄) alcox¡, h¡drox¡ (C₂-C₄) alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and

R² it's triazole (Ci-C4) alkyl, p¡r¡d¡n¡l (Ci-C4) alkylo, p¡r¡z¡n¡l (Ci-C4) alkylo , p¡r¡daz¡n¡l (Ci-C4) rent, p¡r¡m¡d¡n¡l (Ci-C4) rent it, m¡dazol¡l (Ci-C4) alkyl oprolrol (Ci-C4) alkyl, R rings² are optionally mono-, di- or trisubstituted independently with (Ci-C4) alkyl, (Ci-C₄) alkoxy or halo.

A preferred group of compounds, called Group F, contains the compounds having Formula I, as shown above, wherein R¹ it's phenyl and R¹ it is mono-, di- or trisubstituted independently with hydroxyethoxy, methyl, methoxy, fluorine or chlorine.

A preferred group of compounds, called Group G, contains the compounds having Formula I, as shown above, wherein R² is hydrox¡ (C2-C₄) Rent it, day-time (C2-C)₄) rent, carbamoyl (Ci-C₄) alkyl, amino (C₃-C₄) hydroxyalkyl, amino (C2-C₄) alkylcarbamoyl (Ci-C₄) alkyl, (CiC₄) Alkylcarbon (C2-C)₄) alkyl, amino (Ci-C4) alkylcarbonyl (C2-C)₄) alkyl or amino (C2-C₄) rent it.

A preferred group of compounds, called Group H, contains the compounds having Formula I, as shown above, wherein R² is (C₁-C₄) mono- or disubstituted alkyl independently with amino, carbamoyl, hydroxyl, (C₁-C₄) alkoxy, amino (C₁-C₄) alkylcarbonylamino, amino (C₂C₄) alkylcarbamoyl, (Ci-C₄) alkylcarbonylamine or diaminomethyleneamine.

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

6- (2,4-dimethoxyphenyl) -1 - (2-h¡drox¡et¡l) -2-t¡oxo-2,3-d¡h¡dropir¡m¡d¡n-4 ( 1 H) -one;

1- (2-am¡noet¡l) -6- (2,4-d¡metox¡fen¡l) -2-t¡oxo-2,3-d¡h¡drop¡rim¡d¡n- 4 (1 H) -one;

2- [6- (2,5-dimethoxyphenyl) -4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) -yl] acetamide; 2- [6- (5-Chloro-2-methoxfen] -4-oxo-2-txox-3,4-d¡h¡drop¡rim¡d¡n-1 (2H) - il] acetamide; 1- (2-am¡noet¡l) -2-t¡oxo-6- (2,4,5-tr¡metoxifen¡l) -2,3-d¡h¡drop¡r¡m¡d¡ n-4 (1 H) -one;

1- (3-am¡noprop¡l) -6- (2-metox¡-5-met¡lfen¡l) -2-t¡oxo-2,3-d¡h¡drop¡rim¡d¡n -4 (1 H) -one; N- {2- [6- (2,4-d¡metox¡fen¡l) -4-oxo-2-tóoxo-3,4-d¡h¡drop¡rim¡d¡n-1 ( 2H) -yl] et¡l} gl¡cinam¡da;

2- {3- [6- (2-Methox¡fen¡l) -4-oxo-2-txox-3,4-d¡h¡drop¡r¡m¡din-1 (2H) -¡ l] prop¡l} guan¡d¡na; 1 - [(2S) -3-am¡no-2-h¡drox¡prop¡l] -6- (5-chloro-2-metox¡fen¡l) -2-tóoxo-2,3- d¡h¡drop¡rim¡d¡n4 (1H) -ona;

1 - [(2R) -3-am¡no-2-h¡drox¡prop¡l] -6- (5-chloro-2-metox¡fen¡l) -2-tóoxo-2,3- d¡h¡drop¡rim¡d¡n4 (1H) -ona;

N- (2-am¡noet¡l) -2- [6- (2,4-d¡metox¡fen¡l) -4-oxo-2-tóoxo-3,4-d¡h¡drop Rim¡d¡n-1 (2H) il] acetamide; or

1- (2-am¡noet¡l) -6- [2- (2-h¡drox¡etox¡) fen¡l] -2-t¡oxo-2,3-d¡h¡dropir¡m¡ dn-4 (1 H) -one or a salt thereof pharmaceutically acceptable.

A compound of special preference is

2- (6- (2,5-d¡metox¡fen¡l) -4-oxo-2-t¡oxo-3,4-d¡h¡drop¡r¡m¡din-1 (2H) - L) acetamide or a salt thereof pharmaceutically acceptable.

In particular, it is preferred that the compound be or

<img file="CU20140049A7_D0003.tif" />

Another compound of special preference is

2- (6- (5-Chloro-2-methoxfen) -4-oxo-2-thoxo-3,4-d¡h¡drop¡r¡m¡d¡n-1 (2H ) -L) acetamido or a pharmaceutically acceptable salt thereof.

In particular, it is preferred that the compound be

<img file="CU20140049A7_D0004.tif" />

A preferred group of compounds of Group C of compounds, called Group J, contains the compounds in which

F¹ it is naphthyl, quinolinyl, isoquinolinyl, indolyl, benzo [b] thiophene, benzothiazolyl, benzo [b] furan or thiophenyl and F¡¹ it is mono-, di- or t-substituted independently with hydroxyethoxy, methyl, methoxy, fluorine or chlorine; and

F² it's d¡am¡nomet¡lenam¡no (C₂-C₄) rent it, carbamoil (C₁-C₄) rent it, hldroxl (C₂C₄) alqullo, amÃno (C₂-C₄) alkylcarbamole (C₁-C₄) rent it, (C₁-C₄) alkylcarbon (C)₂C₄) alqullo, amÃno (Ci-C₄) alkylcarbon (C)₂-C₄) Rent it, am (C)₃-C₄) hydroxyl or alkaline (C₂-C₄) rent it.

A preferred group of compounds, called Group K, contains the compounds wherein the compound is:

2- [6- (2,4-d¡metox¡fen¡l) -4-oxo-2-t¡oxo-3,4-d¡h¡drop¡r¡m¡d¡n-1 (2H ) -L] acetamide; 2- [6- (2-Methoxy-5-methylphenyl) -4-oxo-2-thioxo-3,4-dih, dropirm-din-1 (2H) -l] acetamide;

1- [(2F¡) -2-am¡noprop¡l] -6- (2,4-d¡metox¡fen¡l) -2-t¡oxo-2,3-d¡h¡drop¡r M¡d¡n-4 (1 H) -one;

2- [6- (3-Methox¡-2-naft¡l) -4-oxo-2-t¡oxo-3,4-d¡h¡drop¡r¡m¡d¡n-1 (2H) -L] acetam¡da; or

2- [6- (1 H-¡ndol-4-¡l) -4-oxo-2-t¡oxo-3,4-d¡h¡drop¡r¡m¡d¡n-1 (2H) -L] acetamide or a salt thereof pharmaceutically acceptable.

A preferred group of compounds, called Group L, contains the compounds in which the compound is:

2- {6- [2- (2-hydroxyethoxy) -5-methoxyphenyl] -4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) iljacetamide;

N- (2-am¡noet¡l) -2- {6- [2- (2-h¡drox¡etox¡) -4-metox¡fen¡l] -4-oxo-2-thioxo-3, 4-d¡h¡drop¡r¡m¡d¡n1 (2H) -il} acetamide;

6- [2- (2-h¡drox¡etox¡) -4-metox¡fen¡l] -1- (2-h¡droxiet¡l) -2-tóoxo-2,3-d¡h Drop¡r¡m¡d¡n-4 (1 H) one;

6- [5-Fluoro-2- (2-hydroxyethoxy) phenyl] -1- (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) one; or

2- {6- [2- (2-h¡drox¡etox¡) -4-metox¡fen¡l] -4-oxo-2-thioxo-3,4-d¡h¡drop¡r¡m¡ dn-1 (2H) iljacetamide or a salt thereof pharmaceutically acceptable.

A compound of particular preference is N- (2-aminoethyl) -2- [6- (2,4d¡methox¡fen¡l) -4-oxo-2-thioxo-3,4-d¡h¡drop¡r M¡d¡n-1 (2H) -l] acetamide or a pharmaceutically acceptable salt thereof.

In particular, it is preferred that the compound be

<img file="CU20140049A7_D0005.tif" />

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

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

Pharmaceutically acceptable salts of the compounds of Formulas I or IA include acid and basic addition salts thereof. Suitable acid addition salts are formed of acids that form non-toxic salts. Examples include salts of acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsilate, citrate, cyclamate, edisilate, silate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hibenzate / chloride, hydrobromide / bromide, iodide / iodide, sethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, acid phosphate / phosphate / diacid phosphate, pyroglutamate, sucrate, stearate, succinate, tanate, tartrate, tosylate, trifluoroacetate and xinophoate.

Suitable basic salts are formed from bases that form non-toxic salts. Examples include salts of aluminum, arginine, calcium, choline, diethylamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, trimetamine and zinc. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

The compounds of the invention may exist in non-solvated and solvated form. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. Solvent molecules are those commonly used in the pharmaceutical field, which are known to be harmless to the recipient, for example, water, ethanol and the like. Other solvents can be used as intermediary solvates for the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S) -propylene glycol, (R) -prop¡lengl¡ cabbage, 1,4-butyldiol and the like. The term hydrate is used when the solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates, where the crystallization solvent can be isotopically substituted, for example, D₂O d₆-acetone, d₆DMSO The term "hydrate" refers to the complex where the solvent molecule is water. Preferably, solvates and / or hydrates exist in crystalline form.

The invention includes complexes, such as clathrates, drug-host inclusion complexes, wherein, unlike the aforementioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes that contain two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For a review of these complexes, see J Pharm Sci, 64 (8), 1269-1288 from Haleblian (August 1975).

Compounds of the invention include compounds of Formulas I or IA, as defined above, polymorphs and isomers thereof (which include optical, geometric and tautomeric isomers), as defined below, and isotopically labeled compounds of Formulas I or IA.

The compounds of the present invention can be administered as prodrugs. Therefore, certain derivatives of the compounds of Formulas I or IA, which may have little or no pharmacological activity, can be converted, when administered in the body, into compounds of Formulas I or IA that have the desired activity , for example, by hydrolytic cleavage. These derivatives are called prodrugs. [More information on the use of prodrugs can be obtained in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposlum Serles (T Hlguchl and W Stella) and' Bloreverslble Carrlers in Drug Design ', Pergamon Press, 1987 ( ed. Roche B Roche, American Pharmaceutical Association).

Prodrugs can be produced, for example, by replacing the appropriate functionalities present in the compounds of the Formulas I or IA with certain portions known by the people of the medium level trade as proportions as described, for example, in Design of Prodrugs by H Bundgaard (Elsevler, 1985).

Some examples of these prodrugs include:

(I) wherein the compound of Formulas I or IA contains a carboxylic acid (-COOH) functionality, an ester thereof, for example, the replacement of hydrogen by (Ci-C₈) alqullo;

(¡I) wherein the compound of Formulas I or IA contains an alcohol functionality (-OH), an ether thereof, for example, the replacement of hydrogen by (Cr C₆) alkanoyloxymethyl; and (¡II) wherein the compound of Formulas I or IA contains a primary or secondary amino functionality (-NH₂ or -NHR, where R # H), an amine thereof, for example, the replacement of one or both hydrogens by (CiCio) alkanoyl.

In addition, certain compounds of Formulas I or IA may act as prodrugs of other compounds of Formulas I or IA.

Compounds of Formulas I or IA containing an asymmetric carbon atom may exist as two or more stereoisomers. When a compound of Formulas I or IA contains an alkenyl or alkenylene group, or a cycloalkyl group, cis / trans (or Z / E) geometric isomers are possible. When the compound contains, for example, a keto or oxlma group or an aromatic portion, tautomeric isomerism ('tautomerism') occurs. Therefore, a single compound can exhibit more than one type of Isomerism. For example, then tautomers of the compounds of Formulas I or IA are illustrated.

Thiouracil tautomers x, ** yes

T Η Ά R-í

H H*

OH

X

S * '%' R &lt;

Most dominant tautomer, Χχ.Α

S '· W Έ · ι s

Another 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 geometric isomers or

OR

<td>AA MN 'A</td><td>K H H</td><td>i HN j</td>

<td>'.'X aL Á¹'¹'¹'</td><td>8 NR</td><td>*,&gt; SN</td>

<td>For H H</td><td></td><td>TO⁵</td>

<td></td><td>&gt; Ab</td><td>'H „NH®</td>

H

H

HN * 'A .A., A,

OR

ΗνΑ .A.

S-NR,

X or H

v .. ..,

H RH® H

The claimed compounds of the present invention include all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula (I), which include compounds exhibiting more than one type of isomerism, and mixtures of one or more of these. Also included are acid or basic addition salts, wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

The present invention includes all compounds of Formula (I) labeled in a pharmaceutically acceptable Isotopic manner, 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 atomic mass number that is usually found in nature.

Examples of Isotopes suitable for Inclusion in the compounds of the invention include hydrogen isotopes, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶IC, fluorine, such as ¹⁸F, of iodine, such as ¹²³you ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, of oxygen, such as ¹⁵OR, ¹⁷O and ¹⁸Or, phosphorus, such as ³²P, and sulfur, such as ³⁵S.

Certain compounds of Formula (I) labeled in an Isotopic manner, for example, those incorporating a radioactive Isotope, are useful in studies of tissue distribution in substrates and / or drugs. Tritium radioactive isotopes, that is,³H, and carbon-14, that is, ¹⁴C, are particularly useful for this purpose due to its simple incorporation and detection means.

Substitution with heavier isotopes, such as deuterium, that is, ²H, can provide certain therapeutic advantages that are the result of greater metabolic stability, for example, longer half-life in vivo or less dosage requirements and, therefore, may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, they may be useful in positron emission tomography (PET) studies to evaluate substrate receptor occupancy.

In general, compounds of the Formula (I) labeled in an isotopic manner can be prepared by conventional techniques known to the people of the medium level or by processes analogous to those described in the Examples and Preparations attached by using suitable labeled reagents Isotopically instead of the unlabeled reagents that were previously used. References herein to be treated, treated, "treatment" and the like include curative, palliative and prophylactic treatment.

As used herein, the terms "Inert to reaction" and "Inert solvent" refer to a solvent or a mixture of solvents that does not interfere with the ice materials, reagents, intermediates or products in a manner that impairs the performance of the desired product

The pharmaceutically acceptable expression means that the carrier, vehicle, diluent and / or salt must be compatible with the other Ingredients of the formulation and not harmful to the recipient.

As used herein, the term "pharmaceutically effective amount" refers to an amount of the compound of Formulas I or IA (or a combination agent or a compound of Formulas I or IA combined with a combination agent) sufficient to treat, prevent the onset, delay or decrease symptoms and physiological manifestations of the indications described herein.

The expression "room temperature" means a temperature of 18 to 25 ^andC; "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, mass spectroscopy or mass spectrometry; "MNR" refers to nuclear magnetic resonance spectrometry; "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 should be borne in mind that if a carbocyclic or heterocyclic portion can be linked or otherwise bound to a particular substrate by various ring atoms without indicating a specific binding point, then all possible points are provided, either by an atom of carbon 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 on. In general, the compounds of the present invention can be obtained by processes that include processes analogous to those known in the field of chemistry, in particular, depending on the description herein.

As used herein, the expression mono-N- or di-N, N- (Ci-C_x) alkyl ... refers to the (Ci-C) alkyl portion_x) alkyl considered independently when it is di-N, N- (Ci-C_x) alkyl ... (x refers to integers).

Halo means chlorine, bromine, iodine or fluorine.

Alkyl means saturated straight chain hydrocarbon or branched chain saturated hydrocarbon. Examples of alkyl groups (if the indicated length is considered to cover the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3 -methyl butyl, hexyl, sohexyl, heptyl and octyl.

Alkoxy means saturated straight chain alkyl or saturated branched chain alkyl linked by an oxy. Examples of alkoxy groups (if the indicated length is considered to cover the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxl, sohexoxl, heptoxl and octoxl.

The following paragraphs describe sample rings for the generic ring descriptions found herein.

Examples of 5- to 6-membered aromatic rings that optionally have 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur include phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, midazolyl, pyrazolyl, Isoxazolyl, Isothiazolyl, plrldinyl, plrldlazlnllo, pyrimidinyl and pyrazinyl.

Examples of 6-membered rings include 2H-pyranyl, 4H-pyranyl, plrldinyl, piperidinyl, 1,2-dloxlnllo, 1,3-dloxlnllo, 1,4-dloxanllo, morpholinyl, 1,4-dltlanllo, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-trlazlnllo, 1,2,4triazinyl, 1,2,3-triazinyl, 1,3,5-trityanyl, 4H-1,2-oxazinyl, 2H-1,3- oxazinyl, 61-1-1,3oxazlnllo, 6H-1,2-oxazlnllo, 1,4-oxazlnllo, 2H-1,2-oxazlnllo, 4H-1,4-oxazlnllo, 1,2,5oxatlazlnllo, 1,4- oxazlnllo, o-lsoxazlnllo, p-lsoxazlnllo, 1,2,5-oxatlazlnllo, 1,2,6oxatlazlnllo, 1,4,2-oxadlazlnllo and 1,3,5,2-oxadlazlnllo.

Examples of bicyclic rings consisting of two fused 5 or 6-membered rings, partially saturated, fully saturated or fully saturated, considered independently, which have opclonally 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen include Indolizinyl , Indolyl, Isoindolyl, 3H-lndolllo, 1 H-Isolndolllo, ndollnllo, clclopenta (b) plr¡d¡n, plrano (3,4-b) plrrol¡lo, benzofuril, sobenzofurllo, benzo (b) tlenllo, benzo (c) tlenllo, 1 H-Indazolllo, ndoxazlnllo, benzoxazolyl, benzimidazolyl, benztiazolyl, purinyl, 4H-qulnollznlo, quinolinyl, Isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinxalloyl naphinyloyl ¡Ndenllo, solndenllo, naphthyl, tetrallnllo, decallnllo, 2H-1-benzoplranllo, plr¡do (3,4-b) -p¡rld¡n¡lo, plr¡do (3,2-b) -p¡ rld¡n¡lo, plr¡do (4,3-b) -p¡rld¡n¡lo, 2H-1,3-benzoxazlnllo, 2H-1,4-benzoxazlnllo, 1H-2,3benzoxazlnllo, 4H-3 , 1-benzoxazlnllo, 2H-1,2-benzoxazlnllo and 4H-1,4-benzoxazlnllo.

Certain processes for the manufacture of the compounds of the present invention are provided as additional features of the invention and are illustrated by the following reaction schemes. Other processes can be described in the experiments section. Specific synthesis schemes for the preparation of the compounds of Formulas I or IA are indicated below.

It should be mentioned that in the preparation of the compounds of Formulas I or IA it is noted that some of the preparation methods useful for preparing the compounds described herein may require protection of remote functionality (eg, primary amine, secondary amine, carboxyl in the precursors of Formulas I or IA). The need for protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for protection can easily be determined by a person of the medium level trade. The use of these protection / deprotection methods is also within the scope of the people of the middle level trade. For an overview of protective groups and their use, see TW Greene, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, New York, 1991.

For example, certain compounds contain functionalities of primary amines or carboxylic acid that may interfere with reactions at other sites in the molecule, if not protected. Consequently, these functionalities can be protected by a suitable protective group that can be removed at a later stage. Suitable protecting groups for the protection of amine and carboxylic acid include the protecting groups that are commonly used in the synthesis of peptides (such as N-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl for amines, and benzyl or lower alkyl esters for carboxylic acids) which , usually, they do not react chemically under the reaction conditions described and can be removed without the chemical alteration of other functionality in the compound of the Formulas or IA.

OR

O ^ R¹

X

O ^ R¹

XVII

SCHEME I

<img file="CU20140049A7_D0006.tif" />

XXV (HO)₂BR¹

Eto₂c.

OEt

OH

O ^ R¹

XV

XXXV ^X'R¹

XX XXII

RO₂C ^

XXXII

People in the medium-level trade will recognize that there are several methods for preparing thiouracils, which include the condensation of a thiourea with various compounds containing carbonyl, or by reacting an uracil with a thiating agent, such as phosphorus pentasulfide or reagent of Lawesson. For the formation of thiouracils of the present invention, it is useful to consider the construction method in order to improve the desired compounds over the variety of possible isomers in a specific region.

The thiouracil compounds of Formulas I or ΙΑ, where R¹ and R² they are as described above, they can be prepared from the enamine of Formula lll by cyclization reaction. The enamine of Formula lll is cyclized in the corresponding thiouracil of Formulas I or ΙΑ, for example, by reaction with an isothiocyanate, such as benzoyl, carboxyethyl or, preferably, (trimethylsilyljisothiocyanate (TMSNCS). The reaction is carried out under reaction conditions, such as a polar aprotic solvent (for example, methyl tetrahydrofuran, tetrahydrofuran, dioxane, butylnitrile or pure in the isothiocyanate) at a temperature of about 20 Ό to about 150 ° C, in general around 85 ° C (by thermal or microwave heating), from about 3 hours to about 48 hours.

The enamine of Formula lll can be conveniently prepared from the β-ketoester of Formula VI by reaction with an R amine²-NH2 adequate (where R² It is as described above or where reactive functionality in R², such as a primary amine, is in a suitable protected form, such as Oter-butllcarbamate). For example, the β-ketoester of Formula VI is reacted with the R amine²-NH2 in the presence of a weak acid, such as acetic acid in a polar solvent (for example, methanol, ethanol, isopropanol, toluene or pure in the amine) at a temperature of about 20 ° C to about 120 ° C, for about 4 hours to about 72 hours, in general, about 80 ° C for about 12 hours.

As described above, the β-ketoester of Formula VI can be prepared, for example, from a methyl ketone of Formula X, a carboxylic acid of Formula XV, an aryl halide of Formula XX or other precursors known from middle-level office people.

The β-ketoester of Formula VI is prepared from the methyl ketone of Formula X by carboalkoxylation. For example, the methyl ketone of the Formula X is reacted with a dlalqullcarbonate, preferably dlmetyl carbonate, in the presence of an alkoxide base, such as potassium tert-butoxide, in a polar solvent, such as methyl ether or the corresponding alcohol for dlalqullcarbonate, at a temperature of about 15 ° C to about 100 ° C, generally at room temperature, for about 4 hours to about 48 hours, generally 12 hours.

The β-ketoester of Formula VI can also be prepared, for example, from a carboxylic acid. For example, the β-ketoester of Formula VI can be prepared from an activated carboxylic acid. The acid of Formula XV is conveniently converted to a corresponding aclllmldazole XVII by reaction with 1,1'carbonlldllmldazol in a polar solvent, generally tetrahydrofuran, at a temperature of 0 ° C to 100 ° C, preferably at room temperature , for 1 hour to 24 hours, preferably 3 hours. A solution of the resulting aclllmldazole XVII in a polar aprotic solvent, such as tetrahydrofuran, is converted to the corresponding β-ketoester of Formula VI by reaction with a solution of a kind of activated acetate, such as the acetate steroid enolate or, preferably, ethyl magnesium malonate in a polar aprotic solvent, such as tetrahydrofuran, at a temperature of -80 ° C to 100 ° C, preferably at room temperature, for 1 to 48 hours, preferably 12 hours, to prepare the corresponding β-ketoester of Formula VI.

People of the medium level trade will recognize that a variety of other methods can be used to prepare the β-ketoester of an acid.

The people of the medium level trade will recognize that the β-ketoesters of the Formula VI can also be prepared from esters of carboxylic acids of the Formula XV, such as methyl, ethyl, isopropyl or tert-butyl, preferably, the isopropyl ester of the carboxylic acid of Formula XV by a condensation reaction with a kind of activated acetate, such as the enolate of an acetate ester, preferably the isopropyl acetate enolate, in a polar aprotic solvent, such as tetrahydrofuran, dioxane or toluene, preferably tetrahydrofuran, at a temperature of -80 ° C to 40 ° C, preferably at room temperature, for 1 to 24 hours, preferably 12 hours, to prepare the corresponding β-ketoester of Formula VI .

In addition, people of the medium level trade will recognize that there are many methods to convert an aryl halide into a β-ketoester, which include the following example procedures. An aryl halide of the Formula XX (for example, an aryl bromide) is combined by a palladium-mediated coupling with a β-alkoxylachlate of the Formula XXII, such as ethyl 3-ethoxylacrlate, by using a catalyst of palladium, in general bls (trl-ter-butylphosphine) palladium (opclonally with lithium chloride), in the presence of an amine, such as an N, Nd.clclohexllmetllamlna, in an inert atmosphere, such as nitrogen , at a temperature of about 90 ° C to about 140 ° C, generally around 110 ° C, for about 4 hours to about 48 hours, generally 12 hours. The resulting enolether XXV is converted to the corresponding β-ketoester of the corresponding Formula VI by treatment with an acid, such as aqueous HCI, in a polar solvent (for example, dichloromethane, methanol, acetic acid) at a temperature of about 15 ° C at around 40 ° C, generally at room temperature, for about 30 minutes to about 6 hours.

Alternatively, the enamlna of Formula lll can be prepared from the propriolate of Formula XXX by the following two-stage reaction.

An alkyne of Formula XXXII is coupled to the boronic acid of Formula XXXV, where F¡¹ it is as described above, to prepare the propriolate of Formula XXX by a transition metal-mediated coupling. For example, the R¹- A suitable boronic acid in a polar aprotic solvent, such as dichloromethane, is reacted with cesium carbonate, copper iodide, silver oxide (I) and tert-butyl propiolate, at a temperature of around 60 ° C to around 100 ° C, generally around 80 ° C, for about 30 minutes to about 6 hours.

The propriate of the resulting Formula XXX is transformed into the enamine of the corresponding Formula lll by amination with the amine R²-NH₂ adequate (where R² it is as defined above) in the presence of a weak acid, such as acetic acid. The reaction is carried out in a polar solvent, such as ethanol or isopropanol, at a temperature of about 60 Ό to about 100 ° C, generally about 80 ° C, for about 24 hours to about 72 hours.

SCHEME II fi

R²

LV

<img file="CU20140049A7_D0007.tif" />

LVII

R¹B (OH)₂ PddppfCI₂Na₂CO₃

<img file="CU20140049A7_D0008.tif" />

(NH₄)₂S, pyr

HN '

<img file="CU20140049A7_D0009.tif" />

R¹

R²

The thiouracil of Formulas I or IA can also be prepared from a 6halotiouracil of Formula LVI, as shown in Scheme II.

The thiocarbonyl of a halothiouracil of the Formula LVI is protected, for example, by reaction with iodomethane in the presence of a base, such as diisopropylethylamine in a polar solvent (for example, acetonitrile) at a temperature of about 15 ° C to about 40 ° C, generally at room temperature, for about 8 hours to about 24 hours. The halide of the resulting Formula LVII is subjected to transition metal-mediated coupling with the species R¹- suitable metal (where R¹ it is as defined above), for example, by reacting with [1,1'-b¡s (d¡phenylphosphino) ferrocen] d¡chloropalladium (lI) and R¹- boronic acid (where R¹ is as described above) with 1,4-dioxane and aqueous sodium carbonate. The mixture is heated at a temperature of about ° C to about 150 ° C, generally subjecting it to microwave irradiation at 120 ° C for about 15 minutes to about 1 hour. The compound of the resulting Formula LVIII is deprotected by reaction with a nucleophile, in general by reaction with ammonium sulfide, in a polar solvent, such as pyridine, at a temperature of about 60 Ό to about 150 ° C, in general by microwave irradiation at 75 ° C for about 15 minutes to about 1 hour to prepare the thiouracil of Formulas I or IA.

Halotiouracils of Formula LVI can be prepared from the corresponding thiouracils of Formula LV, for example, by two-stage deprotonation / exchange of lithium-halogen with iodine. In general, thiouracil is treated with a base, such as lithium diisopropylamide, in a polar aprotic solvent, such as tetrahydrofuran, at a temperature of about -20 ° C to about -100 ° C, in general -78 ° C. Then, the solution is heated at a temperature of about 0 ° C to about -25 ° C, generally -10 ° C, for about 15 minutes to about 1 hour to prepare the corresponding lithium intermediate and then , it is cooled to a temperature of about -60 ° C to about -80 ° C, in general -78 ° C, at which time the lithium intermediate is reacted with iodine in a suitable polar aprotic solvent for about 5 minutes to about 48 hours, in general 8 hours.

ro₂cl

HN ^ R¹ ° ^) n

OR

Lx

<img file="CU20140049A7_D0010.tif" />

<img file="CU20140049A7_D0011.tif" />

The thiouracil compounds of Formulas IB and LXI (where R¹ was described previously, and while R³ and R⁴ have not been specifically indicated above, they refer to substituents which, in general, were previously described) can be prepared from the enamines of the Formula LX, as indicated in Scheme lll. The thiouracils of the Formula LXI, wherein R is an alkyl group, such as methyl, ethyl, isopropyl or tert-butyl, preferably methyl or ethyl, can be converted into the corresponding carboxylic acid, wherein R = H, by various methods known by the persons of the medium level trade, such as acidic or basic hydrolysis, preferably treatment with 5 equivalents of lithium or sodium hydroxide, in a polar solvent, such as water, methanol, ethanol, tetrahydrofuran or a mixture of these solvents, preferably water and ethanol, at a temperature of 0 ° C to about 100 ° C, preferably at room temperature, for a period of 1 hour to 24 hours, preferably 4 hours. The resulting carboxylic acid of the Formula LXI can be converted to the amide of the Formula IB by the use of amide coupling reagents known to the people of the medium level trade, such as propanphosphonic acid anhydride (T3P) or (CDI) , preferably propanphosphonic acid anhydride, in the presence of an organic base, such as pyridine, triethylamine, imidazole or diisopropylethylamine, preferably diisopropylmethylamine, in a polar solvent, such as N, N'methylformamide, methylene chloride or ethyl acetate, preferably methylene chloride, at a temperature of 0 ° C at reflux of the solvent, preferably at room temperature, for a period of 15 minutes to 48 hours, preferably 18 hours.

The thiouracil compounds of the Formula LXI can be prepared from enamines of the Formula LX by reaction with an isothiocyanate, such as Nbenzoyl-, N-carboxyethyl- or, preferably, (trimethylsilyljisothiocyanate (TMSNCS), optionally, in the presence of a polar aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, butylnitrile, n-butylacetate, N, N-dimethylformamide, preferably pure in the isothiocyanate, at a temperature of 20 ° C to 150 ° C, in general around 85 ° C, with heating in a microwave reactor or a conventional heat source, for 15 minutes to 48 hours, preferably 3 hours.

SCHEME IV η

η

OR

<img file="CU20140049A7_D0012.tif" />

\

IC

<img file="CU20140049A7_D0013.tif" />

LXXI

The thiouracils of Formulas IC, LXXI and LXXII can be prepared from the formulas of Formula LXX, as shown in Scheme IV.

Thiouracils of Formula IC (where R¹ was described previously, and while R³-R⁹ have not been specifically indicated previously, refer to substituents that, in general, were previously described, and where at least one of R⁶ to R⁹ binds to the corresponding guanidine nitrogen by a portion of carbonyl) can be prepared from tlouracllos of the Formula LXXII, which can exist in various tautomeric forms, such as those shown, by the reaction of the guanidines LXXII with a reagent of acylation known to people of the medium level trade, such as acyl chloride or alkyl chloroformate, in the presence of an aqueous base, such as sodium carbonate or sodium bicarbonate, in a polar aprotic solvent, such as tetrahydrofuran, at a temperature of 0 ° C at reflux of the solvent, preferably at room temperature, to provide the corresponding guanidines of Formula IC. Alternatively, the reaction of thiouracils LXXII with a dialkyl carbonate, in the presence of an alkoxide base, such as sodium ethoxide, in a polar solvent, such as the corresponding alcohol of dlalqullcarbonate, at a temperature of 15 Ό a around 100 ° C, preferably 50 ° C, for 4 to 48 hours, preferably 15 hours, provides the corresponding formula ICs.

Tlouracllos of Formula LXXII can be prepared from the corresponding tlouracllos of Formula LXX by reaction with guanllation reagents containing R⁷R⁸NCN, such as benzotrlazole-R⁷R⁸N-methane, mldazol-R⁷R⁸Nmetanlmlna or plrazol-R⁷R⁸N-methanol in a polar aprotic solvent, preferably Ν, Ν'-dlmetllformamlda, in the presence of a base, preferably diisopropylethylamine, at a temperature of 15 ° C to 60 ° C, preferably at room temperature, for 4 to 72 hours, preferably 18 hours. Alternatively, the amines of the Formula LXX can be converted to an activated LXXI tlouracllo, wherein X is a leaving group, such as benzotriazole, imidazole and pyrrazole, by reaction with a methanemlna reagent, such as 1,1- d¡ (1 H-benzotrlazol1 -ll) methanlm¡na, 1,1-d¡ (1 H-lmldazol-1 -ll) methanlm¡na or 1,1 -d¡ (1 H-plrazol-1 ¡l- ) methanemlna, in the presence of a base, such as diisopropylamine, in a polar aprotic solvent, such as Ν, Ν'-dlmetllformamlda, at a temperature of 15 ° C to 100 ° C, preferably at room temperature, for 4 to 48 hours, preferably 18 hours. The resulting activated tlouracllos of the Formula LXXI can then be treated with R⁷R⁸NH in the presence of a base, such as diisopropylethylamine, in a polar aprotic solvent, such as Ν, Ν'-dlmetllformamlda, at a temperature of 20 ° C to 120 ° C, preferably 60 ° C, for 1 hour to 24 hours, preferably 3 hours, to obtain the guanidine thiouracils of the Formula LXXII.

The ice materials and reagents for the compounds of Formulas I or IA described above are also readily available, or people of the medium level trade can easily synthesize them by conventional methods of organic synthesis. For example, vapors of the compounds used herein are referred to or derived from compounds in which there is great scientific interest and commercial need and, consequently, vapors of those compounds are commercially available or reported in the literature. or they can be easily prepared from other available substances by methods that are reported in the literature.

Cis / trans isomers can be separated by conventional techniques known to medium-level people, for example, chromatography and fractional crystallization.

Mixtures of stereoisomers can be separated by conventional techniques known to people of the mid-level trade. [See, for example, "Stereochemistry of Organic Compounds" by EL Ellel (Wiley, New York, 1994).]

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

Alternatively, the racemate (or a racemic precursor) may react with a suitable optically active compound, for example, an alcohol, or in the event that the compound of Formula (I) contains an acidic or basic portion, a acid or a base, such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted into the corresponding pure enantiomers by means known to the people of the medium level trade.

The chiral compounds of the invention (and their chiral precursors) can be obtained in an enantiomerically enriched form by chromatography, in general HPLC, in a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, in general , heptane or hexane, which contains 0 to 50% of isopropanol, in general 2 to 20% and 0 to 5% of an alkylamine, in general 0.1% of diethylamine. The concentration of the eluate generates the enriched mixture.

Pharmaceutically acceptable salts of the compounds of Formulas I or IA can be prepared by one or more of the following three example methods:

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

(I) remove an acid or base labile protecting group from a suitable precursor of the compound of Formulas I or IA, or open the ring of a suitable cyclic precursor, for example, a lactone or lactam, by using the acid or suitable base; or (iii) convert a salt of the compound of Formulas I or IA into another by reaction with a suitable acid or base or by a suitable ion exchange column.

In general, all three reactions are performed in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

The compounds of the present invention can also be used together with other pharmaceutical agents (for example, antiarosclerotic and antithrombotic agents) for the treatment of the diseases / conditions described herein.

COMBINATION AGENTS

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. The terms administered in combination or combination therapy refer to a compound of the present invention and one or more additional therapeutic agents being administered concurrently to the mammal being treated. When administered in combination, each component can be administered at the same time or sequentially in any order, at different time points. Therefore, each component can be administered separately, but close enough over time to provide the desired therapeutic effect. Therefore, the prevention and treatment methods described herein include the use of combination agents.

The combination agents are administered to a mammal in a therapeutically effective amount. The term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective in treating the desired disease / condition, for example, a condition. cardiovascular, such as acute coronary syndrome.

Additional therapeutic agents include anticoagulants or coagulation inhibitors, antiplatelet or platelet inhibitors, thrombin, thrombolytic or fibrinolytic inhibitors, antiarrhythmics, antihypertensors, calcium channel blockers (type L and type T), cardiac glycosides, dirumetics, antagonists mineralocorticoid receptor, NO donating agents, such as organonitrates, NO promoting agents, such as phosphodiesterase inhibitors, hypocholesterolemiants / lipid-lowering agents and lipid profile therapies, antidiabetics, antidepressants, anti-inflammatories (steroids and non-steroids), antiosteoporotics, hormone replacement therapies, oral contraceptives, obesity agents, anxiolytics, antiproliferatives, anti-tumor agents, ulcer and disease agents gastroesophageal reflux, growth hormone and / or growth hormone secretagogues, thyroid mimetics (which includes the thyroid hormone receptor antagonist), anti-infectives, antivirals, antibacterials and antifungals.

Agents used in the intensive care unit (ICU) are included, for example, dobutamine, dopamine, dpinephrine, nitroglycerin, nitroprusside, etc.

Combination agents useful for the treatment of vasculitis are included, for example, azathloprlne, cyclophosphamlde, mycophenolate, mofetll, rituximab, etc.

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

Example factor Xa inhibitors include aplxaban and rlvaroxaban.

Examples of antlcoagulants suitable for use in combination with the compounds of the present invention include heparins (for example, unfractionated and low molecular weight heparins, such as enoxaparlna and dalteparlna).

In another preferred embodiment, the second agent is at least one agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasacchards, hlrudln, argatrobanas, aspirin, Ibuprofen, naproxen, sulindac, ndomethacln, mefenamate, droxicam , diclofenac, sulflnpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, dlsulfatohlrudln, tissue plasminogen activator, Modified tissue plasminogen activator, anlstreplase, uroqulnase and streptoqulnase.

A second preferred agent is at least one anti-platelet agent. The anti-platelet agents of particular preference are aspirin and clopidogrel.

As used herein, anti-platelet agents (or platelet Inhibitory agents) refers to agents that inhibit platelet function, for example, by inhibiting platelet aggregation, adhesion or secretion. Agents include, among others, various known nonsteroidal anti-inflammatory agents (NSAIDs), such as aspirin, ibuprofen, naproxen, sulindac, ndomethacln, mefenamate, droxicam, diclofenac, sulflnpyrazone, piroxicam, and salts or prodrugs thereof acceptable from the point Pharmaceutical view. Of the NSAIDs, aspirin (acetylsalicylic acid or ASA) and COX-2 inhibitors, such as CELEBREX or piroxicam, are preferred. Other suitable platelet inhibitor agents include llb / llla antagonists (e.g., tirofiban, eptifibatide and abciximab), thromboxane-A2 receptor antagonists (e.g., fetroban), thromboxane-A2 synthetase inhibitors, PDE-lll inhibitors ( for example, Pletal, dlpyrldamole), and pharmaceutically acceptable salts or prodrugs thereof.

As used herein, the term "anti-platelet agents" (or platelet inhibitor agents) also includes ADP receptor antagonists (adenosine diphosphate), preferably, P2Y1 purinergic receptor antagonists and ^P2^AND12¡ ^P2^AND12 ^{It is} more preference P2 receptor antagonists^AND12 Preferred include ticagrelor, prasugrel, ticlopidine and clopidogrel, including salts or prodrugs thereof pharmaceutically acceptable. Clopidogrel is a more preferred agent. The compounds ticlopidine and clopidogrel are also preferred, because they do not cause damage to the gastrointestinal tract.

As used herein, the term thrombin inhibitors (or thrombin agents) refers to inhibitors of serine protease thrombin. By inhibiting thrombin, several thrombin-mediated processes are interrupted, such as thrombin-mediated platelet activation (i.e., for example, platelet aggregation and / or granular secretion of plasminogen activator inhibitor 1 and / or serotonin) and / or fibrin formation. The people of the medium level trade know several thrombin inhibitors, and the use of these inhibitors in combination with the compounds herein is contemplated. These inhibitors include, among others, derivatives of boroarginine, boropeptides, heparins, hirudin, argatroban and melagatran, including salts and prodrugs thereof pharmaceutically acceptable. Boroarginine and boropeptide derivatives include peptide and N-acetyl derivatives of boronic acid, such as lysine, ornithine, arginine, homoarginine alpha-aminoboronic acid derivatives of the C-terminal and corresponding isothiouronium analogs. As used herein, the term hirudin includes suitable analogs or derivatives of hirudin, referred to herein as hirologists, such as disulfatohirudin. As used herein, the term "thrombolytic or fibrinolytic (or thrombolytic or fibrinolytic) agents" refers to 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), Vlla factor inhibitors, PAI-1 inhibitors (i.e. inactivators). of tissue plasminogen activator inhibitors), alpha 2-antiplasmin inhibitors and anisoylated plasminogen / streptokinase activator complex, which include the salts and prodrugs thereof pharmaceutically acceptable. As used herein, the term "anistreplase" refers to the anisolated plasminogen / streptokinase activator complex, as described, for example, in EP 028,489, the description of which is incorporated herein by reference. As used herein, the term urokinase refers to double stranded and single stranded urokinase, the latter is also referred to as prourokinase herein.

Examples of suitable antiarrhythmic agents include: Class I agents (such as propafenone); Class II agents (such as metoprolol, atenolol, carvadiol and propranolol); Class lll agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K + channel openers, such as l ^ ch θ inhibitors iKur inhibitors (P °^r example, compounds as described in WO01 / 40231).

The compounds of the present invention can be used in combination with antihypertensives, and the activity against hypertension can easily be determined by people of the mid-level trade according to standard tests (for example, blood pressure measurements). Examples of suitable antihypertensive agents include alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (for example, diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g. hydralazine), diuretics (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 (for example, captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (eg, losarran, irbesartan, waltz); ET receptor antagonists (for example, sitaxsentan, atrsentan and the compounds described in US Pat.^you 5,612,359 and 6,043,265); dual ΕΤ / All antagonist (for example, the compounds described in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (for example, gemopatrilat and nitrates). An example of an antianginal agent is ivabradine.

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

Examples of suitable cardiac glycosides include digitalis and ouabain.

In one embodiment, a compound of Formulas I or IA can 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, methicide trichlormethiazide and ndapamide (such as LOZOL ™); (c) ftallmldlna type diuretics, such as chlorthalldone (such as HYGROTON ™) and metolazone (such as ZAROXOLYN ™); (d) quinazoline-type diuretics, such as quinetazone; and (e) potassium moderating diuretics, such as triamterene (such as DYRENIUM ™) and amiloride (such as M ID AMOR ™ or MODURETIC ™).

In another embodiment, a compound of Formulas I or IA can be co-treated with a loop diuretic. In yet another embodiment, the loop diuretic is selected from furosemlde and torsemlde. In yet another embodiment, one or more compounds of Formulas I or IA can be co-administered with furosemlde. In yet another embodiment, one or more compounds of Formulas I or IA can be co-treated with torseml, which, optionally, can be a controlled or modified form of torsemide release.

In another embodiment, a compound of Formulas I or IA can be co-treated with a tlazlda diuretic. In yet another embodiment, the thiazide type diuretic is selected from the group consisting of chlorothiazide and hydrochlorotlazide. In yet another embodiment, one or more compounds of Formulas I or IA can be co-treated with chlorothiazide. In yet another embodiment, one or more compounds of Formulas I or IA can be co-treated with hldrochlorotlazlda.

In another embodiment, one or more compounds of Formulas I or IA can be co-treated with a diuretic type ftallmldlna. In yet another embodiment, the ftallmldlna diuretic is chlorthalldone.

Examples of suitable combinations of mlneralocortlcolde receptor antagonists include sprlonolactone and eplerenone.

Examples of suitable combinations of phosphodiesterase inhibitors include: PDE lll inhibitors (such as cllostazole); and PDE V inhibitors (such as sildenafil).

The compounds of the present invention can be used in combination with cholesterol modulating agents (which include hlpocolesterolemlantes), such as a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA slntase inhibitor, an expression inhibitor HMG-CoA reductase gene, an HMG-CoA slntase gene expression inhibitor, an MTP / Apo B secretion inhibitor, a CETP inhibitor, a billiard acid absorption inhibitor, a Cholesterol absorption inhibitor, a Cholesterol synthesis inhibitor, a squalene slntetase inhibitor, a squalene epoxldasa inhibitor, a squalene cyclase inhibitor, a combined squalene epoxylase / squalene cyclase inhibitor, a flbrate, nlaclna, a Ionic Exchange resin, an antloxldant, an ACAT inhibitor, a bile acid sequestrant or an agent, such as mipomersen.

Examples of hlpocolesterolemlantes / hlpollpemlantes appropriate therapies and lipid profile include: HMG-CoA reductase inhibitors (e.g. pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (also known as ¡tavastatln, nlsvastatln or nlsbastatln) and ZD-4522 (also known as rosuvastatln, atavastatln or vlsastatln)); Squalene slntetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; Llpooxlgenase inhibitors; Cholesterol absorption inhibitors; and Cholesterlyester transfer protein inhibitors.

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

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

Cardiovascular complications of type 2 diabetes are associated with harmful levels of MPO; consequently, the compounds of the present invention can be used in combination with anti-diabetes agents, in particular anti-type 2 diabetes agents. Examples of suitable anti-diabetes agents include, for example, Insulins, methotomline, DPPIV inhibitors, GLP-1 agonists, analogs and mimetics, SGLT1 and SGLT2 inhibitors). Suitable agents against diabetes include an Acetyl-CoA carboxylase inhibitor (ACC), such as those described in W02009144554, W02003072197, W02009144555 and W02008065508, a Diacylglycerol O-aclltransferase 1 (DGAT-1) inhibitor, such as those described in W009016462 or WO2010086820, AZD7687 or LCQ908, Diacylglycerol O-aclltransferase 2 (DGAT-2) inhibitor, Monoacylglycerol Oaclltransferase inhibitors, a phosphodiesterase (PDE) -10 inhibitor, an AMPK activator, a sulphonylurea (for example, acetohexamlde, chlorpropamlde, dlablnese, gllbenclamlde, gllplzlde, glyburlde, gllmeplrlde, gllclazlde, gllpentlde, gllquldone, gllsolamlde, tolazamlde and tolbutamit, untathlite, untathlite, anitl three-chain-type, for example AL-3688), an α-glucosyl hydrolase inhibitor (for example, acarbose), an α-glucosldasa inhibitor (for example, adlposlne, camlgllbose, emlglltate, miglitol, vogllbose, pradlmlcIn-Q and salbostatln), a PPARy agonist (for example, balaglitazone, ciglitazone, darglitazone, englitazone, saglitazone, pioglitazone and rosiglitazone), a PPAR α / γ agonist (for example, CLX-0940, GW-1536, GW1929, GW-2433, KRP -297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (for example, metformin), a glucagon 1 peptide modulator (GLP-1), such as an agonist (for example, exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Byetta®), albiglutide, lixisenatide, dulaglutide, semaglutide, NN-9924, TTP-054, a tyrosine phosphatase-1B protein inhibitor (PTP-1B) (for example, trodusquemine, hyrtiosal extract and the compounds described in Zhang, S., et al., Drug Discovery Today , 12 (9/10), 373-381 (2007)), a SIRT-1 inhibitor (for example, resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor (for example, those described in W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), an insulin secretagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase inhibitor (JNK), glucokinase activators (GKa), such as those described in WO2010103437, WO2010103438 , WO2010013161, W02007122482, TTP-399, TTP355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, an insulin mimetic, a glycogen phosphorylase inhibitor (for example, GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors, such as those described in EC Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010), which include dapagliflozin, canagliflozin, empagliflozin, tofogliflozin (CSG452), ASP-1941, THR1474, TS-071, ISIS388626 and LX4211, and those described in

WO2010023594, a glucagon receptor modulator, such as those described in Demong, DE et al. Annual Reports in Medicinal Chemistry 2008, 43, 119-137, modulators of GPR119, in particular agonists, such as those described in WO2010140092, WO2010128425, W02010128414, WO2010106457, Jones, RM et al. in Medicinal Chemistry 2009, 44, 149-170 (for example, MBX-2982, GSK1292263, APD597 and PSN821), derivatives or analogs of FGF21, such as those described in Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, 10 (4) 359-364, TGR5 receptor modulators (also called GPBAR1), in particular agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10 (4), 386-396, and INT777, GPR40 agonists, such as those described in Medina, JC, Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, which include, among others, TAK-875 , modulators of GPR120, in particular agonists, high affinity nicotinic acid receptor activators (HM74A) and SGLT1 inhibitors, such as GSK1614235. Another representative list of anti-diabetes agents that can be combined with the compounds of the present invention can be found, for example, from page 28, line 35 to page 30, line 19 of WO2011005611. Preferred anti-diabetes agents are metformin and DPP-IV inhibitors (for example, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other anti-diabetes agents could include inhibitors or modulators of carnitine palmitoyl transferase enzymes, fructose 1,6-diphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, CCR2 and / or CCR5 inhibitors, inhibitors of PKC isoforms (for example, PKCa, ΡΚΟβ, PKCy), fatty acid synthetase inhibitors, palmitoyl transferase serine inhibitors, GPR81, GPR39, GPR43, GPR41 modulators, 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 the family of IL1, including ILIbeta, and RXRalfa modulators. In addition, suitable agents against diabetes include the mechanisms listed in Carpino, PA, Goodwin, B. Expert Opin. Ther. Pat, 2010, 20 (12), 1627-51.

People of the mid-level trade will recognize that the compounds of the present invention can also be used in conjunction with other cardiovascular or cerebrovascular treatments including percutaneous coronary intervention (PCI), stenting, drug eluting stents, cell therapy mothers and medical devices, such as pacemaker implants, defibrillators or cardiac resynchronization therapy.

Myeloperoxidase activity has been demonstrated in neuroinflammatory conditions; consequently, the compounds of the present invention can be used in combination with neuroinflammatory and neurodegenerative agents in mammals.

Examples of additional neuroinflammatory and neurodegenerative agents include antidepressants, antipsychotics, analgesics, Alzheimer's disease agents and anxiolytics. Examples of particular classes of antidepressants that can be used in combination with the compounds of the invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors. (MAOI), reversible inhibitors of monoamine oxidase (RIMA), inhibitors of serotonin and norepinephrine reabsorption (SNRI), antagonists of cortlcotroplna release factor (CRF) and atypical antidepressants. Suitable noreplnefrlna reabsorption inhibitors include tricyclic tertiary amines and tricyclic secondary amines. Examples of suitable tricyclic tertiary amines and suitable tricyclic secondary amines include amitriptyline, clomipramine, doxepin, mlpramlne, trlmlpramlne, dothlepln, butrlptyllne, nortrlptyllne, protrlptyllne, amoxaplne, deslpramne, slotramne, slotramne, slotramne, slotramne, slotramne. Examples of suitable SSRIs include fluoxetlne, fluvoxamine, paroxetine and sertraline. Examples of monoamine oxldasa inhibitors include Isocarboxazid, phenelzlne and tranylcyclopramlne. Examples of suitable reversible inhibitors of monoamine oxldasa include moclobemlde. Examples of SNRI suitable for use in the present invention include venlafaxine. Examples of suitable atypical antidepressants include buproplon, llthlum, trazodone and vlloxazlne. Examples of agents against Alzheimer's disease include NMDA receptor antagonists, such as memantine; and cholnesterase inhibitors, such as donepezll and galantamlne. Examples of suitable classes of anslolitic that can be used in combination with the compounds of the invention include benzodiazepines, serotonin 1A receptor agonists (5-HT1A) and CRF antagonists. Suitable benzodiazepines include alprazolam, chlordlazepoxlde, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam and prazepam. Suitable 5-HT1A receptor agonists include busplrone and psaplrone. Suitable CRF antagonists include verucerfont. Suitable atypical antlpslcótlcos include pallperldone, zlprasldone, rlsperldone, arlplprazole, olanzaplne and quetlaplne. Suitable nicotinic acetylcholine agonists include CP-601927 and varenlcllne. Pain relievers include pregaballn, gabapentln, clonldlne, neostlgmlne, baclofen, midazolam, ketamlne and zlconotlde.

In particular, when administered as a single dose unit, a chemical Interaction between the combined active Ingredients may occur. Therefore, when a compound of Formulas I or IA and a second therapeutic agent are combined in a single dose unit, they are formulated so that while the active Ingredients are combined in a single dose unit, physical contact between the Active ingredients are minimized (ie reduced). For example, an active ingredient may have an enteric coating. Through the enteric coating of the active Ingredients, it is not only possible to minimize the contact between the combined active Ingredients, but also to control the release of one of these components in the gastrointestinal tract, so that one of these components is not released in the stomach , but in the intestines. One of the active ingredients can also be coated with a material that affects sustained release along the gastrointestinal tract and also minimizes physical contact between the combined active ingredients. In addition, the sustained release component may have an additional enteric coating, so that the release of this component occurs only in the intestine. Another method would involve the formulation of a combined product in which one component is coated with a sustained-release and / or enteric polymer, and the other component is also coated with a polymer, such as hydroxypropyl methylcellulose (HPMC) with a low degree of viscosity. or other suitable materials known in the state of the art, in order to further separate the active components. The polymeric coating serves to form an additional barrier against interaction with the other component.

This and other ways of minimizing contact between the components of the combined products of the present invention, whether administered in a single dosage form or in separate forms but at the same time and in the same way, will be apparent to people. of the mid-level trade after analyzing this description.

For the treatment of the combination therapy, both the compounds of the present invention and the other drug therapies are administered to mammals (eg, humans, men or women) by conventional methods.

The compounds of Formulas I or IA of the present invention, their prodrugs and the salts of these compounds and prodrugs are adapted for therapeutic use as agents that inhibit myeloperoxidase in mammals, in particular in humans, and therefore, are useful for the treatment of various conditions (for example, those described herein) in which this action is involved.

It is believed that myeloperoxidase participates in the pathological oxidation of proteins, lipids and nucleic acids, contributes to dysfunctional metabolism of cholesterol, tissue damage and organ failure, and can induce or contribute to the development of cardiovascular diseases and related adverse pathologies.

Diseases / conditions that can be treated in accordance with the present invention include, but are not limited to, cardiovascular conditions, diabetes (e.g., type II) and diabetic complications, vascular conditions, neuroinflammatory conditions, neurodegenerative conditions, pain, cancer, sepsis, NASH (non-alcoholic steatohepatitis), hypertension and lung injury, kidney diseases, vasculitis syndromes, especially those related to ANCA (anti-neutrophil cltoplasmic antibodies) and the like.

Due to the positive correlation between myeloperoxidase activation and the development of cardiovascular diseases / conditions associated with them, the compounds of Formulas I or IA of the present invention, their prodrugs and the salts of these compounds and prodrugs are useful, thanks to its pharmacological action, for the prevention, interruption and / or regression of the atherosclerosls and their associated pathologies. It is believed that MPO exhibits proatrogenic biological activity during the evolution of cardiovascular disease. In addition, it has been observed that oxidants generated by MPO reduce the bioavailability of nitric oxide, an important vasodilator. Likewise, it was demonstrated that MPO plays a role in plaque destabilization by causing activation of metalloproteinases; this causes a weakening of the fibrous layer of the plates and the subsequent destabilization and rupture of the plates. Due to these various effects, MPO is involved in a wide variety of cardiovascular diseases.

Cardiovascular conditions include, but are not limited to, coronary heart disease, acute coronary syndrome, ischemic heart disease, primary or recurrent myocardial infarction, secondary myocardial infarction, non-ST-segment elevation myocardial infarction, or ST-segment elevation elevation, sudden death Ischemic, transient ischemic accident, peripheral occlusive arterlopathy, angina, atherosclerosls, hypertension, Heart failure (such as congestive heart failure), dlastolic dysfunction (such as left ventricular dlastolic dysfunction, dlastolic heart failure and decreased elastomeric filling), systolic dysfunction (such as systolic heart failure with decreased ejected fraction), atrial flbrllaclón, arrhythmia (ventricular), ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, decrease in arterial difficulty, necrotic lesions of the myocardium, vascular lesions, left ventricular hypertrophy, decrease in the ejected fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, flbrlnolde coronary artery necrosis, adverse restructuring, stroke and the like. Also included are phlebotrombosls, deep phlebotrombosls, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis, which are the result of (a) prosthetic valves or other Implants, (b) permanent catheters, (c) stents, (d) cardlopulmonary bypass, (e) hemodialysis or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It should be noted that thrombosis includes occlusion (for example, after a bypass) and reocclusion (for example, during or after percutaneous transluminal coronary angioplasty).

Cardiovascular complications of type 2 diabetes are associated with harmful levels of MPO; consequently, the compounds of the present invention can be used to treat diabetes and diabetic complications, such as macro vascular disease, hyperglycemia, metabolic syndrome, glucose intolerance, hyperuricemia, glucosuria, cataracts, diabetic neuropathy, diabetic nephropathy, retinopathy diabetic, obesity, dyslididemia, hypertension, hyperinsulinemia and insulin resistance syndrome.

In addition, the relationship between myeloperoxidase activity and disease in neuroinflammatory and neurodegenerative conditions has been demonstrated. Therefore, the compounds of the present invention are indicated in particular for use in the treatment of neuroinflammatory and neurodegenerative conditions (ie, disorders or diseases) in mammals, including humans, such as multiple sclerosis, migraine; epilepsy; Alzheimer disease; Parkinson's disease; brain injury; apoplexy; cerebrovascular diseases (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage and cerebral hypoxia-ischemia); cognitive disorders (including amnesia, senile dementia, HIV-associated dementia, dementia associated with Alzheimer's disease, dementia associated with Huntington's disease, dementia of Lewy bodies, vascular dementia, drug-related dementia, delirium and cognitive deficiency mild); mental deficiency (which includes Down syndrome and fragile X chromosome syndrome); sleep disorders (including hypersomnia, circadian sleep rhythm disorders, insomnia, parasomnia and sleep deprivation) and psychiatric disorders, such as anxiety (which include acute stress disorders, generalized anxiety disorders, social anxiety disorders, disorders of distress, posttraumatic stress disorders and obsessive compulsive disorder); factitious disorders (including acute hallucinatory mania); impulse control disorders (including gambling and intermittent explosive disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective episode, major depression, chronic depression, seasonal depression, psychotic depression and postpartum depression); psychomotor disorder; psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform disorder and delusional disorder); drug dependence (which includes drug addiction, alcoholism, amphetamine addiction, cocaine addiction, smoking and withdrawal symptoms); eating disorders (including anorexia, bulimia, binge eating disorders, hyperphagia and pagophagia); and pediatric psychiatric disorders (including attention deficit disorder, attention deficit hyperactivity disorder, behavioral disorders and autism) in a mammal, preferably a human being, comprising administering to the mammal a therapeutically effective amount of a compound of the Formulas I or IA or a pharmaceutically acceptable salt thereof.

Other inflammatory diseases or disorders include, for example, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, sinusitis, rhinitis, psoriasis, dermatitis, uveitis, gingivitis, atherosclerosis, inflammatory bowel disease, glomerular damage renal, hepatic fibrosis, sepsis, proctitis, rheumatoid arthritis and inflammation associated with revascularization injury, spinal cord injury and tissue injury / scarring / adhesion / rejection.

The term "nephropathy caused by contrast agents" includes contrast-induced nephropathy caused by procedures that use imaging agents, including cardiac surgery, non-cardiac surgery and transplant surgery. Nephropathy caused by contrast agents also includes nephropathy caused by the use of contrast agents that improve images in patients, even in those at risk of primary Ml or secondary Ml.

The utility of the compounds of the Formulas I or IA of the invention, their prodrugs and the salts of these compounds and prodrugs as medicinal agents in the treatment of the diseases / conditions described above in mammals (for example, humans, men or women) ) is demonstrated by the activity of the compounds of the present invention in the conventional in vitro and in vivo assays described below. In vivo assays (with suitable modifications within the state of the art) can be used to determine the activity of other agents, as well as the compounds of the present invention. These assays also provide a means by which the activities of the compounds of Formulas I or IA of the present invention, their prodrugs and the salts of these 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, which include humans, for the treatment of these diseases.

The people of the medium level trade can vary the following protocols.

MPO activity test with Amplex Red.

The activity of MPO peroxidase was measured by controlling the formation of resoruflna generated by the oxidation of Amplex Red (1O-acetll-3,7 dihydroxyphenoxazine) (Invitrogen, Carlsbad, CA) by MPO (Gomes, Fernandes et al. 2005). The test mixtures (100 μΙ total volume) contained 50 mM NaPI, pH 7.4, 150 mM NaCl, 1 mM DTPA (dletllentrlampentaacetic acid), 2% DMSO, 2 μΜ H₂OR₂ and 30 μΜ of Amplex Red; The reaction was initiated by the addition of 100 pM of MPO (purified from human polynuclear leukocytes and acquired from Calblochem / EMD Blosclences, Glbbstown, NJ). All tests were performed on 96-cavity medium-area polystyrene plates with a non-fixed black surface (Corning), and resoruflna production (530 nm excitation, 580 nm emission) was monitored every 20 s on a Spectramax M2 Mlcroplate spectrophotometer ( Molecular Devices, Palo Alto, CA) equipped with Softmax Pro software (Molecular Devices, Palo Alto, CA). The reactions to determine the background reaction rate consisted of all test components and 4 μΙ of 500 unit / ml bovine catalase (Sigma) in 50 mM KPI at pH 7.0. The background velocity of each reaction progress curve was subtracted. All data were analyzed by nonlinear regression analysis in Microsoft Excel and Kaleldagraph (Synergy Software).

To determine the power of the Inhibitor (k_mact/ Ki) against MPO, the first 600 s of the reaction progress curves were adjusted to equation 1, where l /₀ is the Initial speed in RFU / syt is the time in seconds, in order to obtain the first order rate constant for Enzymatic Inactivation (kobs) θη each concentration of Inhibitor.

Products (O

Equation 1 is a variation of the standard equation for a slow Inhibition of fixation, where the speed in the stationary state (V_s) is set to zero. Each kobs value was corrected for the autolnactlvaclón of the enzyme by subtracting the k value_obs of the uninhibited reaction. Then, the k values_obs corrected were plotted with respect to the concentration of Inhibitor ([I]) and adjusted to equation 2 (2) where k_nact is the maximum idle speed and K_} is the concentration of inhibitor that produces half the speed of maximum inactivation (Copeland

2005).

The following Tables 1 and (1A) provide the inhibitory activity of mleloperoxldasa for the Examples indicated below, in accordance with the assay described above.

Table 1. MPO k¡_nact/ K¡ for the Examples

<td>Example No.</td><td>MPO k¡_nact/ K¡ (1 / s per M)</td>

<td> 1</td><td> 11600</td>

<td> 2</td><td> 12500</td>

<td> 3</td><td> 29300</td>

<td> 4</td><td> 8790</td>

<td> 5</td><td> 1280</td>

<td> 6</td><td> 12900</td>

<td> 7</td><td> 10900</td>

<td> 8</td><td> 12100</td>

<td> 9</td><td> 15000</td>

<td> 10</td><td> 619</td>

<td> 11</td><td> 6880</td>

<td> 12</td><td> 5010</td>

<td> 13</td><td> 745</td>

<td> 14</td><td> 5310</td>

<td> 15</td><td> 5420</td>

<td> 16</td><td> 6510</td>

<td> 17</td><td> 4460</td>

<td> 18</td><td> 8280</td>

<td> 19</td><td> 1960</td>

<td> 20</td><td> 1330</td>

<td> 21</td><td> 4530</td>

<td> 22</td><td> 6340</td>

<td> 23</td><td> 991</td>

<td> 24</td><td> 7640</td>

<td> 25</td><td> 9210</td>

<td> 26</td><td> 3180</td>

<td> 27</td><td> 15800</td>

<td> 28</td><td> 13700</td>

<td> 29</td><td> 14900</td>

<td> 30</td><td> 5870</td>

<td> 31</td><td> 7680</td>

<td> 32</td><td> 2120</td>

<td> 33</td><td> 4520</td>

<td>Example No.</td><td>MPO k¡_nact/ K¡ (1 / s per M)</td>

<td> 34</td><td> 13100</td>

<td> 35</td><td> 4110</td>

<td> 36</td><td> 5980</td>

<td> 37</td><td> 6460</td>

<td> 38</td><td> 5240</td>

<td> 39</td><td> 4520</td>

<td> 40</td><td> 6430</td>

<td> 41</td><td> 5000</td>

<td> 42</td><td> 6070</td>

<td> 43</td><td> 34600</td>

<td> 44</td><td> 3440</td>

<td> 45</td><td> 4000</td>

<td> 46</td><td> 1110</td>

<td> 47</td><td> 2340</td>

<td> 48</td><td> 6570</td>

<td> 49</td><td> 2230</td>

<td> 50</td><td> 2610</td>

<td> 51</td><td> 6180</td>

<td> 52</td><td> 33.4</td>

<td> 53</td><td> 3290</td>

<td> 54</td><td> 7070</td>

<td> 55</td><td> 7740</td>

<td> 56</td><td> 4770</td>

<td> 57</td><td> 13100</td>

<td> 58</td><td> 11700</td>

<td> 59</td><td> 8480</td>

<td> 60</td><td> 3470</td>

<td> 61</td><td> 3530</td>

<td> 62</td><td> 6930</td>

<td> 63</td><td> 12200</td>

<td> 64</td><td> 22500</td>

<td> 65</td><td> 7940</td>

<td> 66</td><td> 1580</td>

<td> 67</td><td> 7520</td>

<td> 68</td><td> 1160</td>

<td> 69</td><td> 4250</td>

<td> 70</td><td> 1590</td>

<td> 71</td><td> 3570</td>

<td> 72</td><td> 3580</td>

<td> 73</td><td> 9870</td>

<td> 74</td><td> 14400</td>

<td> 75</td><td> 2040</td>

<td> 76</td><td> 4190</td>

<td> 77</td><td> 6660</td>

<td> 78</td><td> 9730</td>

<td> 79</td><td> 1580</td>

<td> 80</td><td> 4130</td>

<td> 81</td><td> 24300</td>

<td> 82</td><td> 3390</td>

<td>Example No.</td><td>MPO / &lt;nact / K¡ (1 / s per M)</td>

<td> 83</td><td> 3510</td>

<td> 84</td><td> 6630</td>

<td> 85</td><td> 10700</td>

<td> 86</td><td> 3960</td>

<td> 87</td><td> 15400</td>

<td> 88</td><td> 898</td>

<td> 89</td><td> 276</td>

<td> 90</td><td> 11600</td>

<td> 91</td><td> 9360</td>

<td> 92</td><td> 22100</td>

<td> 93</td><td> 5120</td>

<td> 94</td><td> 6930</td>

<td> 95</td><td> 15400</td>

<td> 96</td><td> 2200</td>

<td> 97</td><td> 6310</td>

<td> 98</td><td> 1870</td>

<td> 99</td><td> 2920</td>

<td> 100</td><td> 16100</td>

<td> 101</td><td> 4140</td>

<td> 102</td><td> 4200</td>

<td> 103</td><td> 41800</td>

<td> 104</td><td> 1210</td>

<td> 105</td><td> 27300</td>

<td> 106</td><td> 10500</td>

<td> 107</td><td> 1280</td>

<td> 108</td><td> 5800</td>

<td> 109</td><td> 914</td>

<td> 110</td><td> 864</td>

<td> 111</td><td> 10300</td>

<td> 112</td><td> 14900</td>

<td> 113</td><td> 25900</td>

<td> 114</td><td> 9770</td>

<td> 115</td><td> 4380</td>

<td> 116</td><td> 9920</td>

<td> 117</td><td> 11400</td>

<td> 118</td><td> 5500</td>

<td> 119</td><td> 25600</td>

<td> 120</td><td> 9720</td>

<td> 121</td><td> 15800</td>

<td> 122</td><td> 9310</td>

<td> 123</td><td> 3780</td>

<td> 124</td><td> 4610</td>

<td> 125</td><td> 10600</td>

<td> 126</td><td> 18200</td>

<td> 127</td><td> 5810</td>

<td> 128</td><td> 7680</td>

<td> 129</td><td> 18700</td>

<td> 130</td><td> 4830</td>

<td> 131</td><td> 14500</td>

<td>Example No.</td><td>MPO k¡_nact/ K¡ (1 / s per M)</td>

<td> 132</td><td> 3840</td>

<td> 133</td><td> 15300</td>

<td> 134</td><td> 5350</td>

<td> 135</td><td> 6750</td>

<td> 136</td><td> 1920</td>

<td> 137</td><td> 701</td>

<td> 138</td><td> 4530</td>

<td> 139</td><td> 2890</td>

<td> 140</td><td> 10400</td>

<td> 141</td><td> 10500</td>

<td> 142</td><td> 4210</td>

<td> 143</td><td> 8110</td>

<td> 144</td><td> 6010</td>

<td> 145</td><td> 5080</td>

<td> 146</td><td> 8950</td>

<td> 147</td><td> 6500</td>

<td> 148</td><td> 6690</td>

<td> 149</td><td> 9770</td>

<td> 150</td><td> 8970</td>

<td> 151</td><td> 3740</td>

<td> 152</td><td> 4770</td>

<td> 153</td><td> 2200</td>

<td> 154</td><td> 1070</td>

<td> 155</td><td> 8090</td>

<td> 156</td><td> 16800</td>

<td> 157</td><td> 7320</td>

<td> 158</td><td> 1750</td>

<td> 159</td><td> 11400</td>

<td> 160</td><td> 7540</td>

<td> 161</td><td> 29600</td>

<td> 162</td><td> 8950</td>

<td> 163</td><td> 8090</td>

<td> 164</td><td> 14900</td>

<td> 165</td><td> 1280</td>

<td> 166</td><td> 8920</td>

<td> 167</td><td> 20300</td>

<td> 168</td><td> 8890</td>

<td> 169</td><td> 17800</td>

<td> 170</td><td> 4030</td>

<td> 171</td><td> 8590</td>

<td> 172</td><td> 2950</td>

<td> 173</td><td> 2910</td>

<td> 174</td><td> 10500</td>

<td> 175</td><td> 459</td>

<td> 176</td><td> 2160</td>

<td> 177</td><td> 5130</td>

<td> 178</td><td> 11100</td>

<td> 179</td><td> 2790</td>

<td> 180</td><td> 6960</td>

<td>Example No.</td><td>MPO k¡_nact/ K¡ (1 / s per M)</td>

<td> 181</td><td> 7160</td>

<td> 182</td><td> 8200</td>

<td> 183</td><td> 4830</td>

<td> 184</td><td> 5970</td>

<td> 185</td><td> 9740</td>

<td> 186</td><td> 3930</td>

<td> 187</td><td> 5640</td>

<td> 188</td><td> 2180</td>

<td> 189</td><td> 2210</td>

<td> 190</td><td> 4090</td>

<td> 191</td><td> 14100</td>

<td> 192</td><td> 10800</td>

<td> 193</td><td> 458</td>

<td> 194</td><td> 2560</td>

<td> 195</td><td> 5350</td>

<td> 196</td><td> 5640</td>

<td> 197</td><td> 5650</td>

<td> 198</td><td> 8460</td>

<td> 199</td><td> 9080</td>

<td> 200</td><td> 4930</td>

<td> 201</td><td> 4350</td>

<td> 202</td><td> 8280</td>

<td> 203</td><td> 3450</td>

<td> 204</td><td> 3900</td>

<td> 205</td><td> 4900</td>

<td> 206</td><td> 7690</td>

<td> 207</td><td> 2400</td>

<td> 208</td><td> 3760</td>

<td> 209</td><td> 4360</td>

<td> 210</td><td> 968</td>

<td> 211</td><td> 6090</td>

<td> 212</td><td> 7590</td>

<td> 213</td><td> 4690</td>

<td> 214</td><td> 10700</td>

<td> 215</td><td> 1920</td>

<td> 216</td><td> 3260</td>

<td> 217</td><td> 3940</td>

<td> 218</td><td> 14100</td>

<td> 219</td><td> 1970</td>

<td> 220</td><td> 2420</td>

<td> 221</td><td> 6230</td>

<td> 222</td><td> 9820</td>

<td> 223</td><td> 3000</td>

<td> 224</td><td> 3280</td>

<td> 225</td><td> 5490</td>

<td> 226</td><td> 6280</td>

<td> 227</td><td> 745</td>

<td> 228</td><td> 615</td>

<td> 229</td><td> 5900</td>

<td>Example No.</td><td>MPO k¡_nact/ K¡ (1 / s per M)</td>

<td> 230</td><td> 1740</td>

<td> 231</td><td> 1910</td>

<td> 232</td><td> 4520</td>

<td> 233</td><td> 2510</td>

<td> 234</td><td> 3060</td>

<td> 235</td><td> 2690</td>

<td> 236</td><td> 5740</td>

<td> 237</td><td> 2360</td>

<td> 238</td><td> 8740</td>

<td> 239</td><td> 1850</td>

<td> 240</td><td> 7070</td>

<td> 241</td><td> 7060</td>

<td> 242</td><td> 142</td>

<td> 243</td><td> 952</td>

<td> 244</td><td> 8970</td>

<td> 245</td><td> 1520</td>

<td> 246</td><td> 246</td>

<td> 247</td><td> 3060</td>

<td> 248</td><td> 3590</td>

<td> 249</td><td> 1050</td>

<td> 250</td><td> 7510</td>

<td> 251</td><td> 68</td>

<td> 252</td><td> 2480</td>

<td> 253</td><td> 12700</td>

<td> 254</td><td> 5630</td>

<td> 255</td><td> 3550</td>

<td> 256</td><td> 6520</td>

<td> 257</td><td> 3700</td>

<td> 258</td><td> 1460</td>

<td> 259</td><td> 4000</td>

<td> 260</td><td> 19700</td>

<td> 261</td><td> 2280</td>

<td> 262</td><td> 1730</td>

<td> 263</td><td> 4340</td>

<td> 264</td><td> 3620</td>

<td> 265</td><td> 3730</td>

<td> 266</td><td> 604</td>

<td> 267</td><td> 3840</td>

<td> 268</td><td> 6640</td>

<td> 269</td><td> 9510</td>

<td> 270</td><td> 20500</td>

<td> 271</td><td> 2010</td>

<td> 272</td><td> 3160</td>

<td> 273</td><td> 8180</td>

<td> 274</td><td> 22800</td>

<td> 275</td><td> 4730</td>

<td> 276</td><td> 6710</td>

<td> 277</td><td> 767</td>

<td> 278</td><td> 1560</td>

<td>Example No.</td><td>MPO k¡_nact/ K¡ (1 / s per M)</td>

<td> 279</td><td> 386</td>

<td> 280</td><td> 430</td>

<td> 281</td><td> 1060</td>

<td> 282</td><td> 1180</td>

<td> 283</td><td> 2790</td>

<td> 284</td><td> 1470</td>

<td> 285</td><td> 1750</td>

<td> 286</td><td> 1500</td>

<td> 287</td><td> 2130</td>

<td> 288</td><td> 4230</td>

<td> 289</td><td> 1580</td>

<td> 290</td><td> 1890</td>

<td> 291</td><td> 2450</td>

<td> 292</td><td> 1070</td>

<td> 293</td><td> 1810</td>

<td> 294</td><td> 1910</td>

<td> 295</td><td> 793</td>

<td> 296</td><td> 1570</td>

<td> 297</td><td> 762</td>

<td> 298</td><td> 1080</td>

<td> 299</td><td> 2060</td>

<td> 300</td><td> 2460</td>

<td> 301</td><td> 3330</td>

<td> 302</td><td> 3630</td>

<td> 303</td><td> 5270</td>

<td> 304</td><td> 6290</td>

<td> 305</td><td> 6370</td>

<td> 306</td><td> 6740</td>

<td> 307</td><td> 14400</td>

<td> 308</td><td> 5340</td>

<td> 309</td><td> 3160</td>

<td> 310</td><td> 3110</td>

<td> 311</td><td> 2080</td>

<td> 312</td><td> 17100</td>

<td> 313</td><td> 973</td>

<td> 314</td><td> 429</td>

<td> 315</td><td> 1420</td>

<td> 316</td><td> 3060</td>

<td> 317</td><td> 7380</td>

<td> 318</td><td> 5240</td>

<td> 319</td><td> 7810</td>

<td> 320</td><td> 2390</td>

<td> 321</td><td> 2480</td>

<td> 322</td><td> 2800</td>

<td> 323</td><td> 10200</td>

<td> 324</td><td> 11300</td>

<td> 325</td><td> 1160</td>

<td> 326</td><td> 7480</td>

<td> 327</td><td> 1880</td>

<td>Example No.</td><td>MPO / &lt;nact / K¡ (1 / s per M)</td>

<td> 328</td><td> 4370</td>

<td> 329</td><td> 963</td>

<td> 330</td><td> 5210</td>

<td> 331</td><td> 6330</td>

<td> 332</td><td> 3270</td>

<td> 333</td><td> 6100</td>

<td> 334</td><td> 6840</td>

<td> 335</td><td> 9820</td>

<td> 336</td><td> 589</td>

<td> 337</td><td> 13200</td>

<td> 338</td><td> 1280</td>

<td> 339</td><td> 10400</td>

<td> 340</td><td> 1450</td>

<td> 341</td><td> 14300</td>

<td> 342</td><td> 817</td>

<td> 343</td><td> 3570</td>

<td> 344</td><td> 8480</td>

<td> 345</td><td> 946</td>

<td> 346</td><td> 5890</td>

<td> 347</td><td> 378</td>

<td> 348</td><td> 1400</td>

The following Table 1A provides the myeloperoxidase inhibitory activity for the Examples indicated below, in accordance with the assay described above.

Table 1A MPO k¡_nact/ K¡ for the Examples

<td>Examplo No.</td><td>MPO / &lt;nact / K¡ (1 / s per M)</td>

<td> 349</td><td> 3630</td>

<td> 350</td><td> 8740</td>

<td> 351</td><td> 7870</td>

<td> 352</td><td> 6720</td>

<td> 353</td><td> 11000</td>

<td> 354</td><td> 1830</td>

<td> 355</td><td> 1540</td>

<td> 356</td><td> 2910</td>

<td> 357</td><td> 2940</td>

<td> 358</td><td> 1710</td>

<td> 359</td><td> 2660</td>

<td> 360</td><td> 2280</td>

<td> 361</td><td> 2060</td>

<td> 362</td><td> 2690</td>

<td> 363</td><td> 9680</td>

<td> 364</td><td> 6580</td>

<td> 365</td><td> 9290</td>

<td> 366</td><td> 13600</td>

<td> 367</td><td> 1340</td>

<td> 368</td><td> 3270</td>

<td> 369</td><td> 8040</td>

<td> 370</td><td> 9060</td>

<td> 371</td><td> 4570</td>

<td> 372</td><td> 6250</td>

<td> 373</td><td> 12800</td>

<td> 374</td><td> 4600</td>

<td> 375</td><td> 11300</td>

<td> 376</td><td> 7870</td>

<td> 377</td><td> 8770</td>

<td> 378</td><td> 5040</td>

<td> 379</td><td> 7370</td>

<td> 380</td><td> 4470</td>

<td> 381</td><td> 1970</td>

<td> 382</td><td> 2310</td>

<td> 383</td><td> 5230</td>

<td> 384</td><td> 2930</td>

<td> 385</td><td> 3530</td>

<td> 386</td><td> 4960</td>

<td> 387</td><td> 4720</td>

<td> 388</td><td> 8690</td>

<td> 389</td><td> 4910</td>

<td> 390</td><td> 6250</td>

<td> 391</td><td> 3480</td>

<td> 392</td><td> 5830</td>

<td> 393</td><td> 13600</td>

<td> 394</td><td> 4020</td>

<td> 395</td><td> 6980</td>

<td> 396</td><td> 10900</td>

<td> 397</td><td> 4050</td>

<td> 398</td><td> 4780</td>

<td> 399</td><td> 4860</td>

<td> 400</td><td> 2650</td>

<td> 401</td><td> 4060</td>

<td> 402</td><td> 4810</td>

<td> 403</td><td> 13300</td>

<td> 404</td><td> 6200</td>

<td> 405</td><td> 5970</td>

<td> 406</td><td> 4480</td>

<td> 407</td><td> 18700</td>

<td> 408</td><td> 9890</td>

<td> 409</td><td> 18000</td>

<td> 410</td><td> 3150</td>

<td> 411</td><td> 15000</td>

<td> 412</td><td> 3980</td>

<td> 413</td><td> 6560</td>

<td> 414</td><td> 1680</td>

<td> 415</td><td> 3910</td>

<td> 416</td><td> 4480</td>

<td> 417</td><td> 9280</td>

<td> 418</td><td> 11500</td>

<td> 419</td><td> 1200</td>

<td> 420</td><td> 5210</td>

<td> 421</td><td> 4950</td>

<td> 422</td><td> 4460</td>

<td> 423</td><td> 3290</td>

<td> 424</td><td> 6870</td>

<td> 425</td><td> 13400</td>

<td> 426</td><td> 4410</td>

<td> 427</td><td> 5360</td>

<td> 428</td><td> 5890</td>

<td> 429</td><td> 6620</td>

<td> 430</td><td> 9440</td>

<td> 431</td><td> 3440</td>

<td> 432</td><td> 1410</td>

<td> 433</td><td> 3490</td>

<td> 434</td><td> 4070</td>

<td> 435</td><td> 2420</td>

<td> 436</td><td> 3710</td>

<td> 437</td><td> 3400</td>

<td> 438</td><td> 7550</td>

<td> 439</td><td> 9200</td>

<td> 440</td><td> 3310</td>

<td> 441</td><td> 3260</td>

<td> 442</td><td> 12300</td>

<td> 443</td><td> 7330</td>

<td> 444</td><td> 17400</td>

<td> 445</td><td> 7350</td>

<td> 446</td><td> 14200</td>

<td> 447</td><td> 17200</td>

<td> 448</td><td> 6490</td>

<td> 449</td><td> 12000</td>

<td> 450</td><td> 7730</td>

<td> 451</td><td> 16000</td>

<td> 452</td><td> 11600</td>

<td> 453</td><td> 27800</td>

TPO activity test with Amplex Red.

TPO activity was measured using the same assay as for MPO with 2 μΜ of H₂OR₂ and 30 μΜ of Amplex Red; The reactions were labeled with 1.3 pg of HEK293 cell membrane protein expressing human TPO. The cDNA encoding 933 amino acids of full length human TPO were cloned into the Inducible expression vector pcDNA5 / frt / to (InVItrogen), and 293 stable clones were selected using 100 ug / ml of hygromycin and 15 ug / ml of blasticidine in DMEM weight / 10% FBS. When the cells reached 50-60% confluence, TPO expression was induced in a medium containing all the above components plus 10 ug / ml of doxycycline and 5 ug / ml of hemlna (Sigma). The membranes were isolated from HEK293hTPO by collecting the cells in PBS. The cells were converted to pellets at 1000 xg for 5 minutes at 4 ° C, resuspended in a homogenelzaclone buffer (1 mM sodium bicarbonate, pH 7.4) containing EDTA free protease inhibitor (Roche) , were incubated on ice for 10 minutes and homogenized with Dounce. Nuclear and unused cells were removed by fighting at 1000 xg for 10 minutes at 4 ° C. Then, the supernatant was centrifuged at 25,000 xg for 20 minutes at 4 ° C. The pellet was resuspended in a homogenization buffer and centrifuged again at 25,000 xg for 20 minutes at 4 ° C. The final pellet was resuspended in a storage buffer (50 mM Tris, pH 7, 150 mM NaCI) containing Protease inhibitors, as described above. The membrane concentration was determined with the BCA protein assay (Pierce). TPO activity was measured using the Amplex Red assay, as described above. Consequently, aliquots were obtained based on the activity and stored at -80 ° C.

IC values₅₀ they were determined by representing the Initial velocities (of the first 200 s of each reaction progress curve) as a percentage of Inhibition with respect to the Non-Inhibited reaction (DMSO) as a function of the Inhibitor concentration. The data were adjusted to equation 3

100 y = —- (3) + C ^ c ^ where IC₅₀ It is the concentration of Inhibitor with 50% Inhibition and z is the slope (the slope of the curve at its point of Inflection).

REFERENCES

Copeland, RA (2005). Evaluatlon of Enzyme Inhibitors ¡n Drug Discovery A

Guide for Meclclnal Chemests and Pharmacoloqlsts. Hoboken, Wiley.

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

Human blood test for irreversible inhibition of MPO

To measure the inhibition of MPO activity in a biological system in the present invention, bioassays were performed with human blood collected from human volunteers who were not taking medications, in heparin-treated tubes (APP Pharmaceuticals, LLC, cat # NDC # 63323- 047-10, # 4710). The blood was divided into aliquots, treated with different concentrations of the MPO inhibitor or control vehicle, and quoted with or without bacterial lipopolysaccharides (LPS, InVivogen, cat # tlrl-pelps) to stimulate blood leukocytes in order to simultaneously generate H₂0₂ (a necessary MPO substrate) and release MPO. After 4 hours of incubation at room temperature, the plasma fraction was collected after centrifugation at 2000 xga 4 Ό.

The plasma fraction was divided in two to analyze the total MPO and the active MPO. The total MPO content was determined using a standard sandwich ELISA (capture and detection antibodies: Cell Sciences, Cat # HP9048 and Cell Sciences, Cat # HM2164, clone 266-6K1) and calculated with respect to a standard MPO curve purified (myeloperoxidase, Calbiochem, cat # 475911) prepared by dilution in the autologous donor plasma. MPO activity was determined by capturing total plasma MPO using the capture stage described for the ELISA method. After washing the unbound plasma material, which included the unreacted MPO inhibitor, MPO reaction substrates were added [H₂0₂ (2uM) and Amplex Red (Invitrogen, Cat # A12222)], and the Vmax of the MPO-catalyzed conversion of the Amplex Red substrate into resorufin was determined by measuring the increase in fluorescence (excitation 530 nM, emission 580 nm) with a reader fluorescent plate in a kinetic analysis. The MPO activity of the captured material was compared with that obtained with a standard curve of purified MPO (myeloperoxidase, Calbiochem, cat # 475911) prepared in the autologous donor plasma. The percentage of active myeloperoxidase for each sample was calculated from the relationship between active myeloperoxidase in the Amplex Red test and the total myeloperoxidase obtained from ELISA for each sample. Then, a dose response curve of the MPOi concentration with respect to the MPO activity was plotted, in order to determine the IC value₅₀The administration of the compounds of the present invention can be performed by any method that supplies a compound of the present invention systemically and / or locally. These methods include oral, parenteral, intraduodenal, buccal, intranasal, etc. In general, the compounds of the present invention are administered orally, but parenteral administration (eg, intravenous, intramuscular, subcutaneous or intramedullary) may be used, for example, when oral administration is not suitable for the purpose or If the patient cannot ingest the drug.

For administration to human patients, a daily oral dose of the compounds herein may be in the range of 1 mg to 5000 mg, depending on the mode and frequency of administration, the stage of the disease, the age and the condition of the patient, etc. A daily oral dose in the range of 3 mg to 2000 mg can be used. Another daily oral dose is in the range of 5 mg to 1000 mg. For convenience, the compounds of the present invention can be administered in a unit dose form. If desired, multiple daily doses of the unit dose form may be used to increase the total daily dose. The unit dose form may be, for example, a tablet or a 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 present invention. The total daily dose can be administered in a single dose or in divided doses and, according to the doctor's criteria, can be administered outside the typical range indicated herein.

For administration to human patients, a daily infusion dose of the compounds herein may be in the range of 1 mg to 2000 mg, depending on the mode and frequency of administration, the stage of the disease, age and condition. of the patient, etc. Another daily dose of infusion may be in the range of 5 mg to 1000 mg. The total daily dose can be administered in a single dose or in divided doses and, according to the doctor's criteria, can be administered outside the typical range indicated herein.

These compounds can also be administered to animals, other than humans, for example, for the indications detailed above. The exact administered dose of each active ingredient will vary according to various factors that include, among others, the type of animal and the stage of the disease being treated, the age of the animal and the routes of administration.

A dose of the combined pharmaceutical agents used together with the compounds of Formulas I or IA, which is effective for the condition in question, is used. Doses can be determined by standard tests, such as those referred to and provided herein. The combined agents can be administered simultaneously or sequentially in any order.

These doses are based on an average human subject with a weight of about 60 kg to 70 kg. The doctor can easily determine the doses for subjects whose weight is not in this range, such as children and the elderly.

The dosage regimens can be adjusted to provide the desired optimal response. For example, a single bolus, several divided doses may be administered over a period of time, or the dose may be reduced or increased proportionally, as required by the therapeutic situation. It is especially convenient to formulate parenteral compositions in unit dose form to facilitate administration and dose uniformity. As used herein, the unit dose form refers to physically differentiated units useful as unit doses for the mammalian subjects being treated; Each unit contains a predetermined amount of active compound, calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specification of the unit dose forms of the Invention is determined and depends directly on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the state of the technique to form an active compound for the treatment of sensitivity in individuals.

In this way, the person of the medium level trade will take into account, depending on the description provided herein, that the dose and dosage regimen are adjusted according to the methods known in the therapeutic field. That is, the maximum tolerable dose, the effective amount that provides a detectable therapeutic benefit to a patient and the temporary requirements to administer each agent in order to provide a detectable therapeutic benefit to the patient can be readily determined. Accordingly, while certain doses and administration regimens are exemplified herein, these examples do not limit in any way the dose and the administration regimen that can be provided to a patient when practicing the present Invention.

It should be borne in mind that dose values ​​may vary depending on the type and severity of the condition that is to be relieved, and may include single or multiple doses. It should be taken into account that for any particular subject, the specific dosage regimens must be adjusted over time according to the individual needs and professional criteria of the person who administers or supervises the administration of the compositions; The dose ranges indicated herein are only exemplary and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted according to pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, such as toxic effects and / or laboratory values. Thus, the present invention encompasses the increase in the intra-patient dose as determined by a person of the mid-level trade. The determination of appropriate doses and administration regimens of the chemotherapeutic agent is known in the relevant field, and the person of the medium level profession would understand that it is understood once the explanations provided herein are provided.

The present invention also includes the use of a compound of Formulas I or IA for use as a medicament (such as a unit dose tablet or a unit dose capsule). In another embodiment, the present invention comprises the use of a compound of Formulas I or IA for the manufacture of a medicament (such as a unit dose tablet or a unit dose capsule) to treat one or more of the conditions Previously identified in the previous sections that analyze the treatment methods.

A pharmaceutical composition of the invention can be prepared, packaged or sold in quantities, as a single unit dose or as a plurality of single unit doses. As used herein, a unit dose is a differentiated amount of the pharmaceutical composition comprising a predetermined amount of the active Ingredient. In general, the amount of active ingredient is equal to the dose of active ingredient that will be administered to a subject or a convenient fraction of that dose, for example, half or a third of that dose.

The compounds described herein may be administered as a formulation comprising a pharmaceutically effective amount of a compound of Formulas I or IA, together with one or more pharmaceutically acceptable excipients, which include carriers, carriers and diluents. The term "excipient" herein means any substance, which is not a therapeutic agent in itself, that is used as a diluent, adjuvant or vehicle for the delivery of a therapeutic agent to a subject or that is added to a pharmaceutical composition for improve its storage or handling properties, or to allow or facilitate the formation of a solid dosage form, such as a tablet, a capsule, a solution or suspension suitable for oral, parenteral, intraradmal, subcutaneous or topical application. Excipients may include, by way of illustration, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, sliding agents, stabilizers, substances added to disguise or counteract an unpleasant taste or smell, flavorings, tinctures, fragrances and substances added to improve the appearance of the composition. Acceptable excipients include, but are not limited to, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acid, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrlna , mannitol, sorbitol, lactose, sucrose, starches, gelatin, cellulosic materials, such as cellulose esters of alkanoic acids and cellulose alkylsters, will be with low melting point, cocoa butter or powder, polymers, such as polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol, and other pharmaceutically acceptable materials. Examples of excipients and their use can be found in Remington's Pharmaceutical Sciences,

20.^to edition (Llpplncott Williams &amp; Wllklns, 2000). The choice of excipient will largely depend 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.

The compounds herein may be formulated for oral, buccal, intranasal, parenteral (eg, intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by Inhalation. The compounds of the invention can also be formulated for sustained delivery.

The methods for preparing various pharmaceutical compositions with a certain amount of active Ingredient are known by the people of the medium level trade or will be apparent after analyzing the present description. For examples of methods for preparing pharmaceutical compositions see Remington's Pharmaceutical Sciences, 20.^to edition (Llpplncott Williams &amp; Wllklns, 2000).

The pharmaceutical compositions according to the invention may contain 0.1% -95% of the compounds of the present invention, preferably 1% -70%. In any case, the composition to be administered contains an amount of compounds according to the invention in an amount effective to treat the disease / condition of the subject being treated.

Because one aspect of the present invention relates to the treatment of the diseases / conditions described herein with a combination of active ingredients that can be administered separately, the invention also refers to the combination of separate pharmaceutical compositions in the form of kit The kit comprises two separate pharmaceutical compositions: a compound of Formulas I or IA, a prodrug of this or a salt of that 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 aluminum foil wrapper. In general, the kit comprises instructions for the administration of the separate components. The form of the kit is of particular convenience when the separated components are preferably administered in different dosage forms (for example, orally and parenterally), when they are administered at different dosage intervals or when the treating physician desires the titration of the individual components of the combination.

An example of a kit is called blister. Blister packs are known in the packaging industry and are widely used for the packaging of pharmaceutical unit dose forms (tablets, capsules and the like). In general, the blister packs consist of a film of relatively rigid material covered with a sheet, preferably of a transparent plastic material. Cavities are formed in the plastic sheet during the packaging process. The cavities have the size and shape of the tablets or capsules to be packaged. Then, the tablets or capsules are placed in the cavities, and the film of relatively rigid material is sealed against the plastic sheet on the face of the sheet opposite the direction in which the cavities formed. Consequently, the tablets or capsules are sealed in the cavities between the plastic sheet and the film. Preferably, the strength of the film is such that the tablets or capsules can be manually removed from the blister by pressing the cavity; In this way, the film opens in the place of the cavity. The tablet or capsule can then be removed through that opening.

It may be convenient to provide a memory aid in the kit, for example, numbers next to the tablets or capsules, so that the numbers correspond to the days of the regimen during which the specified tablets or capsules should be ingested. Another example of a memory aid is a calendar printed on the card, for example, First week, Monday, Tuesday, etc ... Second week, Monday, Tuesday, ... etc. Other variations of memory aid may also be noted. A daily dose may be a single tablet or capsule or several pills or capsules administered on a given day. In addition, a daily dose of the compound of Formulas I or IA may consist of one tablet or one capsule, while a daily dose of the second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

In another specific embodiment of the invention, a dispenser is provided designed to deliver daily doses one at a time, in the order in which they should be used. Preferably, the dispenser has a memory aid to further facilitate compliance with the regimen. An example of that memory aid is a mechanical counter that indicates the amount of daily doses that were administered. Another example of a memory aid is a battery-powered memory microchip coupled to a liquid crystal display, or an audible reminder signal that, for example, reads aloud the date the last dose was taken and / or reminds the subject when You must take the next dose.

In addition, because one aspect of the present invention relates to the treatment of the diseases / conditions described herein with a combination of active ingredients that can be co-administered, the invention also relates to the combination of separate pharmaceutical compositions. in a single dosage form, such as a single tablet or capsule, a tablet or a two-layer or multi-layer capsule, or by using components or compartments segregated within a tablet or capsule.

The active ingredient can be supplied as a solution in an aqueous or non-aqueous vehicle, with or without solvents, cosolvents, excipients or additional complexing agents selected from pharmaceutically acceptable diluents, excipients, carriers or carriers.

An example intravenous formulation is prepared as follows: Formulation: Intravenous solution

Ingredient_Quantity

Active ingredient dissolved in 5% dextrose injection, USP 150 mg 5% dextrose injection, USP_1.0 ml

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

The active ingredient can be formulated as a solid dispersion or as a self-emulsifying drug delivery system (SEDDS) with pharmaceutically acceptable excipients.

The active ingredient can be formulated as a tablet or an immediate-release or modified-release capsule. Alternatively, the active ingredient can be supplied as the active ingredient only within a capsule shell, without additional excipients.

GENERAL EXPERIMENTAL PROCEDURES

All chemicals, reagents and solvents were purchased from commercial sources when available and used without further purification. Proton nuclear magnetic resonance spectroscopy (¹H NMR) was recorded with 400 and 500 MHz Vanan spectrometers. Chemical shifts are expressed in parts per million with respect to tetramethylsilane. The shapes of the peaks are indicated as follows: s, singlet; d, double up; t, triplet; q, quartet; m, multiplet; br s, broad singlet. Mass spectrometry (MS) was performed using atmospheric pressure chemical ionization (APCI) or electron dispersion ionization (ES) sources. The observed mass (obs. Mass) indicated in the Tables corresponds to the exact mass of the molecule of origin plus one, unless otherwise indicated. Silica gel chromatography was mainly performed using Biotage or ISCO medium pressure systems with columns filled by several commercial vendors, including Biotage and ISCO. The microanalyses were performed using Quantitative Technologies Inc. and were within 0.4% of the calculated values. The terms "concentrated" and "evaporated" refer to the removal of solvent under reduced pressure in a rotary evaporator with a bath at a temperature below 60 ° C. The abbreviations "min" and "h" mean "minutes" and "hours", respectively.

X-ray powder diffraction

The powder diffraction analysis was performed with a Bruker D8 diffractometer equipped with a Cu radiation source, fixed slots (divergence = 1.0 mm, anti-dispersion = 0.6 mm and reception = 0.6 mm) and a counting detector by scintillation Data were collected on the zeta-zeta goniometer with a wavelength of Cu Και = 1,54056 Á from 3.0 to 40.0 degrees 2-zeta with a stage size of 0.040 degrees and a stage time of 2 , 0 seconds. The voltage and amperage of the X-ray tube were set at 40 kV and 40 mA, respectively. Samples were prepared by placing them on a Nickel Disk plate (Gasser &amp; Sons, Inc. Commack, NY) and rotating them during data collection. Data were collected and analyzed with Bruker DIFFRAC Plus software (version 2.6).

I. Section of the beta ketoester pathway

A. Section of the carboxylic acid pathway

Preparation 1

OMe

EtO₂C

Cl

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

A 3000 ml three-necked flask with a nitrogen-purged round bottom was charged with magnesium ethoxide (67.46 g, 589.51 mmol) and THF (1100 ml), and the resulting mixture was stirred while adding acidic malonate of ethyl (162.26 g, 1.18 mol; 145.00 ml diluted in 100 ml of THF); The mixture was heated at 45 ° C for 4 hours. Meanwhile, a 2000 ml three-necked flask with a nitrogen-purged round bottom was charged with 5-chloro-2-methoxybenzoic acid (100 g, 536 mmol) and THF (600 ml). To this stirred mixture at room temperature was added 1,1'carbonyldiimidazole (95.59 g, 589.5 mmol) in portions to avoid excess foam. After 3 hours of stirring at room temperature, the second solution was gradually added to the first solution. After the 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 I) and then 2N HCI (500 ml). After mixing, the layers were separated, and the organic phase was washed sequentially with 2N HCI (500 ml), saturated sodium bicarbonate (500 ml) and water (500 ml). The organic phase was concentrated under reduced pressure, and the residue was absorbed in ethyl acetate (1000 ml) and concentrated again to obtain the title compound (104.94 g).

MS (ES +) 257.2 [M + 1] *. ¹H NMR showed the product as a 7.5: 1 mixture of keto: enol. 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).

(Z) -ethyl 3 ((2-amino-2-oxoethyl) amino) -3- (5-chloro-2-methoxyphenyl) acrylate

<img file="CU20140049A7_D0014.tif" />

A 5 I reaction vessel was charged with methanol (3.3 I), sodium methoxide (102.4 g, 1.8 mol) and gllclnamlda hydrochloride (202 g, 1.8 mol). The mixture was heated at 65 ° C for 1 hour before cooling to 50 ° C and adding acetic acid (514.25 mmol, 30.88 g, 29.47 ml) and 3- (5-chloro-2-methoxyphenyl) -3-ethyl oxopropanoate (300 g, 1.03 mol). After heating at reflux for 16 hours, the reaction mixture was stirred as it cooled to 10 ° C. After 30 min, the resulting solid was collected by vacuum filtration and removed dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65 ° C) for 14 hours to obtain the title compound ( 339.4 g).

MS (ES +) 313.2 [M + 1]⁺. ¹H NMR (500 MHz, DMSO-d₆) 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, &lt;7 = 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) 3.56 (br. S., 1 H) 3.45 (br. S., 1 H) 1.18 (t, J = 7.Q7 Hz, 3 H).

Example 1

NH₂ Cl

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

A reaction vessel equipped with an efficient agitator was charged with 3 ((2-amine-2-oxoethyl) amine) -3- (5-chloro-2-methoxylfenol) acrylate of ( Z) -etyl (15 g, 50.2 mmol), butyl acetate (150 ml) and trimethylsilyl isothiocyanate (160.7 mmol, 21.1 g, 22.7 ml), and the mixture was heated to reflux. After 15 hours, the mixture was cooled to 30 Ό and treated with 1 N aqueous sodium hydroxide (112.5 ml, 112.5 mmol). After 30 min, the organic layer was separated and extracted with another portion of 1 N sodium hydroxide (37.5 ml, 37.5 mmol). The combined aqueous phases were extracted twice with dichloromethane (2 x 45 ml), filtered and treated with 6 N HCI until a pH of 2.5 was achieved. After 1 hour of stirring, the resulting solid was isolated by vacuum filtration, resuspended in 100 ml of a 1: 1 solution of methanolagua, heated while stirring at 50 ° C for 2 hours and cooled to temperature Ambient before collecting the solid by vacuum filtration, remove it dry and dry it in a vacuum oven (20 mm Hg, 50 ° C) for 12 hours to obtain 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 = 1.71 Hz, 1 H) 5.41 (br. s, 1 H) 3.89 (br. s, 1 H) 3.84 (s, 3 H).

Alternative preparation of Example 1

<img file="CU20140049A7_D0015.tif" />

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

A suspension of 3 - ((2-aml-2-oxoetll) amine) -3- (5-chloro-2-methoxlfenll) acrylate of (Z) -ethyl (20 g, 63 mmol) in an acetate mixture of butyl (140 ml) and DMF (38 ml) was treated with trimethylsilyl sotlocyanate (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 suspended for 8 hours. The solids formed 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 obtain a tan solid. The solid was dissolved in a 5: 1 mixture of DMF and water at room temperature, and more water was added slowly to crystallize the material. The suspension was cooled to 10 ° C and stirred for 8 hours; It was then filtered and washed 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 suspension was heated to 50 ° C and maintained at this temperature for 2 hours. After cooling to 10 ° C for 30 minutes, the suspension was maintained at this temperature for 1 hour, filtered, washed with water and dried in a vacuum oven at 50 ° C for 8 hours to obtain the title compound. Like a white solid

MS (ES +) 326.0 [M + 1]⁺. ¹H NMR (500 MHz, DMSO-cQ 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).

Preparation 3

OMe

EtO₂C

NaO '

OMe

- (2,5-Dimethoxyphenyl) -3-ethoxy-3-oxoprop-1-en-1-sodium lalate

A 20 ml reaction vessel was charged with magnesium ethoxide (3.61 mol; 413.52 g) and THF (6.6 I), and the resulting mixture was stirred while adding ethyl acid malonate (7.23 moles; 888.89 ml; 994.67 g; diluted with 20 ml of THF); The mixture was heated at 45 ° C for 4 hours. Meanwhile, a 20 I reactor was charged with 2,5-dlmethoxylbenzolco acid (3.29 mol; 600.00 g) and THF (3.6 I). To this stirred mixture at room temperature was added 1, Τ-carbonlldllmldazol (3.61 mol; 585.98 g) in portions to avoid excess foam. After 3 hours of stirring at room temperature, the second solution was gradually added to the first solution. After the 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 I) and then 2 N HCI (3 I). After mixing, the layers were separated, and the organic phase was washed sequentially with 2N HCI (3 I), saturated sodium bicarbonate (3 I) and water (3 I). The organic solution was concentrated under reduced pressure, the residue was absorbed in ethyl acetate (6 I) and concentrated again to obtain an oil, which was transferred to a 20 I reaction vessel with 5 I of ethyl acetate and It was treated with sodium methoxide (3.45 mol; 793.00 ml of a 4.35 M solution in methanol). After 3 hours of stirring at room temperature, an additional 6 I of ethyl acetate was added, and the solid was collected by vacuum filtration and dried overnight in a vacuum oven at 40 ° C to obtain 661 grams of the product of the title.

MS (ES +) 253.1 [M + 1]⁺. ¹H NMR (400 MHz, DMSO-cfe) 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).

<img file="CU20140049A7_D0016.tif" />

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

A 5 I reaction vessel was charged with methanol (3.3 I), sodium methoxide (102.4 g, 1.8 mol) and glycinamide hydrochloride (202 g, 1.8 mol). The mixture was heated at 65 ° C for 1 hour before cooling to 50 ° C and adding acetic acid (514.25 mmol, 30.88 g, 29.47 ml) and 3- (2,5-dlmethoxlfenil) -3-ethyl oxopropanoate (300 g, 1.03 mol). After heating at reflux for 16 hours, the reaction mixture was stirred as it cooled to 10 ° C. After 30 min, the resulting solid was collected by vacuum filtration and removed dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65 ° C) for 14 hours to obtain the title compound ( 339.4 g).

MS (ES +) 309.1 [M + 1]⁺. ¹H NMR (400 MHz, DMSO-cfe) 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 I reaction vessel equipped with an efficient stirrer was charged with 3 - ((2-amine-2-oxoethyl) amine) -3- (2,5-dimethoxyphenyl) ) (Z) -ethyl acrylate (1.30 mol; 400.00 g), butyl acetate (3.4 I) and trimethylsilyl isothiocyanate (4.15 mol; 585.67 ml; 544.96 g ), and the mixture was heated to reflux. After 16 hours, the mixture was cooled to 40 ° C and treated with 2N aqueous sodium hydroxide (1.95 I). The organic layer was separated and extracted with another portion of 2 N sodium hydroxide (0.325 I). The combined aqueous phases were filtered, extracted twice with dichloromethane (2 x 1.6 I) and slowly added to a stirred 3N aqueous HCI solution (1.3 I) at room temperature. After 30 min of stirring, the resulting solid was isolated by vacuum filtration, rinsed with water and removed dry to obtain a cake moistened with water (640 g). The cake was dissolved in dimethylformamide (2.4 I) at ° C and stirred while adding water (2 I) slowly to the solution. The mixture was gradually cooled to room temperature, and the resulting solid was isolated by vacuum filtration, rinsed with water and dried to obtain 245 g of solid. Then, this solid was suspended in 1.25 I of methanol and stirred while 1.25 I of water was added. The mixture was heated while stirring at 50 ° C for 2 hours and then cooled to 10 ° C for 2 hours before collecting the solid by vacuum filtration; Dry removed before drying in a vacuum oven (20 mm Hg, 60 ° C) to obtain 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 pathway section

<img file="CU20140049A7_D0017.tif" />

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

To a three-necked round bottom flask equipped with a mechanical stirrer in N₂, potassium tert-butoxide (1 M in THF, 108.77 ml, 108.77 mmol) was added, and then a solution of 2,4-dimethoxyacetophenone (10.00 g, 54.38 mmol) and dimethyl carbonate (13.93 ml, 163.15 mmol) in methyl tert-butyl ether (50 ml) by dripping by an addition funnel for 1.5 hours. During the addition, the reaction changed from an initial cloudy yellow mixture to a thick orange-red suspension. The reaction mixture was stirred at room temperature overnight. A solution of aqueous citric acid (0.5 N, 110.95 ml, 54.39 mmol) was added by an addition funnel to inactivate the reaction. The exotherm was observed during inactivation, and the solids dissolved to obtain an orange mixture. The layers were separated, and the aqueous layer was extracted with methyl tert-butyl ether (2 x 25 ml). The combined organic extracts were concentrated in low volume. Heptane (50 ml) was added, and the brown solids precipitated. The resulting suspension was stirred in N₂overnight at room temperature. The solids were filtered and dried in N₂to obtain the title compound (11.05 g, 85% yield) as a beige powder.

MS (ES +) 239.1 [M + 1]⁺. ¹H NMR (500 MHz, CDCI₃) δ 7.95 (d, J = 8.78 Hz, 1 H) 6.57 (dd, J = 8.78, 2.20 Hz, 1 H) 6.45 (d, J = 2.2Q Hz, 1 H) 3.94 (s, 2 H) 3.88 ( s, 3 H) 3.87 (s, 3 H) 3.73 (s, 3 H).

Preparation 6

MeO₂C

HN

<img file="CU20140049A7_D0018.tif" />

OMe

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), ethanolamine (0.88 ml, 14.69 mmol) was added, and the reaction mixture was heated to 83 ° C. More ethanolamine (0.88 ml, 14.69 mmol) was added to the reaction mixture at 2, 4 and 6 hours. After 48 hours of stirring at 80 ° C, the reaction mixture was cooled and concentrated under reduced pressure before suspending the residue in equal parts of a solution of saturated sodium bicarbonate and water in N₂. After stirring overnight, the solids were collected by vacuum filtration and dried in a vacuum oven at 30 ° C overnight to obtain the title compound (2.72 g, 63%) as a beige powder .

¹H NMR (400 MHz, CDCI₃) δ 8.77 (t, J = 5.37 Hz, 1 H) 7.13 (d, J = 8.29 Hz, 1 H) 6,476.52 (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, J = 5.53, 5.53 Hz, 2 H).

Example 3

OMe

OH

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

To a solution of 3- (2,4-dimethoxyphenyl) -3 - ((2-hydroxyl) amine) (Z) methyl acrylate (9.50 g, 33.77 mmol) in 2-MeTHF (100 ml), (trimethylsilyl) isothiocyanate (23.80 ml, 168.79 mmol) was added, and the reaction mixture was heated to 85 ° C. After stirring overnight, the reaction mixture was cooled, extracted with a solution of 1 N aqueous NaOH (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 was acidified to pH 4 with concentrated HCI. The resulting solids were filtered, washed with water (2 x 50 ml) and dried in N₂ overnight to get 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 cooling to room temperature and stirring overnight, the solids were collected by vacuum filtration, washed with water and dried under high vacuum to obtain 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. Section of the aryl halide pathway

Preparation 7

<img file="CU20140049A7_D0019.tif" />

3- (2,6-dimethoxypyridin-3-yl) -3-ethoxy acrylate of (Z, E) -ethyl

Bis (tr¡-f-butylphosphine) palladium (47 mg, 0.092 mmol)) and lithium chloride (292 mg, 0.27 mmol) were added to a flask equipped with a reflux condenser, and the apparatus it was evacuated in a vacuum and it was refilled several times with N₂. Using a cannula, a degassed solution of anhydrous 1,4-dioxane (8 ml) in N was added to this flask₂, and then 3-bromo-2,6-d-methoxypropylene (500 mg, 2.29 mmol), N, Nichlorhexylmethylamine (540 ul, 2.52 mmol) and ethyl 3-ethoxy acrylate (1 , 0 ml, 6.88 mmol), and the resulting orange solution was heated to 110 O. After 20 hours, the reaction mixture was cooled to room temperature, nated 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 Na₂SW₄ and concentrated in vacuo. The residue was purified by silica chromatography eluted with 0-50% EtOAc / heptane to obtain the title compound (604 mg, 94%) as an amber oil.¹H NMR showed that the product was composed of a 2.5: 1 mixture of E / Z isomers.

<img file="CU20140049A7_D0020.tif" />

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

To a solution of 3- (2,6-dlmethox¡p¡r¡d¡n-3-¡) -3-ethoxy ethyl acrylate (600 mg,

2.13 mmol) in CH₂CI₂ (18 ml) 3N aqueous HCI (3.5 ml) was gradually added. The reaction mixture was stirred at room temperature for 2 hours and then carefully added to a saturated sodium bicarbonate solution (30 ml). The layers were separated, and the aqueous layer was extracted with CH₂CI₂. The combined organic extracts were passed through a cotton plug to dry and concentrate in vacuo. The resulting oil was purified by flash chromatography (060% EtOAc / heptanes) to obtain 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) 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. Derivatization and amine deprotection pathway

Preparation 9

<img file="CU20140049A7_D0021.tif" />

3- (2,6-Dimethoxypyridin-3-yl) -3 - ((2-hydroxyethyl) amino) (Z) -ethyl acrylate

To a solution of ethyl 3- (2,6-d ¡methox¡plr¡d¡n-3-l) -3-oxopropanoate (500 mg,

1.97 mmol) in EtOH (4 ml), 2-aminoethanol (0.60 ml, 9.9 mmol) was added and then acetic acid (0.63 ml, 9.9 mmol). The reaction mixture was heated at 90 ° C for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was divided into EtOAc and water. The organic layer was concentrated in vacuo, and the crude material was purified by silica gel chromatography eluted with 20-80% EtOAc / heptane to obtain 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., 1 H) 1.27 (t, J = 7.07 Hz, 3 H).

Example 4

OMe

OH

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

To a solution of 3- (2,6-d¡metox¡p¡r¡d¡n-3-¡) -3 - ((2-h¡drox¡et¡l) amÃno) acrylate of (Z) -ethyl (100 mg, 0.34 mmol) in 2-MeTHF (1.0 ml), was added (trimetlslsl) sotocotanate (0.30 ml, 2 , 0 mmol), and the reaction mixture was heated 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 obtain 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)

Preparation 10

OMe

EtO₂C

<img file="CU20140049A7_D0022.tif" />

OMe

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

A solution of ethyl 3- (2,4-dlmethoxlfenyl) -3-oxopropanoate (41.91 g, 166 mmol), tert-butyl 2-amnoethylcarbamate (54.7 g, 342 mmol) and acetic acid 16.14 g, 269 mmol) in ethanol (180 ml) was heated at reflux for 5.3 h. After removing most of the solvent by rotary evaporation, the resulting oil was partitioned into EtOAc (ca. 300 ml) and 10% aqueous ammonium chloride (w / v). The EtOAc layer was separated and washed with water, 10% aqueous ammonium chloride (w / v) (3 ml) and brine (10 ml). The EtOAc layer was washed with saturated aqueous sodium bicarbonate, brine (6 ml) was added, and the emulsion was allowed to settle. Finally, the EtOAc layer was washed with brine and dried over sodium sulfate. Evaporation of the volatile components of the EtOAc layer produced a viscous amber candy (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).

<img file="CU20140049A7_D0023.tif" />

Terbutyl 2- (6- (2,4-dimethoxyphenyl) -4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) -yl) ethylcarbamate

(Trlmetllslllljlsotloclanate (66 ml, 470 mmol) was added to a solution of 3- (2 (tert-butoxycarbonyl) ethnolamine) -3- (2,4-dimethoxyphenyl) (Z) -ethyl acrylate (62.3 g, 158 mmol) in 2-MeTHF (160 ml) After refluxing under nitrogen for 15 h, the reaction mixture was cooled to room temperature and It was born by careful addition of saturated aqueous sodium bicarbonate (470 ml). The reaction mixture was extracted with dichloromethane, and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to obtain a yellow-amber foam, which was purified by silica chromatography eluted with 0-80% ethyl acetate in heptane to obtain 49.2 g of solid. These solids were resuspended in 1: 1 EtOAc / heptane at 70 Ό for 1 h and then at room temperature for an additional 1 h. The resulting solids were isolated by vacuum filtration, rinsed with additional 1: 1 EtOAc / heptane and dried in the filter. The title compound was obtained as a white solid mlcrocrystalline (38.3 g, 59.5% yield): LCMS (ESI) m / z: 408.3 [M + H] (100%).¹H NMR (500 MHz, CDCI₃, main 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).

Example 6

<img file="CU20140049A7_D0024.tif" />

1 - (2-Aminoethyl) -6- (2 hydrochloride_!4-dimethoxyphenyl) -2-thioxo-2,3-dihydropyrimidin-4 (1H) one

To a solution of EtOH (50 ml, 860 mmol) in EtOAc (390 ml), cooled in an ice / water bath, acetyl chloride (55 ml, 770 mmol) was slowly added over 3 minutes. After 5 minutes, the cooling bath was removed, and after 45 min of stirring, the solution was added at 2- (6- (2,4-dlmethoxfen) -4-oxo-2-thoxo- 3,4dlhldroplrlmldln-1 (2H) -ll) tert-butyl carbamate (31.7 g, 77.8 mmol). Over time, a suspension formed, and after stirring for 5 h, the solid was collected by vacuum filtration and rinsed with EtOAc. The solid was dried dry and dried further under vacuum to obtain 26.6 g (99.3%) of the 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).

<img file="CU20140049A7_D0025.tif" />

nh₂

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

Diisopropylethylamine (0.22 ml, 1.3 mmol) was added to a hydrochloride suspension of 1- (2-amnoetl) -6- (2,4-dmethoxyphenyl) -2- thio-2,3-d¡h¡drop¡rim¡d¡n-4 (1 H) one (181.6 mg, 0.528 mmol) (the product of Example 6) and 1 H-pyrazole hydrochloride- 1-carboxamidine (90.6 mg, 0.618 mmol) in DMF (0.55 ml). After 1 h of heating at 55 ° C, the reaction mixture was cooled to room temperature, diluted with EtOH (1.6 ml), and the solid product was collected by vacuum filtration and rinsed with additional EtOH. The isolated solid was resuspended in EtOH (2.1 ml) for 3 h at room temperature before collecting it again by vacuum filtration and rinsing it with additional EtOH. After drying, the desired product was obtained as a colorless solid. The solubility data of this product coincide with those of 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 of the previous reaction (116.3 mg, 0.333 mmol) was suspended in dioxane and treated with a solution of 4.0 M HCI / dioxane (0.30 ml, 1.2 mmol). After stirring in a vortex, volatile components of the mixture were removed to obtain a white solid (130.6 mg, 0.338 mmol). LCMS (ESI) m / z: 350.1 [M + H] (100%).

Preparation 11

<img file="CU20140049A7_D0026.tif" />

2- (2- (6- (2,4-Dimethoxyphenyl) -4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) -yl) ethylamino) -2-butyloethylcarbamate tert-butyl ester

To a hydrochloride solution of 1- (2-amnoetl) -6- (2,4-dlmethoxphafen) -2-thoxo2,3-d¡h¡drop¡r¡m¡ dn-4 (1 H) -one (123 mg, 0.4 mmol) (the product of Example 6) in dry methane chloride (4 ml), 0- (7-azabenzotrlazole-1-hexafluorophosphate) was added -N, N, N ', N'-tetramethyluronium (182 mg, 0.48 mmol), tert-butoxycarbonyllaminoacetic acid (70 mg, 0.4 mmol) and diisopropylethylamine (336 mg, 1.6 mmol) . After stirring overnight at RT, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (1: 1 petroleum ether: ethyl acetate) to obtain 2- (2- ( 6- (2,4-d¡metox¡fen¡l) -4-oxo-2-t¡oxo-3,4d¡h¡drop¡r¡m¡d¡n-1 (2H) -¡l) ethanol) -2-oxoetylcarbamate tert-butyl (120 mg, 65%).

Example 8

<img file="CU20140049A7_D0027.tif" />

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

To a solution of 2- (2- (6- (2,4-d¡metox¡fen¡l) -4-oxo-2-tóoxo-3,4-d¡h¡drop¡r¡m¡ dnn74

1 (2H) -l) ethylamine) -2-oxoethylcarbamate tert-butyl (70 mg, 0.15 mmol) in ethyl acetate (2 ml) a solution of HCI in acetate was added ethyl (2 ml). After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure to obtain 2-amino-N- (2- (6- (2,4-dimethoxyphenyl) -4-oxo-2-thioxo-) hydrochloride. 3,4-d¡h¡drop¡r¡mid¡n-1 (2H) -yl) ethyl) acetamide as a solid (65 mg, 100%).

II. Section of the 6-iodo-thiouracil route

Preparation 12

SW

<img file="CU20140049A7_D0028.tif" />

N - ((2-methoxyethyl) carbamothioyl) benzamide

2-Methoxyethylamine (17.7 ml, 202.2 mmol) was added dropwise over 30 minutes to a stirred solution of benzoylisothiocyanate (30.00 g, 183.8 mmol) in CH₂CI₂ (300 ml) at room temperature under argon, and the mixture was stirred at room temperature 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 was solidified at rest to obtain the title compound (41.85 g, 96%). The material was used directly in the next step without further purification.

Preparation 13

NH

OMe

- (2-methoxyethyl) thiourea

A solution of / V - ((2-methoxyethyl) carbamotyl or 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 temperature 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 in Na₂SW₄ and concentrated in vacuo. The resulting yellow oil was solidified at rest to obtain 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).

Preparation 14

OR

OMe

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

To a stirred solution of 1- (2-methoxyletl) tlourea (21.38 g, 159.3 mmol) and ethyl 3,3dletoxylpropanoate (46.5 ml, 239.0 mmol) in MeOH (300 ml), a freshly prepared solution of 0.96 N sodium methoxide in MeOH (250 ml, 239.0 mmol) was added dropwise over 30 minutes at room temperature under argon. The reaction mixture was heated at 60 ° C for 45 minutes and cooled to room temperature. The solvent was removed under reduced pressure, and toluene (250 ml) was added to the residue. The mixture was stirred at reflux for a further 3 hours and then cooled to room temperature. Water (200 ml) was added, and the layers separated. The aqueous layer was washed with CH₂CI₂ (50 ml), neutralized with 2N aqueous HCI and extracted with CH₂CI₂ (3 x 200 ml). The combined organic layers were dried in Na₂SW₄ and concentrated in vacuo. The residue was recrystallized from / -PrOH (200 ml) to obtain 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).

Preparation 15

OMe

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

To a stirred solution of diisopropylamine (8.3 ml, 59.10 mmol) in THF (50 ml) n-butyllithium (2 N in hexanes, 30.0 ml, 60.0 mmol) was added dropwise to -78 ° C in argon. The reaction mixture was slowly heated to -20 ° C and then cooled to -78 ° C. A solution of 1- (2-methoxetl) -2-txox-2,3-d¡hldrop¡r¡m¡d¡n-4 (1 H) -one (5.0 g, 26.85 mmol) in THF (50 ml) was added dropwise at -78 ° C. The reaction mixture was slowly heated at -10 ° C for 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 temperature for 20 hours. The 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 1 N aqueous HCI 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 temperature, and the solids were collected by filtration to obtain 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 obtain a second batch of the title compound (3.10 g, 18%) as a cream-colored solid (72% combined yield).

MS (ES +) 313.0 [M + 1]⁺. 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).

Preparation 16

MeS N

OMe

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

To a stirred solution of 6-iodo-1- (2-methoxetl) -2-tiox-2,3-d¡h¡drop¡rlm¡d¡n4 (1H) -ona (9 , 00 g, 28.83 mmol) in MeCN (200 ml), diisopropylethylamine (5.0 ml, 28.83 mmol) and also iodomethane (9.0 ml, 144.17 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was divided by CH₂CI₂ (200 ml) and 1 N 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 crushing with CH₂CI₂/ heptane to obtain 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).

HE HAS. Suzuki track section

Preparation 17

<img file="CU20140049A7_D0029.tif" />

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

To a mixture of 6-iodo-1- (2-methoxetl) -2- (methyl) p¡r¡m¡d¡n-4 (1H) -one (100 mg, 0.31 mmol), (2,5-dimethoxyphenyl) boron acid (0.37 mmol, 1.2 equiv.) And dichloropaladium (ll) of [1,1'-bis (d ¡fen¡lfosf No) ferrocene] (14 mg, 0.017 mmol, 0.05 equiv) degassed 1,4-dioxane (2 ml) was added, and then 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

<img file="CU20140049A7_D0030.tif" />

6- (2,5-dimethoxyphenyl) -1 - (2-methoxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) -one

Ammonium sulphide (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 (theoretical yield of 0.31 mmol), and The mixture was subjected to microwave irradiation at 75 ° C for 30 minutes. The reaction mixture was cooled to room temperature, absorbed in CH₂CI₂ (10 ml) and water (10 ml), then made basic with 2N NaOH. The layers were separated, and the aqueous layer was washed with CH₂CI₂ (2x10 ml). Then, the aqueous layer was acidified to pH 6 with 2N aqueous HCI 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 obtain the desired product (38 mg, 38% in two steps) as a 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)

II B. Neqlshl track section

Preparation 18

<img file="CU20140049A7_D0031.tif" />

- (2-Methoxyethyl) -2- (methylthio) -6- (pyridin-2-yl) pyrimidin-4 (1 H) -one

N-Butyl lithium (2.0 M, 0.32 ml, 0.64 mmol) was added slowly to 2-bromopyrldine (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 a further 30 minutes, while heating at room temperature. To the reaction mixture was added 6-iodo-1- (2-methoxetl) -2- (methyl) plrmmd-4 (1H) -one (200 mg , 0.61 mmol), and then, three (d¡benc¡l¡denaceton) dlpalad¡o (0) (27 mg, 0.03 mmol), 2d¡c¡clohex¡lfosf¡no-2 ' , 6'-d¡methox¡b¡fenllo (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 (3 x 10 ml) and washed with water (3x10 ml). The aqueous layer was then acidified with 2M HCI at pH 4, and the product was extracted with DCM (3 x 10 ml) and dried over MgSO₄. The solvent was removed in vacuo to obtain an orange oil (100 mg) as a mixture of 1- (2-methoxyl) -2- (methyl) -6- (pldrn- 2-¡l) p¡r¡m¡d¡n-4 (1 H) -ona (37%) and 1- (2-methoxetl) -2- (met¡lt¡o) p¡ rlmld¡n-4 (1 H) -one (32%).

<img file="CU20140049A7_D0032.tif" />

1- (2-Methoxyethyl) -6- (pyridin-2-yl) -2-thioxo-2,3-dihydropyrimidin-4 (1H) -one

A mixture of 1 - (2-methoxetl) -2- (metllt) -6- (p¡r¡d¡n-2-¡) p¡r¡m¡d¡n -4 (1 H) -one crude (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), made basic with 2M NaOH and washed with dichloromethane (3x10 ml). The aqueous layer was acidified to pH 6 with 2M HCI 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 acid method to obtain the product as a brown solid (3 mg, 3%).

MS (ES +) 264.07 [M + H]⁺. 1H NMR (400 MHz, CDCI3) δ 8.76 (br s, 1 H), 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 in Table 2 were prepared from the corresponding carboxylic acid to obtain the beta-ketoester intermediate as described above for the Preparations in the Section of the above carboxylic acid pathway, and employing other methods described above in Section I. the beta-ketoester pathway, as well as standard techniques and methods known to the people of the medium level trade.

Table 2. Examples of the carboxylic acid pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 11</td><td>or sAAA. /or nh₂</td><td>1- (2amlnoetll) -6- (2methoxlfenll) -2-txox-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - Hydrochloride ona</td><td> 278.1</td><td>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)</td>

<td> 12</td><td>or s ^ kukg ^^ OH I</td><td>1 - (2-hldroxletll) -6- (4metoxlfenll) -2-t¡oxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 279.0</td><td>1H NMR (500 MHz, METANOL-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)</td>

<td> 13</td><td>0 ys sA / γΝ l Uk ° \</td><td>4- [3- (2-Methoxletll) -6-oxo2-tloxo-1,2,3,6tetrahldroplrlmldln-4¡Ijbenzonltrllo</td><td> 288.1</td><td>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)</td>

<td> 14</td><td>or nh₂ '—!</td><td>1- (2amlnoetll) -6- (2,3-d¡h¡dro1-benzofuran-5-ll) -2-txoxo-2,3- hydrochloride dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 290.0</td><td>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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 15</td><td>or^HN^ ll OH '- /</td><td>6- (2,3-dihydro-1 benzofuran-5-yl) -1- (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1-pona</td><td> 291.0</td><td>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)</td>

<td> 16</td><td>OR OH</td><td>6- (2,3-dihydro-1 benzofuran-7-yl) -1- (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1-pona</td><td> 291.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 17</td><td>OR hít \ rfi nh₂</td><td>2- [6- (2-Methoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin-1 (2H) Ijacetamide</td><td> 292.0</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 18</td><td>or HI \ T% &lt;β yTj h₂iv</td><td>1- (3aminopropyl) -6- (2-methoxyphenyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) hydrochloride - ona</td><td> 292.0</td><td>1H NMR (400 MHz, METANOL-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), 1.942.07 (m, 1 H), 1.75-1.88 (m, 1 H)</td>

<td> 19</td><td>or^HN|| οβ nh₂ I</td><td>1- (2-aminoethyl) -6- (2-methoxy-5-methylpyridin-3-yl) -2-thioxo2,3-dihydropyrimidin4 (1 H) -one trifluoroacetate</td><td> 292.9</td><td>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).</td>

<td> 20</td><td>or ΗΗτΦ θβ / Ό / °</td><td>1 - (2-methoxyethyl) -6- (3methoxypyridin-2-yl) -2thioxo-2,3- dihydropyrimidin-4 (1 H) - ona</td><td> 294.0</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 21</td><td>or ηι \ γΦ ​​β ΑΧ ΟΗ</td><td>1- (2-hydroxyethyl) -6- (2methoxy-6-methylpyridin-3-yl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 294.1</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 22</td><td>or HiXji A i Ύ 1 r ^N v OH 1</td><td>1 - (2-hydroxyethyl) -6- (3methoxy-6-methylpyridin-2il) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 294.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 23</td><td>OR hn ^ AA or</td><td>1 - (2-methoxyethyl) -6- (2methoxypyridin-3-yl) -2thioxo-2,3- dihydropyrimidin-4 (1 H) - ona</td><td> 294.2</td><td>1H NMR (400 MHz, CHLORFORM-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, 3H), 3.69-3.86 (m, 2 H), 3.40 (dt, J = 10.00, 4.20 Hz, 1 H), 3.15 (s, 3 H)</td>

<td> 24</td><td>or hnA A /or OH</td><td>1 - (2-hydroxyethyl) -6- [2 (methylthio) phenyl] -2-thioxo2,3-dihydropyrimidin4 (1 H) -one</td><td> 295.0</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 9.54 (br.s, 1 H), 7.447.52 (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)</td>

<td> 25</td><td>OR Ύζ) Í | ^^NHuAAxnAs --ace nh₂</td><td>1- (2-aminoethyl) -6- (4-fluoro-2-methoxyphenyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) hydrochloride - ona</td><td> 296.0</td><td>Ή 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), 4,544.66 (m, 1 H), 3.86 (s, 3 H), 3.79-3.85 (m, 1 H), 2.88 (br. S, 2 H)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 26</td><td>H₂N-_ \ 5 F</td><td>1- (2-aminoethyl) -6- (5-fluoro-2-methoxyphenyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) hydrochloride - ona</td><td> 296.2</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (s, 1 H), 7.88 (br. S., 3H), 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), 3.85 - 3.93 (m, 1 H), 3.83 (s, 3 H), 2.85 -2.99 (m, 2 H)</td>

<td> 27</td><td>OR OH</td><td>6- (4-fluoro-2- methoxyphenyl) -1- (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 297.0</td><td>1H NMR (400 MHz, METANOL-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), 4,574.69 (m, 1 H), 3.87 (s, 3 H), 3.67-3.83 (m, 2 H), 3.55-3.62 (m, 1 H)</td>

<td> 28</td><td>HO '—O YtXmh F</td><td>6- (5-fluoro-2- methoxyphenyl) -1- (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 297.3</td><td>1H NMR (500 MHz, DMSO-d6) δ ppm 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)</td>

<td> 29</td><td>0 ° Y ^ XÍ? nh₂</td><td>2- [6- (1 H-indole-4-¡l) -4- oxo-2-thioxo-3,4dihydropyrimidin-1 (2H) iljacetamide</td><td> 301.0</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 30</td><td>OR^HN^ il_sTO_nAX /^nhand ^andh₂i &lt;</td><td>Trifluoroacetate 1- (3aminopropll) -6- (1 H¡ndol-4-ll) -2-tloxo-2,3dih¡dropir¡m¡din-4 (1 H) - ona</td><td> 301.1</td><td>1H NMR (300 MHz, METANOL-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, 2H)</td>

<td> 31</td><td>or ΗΥΥ O — Λ xW NH₂</td><td>2- [6- (1-benzofuran-7-ll) 4-oxo-2-thioxo-3,4dihldropirlmldin-1 (2H) il] acetam¡da</td><td> 301.9</td><td>1H NMR (300 MHz, METANOL-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 HOUR)</td>

<td> 32</td><td>H</td><td>1- (3aminopropyl) -6- (1 Hindazol-3-yl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) one formate</td><td> 302.1</td><td>1.36 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, ΜΑΝΤΕΝΙΜ. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 33</td><td>OR HN ^^ i / X | And NH me</td><td>6- (1 H-indole-3-yl) -1 - (2methoxletll) -2-txox-2,3- dihydropyrimidin-4 (1 H) one</td><td> 302.1</td><td>1H NMR (400 MHz, METANOL-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), 7.16 (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)</td>

<td> 34</td><td>0 H [\ rYes O — λ j 1 /&gt; h₂n ^^</td><td>1- (3aminopropyl) -6- (1 benzofuran-7-l) -2-thioxo- hydrochloride 2,3-dlhydroplrimidln4 (1 H) -one</td><td> 302.1</td><td>1H NMR (400 MHz, METANOL-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, 2 H), 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, 2 H)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 35</td><td>0 JU^N \ ^H</td><td>1 - (2-methoxetl) -6- (1 Hprolo [2,3-b] p¡r¡d¡n-3-¡) 2-tloxo-2,3dlh¡drop¡rlm D¡n-4 (1 H) - ona</td><td> 303.1</td><td>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)</td>

<td> 36</td><td>0 NH ^</td><td>1- (2-amnoyl) -6- (1 benzotlen-3-ll) -2-txox hydrochloride 2,3-dlhldroplrlmldln4 (1 H) -one</td><td> 304.0</td><td>1H NMR (400 MHz, D2O) δ ppm 7.92-7.94 (m, 1H), 7.82 (s, 1H), 7.51-7.48 (m, 1H), 7.39-7.37 (m, 2H), 5.99 (s, 1H), 4,724.71 (m, 1H), 4.05-3.99 (m, 1H), 3.01-2.94 (m, 2H)</td>

<td> 37</td><td>OR VX nh₂ '—/</td><td>2- [6- (2,3-d¡h¡dro-1benzofuran-5-ll) -4-oxo2-tloxo-3,4dlhldroplrlmldln-1 (2H) l] acetam¡da</td><td> 304.0</td><td>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)</td>

<td> 38</td><td> 0</td><td>Hydrochloride 1- (3-aminopropll) -6- (2,3dlhldro-1-benzofuran-5¡l) -2-tloxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) one</td><td> 304.1</td><td>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, 2H), 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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 39</td><td>0 OH</td><td>6- (1-benzothien-3-yl) -1 - (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 305.0</td><td>1H NMR (400MHz, METANOL-d4) 7.97 (d, 1H), 7.92 (s, 1H), 7.61 (dd, 1H), 7.46-7.45 (m, 2H), 5.92 (s, 1H), 4,654.63 (m, 1H), 3.90-3.85 (m, 1H), 3.84-3.80 (m, 1H), 3.62-3.61 (m, 1 H)</td>

<td> 40</td><td>0 OH</td><td>6- (1-benzothien-2-yl) -1 - (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1-pona</td><td> 305.0</td><td>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)</td>

<td> 41</td><td>or / °</td><td>6- (2,3-dihydro-1 benzofuran-7-yl) -1- (2-methoxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 lp- ona</td><td> 305.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 42</td><td>or HlsrX S — Λ j X i&gt; OH</td><td>6- (1,3-benzothiazol-7-yl) 1 - (2-hid roxieti l) -2-thioxo2,3-dihydropyrimidin4 (1H) -one</td><td> 305.9</td><td>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) 4,224.31 (m, 1 H) 3.86-3.96 (m, 1 H) 3.43-3.56 (m, 2 H)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 43</td><td>NHL Λ L u -o Yr ί \ ιη XXA</td><td>1- (3-aminopropll) -6- (2-methoxl-5-metllfen¡l) -2-txoxo-2,3- hydrochloride dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 306.1</td><td>Ή NMR (500 MHz, DMSO-d6) δ ppm 12.79 (s, 1 H), 7.92 (br. S., 3H), 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)</td>

<td> 44</td><td>or skA / Y_N^ογ ^ Y NH₂ 1</td><td>2- [6- (2-methox¡-5- metllplr¡d¡n-3-¡l) -4-oxo-2- tloxo-3,4- dlhldroplrlmldln-1 (2H) ¡Ijacetamlda</td><td> 306.7</td><td>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).</td>

<td> 45</td><td>0 Hl / Y</td><td>Trifluoroacetate 1- (3amlnopropll) -6- (2methoxl-5-metllp¡r¡d¡n-3¡l) -2-tloxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 306.9</td><td>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, 1H), 2.50-2.65 (m, 2H), 2.30 (s, 3H), 1901.65 (m, 2H).</td>

<td> 46</td><td>Or oh / °</td><td>6- [2- (2-hldroxlet¡l) fen¡l] 1 - (2-metoxletll) -2-tloxo- 2,3-dlhldroplrlmldln4 (1 H) -one</td><td> 307.1</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 9.44 (br.s., 1 H), 7.447.52 (m, 1 H), 7.41 (d, J = 7.10 Hz, 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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 47</td><td>OR To o OH</td><td>6- (2,3-dihydro-l, 4-benzodioxin-5-yl) -1- (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) one</td><td> 307.1</td><td>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), 3.83-3.92 (m, 1 H), 3.67-3.78 (m, 1 H)</td>

<td> 48</td><td>0 NH, φ</td><td>1- (2-aminoethyl) -6- (3,5-dimethoxyphenyl) -2-toxic-hydrochloride 2,3-dihydropyrimidin4 (1 H) -one</td><td> 308.0</td><td>3,442 min Column: XBRIDGE-C18 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, Temp. column = 40 ° C; Diluent: CAN</td>

<td> 49</td><td>0 ΗΓ + Φ θβ 1</td><td>1 - (2-Methoxyethyl) -6- (3methoxy-6-methylpyridin-2il) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 308.1</td><td>1H NMR (400 MHz, CHLORFORM-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, 3H)</td>

<td> 50</td><td>OR^H™|] /°</td><td>1- (2-Methoxyethyl) -6- (2-methoxy-6-methylpyridin-3-yl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) one</td><td> 308.1</td><td>1H NMR (400 MHz, METANOL-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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 51</td><td>or HN ^ jl X X '</td><td>1 - (2-methoxyethyl) -6- (2methox¡-5-met¡lp¡r¡d¡n-3il) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) one</td><td> 308.1</td><td>1H NMR (400 MHz, METANOL-d3) opp 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)</td>

<td> 52</td><td>Ax OH</td><td>6- [2- (2-aminoethoxy) phenol] -1 - (2-hydroxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) one</td><td> 308.2</td><td>2.14 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. TO 5% H2O / 95% MeCN at 5.0min. (0.05% TFA). Velocity flow rate: 2 mL / min</td>

<td> 53</td><td>^OHX / / u nh₂</td><td>1- (2-aminoethyl) -6- [2- (2-hydroxyethoxy) phenyl] -2-thioxo-2,3- hydrochloride dihydropyrimidin-4 (1 H) - ona</td><td> 308.2</td><td>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)</td>

<td> 54</td><td>0 OH 0 ^</td><td>6- (3,5-dimethoxyphenyl) -1 (2-hydroxyethyl) -2-thioxo2,3-dihydropyrimidin4 (1 H) -one</td><td> 309.1</td><td>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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 55</td><td>or /or / °</td><td>1- (2-Methoxyethyl) -6- [2 (methylthio) phenyl] -2-thioxo2,3-dihydropyrimidin4 (1 H) -one</td><td> 309.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 56</td><td>or Hfíú cN εΧ'ϊτ'υ'Χ θγ¹ THE nh₂</td><td>2- [6- (4-fluoro-2- methoxyfen) -4-oxo-2- thioxo-3,4- dihydropyrimidin-1 (2H) iljacetamlda</td><td> 310.0</td><td>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 = 2.15 Hz, 1 H), 5.36 (br. S., 2 H), 3.28 (s, 3 H)</td>

<td> 57</td><td>or HN | 1 A sAAÁ η₂ι \ γ</td><td>1- (3-Amnopropyl) -6- (4-fluoro2-methoxyphenyl) -2-toxic-hydrochloride 2,3-dihydropyrimidin4 (1 H) -one</td><td> 310.0</td><td>1H NMR (400 MHz, METANOL-d4) ppm 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, 2H), 1.932. 07 (m, 1 H), 1.74-1.88 (m, 1 H)</td>

<td> 58</td><td>or hi \ tA cN and V H₂I \ í</td><td>1- (3-Amnopropyl) -6- (5-fluoro2-methoxyphenyl) -2-thioxo- hydrochloride 2,3-dihldropirlmldin4 (1 H) -one</td><td> 310.0</td><td>1H NMR (400 MHz, METANOL-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, 2H), 1,952.09 (m, 1 H), 1,777-1.91 (m, 1 H)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 59</td><td>nX ^ NH φΑΑ F</td><td>2- [6- (5-fluoro-2- methoxyphenyl) -4-oxo-2- thioxo-3,4- dihydropyrimidin-1 (2H) iljacetamide</td><td> 310.0</td><td>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)</td>

<td> 60</td><td>or Hhry fX) z °</td><td>6- (2-fluoro-6- methoxyphenyl) -1- (2-methoxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 311.1</td><td>1H NMR (400 MHz, CHLORFORM-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), 3.88 - 3.97 (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)</td>

<td> 61</td><td>or HN ^ X Ol sAnOOx nh₂</td><td>1- (2-aminoethyl) -6- (2-chloro-4-methoxyphenyl) -2-thio-2,3-dihydropyrimidin-4 (1 H) hydrochloride - ona</td><td> 311.9</td><td>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), 3,733.84 (m, 1 H), 2.92-3.08 (m, 1 H), 2.77-2.90 (m, 1 H)</td>

<td> 62</td><td>0 fXAX, nh₂</td><td>1- (2-aminoethyl) -6- (4-chloro-2-methoxyphenyl) -2-thio-2,3-dihydropyrimidin-4 (1 H) hydrochloride - ona</td><td> 312.0</td><td>1H NMR (400 MHz, METANOL-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), 4,684.81 (m, 1 H), 4.01 -4.12 (m, 1 H), 3.91 (s, 3 H), 2.97 - 3.16 (m, 2 H)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 63</td><td>or nh₂ ci</td><td>1- (2-amnoyl) -6- (5-chloro-2-methoxlfenll) -2-txox-2,3-hydrochloride-4-1 (1 H) hydrochloride - ona</td><td> 312.2</td><td>1.67 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% linear MeCN at 5% H2O / 95% MeCN for 4.0 min, ΜΑΝΤΕΝΙΜ. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 64</td><td>or HisrX X I heard / Cl</td><td>6- (5-Chloro-2-methoxylfenyl) 1 - (2-hid roxieti l) -2-tloxo2,3-dlhydroplrimidln4 (1 H) -one</td><td> 313.2</td><td>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)</td>

<td> 65</td><td>or HisrX X OH Cl</td><td>6- (5-Chloro-2methox¡plr¡d¡n-3-¡l) -1- (2hidroxletll) -2-tloxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 314.0</td><td>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)</td>

<td> 66</td><td>0 ΗΓτ \ ι_SA ^ \ X ~</td><td>1 - (2-methoxletll) -6- (1 metll-1 H-lndol-2-ll) -2tloxo-2,3- dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 316.0</td><td>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), 3.72-3.84 (m, 1 H), 3.69 (s, 3 H), 3.43-3.58 (m, 1 H) , 3.11 (s, 3 H)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 67</td><td> 0 \</td><td>1 - (2-methoxyethyl) -6- (1 methyl-1 H-indole-3-ll) -2thioxo-2,3- díhydrop¡rimid¡n-4 (1 I-pona</td><td> 316.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 68</td><td>0 TO/ nh₂</td><td>2- [6- (1-benzotien-3-yl) -4oxo-2-tloxo-3,4dlhldropirlmldln-1 (2H) ¡Ijacetamlda</td><td> 318.0</td><td>1H NMR (400 MHz, METANOL-d3) 5ppm 7.99 - 8.12 (m, 1 H), 7.92 (s, 1 H), 7.77 (d, J = 6.18 Hz, 1 H), 7.42 - 7.57 (m, 2 H), 6.02 (s, 1 H), 5.17-5.68 (m, 1 H), 3.77-4.25 (m, 1 H)</td>

<td> 69</td><td> 0 _sTO_NJAs \ ^ ° V \ Z /&gt; nh₂</td><td>2- [6- (1-benzotien-2-ll) -4oxo-2-tloxo-3,4dlhldropirlmldln-1 (2H) ¡Ijacetamlda</td><td> 318.0</td><td>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)</td>

<td> 70</td><td>or HhTYi O aAx AA / °</td><td>3-methox¡-4- [3- (2- metoxletll) -6-oxo-2tloxo-1,2,3,6tetrahldropirlmldln-4iljbenzonltrllo</td><td> 318.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 71</td><td>OR ys. / b '' H / r</td><td>1- (3amlnopropll) -6- (1benzotlen-2-ll) -2-txox2,3-dlhldroplrlmldln4 (1 H) -one hydrochloride</td><td> 318.1</td><td>1H NMR (300 MHz, DMSO-d6) δ ppm 12.90 (br.s., 1 H), 8.06-8.11 (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)</td>

<td> 72</td><td>0 ill Y Xw</td><td>Trifluoroacetate 1- (3-aminopropll) -6- (1,3-benzotlazol-7-ll) -2-txox2,3-dlhldroplrlmldln4 (1 H) -one</td><td> 319.2</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 12.98 (s, 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., 3H), 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)</td>

<td> 73</td><td>OR Hl / YS — λ AW / °</td><td>6- (1-benzotlen-7-ll) -1 - (2.metoxletll) -2-tloxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 319.4</td><td>1H NMR (400 MHz, CHLORFORM-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, 3H)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 74</td><td>or Hwfi f = \ / °</td><td>6- (1-benzothien-4-yl) -1 - (2-methoxyethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 319.4</td><td>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)</td>

<td> 75</td><td>0 Yy</td><td>6- (1,3-benzothiazol-2-yl) 1 - (2-methoxyetl) -2-thoxo2,3-dihydropyrimidin4 (1 H) -one</td><td> 320.0</td><td>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)</td>

<td> 76</td><td>0 Η, Ν ^ ° 0</td><td>1- (3aminopropyl) -6- (2,3-dihydro-1,4-benzodioxin6-yl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) hydrochloride - ona</td><td> 320.0</td><td>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, 2 H)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 77</td><td>OR OR''' ili r³ X Η, Ν ^ Ν ΝΗ_ξ</td><td>2- {2- [6 (2-Methoxyphenyl) -4-oxo-2-thioxo-3,4- hydrochloride dihydropyrimidin-1 (2H) yl] ethyl} guanidine</td><td> 320.0</td><td>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, 1 H)</td>

<td> 78</td><td>or 1 II ΓΛ 4 1 1 „^NsTnXA / Xj V</td><td>6- (1,3-benzothiazol-7-yl) 1 - (2-methoxyethyl) -2-thioxo- 2,3-dihydropyrimidin4 (1 H) -one</td><td> 320.4</td><td>1H NMR (301 MHz, CHLORFORM-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), 3.45 -3.69 (m, 2 H), 3.06 (s, 3 H)</td>

<td> 79</td><td>0 HhrN r / '-^z^^x'nh₂•me nh₂</td><td>1- (2-aminoethyl) -6- [2- (3 aminopropox) phenol] -2-thioxo-2,3- hydrochloride dihydropyrimidin-4 (1 H) one</td><td> 321.0</td><td>1H NMR (400 MHz, METHANOL-d4) 5ppm 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), 4.02 -4.13 (m, 1 H), 2.97 3.18 (m, 4 H), 2.08-2.20 (m, 2 H )</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 80</td><td>0 To yy TO</td><td>6- (2,3-dlhydro-1,4benzodloxln-5-¡) -1- (2-methoxyethyl) -2-thioxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 321.2</td><td>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)</td>

<td> 81</td><td>or ΗΙ \ Γ% cN sAaA nh₂ You</td><td>1- (2 -amnoethyl) -6- (2,4-dimethoxy-5-methylfenll) -2-thioxo-2,3- hydrochloride dihldropirlm¡din-4 (1 H) - ona</td><td> 321.8</td><td>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):</td>

<td> 82</td><td>or yy '</td><td>1- (3aminopropll) -6- (3,4dlmethoxlfen¡l) -2-txox2,3-dlhldroplrlmldln4 (1 H) -one hydrochloride</td><td> 322.0</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 12.76 (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), 4.09-4.20 (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)</td>

<td> 83</td><td>0 sAA /% GOES nh₂ i</td><td>2- [6- (3,4-dlmethoxlfen¡l) 4-oxo-2-tloxo-3,4dlhldroplrlmldln-1 (2H) ¡Ijacetamlda</td><td> 322.0</td><td>1H NMR (300 MHz, DMSO-d6) δ ppm 12.75 (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)</td>

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 84</td><td>or nh₂ 0^</td><td>1- (2-aminoethyl) -6- (2,5-dimethoxy-4-methylphenyl) -2-thioxo-2,3- hydrochloride dihydropyrimidin-4 (1 H) - ona</td><td> 322.0</td><td>1H NMR (400 MHz, METANOL-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), 2,953.08 (m, 2H), 2.18 (s, 3H).</td>

<td> 85</td><td>0 ) ° x H₂N ^ A</td><td>1- (3aminopropyl) -6- (3,5-dimethoxyphenyl) -2-txox2,3-dihydropyrimidin4 (1 H) -one hydrochloride</td><td> 322.0</td><td>3,567 min (Column: XBRIDGE-C18 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, Temp. column = 40 ° C; Diluent: CAN)</td>

<td> 86</td><td>0 Hhrxi Governess VV nh₂ 0^</td><td>2- [6- (3,5-dimethoxyphenyl) - 4-oxo-2-thioxo-3,4dihydropyrimidin-1 (2H) il] acetamide</td><td> 322.1</td><td>1H NMR (300 MHz, DMSO-d6) δ ppm 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)</td>

<td> 87</td><td>or HIT% s ^ A_nX \ Xx ./ χ</td><td>1- (3aminopropyl) -6- (2,5-dimethoxyphenyl) -2-thioxo2,3-dihydropyrimidin4 (1 H) -one hydrochloride</td><td> 322.1</td><td>1H NMR (400 MHz, METANOL-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)</td>

100

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 88</td><td> °^h"TO / Vó</td><td>Hydrochloride 1- (3-aminopropll) -6- [2- (2hldroxletox¡) fenl] -2- tloxo-2,3- dlh¡drop¡rlm¡d¡n-4 (1 I-pona</td><td> 322.2</td><td>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)</td>

<td> 89</td><td>0 HrrA cA '.i'tr'U and ΧΛ- OH</td><td>Acid [6- (2,4dlmethoxlfen¡l) -4-oxo-2tloxo-3,4- dlhldropirlmldln-1 (2H) ¡Ijacétlco</td><td> 323.1</td><td>2.09 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 90</td><td>or Hi \ rX cfi sAAAx nh₂ F</td><td>1- (2amlnoetll) -6- (5-fluoro2,4-dlmethox¡fenll) -2- hydrochloride tloxo-2,3- dlhldropir¡m¡d¡n-4 (1 I-pona</td><td> 325.9</td><td>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).</td>

<td> 91</td><td>or hi ci sAAxA and ' h₂TO</td><td>1- (3-amnopropyl) -6- (2-chloro4-methoxylfenyl) -2-tloxo- hydrochloride 2,3-dlhldroplrlmldln4 (1 H) -one</td><td> 326.0</td><td>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), 4.36-4.46 (m, 1 H), 3.85 (s, 3 H), 3.57-3.63 (m, 1 H), 2.53-2.64 (m, 2 H), 1.86 - 1.95 (m, 1 H ), 1.67-1.76 (m, 1 H)</td>

101

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 92</td><td>0 Hí + | i X and V h₂Item</td><td>1- (3-amylpropyl) -6- (5-chloro-2-methoxylfenll) -2-txox hydrochloride 2,3-dlhydroplrimidln4 (1 H) -one</td><td> 326.3</td><td>Ή NMR (500 MHz, METANOL-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), 4,534.63 (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)</td>

<td> 93</td><td>or m \ r% X sAxxA / Ám and V h₂Item</td><td>1- (3-amnopropyl) -6- (5-chloro-2-methoxy-lplr-d-n-3-1) -2-chloro-2,3- hydrochloride dlh¡drop¡r¡mld¡n-4 (1 H) ona</td><td> 326.9</td><td>1H NMR (400 MHz, METANOL-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, 2H), 1,982.09 (m, 1 H), 1.81 - 1.94 (m, 1 H)</td>

<td> 94</td><td>or HN ^ hee X J Cl Hcr</td><td>6- (5-Chloro-2-methoxylfenyl) 1 - (3-hldroxlpropll) -2tloxo-2,3- dlh¡drop¡rlm¡d¡n-4 (1 I-pona</td><td> 327.0</td><td>1H NMR (400 MHz, METANOL-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, 3H), 3.78 (ddd, J = 14.43, 10.08, 5.27 Hz, 1 H), 3.36 (t, J = 6.18 Hz, 2H), 1,821.96 (m, 1 H), 1.62-1.76 (m, 1 H)</td>

<td> 95</td><td>or ΗΝ ^ ιΙ X nh₂</td><td>1- (2amlnoetll) -6- (3-methox¡-2naftll) -2-tloxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - Hydrochloride ona</td><td> 327.9</td><td>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)</td>

102

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 96</td><td>or HN ^ il cX 0 Cl</td><td>6- (5-Chloro-2methoxypyldin-3-¡1) -1 - (2methoxletll) -2-tloxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 328.0</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 97</td><td>or HlSrji tX nh₂ tk</td><td>Trifluoroacetate 1- (2amlnoetll) -6- (2methoxyquinolin-3-yl) -2thioxo-2,3- dihydropyrimidin-4 (1 H) - ona</td><td> 328.8</td><td>1H NMR (400 MHz, DMSO-d6): δ 12.92 (br.s., 1 H), 8.20 (S, 1 H), 7,837.65 (m, 6 H), 7.38 (t, 1 H), 6.01 (s, 1 H), 4.524.61 (m, 1 H), 3.70-3.80 (m, 1H), 3.68 (s, 3 H), 2.98-3.18 (m, 2 H).</td>

<td> 98</td><td>íl rx ηνΛ V skkyk H₂N ^ k YY</td><td>1- (3 amlnopropyl) -2-tloxo-6 [2- (2H-1,2,3-triazol-2l) fenll] hydrochloride -2,3- dlh¡drop¡rlm¡d¡n-4 (1 I-pona</td><td> 328.9</td><td>0.893 min Column: LCMS-0 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)</td>

<td> 99</td><td>í¡ rx TO ^N\/^Nhit X Xr sk ^ k ^ xk kk nh₂</td><td>2- {4-oxo-2-tloxo-6- [2 (2H-1,2,3-trlazol-2l) fenll] -3,4- dlhldroplrlmldln-1 (2H) ¡IJacetamlda</td><td> 329.0</td><td>1H NMR (400 MHz, DMSO-d6): δ 12.76 (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, 1H), 7.04 (s, 1H ), 5.68 (s, 1H), 5.22 (d, 1H), 3.79 (d, 1H) .:</td>

103

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 100</td><td>or HíAA ζβ OH AA</td><td>1 - (2-hydroxyethyl) -6- (3-methoxy-2-naphthyl) -2-thioxo2,3-dihydropyrimidin4 (1 H) -one</td><td> 329.4</td><td>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)</td>

<td> 101</td><td>π ΓΛ ηΛ v</td><td>1 - (2-Methoxyethyl) -2-thioxo6- [2- (2H-1,2,3-triazol-2yl) phenyl] -2,3- dihydropyrimidin-4 (1 H) - ona</td><td> 330.1</td><td>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, 2H), 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)</td>

<td> 102</td><td>AJ ¿^</td><td>6- (2-ethoxyphenyl) -1 (tetrahydrofuran-2-methylmethyl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) - ona</td><td> 333.1</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 10.25-10.39 (m, 1 H) 7.39-7.50 (m, 1 H) 7.307.36 (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) 4.56 4.65 (m, 1 H) 4.05-4.14 (m, 2 H) 3.49-3.57 (m, 1 H) 3.34-3.44 (m, 1 H) 3.05-3.13 (m, 1 H) 1,902.01 (m, 1 H) 1.63 - 1.78 (m, 1 H) 1.40 - 1.49 (m, 1 H) 1.32-1.38 (m, 3 H) 1.23 - 1.32 (m, 1 H)</td>

104

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 103</td><td>OR hXX X a ^ Η₂Γ®1νΗ₂</td><td>2- {3- [6- (2-methoxyphenyl) -4oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) Ijproplljguanldlna</td><td> 334.1</td><td>1.31 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0min. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 104</td><td>XAA AND</td><td>6- (2-ethoxyphenyl) -1 - (2isopropoxyethyl) -2-thioxo2,3-dihydropyrimidin4 (1 H) -one</td><td> 335.1</td><td>1H NMR (400 MHz, CHLORFORM-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) 3,683.85 (m, 2 H) 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)</td>

<td> 105</td><td>or HY! xXa χχ h₂t</td><td>1- (3aminopropyl) -6- (2,4-dimethoxy-5-methylphenyl) -2-thioxo-2,3- hydrochloride dihydropyrimidin-4 (1 H) - ona</td><td> 335.9</td><td>1H NMR (400 MHz, DMSO-d6): δ 12.76 (s, 1H), 7.68 (br.s., 3H), 7.11 (s, 1H), 6.74 (s, 1H), 5.73 (s, 1H), 4.35-4.45 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.59-3.68 (m, 1H), 2,522.51 (m, 2H), 2.09 (s, 3H), 1.81-1.71 (m, 2H) .:</td>

<td> 106</td><td>or hXY cX s ^ X ^ xU, X χ X \</td><td>1- (3aminopropyl) -6- (2,5-dimethoxy-4-methylphenyl) -2-thioxo-2,3- hydrochloride dihydropyrimidin-4 (1 H) - ona</td><td> 336.0</td><td>1H NMR (400 MHz, METANOL-d4): δ 6.91 (s, 1H), 6.79 (s, 1H), 5.72 (s, 1 H), 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), 1,891.94 (m, 1H), 1.76-1.86 (m, 1H).</td>

105

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 107</td><td>0 Hi \ rX oA goes nh₂ F ¹</td><td>2- [6- (5-fluoro-2,4- dimethoxyphenyl) -4-oxo-2- thioxo-3,4- dihydropyrimidin-1 (2H) yl] acetamide</td><td> 339.9</td><td>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).</td>

<td> 108</td><td>0 HN^zj cA sXOAx already h₂iA</td><td>1- (3aminopropyl) -6- (5-fluoro2,4-dimethoxyphenyl) -2-thioxo-2,3- hydrochloride dihydropyrimidin-4 (1 H) - ona</td><td> 339.9</td><td>1H NMR (400 MHz, DMSO-d6): δ 7.36 (d, 1H), 6.95 (d, 1H), 5.80 (s, 1H), 4.38-4.48 (m, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.59-3.67 (m, 1H), 2,452.61 (m, 2H), 1.67-1.78 (m, 2H) .:</td>

<td> 109</td><td>0 HN ^ Al 0 i 1 / sAuvA / y TO ° \</td><td>1- (2-Methoxyethyl) -6- [3- (methylsulfonyl) phenyl] -2- thioxo-2,3- dihydropyrimidin-4 (1 H) - ona</td><td> 341.0</td><td>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)</td>

<td> 110</td><td>0 HITA already X Uv ° 1 a / Ω 0</td><td>1- (2-Methoxyethyl) -6- [4- (methylsulfonyl) phenyl] -2- thioxo-2,3- dihydropyrimidin-4 (1 H) one</td><td> 341.1</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 8.08 (d, J = 8.24 Hz, 2H), 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)</td>

<td> 111</td><td>0 HITA A yAÁ νη_ξ Cl</td><td>1- (2-aminoethyl) -6- (5-chloro-2,4-dimethoxyphenyl) -2-thioxo- hydrochloride 2,3-dihydropyrimidin4 (1 H) -one</td><td> 342.0</td><td>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)</td>

106

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 112</td><td>or HN | 1 cA V% nh₂</td><td>2- [6- (3-methoxl-2-naftll) 4-oxo-2-tloxo-3,4dlhldroplrlmldln-1 (2H) l] acetam¡da</td><td> 342.0</td><td>1H NMR (400 MHz, METANOL-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)</td>

<td> 113</td><td>ABS 0 HIST ^ h oA s ^ xAaA^H0'/ J Cl he has</td><td>Trifluoroacetate 1 [(2S) -3-amino-2hldroxlpropll] -6- (5-chloro- 2-metoxlfenll) -2-txox- 2,3-dlhldroplrlmldln4 (1 H) -one</td><td> 342.1</td><td>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)</td>

<td> 114</td><td>ABS 0 HIST ^ h oA εΤχΑγΧ - ¹ γ h₂Item</td><td>Trifluoroacetate of 1 [(2R) -3-amino-2hydroxlpropll] -6- (5-chloro- 2-metoxlfenll) -2-txox- 2,3-dlhldroplrlmldln4 (1 H) -one</td><td> 342.2</td><td>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)</td>

107

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 115</td><td>0 Hi \ rX ofi ili } lO / °</td><td>1 - (2-methoxyletl) -6- (1 methoxl-2-naphthl) -2-tloxo2,3-dlhldroplrlmldln4 (1 H) -one</td><td> 343.0</td><td>1H NMR (400 MHz, CHLORFORM-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), 3.683.78 (m, 1 H), 3.36 (dt, J = 9.90, 4.78 Hz, 1 H), 3.06 (s, 3 H)</td>

<td> 116</td><td>ABS 0 ηυΧ (A sAAyA HCy J XX J Cl Hcr</td><td>6- (5-chloro-2-methoxfen) 1 - [(2R) -2,3dihldroxypropyl] -2-thioxo2,3-dlhldroplrlmldln4 (1 H)</td><td> 343.0</td><td>1,942 min (Column: AQUITY BEH C-18,2.1x50mm, 1.7pm; Mobile phase: A-0.1% FA IN ACN, B-0.1% FA EN WATER; T /% B (mln): 0/90, 0.7 / 90, 2/55, 3/55, 3.8 / 5, 5.8 / 5, 6/90; Flow: 0.5mL / mln, Dlluent: CAN)</td>

<td> 117</td><td>or ofi sA_NAAx / ° Xj</td><td>1 - (2-methoxyletl) -6- (3methoxl-2-naphthl) -2-txox2,3-dlhldroplrlmldln4 (1 H) -one</td><td> 343.4</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

108

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 118</td><td>OF „AA JU TO</td><td>1 - (2-methoxyethyl) -2-txox6- [2- (trifluoromethoxy) phenylj2,3-dihydropyrimidin4 (1 H) -one</td><td> 347.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 119</td><td>OR β Λφφ H₂ruXlH₂</td><td>2- {3- [6- (2-methox¡-5- met¡lfen¡l) -4-oxo-2-thioxo- 3,4-dihydropyrimidin1 (2H) -yl] propyl} guanidine</td><td> 348.2</td><td>1.37 min Waters XBridge C18 4.6x50mm, 5um 95% H20 / 5% Linear MeCN at 5% H20 / 95% MeCN for 4.0min, MAINTAIN. a5% H20 / 95% MeCN at 5.0min. Flow: 2.0mL / min. NH4OH 0.03%. Velocity flow rate: 2 ml / min</td>

<td> 120</td><td>or ηνγΑ u TO? Or NH I H₂hT</td><td>N- {2- [6- Hydrochloride (2-Methoxy-5-methylphenol) -4oxo-2-thioxo-3,4dihydropyrimidin-1 (2H) yljethyljglycinamide</td><td> 349.2</td><td>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)</td>

<td> 121</td><td>OR yy γ sA ^ AU Η, Ν ^ Ν (φ ΝΗ_ξ</td><td>2- {2- [6- Hydrochloride (2,5-dimethoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin-1 (2H) yljethyljguanidine</td><td> 350.1</td><td>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., 3H), 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), 3.15 3.26 (m, 1 H)</td>

109

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 122</td><td>ABS OR HI &lt;| 1 X 9 9</td><td>6- (5-Chloro-2-Methoxlfenll) Hydrochloride -1 [(2R) -plrrolld¡n-2-¡lmet¡l] 2-tloxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) ona</td><td> 352</td><td>3.641 min Column: XBRIDGE-018 4.6X75mm 3.5pm; Mobile phase- A = 0.1% FAEN ACN, B = 0.1% FA IN WATER; Time (mln) /% B = 0/90, 0.8 / 90, 1.8 / 55, 3/5, 6.5 / 5, 7/90; Flow: 0.8mL / mln, Temp. column = 40 ° C; Diluent: CAN</td>

<td> 123</td><td>ABS OR Hl &lt;\ cU S ^ N-AyA &lt;A^J τ</td><td>6- (5-Chloro-2-Methoxlfenll) Hydrochloride -1 [(2S) -plrrolld¡n-2-¡lmet¡l] 2-tloxo-2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 352.1</td><td>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), 7.50 - 7.58 (m, 1 H), 7.23 7.28 (m, 1 H), 5.92-6.00 (m, 1 H), 4.90-5.04 (m, 1 H), 3.83 - 3.88 (m, 3 H), 3.63-3.77 (m, 1 H), 2.98 -3.20 (m, 3 H), 1,761.89 (m, 2H), 1.62-1.75 (m, 2 H)</td>

<td> 124</td><td>oh ^ -O</td><td>2- [4-oxo-2-tloxo-6 (2,4,5-trimethoxylfenyl) -3,4dlhldroplrlmldln-1 (2H) ¡Ijacetamlda</td><td> 352.1</td><td>1.23 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, ΜΑΝΤΕΝΙΜ. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / rnln</td>

<td> 125</td><td>NH, and , Ν - ^^ ΝΗ OR</td><td>Hydrochloride 1- (3 amlnoprop¡l) -2-tloxo-6 (2,4,5-trlmethoxlfen¡l) -2,3dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 352.1</td><td>1H NMR (500 MHz, DMSO-d6) δ ppm 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) 6.82 (s, 1 H) 7.00 ( s, 1 H) 7.86 (br. s „2 H) 12.76 (s, 1 HOUR)</td>

110

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 126</td><td>0 AA and V Λ η₂γγ ^ νη₂</td><td>2- {3- [6- (5-fluoro-2- metoxlfen¡l) -4-oxo-2- tloxo-3,4- dlhydroplrimidln-1 (2H) ¡l] prop¡l} guan¡d¡na</td><td> 352.2</td><td>1.22 min Waters XBridge C18 4.6x50mm, 5um; 95% H20 / 5% MeCN linear at 5% H20 / 95% MeCN for 4.0min, MAINTAIN. a5% H20 / 95% MeCN at 5.0min. Flow: 2.0mL / mln.NH4OH 0.03% Veloc. Flow rate: 2 m L / min</td>

<td> 127</td><td>or HlsrA cA Aa fu ° NH F H₂to go</td><td>N- {2- [6 (5-fluoro-2-methoxlfenll) 4-oxo-2-tloxo-3,4dlhldroplrlmldln-1 (2H) hydrochloride! Ijetlljgllclnamlda</td><td> 353.2</td><td>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)</td>

<td> 128</td><td>OR histA V^N\^^{N Cl}nh₃</td><td>2- {2- [6- Hydrochloride (5-Chloro-2-Methoxlfenll) -4oxo-2-tloxo-3,4dlhydroplrimidln-1 (2H) Ijetlljguanldlna</td><td> 354.0</td><td>1H NMR (500 MHz, DMSO-d6) δ ppm 12.88 (s, 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)</td>

<td> 129</td><td>or Hhr \ A AA AW J ^ClH₂rr</td><td>1- (3-aminopropll) -6- (5-chloro2,4-dlmethoxlfen¡l) -2-txoxo-2,3- hydrochloride dlh¡drop¡rlm¡d¡n-4 (1 H) ona</td><td> 356.0</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 12.78 (s, 1 H), 7.75 (br. S., 3H), 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, 2 H)</td>

111

<td>Example No.</td><td colspan="2">Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td></td><td></td><td></td><td></td><td></td><td>1H NMR (400 MHz,</td>

<td></td><td> 0</td><td>Bx</td><td>Hydrochloride 1- (2- (4-</td><td></td><td>METHANOL-d4): δ 8.12 (d,</td>

<td></td><td>^ΗιΊ</td><td>V</td><td>oxo-2-tloxo-6- [2- (2H-</td><td></td><td>1H), 7.91 (s, 2H), 7.75 (t,</td>

<td> 130</td><td>] II</td><td>yS</td><td>1,2,3-trlazol-2-l) phen] -</td><td> 357.1</td><td>1H), 7.55-7.59 (m, 2H),</td>

<td></td><td></td><td>OR</td><td>3,4-dlhldroplrlmldln-</td><td></td><td>5.74 (s, 1H), 4.40 (m, 1H),</td>

<td></td><td>HrJ | H T NH</td><td></td><td>1 (2H) -ll} etll) guan¡d¡na</td><td></td><td>3.75 (m, 1H), 3.55 (m, 1H), 3.35 (m, 1H).</td>

<td></td><td></td><td></td><td></td><td></td><td>2.44 min Waters Atlantis</td>

<td></td><td>OR</td><td></td><td></td><td></td><td>dC18 5um 4.6x50mm,</td>

<td></td><td>Hhr ^</td><td>&gt; &lt;x</td><td>2- {3- Trifluoroacetate</td><td></td><td>95% H2O / 5% linear MeCN</td>

<td></td><td>skr</td><td>IX</td><td>[6- (2,5-dlmetox¡fenll) -4-</td><td></td><td>at 5% H2O / 95% MeCN</td>

<td> 131</td><td></td><td>V</td><td>oxo-2-txox-3,4-</td><td> 364.1</td><td>for 4.0 min,</td>

<td></td><td>J</td><td></td><td>dlhldroplrlmldln-1 (2H) -</td><td></td><td>MAINTAIN</td>

<td></td><td>II</td><td>X</td><td>Ijproplljguanldlna</td><td></td><td>a5% H2O / 95% MeCN a</td>

<td></td><td>H₂hT ^ NH₂</td><td></td><td></td><td></td><td>5.0m. (0.05% TFA). Velocity flow rate: 2 mL / min</td>

<td></td><td></td><td></td><td></td><td></td><td>3,639 min Column: XBRIDGE-C18</td>

<td></td><td> 0</td><td></td><td>Hydrochloride 6- (5-</td><td></td><td rowspan="2">4.6X75mm 3.5pm Mobile phase- A = 0.1% FAEN ACN, B = 0.1% FA EN WATER Time (m¡n) /% B =</td>

<td> 132</td><td>Hisr ' sY</td><td>, cY</td><td rowspan="2">chloro-2-metoxlfenll) -1 (p¡perld¡n-4-¡lmet¡l) -2tloxo-2,3- dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td> 366.0</td>

<td rowspan="3"></td><td rowspan="3">k^HN^</td><td rowspan="3">kY Cl</td><td rowspan="3"></td><td rowspan="3">0/90, 0.8 / 90, 1.8 / 55, 3/5, 6.5 / 5, 7/90 Flow: 0.8mL / min, Temp. column = 40O; Diluent: MEOH</td>

<td></td>

<td></td>

<td></td><td></td><td></td><td></td><td></td><td>1.38 min Waters XBridge</td>

<td></td><td></td><td></td><td></td><td></td><td>C18 4.6x50mm, 5um</td>

<td rowspan="2"> 133</td><td>HIT Λ</td><td>1st lil</td><td rowspan="2">2- {3- [6- (5-chloro-2- methoxfen) -4-oxo-2- tloxo-3,4- dlhldroplrlmldln-1 (2H) Ijproplljguanldlna</td><td rowspan="2"> 368.1</td><td>95% H20 / 5% linear MeCN at 5% H20 / 95% MeCN for 4.0m¡n,</td>

<td>Λ</td><td>X Cl</td><td>MAINTAIN a5% H20 / 95% MeCN at 5.0m¡n. Flow: 2.0mL / min.NH4OH</td>

<td></td><td></td><td></td><td></td><td></td><td>0.03% Speed flow rate: 2 ml / mln</td>

112

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 134</td><td>0 hv \ C0 / V hit X</td><td>N- {3- [6- (5-Chloro-2- metoxlfenll) -4-oxo-2- tloxo-3,4- dlhldroplrlmldln-1 (2H) - L] propll} acetamlda</td><td> 368.1</td><td>1H NMR (400 MHz, DMSO-d6) d ppm 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)</td>

<td> 135</td><td>or hXX X xaa CU ^ NH Cl H₂IXT</td><td>N- {2- [6- Hydrochloride (5-chloro-2-methoxlfenll) -4oxo-2-tloxo-3,4dlhldroplrlmldln-1 (2H) Ijetlljgllclnamlda</td><td> 369.2</td><td>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)</td>

<td> 136</td><td>OR Hh / Si Cr '' Xa r¹ XY NH_hnYnh II N</td><td>1 -clane-3- {2- [6- (2,4dlmethoxlfen¡l) -4-oxo-2tloxo-3,4- dlhldroplrlmldln-1 (2H) l] etll} guan¡dlna</td><td> 375.0</td><td>1H NMR (400 MHz, DMSO-d6): δ 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), 3.163.17 (m, 1 H).</td>

<td> 137</td><td>0 c0 and YV Y</td><td>[6- (2,4-dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln-1 (2H) Ter-butyl acetate</td><td> 379.1</td><td>2.59 min Waters XBridge C18 4.6x50mm, 5um 95% H20 / 5% MeCN linear at 5% H20 / 95% MeCN for 4.0mln, MAINTAIN. a5% H20 / 95% MeCN at 5.0mln. Flow: 2.0mL / mln.NH4OH 0.03% Veloc. flow rate: 2 ml / mln</td>

113

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 138</td><td>0 hnA A ΑΛΑ h₂n ^ n 0 ^ nh₂</td><td>2- {2- [4oxo-2-thioxo-6- (2,4,5trimethoxyphenyl) -3,4-dihydropyrimidin-1 (2H) yl] ethyl} guanidine hydrochloride</td><td> 380.1</td><td>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), 3.15-3.25 (m, 1 H)</td>

<td> 139</td><td>_n^s. ^H ^-0</td><td>[4-Oxo-2-thioxo-6- (2,4,5-trimethoxyphenyl) -3,4-dihydropyrimidin-1 (2H) ethyl iljacetate</td><td> 381.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 140</td><td>0 ηγγΑ ό aAA J h / Anh</td><td>Formation of 1 - (2- {2- [6- (2,4-dimethoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin-1 (2H) - il] ethoxy} ethyl) guanine</td><td> 393.8</td><td>1H NMR (400 MHz, METANOL-d4): δ 8.38 (br.s., 1H), 7.21 (d, 1H), 6.66-6.62 (m, 2H), 5.73 (s, 1H), 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), 3.27-3.22 (m, 2H).</td>

<td> 141</td><td>0 HisrYi cf aAA AA Λ H₂h &lt;NMH₂</td><td>2- {3 [4-Oxo-2-thioxo-6- (2,4,5-trimethoxyphenyl) -3,4-dihydropyrimidin-1 (2H) yl] propyl} guanidine trifluoroacetate</td><td> 394.1</td><td>1.60 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0min. (0.05% TFA). Velocity flow rate: 2 mL / min</td>

114

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 142</td><td>0 HnA P = \ i 1,^NHsA &lt;AV nh₂</td><td>1- (2-amino-ethyl) -6- (1 H-indole-4-yl) -2-thioxo-2,3-dihydropyrimidin-4 (1 H) one trifluoroacetate</td><td>270.1 [M- NH3 + 1] +</td><td>1H NMR (300 MHz, METANOL-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, 2 H)</td>

<td> 143</td><td>OR NH,</td><td>1- (2amlnoetll) -6- (1 benzofuran-7-ll) -2-tloxo- hydrochloride 2,3-dlhldroplrlmldln4 (1 H) -one</td><td>270.9 [M- NH3 + 1] +</td><td>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)</td>

<td> 144</td><td>ÍÍ ηνΛ V_sA \ YaA nh₂</td><td>1- (2-amnoyl) -2-tloxo-6- [2 (2H-1,2,3-trlazol-2yl) phenyl] -2,3- hydrochloride dlh¡drop¡rlm¡d¡n-4 (1 H) - ona</td><td>297.9 [M- NH3 + 1] +</td><td>1H NMR (400 MHz, METANOL-d4): δ 8.11 (d, 1 H), 7.90 (s, 2H), 7.74 (t, 1H), 7.60 (d, 2H), 5.62 (s, 1H), 4.67 (m, 1H), 4.10 (m, 1H), 3.28 (m, 1 HOUR), 3.05 (s, 1H) .:</td>

<td> 145</td><td>or hXA (β ° and τ NH₂ Cl</td><td>2- [6- (5-Chloro-2methoxlplr¡d¡n-3-¡) -4-oxo2-tloxo-3,4dlhldroplrlmldln-1 (2H) Ijacetamlda</td><td>325.0 [MH] -</td><td>1H NMR (400 MHz, METANOL-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), 4.06-4.21 (m, 1 H), 3.95 (s, 3 H)</td>

115

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 146</td><td>0 HN ^ ij goes nh₂^{1 1}</td><td>2- [6- (2,4-d¡metox¡-5metllfenll) -4-oxo-2-t¡oxo3,4-dlhldroplrlmldln1 (2H) -¡l] acetam¡da</td><td>358.0 [M + Na]⁺</td><td>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).</td>

<td> 147</td><td>or HN'j zfi ° X ίγΑ nh₂</td><td>2- [6- (2,5-dlmetox¡-4metllfenll) -4-oxo-2-t¡oxo3,4-d¡h¡drop¡r¡m¡d¡n1 (2H) -¡l] acetam¡ gives</td><td>358.0 [M + Na] +</td><td>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).</td>

<td> 148</td><td>or HhrX cU XÁA / v hist o ^ Xh₂</td><td>1 - {3- [6- (5-chloro-2methoxlfenll) -4-oxo-2tloxo-3,4- dlhldroplrlmldln-1 (2H) Ijproplljurea</td><td>367.2 [M-1] '</td><td>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, 2 H), 1.65 (m, 1 H), 1.49 (dd, J = 11.6, 5.7 Hz, 1 H)</td>

<td> 149</td><td>0 aaa /and TO nh₂</td><td>N- {3- [6- Hydrochloride (5-chloro-2-methoxlfen¡l) -4oxo-2-tloxo-3,4dlhldropirlmldln-1 (2H) il] propil} gllclnam¡da</td><td>381.2 [M-1] '</td><td>1H NMR (500 MHz, DMSO-d6) d ppm 8.29 (t, J = 5.6 Hz, 1 H), 7.878.16 (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), 4.17-4.32 (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), 1.55 - 1.64 (m, 1 H)</td>

116

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 150</td><td>or HisrX X OH I</td><td>1- (2-hldroxletll) -6- (2metox¡-5-met¡lplr¡d¡n-3¡l) -2-tloxo-2,3dlh¡drop¡r¡m¡d¡n-4 (1 H) - ona</td><td> 293.8</td><td>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, 3H)</td>

The following examples in Table 3 were prepared from the corresponding methyl ketone to obtain the beta-ketoester intermediate as described above for the Preparations in the Metllketone pathway section, and using other methods described above in the I. Pathway section. of beta-ketoester, as well as standard techniques and methods known to the people of the medium level trade.

Table 3. Examples of the metllcetone pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 151</td><td>ABS 0 χΑχ and^rXH</td><td>Hydrochloride 6- (2,4-dlmethoxlfenll) 1 - [(3R) -plperidln-3¡lmetll] -2-tloxo-2,3dlhydroplrimidln4 (1 H) -one</td><td> 362.0</td><td>3,653 min Column: XBRIDGEQ18 4.6X75mm 3.5pm Mobile phase- A = 0.1% ACN FAEN, B = 0.1% WATER FA Time (m¡n) /% B = 0/90, 0.8 / 90, 1.8 / 55, 3/5, 6.5 / 5, 7/90 Flow: 0.8mL / mln, Temp. from column = 40 ° C; Diluent: GAN</td>

<td> 152</td><td>0 xAx H</td><td>6 (2,4-dlmethoxlfenil) hydrochloride 1- (2-plperldln-4¡letll) -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -one</td><td> 376.1</td><td>1 HNMR (400 MHz, METANOLd4): or 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), 3.72-3.80 (m, 1H), 3.22- 3.25 (m, 2H), 2.82-2.89 (t, 2H), 1.63-1.75 (m, 3H), 1,341.48 (m, 2H), 1.08-1.29 (m, 2H).</td>

117

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 153</td><td>0 HlkS (A ΑΛΑ TO Ao</td><td>1- [2- (1- acetylpiperidin-4il) ethyl] -6- (2,4d¡methox¡fen¡l) -2thioxo-2,3dlhldropinmldln4 (1 H) -one</td><td>440.1 [M + Na ] +</td><td>1 HNMR (400 MHz, METANOLd4): or 7.25 (d, 1H), 6.71 (d, 1H), 6.68 (dd, 1H), 5.75 (s, 1H), 4.524.65 (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), 0.681.10 (m, 2H).</td>

<td> 154</td><td>0 hitA i I ^HNk A °</td><td>6- (1 H-¡m¡dazol-2¡l) -1 - (2-methoxletll) 2-txox-2,3dlhldropinmldln4 (1 H) -one</td><td> 253.1</td><td>1 H NMR (400 MHz, METANOLd3) 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)</td>

<td> 155</td><td>0 A-Xa OH</td><td>1 - (2-hydroxyethyl) -6 (3-methoxlfenll) -2thioxo-2,3- dlhldropinmldln4 (1 H) -ona</td><td> 279.1</td><td>1 H NMR (400 MHz, METANOLd3) 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)</td>

<td> 156</td><td>or hnA cX sk \ | kxkA OH ^</td><td>1 - (2-hydroxyethyl) -6 (2-methoxlfenll) -2thioxo-2,3dihydropymidin4 (1 H) -one</td><td> 279.1</td><td>1H NMR (400 MHz, CHLORFORM-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), 3.643.72 (m, 1 H)</td>

<td> 157</td><td>0 hnA cU sYYyk¹ oyk 1</td><td>6- (2,6- d¡metoxlfen¡l) -1 methyl-2-thioxo-2,3- dlhldropinmldln4 (1 H) -ona</td><td> 279.2</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

118

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 158</td><td>0 ηγΑΑ f / °</td><td>6- (2-fluorophenyl) -1 - (2-Methoxyethyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 281.1</td><td>1 H NMR (400 MHz, METANOLd3) 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)</td>

<td> 159</td><td>or ηγτΑ cA_sX \ nX ^ X% nh₂ I</td><td>1 (2-Aminoethyl) -6- (2-methoxy-5-methylphenyl) -2-txox2,3- hydrochloride dihydropyrimidin4 (1 H) -one</td><td> 292</td><td>1 H 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) 4,544.65 (m, 1 H) 3.86 -3.96 (m, 1 H) 3.81 (s, 3 H) 2.82-2.95 (m, 2 H) 2.29 (s, 3 H)</td>

<td> 160</td><td>0 ηγ + Α cA or / °</td><td>1- (2-Methoxyethyl) -6- (2-methoxyphenyl) -2- thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 293.1</td><td>1 H NMR (400 MHz, METANOLd3) 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)</td>

<td> 161</td><td>or ηιτΑ cd 's ^ fa ^ a OH ^</td><td>1 - (2-hydroxyethyl) -6 (2-methoxy-5methylphenyl) -2-thioxo2,3- dihydropyrimidin4 (1 H) -one</td><td> 293.2</td><td>1 H 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 = 2.15 Hz, 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)</td>

119

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 162</td><td>0 HItSi rf ^ i aX-U OH</td><td>1 - (2-h¡drox¡et¡l) -6 (1 -naft¡l) -2-t¡oxo- 2,3- dlhldroplrlmldln4 (1 H) -ona</td><td> 299.1</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 12.82 (br.s., 1 H), 7.99 8.13 (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), 3,343.51 (m, 3 H)</td>

<td> 163</td><td>HCL S “Ό tEAjH ^ ΑΛ N</td><td>3- [3- (2-h¡drox¡et¡l) - 6-oxo-2-tloxo- 1,2,3,6- tetrahldroplrlmldln- 4-¡] -4- methoxybenzonitrile</td><td> 304.2</td><td>1 H 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)</td>

<td> 164</td><td>or HhrY cX s ^ X ^^ Y ° VT NH₂ 1</td><td>2- [6- (2-methox¡-5- met¡lfen¡l) -4-oxo-2- tloxo-3,4- dlhldroplrlmldln- 1 (2H) -¡l] acetam¡da</td><td> 306.0</td><td>1.44 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 165</td><td>0 / AND / ° ¹</td><td>6- [6- (d¡met¡lam¡no) p¡r¡d¡ n-3-ll] -1- (2- metox¡et¡l) -2-txox- 2,3- dlhldroplrlmldln4 (1 H) -ona</td><td> 307.2</td><td>1 H NMR (400 MHz, METANOLd3) δ ppm 8.07 (d, J = 1.83 Hz, 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)</td>

<td> 166</td><td>0 HhrY X s ^ XY ^ Y</td><td>1 (2-amlnoetll) -6 (2,5-dlmethoxlfenll) 2-tloxo-2,3dlhldroplrlmldln4 (1 H) -one hydrochloride</td><td> 308.0</td><td>1 H 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)</td>

<td> 167</td><td>or HlX || Y s ^ 'X ^ X ^ Y OH 1</td><td>6- (2,6- dlmetoxlfen¡l) -1- (2- hldroxlet¡l) -2-t¡oxo- 2,3- dlhldroplrlmldln4 (1 H) -ona</td><td> 309.0</td><td>1 H 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)</td>

120

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 168</td><td>.OH TO / OH</td><td>6- [2- (2- hldroxletoxljfenllj1- (2-hldroxletll) -2tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 309.1</td><td>1.57 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0min. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 169</td><td>0 hYY &lt;y sA ^ nAaA OH 0 ^</td><td>6- (2,5- dlmethoxlfenil) -1- (2- hldroxlet¡l) -2-t¡oxo- 2,3- dlhldroplrlmldln4 (1 H) -ona</td><td> 309.2</td><td>1 H 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)</td>

<td> 170</td><td>TO L —0 Y% H FOR N</td><td>2- [6- (5-clano-2- metoxlfenll) -4-oxo- 2-tloxo-3,4- dihydropyrimidin- 1 (2H) -¡l] acetam¡da</td><td> 317.2</td><td>1 H NMR (500 MHz, DMSO-d6) δ ppm 3.76-3.94 (m, 2 H), 3.93 (s, 3H), 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)</td>

<td> 171</td><td>Λ ^sLS -o \ τΑη AA N</td><td>4-methox¡-3- [3- (2- metoxletll) -6-oxo-2tloxo-1,2,3,6tetrahldroplrlmldln4-¡l] benzon¡tr¡la</td><td> 318.1</td><td>2.34 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% linear MeCN at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 172</td><td>0 and</td><td>1 - (2-isopropoxletll) 6- (4-methoxfen) -2-txox-2,3dlhldroplrlmldln4 (1 H) -one</td><td> 321.1</td><td>1H NMR (400 MHz, CHLORFORM-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 = 2.15Hz, 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)</td>

121

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 173</td><td>OR ην ^^, cA AND</td><td>1 - (2-isopropoxletll) 6- (2-methoxlfenll) -2-tloxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 321.5</td><td>1 H NMR (400 MHz, METANOLd4) 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) 3.64-3.72 (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)</td>

<td> 174</td><td>0 HhrX A aaa χΥΧ nh₂¹</td><td>2- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dlhldroplrlmldln- 1 (2H) -¡l] acetam¡da</td><td> 322.2</td><td>1 H 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)</td>

<td> 175</td><td>ABS 0 and oh χΥΧ nh₂¹</td><td>1 [(2R) -2amlnopropll] -6 (2,4-dlmethoxlfenll) 2-tloxo-2,3- hydrochloride dlhldroplrlmldln4 (1 H) -ona hldrochlorlde</td><td> 322.1</td><td>1 H NMR (400 MHz, METANOLd3) 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)</td>

<td> 176</td><td>ABS OR HhrX A xAx χΥΥ nh₂¹</td><td>1 [(2S) -2amlnopropll] -6 (2,4-dlmethoxlfenll) 2-tloxo-2,3- hydrochloride dlhydroplrimidln4 (1 H) -one</td><td> 322.1</td><td>1 H NMR (400 MHz, METANOLd3) 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), 0.95 -1.16 (m, 3 H)</td>

<td> 177</td><td>0 HirY cX aaa yYY ^ NH ¹</td><td>Formation of 6- (2,4dlmethoxlfen¡l) -1- [2 (methylamine) etl] -2tloxo-2,3dlhydroplrimidln4 (1 H) -one</td><td> 322.1</td><td>1 H NMR (400 MHz, METANOLd3) 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)</td>

122

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 178</td><td>OR ΗΐΑΑ β aaa γλ Ηφ</td><td>1- (3aminopropyl) -6 (2,4-dlmethoxlfenll) 2-thioxo-2,3-dihydropyrimidin4 (1 H) -one formate</td><td> 322.1</td><td>1 H 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, 2 H)</td>

<td> 179</td><td>0 ηντΥ cY AND vy OH ¹</td><td>6- (2,4- dimethoxyphenyl) -1 - (2-hydroxypropyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 323.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 180</td><td> \ &lt;°_sl χ ~ -Ό ^ΧΆϊ, Η TO 1</td><td>6- (2,6- dimethoxyphenyl) -1 - (2methoxyethyl) -2-thioxo2,3- dihydropyrimidin4 (1 H) -one</td><td> 323.1</td><td>2.50 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% linear MeCN at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 181</td><td>or ηγΑΑ β AND /TO HCT</td><td>6- (2,4- dimethoxyphenyl) -1 - (3-hydroxypropyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 323.1</td><td>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)</td>

<td> 182</td><td>0 h / \ cY Oh AND</td><td>6- (2,4- dimethoxyphenyl) -1 - (2methoxyethyl) -2-thioxo2,3- dihydropyrimidin4 (1 H) -one</td><td> 323.2</td><td>1 H NMR (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, 1 H), 3.86 (s, 3H), 3.83-3.91 (m, 1 H) 3.82 (s, 3H), 3.66-3.74 ( m, 1H), 3,413.47 (m, 1H), 3.16 (s, 3H)</td>

123

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 183</td><td>0 ΛΧγ fifi nh₂</td><td>1 (2-amlnoetll) -6- (3bromofenll) -2-txoxo-2,3dihldroplrlmldin4 (1 H) -one hydrochloride</td><td>M + 1 (NH2) 311.0</td><td>1 H 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)</td>

<td> 184</td><td>or HhrX &lt;H ArS OH FI</td><td>6- (5-fluoro-2,4- dlmetoxlfen¡l) -1- (2- hldroxlet¡l) -2-t¡oxo- 2,3- dlhldroplrlmldln4 (1 H) -ona</td><td> 326.8</td><td>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)</td>

<td> 185</td><td>0 HnX AA sAAyAy ní- ^ I</td><td>1 (2-amlnoetll) -6- (4-methoxy-1-naphthyl) -2-thioxo-2,3dihldroplrlmldin4 (1 H) -one hydrochloride</td><td> 327.9</td><td>1 H 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)</td>

<td> 186</td><td>TO OH</td><td>1- (2-hldroxyethyl) -2- tloxo-6- [2- (trlfluoromethoxl) fenl l] -2,3- dihldroplrlmldin4 (1 H) -ona</td><td> 333.0</td><td>1H NMR (400 MHz, CDCI3): 5 9.89 (br.s., 1H), 7.63-7.58 (m, 1H), 7.45-7.40 (m, 3H), 5.89 (d, 1 H), 4.74-4.67 (m, 1H), 4.013.95 (m, 1H), 3.82-3.75 (m, 1H), 3.71-3.66 (m, 1H), 1.83 (s, 1H).</td>

<td> 187</td><td>0 HhrX cR fia /TO Η / ΓίΊΗ</td><td>Trifluoroacetate 3- [6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dihldroplrlmldin1 (2H) - Ijpropanlmldamlda</td><td> 335.1</td><td>1 H NMR (400 MHz, METANOLd4) δ ppm 7.23 (d, J = 8.22 Hz, 1 H), 6.71 (d, J = 2.15 Hz, 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)</td>

124

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 188</td><td>0 HlY&gt; i cY aáx^Η2ΝγΑ XXxx 0</td><td>2- [6- (2,4- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljpropanamide</td><td> 336.1</td><td>1H NMR (400 MHz, CHLORFORM-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), 3.85-3.90 (m, 3 H), 3.81 -3.85 (m, 3 H), 1.85 (m, J = 6.87 Hz, 3 H)</td>

<td> 189</td><td>0 Hl / S λΑα / α ck \ ih₂</td><td>3- [6- (2,4- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljpropanamide</td><td> 336.1</td><td>1 H 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)</td>

<td> 190</td><td>0 HITA aaa «/ ΑΧ ^ NH ¹</td><td>2- [6- (2,4- dimethoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin1 (2H) -yl] -Nmethylacetamide</td><td> 336.2</td><td>1 H 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, 3 H), 2.45 (d, J = 4.58 Hz, 3 H)</td>

<td> 191</td><td>0 Hi / y j il i sA / VX nh₂</td><td>1 (4-aminobutyl) -6 (2,4-dimethoxyphenyl) 2-thioxo-2,3-dihydropyrimidin4 (1 H) -one hydrochloride</td><td> 335.9</td><td>1 H 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), 4.294.48 (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)</td>

<td> 192</td><td>0 HhrA cY λΑα /TO HIT 1</td><td>Hydrochloride 6- (2,4-dimethoxyphenyl) - 1- [3- (methylamino) propyl] 2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 336.1</td><td>1 H 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), 1,631.92 (m, 2 H )</td>

125

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 193</td><td>0 ΗνΆ qU Aa σ ^ Χ)_Η</td><td>3- [6- (2,4-dimethoxyphenyl) -4oxo-2-thioxo-3,4-dihydropyrimidin1 (2H) -yl] propanoic acid</td><td> 337.1</td><td>1 H 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)</td>

<td> 194</td><td>-or</td><td>6- (2,4- dimethoxyphenyl) -1 - (2-hydroxy-2- methylpropyl) -2-thioxo- 2,3- dihydropyrimidin4 (1 H) -one</td><td> 337.1</td><td>1 H 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)</td>

<td> 195</td><td>0 hi / AX aaa yX</td><td>6- (2,4- dimethoxyphenyl) -1- (3- hydroxy-2- methylpropyl) -2-thioxo- 2,3- dihydropyrimidin4 (1 H) -one</td><td> 337.1</td><td>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)</td>

<td> 196</td><td>0 HiXY X aaa F¹OH</td><td>6- (2,4- dimethoxyphenyl) -1 - (4-hydroxybutyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 337.1</td><td>Ή NMR (400 MHz, METANOLd4) 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), 1.66 -1.81 (m, 1 H), 1.40 -1.56 (m, 1 H), 1.16-1.32 (m, 2 H)</td>

<td> 197</td><td>ABS 0 «XA X λΛχ H₂rr</td><td>Trifluoroacetate 1 - [(2R) -3-amino-2h¡drox¡prop¡l] -6 (2,4-dlmethoxlfenll) 2-t¡OXO-2,3dlhldropirlmldln4 (1 H) -one</td><td> 338.0</td><td>1 H 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), 5.705.79 (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)</td>

126

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 198</td><td>Η, Ν. \ 1 -o Anh</td><td>1 (2-amlnoetll) -2-txoxo-6- (2,4,5-) hydrochloride trimethoxylfenyl) -2,3dlhydroplrimidln4 (1 H) -one</td><td> 338.1</td><td>1 H 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)</td>

<td> 199</td><td>0 hnY A AA AND H₂hr</td><td>1 (3-aml-2-hydroxypropyl) -6 (2,4-dimethoxyphenyl) 2-tloxo-2,3dlhldroplrlmldln4 (1 H) -one hydrochloride</td><td> 338.1</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 12.69 - 12.76 (m, 1 H), 7.61 -8.08 (m, 3 H), 7.13-7.26 (m, 1 H), 6.56-6.71 (m, 2 H), 5,655.76 (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)</td>

<td> 200</td><td>ABS 0 HirUi ν ' λΥ^H° · A ^ h₂Item</td><td>Trifluoroacetate 1 - [(2S) -3-amlno-2hldroxlpropllj-6 (2,4-dimethoxyphenyl) 2-tloxo-2,3dlhydroplrimidln4 (1 H) -one</td><td> 338.2</td><td>1 H 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), 6.606.75 (m, 2H), 5.71-5.80 (m, 1H), 5.58-5.66 (m, 1H), 4.54-4.62 (m, 1H), 4.08-4.23 (m, 1H), 3.783.85 (m, 6H), 3.23-3.41 (m, 1H), 2.71 -2.83 (m, 1H), 2.38-2.45 (m, 1H)</td>

<td> 201</td><td>OH TO l 3 ~~ -o Ah YÍr ^</td><td>1- (2,3- dlhydroxlpropll) -6 (2,4-dlmethoxlfenil) 2-tloxo-2,3dlhydroplrimidln4 (1 H) -one</td><td> 339.2</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 202</td><td>HO. \ I --o nAih</td><td>1 - (2-hldroxletll) -2tloxo-6- (2,4,5trimethoxlfenil) -2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 339.2</td><td>1 H 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)</td>

127

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 203</td><td>ABS OH^HOz / i ³Y * nHnh Yy</td><td>1- [(2S) -2,3d¡h¡drox¡prop¡l] -6 (2,4-dlmetoxlfenll) - 2- thio-2,3-dihydropyrimidine 4 (1 H) -one</td><td> 339.2</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 204</td><td>ABS OH γ vY</td><td>1- [(2R) -2,3d¡h¡drox¡prop¡l] -6 (2,4-dlmetoxlfenll) - 2- thio-2,3-dihydropyrimidine 4 (1 H) -one</td><td> 339.2</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 205</td><td>0 Mr. YY aXJU yU NH₂¹</td><td>2- [6- (4-methox¡-1 - naft¡l) -4-oxo-2- thioxo-3,4- dihydropyrimidin- 1 (2H) -¡l] acetam¡da</td><td> 342.2</td><td>1 H 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), 7,387.47 (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)</td>

<td> 206</td><td>0 x \ x rV ° OH ^ 0</td><td>6- (4-chloro-2,5- d¡metoxifen¡l) -1- (2- h¡drox¡et¡l) -2-t¡oxo- 2,3- dihydropyrimidin4 (1 H) -one</td><td> 343</td><td>1H NMR (400 MHz, CHLORFORM-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 HOUR)</td>

<td> 207</td><td>0 HhrY cY Υγ and χχ N-νη 1</td><td>6- (2,4- dimethoxyphenyl) -1 (1 Hp¡razol-5¡lmet¡l) -2-txox-2,3- dihydropyrimidin4 (1 H) -one</td><td> 345.1</td><td>1 H NMR (500 MHz, METANOLd4) 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)</td>

128

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 208</td><td>AA Υύ νη_ξ</td><td>2- {4-oxo-2-tloxo-6- [two- (trlfluoromethoxl) fenl lj-3,4- dlhldroplrlmldln1 (2H) -¡l} acetam¡da</td><td> 345.9</td><td>1H NMR (400 MHz, Metoanold3) 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)</td>

<td> 209</td><td>0 ΗνΆ β γ A &lt;A V-NH I</td><td>6- (2,4- d¡metox¡fen¡l) -2t¡0X0-1- (1 H-1,2,4tr¡azol-5-lmet¡l) 2,3- dihydropyrimidin4 (1 H) -one</td><td> 346.0</td><td>1.84 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 210</td><td>0 there are F Oops / °</td><td>1 - (2-methoxyethyl) -2-txoxo-6- [4 (trfluoromethox!) Fen¡ lj-2,3- dihydropyrimidin4 (1 H) -one</td><td> 347.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 211</td><td>or HnA β ili AAA cY</td><td>Hydrochloride 6- (2,4-dlmetoxlfenll) 1 - (plrrolldln-2¡lmetll) -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 348.4</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 12.89 (s, 1 H), 9.25 (br. S, 1 H), 8.08-8.71 (br. M., 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), 4,975.07 (m, 1 H), 3.81 -3.88 (m, 6 H), 3.61 -3.78 (m, 2 H), 2,963.17 (m, 2 H), 1.73 - 1.90 (m, 1 H), 1.65 (m, 2 H), 1.13 -1.26 (m, 1 HOUR)</td>

<td> 212</td><td>OR hiAA β AND γΥ Η</td><td>Hydrochloride 6- (2,4-dlmetoxlfenll) 1 - (plrrolldln-3¡lmetll) -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 348.4</td><td>1 H 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)</td>

129

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 213</td><td>ABS 0 hAA R xAx fifi-</td><td>6- (2,4- d¡metoxlfen¡l) -1 [(2S) - tetrah¡drofuran-2¡lmetll] -2-txox-2,3-dihydropyrimidin4 (1 H) -one</td><td> 349.1</td><td>1H NMR (400 MHz, CHLORFORM-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), 4.53-4.62 (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)</td>

<td> 214</td><td>ABS OR TO AC</td><td>6- (2,4- d¡metoxlfen¡l) -1 - [(2R) - tetrah¡drofuran-2¡lmet¡l] -2-txox-2,3-dihydropyrimidin4 (1 H) -one</td><td> 349.1</td><td>1 H NMR (400 MHz, METANOLd4) δ ppm 7.20 - 7.28 (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) 1.43-1.55 (m, 1 H) 1.31 1.40 (m, 1 H)</td>

<td> 215</td><td>OR Hl /% &lt;R Aa ZA V or</td><td>N- {2- [6- (2,4- d¡metox¡fen¡l) -4- oxo-2-txox-3,4- dihydropyrimidin- 1 (2H) - L] et¡l} acetam¡da</td><td> 350.1</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 12.70 (br. S., 1 Η), ΊΊΊ (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), 3.15-3.28 (m, 2 H), 1.67 (s, 3 H)</td>

<td> 216</td><td>0 HisrX R * Aa /TO crAH I</td><td>3- [6- (2,4d¡methox¡fen¡l) -4oxo-2-txox-3,4dihydropyrimidin1 (2H) -II] -Nmethylpropanamide</td><td> 350.1</td><td>1 H 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), 4.374.53 (m, 2 H), 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)</td>

130

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 217</td><td>0 αΑλ /TV ίαχ</td><td>3- [6- (2,4- dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) -ll] -2methylpropanamide</td><td> 350.2</td><td>1 H NMR (500 MHz, DMSO-d6) δ ppm 12.50 - 12.85 (m, 1 H) 7.15 -7.34 (m, 2 H) 6.55 -6.83 (m, 3 H) 5.64-5.77 (m, 1 H) 4,344.67 (m, 1 H) 3.75 -3.89 (m, 6 H) 3.46-3.71 (m, 1 H) 2,753.13 (m, 1 H) 0.66 -0.90 (m, 3 H)</td>

<td> 218</td><td>0 ηνΧ A aaa</td><td>1 (5-amlnopentll) -6 (2,4-dlmethoxlfenll) 2-tloxo-2,3dlhydroplrimidln4 (1 H) -one hydrochloride</td><td> 349.9</td><td>Ή NMR (400 MHz, METANOLd4) 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 1.24 (m, 2 H)</td>

<td> 219</td><td>0 jfAA + r'Ys Or Oy \ iH₂</td><td>1 (3-amlno-3metllbutll) -6- (2,4dlmethoxlfen¡l) -2-txoxo-2,3dlhydroplrimidln4 (1 H) -one hydrochloride</td><td> 350.1</td><td>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), 1.821.95 (m, 1 H), 1.42-1.55 (m, 1 H), 0.89 (s, 3 H), 0.80 (s, 3 H):</td>

<td> 220</td><td>0 Hi \ r% A aU 7 ^toI</td><td>6- (2,4- dlmethoxlfen¡l) -1- [3 (dlmet¡lamlno) prop¡ l] -2-tloxo-2,3dlhydroplrimidln4 (1 H) -ona</td><td> 350.2</td><td>1 H 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), 1.79 - 1.94 (m, 1 H), 1.63 1.78 (m, 1 H)</td>

<td> 221</td><td>0 ΗΙ \ Γ7ι (X AU 0¼ or I</td><td>[6- (2,4- dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) -il] ethyl acetate</td><td> 351.2</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 12.94 (s, 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 (dtt, 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)</td>

131

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 222</td><td>0 HITA θ '' aaa /OR.</td><td>Acetate 2- [6- (2,4-dimethoxyphenyl) 4-oxo-2-thioxo-3,4dihydropyrimidin1 (2H) -yl] ethyl</td><td> 351.2</td><td>1 H 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)</td>

<td> 223</td><td>0 HITA A aaa Λα ° &lt;γ^ΝΗ 'nh₂</td><td>1- {2- [6- (2,4- dimethoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin1 (2H) -yl] ethyl} urea</td><td> 351.2</td><td>1.80 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0min. (0.05% TFA). Velocity flow rate: 2 mL / min</td>

<td> 224</td><td>0 HITA cO aaa and ^to</td><td>6- (2,4- dimethoxyphenyl) -1- (3-hydroxy-2,2-dimethylpropyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 351.1</td><td>1 H NMR (400 MHz, METANOLd3) 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 = 10.99 Hz, 1 H), 0.83 (s, 3 H), 0.66 (s, 3 H)</td>

<td> 225</td><td>0 Hi / y cY aaa go ^</td><td>6- (2,4- dlmethoxlfen¡l) -1 - (5-hydroxypentyl) -2thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 351.1</td><td>^]H NMR (500 MHz, METHANOLd4) 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), 1.68 - 1.79 (m, 1 H), 1.39 - 1.51 (m, 1 H), 1.25 - 1.36 (m, 2 H), 1.03 - 1.20 (m, 2 H)</td>

132

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 226</td><td>-or</td><td>6- (2,4- dlmetoxlfen¡l) -1 - (2- Sopropoxletll) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 351.1</td><td>1H NMR (400 MHz, CHLORFORM-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) 3.69-3.81 (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)</td>

<td> 227</td><td>for yk ° \ -or</td><td>6- (2,4- dlmetox¡fenll) -1 - [3 (metllt¡o) propll] -2tioxo-2,3- dlhldropirlmldln4 (1 H) -ona</td><td> 353.1</td><td>1 H 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)</td>

<td> 228</td><td>0 «XA X aAx AND</td><td>1-benzll-6- (2,4dlmethoxphenll) -2thioxo-2,3dlhldropirlmldln4 (1 H) -ona</td><td> 355.2</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 9.84 (br. S., 1 H), 7.14-7.22 (m, 3H), 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)</td>

<td> 229</td><td>0 HtrSi cA ΛΜ Υ ΙγΧ,^NH2</td><td>2- [6- (4-Chloro-2,5- dlmetox¡fenll) -4- oxo-2-txox-3,4- dlhldropirlmldln- 1 (2H) -¡l] acetam¡da</td><td> 356.1</td><td>1 H NMR (400 MHz, METANOLd3) 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)</td>

133

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 230</td><td>0 hXX J ΛΑ χΥΧ</td><td>6- (2,4- d¡metoxifen¡l) -1 - (p¡r¡d¡n-2-lmet¡l) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 356.1</td><td>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)</td>

<td> 231</td><td>0 aaa θ / ΧΥ</td><td>6- (2,4- d¡metox¡fen¡l) -1 - (pyridin-3-lmetl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 356.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 232</td><td>or «XA X aaa Yu V¹</td><td>6- (2,4- d¡metox¡fen¡l) -1 - (pyridin-4-lmetl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 356.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 233</td><td>OR hXAi A lll sAAA, AA</td><td>6- (4-chloro-2,5- d¡metoxifen¡l) -1- (2- metox¡et¡l) -2-txox- 2,3- dihydropyrimidin4 (1 H) -one</td><td> 357.1</td><td>1 H 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)</td>

134

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 234</td><td>0 hYX Y Oh fT AND^N</td><td>6- (2,4- dlmetox¡fenll) -1 (pirlmldin-2-llmetll) 2-t¡oxo-2,3- dlhldroplrlmldln4 (1 H) -ona</td><td> 357.0</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 235</td><td>0 hi / yy aaa AND V</td><td>Hydrochloride 6- (2,4-dlmetoxlfenll) 1 - (plperldln-4¡lmetll) -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 362.1</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (d, J = 1.86 Hz, 1 H), 8.66 -8.77 (m, 1 H), 8.17-8.31 (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, 2 H), 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)</td>

<td> 236</td><td>0 hYX Y yY HN ^^ NH 1 nh₂</td><td>Trifluoroacetate N- [amlno (lm¡no) met¡l] -2- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dlhldroplrlmldln- 1 (2H) -ll] acetamlda</td><td> 364.0</td><td>1 H NMR (400 MHz, METANOLd4) δ ppm 7.19 (d, J = 8.41 Hz, 1 H), 6.68 (d, J = 2.15 Hz, 1 H), 6.63 (dd, J = 8.41.2.35 Hz, 1 H ), 5.84 (s, 1 H), 5.44 (br. D, J = 15.10 Hz, 1 H), 4.55 (br. D, J = 17.40 Hz, 1 H), 3.88 (s, 3 H), 3.85 (S, 3 H)</td>

<td> 237</td><td>0 λΛλ VY Yy ¹ 1</td><td>3- [6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) -il] -N, Ndlmetllpropanamld to</td><td> 364.1</td><td>1 H 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)</td>

135

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 238</td><td>0 Hr / X (Y NOW ΗΝ-Ύ VAo Y '</td><td>Hydrochloride 6- (2,4-dlmetoxlfenll) 1 - (morfolln-2¡lmetll) -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 364.2</td><td>1 H NMR (400 MHz, METANOLd4) 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, 3 H), 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)</td>

<td> 239</td><td> 0 ...... 0</td><td>2- [6- (2,4- dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) -ll] ethyl propanoate</td><td> 365.1</td><td>1 H 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), 4,444.57 (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 3 H)</td>

<td> 240</td><td>0 HhrX Y AND</td><td>3- [6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) -ll] ethyl propanoate</td><td> 365.1</td><td>1 H 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)</td>

<td> 241</td><td>AND Cr \ - O</td><td>N (2-amlnoetll) -2- [6 (2,4-dlmethoxlfenll) 4-oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) -ll] acetamlda hydrochloride</td><td> 364.8</td><td>1 HNMR (400 MHz, METANOLd4): 6 8.28 (m, 1H), 7.15 (d, 1H), 6.66 (d, 1H), 6.62 (dd, 1H), 5.79 (s, 1H), 5.42-5.40 (m , 1H), 4,374.23 (m, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.20-3.15 (m, 1H), 3,053.12 (m, 1H), 2.95-2.85 (m , 2H).</td>

<td> 242</td><td>0 ΗΙ \ Γ&gt; | AND aaa AND .NH ¹cayh₂</td><td>N ~ 2 ~ - {2- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dlhldroplrlmldln- 1 (2H) - Ijetlljgllclnamlda</td><td> 365.1</td><td>1 HNMR (400 MHz, METANOLd4): δ 7.14 (d, 1H), 6.55-6.60 (m, 2H), 5.65 (s, 1H), 4.55-4.62 (m, 1H), 4.51 (s, 1H), 3.77 (s, 6H), 3.00 (s, 2H), 2.64-2.79 (m, 2H).</td>

136

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 243</td><td>Or -^{o =}CZ / Η X OR</td><td>N {2- [6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dihldroplrlmldin1 (2H) -ll] ethyl} glycine hydrochloride</td><td> 365.9</td><td>1H NMR (400MHz, DMSO-d6): δ 12.88 (br, 1H), 7.26 (d, 1H), 6.66-6.74 (m, 2H), 5.78 (s, 1 H), 4.76 (m, 1H), 3.92 (m, 1H), 3.83 (s, 6H), 3.70 (s, 2H), 3.02 (m, 2H).</td>

<td> 244</td><td>0 ΗΓτΑ R TO Αχ γ ¹H₂to go</td><td>2- [6 (2,4-Dimethoxyphenyl) 4-oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) -ll] etll0 tosylate glycinate</td><td> 366.2</td><td>1 H NMR (400 MHz, OD₃OD) 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), 6.65-6.72 (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)</td>

<td> 245</td><td>0 hi / ar Aa fifi</td><td>6- (2,4- dlmetoxifenll) -1 - {3 [(2- hldroxlet¡l) am¡no] pr opll} -2-tloxo-2,3dihldroplrlmldin4 (1 H) -ona</td><td> 365.9</td><td>1.58 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 246</td><td>0 hiAA A Za X</td><td>Acid {2- [6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) - L] ethoxy} acetic</td><td>388.9 [M + Na ] +</td><td>1 HNMR (400 MHz, METANOLd4): 5 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).</td>

<td> 247</td><td>0 Hi \ r&gt; i cfi a.'u, FOR</td><td>6- (2,4- dlmethoxifenll) -1 - [(5metllplrazln-2¡l) metll] -2-tloxo-2,3dihldroplrlmldin4 (1 H) -ona</td><td> 371.1</td><td>1 H 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)</td>

137

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 248</td><td>0 ηνΑ cA sk ^ kx / ki kk okkNH₂ 0</td><td>2- [6- (2,4- dlmetox¡fenll) -4- oxo-2-txox-3,4- dihydropyrimidin- 1 (2H) - Ijetansulfonamide</td><td> 372.0</td><td>1 H 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)</td>

<td> 249</td><td>0 ΗΐΥΥ cA sAAk I Cite</td><td>6- (2,4- dlmethox? fenll) -1 - [2 (1 H-¡m¡dazol-2-lamino) ethyl] -2thioxo-2,3dlhldropirlmldln4 (1 H) -one</td><td> 374.0</td><td>1 H NMR (500 MHz, METANOLd4) 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 ) 3.90-3.93 (m, 1 H) 3.88 (s, 3 H) 3.84 (s, 3 H) 3.26-3.33 (m, 2 H)</td>

<td> 250</td><td>0 ηγΑΧ cA sAA / k x ^ ¹(or XN</td><td>1- [2- (4,5-dihydro- 1 H-¡¡¡¡¡¡¡zol-2 -lamino) ethyl] -6- (2,4d¡metox¡fen¡l) -2thioxo-2,3- dlhldropinmldln4 (1 H) -ona</td><td> 376.1</td><td>1 H NMR (400 MHz, METANOLd4) 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, 2 H), 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)</td>

<td> 251</td><td>0 HhrS Y For /FOR 0</td><td>6- (2,4- dlmethoxlfen¡l) -1 - (2morfolin-4-lethyl) -2thioxo-2,3dlhldropinmldln4 (1 H) -ona</td><td> 377.8</td><td>1 HNMR (400 MHz, CDCI3): δ 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), 2,522.66 (m, 2H), 2.28 -2.38 (m, 4H).</td>

138

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 252</td><td>0 Hl / Si Y already A- A</td><td>Hydrochloride 6- (2,4-dimethoxyphenyl) - 1 - [(4- hydroxypiperidin-4il) methyl] -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 378.1</td><td>1 H 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)</td>

<td> 253</td><td>or hna ό aaa /AND Η / Ιγ, ΝΗ NH</td><td>1- {4- [6- (2,4- dimethoxyphene) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljbutiljguanidine</td><td> 378.0</td><td>1 HNMR (400 MHz, METANOLd4): 5 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), 1.76-1.78 (m, 1H), 1.52-1.55 (m, 1H), 1.33-1.40 (m, 2H).</td>

<td> 254</td><td>OR ΗνΆ Y NOW goes NH ¹H₂hr ^ o</td><td>N ~ 2 ~ - {[6- (2,4- dimethoxyphene) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetylglycineamide</td><td>305.1 [M- NHCH 2CON H2] +</td><td>1 H NMR (400 MHz, CD₃OD) δ 3.69 (d, J = 17.0 Hz, 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)</td>

<td> 255</td><td>ABS 0 ημΆ Y aAx XX ° ^NH 1 to</td><td>N- {2- [6- (2,4-dimethoxyphenyl) -4oxo-2-thioxo-3,4-dihydropyrimidin1 (2H) -yl] ethyl} -Dalaninamide trifluoroacetate</td><td> 379.2</td><td>7.51 min Chiralcel OD-H 4.6mmx25cm, 75% CO2 / 25% MeOH (0.2% PrNH2). Velocity flow rate: 2.5 ml / min</td>

139

<td>Example No.</td><td colspan="2">Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td></td><td></td><td></td><td>Trifluoroacetate</td><td></td><td></td>

<td> 256</td><td>0 xi and O ^^ NH</td><td>ν ' and I</td><td>N- {2- [6- (2,4- dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhydroplrimidln1 (2H) -ll] ethyl} -Lalanlnamlda</td><td> 379.2</td><td>6.32 min Chiralcel OD-H 4.6mmx25cm, 75% CO2 / 25% MeOH (0.2% PrNH2). Velocity flow rate: 2.5 mL / mln</td>

<td></td><td></td><td></td><td></td><td></td><td>1H NMR (400 MHz,</td>

<td></td><td></td><td></td><td>N- {2- [6- (2,4-</td><td></td><td>CHLOROFORM-d) δ ppm 9.48</td>

<td></td><td> 0</td><td></td><td>dlmethoxlfenil) -4-</td><td></td><td>(br. s., 1 H), 7.21 (d, J = 8.70 Hz,</td>

<td></td><td>^Hhe</td><td>TO</td><td>oxo-2-tloxo-3,4-</td><td></td><td>1 H), 6.61 (dd, J = 8.24, 2.29 Hz,</td>

<td> 257</td><td></td><td></td><td>dlhldroplrlmldln-</td><td> 386.1</td><td>1 H), 6.54 (d, J = 2.29 Hz, 1 H),</td>

<td></td><td>V</td><td></td><td>1 (2H) -</td><td></td><td>5.85 (d, J = 2.29 Hz, 1 H), 4.62 (t,</td>

<td></td><td>I V^NH</td><td>I</td><td>Ijetlljmetansulfone</td><td></td><td>J = 6.64 Hz, 2 H), 3.88 (s, 3 H),</td>

<td></td><td>Xi 0</td><td></td><td>measure</td><td></td><td>3.85 (s, 3 H), 3.27-3.47 (m, 2</td>

<td></td><td></td><td></td><td></td><td></td><td>H), 2.86 (s, 3H)</td>

<td></td><td></td><td></td><td>Trifluoroacetate</td><td></td><td>1.72 min Waters Atlantis dC18</td>

<td></td><td> 0</td><td></td><td> 2-{[6-(2,4-</td><td></td><td>5um 4.6x50mm,</td>

<td></td><td></td><td>TO</td><td>dlmetoxlfen¡l) -4-</td><td></td><td>95% H2O / 5% linear MeCN at</td>

<td rowspan="2"> 258</td><td></td><td>TO</td><td>oxo-2-tloxo-3,4-</td><td rowspan="2"> 390.1</td><td>5% H2O / 95% MeCN for 4.0</td>

<td rowspan="2">&lt;v</td><td>Ha</td><td>dlhydroplrimidln-</td><td>min, MAINTAIN</td>

<td></td><td>i</td><td>1 (2H) -</td><td></td><td>a5% H2O / 95% MeCN at 5.0min.</td>

<td></td><td>ν</td><td></td><td>L] metll} p¡rrol¡d¡n-1 -</td><td></td><td>(0.05% TFA). Velocity flow: 2</td>

<td></td><td>HN</td><td></td><td>carboximldamide</td><td></td><td>mL / mln</td>

<td></td><td></td><td></td><td>Trifluoroacetate</td><td></td><td>1.69 min Waters Atlantis dC18</td>

<td></td><td></td><td></td><td> 3-{[6-(2,4-</td><td></td><td>5um 4.6x50mm,</td>

<td></td><td> 0</td><td></td><td>dlmetoxlfen¡l) -4-</td><td></td><td>95% H2O / 5% linear MeCN at</td>

<td> 259</td><td>hnA sAA</td><td>q ' tj</td><td>oxo-2-tloxo-3,4- dlhldroplrlmldln-</td><td> 390.1</td><td>5% H2O / 95% MeCN for 4.0 min, MAINTAIN.</td>

<td></td><td></td><td></td><td>1 (2H) -</td><td></td><td>a5% H2O / 95% MeCN at 5.0min.</td>

<td></td><td>^hAND_nh</td><td></td><td>L] metll} p¡rrol¡d¡n-1 -</td><td></td><td>(0.05% TFA). Velocity flow: 2</td>

<td></td><td></td><td></td><td>carboximldamide</td><td></td><td>mL / mln</td>

<td></td><td></td><td></td><td></td><td></td><td>1 H NMR (400 MHz, METHANOL-</td>

<td></td><td>or</td><td></td><td></td><td></td><td>d4) δ ppm 7.23 (d, J = 8.20 Hz, 1</td>

<td></td><td></td><td>X</td><td>Hydrochloride 6- [6-</td><td></td><td>H), 6.68 (d, J = 2.15 Hz, 1 H),</td>

<td></td><td rowspan="2">xi /</td><td></td><td>(2,4-dlmetoxlfenll) -</td><td></td><td>6.66 (dd, J = 8.39, 2.54 Hz, 1 H),</td>

<td> 260</td><td>and I</td><td>4-oxo-2-tloxo-3,4- dlhydroplrimidln-</td><td> 393.1</td><td>5.75 (s, 1 H), 4.48-4.59 (m, 1 H), 3.87 (s, 6 H), 3.75-3.81 (m,</td>

<td></td><td></td><td></td><td>1 (2H) -</td><td></td><td>1 H), 3.65-3.74 (m, 1 H), 1.73 -</td>

<td></td><td>A \ / NH^HxAND</td><td></td><td>Ijnorleuclnamide</td><td></td><td>1.83 (m, 1 H), 1.63 - 1.73 (m, 2</td>

<td></td><td> 0</td><td></td><td></td><td></td><td>H), 1.45-1.57 (m, 1 H), 1.14-</td>

<td></td><td></td><td></td><td></td><td></td><td>1.25 (m, 2 H)</td>

140

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 261</td><td>0 hit'Xi cX or, XX ΙΨ-Ν I s = y nh₂</td><td>3 - {[6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) -ll] metll} -1 H- p¡razole-1 carbothioamide</td><td> 404.2</td><td>1 H 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)</td>

<td> 262</td><td>0 TODAY 0 ^ aU AA h₂n</td><td>Hydrochloride 6- (2,4-dimethoxyphenyl) 1 - [(1 -gllcllplrrolldln2-¡l) metll] -2-tloxo2,3- dlhldroplrlmldln4 (1 H) -ona</td><td> 405.1</td><td>0.83 min Column: Xtlmate 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</td>

<td> 263</td><td>ABS OR HlAA A au already ° ^NH ι Η, ΙΑ</td><td>N- {2- [6- (2,4dlmethoxlfenl) -4oxo-2-tloxo-3,4dlhydroplrimidln1 (2H) -ll] etll} -Lvallnamlda trifluoroacetate</td><td> 407.3</td><td>5.74 min Column: XBRIDGEC18 4.6mmX150mm 5pm Mobile phase- A = 0.1% TFA IN MeCN, B = 0.1% TFA IN WATER: Phase A = 5% at 1.5 min, linear at 100% at 10 minutes. Velocity flow rate = 1.5 mL / mln.</td>

<td> 264</td><td>or hitA_STO_rAa nh₂</td><td>1 (2-amlnoetll) -6- (3methoxlfenll) -2-txoxo-2,3dlhydroplrimidln4 (1 H) -one hydrochloride</td><td> 278.1</td><td>1 H 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)</td>

<td> 265</td><td>or Χ to</td><td>1 (3-amlnopropll) -6 (3-methoxlfenll) -2-txoxo-2,3dlhydroplrimidln4 (1 H) -one hydrochloride</td><td> 292.0</td><td>1 H 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, 2H)</td>

141

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 266</td><td>0 HisrY 00</td><td>1 -alll-6- (2,4dlmethoxlfen¡l) -2tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 305.1</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 10.35 (br.s., 1 H), 7.04 (d, J = 8.19Hz, 1 H), 6.52 (d, J = 2.34 Hz, 1 H), 6.47-6.50 (m, 1 H), 5.82 (d, J = 2.15 Hz, 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)</td>

<td> 267</td><td>ABS AND, i 1 —O tY + ih</td><td>Hydrochloride 6- (2,4-dlmethoxlfenll) 1 - [(2R) -plrrolld¡n-2¡lmetll] -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 348.1</td><td>1 H NMR (500 MHz, DMSO-d6) δ ppm 12.89 (br. S „1 H), 9.25 9.43 (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), 1,731.90 (m, 1 H), 1.50 - 1.73 (m, 2 H), 1.14-1.25 (m, 1 H)</td>

<td> 268</td><td>ABS --- 0 l + ^ NH AND</td><td>Hydrochloride 6- (2,4-dlmethoxlfenll) 1 - [(2S) -plrrolld¡n-2¡lmetll] -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 348.1</td><td>1 H NMR (500 MHz, DMSO-d6) δ ppm 12.89 (br. S „1 H), 9.25 9.43 (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), 1,731.90 (m, 1 H), 1.50 - 1.73 (m, 2 H), 1.14-1.25 (m, 1 H)</td>

<td> 269</td><td>0 and</td><td>Hydrochloride 1- [2 (2-2-amnoxytox) etll] 6- (2,4- dlmetoxlfen¡l) -2tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 352.3</td><td>1 H 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), 3.343.41 (m, 2 H), 2.80-2.90 (m, 2 H)</td>

142

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 270</td><td>0 Hhr \ aXa AND Λ η₂ν · Ύη₂</td><td>2- {3- [6- (2,4-dimethoxyphenyl) -4oxo-2-thioxo-3,4-dihydropyrimidin1 (2H) trifluoroacetate (2H) - iljpropiljguanidine</td><td> 364.1</td><td>1 H NMR (400 MHz, METANOLd4) 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, 2 H), 1.86 2.00 (m, 1 H), 1.67-1.79 (m, 1 H)</td>

The following Examples in Table 4 were prepared from the corresponding aryl halide to obtain the beta-ketoester intermediate as described above for the Preparations in the section of the aryl halide pathway, and then using the methods described in I. Section of the beta-ketoester pathway, as well as standard techniques and methods known by the people of the medium level trade.

Table 4. Examples of the aryl halide pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 271</td><td>HO^xcY nYh</td><td>1- (2-hydroxyethyl) -6- [2- (2methoxyethyl) phenyl] -2-thioxo2,3-dihydropyrimidin4 (1 H) -one</td><td> 306.9</td><td>1H NMR (500 MHz, CHLORFORM-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 HOUR)</td>

143

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 272</td><td>^H2^N\ X</td><td>2- {2 [3- (2-amlnoetll) -6-oxo-2-thioxo-1,2,3,6-tetrahydroplrlmldin-4 trifluoroacetate!</td><td> 320.9</td><td>1H NMR (500 MHz, METANOL-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 = 6.10 Hz, 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)</td>

<td> 273</td><td>HO. \ 5 -o VXh fi</td><td>6- (2,5-dlmetox¡-4methylfenll) -1 - (2hldroxlet¡l) -2-txox-2,3dihldroplr¡m¡din-4 (1 H) - ona</td><td> 323.2</td><td>1H NMR (500 MHz, METANOL-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), 3.793.81 (m, 1 H), 3.59-3.67 (m, 1 H), 2.28 (s, 3H)</td>

<td> 274</td><td>0 hiZSi rA OH I</td><td>1 - (2-hldroxlet¡l) -6- (4methox¡-1-naphthyl) -2-thioxo2,3-dihldropirlmldln4 (1 H) -ona</td><td> 329.0</td><td>2.53 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

<td> 275</td><td>l I Ό l \ r + JH ^ AjXA₀fi</td><td>6- (2,5-dlmetox¡-4methylfenll) -1 - (2metoxletll) -2-t¡oxo-2,3dihldroplr¡m¡din-4 (1 H) - ona</td><td> 337.1</td><td>2.79 min Waters Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% TFA). Velocity flow rate: 2 mL / mln</td>

The following examples in Table 5 were prepared from 6-iodo-1- (2-methoxyethyl) 2- (methylthio) pimirin-4 (1 H) -one and the appropriate aryl boronate as described above for the Preparations and procedures in the section of the Suzuki pathway, as well as standard techniques and methods known by the people of the middle level trade.

144

Table 5. Examples of the Suzuki route

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 276</td><td>0 jCO X^or</td><td>1 - (2-methoxletll) -6 (2-naftll) -2-tloxo2,3-dlhldroplrlmldln4 (1 H) -ona</td><td> 313.1</td><td>1H NMR (400 MHz, METANOL-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)</td>

<td> 277</td><td>or ηγτΑ XX AND x °</td><td>6- (2-furll) -1- (2methoxletll) -2-txox2,3-dlhldroplrlmldln4 (1 H) -ona</td><td> 253.1</td><td>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)</td>

<td> 278</td><td>or HMil aXj¡ i 1 /</td><td>1 - (2-methoxyethyl) -6 (1 H-plrazol-5-ll) -2-txoxo-2,3dlhldroplrlmldln4 (1 H) -one</td><td> 253.1</td><td>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)</td>

<td> 279</td><td> 0 _sk \ kkx AND x °</td><td>1 - (2-methoxyethyl) -6plrld¡n-3-¡l-2-txox2,3-dlhldroplrlmldln4 (1 H) -ona</td><td> 264.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 280</td><td>0 sk ^ njxkjX ^ N AND x °</td><td>3- (2-Methoxletll) -2- tloxo-2,3-dlhldro- 4,5'-blplr¡m¡d¡n- 6 (1H) -one</td><td> 265.1</td><td>1H NMR (400 MHz, METANOL-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)</td>

145

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 281</td><td>or TO</td><td>1- (2-methoxyletl) -6- (1-methyl-1 H-pyrrole-2il) -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -one</td><td> 266.1</td><td>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)</td>

<td> 282</td><td>or Xv V \ TO</td><td>1- (2-Methoxyethyl) -6- (2-tlenll) -2-txox2,3-dlhldroplrlmldln4 (1 H) -ona</td><td> 269.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 283</td><td>or he has /or TO</td><td>1- (2-Methoxyethyl) -6- (3-methylfenll) -2tloxo-2,3dlhldroplrlmldln4 (1 H) -one</td><td> 277.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 284</td><td>or sJJa /or TO</td><td>1- (2-Methoxletll) -6- (2-metllfenil) -2tloxo-2,3dlhldroplrlmldln4 (1 H) -one</td><td> 277.2</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

146

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 285</td><td>or hiYT I^to· X</td><td>1 - (2-methoxetl) -6- (4-metllfen¡l) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 277.2</td><td>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)</td>

<td> 286</td><td>0 / TX</td><td>6- (4-hldrox¡fenll) -1 (2-methox¡et¡l) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 279.1</td><td>1H NMR (400 MHz, DMSOd6) d ppm 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)</td>

<td> 287</td><td> 0 /°</td><td>6- (3-hldrox¡fenll) -1 (2-methoxyethyl) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 279.1</td><td>1H NMR (301 MHz, DMSOd6) δ ppm 12.75 (br. S., 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)</td>

<td> 288</td><td>or Hhrx oh 1st / °</td><td>6- (2-hldrox¡fenll) -1 (2-methox¡et¡l) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 279.1</td><td>1H NMR (400 MHz, METANOL-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)</td>

<td> 289</td><td>0 XXyy^F</td><td>6- (3-fluorophenol) -1 - (2-Methoxletll) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 281.1</td><td>1H NMR (400 MHz, CHLORFORM-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 = 1.37Hz, 1 H), 4.36 (br. S., 2 H), 3.66 (br. S., 2 H ), 3.21 (s, 3 H)</td>

147

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 290</td><td>or / XX X^or</td><td>6- (4-fluorophenyl) -1 - (2-Methoxyethyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 281.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 291</td><td>or XX ^ X / °</td><td>3- [3- (2-Methoxyethyl) - 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin- 4-yl] benzonitrile</td><td> 288.1</td><td>1H NMR (400 MHz, CHLORFORM-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, 2 H), 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)</td>

<td> 292</td><td>0 JL .OH^HN ll 1 sX ^ nXaXa, or X</td><td>6- [2- (hydroxymethyl) phenyl] 1- (2-methoxyethyl) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 293.0</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 12.77 (br. S., 1 H), 7.43-7.56 (m, 2H), 7.307.41 (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), 3.69-3.82 (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)</td>

<td> 293</td><td> 0 _saX ^ ya /or X</td><td>1 - (2-methoxyethyl) -6 (3-methoxyphenyl) -2thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 293.2</td><td>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)</td>

<td> 294</td><td>0 sAjJUyx X ¹</td><td>1 - (2-methoxyethyl) -6 (4-methoxyphenyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 293.2</td><td>1H NMR (400 MHz, CHLORFORM-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 (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)</td>

148

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 295</td><td>0 (Cx X</td><td>1- (2-methoxetl) -6 (6-methox¡p¡r¡d¡n-3¡l) -2-txox-2,3-dihydropyrimidin4 (1 H) -one</td><td> 294.1</td><td>1H NMR (400 MHz, CHLORFORM-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, 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)</td>

<td> 296</td><td>or HhrX X ^ A X</td><td>1 - (2-methoxetil) -6 (3-methoxypridrid-4l) -2-txox-2,3-dihydropyrimidin4 (1 H) -one</td><td> 294.1</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 9.61 (br. S., 1 H), 8.42 (s, 1 H), 8.40 (d, J = 4.81 Hz, 1 H), 7.18 (d, J = 4.81 Hz, 1 H), 5.77 (d, J = 2.29 Hz, 1 H), 4.73 (dt, J = 13.97, 3.43 Hz, 1 H), 3.97 (s, 3 H), 3.80 (td, J = 9.62 , 3.89 Hz, 1 H), 3.68 (ddd, J = 13.80, 9.33, 4.58 Hz, 1 H), 3.36 (dt, J = 10.08, 3.89 Hz, 1 H), 3.14 (s, 3 H)</td>

<td> 297</td><td>0 ηψ \ i ^NX ° \</td><td>1 - (2-methoxetil) -6 (2-methoxypridrid-4l) -2-txox-2,3-dihydropyrimidin4 (1 H) -one</td><td> 294.2</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 9.59 (br. S., 1 H), 8.29 (dd, J = 5.04, 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 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)</td>

<td> 298</td><td>0 X</td><td>6- (4-chlorophenol) -1 (2-methoxether) -2thioxo-2,3-dihydropyrimidin4 (1H) -one</td><td> 297.1</td><td>1H NMR (400 MHz, METHANOL-d3) δ ppm 7.53 (d, 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, J = 5.72 Hz, 2 H), 3.16 (s, 3 H)</td>

149

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 299</td><td>or</td><td>6- (2-Chlorophenol) -1 (2-methoxyethyl) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 297.1</td><td>1H NMR (400 MHz, CHLORFORM-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, 2 H), 3.41-3.47 (m, 1 H), 3.17 (s, 3 H)</td>

<td> 300</td><td>0 V</td><td>6- (3-chlorophenyl) -1 (2-methoxyethyl) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 297.1</td><td>1H NMR (400 MHz, METHANOL-d3) δ ppm 7.477.57 (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)</td>

<td> 301</td><td> 0</td><td>6- (1 H-indole-6-¡1) -1 (2-methoxyethyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 302.1</td><td>1H NMR (400 MHz, OLOROFORM-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 (s, 3 H)</td>

<td> 302</td><td>0 Already AND</td><td>6- (1 H-indole-2-ll) -1 (2-methoxyethyl) -2thioxo-2,3 dihydropyrimidin4 (1 H) -one</td><td> 302.1</td><td>1H NMR (400 MHz, DMSOd6) 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)</td>

150

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 303</td><td>0 fi</td><td>6- (1 H-¡ndol-5-yl) -1 (2-methoxy¡et¡l) -2thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 302.1</td><td>1H NMR (400 MHz, CHLORFORM-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, 2 H), 3.08-3.18 (m, 3 H)</td>

<td> 304</td><td>0 Hl / A í = \ 1 ii,^nhsXxyV fi</td><td>6- (1 H-¡ndol-4-yl) -1 (2-methoxletll) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 302.1</td><td>1H NMR (400 MHz, METHANOL-d3) ppm 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)</td>

<td> 305</td><td>0 fi</td><td>6- (1-benzofuran-3¡l) -1- (2-methoxetl) 2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 303.0</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 306</td><td>0 fi ~</td><td>6- (1-benzofuran-2¡l) -1- (2-methoxetl) 2-thio-2,3-dihydropyrimidin4 (1 H) -one</td><td> 303.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

151

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 307</td><td>or HirX O — Λ xu&gt; x °</td><td>6- (1-benzofuran-7¡l) -1 - (2-methoxyethyl) 2-thioxo-2,3dlhydroplrimidin4 (1 H) -one</td><td> 303.4</td><td>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), 3,593.75 (m, 1 H), 3.33-3.50 (m, 1 H), 3.03 (s, 3H)</td>

<td> 308</td><td>0 x °</td><td>6- (2,3-d¡h¡dro-1 benzofuran-5-¡l) -1 (2-methoxyethyl) -2thioxo-2,3dlhydroplrimldin4 (1 H) -one</td><td> 305.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 309</td><td>0 AND x °</td><td>6- (1,3-benzodoxox5-11) -1- (2methoxyethyl) -2-thioxo2,3-dlhydropirlmldin4 (1 H) -one</td><td> 307.1</td><td>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), 5.78 (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)</td>

<td> 310</td><td>XY</td><td>6- (2-ethoxlfenll) -1 (2-methoxletll) -2thioxo-2,3dlhydroplrimldin4 (1 H) -one</td><td> 307.1</td><td>1H NMR (400 MHz, METANOL-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)</td>

152

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 311</td><td> 0</td><td>6- (4-ethoxlfenll) -1 (2-methoxletll) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 307.2</td><td>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)</td>

<td> 312</td><td>or hXY X</td><td>1- (2-methoxetl) -6 (2-methoxy-5-methylphenol) -2-thoxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) - ona</td><td> 307.2</td><td>1H NMR (400 MHz, CHLORFORM-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, 1 H), 3.14 (s, 3 H), 2.34 (s, 3 H)</td>

<td> 313</td><td>0 ACE S ^ XX ^ N AND X</td><td>6- (6-Etox¡p¡r¡d¡n-3¡l) -1 - (2-Methoxletll) 2-Txox-2,3-Dihydropyrimidin4 (1 H) -one</td><td> 308.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 314</td><td> 0 ^HNn ¿AYx X ¹</td><td>2 '- (d¡met¡lam¡no) -3- (2-Methoxletll) -2- t¡oxo-2,3-d¡h¡dro- 4,5'-b¡p¡r¡m¡d¡n- 6 (1H) -one</td><td> 308.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

153

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 315</td><td>or And it is TO '</td><td>6- (3-fluoro-4methox¡fen¡l) -1 - (2.metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H ) -one</td><td> 311.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 316</td><td>OR F sAAA / Oops TO '</td><td>6- (2-fluoro-4methox¡fen¡l) -1 - (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) - ona</td><td> 311.1</td><td>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)</td>

<td> 317</td><td>or hnA A sAAA XF</td><td>6- (5-fluoro-2methox¡fen¡l) -1 - (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) - ona</td><td> 311.1</td><td>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), 3,373.43 (m , 1 H), 3.16 (S, 3 H)</td>

<td> 318</td><td>OR Hi A TO</td><td>6- (4-fluoro-2methox¡fen¡l) -1 - (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) - ona</td><td> 311.2</td><td>1H NMR (400 MHz, CHLORFORM-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, 2H), 3,383.47 (m, 1 H), 3.16 (s, 2 H)</td>

154

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 319</td><td>or^H™ | i AA _S&lt;A_NA \ A ^ A X</td><td>1- (2-Methox¡et¡l) -6 (1 -naft¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 313.1</td><td>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), 7.667.71 (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)</td>

<td> 320</td><td>0 X</td><td>1 - (2-methoxetl) -6qu¡nol¡n-3-¡l-2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 314.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 321</td><td>or AAaa</td><td>1- (2-Methox¡et¡l) -6qu¡nol¡n-5-¡l-2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 314.1</td><td>1H NMR (400 MHz, CHLORFORM-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), 3.83-3.98 (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)</td>

155

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 322</td><td>or hiAA nA AYU TO</td><td>1 - (2-Methoxyethyl) -6quinolin-8-yl-2-thioxo2,3-dihydropyrimidin4 (1 H) -one</td><td> 314.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 323</td><td> 0 ^{hn /}| 1 AND TO</td><td>6- (1-benzotien-2-il) - 1- (2-Methoxyethyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 319.4</td><td>1H NMR (400 MHz, OLOROFORM-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, 2 H), 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)</td>

<td> 324</td><td> 0 ^LsTO</td><td>6- (1-benzotien-3-il) - 1 - (2-methoxyethyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 319.4</td><td>1H NMR (400 MHz, OLOROFORM-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)</td>

<td> 325</td><td>0 HhrY o sAA / Xa JXT β</td><td>3- [3- (2-Methoxyethyl) - 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin- 4-il] -N- methylbenzamide</td><td> 320.1</td><td>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)</td>

156

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 326</td><td>0 λλγΛ r CQ x °</td><td>6- (2,3-dihydro-l, 4-benzodioxin-6-yl) -1 (2-methoxyethyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 321.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 327</td><td> 0</td><td>6- (4- isopropoxyphenyl) -1 - (2-Methoxyethyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 321.2</td><td>1H NMR (400 MHz, CHLORFORM-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, 2H), 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)</td>

<td> 328</td><td>1 a ηιψΑ crA_sto_naJx or x °</td><td>6- (2- isopropoxyphenyl) -1 - (2-Methoxyethyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 321.2</td><td>1 H NMR (400 MHz, CHLORFORM-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)</td>

157

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 329</td><td>0 hi + Ai fi fi</td><td>6- (2,3- d¡metox¡phenyl) -1- (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 323.1</td><td>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)</td>

<td> 330</td><td>0 XXqAK fi fi</td><td>6- (3,5- d¡metoxifen¡l) -1- (2methoxyethyl) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 323.1</td><td>1H NMR (300 MHz, CHLORFORM-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)</td>

<td> 331</td><td>or fi '</td><td>6- (3,4- d¡metoxifen¡l) -1 - (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 323.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 332</td><td>0 hnX fi / Xv fi</td><td>6- (2,6- dimethoxypindin-3-yl) - 1- (2-Methoxetl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 324.1</td><td>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)</td>

158

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 333</td><td>or^η,Ά | 1 Y Or Cl</td><td>6- (5-Chloro-2methox¡phenyl) -1 - (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 327.1</td><td>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 = 9.16 Hz, 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)</td>

<td> 334</td><td>or ηνΥ Cl s ^ iAyA X '</td><td>6- (2-Chloro-4methox¡phenyl) -1 - (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 327.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 335</td><td>0 HlXX c / fYX, X</td><td>6- (4-Chloro-2methox¡phenyl) -1 - (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡n4 (1 H) -ona</td><td> 327.1</td><td>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)</td>

<td> 336</td><td>0 X ⁰</td><td>4- [3- (2-methoxetl) - 6-oxo-2-txox- 1,2,3,6- tetrahydropyrimidin- 4-¡] -N, N- dimethylbenzamide</td><td> 334.2</td><td>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)</td>

159

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 337</td><td>or ηιτΧ cA xaa x ° Y</td><td>6- (5-¡sopropll-2metoxlfenll) -1 - (2methoxyethyl) -2-thioxo2,3-dlhydropirlmldin4 (1 H) -one</td><td> 335.2</td><td>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)</td>

<td> 338</td><td>0 hwA A For / X x ° '</td><td>6- [6- (dlmet¡lam¡no) 4-metoxlplr¡d¡n-3-¡] 1- (2-metox¡et¡l) -2thioxo-2,3dlhydroplrimldin4 (1 H) -one</td><td> 337.2</td><td>1H NMR (400 MHz, CHLORFORM-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), 3.673.76 (m, 1 H), 3.42-3.51 (m, 1 H), 3.21 (s, 3 H), 3.16 (s, 6 H)</td>

<td> 339</td><td>or X ° ¹</td><td>1 - (2-methoxyethyl) -6 (2-methox¡-1-naftll) 2-thio-2,3-dihydropyrimidin4 (1 H) -one</td><td> 343.4</td><td>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, 1H), 3.31-3.39 (m, 1H), 2.88 (s, 3H)</td>

<td> 340</td><td>0 kx / or - TO</td><td>1- (2-Methoxyethyl) -2Tloxo-6- [3 (trlfluoromethox¡) fenll] -2,3- dlhydroplrimidin4 (1 H) -one</td><td> 347.1</td><td>1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.56 (br.s., OH), 7.53 (dd, J = 7.80, 7.80 Hz, 1 H), 7.37 (d, J = 9.16Hz, 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)</td>

160

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 341</td><td>or m \ rX X _δΑχΑ \ Υ- X kJ</td><td>1- (2-methoxetl) -6- (3-Methox¡-5,6,7,8 tetrahydronaphthalen- 2- ¡l) -2-txox-2,3-dihydropyrimidin- 4 (1 H) -one</td><td> 347.5</td><td>1H NMR (400 MHz, METANOL-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., 2 H), 2.72 (br. s., 2 H), 1.75 - 1.86 (m, 4 H)</td>

<td> 342</td><td>or I / 0 I</td><td>1 - (2-methoxetil) -2txoxo-6- (3,4,5trmethoxfen) -2,3 dihydropyrimidin4 (1 H) -one</td><td> 353.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 343</td><td>0 HiXy X /to</td><td>1 - (2-methoxether) -2 txoxo-6- (2,3,4trmethoxfen) -2,3 dihydropyrimidin4 (1 H) -one</td><td> 353.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 344</td><td>or ΗΙψΧ X sAxAxAy X bx</td><td>6- (4-fluoro-5¡soprop¡l-2metox¡fen¡l) -1 - (2metox¡et¡l) -2-t¡oxo2,3-d¡h¡drop¡r¡m¡d¡ n4 (1 H) -one</td><td> 353.1</td><td>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)</td>

161

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 345</td><td>0 / χ</td><td>1- (2-Methoxyethyl) -6- (8-Methoxy-2-methylquinolin-5-yl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 358.2</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 346</td><td>OF XX^FηιψΑ c / ύ X ^F</td><td>6- [5-fluoro-2- (trifluoromethoxy) phenyl] -1 - (2-methoxyethyl) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 365.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 347</td><td>OR HITA xaa, ITV oo</td><td>4- [3- (2-Methoxyethyl) - 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin- 4-il] -N, N- dimethylbenzenesulf namida</td><td> 370.1</td><td>1H NMR (400 MHz, CHLORFORM-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, J = 4.35 Hz, 2 H), 3.20 (s, 3 H), 2.81 (S, 6 H)</td>

<td> 348</td><td>0 O ° O T 1 V sA / YvV αχ x °</td><td>3- [3- (2-Methoxyethyl) - 6-oxo-2-thioxo- 1,2,3,6- tetrahydropyrimidin- 4-il] -N, N- dimethylbenzenesulf namida</td><td> 370.1</td><td>1H NMR (400 MHz, CHLORFORM-d) δ ppm 10.14 (br. S., 1 H), 7.91 (ddd, J = 8.24, 1.80, 1.50 Hz, 1 H), 7.84 (dd, J = 1.60, 1.60 Hz , 1 H), 7.69 (dd, J = 7.80, 7.80 Hz, 1 H), 7.59 (ddd, J = 7.80, 1.40, 1.40 Hz, 1 H), 5.85 (d, J = 1.83 Hz, 1 H), 4.31 (br. S, 2 H), 3.67 (br. S. , 2 H), 3.21 (s, 3 H), 2.77 (s, 6 H)</td>

Additions to I. Section of the beta ketoester pathway

162

E. Section of the ester pathway

HO

Preparation 19

<img file="CU20140049A7_D0033.tif" />

Tert-Butyl 3- (2- (2-hydroxyethoxy) phenyl) -3-oxopropanoate

To a solution of tert-butyl acetate (7.96 g, 68.5 mmol) in anhydrous THF (100 ml), freshly prepared lithium diisopropylamine (37 ml, 1.85 M in THF) was added dropwise over 15 min at -78 ° C, and the mixture was stirred at -78 ° C for 30 min. 2H-benzo [e] [1,4] dloxepln-5 (3H) -one (10.2 g, 62.3 mmol) was added dropwise as a solution in THF (50 ml) at -78 ° C, and stirring was continued for 30 min. A solution of NaHCO was added₃ saturated, and the mixture was extracted with EtOAe. The organic layer was dried (Na₂SW₄) and concentrated under reduced pressure to obtain the title compound (6.0 g, 77.9%) as a yellow oil, which was used directly in the next step without further purification.

MS (ES +) 303.2 [M + Na]⁺. ¹H NMR (500 MHz, CDCI₃) δ 7.85 (dd, J = 7.8, 1.8 Hz, 1 H) 7.50 (ddd, J = 8.5, 7.1, 1.8 Hz, 1 H) 7.05 (td, J = 7.5, 1.0 Hz, 1 H) 6.97 (d, J = 8.4 Hz, 1 H) 4.16-4.20 (m, 2 H) 4.01 (d, J = 4.3 Hz, 2 H) 3.90 (s, 2 H) 2.79 (br. S, 1 H) 1.33 (s, 9 H).

HO.

Preparation 20

Ethyl 3- (2- (2-hydroxyethoxy) phenyl) -3-oxopropanoate

3- (2- (2-Hldroxletox) phenol) -3-tert-butyl oxopropanoate (2.0 g, 7.14 mmol) in ethanol (20 ml) was heated in a microwave reactor at 120 ° C for 90 min. The mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure to obtain a yellow oil. The crude product was purified by flash chromatography (30-40% EtOAe: petroleum ether) to obtain the title compound as a yellow solid.

163

Preparation 21

<img file="CU20140049A7_D0034.tif" />

NH₂

OH

3 - ((2-Amino-2-oxoethyl) amino) -3- (2- (2-hydroxyethoxy) phenyl) acrylic of (Z) -ethyl

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) triethylamine (3.21 g, 31.7 mmol) was added at room temperature. 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 temperature, and saturated sodium bicarbonate (200 ml) was added. The organic layer was separated, dried (Na₂SW₄) and concentrated to obtain a yellow solid. The solid was washed with EtOAc (20 ml), and the residue was dried under reduced pressure to obtain the title compound as a white solid. This material is used without further purification.

Example 349

OH

NH₂

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

To a solution of 3 - ((2-amine-2-oxoetyl) ammonium) -3- (2- (2-hydroxyx) ethoxy) acrylate of (Z ) -ethyl (1.0 g, 3.25 mmol) in tetrahydrofuran (15 ml), trimethylsilyl isothiocyanate (1.7 g, 12.9 mmol) was added, and the mixture was stirred at 80 ° C for 18 hours. The reaction mixture was cooled to room temperature, 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 obtain a yellow solid, which was purified by flash chromatography (2-5% MeOH: CH₂CI₂) to obtain the title compound (330 mg, 31.7%) as a yellow solid.

164

MS (ES +) 343.9 [M + Na], ¹H NMR (DMS0-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, 1H),

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) lll. Amide coupling path section

Preparation 22

<img file="CU20140049A7_D0035.tif" />

3- (2,4-dimethoxyphenyl) -3 - ((2-ethoxy-2-oxoethyl) amino) (Z) -methyl acrylic

To a solution of methyl 3- (2,4-dlmethoxylfenyl) -3-oxopropanoate (5.0 g, 21 mmol) in EtOH (30 ml) was added glycine methyl ester hydrochloride (10.5 g, 83 , 9 mmol) and then 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 temperature, the residue was partitioned between EtOAe 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), was filtered through a plug of silica gel, which was eluted with 15-35% EtOAe in heptanes and dried under vacuum to obtain the title compound (4.7 g, 69%) as a yellow solid. This material is used in the next stage without further purification.

MS (ES +) 324.3 [M + 1]⁺. 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).

Preparation 23

<img file="CU20140049A7_D0036.tif" />

2- (6- (2,4-Dimethoxyphenyl) -4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) -yl) ethyl acetate 165

To a solution of 3- (2,4-dimethoxyphenyl) -3 - ((2-ethoxy-2-oxoethyl) amine) (Z) -methyl acrylate (4.68 g, 15.1 mmol) in 2-methyltetrahydrofuran (38 ml) (trimethylsilyl) isothiocyanate (12.9 ml, 90.8 mmol) was added. The resulting solution was purged with nitrogen gas 3 times, and the mixture was heated at 110 ° C for 18 hours. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to obtain a red solid. This residue was suspended in a mixture of 3: 1 heptane / EtOAc (200 ml), and stirred at room temperature for 1 hour. The solid was filtered and triturated with CH₂CI₂ (100 ml), concentrated under reduced pressure and dried under vacuum to obtain 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 + 1]⁺. 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).

Preparation 24

<img file="CU20140049A7_D0037.tif" />

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

To a solution of 2- (6- (2,4-d¡metox¡fen¡l) -4-oxo-2-tóoxo-3,4-d¡h¡drop¡rlm¡d¡n1 (2H ) -ll) ethyl acetate (6.8 g, 20.3 mmol) in methanol (34 ml), 6N aqueous NaOH (16.9 ml) was added, 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 HCI at pH ~ 2. The resulting 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 obtain 6.53 g of the title compound (99%) as a solid. White.

MS (ES +) 323.2 [M + 1] *. 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).

Preparation 25

166

<img file="CU20140049A7_D0038.tif" />

(2- (2- (6- (2,4-Dimethoxyphenyl) -4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) yl) acetamido) ethyl) tert-butyl carbamate

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 (2-aminoethyl) tert-butyl carbamate (40 g, 250 mmol) and pyridine (30 ml), and the mixture was stirred at room temperature for 15 minutes. The solution was cooled to 0 ° C and purged with nitrogen gas 3 times. After 10 minutes, a 50% solution of T3P in DMF (109 ml) was added dropwise at 0 ° C, and stirring was continued for 1 hour, when the water / ice bath was removed and stirring was continued. During 4 hours. The reaction solution was slowly poured into a stirred solution of aqueous HCI (2500 ml, 0.5 M), and the suspension was stirred at room temperature for 1 hour. The solid formed was filtered, and the filter cake was washed with 0.5 M HCI solution (500 ml) and then with water (500 ml). The solid was dried in the vacuum oven at 50 ° C for 20 hours to obtain 54.6 g of light beige powder. This solid was suspended in EtOAc (500 ml), heated at 70 ° C in a stream of nitrogen gas while stirring for 1 hour, and then at room temperature for 18 h. The suspension was cooled to 0 ° C, and the solid was filtered, the filter cake was washed with cold EtOAc (100 ml) (0 ° C) and dried in the vacuum oven at 50 ° C for 9 hours to obtain 49.0 g of off-white solid. This solid was suspended in acetonitrile (300 ml) and stirred at 70 Ό in a nitrogen stream for 18 h. The mixture was cooled to 0 ° C, and the resulting solid was filtered, washed with cold acetonitrile (50 ml) and dried in the vacuum oven at 50 ° C for 8 hours to obtain 46.5 g of off-white solid. This solid was suspended in EtOAc (350 ml), heated to 70 Ό in a nitrogen gas stream with stirring for 1 hour, and then at room temperature for 18 h. The suspension was cooled to 0 ° C, and the solid was filtered, the filter cake was washed with cold EtOAc (50 ml) (0 ° C) and dried in the vacuum oven at 50 ° C for 9 hours to obtain 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) 4.22167

4.14 (m, 1 Η) 3.87 (s, 3 Η) 3.85 (s, 3 Η) 3.19-3.11 (m, 2 Η) 3.06-3.00 (m, 2 Η) 1.42 (s, 9 Η).

Example 241

<img file="CU20140049A7_D0039.tif" />

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

To cold ethanol (21.5 ml) in nitrogen (0 ° C) in acetyl chloride (1.55 ml) was added dropwise over 5 minutes, and the reaction mixture was then heated at 50 ° C for 30 minutes. The reaction mixture was cooled to room temperature, (2- (2 (6- (2,4-d-methoxyphenyl) -4-oxo-2-thoxo-3,4-d¡) was added hrodrrmmdn-1 (2H) l) acetamldo) etll) tert-butyl carbamate (1.0 g, 2.15 mmol), and then heated at 50 ° C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in ethanol (10 ml), heated at 75 ° C for 20 minutes, EtOAc (20 ml) was added, and heating was continued for a further 20 minutes. The mixture was slowly cooled to room temperature while stirring for 18 hours. The resulting precipitate was filtered and dried in a vacuum oven at 70 ° C for 20 hours to obtain 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 pathway section

Example 350

168 or

<img file="CU20140049A7_D0040.tif" />

HN U

<img file="CU20140049A7_D0041.tif" />

[amino ({3- [6- (5-Chloro-2-methoxyphenyl) -4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) yl] propyl} amino) methylidene) methyl carbamate

To a solution of 1- (3-amlnopropll) -6- (5-chloro-2-methoxfen) -2-txox-2,3d¡h¡drop¡r¡m¡d¡n- 4 (1 H) -one (prepared analogously to Example 6; 50 mg, 0.14 mmol) and [amlno (1 H-plrazol-1-1) methyl] methyl carbamate (28 mg , 0.16 mmol) in DMF (0.46 ml), Ν, Ν-dllsoproplletllamlna (0.024 ml, 0.14 mmol) was added at room temperature, 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 by mass-induced automatic purification to obtain the title compound (4.9 mg)

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

4.6 x 50 mm, 95% H₂O / 5% linear MeCN with respect to 5% H₂O / 95% MeCN for 4.0 min, maintenance with 5% H₂O / 95% MeCN up to 5.0 min. (NH₄0.03% OH). Flow rate: 2 ml / mln.

Preparation 26

F

3,3-Difluoroazetidine-1-carbonitrile

A suspension of 3,3-dlfluoroazetldlna 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 organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product dissolved in

169 dichloromethane (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 obtain the title compound as a light brown solid (490 mg, 89%).

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

<img file="CU20140049A7_D0042.tif" />

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

A mixture of 3,3-dlfluoroazetldln-1-carbonitrile (135 mg, 1.14 mmol) and benzotriazole (136 mg, 1.14 mmol) in 1,2-dlchloroethane (0.2 ml) was heated to 80 ° C in nitrogen for 30 min. A needle was inserted to facilitate evaporation of the solvent, and the mixture was heated at 80 ° C for 45 min. The resulting solids were washed with ether (2x3 ml) and dried under reduced pressure to obtain the title compound as an off-white solid (160 mg, 51%).

¹H NMR (500 MHz, DMSO-d6) δ 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).

<img file="CU20140049A7_D0043.tif" />

TO ^NH

F

3_!3-Difluoro-N- {3- [6- (5-fluoro-2-methoxyphenyl) -4-oxo-2-thioxo-3,4-dihydropyrimidin-1 (2H) yl] propyl} azetidin-1-carboximidamide

To a mixture of 1- (3-amnopropll) -6- (5-fluoro-2-methoxfen) -2-txoxo-2,3dlh¡drop¡rlm¡d¡n-4 ( 1 H) -one (prepared analogously to Example 6; 50 mg, 0.14

170 mmol) and 1- (1 H-benzotriazol-1 -11) -1 - (3,3-dfluoroazetld¡n-1-l) methane (47.5 mg, 0.174 mmol) in DMF (0.46 ml), Ν, Ν-dllsoproplletllamlna (0.061 ml, 0.35 mmol) was added in nitrogen and heated at 60 Ό in nitrogen for 1 h. The reaction mixture was cooled to room temperature and treated with 4N HCl in dioxane (0.25 ml). The mixture was stirred at room temperature for 10 min, then concentrated in vacuo and azeotroped with heptanes (3x10 ml). The residue was dissolved in water (1 ml) and purified using medium pressure reverse phase chromatography (C18) (100: 0 to 70:30 water / acetonitrile) to obtain the title compound as a white solid (22 mg, 33%)

MS (ES +) 428.2 [M + H]⁺. 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 (br s, 1 H), 4.45 (td, 4H, J = 11.4, 4.7 Hz), 3.92 (s, 3H), 3.80 (br s, 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 in Table 6 (additions to Table 2) were prepared from the corresponding carboxylic acid to obtain the Beta-ketoester Intermediate as described above for the Preparations in the carboxylic acid pathway section, and then using other methods described. in I. Section of the beta-ketoester pathway, as well as standard techniques and methods known by the people of the medium level trade.

Table 6. Examples of the carboxylic acid pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 352</td><td>0 HNy fi sYn-Y || Y CU, NH 0 ,. Hy</td><td>N- {2- [6- (2,5- dimethoxyfen) - 4-oxo-2-thioxo- 3,4- dlhldropirlmldl n-1 (2H) Ijetlljglicinami da</td><td> 365.2</td><td>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 EN WATER; Mobile phase B: 0.1% ammonia in MeCN Flow 1.25ml / min</td>

<td> 353</td><td>OR Λ f / AA V Μ oori \ L Ύ H</td><td>N- {3- [6- (5- chlorine-2- methoxyphenyl) -4- oxo-2-thioxo- 3,4-di hldroplrimidin1 (2H) -yl] propyl} methanesulfone measure</td><td> 404.0</td><td>1H NMR (400 MHz, OLOROFORM-d) δ ppm 7.59 (dd, J = 8.8, 2.7 Hz, 1H) 7.54 (d, J = 2.7 Hz, 1 H) 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) 2.75-2.78 (m, 3H) 2.71 (tt, J = 12.7, 6.3 Hz, 2H) 1.71-1.81 (m, 1H) 1.56-1.66 (m, 1H)</td>

171

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 354</td><td>0 NIX</td><td>1- (2-amino ethyl) -6- (1benzothiophene-2il) -2-thioxo-2,3dlhldro pyrimidin4 (1 H) -one</td><td> 305.0</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (br. S., 1H), 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)</td>

<td> 355</td><td>OR skrYN k tA OH / O ¹</td><td>6- (3,4-d¡ methoxyphenyl) -1- (2-hydroxyethyl) - 2-thioxo-2,3-dihydropyrimidi n-4 (1 H) -one</td><td> 309.1</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 7.12 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.1, 1.9 Hz, 1 H), 5.74 (s, 1 H), 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)</td>

<td> 356</td><td>OR to Already oh \ z</td><td>6- (2,3-dlhldro- 1,4- benzodloxln-6il) -1 - (2-hydroxl ethyl) -2-thioxo2,3-dlhldro pyrimidin4 (1 H) -one</td><td> 307.1</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, J = 1.8 Hz, 1H), 6.946.97 (m, 1H), 6.92 (dd, J = 8.3, 1.8 Hz, 1 H), 5.70 (s, 1 H), 4.72 (t, J = 5.7 Hz, 1 H), 4.25-4.33 (m, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.55 ( q, J = 6.1 Hz, 2H)</td>

<td> 357</td><td>0 εΑχΥχα k T) nh₂ XU</td><td>1- (2- aminoetll) -6 (2,3-dlhldro1,4-benzo dioxin-6-yl) -2thioxo-2,3dihydropyrimidi n-4 (1 H) -one</td><td> 306.0</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 7.89-8.01 (m, 3H), 7.07 (d, J = 1.8 Hz, 1H), 6.92-7.02 (m, 2H), 5.75 (s, 1H), 4.34 (br. S „2H), 4.30 (br. S., 4H), 2.91-2.98 (m, 2H)</td>

<td> 358</td><td>OR goes mh₂</td><td>2- [6- (2,3-dihydro-1,4-benzodioxy-6-yl) -4-oxo-2-thioxo-3,4-dihydropyrimidi n-1 (2H) - Ijacetamlda</td><td> 320.0</td><td>2,039 min Symmetry-C18 2.1X50mm 3.5pm Mobile phase- A = 0.1% FA in MeCN, B = 0.1% FA IN WATER; Time (m¡n) /% B = 0 / 90.0.5 / 90, 2 / 55.3 / 55.3.5 / 10.6.5 / 10.7 / 90; Flow: 0.5mL / mln, Temp. column = 40^thatC; Diluent: ACN</td>

<td> 359</td><td>ABS OR HN'¡i 0 ^ av^Η° * γΑ kJ J Cl Hcr</td><td>6- (5-Chloro-2methoxlfenll) -1 [(2S) -2,3dihydroxypropyl] -2-thioxo-2,3dihydropyrimidi n-4 (1 H) -one</td><td> 343.0</td><td>2,018 min AQUITY BEH C18,2.1x50mm, 1,7pm Mobile phase0.1% FA IN MeCN, B-0.1% FA IN WATER T /% B (mln): 0 / 90.0.7 / 90.2 / 55.3 / 55.3. 8 / 5.5.8 / 5.6 / 90 Flow: 0.5mL / mln, Diluent: ACN, Temp - 40 ° C</td>

172

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 360</td><td>OR Aye nh₂¹</td><td>1- (2-amino ethyl) -6- (3,4- dimethoxy phenyl) - 2- thioxo-2,3 dihydropyrimidi n-4 (1 H) -one</td><td> 308.1</td><td>1 H NMR (600MHz, DMSO-d6) δ ppm 8.44 (br. S., 4H), 7.17 (d, J = 1.3 Hz, 1H), 7.09 -7.05 (m, 1 H), 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)</td>

<td> 361</td><td>ABS OR Λ r XQ nh₂ Cl</td><td>1 - [(2S) -2amlnopropllj-6 (5-chloro-2methoxyphenyl) -2thioxo-2,3dihydropyrimidi n-4 (1 H) -one</td><td> 326.1</td><td>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 / mln, Diluent: ACN</td>

<td> 362</td><td>0 AND nh₂</td><td>1- (2- aminoethyl) -6- (1,3-benzo thiazol-7-yl) -2-thioxo-2,3-dihydropyrimidi n-4 (1 H) -one</td><td> 305.1</td><td>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, 1 H), 4.44-4.54 (m, 1 H), 4.02 (br. S., 1H), 2.92-2.98 (m, 1H), 2.83-2.91 (m, 1H)</td>

<td> 363</td><td>0 HisrT cY yy nh₂</td><td>2- [6- (2,3-dihydro-1,4-benzodioxy-5-yl) -4-oxo-2- thioxo-3,4dihydropyrimidi n-1 (2H) -yl] acetamide</td><td> 319.8</td><td>1 H NMR (400 MHz, DMSO-d6) 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, 1H), 4.26-4.38 (m, 4H), 3.93-4.07 (m, J = 7.0 Hz, 1H)</td>

<td> 364</td><td>0 Hi \ r&gt; o— \ ffAf ° and U nh₂</td><td>2- [6- (2,3-dihydro-1- benzofuran-7- il) -4-oxo-2- thioxo-3,4- dihydropyrimidi n-1 (2HJ-II] acetamide</td><td> 304.1</td><td>1 H NMR (400 MHz, DMSO-d6) 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), 5.38-5.53 (m, 1 H), 4.61 (t, J = 8.8 Hz, 2H), 3.98-4.11 (m, 1 H) , 3.24 (t, J = 9.0 Hz, 3H)</td>

<td> 365</td><td> 0 ^H™ | 1 X ° and U NH,</td><td>2- {6- [2- (methyl sulfanlljfenllj4-oxo-2-thioxo 3,4-dihydro pyrimidin-1 (2H) iljacetamide</td><td> 307.8</td><td>1 H NMR (400 MHz, METHANOL-d4) δ ppm 7.48-7.55 (m, 1H), 7.43 (d, J = 8.0 Hz, 1 H), 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)</td>

173

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 366</td><td>or HlAA OH Xa / u OH</td><td>1 - (2-hldroxl etll) -6- (2hldroxlfen¡l) -2tloxo-2,3dlhldroplrlmldl n-4 (1 H) -one</td><td> 264.7</td><td>1 H NMR (400 MHz, DMSO-d6) 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, 1 H), 3.43-3.55 (m, J = 6.0 Hz, 2H)</td>

<td> 367</td><td>0 Hi \ r&gt; Yk kY γ Xk nh₃</td><td>2- [4-oxo-6 (qulnolln-5-ll) 2-tloxo-3,4dlhldroplrlmldl n-1 (2H) ¡Ijacetamlda</td><td> 313.1</td><td>1H NMR (400 MHz, DMSO-d6) 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), 7,827.91 (m, 1H), 7.62 (br. S., 2H), 7.22 (s, 1H), 6.98 (br. S „1H), 6.00 (s, 1 HOUR)</td>

<td> 368</td><td>or HlYji OH Yu nh₂</td><td>2- (6- (2- hldroxlfen¡l) -4- oxo-2-tloxo- 3,4- dlhldroplrlmldl n-1 (2H) - Ijacetamlda</td><td> 277.8</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 10.37 (br. S., 1H), 7.37 (br. S., 1 H), 7.30-7.36 (m, J = 7.8, 7.8 Hz, 1H), 7.09 (dd, J = 7.8, 1.8 Hz, 1H), 6.98 (br. S „1H), 6.96 (d, J = 8.5 Hz, 1 H), 6.84-6.90 (m, 1 H), 5.76 (s, 1 H), 5.43 (br. S „1H), 3.94 (br.s., 1H), 3.16 (d, J = 5.0 Hz, 1H)</td>

<td> 369</td><td>0 HN^{/ J}| i cA AAA ° ky .NH Cl H / k</td><td>N- (2- amlnoetll) -2- [6- (5-Chloro-2- metoxlfenll) -4- oxo-2-tloxo- 3,4- dlhldroplrlmldl n-1 (2H) - Ijacetamlda</td><td> 369.2</td><td>1 H NMR (400MHz, DMSO-d6) δ ppm 12.93 (br. S., 1H), 8.24 (br. S., 1H), 7.88 (br. S., 3H), 7.57 (d, J = 9.0 Hz, 1 H), 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)</td>

<td> 370</td><td>0 ηνΥί cA ΑΛΑ VT .NH ^ .0 H₂hk</td><td>N- (2- amlnoetll) -2- [6- (2,5- dlmetoxlfenll) - 4-oxo-2-tloxo- 3,4- dlhldroplrlmldl n-1 (2H) - Ijacetamlda</td><td> 365.2</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 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, 1H), 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), 2,592.75 (m, 2H)</td>

174

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 371</td><td>0 ΗΝ- | Ί cfi AAA or ^ A τ , ΝΗ F H₂X</td><td>N- (2-amino ethyl) -2- [6- (5fluoro-2methoxyphenyl) -4oxo-2-thioxo3,4-dihydro pyrimidin-1 (2H) iljacetamide</td><td> 353.1</td><td>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% MeON (0.1% TFA) IN WATER (0.1% TFA)</td>

<td> 372</td><td>0 Λ í TO .NH Η₂ΝΓ</td><td>N- (2-amino ethyl) -2- [6- (2- methoxyphenyl) -4- oxo-2-thioxo- 3,4- dihydropyrimidi n-1 (2H) ¡Ijacetamide</td><td> 335.1</td><td>Ή NMR (400 MHz, METANOL-d₄) δ ppm 8.28 (t, J = 5.5 Hz, 1H), 7.517.59 (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), 2.87-3.00 (m, 2H)</td>

<td> 373</td><td>0 hXjI fi o ^ Ó JMH 1 H₂to go</td><td>N- (2- aminoethyl) -2- [6- (2-Methox¡-5- methylphenyl) -4- oxo-2-tloxo- 3,4- dihydropyrimidi n-1 (2H) ¡Ijacetamide</td><td> 349.1</td><td>1 H 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), 3.24-3.29 (m, 1H), 2.85-3.00 (m, 2H), 2.30 (S, 3H)</td>

<td> 374</td><td>0 HhrS cfi λΛλ fié Hhr 1</td><td>6- (5-fluoro-2methoxyphenyl) -1 [3- (methyl aminojpropyl] 2-thioxo-2,3-dihydropyrimidi n-4 (1 H) -one</td><td> 324.1</td><td>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 (br m, 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)</td>

<td> 375</td><td>0 HN '^x&gt;| i (X N, AV hAX ^FI</td><td>1 - {3- [6- (5fluoro-2methoxyphenyl) -4oxo-2-tloxo- 3,4-dihydro pyrimidin-1 (2H) yl] propyl} -1 methyl guanidine</td><td> 366.1</td><td>1H NMR (400 MHz, DMSO-d6): δ ppm 12.82 (s, 1H), 7.43-7.35 (m, 2H), 7.23-7.17 (m, 1 H), 7.17-7.06 (br m, 4H), 5.86 (d, J = 2.01 Hz, 1H), 4.45-4.31 (brs, 1H), 3.82 (s, 3H) , 3.67-3.54 (brm, 1H), 3.19-3.12 (br m, 2H), 2.75-2.65 (m 3H), 1,911.73 (m, 1H), 1.72-1.56 (m, 1H)</td>

175

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 376</td><td>OR Hlriji cA^ΗΝ^ γΧ^ΝΗ Cl nh₂</td><td>N-carbam Midoil-2- [6- (5- chloro-2-methoxy phenyl) -4-oxo-2- thioxo-3,4dihydropyrimidi n-1 (2H) -yl] acetamide</td><td> 367.9</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (s, 1 H), 11.64 (brs, 1 H), 8.19 (brs, 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 (brs, 1 H), 4.45 (brs, 1 H), 3.83 (s, 3 H)</td>

<td> 377</td><td>0 HN ^ A OH aAA VV NH, Cl</td><td>2- [6- (5-chloro-2- hydroxy phenyl) -4oxo-2-thioxo3,4- dihydropyrimidi n-1 (2H) - iljacetamide</td><td> 312.0</td><td>1 H NMR (400 MHz, DMSO-d6) 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., 1H), 3.92 (br. S., 1H)</td>

The following examples in Table 7 (additions to Table 3) were prepared from the corresponding methyl ketone to obtain the beta-ketoester intermediate as described above for the Preparations in the Section of the methyl ketone pathway, and using other methods described above in I. Section of the beta-ketoester pathway, as well as standard techniques and methods known by the people of the medium level trade.

Table 7. Examples of the methyl ketone pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 378</td><td>OR XX x \ _-OH HN AO AX sXXX VT .NH H / X</td><td>N- (2-amino etil) -2- {6- [2- (2- hydroxyethoxy) -5- methoxyphenyl] -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 395.1</td><td>1.10min Xtimate C18, 2.1 * 30mm Mobile phase: 0% MeCN IN WATER (0.1% TFA IN WATER) at 30% MeCN IN WATER (0.1% TFA IN WATER)</td>

<td> 379</td><td>OR JL χΟΗ ΛλΑ ZV OH χ®</td><td>6- (2- (2- hydroxyethoxy) -5methoxyphenyl] -1 (2-hydroxyethyl) -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 339.2</td><td>1H NMR (400 MHz, methanold4): 5ppm 7.11-7.04 (m, 2H), 6.94-6.91 (m, 1H), 5.79 (s, 1H), 4.74-4.59 (m, 2H), 4.124.06 (m, 2H), 3.95-3.83 (m, 1H), 3.83-3.76 (m, 6H), 3.683.60 (m, 1H)</td>

176

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 380</td><td>0 yy / OH FOR νη_ξ ο_χ</td><td>2- {6- [2- (2- hydroxyethoxy) -5- methoxyphenylj-4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 374.1</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 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, 1H), 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)</td>

<td> 381</td><td>0 HW''Y θβ sAAAú 1 IXo .NH ¹h₂n^/&gt;</td><td>1- {2 - [(2- aminoethyl) amino] ethyl} -6- (2,4-dimethoxy phenyl) 2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 351.1</td><td>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</td>

<td> 382</td><td>0 F »Λ Ά ΑΛ _rJ 0 nh₂</td><td>1- (2-amino ethyl) 2-thioxo-6- [2 (trifluoro methoxy) phenylj2,3-dihydro pyrimidin-4 (1 H) one</td><td> 331.9</td><td>3.41 min Waters symmetry 2.1x50 mm 5 um Mobile phase: from 0% MeCN ENAGUA (0.1% TFA) to 30% MeCN IN WATER (0.1% TFA)</td>

<td> 383</td><td> 0 ^HN'| l cA sAAA 1 Alo .NH ¹HcX</td><td>6- (2,4- dimethoxyphenyl) -1 {2 - [(2- hydroxyethyl) amin ojetilj-2-thioxo- 2,3- dihydropyrimidin4 (1 H) -one</td><td> 351.9</td><td>At 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, 1 H) 2.84 (br.s., 2H)</td>

<td> 384</td><td>OR ΗΐΧΥ TO nh₂ Οχ</td><td>2- [6- (3- methoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 292.0</td><td>3,661 min XBRIDGE-O18 4.6X75mm 3.5pm Mobile phase A = 0.1% FA IN MeCN, B = 0.1% FA IN WATER Time (m¡n) /% B = 0/90, 0.8 / 90, 1.8 / 55, 3/5, 6.5 / 5, 7/90 Flow: 0.8mL / mln, Temp. column = 40^thatC; Diluent: AON</td>

<td> 385</td><td>or HN | 1 cA Ύ¹.NH ¹hcA¹</td><td>2- [6- (2,4- dimethoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin1 (2H) -yl] -N- (2hldroxyethyljaceta measure</td><td> 365.4</td><td>1H NMR (400 MHz, METANOL-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)</td>

177

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 386</td><td>OR hX \ X TO nh₂¹</td><td>2- [6- (2,6- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 321.8</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 12.75 (br. S „1 H) 7.45 (t, J = 8.5 Hz, 1H) 7.13 (br. S., 1H) 6.92 (s, 1H) 6.77 (d, J = 8.0 Hz, 2H) 5.76 (s, 1H) 4.33-4.80 (m, 2H ) 3.74 (s, 1H)</td>

<td> 387</td><td>or Hi \ r&gt; fi aaa nh₂</td><td>2- {6- [4- (2- hydroxyethoxy) -2- methoxyphenyl] -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 352.1</td><td>And NMR (400 MHz, DMSO-d₆) 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., 1H), 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)</td>

<td> 388</td><td>ABS 0 HN '^' Y (A An-yy GOES_orAND H</td><td>2- [6- (2,4- dimethoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin1 (2H) -yl] -N [(3R) -pyrrolidin3-yl] acetamide</td><td> 391.2</td><td>0.965 min LCMS-AI (4 # -302) Ultimate XB-C18 2.1 x30mm Mobile phase: from 0 MeCN (0.1% TFA) ENAGUA (0.1% TFA) to 60% MeCN (0.1% TFA) ENAGUA (0.1% TFA)</td>

<td> 389</td><td>ABS 0 THERE IS ° j aa_oror h₂n</td><td>1 - {2 - [(3R) -3aminopyrrolidin-1-yl] -2-oxoethyl} 6- (2,4- dimethoxyphenyl) -2thioxo-2,3 dihydropyrimidin4 (1 H) -one</td><td> 413.2</td><td>0.972 min LQMS-AI (4 # -302) Ultimate XB-C18 2.1 x30mm Mobile phase: from 0 MeCN (0.1% TFA) ENAGUA (0.1% TFA) to 60% MeCN (0.1% TFA) ENAGUA (0.1% TFA)</td>

<td> 390</td><td>0 HN '| i fi sYYY V and Xo /^Nh₂n</td><td>Acetamide N- (2-aminoethyl) 2- [6- (2,4-dimethoxyphenyl) -4oxo-2-thioxo-3,4-dihydropyl imidin-1 (2H) -yljN-methyl</td><td> 379.0</td><td>1H NMR (400 MHz, METANOL-d4) δ ppm 7.17 (d, J = 8.5 Hz, 1H), 6.68 (s, 1H), 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, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.59-3.70 (m, 1H), 3.36-3.49 (m, 1H), 3.02 (br .s., 2H), 2.97 (s, 3H)</td>

178

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 391</td><td>OR Η, Λ cY VV + V ° I Al? J \ IH ' Ύ H</td><td>2- [6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dihydropyrimidin1 (2H) -¡l] -N- [2 (methalamine) etl] acetamide</td><td> 379.2</td><td>Ή NMR (400 MHz, METANOL-d₄) δ ppm 8.34 (t, J = 5.8 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 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)</td>

<td> 392</td><td>0 ΗΝ - '' VX VVV, ° I VI .NH ¹vV 1</td><td>2- [6- (2,4- dlmethoxlfen¡l) -4oxo-2-thioxo-3,4dihydropyrimidin1 (2H) -ÍI] -N- [2 (dimethylamino) et iljacetamide</td><td> 393.2</td><td>'H NMR (400 MHz, DMSO-de) δ ppm 12.82 (s, 1H), 10.19 (br.s., 1H), 8.28 (br.s., 1H), 7.09 (d, J = 8.0 Hz, 1H ), 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, 1H ), 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)</td>

<td> 393</td><td>ABS 0 HN- ^ Y θ / AnyA Hey¹0 H</td><td>2- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dlhldroplrlmldln- 1 (2H) -II] -N [(3S) -plrrolld¡n3-¡l] acetam¡da</td><td> 391.2</td><td>Ή NMR (400 MHz, METANOL-d₄) δ ppm 7.16 (dd, J = 8.3, 5.3 Hz, 1H), 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 (S, 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)</td>

<td> 394</td><td>ABS 0 HN '^ AND O' ' sAyy γ Yj and NH ¹h₂AND</td><td>N - [(2S) -1 amlnopropan-2¡l] -2- [6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhldroplrlmldln1 (2H) Ijacetamlda</td><td> 379.2</td><td>'H NMR (400MHz, METANOL-d₄, rothammeric mixture) δ ppm 7.20 (d, 4 = 8.0 Hz, 0.4H) 7.14 (d, 4 = 8.5 Hz, 0.6H) 6.67 (d, 4 = 2.0 Hz, 1H) 6.61 (td, 4 = 2.3, 8.5 Hz, 1H) 5.81 (s, 0.6H), 5.79 (s, 0.4H) 5.63 (d, 4 = 15.6 Hz, 1H) 5.35-5.27 (m, 1H) 4.35-4.27 (m, 0.4H) 4.20 (d, 4 = 16.6 Hz, 0.6H) 4.05-3.94 (m, 1H ) 3.89 (s, 2H), 3.87 (s, 1 H) 3.85 (d, 4 = 1.5 Hz, 3H) 3.04 -2.92 (m, 0.7H) 2.89-2.77 (m, 1.3H) 1.19 (d, 4 = 6.5 Hz, 1 H) 1.05 (d, 4 = 7.0 Hz, 2H)</td>

179

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 395</td><td>ABS 0 ΗΝ | Ί X GOING TO NH '</td><td>N - [(2R) -2- aminopropyl] -2- [6- (2,4- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 379.2</td><td>1H NMR (400 MHz, METANOL-d4) δ ppm 7.22 (t, J = 8.3 Hz, 1H), 6.72 (s, 1H), 6.66 (d, J = 8.5 Hz, 1H), 5.86 (s, 1H), 5.37-5.64 (m, 1H), 4.35 (d, J = 15.1 Hz, 1H), 3.93 (d, J = 2.5 Hz, 3H), 3.90 (s, 3H), 3.34-3.47 (m, 3H), 1.25 (dd, J = 13.3, 5.8 Hz, 3H)</td>

<td> 396</td><td>ABS 0 sAJÁA VX NH ¹hX</td><td>N - [(2S) -2- aminopropyl] -2- [6- (2,4- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 379.2</td><td>H NMR (400 MHz, DMSO-de) 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, 1H), 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), 5.285.50 (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)</td>

<td> 397</td><td>0 ΗνΌι (X_saaa to xx? 0 H</td><td>6- (2,4- dlmethoxyphenyl) -1 [2-oxo-2 (piperazin-1 l) ethyl] -2-thioxo2,3- dihydropyrimidin4 (1 H) -one</td><td> 391.2</td><td>0.879 min Xtimate C18.2.1x30mm, 3um Mobile phase: 0% MeCN EN WATER (0.0685% TFA IN WATER) at 60% MeCN IN WATER (0.0685% TFA IN WATER)</td>

<td> 398</td><td>ABS 0 hn-aSi cX AAA VX or h₂n</td><td>1 - {2 - [(3S) -3aminopyrrolidin-1-yl] -2-oxoethyl} 6- (2,4- dimethoxyphenyl) -2-thioxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 413.0</td><td>0.988 min LCMS-AI (4 # -302) Xtimate 018.2.1 x30mm, 3um Mobile phase: from 0% MeCN (0.1% TFA) ENAGUA (0.1% TFA) to 60% MeCN (0.1% TFA) ENAGUA (0.1% TFA )</td>

<td> 399</td><td>ABS 0 /TO_HNTO O®</td><td>N- [2 - ({[6- (2,4- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - L] acetyl} amino) e til] -L- alaninamide</td><td> 436.0</td><td>To NMR (400 MHz, DMSO-d₆) δ ppm 8.33 (s, 1H) 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, 1H) 6.56-6.63 (m, 1H) 5.77 (s, 1H), 5.38 (br. S „1H) 4.22 (br., 3H) 3.97 (d, J = 13.6 Hz, 1H) 3.82-3.88 (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)</td>

180

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 400</td><td>0 HN '^ ii fi yy V W H</td><td>2- [6- (2,4- dlmethoxphenyl) -4- oxo-2-tloxo-3,4- dihydropyrimidin- 1 (2H) -yl] -Nmet¡lN- [2 (methylamino) etl] acetamide</td><td> 393.2</td><td>V NMR (METANOL-d₄, rotamerica mix) 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, 1H) 6.56-6.63 (m, 1H) 5.74-5.81 (m, 1H) 5.66 (d, J = 16.6 Hz, 1H) 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, 1 H)</td>

<td> 401</td><td>ABS 0 HN '^ X (fi sX'NXyX and XX ^ NH I hX</td><td>N - [(2R) -1- aminopropan-2- L] -2- [6- (2,4- dimethoxyphene) -4- oxo-2-txox-3,4- dihydroplrimidin- 1 (2H) - Ijacetamide</td><td> 379.1</td><td>Ή NMR (400MHz, METANOL-d₄, rotamerica mix) 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, J = 2.3, 8.5 Hz, 1H) 5.81 (s, 0.6H) 5.79 (s, 0.4H) 5.63 (d, J = 15.6 Hz, 1H) 5.35-5.27 (m, 1H) 4.35-4.27 (m, 0.4H) 4.20 (d, J = 16.6 Hz, 0.6H) 4.05-3.94 (m, 1H ) 3.89 (s, 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, 1H) 1.05 (d, J = 7.0 Hz, 2H)</td>

<td> 402</td><td>0 Χχ X °^H</td><td>1- (3- aminoprop¡l) -6- [2- (2- hydroxletox¡) -4methoxyphenyl] -2thioxo-2,3dihydropyrimidin4 (1 H) -one</td><td> 352.2</td><td>1H NMR (400 MHz, DMSOde) δ ppm 12.75 (s, 1H), 7.73 (brs, 3 H), 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 (brs, 1H), 4.10 (t, J = 5.02 Hz, 2H), 3.82 (s, 3H), 3.75-3.66 (brs, 1H), 3.64 (t , J = 5.02 Hz, 2H), 2.50-2.51 (m, 2H), 1.901.78 (m, 1H), 1.78-1.66 (m, 1 HOUR)</td>

<td> 403</td><td>xXC °^HNH A XX hXA ¹H</td><td>1 - (3- {6- [2- (2hydroxletox¡) -4methox¡phenyl] -4oxo-2-tloxo-3,4dihydropyrimidin1 (2H) - il} propil) guanidi na</td><td> 394.1</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 12.70 (s, 1H), 7.35 (t, J = 6.02 Hz, 1H), 7.25 (d, J = 8.53 Hz, 1H), 7.22-6.74 (br s, 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 (brs, 1H), 4.39 (br s, 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, IH)</td>

181

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 404</td><td>OR YX \ / OH HN XO sAw-YY V γ .NH ' H₂N ^</td><td>N- (2-amlnoetll) - 2- {6- [2- (2- hldroxletox¡) -4- metox¡fen¡l] -4- oxo-2-tloxo-3,4- dlhldroplrlmldln- 1 (2H) - IJacetamlda</td><td> 395.12</td><td>1H NMR (400 MHz, Metanold4) δ ppm 8.35-8.26 (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, 1 H), 5.52-5.37 (brm, 1H), 4.42-4.29 (brm, 1H), 4.20-4.09 (m, 2H), 3,903.79 (m, 5H), 3.43-3.33 (m, 2H), 3.00-2.90 (m, 2H)</td>

<td> 405</td><td>0 k \ x \ / OH HN ^ AO ΑΛΑ v 9 .NH F Η₂Ν^&gt;</td><td>N- (2-am¡noet¡l) - 2- {6- [5-fluoro-2- (two- hldroxletox¡) fen¡ l] -4-oxo-2-txox- 3,4- dlhldroplrlmldln- 1 (2H) - IJacetamlda</td><td> 383.1</td><td>1H NMR (400 MHz, Metanold4) 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 (brm, 1H), 4.36-4.26 (brm, 1H), 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)</td>

<td> 406</td><td>OR ηΛ oX-^OHAND H₂hT ^F</td><td>1- (3- amlnopropll) -6 [5-fluoro-2- (2hldroxletox¡) fen¡l] -2-tloxo-2,3-dihydropyrimidin4 (1 H) -one</td><td> 340.1</td><td>1H NMR (400 MHz, Metanold4) δ ppm 7.31 (td, J = 9.03, 3.01 Hz, 1H), 7.25-7.18 (m, 2H), 5.85 (s, 1 H), 4.57-4.44 (brs, 1H), 4.03-3.90 (brm, 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 , 1 HOUR)</td>

<td> 407</td><td>0 Y x \ / OH HN AO sAAA NH k Y ^ YJF h₂nn H</td><td>1- (3- {6- [5- fluoro-2- (2- hldroxletox¡) fen¡ l] -4-oxo-2-txox- 3,4- dlhldroplrlmldln- 1 (2H) - L} propll) guan¡d¡ na</td><td> 382.1</td><td>1H NMR (400 MHz, Metanold4) δ ppm 7.30 (td, J = 9.03, 3.01 Hz, 1H), 7.25-7.15 (m, 2H), 5.84 (s, 1H), 4.60-4.46 (brm, 1H), 4.19-4.10 (m, 2H), 3.96-3.79 (m, 3H), 3.10-3.01 (m, 2H), 2.06-1.93 ( m, 1H), 1.83-1.68 (m, 1H)</td>

<td> 408</td><td>OR ALREADY AAx AND N</td><td>3- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dlhldroplrlmldln- 1 (2H) - Ijpropanenitrile</td><td> 318.1</td><td>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 (br m, 1H), 4,194.05 (brm, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.19-3.06 (m, 1H), 2.71-2.63 (m, 1H)</td>

182

<td>Example No.</td><td colspan="2">Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 409</td><td>0 ΗΙίΥ AÁ and OH</td><td>J3H 0 to I</td><td>6- [2- (2- h¡droxletox¡) -4metoxlfen¡l] -1 (2-h¡droxletll) -2tloxo-2,3dihydropyrimidin4 (1 H) -ona</td><td> 338.9</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 12.65 (s, 1 H), 7.22 (brs, 1 H), 6.78-6.53 (br m, 2 H), 5.68 (br s, 1H), 4.90-4.78 (brm , 1H), 4.72-4.62 (brm, 1H), 4.59-4.42 (brm, 1H), 4.19-3.97 (br m, 2H), 3.81 (br s, 3H), 3.64 (brs, 3H)</td>

<td> 410</td><td>OR AND- V nh₂</td><td>to I</td><td>2- [6- (4- metoxlfenll) -4- oxo-2-tloxo-3,4- dlhidroplrimldln- 1 (2H) - Ijacetamide</td><td> 314.1</td><td>0.905 min LCMS-C (4 # -302) Ultimate XB-C18 2.1 x30mm Mobile phase: from 0 MeCN (0.1% TFA) ENAGUA (0.1% TFA) to 60% MeCN (0.1% TFA) ENAGUA (0.1% TFA)</td>

<td> 411</td><td>0 to\ and OH</td><td>c &lt;aa^0HΦ F</td><td>6- [5-fluoro-2- (2- h¡droxletoxl) fen¡ l] -1- (2- hldroxletll) -2- tloxo-2,3- dlhydroplrimidln4 (1 H) -one</td><td> 326.8</td><td>1H NMR (400 MHz, methanold4) δ ppm 7.25 (td, J = 9.03, 3.01 Hz, 1H), 7.19-7.13 (m, 2H), 5.80 (s, 1H), 4.76-4.65 (m, 1H), 4.61 (brs, 1H), 4,164.09 (m, 2H), 3.88-3.78 (m, 3H), 3.66-3.60 (m, 1H)</td>

<td> 412</td><td>0 AÁ V nh₂</td><td>cXO /⁰¹¹0 F</td><td>2- {6- [5-fluoro-2- (two- h¡droxletoxl) fen¡ l] -4-oxo-2-thioxo- 3,4- dlhldroplrlmldln- 1 (2H) - IJacetamide</td><td> 362.1</td><td>1H NMR (400 MHz, methanold4) 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 (brs, 1H), 4.37-4.18 (brs, 1H), 4.14 (t, J = 4.52 Hz, 2H), 3.83 (t, J = 4.02 Hz, 2H)</td>

<td> 413</td><td>0 AA OH</td><td>ο ^ Ό-⁰¹¹and</td><td>6- [4-fluoro-2- (2- h¡droxletoxl) fen¡ l] -1- (2- h¡droxletll) -2- tloxo-2,3- dlhydroplrimidln4 (1 H) -one</td><td> 327.2</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 12.71 (s, 1H), 7,397.33 (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, 1H), 4.97-4.79 (brs, 1H), 4.77-4.62 (brs, 1H), 4.53-4.43 (m, 1H), 4.16-4.04 (m, 2H), 3.64 (br t, J = 4.52 Hz, 2H), 3.61-3.49 (m, 2H)</td>

183

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 414</td><td>0 ηνΆ ο '^ΧΧχ-^{/ ΟΗ}χΛχ θγ-¹ XX ^ nh₂</td><td>2- {6- [4-fluoro-2- (two- hydroxyethoxyjfeni l] -4-oxo-2-thioxo- 3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 362.2</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 12.80 (s, 1H), 7.33 (brs, 1H), 7.24-7.17 (m, 1H), 7.12 (d, J = 11.54 Hz, 1H), 7.01 (brs, 1H ), 6.91-6.83 (m, 1H), 5.79 (s, 1H), 5.52-5.22 (brs, 1H), 4.97-4.81 (brm, 1H), 4.17-4.05 (br m, 2H), 4,023.85 ( brs, 1H), 3.69-3.60 (br m, 2H)</td>

<td> 415</td><td>0 X / OH HN | Ί σ AXA ° A lX_F.NH h₂N '^{/ I}</td><td>N- (2-aminoethyl) - 2- {6- [4-fluoro-2- (two- hldroxietoxijfenl l] -4-oxo-2-thioxo- 3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 383.2</td><td>1H NMR (400 MHz, methanold4) δ ppm 8.33-8.24 (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 (brm, 1H), 4.37-4.26 (brm, 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)</td>

<td> 416</td><td>0 Hlí β V nh₂</td><td>2- [6- (2,3- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 322.1</td><td>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„ 1H), 4.11 (br. s., 1H), 3.85 (s , 3H), 3.72 (s, 3H)</td>

<td> 417</td><td>0 Hhr '' || β vu nh₂</td><td>2- [6- (4-chloro-2- methoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 326.2</td><td>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)</td>

<td> 418</td><td>0 F lAA θγ¹ Xx nh₂</td><td>2- [6- (2-methox¡- 4-methylphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 306.0</td><td>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)</td>

<td> 419</td><td colspan="2">j? 1- {2- [6- (5- hn A β fluoro-2- = n metox¡fen¡l) -4- 1 γ oxo-2-thioxo-3,4-_HN^{0 F} dihydropyrimidin- hXnh 1 (2H) - | iljetoxijguanidin I ^to</td><td> 354.2</td><td>1H NMR (400 MHz, METANOL-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)</td>

184

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or retention time of HPLC and conditions</td>

<td> 420</td><td>Yr nh₂ '</td><td>2- {6- [2- (2- h¡drox¡etox¡) -4- metox¡fen¡l] -4- oxo-2-txox-3,4- dlhidroplrimldln- 1 (2H) - Ijacetamide</td><td> 374.0</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 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 „1H), 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)</td>

<td> 421</td><td>0 Η A χγ ΛνΑΙ ⁰xp nh₂ F</td><td>Acetate of 2 {2- [3- (2-am2no2-oxoetll) -6oxo-2-txox1,2,3,6tetrahydroplrlml din-4-yl] -4fluorophenoxljetll</td><td> 404.1</td><td>1H NMR (400 MHz, METANOL-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), 4,304.46 (m, 2H), 4.22-4.30 (m, 2H), 4.12 (d, J = 17.1 Hz, 1H), 2.06 (s, 3H)</td>

The following Examples of Table 8 (additions to Table 4) were prepared from the corresponding aryl halide to obtain the beta-ketoester intermediate as described above for the Preparations in the aryl halide pathway section, and then using the methods described in I. Section of the beta-ketoester pathway, as well as standard techniques and methods known by the people of the medium level trade.

Table 8. Examples of the aryl halide pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 422</td><td>0 ηνγΥ cY ΛλΑ Xp NH₂ CL yx \ h</td><td>2- {6- [5- (2- h¡droxletox¡) -2- metoxlfenllj-4- oxo-2-txox-3,4- dlhldropirlmldln- 1 (2H) - Ijacetamide</td><td> 352.0</td><td>1H NMR (400 MHz, METANOL-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)</td>

185

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 423</td><td>0 HN ^ | 1 fi sYnYY NH₂ 0</td><td>2- {4- [3- (2- am¡noet¡l) -6-oxo- 2-tloxo-1,2,3,6tetrahldropirlmldl n-4-¡l] -3methoxyphenoxijac etamide</td><td> 351.2</td><td>1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (s, 1H) 8.06 (brs, 3H) 7.69 (s, 1H) 7.48 (s, 1H) 7.30 (d, J = 8.53 Hz, 1 H) 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 (brs, 1H) 4.51 (s, 2H) 3.94-3.81 (m, 4H) 2,952.80 (m, 2H)</td>

The following Examples of Table 9 were prepared from the aryl ester or the corresponding lactone to obtain the Beta-ketoester Intermediate as described above for the Preparations in the ester pathway section, and then using the methods described in the I. Section of the beta-ketoester pathway, as well as standard techniques and methods known to the people of the medium level trade.

Table 9. Examples of the ester pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 424</td><td>OR JL AH HIT YO_sYnYA V r , NH Cl HjY</td><td>N- (2-am¡noetll) - 2- {6- [5-chloro-2- (two- h¡drox¡etox¡) fen¡l] -4-oxo-2-txox3,4-dihldroplr imidin-1 (2H) IJacetamide</td><td> 398.9</td><td>1H NMR (400 MHz, Metanold4) 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 (br m, 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)</td>

<td> 425</td><td>OR JA YH HY AND 0 OH Cl</td><td>6- [5-Chloro-2- (2- hydroxylxyl) phenol] -1 - (2-hydroxyethyl) 2-tloxo-2,3dlhydropyrimldin4 (1 H) -one</td><td> 342.7</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 12.73 (brs, 1H), 7.52 (br s, 1H), 7.40 (brs, 1H), 7.287.15 (br m, 1H), 5.88-5.72 (br m, 1H), 4.92 (brs, 1H), 4.78 (br s, 1H), 4.48 (brs, 1H), 4.08 (br s, 2H), 3.73-3.52 (br m, 4H)</td>

186

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 426</td><td>0 o- ^ °^HαΛα AX NH₂ Cl</td><td>2- {6- [5-chloro-2- (two- hydroxyethoxy) phenyl] -4-oxo-2-thioxo- 3,4- dihydropyrimidin- 1 (2H) - IJacetamide</td><td> 378.1</td><td>1 H NMR (400 MHz, DMSO-d6) 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, 1 H), 4.04-4.13 (m, 2H), 3.95 (br. S., 1H), 3.58-3.70 (m, 2H)</td>

<td> 427</td><td>^λ—Z Ao or X</td><td>1 - (2-aminoethyl) 6- [5-chloro-2- (2-hydroxyethoxy) phenyl] -2-thio-2,3-dihydropyrimidin4 (1 H) -one</td><td> 341.9</td><td>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, 1 H) 5.87 (s, 1H) 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)</td>

<td> 428</td><td>0 JL / OH HN V 0 V XX .NH η₂ν ''^&gt;</td><td>N- (2-aminoethyl) - 2- {6- [2- (2- hydroxyethoxy) phenyl] -4-oxo-2-txox- 3,4- dihydropyrimidin- 1 (2H) - IJacetamide</td><td> 365.1</td><td>Ή NMR (400 MHz, METANOLd₄) 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, 1H) 7.06 (td, J = 7.5, 1.0 Hz, 1H) 5.85 (s, 1H), 5.44 (br. S., 1H) 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) 3.33-3.40 (m, 2H) 2.92 (t, J = 5.8 Hz, 2H)</td>

The following Examples of Table 10 were prepared from the corresponding thiouracil carboxylic acid as described above for the Preparations in lll. Section of the amide coupling pathway and through the use of methods described in I. Section of the beta-ketoester pathway, as well as standard techniques and methods known by the people of the medium level trade.

187

Table 10. Examples of the amide coupling pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Obs Mass</td><td>1H spectral data NMR or HPLC retention time and conditions</td>

<td> 429</td><td>0 HN- ^ XA sAAyA, AX .NH I η_?νΎ</td><td>N- (2-amlno-2- methylpropyl) -2- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dihydroplrimidin- 1 (2H) - Ijacetamlda</td><td> 392.2</td><td>'H NMR (400 MHz, METANOL-d₄) δ ppm 8.42 (t, J = 6.3 Hz, 1H), 7.17 (d, J = 8.0 Ηζ, 1Η), 6.68 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 5.82 (s, 1Η), 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), 1.22-1.29 (m, 5H), 1.26 (d, J = 5.5 Hz, 6H)</td>

<td> 430</td><td>0 HN- ^ Xj A sAAA To x_orx^NHHN^Z</td><td>N- (cls-3- amlnoclclobutll) - 2- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dihydroplrimidin- 1 (2H) - Ijacetamlda</td><td> 391.2</td><td>'H NMR (400 MHz, METANOL-d₄) δ ppm 8.31 (d, J = 6.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 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., 1 H), 3,903.98 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.43-3.52 (m, 1H), 2.57-2.76 (m, 2H), 1.932.14 (m, 2H)</td>

<td> 431</td><td>0 AAA OH X nh₂</td><td>1- [2- (3- amlnoazetldln-1- il) -2-oxoethyl] -6- (2,4-dlmethoxl fenll) -2-tloxo-2,3dlhldroplrlmldln4 (1 H) -ona</td><td> 377.1</td><td>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 (br m, 1H), 5.185.09 (br m, 1H), 4.44-4.25 (m, 5H), 4.23-4.11 (m, 2H), 4.113.92 (m, 1H), 3.86 (s, 6H)</td>

<td> 432</td><td>0 hXX A XAX TO Tnh h₂iX</td><td>N- (1-amlno-2- metllpropan-2-ll) - 2- [6- (2,4- dlmetoxlfenll) -4- oxo-2-tloxo-3,4- dihydroplrimidin- 1 (2H) - Ijacetamlda</td><td> 392.9</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 12.81 (brs, 1H), 7.81 (s, 1H), 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 (br s, 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)</td>

188

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Obs Mass</td><td>1H spectral data NMR or HPLC retention time and conditions</td>

<td> 433</td><td>ABS 0 hX \ X AnA-A, α χ H_?N ^</td><td>N - [(2R, 3R) -3- aminobutan-2-yl] - 2- [6- (2,4- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 393.1</td><td>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)</td>

<td> 434</td><td>OR HN ^ ij X ° / LA₀^ NH I</td><td>2- [6- (2,4- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) -yl] -Netilacetamide</td><td> 349.9</td><td>1H NMR (400 MHz, OLOROFORM-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, 1H), 5.87 (s, 1H), 5.62 (br, 1H), 5.12 (br, 1H), 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)</td>

<td> 435</td><td>0 ΗΝ- ^ α x sA_nA_A ° X AA₀^, ΝΗ</td><td>2- [6- (2,4- dimethoxyphenyl) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) -yl] -Npropylacetamide</td><td> 364.1</td><td>1H NMR (400 MHz, CHLORFORM-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)</td>

<td> 436</td><td> 0 _STO._NAyk X χ .NH ¹X * 1</td><td>2- [6- (2,4- dimethoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin1 (2H) -yl] -N- (2methoxyethyl) acetam ida</td><td> 402.1</td><td>1H NMR (400 MHz, CHLORFORM-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, 1H), 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)</td>

189

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Obs Mass</td><td>1H spectral data NMR or HPLC retention time and conditions</td>

<td> 437</td><td>0 hn ^ s (fi υΛλ And Ά_ο,and^NHH₂N '</td><td>N- (trans-3- aminocyclobutyl) - 2- [6- (2,4- dimethoxyphene) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 391.2</td><td>1H NMR (400 MHz, METANOL-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).</td>

<td> 438</td><td>0 Already W γα^νηSr.</td><td>N- (azetidin-3-yl) - 2- [6- (2,4- dimethoxyphene) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 377.1</td><td>1H NMR (400 MHz, METANOL-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 (br s, 1H), 4.59-4.48 (m, 1H), 4.27-4.15 (m, 3H), 4.13-3.98 (m, 2H), 3.88 (s , 3H), 3.85 (s, 3H).</td>

<td> 439</td><td>ABS 0 HnY A Υ-νΎΥ γΥγ Phew nh₂</td><td>N - [(1S, 2S) -2- aminocyclobutyl] - 2- [6- (2,4- dimethoxyphene) -4- oxo-2-thioxo-3,4- dihydropyrimidin- 1 (2H) - iljacetamide</td><td> 391.1</td><td>0.903 min Xtimate C18 2.1x30mm 3um Mobile phase: from 0% MeCN ENAGUA (0.0685% TFA IN WATER) to 60% MeCN IN WATER (0.0685% TFA IN WATER)</td>

<td> 440</td><td>0 ηΥΥ fi i Ty o γ¹, H₂lY</td><td>N- {2- [6- (2,4- dimethoxyphenyl) -4oxo-2-thioxo-3,4dihydropyrimidin1 (2H) -yl] ethyl} -Nmethylglycinamide</td><td> 378.9</td><td>1H NMR (400 MHz, DMSOd6) δ ppm 12.90 (s, 0.33H), 12.75 (s, 0.66H), 8.02 (brs, 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 (brm, 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)</td>

190

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Obs Mass</td><td>1H spectral data NMR or HPLC retention time and conditions</td>

<td> 441</td><td>ABS 0^HN'| ia ΥΑγΑ ° χ aa₀AND nh₂</td><td>N - [(1 R, 2R) -2 aminocyclobutyl] 2- [6- (2,4dlmethoxlfen¡l) -4oxo-2-tloxo-3,4dlhydroplrimidln1 (2H) - Ijacetamide</td><td> 391.2</td><td>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)</td>

<td> 442</td><td>0 Λ and Goes¹nh₂</td><td>N- (3- amlnopropll) -2- [6- (2,4- dlmetoxlfenll) -4- oxo-2-txox-3,4- dlhldroplrlmldln- 1 (2H) - Iljacetamlda</td><td> 379.1</td><td>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, 1H), 4,194.35 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.21-3.05 (m, 2H), 2.98-2.90 (m, 2H), 1.85-1.75 (m, 2H).</td>

<td> 443</td><td>0 HN- ^ to X I already to γγ .NH 1 Η, Ν ^ / kF F</td><td>N- (3-amlno-2,2- dlfluoropropll) -2- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dlhydroplrimidln- 1 (2H) - Ijacetamide</td><td> 437.1</td><td>0.888 min Xtlmate C18 2.1x30mm 3 um Mobile phase: from 0% MeCN IN WATER (0.1% TFA IN WATER) to 60% MeCN ENAGUA (0.1% TFA IN WATER)</td>

<td> 444</td><td>0 Hf / V cY sY-nA — V TO ' r^Jnh₂</td><td>N- (2-am¡noet¡l) -3- [6- (2,4- dlmetoxlfen¡l) -4- oxo-2-tloxo-3,4- dlhydroplrimidln- 1 (2H) - Ijpropanamide</td><td> 379.1</td><td>1H NMR (400 MHz, METANOL-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, 1H), 4.81-4.70 (brs, 1H), 4.07-3.95 (br m, 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).</td>

191

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Obs Mass</td><td>1H spectral data NMR or HPLC retention time and conditions</td>

<td> 445</td><td>0 HN'Yl Y Ynh goes .NH ¹hV AND</td><td>N- {2- [(clclopropllmetll) amÃno] et¡l} -2- [6- (2,4- d¡metox¡fen¡l) -4- oxo-2-txox-3,4- dihydroplrimidin- 1 (2H) - Ijacetamide</td><td> 419.1</td><td>1H NMR (400 MHz, METANOL-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, 1H), 6,696.66 (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).</td>

<td> 446</td><td>0 hY || AND r A HN'A HjAYih</td><td>N-carbammmdodo 3- [6- (2,4- d¡metox¡fen¡l) -4- oxo-2-tloxo-3,4- dihydroplrimidin- 1 (2H) - Ijpropanamide</td><td> 377.9</td><td>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 (br m, 1H) 4.03-3.90 (brm, 1H) 3.86-3.78 (m , 6H) 2.82-2.71 (m, 2H).</td>

The following Examples of Table 11 were prepared from the corresponding thiouracil amines as described above for the Preparations in IV. The section of the guanidine pathway and using the methods described in I. Section of the beta ketoester pathway, as well as standard techniques and methods known to the people of the middle level trade.

Table 11. Examples of the guanidine pathway

<td>Example No.</td><td>Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 447</td><td>OR hnY cX sVilyA ¿F HN^NYiYh H</td><td>1-c¡ano-3- {3- [6- (5-fluoro-2- metox¡fen¡l) -4- oxo-2-txox-3,4- dihydroplrimidin- 1 (2H) - L] prop¡l} guanldlna</td><td> 377.2</td><td>1 H NMR (400 MHz, DMSO-d6) δ ppm 12.78 (s, 1H), 7.41-7.34 (m, 2H), 7.16 (dd, J = 9.03.4.02 Hz, 1H), 6.94-6.31 (brs, 3H), 5.85 (s, 1H), 4.26 (brs, 1H), 3.82 (s, 3H), 3.72-3.58 (brm, 1 H), 2.91-2.75 (m, 2H ), 1.77-1.66 (brm, 1H), 1.61-1.46 (brm, 1H).</td>

192

<td>Example No.</td><td colspan="2">Structure</td><td>Compound Name</td><td>Dough obs</td><td>1H NMR spectral data or HPLC retention time and conditions</td>

<td> 448</td><td>0 HN'ji 0 / and</td><td> \/^0H</td><td rowspan="2">1- (2- {6- [5-Chloro2- (2- hldroxletoxljfenllj- 4-oxo-2-tloxo- 3,4- dlhldroplrlmldln1 (2H) -ll} etll) guanldlna</td><td></td><td>1.31 min Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% Linear MeCN at 5% H2O / 95% MeCN</td>

<td></td><td>NH Cl h₂nXnh</td><td></td><td> 383.9</td><td>for 4.0 min, KEEP. a5% H2O / 95% MeCN at 5.0min. (0.05% formic acid). Velocity Flow rate: 2 mL / min.</td>

<td> 449</td><td> 0 ^HNii sAwA</td><td>(fi x \ fi</td><td rowspan="2">1- {3- [6- (5-chloro- 2- metoxlfenll) -4oxo-2-tloxo-3,4dlhldroplr ¡mldln1 (2H) -il] propll} -2- ethylguanldine</td><td></td><td>1.62 min Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% Linear MeCN at 5% H2O / 95% MeCN</td>

<td></td><td>HN ^^ HN-X ^ NH k</td><td>Cl</td><td> 395.9</td><td>for 4.0 min, KEEP. a5% H2O / 95% MeCN at 5.0min. (0.05% trifluoroacetic acid). Velocity Flow rate: 2 mL / min.</td>

<td> 450</td><td> 0 ^HNll A&gt; A</td><td>(fi for</td><td rowspan="2">N- {3- [ 6- (5-chloro- 2-methoxlfenll) -4- oxo-2-thioxo-3,4- dlhldroprlmldln- 1 (2H) - Ijproplljplrrolldln- 1- carboxlmldamlda</td><td></td><td>2.02 min Atlantis dC18 5um 4.6x50mm, 95% H2O / 5% MeCN</td>

<td></td><td>HN ^^ ^ νΑ_νη</td><td>fifi Cl</td><td> 422.0</td><td>linear at 5% H2O / 95% MeCN for 4.0 min, MAINTAIN. a5% H2O / 95% MeCN at 5.0mln. (0.05% trifluoroacetic acid). Velocity Flow rate: 2 ml / mln.</td>

<td> 451</td><td> 0 ^HN 11 AA HN- ^ Xh and</td><td>or ^ Ιί fifi Cl</td><td>1- {3- [6- (5-chloro- 2- metoxlfenll) -4oxo-2-tloxo-3,4dlhldroplr ¡mldln1 (2H) -il] propll} -3- (2,2- dlfluoropropll) guanidine</td><td> 446.2</td><td>1 H NMR (500 MHz, METANOLd4) 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 (br s, 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).</td>

<td> 452</td><td>0 HN''A] fifi</td><td>(fi</td><td rowspan="3">1-carbamimidoll3- {2- [6- (2,4dlmethoxlfenll) -4oxo-2-tloxo-3,4dlhydropyrimidln1 (2H) -yl] ethyl} urea</td><td></td><td>1,002 min Xtlmate C18</td>

<td></td><td>fixfifi J ι</td><td>\ aX₀</td><td></td><td>2.1x30mm, 3um Mobile phase: from</td>

<td></td><td>r ΟγΝΗ HN NH I NH</td><td></td><td> 393.1</td><td>0% MeCN (0.1% TFA) IN WATER (0.1% TFA) to 60% MeCN (0.1% TFA) ENAGUA (0.1% TFA)</td>

<td> 453</td><td>0 hitA TO η, νΧαιη,</td><td>(fi Ί Λ 1</td><td>2- {3- [6- (2,4- dlmethoxlfenll) -4oxo-2-thioxo-3,4dlhydropyrimidln1 (2H) -¡l] -2,2difluoropropyljgua nidine</td><td> 400.1</td><td>1 H NMR (400 MHz, DMSO-d6) 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)</td>

193

All publications, including, for example, granted patents, patent publications and newspaper articles, cited in the present application are incorporated herein by reference in their entirety.

While the Invention was described above with reference to the described embodiments, middle-level persons will understand that the specific detailed experiments are only illustrative of the invention. It should be borne in mind that various modifications are possible without this meaning departing from the spirit of the Invention.