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NZ624453B2 - 2-thiopyrimidinones - Google Patents

2-thiopyrimidinones Download PDF

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Publication number
NZ624453B2
NZ624453B2 NZ624453A NZ62445312A NZ624453B2 NZ 624453 B2 NZ624453 B2 NZ 624453B2 NZ 624453 A NZ624453 A NZ 624453A NZ 62445312 A NZ62445312 A NZ 62445312A NZ 624453 B2 NZ624453 B2 NZ 624453B2
Authority
NZ
New Zealand
Prior art keywords
alkyl
dihydropyrimidin
compound
thioxo
optionally
Prior art date
Application number
NZ624453A
Other versions
NZ624453A (en
Inventor
Philip Albert Carpino
Edward Lee Conn
Robert Lee Dow
Matthew Scott Dowling
David Hepworth
Daniel Wei Shung Kung
Suvi Tuula Marjukka Orr
Benjamin Neil Rocke
Roger Benjamin Ruggeri
Matthew Forrest Sammons
Original Assignee
Pfizer Inc
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Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Priority claimed from PCT/IB2012/055949 external-priority patent/WO2013068875A1/en
Publication of NZ624453A publication Critical patent/NZ624453A/en
Publication of NZ624453B2 publication Critical patent/NZ624453B2/en

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    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract

Disclosed herein are myeloperoxidase inhibitors of formula I where the substituents are as defined herein, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, cardiovascular conditions. Specific examples of the compounds of formula I include 6-(2,4-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one, 2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide and N-(2-aminoethyl)-2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide. -(2,4-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one, 2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide and N-(2-aminoethyl)-2-[6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide.

Description

-THIOPYRIMIDINONES BACKGROUND OF THE INVENTION This invention relates to compounds that are myeloperoxidase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such tors to treat for example, cardiovascular conditions ing acute coronary syndrome.
Myeloperoxidase (MP0) is a heme-containing enzyme belonging to the peroxidase amily. Examples of animal dases are eroxidase, thyroid peroxidase, eosinophile peroxidase and myeloperoxidase. Myeloperoxidase is present in primary granules of neutrophils and to a lesser extent in tes. |t catalyzes the sis of hypochlorous acid from chloride and hydrogen peroxide. The hypochlorous acid formed is a powerful oxidant that reacts with a variety of cellular substrates including heme proteins, porphyrins, thiols, iron sulfur centers, nucleotides, DNA, unsaturated lipids, amines and amino acids.
In addition, MPO-catalyzed reactions and their products have been found to exhibit pro-atherogenic biological activity during the pment of sclerosis and cardiovascular disease. For example, the eroxidase plasma content is correlated with the appearance of cardiovascular disorders in patients suffering unstable angina pectoris. Myeloperoxidase has been reported to contribute to the development of atherosclerosis by the ion of lipid and protein in LDL and HDL. rmore, it has been observed that MPO-generated oxidants reduce the bioavailability of nitric oxide, an important vasodilator. Accordingly, high MPO plasma levels are inversely correlated with the success of y to establish reperfusion of occluded arteries. High MPO levels are also associated with decreased survival from congestive heart failure. Additionally, it has been shown that MPO plays a role in plaque destabilization which leads to plaque rupture and myocardial infarction.
Therefore, MP0 is thought to play a role in l processes that lead to cardiovascular disease including 1) impaired cholesterol trafficking and progession of the atherosclerotic plaque towards an unstable state , 2) destabilization of the 3O atherosclerotic plaque and plaque rupture, 3) consumption of nitric oxide leading to impaired endothelial function and flow, and 4) pathological tissue damage post ischemia contributing to atrial fibrillation and e c remodeling with left ventricular hypertrophy leading to congestive heart failure. As such inhibitors of MPO activity are proposed to offer significant therapeutic benefit in the prevention and treatment of cardiovascular disease.
Nevertheless, although MPO has been ated extensively in the etiology and progression of cardiovascular disease, a biologically safe and non-toxic inhibitor of MPO has yet to be developed. Accordingly, there remains a need for ceutical agents that have myeloperoxidase inhibiting activity and are useful in the treatment, prevention or diminution of the manifestations of the maladies described herein.
SUMMARY OF THE INVENTION The present invention is directed to a compound of the Formula |, 8%N R1 R2 Formula | or a pharmaceutically acceptable salt or prodrug thereof wherein R1 is a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen or a bicyclic ring consisting of two fused partially saturated, fu||y saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said R1 is ally mono-, di-, substituted independently with cyano, halo, hydroxyl, amino, (C1-C4)a|kyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)a|ky|, hydroxy(Cg- oxy, carbamoyl(C1-C4)a|koxy, amino(Cg-C4)alkoxy, C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylamino, aminocarbonyl, - or di-N,N(C1-C4)alkylaminocarbonyl, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, or mono-N- or di-N,N(C1-C4)alkylaminosulfonyl, wherein any of the (C1-C4)alkyl or (C1-C4)alkoxy may be optionally mono-, di- or tri-substituted with fluoro; or wherein R1 is optionally substituted with a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and ; R2 is a fully ted, partially unsaturated or fully unsaturated one to en membered straight carbon chain wherein the carbons, other than the connecting carbon, a. may be branched b. may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur is optionally mono- or di-substituted with oxo, c. may optionally be mono-, di- or tri-substituted independently with halo, d. may optionally be mono-substituted with hydroxy, and e. may optionally be mono-substituted with oxo, and wherein the carbon chain is optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring ting of two fused lly saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Z is optionally mono-, di- or bstituted independently with halo, (C1-C6)alkyl, (C1-C6)alkylcarbonyl, hioxo, amino(C1-C6)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or (C1-C6)alkoxy and wherein said (C1- yl or (C1-C6)alkoxy substituent is also optionally tuted with one to three halo, and wherein said (C1-C6)alkyl or (C2-C6)alkoxy substituent is also optionally substituted with one to three hydroxy; with the proviso that R1 is not phenyl, and R2 is not )alkyl. In another aspect, the present invention provides compound or a pharmaceutically acceptable salt thereof wherein the compound is 6-(2,4-dimethoxyphenyl)(2-hydroxyethyl)thioxo-2,3- opyrimidin-4(1H)-one; 1-(2-aminoethyl)(2,4-dimethoxyphenyl)thioxo-2,3- dihydropyrimidin-4(1H)-one; 2-[6-(2,5-dimethoxyphenyl)oxothioxo-3,4- dihydropyrimidin-1(2H)-yl]acetamide; 2-[6-(5-chloromethoxyphenyl)oxothioxo- 3,4-dihydropyrimidin-1(2H)-yl]acetamide; 1-(2-aminoethyl)thioxo(2,4,5- trimethoxyphenyl)-2,3-dihydropyrimidin-4(1H)-one; 1-(3-aminopropyl)(2-methoxy methylphenyl)thioxo-2,3-dihydropyrimidin-4(1H)-one; N-{2-[6-(2,4-dimethoxyphenyl)- 4-oxothioxo-3,4-dihydropyrimidin-1(2H)-yl]ethyl}glycinamide; 6-(2- methoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl]propyl}guanidine; 1-[(2S)- 3-aminohydroxypropyl](5-chloromethoxyphenyl)thioxo-2,3-dihydropyrimidin- 4(1H)-one; 1-[(2R)aminohydroxypropyl](5-chloromethoxyphenyl)thioxo- 2,3-dihydropyrimidin-4(1H)-one; (followed by page 3a) N-(2-aminoethyl)[6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- yl]acetamide; or 1-(2-aminoethyl)[2-(2-hydroxyethoxy)phenyl]thioxo-2,3- dihydropyrimidin-4(1H)-one; or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention provides the compound 2-(6-(2,5- dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide or a pharmaceutically acceptable salt thereof.
Also ed in another aspect is the compound 2-(6-(5-chloro methoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide or a pharmaceutically acceptable salt thereof.
In a still further aspect, the present invention provides the compound having the Formula NH OMe S N NH2 OMe .
In another aspect, the present invention provides the nd having the Formula NH OMe S N NH2 Cl .
In yet another , the present invention provides the nd or a pharmaceutically acceptable salt thereof wherein the compound is 2-[6-(2,4- dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide; 2-[6-(2- ymethylphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide; 1- (followed by page 3b) [(2R)aminopropyl](2,4-dimethoxyphenyl)thioxo-2,3-dihydropyrimidin-4(1H)-one; 2-[6-(3-methoxynaphthyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide; or 2-[6-(1H-indolyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide.
Also provided in another aspect is the compound or a pharmaceutically acceptable salt thereof wherein the compound is 2-{6-[2-(2-hydroxyethoxy) methoxyphenyl]oxothioxo-3,4-dihydropyrimidin-1(2H)-yl}acetamide; N-(2-aminoethyl){6-[2-(2-hydroxyethoxy)methoxyphenyl]oxothioxo-3,4- dihydropyrimidin-1(2H)-yl}acetamide; 6-[2-(2-hydroxyethoxy)methoxyphenyl](2- hydroxyethyl)thioxo-2,3-dihydropyrimidin-4(1H)-one; 6-[5-fluoro(2- hydroxyethoxy)phenyl](2-hydroxyethyl)thioxo-2,3-dihydropyrimidin-4(1H)-one; or 2-{6-[2-(2-hydroxyethoxy)methoxyphenyl]oxothioxo-3,4-dihydropyrimidin-1(2H)- yl}acetamide.
In a further aspect, the t invention provides the nd N-(2- aminoethyl)[6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- yl]acetamide or a pharmaceutically acceptable salt f.
In a still further aspect, the present invention provides the compound having the Formula HN OMe S N H2N .
In another , the present invention provides a nd having Formula I A S N R1 Formula I A or a pharmaceutically acceptable salt or prodrug thereof wherein (followed by page 3c) R1 is a five to six membered aromatic ring optionally having one to three heteroatoms ed independently from nitrogen, sulfur and oxygen or a bicyclic ring consisting of two fused partially saturated, fully ted or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said R1 is optionally mono-, di-, or tri-substituted independently with cyano, halo, hydroxyl, amino, (C1-C4)alkyl, )alkoxy, )alkoxy(C 1-C4)alkyl, hydroxy(C2- C4)alkoxy, oyl(C1-C4)alkoxy, amino(C2-C4)alkoxy, cyano(C1-C4)alkyl, (C1- C4)alkylcarbonyloxy(C 1-C4)alkyl, amino(C1-C4)alkylcarbonyloxy(C 1-C4)alkyl, (C1- C4)alkylcarbonyloxy(C 1-C4)alkoxy, amino(C1-C4)alkylcarbonyloxy(C 1-C4)alkoxy, mono- N- or di-N,N-(C1-C4)alkylamino, aminocarbonyl, mono-N- or di-N,N(C1- C4)alkylaminocarbonyl, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfinyl, (C1- C4)alkylsulfonyl, or mono-N- or di-N,N(C1-C4)alkylaminosulfonyl, wherein any of the (C1- yl or (C1-C4)alkoxy may be optionally mono-, di- or tri-substituted with fluoro; or wherein R1 is optionally substituted with a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen; R2 is a fully saturated, partially unsaturated or fully unsaturated one to en membered ht carbon chain wherein the carbons, other than the connecting carbon, a. may be branched b. may optionally be replaced with one or two heteroatoms selected ndently from oxygen and sulfur and may optionally be replaced with one to four nitrogens, n said sulfur is optionally mono- or di-substituted with oxo, c. may optionally be mono-, di- or tri-substituted independently with halo, d. may optionally be mono-substituted with hydroxy, and e. may optionally be mono-substituted with oxo, and wherein the carbon chain is optionally mono-substituted with Z; n Z is a partially ted, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring ting of two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; (followed by page 3d) wherein said Z is optionally mono-, di- or tri-substituted independently with amino, halo, )alkyl, (C1-C6)alkylcarbonyl, hioxo, amino(C1- C6)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or (C1-C6)alkoxy and wherein said (C1-C6)alkyl or (C1-C6)alkoxy substituent is also optionally substituted with one to three halo, and wherein said (C1-C6)alkyl or (C2-C6)alkoxy substituent is also optionally substituted with one to three hydroxy; with the proviso that R1 is not unsubstituted phenyl, and R2 is not tituted(C1- C6)alkyl.
Also provided is the use of the compounds of the invention in the manufacture of a medicament for treating vascular ions in a mammal.
In another aspect, the present invention provides pharmaceutical compositions or pharmaceutical combinations comprising the compounds of the present ion.
Yet another aspect of this invention is directed to a method for treating cardiovascular conditions in a mammal (including a human being either male or female) by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Also provided herein are compositions comprising a pharmaceutically ive amount of one or more of the compounds described herein and a ceutically acceptable carrier, vehicle, or t.
This invention is also directed to pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; [FOLLOWED BY PAGE 4] a second compound, said second compound being an angiotensin converting enzyme inhibitor, a HMG-CoA reductase inhibitor, a non-steroidal anti-inflammatory agent, a Factor Xa inhibitor or warfarin; and/or optionally a pharmaceutical carrier, vehicle, or diluent.
The present invention is directed to a compound of the Formula IA, 8%N R1 Formula IA or a pharmaceutically acceptable salt or prodrug thereof wherein R1 is a five to six ed aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen or a bicyc|ic ring consisting of two fused partially saturated, fu||y saturated or fully unsaturated five to six membered rings, taken ndently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said R1 is optionally mono-, di-, ortri-substituted independently with cyano, halo, hydroxyl, amino, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(Cg- C4)a|koxy, carbamoy|(C1-C4)a|koxy, amino(Cg-C4)alkoxy, cyano(C1-C4)alkyl, (C1- C4)a|ky|carbony|oxy(C1-C4)a|ky|, amino(C1-C4)a|kylcarbonyloxy(C1-C4)a|ky|, (C1- C4)a|kylcarbony|oxy(C1-C4)a|koxy, C1-C4)alkylcarbony|oxy(C1-C4)a|koxy, mono- N- or -(C1-C4)alkylamino, aminocarbonyl, mono-N- or di-N,N(C1- C4)alkylaminocarbonyl, (C1-C4)alkylthio, ulfonyl, (C1-C4)alkylsulfinyl, (C1- C4)alkylsulfonyl, or mono-N- or (C1-C4)alkylaminosulfonyl, n any of the (C1- C4)alkyl or (C1-C4)alkoxy may be optionally mono-, di- or tri-substituted with fluoro; or wherein R1 is optionally tuted with a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen; 2012/055949 R2 is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the carbons, other than the connecting carbon, a. may be branched b. may optionally be replaced with one or two heteroatoms selected independently from oxygen and sulfur and may optionally be replaced with one to four nitrogens, wherein said sulfur is optionally mono- or di-substituted with oxo, c. may optionally be mono-, di- or tri-substituted independently with halo, d. may ally be mono-substituted with y, and e. may optionally be mono-substituted with oxo, and wherein the carbon chain is optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from , sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully rated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Z is ally mono-, di- or tri-substituted ndently with amino, halo, )alkyl, (C1-Ce)alkylcarbonyl, aminothioxo, amino(C1- Ce)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or (C1-Ce)alkoxy and n said (C1-Ce)alkyl or (C1-Ce)alkoxy substituent is also optionally substituted with one to three halo, and wherein said (C1-Ce)alkyl or (Cg-Ce)alkoxy substituent is also optionally substituted with one to three hydroxy; with the proviso that R1 is not unsubstituted phenyl, and R2 is not tituted(C1- Ce)alkyl.
This invention is also directed to a method for treating cardiovascular events and conditions comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula IA or a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug wherein the cardiovascular condition or event is heart failure, congestive heart failure, eral arterial disease, pulmonary hypertension, itis, a primary or secondary myocardial infarction, ischemia, ischemia reperfusion injury, atrial fibrillation or coronary artery bypass graft surgery (CABG).
This invention is also directed to a method for treating a condition comprising administering to a mammal in need of such treatment a therapeutically ive amount of a compound of Formula IA or a g thereof or a pharmaceutically acceptable salt of said compound or of said prodrug wherein the ion is diabetes, renal insufficiency, dialysis, delayed graft function, transplant organ rejection or nephropathy caused by contrasting agents.
Also provided herein are compositions comprising a pharmaceutically effective amount of one or more of the Formula IA nds described herein and a pharmaceutically acceptable carrier, vehicle, or diluent.
This invention is also directed to pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a Formula IA compound, a prodrug f, or a pharmaceutically acceptable salt of said nd or of said prodrug; a second compound, said second compound being an angiotensin converting enzyme inhibitor, a HMG-CoA reductase tor, a non-steroidal anti-inflammatory agent, a Factor Xa inhibitor or warfarin; and/or optionally a pharmaceutical r, vehicle, or diluent.
AII patents and patent applications referred to herein are hereby incorporated by reference.
Other features and advantages of this invention will be apparent from this specification and the appendant claims which describe the invention.
BRIEF DESCRIPTION OF THE DRAWINGS is a characteristic x-ray powder diffraction pattern showing a crystalline form of Example 1(Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)). is a characteristic x-ray powder diffraction pattern showing a lline form of e 2(Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)).
DETAILED DESCRIPTION OF THE INVENTION A preferred group of compounds, designated the A Group, ns those compounds having the Formula I as shown above wherein R1 is , naphthyI, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, nolinyl, pyrazolyl, imidazolinyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; and wherein said R1 is mono-, di-, or tri- substituted independently with cyano, )alkyl, )alkoxy, hydroxy(C2- C4)alkoxy, trifluoro(C1-C4)alkyl, trifluoro(C1-C4)alkoxy or halo.
A group of compounds which is preferred among the A Group of compounds designated the B Group, contains those compounds wherein R2 is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the carbons, other than the connecting carbon, a. may be branched b. may optionally be replaced with one or two heteroatoms ed independently from oxygen, sulfur and nitrogen, wherein said sulfur is optionally mono- or di-substituted with oxo, c. may optionally be mono-, di- or tri-substituted ndently with halo, d. may optionally be mono-substituted with hydroxy, and e. may optionally be mono-substituted with oxo; or R2 is furanyl(C1-C4)alkyl, triazolyl(C1-C4)alkyl, pyridinyl(C1-C4)alkyl, pyrazinyl(C1- C4)alkyl, pyridazinyl(C1-C4)alkyl, pyrimidinyl(C1-C4)alkyl, imidazolyl(C1-C4)alkyl or pyrrolidinyl(C 2 rings ally mono-, di- or tri-substituted 1-C4)alkyl, said R independently with (C1-C4)alkyl, (C1-C4)alkoxy or halo.
A group of compounds which is preferred among the B Group of compounds designated the C Group, contains those compounds n R1 is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, yl, indolyl, benzo[b]thiophenyl, benzothiazolyl, b]furanyl or thiophenyl; wherein said R1 is mono-, di-, or trisubstituted ndently with (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C2-C4)alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and R2 is (C1-C4)alkoxy(C 1-C4)alkyl, carboxy(C1-C4)alkyl, mono-or di-hydroxy(C2-C6)alkyl, amino(C 2-C4)alkyl, diaminomethyleneamino(C2-C4)alkyl, mono-N- or di-N,N(C1- C4)alkylamino(C 2-C4)alkyl, )alkylcarbonyloxy(C 1-C4)alkyl,, (C1- C4)alkoxycarbonyl(C 1-C4)alkyl, carbamoyl(C1-C4)alkyl, carbamoylamino(C2-C4)alkyl, mono-N- or di-N,N(C1-C4)alkylcarbamoyl(C lkyl, amino(C2-C4)alkylcarbamoyl(C 1- C4)alkyl, (C1-C4)alkylcarbonylamino(C 2-C4)alkyl, amino(C1-C4)alkylcarbonylamino(C 2- C4)alkyl, (C1-C4)alkoxycarbonylamino(C 2-C4)alkyl, (C1-C4)alkylsulfonylamino(C 2- C4)alkyl, )alkylaminosulfonyl(C lkyl, aminosulfonyl(C1-C4)alkyl, amino(C3- C4)hydroxyalkyl or (C1-C4)alkylthioalkyl(C 1-C4).
A group of compounds which is preferred among the C Group of compounds designated the D Group, contains those compounds wherein R1 is phenyl and said R1 is mono-, di-, or bstituted independently with hydroxyethoxy, methyl, methoxy, fluoro or ; and R2 is diaminomethyleneamino(C2-C4)alkyl, carbamoyl(C1-C4)alkyl, hydroxy(C2-C4)alkyl, amino(C 2-C4)alkylcarbamoyl(C 1-C4)alkyl, (C1-C4)alkylcarbonylamino(C 2-C4)alkyl, amino(C lkylcarbonylamino(C 2-C4)alkyl, amino(C3-C4)hydroxyalkyl or amino(C2- A group of nds which is preferred among the B Group of compounds designated the E Group, ns those compounds n R1 is phenyl, yl, pyridinyl, quinolinyl, nolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; wherein said R1 is mono-, di-, or trisubstituted independently with (C1-C4)alkyl, (C1-C4)alkoxy, y(C2-C4)alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and R2 is triazolyl(C1-C4)alkyl, pyridinyl(C1-C4)alkyl, pyrazinyl(C1-C4)alkyl, pyridazinyl(C1- C4)alkyl, pyrimidinyl(C1-C4)alkyl, imidazolyl(C1-C4)alkyl or pyrrolidinyl(C1-C4)alkyl, said R2 rings optionally mono-, di- or tri-substituted independently with (C1-C4)alkyl, (C1- C4)alkoxy or halo.
A preferred group of compounds, designated the F Group, contains those compounds having the Formula I as shown above wherein wherein R1 is phenyl and said R1 is mono-, di-, tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro.
A preferred group of compounds, designated the G Group, contains those nds having the Formula I as shown above wherein R2 is hydroxy(C2-C4)alkyl, diaminomethyleneamino(C 2-C4)alkyl, carbamoyl(C1-C4)alkyl, amino(C3-C4)hydroxyalkyl, amino(C lkylcarbamoyl(C 1-C4)alkyl, (C1-C4)alkylcarbonylamino(C 2-C4)alkyl, amino(C 1-C4)alkylcarbonylamino(C 2-C4)alkyl or amino(C2-C4)alkyl.
A preferred group of compounds, designated the H Group, contains those compounds having the Formula I as shown above wherein R2 is (C1-C4)alkyl mono- or di-substituted ndently with amino, carbamoyl, hydroxyl, (C1-C4)alkoxy, amino(C1- C4)alkylcarbonylamino, amino(C2-C4)alkylcarbamoyl, (C1-C4)alkylcarbonylamino or diaminomethyleneamino.
A preferred group of compounds, designated the I Group, contains those compounds wherein the compound is 6-(2,4-dimethoxyphenyl)—1-(2-hydroxyethyl)—2—thioxo-2,3-dihydropyrimidin-4(1H)—one; 1-(2-aminoethyl)—6-(2,4-dimethoxyphenyl)—2—thioxo-2,3-dihydropyrimidin-4(1H)—one; 2-[6-(2,5-dimethoxyphenyl)oxo-2—thioxo-3,4-dihydropyrimidin-1(2H)—yl]acetamide; 2-[6-(5-chloromethoxyphenyl)—4—oxo-2—thioxo-3,4-dihydropyrimidin-1 (2H)- y|]acetamide; 1-(2-aminoethyl)—2—thioxo(2,4,5-trimethoxyphenyl)—2,3-dihydropyrimidin-4(1H)—one; 1-(3-aminopropyl)(2-methoxymethylphenyl)—2-thioxo-2,3-dihydropyrimidin-4(1H)- one; N-{2—[6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- y|]ethyl}glycinamide; 2-{3-[6-(2—methoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- pyl}guanidine; 1-[(28)—3-aminohydroxypropyl](5-chloromethoxyphenyl)thioxo-2,3- dihydropyrimidin-4(1H)—one; 1-[(2R)—3-amino-2—hydroxypropyl]—6-(5-chloromethoxyphenyl)thioxo-2,3- dihydropyrimidin-4(1H)—one; minoethyl)[6-(2,4-dimethoxyphenyl)oxo-2—thioxo-3,4-dihydropyrimidin-1(2H)- yl]acetamide; or 1-(2-aminoethyl)[2—(2—hydroxyethoxy)phenyl]—2-thioxo-2,3-dihyd ropyrimidin-4(1 H )-one or a pharmaceutically acceptable salt thereof.
An especially preferred compound is 2-(6-(2,5-dimethoxyphenyl)oxo-2—thioxo-3,4-dihydropyrimidin-1(2H)—yl)acetamide or a pharmaceutically acceptable salt thereof.
It is ally preferred that the compound is NH OMe NH2 OMe Another especially preferred compound is 2—(6-(5-chloromethoxyphenyl)oxo-2—thioxo-3,4-dihydropyrimidin-1(2H)- yl)acetamide or a pharmaceutically acceptable salt thereof.
It is especially preferred that the compound is NH OMe NH2 CI A group of compounds which is preferred among the C Group of compounds designated the J Group contains those compounds n R1 is naphthyl, quinolinyl, isoquinolinyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or enyl and said R1 is mono-, di-, or bstituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro; and R2 is diaminomethyleneamino(Cg-C4)alkyl, carbamoyl(C1-C4)alkyl, hydroxy(Cg-C4)alkyl, amino(Cg-C4)alkylcarbamoyl(C1-C4)alkyl, (C1-C4)alkylcarbonylamino(Cg-C4)alkyl, C1-C4)alkylcarbonylamino(Cg-C4)alkyl, amino(Cg-C4)hydroxyalkyl or amino(Cg- C4)alkyl.
A preferred group of compounds, designated the K Group, contains those compounds n the compound is 2—[6-(2,4-dimethoxyphenyl)oxo-2—thioxo-3,4-dihydropyrimidin-1(2H)—yl]acetamide; 2-[6-(2—methoxymethylphenyl)—4-oxo-2—thioxo-3,4-dihyd ropyrimidin-1 (2H)- yl]acetamide; 1-[(2R)—2—aminopropyl]—6-(2,4-dimethoxyphenyl)—2-thioxo-2,3-dihyd ropyrimidin-4(1 H)- one; 2—[6-(3-methoxynaphthyl)oxothioxo-3,4-dihydropyrimidin-1(2H)—yl]acetamide; or 2-[6-(1H-indolyl)oxo-2—thioxo-3,4-dihydropyrimidin-1(2H)—yl]acetamide or a pharmaceutically acceptable salt thereof.
A preferred group of compounds, designated the L Group, contains those nds wherein the compound is 2—{6-[2-(2—hydroxyethoxy)—5-methoxyphenyl]—4-oxo—2—thioxo-3,4-dihyd ropyrimidin-1 (2H)- y|}acetamide; N-(2-aminoethyl)—2-{6-[2—(2—hydroxyethoxy)—4-methoxyphenyl]—4-oxothioxo-3,4- dihydropyrimidin-1(2H)—yl}acetamide; 6-[2-(2—hydroxyethoxy)—4-methoxyphenyl]—1-(2-hydroxyethyl)thioxo-2,3- dihydropyrimidin-4(1H)—one; 6-[5-fluoro-2—(2-hydroxyethoxy)phenyl](2-hydroxyethyl)—2—thioxo-2,3-dihydropyrimidin- 4(1H)—one; or 2—{6-[2-(2—hydroxyethoxy)—4-methoxyphenyl]—4-oxo—2—thioxo-3,4-dihyd ropyrimidin-1 (2H)- yl}acetamide or a pharmaceutically able salt f.
An especially preferred compound is N-(2-aminoethyl)[6-(2,4- oxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)—yl]acetamide or a pharmaceutically acceptable salt thereof.
It is especially preferred that the compound is H2N/\/NH Preferred cardiovascular conditions include heart failure, congestive heart failure, peripheral arterial disease, pulmonary hypertension or vasculitis.
Other preferred cardiovascular conditions include unstable angina or a patient that has experienced a myocardial infarction.
Pharmaceutically acceptable salts of the compounds of Formula | or IA include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, te, te, onate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, e, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hloride/chloride, romide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, ylate, 2—napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. 2012/055949 le base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, calcium, choline, diethylamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, trimethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).
The compounds of the invention may exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and one or more ceutically acceptable solvent molecules, for example, ethanol. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, opylene glycol, 1,4-butyne—diol, and the like. The term ‘hydrate’ is employed when said solvent is water. Pharmaceutically acceptable es include hydrates and other solvates n the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO. The term “hydrate” refers to the complex where the solvent le is water. The solvates and/or hydrates preferably exist in crystalline form.
Included within the scope of the invention are complexes such as ates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric s. Also ed are complexes of the drug containing two or more organic and/or nic ents which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, fl (8), 1269-1288 by Haleblian (August 1975).
The compounds of the invention include nds of Formula | or IA as hereinbefore defined, polymorphs, and isomers thereof (including optical, geometric and eric isomers) as hereinafter defined and isotopically-labelled compounds of 3O Formula | or IA.
The nds of the present invention may be administered as prodrugs.
Thus certain derivatives of compounds of Formula | or lA which may have little or no pharmacological activity themselves can, when stered into or onto the body, be converted into compounds of a | or lA having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’. [Further information on the use of prodrugs may be found in ‘Pro—drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and ‘Bioreversible rs in Drug Design’, Pergamon Press, 1987 (ed. E B Roche, American ceutical Association).] Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I or IA with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
Some examples of such prodrugs include: (i) where the compound of Formula I or IA contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (C1-Cg)alkyl; (ii) where the compound of Formula I or IA contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (01-06) alkanoyloxymethyl; and (iii) where the compound of Formula I or IA ns a primary or secondary amino functionality (-NH2 or -NHR where R ¢ H), an amide thereof, for example, replacement of one or both hydrogens with (C1-C1o)alkanoyl.
In addition, n compounds of Formula I or IA may themselves act as gs of other compounds of Formula I or IA.
Compounds of Formula I or IA containing an asymmetric carbon atom can exist as two or more stereoisomers. Where a compound of a I or IA contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an ic , tautomeric isomerism (‘tautomerism’) can occur. It s that a single compound may exhibit more than one type of isomerism. For example, the following is illustrative of tautomers of the compounds of a I or IA.
Thiouracil Tautomers 0 O OH f1 ~ “N I ~ “fl HS 13 R1 32w R1 SAN}: R1 R2 R2 R2 most inant tautomer 2012/055949 onal 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 o o o HN HN A | HN A | | <— <— s [y R1 3 [y R1 8 [y R1 HN’R5 HN’R5 R9‘N//J\NH2 Rg‘N/KNH R9‘N )NL'R5NH2 ll . ”l o o o | HN HN :’ I .:> I s [y R1 3 [)1 R1 8 I}! R1 IfliRS RS‘N R5\ | R9‘MJ\NH2| T/ NH2 HTJ\NH2 R9 R9 Included within the scope of the claimed nds of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically , for example, D-lactate or L-lysine, or c, for e, DL-tartrate or DL-arginine.
The present invention includes all pharmaceutically acceptable isotopically- labelled compounds of Formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of en, such as 2H and 3H, carbon, such as 11C, 130 and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123| and 125l, nitrogen, such as 13N and 15N, , such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 358.
Certain isotopically-labelled compounds of Formula (I), for example, those incorporating a radioactive e, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of oration and ready means of detection.
Substitution with heavier es such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from r metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be red in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Tomography (PET) s for examining substrate receptor occupancy. lsotopically-labelled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.
References herein to ”treat”, ing”, “treatment” and the like include curative, tive and prophylactic treatment.
As used , the sions "reaction-inert solvent" and "inert solvent" refer to a solvent or a mixture thereof which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
By "pharmaceutically acceptable" is meant the carrier, vehicle, or diluent and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The term “pharmaceutically effective amount”, as used herein, refers to an amount of the compound of Formula | or IA (or a combination agent or a Formula | or IA compound in ation with a combination agent) sufficient to treat, prevent onset of or delay or diminish the symptoms and physiological manifestations of the indications bed herein.
The term “room temperature or ambient temperature” means a temperature 3O between 18 to 25 00, “HPLC” refers to high re liquid tography, “MPLC” refers to medium pressure liquid chromatography, “TLC” refers to thin layer chromatography, “MS” refers to mass spectrum or mass oscopy or mass spectrometry, “NMR” refers to nuclear magnetic resonance spectroscopy, “DCM” refers to dichloromethane, “DMSO” refers to dimethyl sulfoxide, “DME” refers to dimethoxyethane, ”EtOAc” refers to ethyl acetate, “MeOH” refers to methanol, “Ph” refers to the phenyl group, ”Pr” refers to propyl, ”trityl” refers to the triphenylmethyl group, “ACN” refers to acetonitrile, “DEAD” refers to diethylazodicarboxylate, and “DIAD” refers to diisopropylazodicarboxylate.
It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridyl” means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or nyl, and so forth. In l the nds of this invention can be made by ses which include processes analogous to those known in the chemical arts, particularly in light of the ption contained herein.
As used herein the term mono-N- or di-N,N-(C1-Cx)alkyl... refers to the (C1- CX)alkyl moiety taken independently when it is di-N,N-(C1-Cx)alkyl...(x refers to rs).
By halo is meant chloro, bromo, iodo, or .
By alkyl is meant straight chain saturated hydrocarbon or branched chain saturated hydrocarbon. ary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched chain saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are y, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.
The following paragraphs describe exemplary ring(s) for the generic ring descriptions contained herein.
Exemplary five to six membered aromatic rings optionally having one to three heteroatoms selected independently from oxygen, nitrogen and sulfur e phenyl, furyl, l, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 3O pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl.
Exemplary six membered rings include 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, oxinyl, 1,4-dioxanyl, linyl, thianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4- triazinyl, triazinyl, 1,3,5-trithianyl, 4H-1,2—oxazinyl, 2H-1,3-oxazinyl, 6H-1,3- oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2—oxazinyl, 4H-1,4-oxazinyl, 1,2,5- oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6- oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2—oxadiazinyl.
Exemplary bicyclic rings consisting of two fused partially ted, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen include indolizinyl, indolyl, isoindolyl, olyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, inyl, isoquinolinyl, cinnolinyl, phthalazinyl, olinyl, quinoxalinyl, 1,8—naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2Hbenzopyranyl, (3,4-b)—pyridinyl, pyrido(3,2-b)—pyridinyl, pyrido(4,3- b)—pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1- benzoxazinyl, 2H-1,2—benzoxazinyl and 4H-1,4-benzoxazinyl.
Certain processes for the manufacture of the compounds of this ion are provided as further features of the invention and are rated by the following reaction schemes. Other processes may be described in the mental section. ic synthetic schemes for preparation of the compounds of Formula | or IA are outlined below.
As an initial note, in the preparation of the Formula | or IA nds it is noted that some of the preparation methods useful for the preparation of the compounds described herein may e protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in a | or IA precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such tion is readily ined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left 3O unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection e those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the Formula | or IA compound.
SCHEMEI R020 HN A R2—NH2 —» R0531 —» | —» A o R1 1 HN R1 s N R1 O R I . x R2 R2 VI | / / .1 ml 0%R1 1 R020 : R1 E“) R1 xvn xxx xxv 1 ' (HO)ZB—R1 EK)C2 xxxv * I A X~ R« OEt o R, + xx xxn XV qu\éa xxx” Those skilled in the art will recognize that there exists a variety of methods for preparing thiouracils, including the condensation of a thiourea with various carbonyl containing compounds, or by reaction of a uracil with a thiating agent such as orous pentasulfide or Lawesson’s reagent. ln forming the thiouracils of the present invention it is useful to consider the method of construction in order to enhance the desired nds over the variety of possible isomers in a regiospecific manner.
The Formula | or IA thiouracil compounds wherein R1 and R2 are as described above may be prepared from the Formula ||| enamine by a cyclization reaction. The Formula lll enamine is cyclized to the corresponding Formula | or IA thiouracil, for example, by reaction with an isothiocyanate such as l, carboxyethyl or preferably (trimethylsilyl)isothiocyanate (TMSNCS). The reaction proceeds under reaction conditions such as a polar aprotic solvent (e.g., methyl tetrahydrofuran, tetrahydrofuran, dioxane, isobutylnitrile or neat in the ocyanate) at a ature of about 20 0C to about 150 OC, lly about 85 OC (via microwave or l g), for about three hours to about forty-eight hours.
The Formula Ill enamine may be conveniently prepared from the a VI [3- ketoester by reaction with an appropriate RZ-NHg amine (wherein R2 is as described above or wherein reactive functionality in R2, such as a primary amine, is in a suitably a protected form, such as an O-tert-butyl carbamate). For example, the Formula VI [3- ketoester is reacted with the R2-NH2 amine in the presence of a weak acid such as acetic acid in a polar solvent (e.g., methanol, ethanol, panol, toluene or neat in the amine) at a temperature of about 20 0C to about 120 0C, for about four hours to about seventy-two hours, typically about 80 0C for about 12 hours.
As described above, the Formula VI B-ketoester may be prepared, for example, from a Formula X methyl ketone, a Formula XV carboxylic acid, a Formula XX aryl halide or other precursors known to those skilled in the art.
The a VI B-ketoester is prepared from the Formula X methyl ketone by carboalkoxylation. For example, the Formula X methyl ketone is reacted with a dialkylcarbonate, preferably dimethyl carbonate, in the presence of an alkoxide base such as potassium tert-butoxide, in a polar solvent such as methyl tert-butyI ether or the corresponding alcohol for the dialkylcarbonate, at a temperature of about 15 0C to about 100 OC, typically ambient temperature, for about four hours to about forty-eight hours, typically twelve hours.
The Formula VI B-ketoester may also be ed for example from a carboxylic acid. For example, the Formula VI B-ketoester may be prepared from an activated carboxylic acid. The Formula XV acid is conveniently converted to a corresponding XVII acyl imidazole by reaction with 1,1’-carbonyldiimidazole in a polar solvent, typically ydrofuran at a temperature between 0 OC and 100 OC, preferably ambient temperature, for between 1 hour and twenty-four hours, ably three hours. A solution of the resulting acyI imidazole XVII in a polar aprotic solvent such as tetrahydrofuran is converted to the corresponding Formula VI B-ketoester by reaction with a on of an activated acetate species, such as the enoIate of an acetate ester or ably ethyl ium malonate in a polar aprotic solvent such as tetrahydrofuran, at a ature between -80 OC and 100 OC, preferably ambient 3O temperature, for n one and fourty-eight hours, preferably twelve hours to prepare the corresponding a VI B-ketoester.
Those skilled in the art will recognize that a variety of other methods can be used to prepare the B-ketoester from an acid.
Those skilled in the art will recognize that the Formula VI B-ketoesters may also be ed from esters of a XV carboxylic acids, such as methyl, ethyl, pyl, or tert-butyl, preferably the isopropyl ester of Formula XV ylic acid by a condensation on with an activated acetate species, such as the eno|ate of an acetate ester, preferably the eno|ate of isopropyl acetate, in a polar aprotic solvent such as tetrahydrofuran, dioxane, or toluene, preferably tetrahydrofuran, at a ature between -80 °C and 40 °C, preferably t temperature, for between one and twenty-four hours, ably twelve hours to prepare the corresponding Formula VI [3- ketoester.
In on, those skilled in the art will recognize that there are a variety of methods for converting an aryl halide into a ester including the following exemplary procedures. A Formula XX aryl halide (e.g., an aryl bromide) is combined via a palladium-mediated coupling with a Formula XXll B-alkoxyacrylate, such as ethyl 3-ethoxyacrylate ing a palladium catalyst, typically bis(tri-tert-buty|phosphine) palladium (optionally with lithium chloride), in the ce of an amine such as N,N-di- cyclohexylmethylamine under an inert atmosphere such as nitrogen at a temperature of about 90 0C to about 140 OC, typically at about 110 0C, for about four hours to about forty-eight hours, typically 12 hours. The resulting XXV enolether is converted to the corresponding Formula Vl B-ketoester by treatment with an acid such as aqueous HCl in a polar solvent dichloromethane, methanol, acetic acid) at a temperature of about 15 0C to about 40 OC, typically at about ambient, for about thirty minutes to about six hours.
Alternatively, the Formula ”I enamine may be prepared from the Formula XXX propiolate via the following two-step reaction.
A Formula XXXll alkyne is coupled with a Formula XXXV boronic acid wherein R1 is as described above, to prepare the Formula XXX propiolate via a transition metal mediated coupling. For e, the appropriate R1-boronic acid in a polar aprotic t such as dichloromethane is reacted with cesium carbonate, copper iodide, silver (I) oxide and tert-butyl propiolate at a temperature of about 60 0C to about 100 OC, typically about 80 0C, for about 30 minutes to about six hours.
The resulting Formula XXX propiolate is transformed to the corresponding 3O Formula I” enamine by amination with the appropriate R2-NH2 amine (wherein R2 is as defined above) in the presence of a weak acid such as acetic acid. The reaction proceeds in a polar solvent such as ethanol or isopropanol at a temperature of about 60 0C to about 100 OC typically, about 80 0C for about 24 hours to about 72 hours.
SCHEMEII HN o LDA HN s N A | Mel,D|EA | NI | s N I —' A R2 2 | Mes I 2 l|\l R LV LVI LV|| 0 o RtB(OH)2 Pddppr|2 N Na co /]|\ | (NH4)2S,pyr | Mes R1 it r11 s N R1 R2 R2 LV||| I The Formula | or IA thiouracil may also be prepared from a Formula LVI 6- halothiouracil as shown in Scheme II.
The thiocarbonyl of a Formula LVI halothiouracil is protected, for example, by reaction with iodomethane in the ce of a base such as diisopropylethylamine in a polar solvent (e.g., acetonitrile) at a ature of about 15 0C to about 40 OC, typically ambient temperature, for about eight hours to about twenty-four hours. The resulting Formula LVll halide undergoes a transition metal mediated coupling with the appropriate R1-metal species (wherein R1 is as defined above) by for example reaction with [1,1’-bis(dipheny|phosphino)ferrocene] ropalladium(||) and R1boronic acid (wherein R1 is as described above) with 1,4 dioxane and aqueous sodium carbonate.
The e is heated at a temperature of about 90 0C to about 150 OC, typically by subjecting to microwave irradiation at 120 0C for about fifteen minutes to about one hour. The resulting Formula LVlll nd is deprotected by reaction with a phile, typically by reaction with ammonium sulfide in a polar t such as pyridine at a temperature of about 60 0C to about 150 OC, lly by microwave irradiation at 75 0C for about fifteen minutes to about one hour to prepare the Formula | or IA thiouracil.
The Formula LVI halothiouracils may be prepared from the corresponding Formula LV thiouracils by for example, a two-step deprotonation/lithium-halogenexchange with iodine. Typically the thiouracil is treated with a base such as lithium diisopropylamide in a polar aprotic solvent such as tetrahydrofuran at a temperature of 2012/055949 about -20 0C to about -100 OC, typically -78 OC. Then the solution is allowed to warm to a temperature of about 0 0C to about -25 OC, typically -10 0C for about fifteen minutes to about one hour to prepare the ponding lithium intermediate followed by cooling to a temperature of about -60 0C to about -80 OC, typically -78 OC pon the lithium intermediate is reacted with iodine in an appropriate polar aprotic solvent for about 5 minutes to about eight hours, typically eight hours.
SCHEMEIII O H O R0201 R3 R4 HN HN l an R1 R1 SAN | R1 HN SAN o )n 03/0)” YO)” OR OR R3.N\R4 LX LXI IB The Formula IB and LXI thiouracil nds (wherein R1 is described above, and while R3 and R4 are not ically denoted above, refer to substituents that are generally described above) may be prepared from the Formula LX enamines as shown in Scheme |||.Formu|a LXI thiouracils,wherein R is an alkyl group such as methyl, ethyl, isopropyl or tert-butyl, preferentially methyl or ethyl, may be converted into the corresponding ylic acid, wherein R = H, by a variety of methods known to those skilled in the art such as acid or base hydrolysis, preferably treatment with 5 equivalents of sodium or lithium hydroxide, in a polar solvent such as water, methanol, ethanol, tetrahydrofuran, or a mixture of such solvents, preferably water and ethanol, at a temperature n 0 °C to about 100 °C, preferably ambient temperature, for a period between one hour and -four hours, preferably four hours. The resulting Formula LXI carboxylic acid may be converted into the Formula lB amide by use of amide coupling reagents known to those d in the art, such as propane phosphonic acid anhydride (T3P) or (CDI), preferably propane phosphonic acid anhydride, in the presence of an organic base, such as pyridine, triethylamine, imidazole or diisopropylethylamine, ably diisopropylethylamine, in a polar solvent, such as N,N’-dimethylformamide, methylene chloride or ethyl e, preferably methylene chloride, at a temperature between 0 °C and solvent reflux, preferably ambient temperature, for a period between 15 minutes and forty-eight hours, preferably eighteen hours. 2012/055949 The Formula LXI thiouracil compounds may be prepared from Formula LX enamines by reaction with an isothiocyanate, such as N-benzoyl-, N-carboxyethyl- or preferably (trimethylsilyl)isothiocyanate (TMSNCS) optionally in the presence ofa polar aprotic solvent , such as., methyl tetrahydrofuran, tetrahydrofuran, dioxane, isobutylnitrile, n-butylacetate, N,N’-dimethylformamide, preferably neat in the isothiocyanate at a temperature between 20 °C and 150 °C, typically about 85 °C, heating with amicrowave reactor or a conventional heat source, for between 15 minutes and forty-eight hours, preferably three hours.
SCHEME IV 0 O O i HNJi ”N ,R7 | HN N | A | X S R‘ SAN R‘ S N R“ SANMEL IIRB N R1 R? R5 R5 ,R5 —> RE ,R5 s N R1 s N R1 R‘i ,R5 RE ,R5 i l HN x H2N x LXXI The a lC, LXXI and LXXll thiouracils may be prepared from the Formula LXX thiouracils as shown in Scheme IV.
The Formula lC (thiouracils (wherein R1 is described above, and while R3 —R9 are not specifically denoted above, refer to substituents that are generally described above and wherein at least one of R6 through R9 is bonded to the corresponding ine nitrogen through a carbonyl moiety) may be prepared from Formula LXXll thiouracils, which may exist in a variety of tautomeric forms such as these shown., by reaction of LXXll ines with an ing t known to those skilled in the art such as an acyl chloride or alkyl chloroformate in the presence of an aqueous base such as sodium carbonate or sodium bicarbonate in polar aprotic solvent, such as ydrofuran, at a temperature between 0 °C and solvent reflux, preferably ambient ature, to provide the corresponding Formula nguanidines. Alternatively, reaction of LXXll 2012/055949 thiouracils with a dialkyl carbonate, in the presence of an alkoxide base such as sodium ethoxide, in a polar t such as the corresponding alcohol for the dialkylcarbonate, at a temperature of between 15 °C to about 100 °C, ably at 50 °C, for between four hours and forty-eight hours, preferably fifteen hours provides the corresponding Formula lC thiouracils.
The Formula LXXll thiouracils may be prepared from the corresponding Formula LXX acils by reaction with R7R8NCN-containing guanylating reagent, such as benzotriazole-R7R8N-methanimine, imidazole-R7R8N-methanimine, or pyrazole-R7R8N- methanimine in a polar aprotic solvent,preferably N,N’-dimethylformamide, in the presence of a base, preferably diisopropylethylamine, at a ature between 15 °C to 60 °C, preferably ambient temperature, for between four to seventy-two hours, preferably eighteen hours. Alternatively, Formula LXX amines may be converted to an activated thiouracil LXXI wherein X is a leaving group, such as benzotriazole, imidazole, pyrrazole, by reaction with a imine t, such as 1,1-di(1H-benzotriazol yl)methanimine, 1,1-di(1H-imidazolyl)methanimine or 1,1-di(1H-pyrazol-1yl- )methanimine, in the presence of a base, such as diisopropylamine, in a polar aprotic solvent, such as N,N’-dimethylformamide, at a temperature n 15 °C and 100 °C, preferably ambient temperature, for between four hours and forty-eight hours, preferably eighteen hours. The ing a LXXI activated thiouracils can then be d with R7R8NH in the presence of a base, such as diisopropylethylamine, in a polar aprotic solvent, such as N,N’-dimethylformamide, at a temperature between 20 °C and 120 °C, preferably 60 °C, for n one hour and 24 hours, preferably three hours to obtain Formula LXXll guanidine thiouracils.
The starting materials and reagents for the above described Formula | or IA compounds, are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein, are related to, or are derived from compounds in which there is a large scientific st and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by s which are reported in the literature.
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. es of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994).] Conventional ques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor.
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or ylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled .
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in omerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, lly heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an mine, typically 0.1% diethylamine.
Concentration of the eluate affords the enriched mixture.
Pharmaceutically acceptable salts of nds of Formula I or IA may be prepared by one or more of three exemplary methods: (i) by reacting the compound of Formula I or IA with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or IA or by ring-opening a suitable cyclic precursor, for example, a Iactone or Iactam, using the desired acid or base; or (iii) by converting one salt of the compound of Formula I or IA to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are lly carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of tion in the resulting salt may vary from completely d to almost non-ionized.
The compounds of this invention may also be used in conjunction with other pharmaceutical agents (e.g., antiatherosclerotic and antithrombotic ) for the treatment of the disease/conditions described herein.
COMBINATION AGENTS The nds of the present ion can be administered alone or in combination with one or more additional therapeutic agents. By "administered in combination" or "combination therapy" it is meant that a nd of the present invention and one or more additional therapeutic agents are administered rently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time.
Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Thus, the methods of prevention and treatment described herein include use of combination agents.
The combination agents are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat the desired disease/condition e.g., cardiovascular condition such as acute coronary syndrome.
Additional therapeutic agents include anti-coagulant or coagulation inhibitory agents, anti-platelet or et inhibitory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents, anti-arrythmic agents, anti-hypertensive agents, calcium channel blockers (L-type and T-type), c glycosides, diruetics, mineralocorticoid receptor antagonists, NO donating agents such as organonitrates, NO promoting agents such as phosphodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti-diabetic agents, anti-depressants, anti-inflammatory agents (steroidal and non-steroidal), anti-osteoporosis , hormone replacement therapies, oral contraceptives, anti-obesity agents, anti-anxiety , anti-proliferative , anti- tumor agents, anti-ulcer and gastroesophageal reflux e agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid e receptor antagonist), nfective , anti-viral agents, anti-bacterial agents, and ungal agents. 3O Agents used in an ICU g are included, for example, dobutamine, dopamine, hrine, nitroglycerin, nitroprusside etc.
Combination agents useful for treating vasculitis are included, for example, azathioprine, cyclophosphamide, mycophenolate, mofetil, 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, an anti- coagulant agent, an anti-platelet agent, a in inhibiting agent, a thrombolytic agent, and a fibrinolytic agent.
Exemplary factor Xa inhibitors e apixaban and rivaroxaban.
Examples of suitable anti-coagulants for use in combination with the compounds of the present invention include ns (e.g., unfractioned and low molecular weight heparins such as enoxaparin and arin).
In another preferred embodiment the second agent is at least one agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, n, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, idine, clopidogrel, tirofiban, eptifibatide, abciximab, tran, disulfatohirudin, tissue plasminogen activator, modified tissue nogen activator, anistreplase, ase, and streptokinase.
A preferred second agent is is at least one anti-platelet agent. Especially preferred anti-platelet agents are aspirin and clopidogrel.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function, for example by inhibiting the aggregation, adhesion or granular secretion of platelets. Agents e, but are not limited to, the various known eroidal anti-inflammatory drugs S) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, enac, sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof.
Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA) and COX-2 inhibitors such as CELEBREX or cam are preferred. Other suitable platelet inhibitory agents include llb/llla antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane—A2— receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, l inhibitors (e.g., Pletal, dipyridamole), and pharmaceutically acceptable salts or prodrugs thereof.
The term anti-platelet agents (or platelet tory agents), as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P2Y1 and P2Y12, with P2Y12 being even more preferred. Preferred P2Y12 receptor antagonists include ticagrelor, prasugrel, ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. idine and clopidogrel are 2012/055949 also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use.
The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By ting thrombin, various thrombin-mediated processes, such as in-mediated platelet activation (that is, for example, the ation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin, argatroban, and melagatran, including ceutically acceptable salts and prodrugs f. Boroarginine tives and boropeptides e N-acetyl and peptide derivatives of boronic acid, such as C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. The term thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, denote agents that lyse blood clots (thrombi). Such agents include tissue plasminogen tor (natural or recombinant) and modified forms thereof, eplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor Vlla inhibitors, PAl-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha2— antiplasmin inhibitors, and anisoylated plasminogen streptokinase tor x, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in EP 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term ase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Examples of suitable anti-arrythmic agents include: Class | agents (such as propafenone); Class II agents (such as metoprolol, atenolol, carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, rone, azimilide and ide); Class IV agents (such as ditiazem and verapamil); K+ channel openers such as lAch inhibitors, and 'Kur inhibitors (e.g., compounds such as those disclosed in WOO1/40231).
The compounds of the present invention may be used in combination with antihypertensive agents and such pertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of suitable anti-hypertensive agents include: a|pha adrenergic blockers; beta adrenergic rs; calcium channel blockers (e.g., diltiazem, mil, pine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., ch|orothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, ch|ortha|idone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, ami|oride, olactone); renin inhibitors; ACE inhibitors (e.g., captopril, pril, fosinopril, ril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, rtan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and nds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389); l endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An ary antianginal agent is ivabradine.
Examples of le calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine and mybefradil.
Examples of suitable cardiac glycosides e lis and ouabain.
In one embodiment, a Formulae | or IA compound may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (such as LASIXT'V'), ide (such as DEMADEXT'V'), bemetanide (such as BUMEXT'V'), and ethacrynic acid (such as EDECRINT'V'); (b) thiazide-type diuretics such as ch|orothiazide (such as DIURILT'V', ESIDRIXT'V' or HYDRODIURILT'V'), hydrochlorothiazide (such as MICROZIDET'V' or ORETICT'V'), benzthiazide, hydroflumethiazide (such as SALURONT'V'), bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, and indapamide (such as LOZOLT'V'); (c) phthalimidine- type ics such as ch|ortha|idone (such as HYGROTONT'V'), and metolazone (such 3O as ZAROXOLYN T""); (d) quinazoline—type diuretics such as quinethazone; and (e) potassium-sparing diuretics such as triamterene (such as DYRENIUMT'V'), and ami|oride (such as RT'V' or MODURETICT'V').
In another embodiment, a compound of Formula | or IA may be co-administered with a loop diuretic. In still another embodiment, the loop diuretic is selected from furosemide and torsemide. In still another embodiment, one or more compounds of 2012/055949 Formulae I or IA may be co-administered with furosemide. In still r embodiment, one or more compounds of Formulae I or IA may be co-administered with torsemide which may ally be a controlled or modified e form of torsemide.
In another embodiment, a compound of Formulae I or IA may be co-administered with a de—type diuretic. In still another embodiment, the thiazide—type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In still another embodiment, one or more compounds of Formulae I or IA may be co- administered with chlorothiazide. In still another embodiment, one or more compounds of ae I or IA may be co-administered with hydrochlorothiazide.
In another embodiment, one or more compounds of ae I or IA may be co- administered with a phthalimidine—type diuretic. In still another embodiment, the phthalimidine—type diuretic is chlorthalidone. es of suitable combination mineralocorticoid receptor antagonists include sprionoIactone and epIerenone.
Examples of suitable combination phosphodiesterase inhibitors include: PDE ||| inhibitors (such as azol); and PDE V inhibitors (such as sildenafil).
The compounds of the present invention may be used in combination with cholesterol modulating agents (including cholesterol lowering agents) such as a Iipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG- CoA reductase gene expression tor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cycIase inhibitor, a combined ne ase/squalene cycIase inhibitor, a fibrate, niacin, an ion- exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant or an agent such as mipomersen..
Examples of suitable cholesterol/lipid lowering agents and lipid profile therapies include: HMG-CoA reductase inhibitors (e.g., pravastatin, Iovastatin, atorvastatin, simvastatin, tatin, NK—104 (a.k.a. tatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; es; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; Iipooxygenase inhibitors; choesterol absorption inhibitors; and cholesteryl ester transfer protein inhibitors.
Anti-inflammatory agents also include sPLA2 and |pPLA2 inhibitors (such as darapladib), 5 L0 inhibitors (such as atrelueton) and |L-1 and |L-1r antagonists (such as canakinumab).
Other atherosclerotic agents include agents that modulate the action of PCSK9 .
Cardiovascular complications of type 2 diabetes are associated with deleterious levels of MPO, accordingly, the compounds of the present invention may be used in combination with anti-diabetic agents, particularly type 2 anti-diabetic agents. Examples of le anti-diabetic agents include (e.g. ns, metfomin, DPPIV inhibitors, GLP- 1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors) Suitable anti- diabetic agents include an acetyl-CoA carboxylase— (ACC) inhibitor such as those described in WO2009144554, WO2003072197, WO2009144555 and W02008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, such as those described in W009016462 or W02010086820, AZD7687 or LCQQO8, diacylglycerol O- acyltransferase 2 (DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)—10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an d-amylase inhibitor (e.g., istat, trestatin and AL-3688), an d- glucoside hydrolase inhibitor (e.g., se), an d-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARV agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, tazone and rosiglitazone), a PPAR d/y agonist (e.g., CLX—0940, GW-1536, GW- 1929, GW-2433, KRP-297, 49, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like e 1 (GLP-1) modulator such as an agonist (e.g., n-3 and exendin-4), liraglutide, albiglutide, exenatide a®), utide, lixisenatide, dulaglutide, semaglutide, NN-9924,TTP-054, a n tyrosine phosphatase-1B (PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and nds disclosed by Zhang, S., et al., Drug Discovery Today, 0), 373-381 (2007)), SlRT-1 tor (e.g., atrol, GSK2245840 or GSK184072), a dipeptidyl 3O peptidease IV (DPP-IV) inhibitor (e.g., those in WO2005116014, sitagliptin, vildagliptin, alogliptin, iptin, linagliptin and saxagliptin), an insulin secreatagogue, a fatty acid oxidation tor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activators (GKa) such as those described in WO2010103437, WO2010103438, WO2010013161, W02007122482, TTP-399, 5, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, an insulin c, a glycogen phosphorylase tor (e.g. 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) including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin (CSG452), 41, THR1474, TS—071, |S|8388626 and LX4211 as well as those in WO2010023594, a glucagon receptor modulator such as those described in , D.E. et al. Annual s in Medicinal Chemistry 2008, 43, 119-137, GPR119 modulators, particularly agonists, such as those described in W02010140092, WO2010128425, WO2010128414, W02010106457, Jones, RM. et al. in Medicinal Chemistry 2009, 44, 149-170 (e.g. 82, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al. et al., Current Opinion in lnvestigational Drugs 2009, 59-364, TGR5 (also termed GPBAR1) receptor modulators, particularly 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, J.C., Annual Reports in nal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nic acid receptor (HM74A) tors, and SGLT1 inhibitors, such as GSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of the present invention can be found, for example, at page 28, line 35 h page 30, line 19 of WO2011005611. Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other abetic agents could include inhibitors or modulators of ine palmitoyl erase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of a|dose reductase, locorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCoc, PKCB, PKCy), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, g|ucocorticoid receptor, somatostain receptors (e.g.
SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of |L1 family including lL1beta, modulators of RXRaIpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.
Those skilled in the art will recognize that the compounds of this invention may also be used in conjunction with other cardiovascular or cerebrovascular treatments including PCI, ng, drug eluting stents, stem cell y and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.
Myeloperoxidase activity has been demonstrated in neuroinflammatory conditions, accordingly, the nds of the present invention may be used in combination with neuroinflammatory and neurodegenerative agents in s. es of additional neuroinflammatory and neurodegenerative agents include antidepressants, ychotics, anti-pain agents, anti-Alzheimer’s agents, and anti- anxiety agents. Examples of particular classes of antidepressants that can be used in combination with the compounds of the ion include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRls), NK-1 receptor nists, ine e inhibitors (MAOls), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRls), corticotropin releasing factor (CRF) antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Examples of suitable ry amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, ramine, dothiepin, butriptyline, nortriptyline, protriptyline, ine, desipramine and maprotiline.
Examples of suitable SSRls include fluoxetine, fluvoxamine, paroxetine, and sertraline.
Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and cyclopramine. Examples of suitable reversible inhibitors of monoamine oxidase include moclobemide. Examples of suitable SNRls of use in the present invention e venlafaxine. Examples of suitable atypical anti-depressants include bupropion, lithium, trazodone and zine. Examples of anti-Alzheimer’s agents include NMDA receptor antagonists such as memantine; and cholinesterase inhibitors such as donepezil and galantamine. Examples of suitable classes of anti-anxiety agents that can be used in combination with the compounds of the invention include benzodiazepines and serotonin 1A receptor (5-HT1A) agonists, and CRF nists.
Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT1A receptor agonists e buspirone and ipsapirone. le CRF antagonists include verucerfont. Suitable atypical antipsychotics include paliperidone, ziprasidone, risperidone, aripiprazole, olanzapine, and quetiapine. le nicotine acetylcholine agonists include CP-601927 and varenicline. Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and ziconotide.
Particularly when provided as a single dosage unit, the potential exists for a chemical ction n the combined active ients. For this reason, when a Formula | or IA compound and a second therapeutic agent are ed in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, d). For example, one active ingredient may be enteric . By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to l the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained- release throughout the gastrointestinal tract and also serves to minimize physical contact between the ed active ingredients. Furthermore, the sustained-released ent can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low ity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
In ation therapy treatment, both the nds of this invention and the other drug therapies are administered to s (e.g., humans, male or female) by conventional methods.
The Formula | or IA compounds of this invention, their prodrugs and the salts of 3O such compounds and prodrugs are all adapted to therapeutic use as agents that inhibit myeloperoxidase in mammals, particularly humans and thus are useful for the treatment of the various conditions (e.g., those described herein) in which such action is implicated.
It is believed that myeloperoxidase is involved in the pathologic oxidation of proteins, lipids and nucleic acids and contributes to dysfunctional cholesterol metabolism, tissue damage, and organ dysfunction and can induce or contribute to the development of vascular diseases and associated adverse outcomes.
The e/conditions that can be treated in accordance with the present invention include, but are not d to, cardiovascular conditions, diabetes (e.g., type II) and diabetic complications, ar conditions, neuroinflammatory conditions, neurodegenerative conditions, pain, cancer, , NASH (non-alcoholic steatatohepatitis), pulmonary injury and hypertension, renal diseases, and vasculitis syndromes especially those related to ANCA (anti-neutrophil cytoplasmic antibodies) and the like.
Given the positive correlation between activation of the myeloperoxidase with the development of cardiovascular and associated disease/conditions, Formula | or IA compounds of this invention, their prodrugs and the salts of such compounds and prodrugs, by virtue of their pharmacologic action, are useful for the prevention, arrestment and/or regression of atherosclerosis and its ated e .
It is believed that MPO exhibits pro-atherogenic biological activity during the evolution of cardiovascular disease. Furthermore, it has been observed that MPO- generated oxidants reduce the bioavailability of nitric oxide, an important vasodilator.
Additionally, it has been shown that MPO plays a role in plaque destabilization by causing the activation of metalloproteinases, g to a ing of the s cap of the plaques and subsequent plaque destabilization and rupture. Given these wide- ranging effects of MP0, MP0 has thus been implicated in a wide variety of cardiovascular diseases.
Cardiovascular conditions include, but are not limited to coronary heart disease, acute coronary syndrome, ischaemic heart disease, first or ent myocardial infarction, secondary myocardial infarction, non-ST segment ion myocardial infarction, or ST segment elevation myocardial infarction, ischemic sudden death, transient ischemic attack, peripheral occlusive arterial disease, angina, atherosclerosis, hypertension, heart failure (such as congestive heart failure), diastolic dysfunction (such as left ventricular diastolic dysfunction, diastolic heart failure, and impaired diastolic 3O filling), systolic dysfunction (such as systolic heart failure with reduced ejection fraction), atrial fibrillation, arrhythmia (ventricular), ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial necrotic lesions, vascular , left cular hypertrophy, decreased ejection fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, fibrinoid is of coronary es, adverse remodeling, stroke, and the like. Also, included are venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary al thrombosis, al arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) pulmonary , (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It is noted that thrombosis includes occlusion (e.g., after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty).
Cardiovascular complications of type 2 diabetes are associated with deleterious levels of MPO, ingly, the compounds of the present invention may be used to treat diabetes and diabetic complications such as macrovascular disease, hyperglycemia, metabolic syndrome, impaired glucose tolerance, hyperuricemia, uria, cataracts, diabetic neuropathy, diabetic nephropathy, ic retinopathy, obesity, dyslididemia, hypertension, hyperinsulinemia, and insulin resistance syndrome.
In addition, linkage of myeloperoxidase activity to disease has been demonstrated in neuroinflammatory and neurodegenerative conditions. Therefore, the compounds of the present invention are particularly indicated for use in the treatment of neuroinflammatory and neurodegenerative conditions (i.e.,disorders or diseases) in mammals including humans such as multiple sclerosis, migraine; epilepsy; Alzheimer’s disease; Parkinson’s disease; brain injury; ; ovascular diseases (including al arteriosclerosis, cerebral amyloid angiopathy, hereditary al hemorrhage, and brain hypoxia-ischemia); cognitive disorders (including amnesia, senile dementia, HIV associated dementia, Alzheimer’s associated dementia, Huntington’s associated ia, Lewy body dementia, vascular dementia, drug related dementia, delirium, and mild ive impairment); mental deficiency (including Down me and fragile X syndrome); sleep disorders (including hypersomnia, ian rhythm sleep disorder, insomnia, parasomnia, and sleep deprivation) and psychiatric disorders (such as anxiety (including acute stress disorder, generalized y er, social y disorder, panic disorder, post-traumatic stress disorder and obsessive-compulsive 3O disorder); factitious disorder (including acute hallucinatory mania); impulse control disorders (including compulsive gambling and intermittent explosive disorder); mood disorders (including bipolarl disorder, bipolar II disorder, mania, mixed affective state, major depression, chronic depression, seasonal depression, psychotic depression, and postpartum depression); psychomotor disorder; tic disorders (including schizophrenia, schizoaffective disorder, schizophreniform, and delusional disorder); drug dependence (including narcotic dependence, alcoholism, amphetamine dependence, cocaine ion, nicotine dependence, and drug withdrawal syndrome); eating disorders (including anorexia, bulimia, binge eating disorder, hagia, and pagophagia); and pediatric psychiatric disorders (including attention deficit disorder, attention deficit/hyperactive disorder, conduct disorder, and autism) in a mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I or IA or pharmaceutically acceptable salt thereof.
Other inflammatory es or disorders such as asthma, chronic obstructive pulmonary e, cystic fibrosis, idiopathic pulmonaryfibrosis, acute respiratory ss syndrome, sinusitis, rhinitis, sis, dermatitis, uveitis, gingivitis, atherosclerosis, inflammatory bowel disease, renal glomerular damage, liver fibrosis, sepsis, proctitis, rheumatoid arthritis, and inflammation associated with reperfusion injury, spinal cord injury and tissue /scarring/adhesion/rejection.
The term “nephropathy caused by contrasting ” includes contrasting induced pathy following procedures that utilize imaging agents ing cardiac y, rdiac surgery and transplant surgery. Nephropathy caused by contrasting agents also es nephropathy caused by the use of enhanced imaging contrasting agents in patients including those at risk of a primary MI or secondary MI.
The utility of the Formula I or IA compounds of the invention, their prodrugs and the salts of such compounds and prodrugs as medical agents in the treatment of the above described disease/conditions in mammals (e.g. humans, male or female) is demonstrated by the activity of the compounds of this invention in conventional in vitro and in vivo assays described below. The in vivo assays (with appropriate modifications within the skill in the art) may be used to determine the activity of other agents as well as the compounds of this invention. Such assays also provide a means whereby the activities of the Formula I or IA compounds of this invention, their prodrugs and the salts of such compounds and prodrugs (or the other agents described herein) can be compared to each other and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, ing humans, for the treatment of such diseases.
The following protocols may of course be varied by those skilled in the art.
MPO Amplex Red Activity Assay.
MPO peroxidase activity was measured by monitoring the formation of resorufin generated from the oxidation of Amplex Red (10-Acetyl-3,7-dihydroxyphenoxazine) (Invitrogen, Carlsbad, CA) by MPO (Gomes, Fernandes et al. 2005). Assay mixtures (100 uL total volume) contained 50 mM NaPi pH 7.4, 150 mM NaCl, 1 mM DTPA (diethylenetriaminepentaacetic acid), 2% DMSO, 2 uM H202, 30 uM Amplex Red and the reaction was initiated by the addition of 100 pM MPO (purified from human clear leukocytes and purchased from Calbiochem/EMD Biosciences, Gibbstown, NJ). All assays were performed in l, half-area, black, nonbinding surface, polystyrene plates (Corning) and the production of resorufin (excitation 530 nm, emission 580 nm) was monitored every 20 sec on a Spectramax M2 Microplate Spectrophotometer (Molecular Devices, Palo Alto, CA) equipped with Softmax Pro software ular Devices, Palo Alto, CA). Reactions to determine the background reaction rate consisted of all assay ents and 4 uL of 500 L bovine catalase (Sigma) in 50 mM KPi pH 7.0. The background rate was subtracted from each reaction progress curve. All data was ed using non-linear regression analysis in Microsoft Excel and Kaleidagraph (Synergy Software).
To determine inhibitor potency (kinact/KI) against MPO, the first 600 sec of the reaction ss curves were fit to equation 1, where V0 is the initial rate in c and t is time in seconds, to obtain the first order rate constant for enzyme inactivation (kobs) at each inhibitor concentration.
Preduet= fj— ll-cxpt-mtjl (1) on 1 is a variation of the standard equation for slow binding inhibition where the steady state ty (V5) is set to zero. Each kobs value was corrected for auto- inactivation of the enzyme by subtracting the kobs value for the uninhibited reaction. The corrected kobs values were then plotted versus inhibitor concentration ([l]) and fit to equation 2 kiflkflll II km = .1+ [1] where kinact is the maximal rate of inactivation and KI is the inhibitor concentration that yields half the rate of l inactivation (Copeland 2005).
WO 68875 Table 1 and (1A) below provides the myeloperoxidase inhibitory activity for the Examples below in accordance with the above-described assay.
Table 1. MP0 kinact/Ki for Examples (JO «3 WO 68875 WO 68875 A _\ WO 68875 WO 68875 WO 68875 Example 251 .3! WO 68875 AO‘l Exampb 318 5240 319 7810 320 2390 321 2480 322 2800 323 10200 324 11300 325 1160 326 7480 327 1880 328 4370 329 963 330 5210 331 6330 332 3270 333 6100 334 6840 335 9820 336 589 337 13200 338 1280 339 10400 340 1450 341 14300 342 817 343 3570 344 8480 345 946 346 5890 347 378 348 1400 Table 1A below provides the myeloperoxidase inhibitory activity for the Examples below in accordance with the above-described assay.
Table 1A. MPO kinact/Ki for es “APO Exampb kinact/Ki 1/s oer M 349 3630 350 8740 351 7870 352 6720 2012/055949 “APO Exampb kinact/Ki 1/s per M 353 11000 354 1830 355 1540 356 2910 357 2940 358 1710 359 2660 360 2280 361 2060 362 2690 363 9680 364 6580 365 9290 366 13600 367 1340 368 3270 369 8040 370 9060 371 4570 372 6250 373 12800 374 4600 375 11300 376 7870 377 8770 378 5040 379 7370 380 4470 381 1970 382 2310 383 5230 384 2930 385 3530 386 4960 387 4720 388 8690 389 4910 390 6250 391 3480 392 5830 393 13600 394 4020 WO 68875 I. “APO Exampb kinact/Ki 1/s per M 395 6980 396 10900 397 4050 398 4780 399 4860 400 2650 401 4060 402 4810 403 13300 404 6200 405 5970 406 4480 407 18700 408 9890 409 18000 410 3150 411 15000 412 3980 413 6560 414 1680 415 3910 416 4480 417 9280 418 11500 419 1200 420 5210 421 4950 422 4460 423 3290 424 6870 425 13400 426 4410 427 5360 428 5890 429 6620 430 9440 431 3440 432 1410 433 3490 434 4070 435 2420 436 3710 IMPO Example kinact/Ki 1/s per M 437 3400 438 7550 439 9200 440 3310 441 3260 442 12300 443 7330 444 17400 445 7350 446 14200 447 17200 448 6490 449 12000 450 7730 451 16000 452 11600 453 27800 TPO Amplex Red activity assay.
TPO activity was measured using the same assay as MP0 with 2 uM H202, 30 uM Amplex Red and the reactions were initiated with 1.3ug of protein from HEK293 cell membranes expressing human TPO. The cDNA encoding 933 amino acids of the full length human TPO was cloned into the ble expression vector pcDNA5/frt/to (InVitrogen), stable 293 clones were selected using 100 ug/ml of hygromycin and 15 ug/ml blasticidine in DMEM w/ 10% FBS. When cells reached 50-60% confluence, TPO expression was induced in medium containing all of above plus 10 ug/ml doxicycline and 5 ug/ml hemin (Sigma). Membranes were isolated from HEK293hTPO by ting the cells in PBS. The cells were pelleted at 1000 x g for 5 minutes at 4°C, resuspended in homogenization buffer (1 mM sodium onate, pH 7.4) containing EDTA-Free protease inhibitor (Roche), and incubated on ice for 10 minutes followed by Dounce homogenization. Nuclei and un|ysed cells were removed by pe||eting at 1000 x g for 10 minutes at 4°C. The supernatent was then centrifuged at 25,000 x g for 20 minutes at 4°C. The pellet was resuspended in homogenization buffer and centrifuged again at 25,000 x g for 20 s at 4°C. The final pellet was resuspended in storage buffer (50 mM Tris pH 7, 150 mM NaCI) containing protease inhibitors as described above. ne concentration was ined using the BCA Protein Assay (Pierce). TPO activity was measured using the Amplex Red assay as bed above.
Aliquots were made based on the activity accordingly and stored at -80°C.
The IC50 values were determined by plotting the initial rates (from the first 200 sec of each reaction progress curve) as percentage of tion relative to the uninhibited (DMSO) on as a function of inhibitor concentration. The data were fit to equation 3 .3”: —. ('33 l +{MCm}? ‘ where IC50 is the inhibitor concentration at 50% inhibition and z is the Hill slope (the slope of the curve at its inflection point).
NCES Copeland, R. A. (2005). tion of Enzyme Inhibitors in Drug Discovery A Guide for Medicinal Chemists and Pharmacologists. Hoboken, Wiley.
Gomes, A., E. Fernandes, et al. (2005). "Fluorescence probes used for detection of reactive oxygen s." J Biochem Biophys Methods 65(2-3): 45-80.
Human Whole Blood Assay for Irreversible Inhibition of MP0 To measure the inhibition of MPO activity in a biological system in the present invention, bioassays are performed with human whole blood that is collected from medication-free, human volunteers in heparin treated tubes (APP Pharmaceuticals, LLC, cat # NDC#6332310, #4710). Blood is ted and treated with different concentrations of the MPO inhibitor or vehicle l and co-treated with or without bacterial lipopolysaccharide (LPS, anivogen, cat# tlrl-pelps) to stimulate blood leukocytes to simultaneously generate H202 (a required MPO substrate) and the release of MPO. After 4 hour incubation at room temperature the plasma fraction is collected following a 2000Xg centrifugation at 4 0C.
The plasma fraction is divided into two for analysis of total MPO and active MP0.
The total MPO content is determined using a standard sandwich ELISA (capture and detection antibodies: Cell es, Cat# HP9048, and Cell Sciences, Cat# HM2164, clone 266-6K1) and calculated relative to a standard curve of purified MPO (myeloperoxidase, Calbiochem, cat# 475911) that is prepared by dilution in the autologous donor plasma. The MPO activity is ined by capturing the total MP0 from plasma using the e step as bed for the ELISA method. After washing unbound plasma material including ted MPO inhibitor, MPO reaction substrates are added [H202 (2uM) and Amplex Red (Invitrogen, Cat# A12222)] and the Vmax of the MPO-catalyzed conversion of the Amplex Red substrate to resorufin is determined by measuring the increase in fluorescence (excitation 530 nM, emission 580 nm) using a fluorescent plate reader in a kinetic analysis. The MPO activity of the captured material is compared to that obtained with a standard curve of purified MPO (myeloperoxidase, Calbiochem, cat# 475911) that was prepared in autologous donor plasma. The percent of ‘active’ myeloperoxidase for each sample is calculated from the ratio of the active myeloperoxidase in the Amplex Red assay and the total myeloperoxidase from the ELISA for each sample. A dose response curve of the MPOi concentration versus MPO activity is then plotted to determine the |C50 value.
Administration of the compounds of this invention can be via any method which delivers a compound of this invention systemically and/or y. These methods include oral routes, parenteral, intraduodenal routes, buccal, intranasal etc. Generally, the compounds of this ion are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intramedullary) may be utilized, for example, where oral administration is inappropriate for the target or where the patient is unable to ingest the drug.
For administration to human patients, an oral daily dose of the compounds herein may be in the range 1 mg to 5000 mg ing, of course, on the mode of and frequency of administration, the disease state, and the age and condition of the t, etc. An oral daily dose is in the range of 3 mg to 2000 mg may be used. A further oral daily dose is in the range of 5 mg to 1000 mg. For convenience, the compounds of the present invention can be administered in a unit dosage form. If desired, multiple doses per day of the unit dosage form can be used to increase the total daily dose. The unit dosage form, for example, may be a tablet or capsule containing about 0.1, 0.5, 1, 5, , 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 ion. The total daily dose may be administered in single or divided doses and may, at the ian’s discretion, fall e of the l ranges given herein.
For administration to human patients, an infusion daily dose of the compounds herein may be in the range 1 mg to 2000 mg ing, of course, on the mode of and frequency of administration, the disease state, and the age and condition of the t, etc. A further infusion daily dose is in the range of 5 mg to 1000 mg. The total daily WO 68875 dose may be administered in single or divided doses and may, at the physician’s discretion, fall outside of the l ranges given herein.
These compounds may also be administered to animals other than humans, for example, for the indications detailed above. The precise dosage administered of each active ingredient will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal, and the route(s) of administration.
A dosage of the combination pharmaceutical agents to be used in conjuction with the Formula | or IA compounds is used that is effective for the indication being d.
Such dosages can be determined by standard assays such as those referenced above and ed herein. The combination agents may be administered simultaneously or sequentially in any order.
These s are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to ine doses for subjects whose weight falls e this range, such as infants and the elderly.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the eutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of . Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to e the desired therapeutic effect in ation with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent 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 art of compounding such an active compound for the treatment of sensitivity in duals.
Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is ed in accordance with methods well- known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the t. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.
It is to be noted that dosage values may vary with the type and ty of the condition to be alleviated, and may e single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional nt of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory . Thus, the present invention encompasses patient dose-escalation as ined by the skilled artisan. Determining appropriate s and regiments for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the ngs disclosed herein.
The present invention further comprises use of a compound of Formula | or IA for use as a medicament (such as a unit dosage tablet or unit dosage capsule). In another embodiment, the present invention comprises the use of a compound of Formula | or IA for the manufacture of a ment (such as a unit dosage tablet or unit dosage capsule) to treat one or more of the ions previously identified in the above sections discussing methods of treatment.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ient which would be stered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one- third of such a dosage.
The compounds described herein may be administered as a formulation comprising a pharmaceutically effective amount of a compound of Formula | or IA, in association with one or more pharmaceutically acceptable excipients including rs, vehicles and diluents. The term “excipient” herein means any substance, not itself a therapeutic agent, used as a diluent, adjuvant, or vehicle for ry of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a solid dosage form such as a tablet, capsule, or a solution or sion suitable for oral, parenteral, intradermal, subcutaneous, ortopical application. Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, rs, lubricants, glidants, stabilizers, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Acceptable ents include (but are not limited to) stearic acid, magnesium te, ium oxide, sodium and calcium salts of oric and sulfuric acids, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches, gelatin, cellulosic materials, such as cellulose esters of alkanoic acids and cellulose alkyl esters, low melting wax, cocoa butter or powder, polymers such as nyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycols, and other pharmaceutically acceptable materials. es of excipients and their use may be found in ton’s Pharmaceutical es, 20th Edition (Lippincott Williams & s, 2000).The choice of ent will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and ity, and the nature of the dosage form.
The compounds herein may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or aneous) or rectal administration or in a form suitable for administration by inhalation. The compounds of the invention may also be formulated for sustained delivery. s of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions see Remington’s Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000).
Pharmaceutical compositions according to the invention may contain 0.1%-95% 3O of the compound(s) of this invention, preferably 1%-70%. In any event, the composition to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the disease/condition of the subject being treated.
Since the t invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula | or IA a prodrug thereof or a salt of such compound or prodrug and a second compound as described above. The kit comprises a means for containing the separate compositions such as a container, a d bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is ularly advantageous when the separate components are preferably stered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the ibing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging ry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, es, and the like). Blister packs generally consist of a sheet of relatively stiff material d with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or es to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were . As a result, the tablets or capsules are sealed in the recesses between the c foil and the sheet.
Preferably the strength of the sheet is such that the tablets or es can be removed from the r pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or es whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday,etc.... Second Week, Monday, Tuesday,..." etc.
Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula | or lA compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several s or capsules and vice versa. The memory aid should reflect this.
In another specific embodiment of the invention, a dispenser ed to dispense the daily doses one at a time in the order of their intended use is provided.
Preferably, the dispenser is ed with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which tes the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
Also, as the present invention has an aspect that relates to the treatment of the disease/conditions bed herein with a combination of active ingredients which may be administered jointly, the invention also relates to ing separate pharmaceutical compositions in a single dosage form, such as (but not limited to) a single tablet or capsule, a bilayer or multilayer tablet or capsule, or through the use of segregated components or compartments within a tablet or capsule.
The active ingredient may be delivered as a solution in an aqueous or non- aqueous vehicle, with or t additional solvents, co-solvents, excipients, or xation agents selected from pharmaceutically acceptable diluents, excipients, vehicles, or carriers.
An ary enous formulation is prepared as follows: Formulation : Intravenous Solution Ingredient Quantity Active ingredient dissolved in 5% Dextrose 150 mg Injection, USP % Dextrose Injection, USP 1.0 mL The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 mL per minute.
The active ingredient may be formulated as a solid dispersion or as a self emulsified drug ry system (SEDDS) with pharmaceutically acceptable excipients.
The active ingredient may be formulated as an immediate release or modified release tablet or e. Alternatively, the active ingredient may be delivered as the active ingredient alone within a capsule shell, without additional excipients.
WO 68875 GENERAL EXPERIMENTAL PROCEDURES All chemicals, reagents and solvents were purchased from commercial sources when available and used without further purification. Proton nuclear magnetic spectroscopy (1H NMR) was recorded with 400 and 500 MHz Varian spectrometers. Chemical shifts are expressed in parts per million downfield from tetramethylsilane. The peak shapes are denoted as s: s, singlet; d, t; t, triplet; q, quartet; m, multiplet; br s, broad singlet. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI) or electron scatter (ES) ionization sources. Observed mass (Obs Mass) reported in the Tables correspond to the exact mass of the parent molecule plus one, unless otherwise noted. Silica gel tography was performed primarily using a medium pressure Biotage or ISCO systems using columns pre-packaged by s commercial vendors including Biotage and ISCO. Microanalyses were performed by Quantitative logies Inc. and were within 0.4% of the calculated . The terms “concentrated” and “evaporated” refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than 60 oC. The abbreviation “min” and “h” stand for “minutes” and “hours” respectively.
Powder X—ray Diffraction Powder diffraction analysis was conducted using a Bruker D8 diffractometer equipped with a Cu radiation source, fixed slits (divergence=1.0 mm, anti-scatter=0.6 mm, and receiving=0.6 mm) and a scintillation counter detector. Data was ted in the Theta-Theta goniometer at the Cu wavelength K01 =1 .54056 A from 3.0 to 40.0 degrees 2—Theta using a step size of 0.040 s and a step time of 2.0 second. X- ray tube voltage and amperage were set at 40 kV and 40 mA respectively. Samples were prepared by placement in a Nickel Disk (Gasser & Sons, Inc. Commack, NY) and rotated during data collection. Data were collected and analyzed using Bruker DIFFRAC Plus software (Version 2.6).
|. Beta Keto Ester Route n A. Carboxylic Acid Route Section Preparation 1 EtOZC Ethyl 3-(5-ch/oro-2—methoxyphenyl)-3—oxopropanoate A 3000 mL 3-necked round-bottomed flask flushed with nitrogen was charged with magnesium ethoxide (67.46 g, 589.51 mmoles) and THF (1100 mL), and the resulting e was stirred as ethyl hydrogen ma|onate (162.26 g, 1.18 moles; 145.00 mL diluted in 100 ml of THF) was added and the mixture was heated at 45 °C for 4 hours.
Meanwhile, a 2000 mL 3-necked bottomed flask flushed with nitrogen was d with 5-chloromethoxybenzoic acid (100 g, 536 mmoles) and THF (600 mL).
To this mixture stirring at room temperature was added 1,1’-carbonyldiimidazole (95.59 g, 589.5 mmoles) in ns to avoid excess foaming. After stirring for 3 hours at room temperature the second solution was added gradually to the first solution. After addition the reaction mixture was heated to 45 °C. After 20 hours, the reaction mixture was concentrated under reduced pressure before adding ethyl acetate (1 L) followed by 2 N HCI (500 mL). After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCI (500 mL), saturated sodium bicarbonate (500 mL), and water (500 mL). The organic phase was concentrated under reduced re, the residue taken up in ethyl acetate (1000 mL) and trated again to afford the title compound (104.94 g).
MS (ES+) 257.2 [M+1]+. 1H NMR showed product as a 75:1 keto:enol mixture. For the keto tautomer: 1H NMR (500 MHz, CDCI3) 6 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).
Preparation 2 Etozc NH2 Cl (Z)-Ethyl 3—((2-amino-2—oxoethy/)amino)—3—(5-ch/oro-2—methoxypheny/)acry/ate A 5-L reaction vessel was charged with methanol (3.3 L), sodium ide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65 °C for 1 hour before cooling to 50 °C and adding acetic acid (514.25 mmoles, .88 g, 29.47 mL) and ethyl 3-(5-chloromethoxyphenyl)oxopropanoate (300 g, 1.03 mole). After heating to reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10 0C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65 °C) for 14 hours to afford the title compound (339.4 g).
MS (ES+) 313.2 [M+1]+. 1H NMR (500 MHz, DMSO-de) 6 ppm 8.80 (t, J=5.00 Hz, 1 H) 7.47 (dd, J=8.90, 2.81 Hz, 1 H) 7.27 (br. s., 1 H) 7.22 (d, J=2.68 Hz, 1 H) 7.14 (d, J=8.78 Hz, 1 H) 7.09 (br. s., 1 H) 4.30 (s, 1 H) 4.03 (q, J=7.07 Hz, 2 H) 3.80 (s, 3 H) 3.56 (br. s., 1 H) 3.45 (br. s., 1 H) 1.18 (t, J=7.07 Hz, 3 H).
Example 1 IL: OMe S N NH2 CI 2—(6-(5-Chloro-2—methoxyphenyl)oxothioxo-3, 4-dihydropyrimidin- 1 (2H)-yl) acetamide A reaction vessel equipped with an efficient stirrer was charged with (Z)-ethyl 3-((2- 2-oxoethyl)amino)(5-chloromethoxyphenyl)acrylate (15 g, 50.2 mmol), butyl acetate (150 mL) and trimethylsilyl isothiocyanate (160.7 mmole, 21.1 g, 22.7 mL) and the e was heated to reflux. After 15 hours, the mixture was cooled to 30 °C and treated with 1 N aqueous sodium hydroxide (112.5 mL, 112.5 mmoles). After 30 min, the c layer was separated and extracted with another n of 1 N sodium hydroxide (37.5 mL, 37.5 mmoles). The ed aqueous phases were extracted twice with dichloromethane (2 x 45 mL), filtered, and treated with 6N HCI until a pH of 2.5 was achieved. After stirring for 1 hour, the resulting solid was ed by vacuum tion, resuspended in 100 mL of a 1:1 methanol-water solution, heated with stirring at 50 °C for 2 hours, and cooled to room temperature before collecting the solid by vacuum filtration, pulling dry and drying in a vacuum oven (20 mm Hg, 50 °C) for 12 hours to afford 8.7 g of the desired product as a tan solid.
MS (ES+) 326.0 [M+1]+. 1H NMR (500 MHz, DMSO-de) 5 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). ative Pre aration of Exam le 1 NH2 CI 2—(6—(5—Chloro-2—methoxyphenyI)oxothioxo-3, 4-dihydropyrimidin- 1 (2H)-yl) acetamide A slurry of (Z)-ethy| 3-((2-amino—2-oxoethyl)amino)(5-chloro methoxyphenyl)acrylate (20 g, 63 mmol) in a mixture of butyl acetate (140 mL) and DMF (38 mL) was treated with trimethylsilyl isothiocyanate (16.8 g, 125 mmol) and the mixture was heated at 115-120 °C for 5-6 hours. The mixture was cooled to 0-5 OC, butyl acetate (100 mL) was added and the mixture was slurried for 8 hours. The formed solids were ed, and the filter cake was washed with butyl acetate (2 x 100 mL). The solid was dried in a vacuum oven at 50 °C for 12 hours to a tan solid. The solid was dissolved in a 5:1 mixture of DMF and water at room temperature and additional water was added slowly to crystallize the material. The slurry was cooled to 10 °C and stirred for 8 hours, followed by filtration and washing with water. The filter cake was dried in a vacuum oven at 50 °C for 8 hours. The solid was dissolved in a 1:1 mixture of methanol and water and the slurry was heated to 50 °C and held at this ature for 2 hours.
After cooling to 10 0C over 30 minutes, the slurry was held at this temperature for 1 hour, ed and washed with water and dried in a vacuum oven at 50 °C for 8 hours to give the title compound as a white solid.
MS (ES+) 326.0 [M+1]+. 1H NMR (500 MHz, DMSO-de) 5 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 EtOZC Sodium 1 -(2, 5-dimethoxypheny/)ethoxy—3-oxoprop- 1-en- 1-o/ate A 20-L reaction vessel was charged with magnesium de (3.61 moles; 413.52 g) and THF (6.6 L), and the resulting mixture was stirred as ethyl hydrogen malonate (7.23 moles; 888.89 mL; 994.67 9; diluted with 20 mL of THF) was added and the mixture was heated at 45 °C for 4 hours. Meanwhile, a 20 L reactor was charged with 2,5- dimethoxybenzoic acid (3.29 moles; 600.00 g) and THF (3.6 L). To this mixture stirring at room temperature was added 1,1’-carbonyldiimidazole (3.61 moles; 585.98 g) in portions to avoid excess foaming. After stirring for 3 hours at room temperature the second solution was added gradually to the first on. After addition the reaction mixture was heated to 45 0C. After 20 hours, the reaction mixture was concentrated under d pressure before adding ethyl acetate (6 L) followed by 2 N HCI (3 L).
After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCI (3 L), saturated sodium bicarbonate (3 L), and water (3 L). The organic phase was concentrated under d pressure, the residue taken up in ethyl acetate (6 L) and trated again to afford an oil, which was transferred to a 20 L reaction vessel with 5 L of ethyl acetate and treated with sodium methoxide (3.45 moles; 793.00 mL of a 4.35 M on in methanol). After stirring at room temperature for 3 hours, an additional 6 L of ethyl acetate was added and the solid collected by vacuum filtration and dried overnight in a vacuum oven at 40 0C to give 661 grams of the title product.
MS (ES+) 253.1[M+1]+. 1H NMR (400 MHz, DMSO-de) 5 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).
Preparation 4 EtOZC NH2 OMe (Z)-Ethyl 3-((2-amino-2—oxoethyl)amino)-3—(2, thoxyphenyl)acrylate A 5-L reaction vessel was charged with ol (3.3 L), sodium methoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65 °C for 1 hour before g to 50 °C and adding acetic acid (514.25 mmoles, .88 g, 29.47 mL) and ethyl 3-(2,5-dimethoxyphenyl)oxopropanoate (300 g, 1.03 mole). After heating at reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10 0C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65 °C) for 14 hours to afford the title compound (339.4 g).
MS (ES+) 309.1[M+1]+. 1H NMR (400 MHz, e) 5 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 IE: OMe S N NH2 OMe 2-(6—(2, 5-Dimethoxyphenyl)—4—oxo—2—thioxo-3, 4-dihydropyrimidin-1 (2H)-yl)acetamide A 5-L reaction vessel equipped with an efficient stirrer was charged with (Z)-ethyl 3-((2- aminooxoethyl)amino)(2,5-dimethoxyphenyl)acrylate (1.30 moles; 400.00 g), butyl acetate (3.4 L) and trimethylsilyl isothiocyanate (4.15 moles; 585.67 mL; 544.96 g) and the mixture was heated to reflux. After 16 hours, the mixture was cooled to 40 °C and treated with 2 N aqueous sodium hydroxide (1.95 L). The organic layer was ted and extracted with another portion of 2 N sodium hydroxide (0.325 L). The combined aqueous phases were filtered, extracted twice with dichloromethane (2 x 1.6 L), and WO 68875 added slowly to a well-stirred 3N aqueous HCI solution (1.3 L) at room temperature.
After stirring for 30 min, the resulting solid was isolated by vacuum filtration, rinsing with water, and pulled dry to afford a water wet cake (640 g). The cake was dissolved in dimethylformamide (2.4 L) at 90 OC and stirred as water (2 L) was added slowly to the solution. The mixture was cooled gradually to room temperature and the ing solid isolated by vacuum filtration, rinsing with water and pulling dry to afford 245 g of solid.
This solid was then suspended in 1.25 L of methanol and stirred as 1.25 L of water was added. The mixture was heated with stirring at 50 °C for 2 hours, and then cooled to 10 °C for 2 hours before collecting the solid by vacuum filtration, pulling dry before drying in a vacuum oven (20 mm Hg, 60 C) to afford the desired product.
MS (ES+) M+1]+. 1H NMR (500 MHz, DMSO-d6) 6 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) .37 (br. s., 1 H) 3.88 (br. s., 1 H) 3.78 (s, 3 H) 3.70 (s, 3 H).
B. Methyl Ketone Route Section Preparation 5 MOC6’2 Methyl 3-(2, 4-dimethoxyphenyl)oxopropanoate To a three-necked round-bottomed flask equipped with a mechanical stirrer under N2 was added potassium tert—butoxide (1M in THF, 108.77 mL, 108.77 mmol), followed by a solution of 2,4-dimethoxyacetophenone (10.00 g, 54.38 mmol) and yl carbonate (13.93 mL, 163.15 mmol) in methyl tert—butyl ether (50 mL) dropwise via an addition funnel over 1.5 hours. During addition, reaction turned from a l cloudy yellow mixture to a thick red-orange slurry. Reaction mixture was stirred at room temperature overnight. Aqueous citric acid on (0.5 N, 110.95 mL, 54.39 mmol) was added via on funnel to quench the reaction. Exotherm was observed during quenching and solids dissolved to give an orange mixture. The layers were separated and the aqueous layer was extracted with methyl tert—butyl ether (2 x 25 mL). The combined organic extracts were trated to low volume. Heptane (50 mL) was added and brown solids precipitated. The resulting slurry was stirred under N2 overnight at room temperature. Solids were ed and dried under N2 to give the title compound (11.05 g, 85% yield) as a beige colored powder.
MS (ES+) 239.1 [M+1]+. 1H NMR (500 MHz, CDCI3) 6 7.95 (d, J=8.78 Hz, 1 H) 6.57 (dd, J=8.78, 2.20 Hz, 1 H) 6.45 (d, J=2.20 Hz, 1 H) 3.94 (s, 2 H) 3.88 (s, 3 H) 3.87 (s, 3 H) 3.73 (s, 3 H). ation 6 M€02C H OMe (Z)-Methy/ 3-(2,4-dimethoxyphenyl)-3—((2-hydroxyethyl)amino)acrylate To a mixture of methyl 3-(2,4-dimethoxyphenyl)oxopropanoate (3.50 g, 14.69 mmol) and acetic acid (0.17 mL, 2.94 mmol) in i-PrOH (70 mL) was added ethanolamine (0.88 mL, 14.69 mmol) and the reaction mixture was heated to 83 OC. Additional ethanolamine (0.88 mL, 14.69 mmol) was added to the on mixture at two, four and six hours. After ng at 80 0C for 48 hours, the reaction mixture was cooled and concentrated under reduced pressure before the residue was suspended in equal parts of a saturated sodium bicarbonate solution and water under N2. After stirring overnight, the solids were collected by vacuum filtration and dried in a vacuum oven at 30 OC overnight to afford the title compound (2.72 g, 63%) as a beige colored power. 1H NMR (400 MHz, CDCI3) 5 8.77 (t, J=5.37 Hz, 1 H) 7.13 (d, J=8.29 Hz, 1 H) 6.47-6.52 (m, 2H) 4.53 (s, 1 H) 3.84 (s, 3 H) 3.82 (s, 3 H) 3.66 (s, 3H) 3.61 (td, J=5.45, 5.45 Hz, 2 H) 3.15 (td, J=5.53, 5.53 Hz, 2 H).
Example 3 H OMe 6-(2,4-Dimethoxyphenyl)—1-(2-hydroxyethy/)thioxo-2, 3-dihydropyrimidin-4(1H)-one To a solution of thyl 3-(2,4-dimethoxyphenyl)((2-hydroxyethyl)amino)acrylate (9.50 g, 33.77 mmol) in 2-MeTHF (100 mL) was added (trimethylsilyl)isothiocyanate (23.80 mL, 168.79 mmol), and the reaction mixture was heated at 85 0C. After stirring overnight, the reaction mixture was cooled, extracted with an aqueous 1N NaOH solution (1 x 250 mL, then 1 x 50 mL), the combined aqueous layers were washed with CH2CI2 (2 x 50 mL) and the aqueous phase acidified to pH 4 with concentrated HCI. The resulting solids were ed, washed with water (2 x 50 mL) and dried under N2 overnight to give a light yellow powder. The product was dissolved in DMF (70 mL) at 90 OC, and then water (80 mL) was added to this hot solution. After allowing to cool to room temperature and ng overnight, the solids were collected by vacuum filtration, washed with water and dried under high vacuum to provide the title compound (6.7 g, 61%) as an off-white .
MS (ES+) 309.1 [M+1]+. 1H NMR (500 MHz, DMSO-de) 6 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, , 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. Ami Halide Route Section Preparation 7 (Z,E)-Ethyl 3-(2, 6-dimethoxypyridinyl)ethoxyacry/ate Bis(tri-t—butylphosphine)pa||adium (47 mg, 0.092 mmol)) and lithium chloride (292 mg, 0.27 mmol) were added to a flask equipped with reflux condenser, and the apparatus was ted under vacuum and refilled with N2 several times. To this flask was added via cannula a degassed solution of anhydrous 1,4-dioxane (8 mL) under N2, followed by 3-bromo-2,6-dimethoxypyridine (500 mg, 2.29 mmol), N,N- dicyclohexylmethylamine (540 uL, 2.52 mmol) and ethyl xyacrylate (1.0 mL, 6.88 mmol), and the resulting orange solution was heated to 110 0C. After 20 hours, the reaction mixture was cooled to room temperature, ed 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 Na2804 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-50% EtOAc/heptane to yield the title compound (604 mg, 94%) as an amber oil. 1H NMR showed the product to be composed of a 2.5:1 e of E/Z isomers.
Preparation 8 EtO OMe Ethyl 3-(2, 6—dimethoxypyridin-3—yl)-3—oxopropanoate To a solution of ethyl 3-(2,6-dimethoxypyridinyl)ethoxyacrylate (600 mg, 2.13 mmol) in CH2CI2 (18 mL) was gradually added 3N aqueous HCI (3.5 mL). The reaction mixture was stirred at room temperature for 2 hours, then carefully added to a saturated sodium bicarbonate solution (30 mL). The layers were separated and the aqueous layer was extracted with CH2C|2. The combined organic extracts were passed though a plug of cotton to dry and concentrated in vacuo. The resulting oil was purified by flash chromatography (0-60% EtOAc/heptanes) to provide the title compound (515 mg, 95% yield) as a white solid. 1H NMR (400 MHz, CDCI3) 6 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. Amine Deprotection Route and tivation ation 9 EtO OMe HN / IN H \ (Z)-Ethyl 3—(2, 6-dimethoxypyridinyl)—3—((2-hydroxyethyl)amino)acrylate To a on of ethyl 3-(2,6-dimethoxypyridinyl)oxopropanoate (500 mg, 1.97 mmol) in EtOH (4 mL) was added 2-aminoethanol (0.60 mL, 9.9 mmol) followed by acetic acid (0.63 mL, 9.9 mmol). The reaction mixture was heated to 90 0C for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned n EtOAc and water. The c layer was concentrated in vacuo and the crude material was ed by chromatography on silica eluting with 20-80% EtOAc/heptane to provide the title compound (573 mg, 98%) as a clear gum.
MS (ES+) 297.3 [M+1]+. 1H NMR (500 MHz, CDCI3) 5 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 H | 6—(2, 6-Dimethoxypyridinyl)- 1-(2-hydroxyethyl)thioxo-2, 3-dihydropyrimidin-4(1H)- To a solution of (Z)—ethyl 3-(2,6-dimethoxypyridinyl)—3-((2- hydroxyethyl)amino)acrylate (100 mg, 0.34 mmol) in 2-MeTHF (1.0 mL) was added (trimethylsilyl)isothiocyanate (0.30 mL, 2.0 mmol) and the reaction mixture was heated at 80 0C for 4 hours. The cooled reaction mixture was diluted with EtOAc and washed with a saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was concentrated in vacuo. The residue was triturated with MeOH and the resulting solids were collected by vacuum filtration to give the title nd (16 mg, 16%) as a white solid.
MS (ES+) 310.2 [M+1]+. 1H NMR (500 MHz, 00300) 5 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 EtOZC XOTH\/\MO I (Z)-ethyl 3-(2-(tert—butoxycarbonylamino)ethy/amino)(2,4-dimethoxyphenyl)acrylate A solution of ethyl 3-(2,4-dimethoxyphenyl)oxopropanoate (41.91 g, 166 mmol), tert- butyl 2-aminoethylcarbamate (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 removal of most of the solvent by rotary evaporation, the resulting oil was partitioned between EtOAc (ca. 300 mL) and % (w/v) aq. ammonium chloride. The EtOAc layer was separated and then washed with water, 10% (w/v) aq. ammonium chloride (3 mL), and brine (10 mL). The EtOAc layer was washed with sat. aq. sodium bicarbonate, brine (6 mL) was added, and the emulsion was allowed to settle. The EtOAc layer was finally washed with brine and dried over sodium sulfate. Evaporation of the EtOAc layer’s volatile components afforded a viscous, amber taffy (62.3 g, 95%). This crude product was used without further purification.
LCMS (ESI) m/z: 395.4 [M+H] (100 %). 1H NMR (500 MHz, CDCI3) 6 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).
H OMe tert—buty/ 2—(6-(2,4-dimethoxyphenyl)oxothioxo-3, 4-dihydropyrimidin- 1 (2H)- y/carbamate (Trimethylsilyl)isothocyanate (66 mL, 470 mmol) was added to a solution of (Z)-ethy| 3- (2-(tert—butoxycarbonylamino)ethylamino)—3-(2,4-dimethoxyphenyl)acrylate (62.3 g, 158 mmol) in 2-MeTHF (160 mL). After heating at reflux under nitrogen for 15 h, the reaction mixture was cooled to ambient temperature and quenched by cautious addition of sat. aq. sodium bicarbonate (470 mL). The rxn. e was ted with romethane, and the aq. layer was twice more extracted with dichloromethane.
The combined organic layers were dried over sodium sulfate and evaporated to afford a -amber foam, which was purified by chromatography on silica eluting with 0-80% ethyl acetate in heptanes to afford 49.2 g of solid. These solids were re-suspended in 1:1 EtOAc/heptane at 70 °C for 1 h and then at r.t. for another 1 h. The resulting solids were isolated by vacuum tion, rinsing with additional 1:1 EtOAc/heptane, and pulled dry on the filter. The title nd was obtained as a white, microcrystalline solid (38.3 g, 59.5 % yield).
LCMS (ESI) m/z: 408.3 [M+H] (100 %). 1H NMR (500 MHz, CDCI3, major rotamer) 6 1.40 (s, 9 H), 3.23-3.45 (m, 2 H), 3.74 (dt, , 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 H OMe 1 inoethy/)(2, 4-dimethoxyphenyl)thioxo—2, 3—dihydropyrimidin-4(1H)-one hydrochloride To a solution of EtOH (50 mL, 860 mmol) in EtOAc (390 mL), cooled in an ice/water bath, was slowly added acetyl chloride (55 mL, 770 mmol) over 3 minutes. After 5 minutes the cooling bath was removed, and after stirring for 45 min, the solution was added to tert-butyl 2-(6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin- 1(2H)-y|)ethylcarbamate (31.7 g, 77.8 mmol). A suspension formed over time, and after stirring for 5 h, the solid was ted by vacuum filtration, rinsing with EtOAc. The solid was pulled dry and dried further under vacuum to afford 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) 6 3.06 (ddd, J=12.9, 7.8, 5.9 Hz, 1 H), 3.12 (ddd, J=12.9, 7.7, 6.4 Hz, 1 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 4.14 (ddd, J=14.0, 7.8, 5.9 Hz, 1 H), 4.82 (ddd, J=14.0, 7.7, 6.4 Hz, 1 H), 5.80 (s, 1 H), 6.70 (dd, J=8.3, 2.2 Hz, 1 H), 6.73 (d, J=2.2 Hz, 1 H), 7.27 (d, J=8.3 Hz, 1 H).
Example 7 IE OMe S N H OMe H2N /N 2-(2-(6-(2, 4-dimethoxypheny/)oxothioxo—3, 4-dihydropyrimidin- 1 (2H)-y/) guanidine Diisopropylethylamine (0.22 mL, 1.3 mmol) was added to a suspension of 1-(2- aminoethyl)(2,4-dimethoxyphenyl)—2-thioxo-2,3-dihydropyrimidin-4(1H)-one hydrochloride (181.6 mg, 0.528 mmol) (the product of Example 6) and 1H-pyrazole—1- carboxamidine hydrochloride (90.6 mg, 0.618 mmol) in DMF (0.55 mL). After heating for 1 h at 55 °C, the reaction mixture was cooled to ambient temperature, diluted with EtOH (1.6 mL), and the solid product collected by vacuum filtration, rinsing with additional EtOH. The isolated solid was re-suspended in EtOH (2.1 mL) for 3 h at r.t. before being collected again by vacuum filtration and rinsing with additional EtOH. The desired product was obtained, after drying, as a colorless solid. Solubility data for this product is consistent with it being in its zwitterionic form. 1H NMR (500 MHz, CD30D+2 drops 20. % DCI in D20) 6 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), .77 (m, 1 H), .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-dimethoxypheny/)oxothioxo—3, 4-dihydropyrimidin- 1 (2H)- y/)guanidine hloride The product from the above reaction (116.3 mg, 0.333 mmol) was suspended in dioxane and treated with a 4.0 M oxane solution (0.30 mL, 1.2 mmol). After thorough vortexing, the le components of the mixture were removed to afford a white solid (130.6 mg, 0.338 mmol). LCMS (ESI) m/z: 350.1 [M+H] (100 %).
Preparation 11 H OMe OFNH BocHN tert-buty/ 2-(2-(6—(2, thoxypheny/)oxothioxo-3, 4-dihydropyrimidin- 1 (2H)- y/)ethy/amino)oxoethy/carbamate To a solution of 1-(2-aminoethyl)(2,4-dimethoxyphenyl)—2-thioxo-2,3- dihydropyrimidin-4(1H)—one hydrochloride (123 mg, 0.4 the product of Example 6) in dry methylene chloride (4 mL) was added O-(7-azabenzotriazolyl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (182 mg, 0.48mmol) and tert- butoxycarbonylamino—acetic acid (70 mg, 0.4 mmol) and diisoproplyethylamine (336 mg, 1.6 mmol). After stirring overnight at RT the reaction mixture was concentrated under d re and the e purified by preparative thin layer chromatography (1 :1 petroleum ether : ethyl acetate) to provide tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)—4— oxothioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylamino)—2-oxoethylcarbamate (120 mg, 65%).
Example 8 HN OMe H OMe Oj,NH 2-amino-N-(2-(6—(2, 4-dimethoxyphenyl)oxothioxo-3, 4-dihydropyrimidin- 1 (2H)- y/)ethy/)acetamide hydrochloride To a solution of tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)oxothioxo-3,4- dihydropyrimidin-1(2H)-yl)ethylamino)oxoethylcarbamate (70 mg, 0.15 mmol) in ethyl e (2 mL) was added a solution of HCI in ethyl acetate (2 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure to afford the desired 2-amino-N-(2-(6-(2,4-dimethoxyphenyl)oxothioxo-3,4- dihydropyrimidin-1(2H)-yl)ethyl)acetamide hydrochloride as a solid (65 mg, 100%). ll. 6-lodo—Thiouracil Route Section Preparation 12 S O MeO\/\NJLN H H N-((2-Methoxyethyl)carbamothioyl)benzamide 2-Methoxyethylamine (17.7 mL, 202.2 mmol) was added dropwise over 30 minutes to a stirring solution of lisothiocyanate (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 solidified on standing to give the title compound (41.85 g, 96%). The al was used directly in the next step without further purification.
Preparation 13 SANH ethoxyethyl)thiourea A solution of N-((2-methoxyethyl)carbamothioyl)benzamide (41.82 g, 175.5 mmol), potassium carbonate (24.25 g, 175.5 mmol) in MeOH (200 mL) and water (200 mL) was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the aqueous layer was extracted with EtOAc (5 x 100 mL). The ed organic layers were dried over Na2804 and concentrated in vacuo. The ing yellow oil fied on standing to provide the title compound (21.38 g, 91%). The material was used directly in the next step without further purification.
MS (ES+) 135.1 (M+1)+.1H NMR (500 MHz, CDCI3) 5 6.66 (br. s., 1 H) 6.46 (br. s., 1 H) .81 (br. s., 1 H) 3.80 (br. s., 2 H) 3.48 - 3.65 (m, 2 H) 3.40 (s, 3 H).
WO 68875 Preparation 14 SAN I 1-(2-Methoxyethyl)—2—thioxo—2, 3-dihydropyrimidin-4(1H)-one To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3 mmol) and ethyl 3,3- diethoxypropanoate (46.5 mL, 239.0 mmol) in MeOH (300 mL) was added a freshly prepared solution of 0.96N sodium methoxide in MeOH (250 mL, 239.0 mmol) dropwise over 30 s at room temperature under argon. The reaction mixture was heated to 60 °C for 45 s and cooled to room temperature. Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue. The mixture was d at reflux for an additional 3 hours and then cooled to room temperature. Water (200 mL) was added and the layers were separated. The s 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 over Na2804 and concentrated in vacuo. The residue was recrystallized from i-PrOH (200 mL) to give the title compound (13.3 g, 45%) as a light yellow crystalline solid.
MS (ES+) 187.1 (M+1)+.1H NMR (400 MHz, CDCI3) 6 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 6-Iodo(2-methoxyethyl)thioxo-2, 3—dihydropyrimidin-4(1H)-one To a stirring solution of diisopropylamine (8.3 mL, 59.10 mmol) in THF (50 mL) was added n—butyl lithium (2N in hexanes, 30.0 mL, 60.0 mmol) dropwise at -78 °C under argon. The reaction mixture was slowly warmed to -20 oC and then cooled to -78 0C. A solution of 1-(2-methoxyethy|)thioxo-2,3-dihydropyrimidin-4(1H)-one (5.0 g, 26.85 mmol) in THF (50 mL) was added se at -78 °C. The reaction mixture was slowly warmed to -10 °C over 1 hour and then cooled to -78 °C. A solution of iodine (15.0 g, 59.07 mmol) in THF (50 mL) was added at -78 OC and the reaction mixture was stirred at room temperature for 20 hours. on was diluted with ted aqueous ammonium chloride (200 mL) and the organic solvents were removed under reduced pressure. The aqueous residue was acidified to pH 4 with 1N aqueous 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 e was stirred in CH2CI2 at room temperature and solids were collected by filtration to give the title compound (9.05 g, 54%) as a pale brown solid. The filtrate was concentrated and purified by flash chromatography (0-25% CH2CI2/EtOAc) to afford a second batch of the title compound (3.10 g, 18%) as a cream colored solid (72% combined yield).
MS (ES+)313.0 [M+1]+.1H NMR (400 MHz, CDCI3) 6 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).
P_p—rearation 16 MeS1:1 6—Iodo(2-methoxyethyl)(methylthio)pyrimidin-4(1H)-one To a stirring solution of 6-iodo(2-methoxyethyl)thioxo-2,3-dihydropyrimidin-4(1H)- one (9.00 g, 28.83 mmol) in MeCN (200 mL) was added diisopropylethylamine (5.0 mL, 28.83 mmol) and iodomethane (9.0 mL, 144.17 mmol). The reaction mixture was stirred at room temperature for 18 hours, and concentrated in vacuo. The residue was partitioned ed between CH2CI2 (200 mL) and 1N aqueous HCI (100 mL). The layers were separated and the organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The ing residue was purified by hot trituration with CH2CI2/heptane to give the title compound (4.05 g, 43%) as a cream colored solid.
MS(ES+) 327.0 . 1H NMR (500 MHz, 00013) 6 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).
”A. Suzuki Route Section Preparation 17 OMe OMe 6—(2, 5-dimethoxypheny/)- 1-(2-methoxyethyl)-2—(methy/thio)pyrimidin-4(1H)-one To a mixture of 6-iodo(2-methoxyethyl)(methylthio)pyrimidin-4(1H)—one (100 mg, 0.31 mmol), (2,5-dimethoxyphenyl)boronic acid (0.37 mmol, 1.2 equiv.) and [1,1’- bis(diphenylphosphino)ferrocene] dichloropalladium(|l) (14 mg, 0.017 mmol, 0.05 equiv) was added degassed 1,4-dioxane (2 mL), followed by a degassed solution of sodium ate (65 mg, 0.61 mmol) in water (0.7 mL). This reaction e was subjected to microwave ation at 120 0C for 30 minutes and the crude reaction mixture was used directly in the next step.
Example 9 HN OMe SAN I OMe OMe 6-(2, thoxypheny/)- 1-(2-methoxyethyl)-2—thioxo—2, 3-dihydropyrimidin-4(1H)-one um sulfide (1 mL, 14.63 mmol) and pyridine (1 mL, 12.41 mmol)were added to the crude reaction mixture obtained from the previous Suzuki coupling reaction (0.31 mmol theoretical yield), and the mixture was subjected to microwave irradiation at 75°C for 30 minutes. The reaction mixture was cooled to room temperature, taken up in CH2CI2 (10 mL) and water (10 mL), then basified with 2N NaOH. The layers were separated and the aqueous layer was washed with CH2CI2 (2 x 10 mL). The aqueous layer was then acidified to pH 6 with 2N aqueous HCI and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo.
The crude reaction mixture was purified by flash chromatography to give the desired product (38 mg, 38% over two steps) as solid.
MS (ES+) 323.1 [M+1]+.1H NMR (400 MHz, CDCI3)610.14(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, 4, 4.35 Hz, 1 H), 3.83-3.92 (m, 1 H), .82 (m, 8 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. Negishi Route Section Preparation 18 Al N Mes N S |\ / OMe 1-(2-MethoxyethyI)(methylthio)-6—(pyridin-2—yl)pyrimidin-4(1H)-one n-Butyl lithium (2.0 M, 0.32 mL, 0.64 mmol) was slowly added to 2-bromopyridine (0.058 mL, 0.61 mmol) in dry THF (2 mL) at -78 °C. After 30 minutes, anhydrous zinc chloride (92 mg, 0.67 mmol) was added and the reaction mixture was stirred for an additional 30 minutes as it warmed to room temperature. To the reaction mixture was added 6-iodo—1- (2-methoxyethyl)(methylthio)pyrimidin-4(1H)—one (200 mg, 0.61 mmol), followed by tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol), 2-dicyclohexylphosphino— 2',6'—dimethoxybiphenyl (26 mg, 0.06 mmol) and DMF (2 mL), and the on mixture was then heated to 80 °C. After stirring overnight, the product was extracted with EtOAc (3 x 10 mL) and washed with water (3 x 10 mL). The aqueous was then ied with 2M HCI to pH 4 and the product was ted with DCM (3 x 10 mL) and dried over MgSO4. The solvent was removed in vacuo to give an orange oil (100 mg) as a mixture of 1-(2-methoxyethyl)(methylthio)—6-(pyridinyl)pyrimidin-4(1H)—one (37%) and 1-(2- methoxyethyl)(methylthio)pyrimidin-4(1H)—one (32%).
Example 10 1 -(2-Methoxyethyl)-6—(pyridiny/)-2—thioxo—2, dropyrimidin-4(1H)-one A e of crude 1-(2-methoxyethyl)(methylthio)(pyridinyl)pyrimidin-4(1H)-one (100 mg, 0.36 mmol), ammonium sulfide solution (0.2 mL, 0.64 mmol) and pyridine (0.2 mL) was stirred in dioxane (2 mL) at 70 °C for 4 hours. The reaction mixture was d with water (10 mL), basified with 2M NaOH and washed with dichloromethane (3 X 10 mL). The aqueous layer was acidified to pH 6 with 2M HCI and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), brine (3 x 10 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by mass directed automatic purification using an acidic method to give the product as a brown solid (3 mg, 3%).
MS(ES+) 264.07 [M+H]+. 1H NMR (400 MHz, 00013) 5 8.76 (br s, 1H), 7.92 (br s, 1H), 7.48-7.54 (m, 2H), 7.32 (br d, 1H), 5.95 (br d, 1H), 4.65 (br s, 2H), 3.64 (br s, 2H).
The following Examples of Table 2 were ed from the corresponding carboxylic acid to afford the intermediate beta-keto-ester as described for the Preparations in the Carboxylic Acid Route Section above followed by employing other methods described above in the l. eto Ester Route Section as well as standard methods and techniques known to those d in the art.
Table 2. Examples from Carboxylic Acid Route Ex- 1H NMR Spectral Data or Com ound ample Napme HPLC Retention Time and # Conditions 1H NMR (400 MHz, DMSO-d6) 1-(2- 5 ppm 7.58 - 7.98 (m, 3 H), aminoethyl)—6- 7.54 (td, J=8.20, 1.80 Hz, 1 H), (2- 7.35 (dd, J=7.56, 1.60 Hz, 1 H), methoxyphenyl) 7.19 (d, J=8.24 Hz, 1 H), 7.08 thioxo-2,3- (t, J=7.44 Hz, 1 H), 5.77 (s, 1 dihydropyrimidin H), 4.60 (ddd, 1, 7.79, -4(1H)-one 6.41 Hz, 1 H), 3.82 - 3.87 (m, 1 hydrochloride H), 3.81 (s, 3 H), 2.76 - 2.91 (m, 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1-(2- 1H NMR (500 MHz, hydroxyethyl)—6- METHANOL-d4) 6 ppm 7.38 (d, J=8.54 Hz, 2 H) 7.05 (d, J=8.54 methoxyphenyl) Hz, 2 H) 5.77 (s, 1 H) 4.37 (t, thioxo-2,3- J=6.22 Hz, 2 H) 3.86 (s, 3 H) opyrimidin 3.74 (t, J=6.34 Hz, 2 H) -one 4-[3-(2- 1H NMR (400 MHz, methoxyethyl)— CHLOROFORM-d) 6 ppm 9.53 6-oxothioxo- (br. s, 1 H), 7.80 (d, J=8.70 Hz, 1,2,3,6- 288.1 2 H), 7.50 (d, J=8.70 Hz, 2 H), tetrahyd ropyrimi 5.80 (s, 1 H), 4.30 (br. s., 2 H), din 3.65 (t, J=5.04 Hz, 2 H), 3.21 y|]benzonitri|e (s, 3 H) 1H NMR (300 MHz, DMSO-d6) 1-(2- 6 ppm 12.82 (br. s., 1 H), 7.79 thyl)—6- (br. s., 3 H), 7.38 (s, 1 H), 7.24 ihydro (dd, J=8.01, 1.74 Hz, 1 H), 6.90 benzofu ran 290.0 (d, J=8.36 Hz, 1 H), 5.76 (d, y|)thioxo—2,3- J=2.09 Hz, 1 H), 4.61 (t, J=8.71 dihydropyrimidin Hz, 2 H), 4.34 (t, J=8.01 Hz, 2 -4(1H)-one H), 3.24 (t, J=8.71 Hz, 2 H), hydrochloride 2.89 - 3.02 m, 2 H 1H NMR (300 MHz, DMSO-d6) 6-(2,3-dihydro- 6 ppm 12.68 (br. s., 1 H), 7.34 1-benzofuran (s, 1 H), 7.20 (d, J=8.36 Hz, 1 y|)(2- H), 6.86 (d, J=8.36 Hz, 1 H), hydroxyethyl)—2- 291.0 5.70 (d, J=2.09 Hz, 1 H), 4.75 thioxo-2,3- (t, J=5.57 Hz, 1 H), 4.60 (t, dihydropyrimidin J=9.06 Hz, 2 H), 4.19 (t, J=6.62 -4(1H)—one Hz, 2 H), 3.53 (td, J=5.60 Hz, 2 , 3.23 t, J=8.71 Hz, 2 H 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.50 6-(2,3-dihydro— (br. s., 1 H), 7.33 (d, J=7.10 Hz, ofuran 1 H), 7.04 (d, J=7.56 Hz, 1 H), y|)(2- 6.95 (t, J=7.56 Hz, 1 H), 5.86 hydroxyethyl)—2- 291.1 (s, 1 H), 4.70 -4.81 (m, 1 H), thioxo-2,3- 4.64 (t, J=8.70 Hz, 2 H), 3.98 - dihydropyrimidin 4.10 (m, 1 H), 3.81 - 3.90 (m, 1 -4(1H)—one H), 3.65 - 3.78 (m, 2 H), 3.30 (t, J=8.70 Hz, 1 H), 1.86 (t, J=5.95 Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1H NMR (400 MHz, 6) 2-[6-(2- 6 ppm 12.78 (br. s., 1 H), 7.48 methoxyphenyl) (td, J=7.90, 1.60 Hz, 1 H), 7.26 oxothioxo- (br. s., 1 H), 7.08 - 7.17 (m, 2 3,4- H), 7.00 (t, J=7.44 Hz, 1 H), dihydropyrimidin 6.96 (br. s., 1 H), 5.76 (d, -1(2H)— J=2.06 Hz, 1 H), 5.22 - 5.48 (m, y|]acetamide 2 H , 3.80 s, 3 H 1H NMR (400 MHz, METHANOL-d4) 6 ppm 7.55 1-(3— (ddd, J=8.00, 8.00, 1.30 Hz, 1 aminopropyl)—6- H), 7.33 (dd, J=7.42, 1.37 Hz, 1 H), 7.17 (d, J=8.39 Hz, 1 H), yphenyl) 292 0 7.10 (dd, J=7.40, 7.40 Hz, 1 H), thioxo-2,3- .78 (s, 1 H), 4.58 (dt, 3, dihydropyrimidin 7.66 Hz, 1 H), 3.88 (s, 3 H), -4(1H)—one 3.72 - 3.83 (m, 1 H), 2.73 (t, hydrochloride J=7.81 Hz, 2 H), 1.94 - 2.07 (m, ,1.75- 1.88 m, 1 H 1-(2- aminoethyl)—6- 1H NMR (400 MHz, DMSO-d6): (2-methoxy 612.99(br, 1H), 8.27 (s, 1H), methylpyridin 292.9 7.81 (br, 3H), 7.74 (s, 1H), 5.96 y|)—2-thioxo—2,3- (s, 1H), 3.96-4.02 (m, 5H), 3.00 dihydropyrimidin (m, 2H), 2.38 (s, 3H). -4(1H)—one trifluoroacetate 1-(2- 1H NMR (400 MHz, methoxyethyl)— CHLOROFORM-d) 6 ppm 8.30 6—(3- (dd, J=4.81, 1.14 Hz, 1 H), 7.43 ypyridin- (dd, J=8.70, 4.58 Hz, 1 H), 7.35 294.0 2-y|)thioxo- (dd, , 1.37 Hz, 1 H), 5.92 2,3- (s, 1 H), 4.33 (br. s., 2 H), 3.88 dihydropyrimidin (s, 3 H), 3.55 (t, J=6.41 Hz, 2 -one H , 3.13 s, 3 H 1H NMR (400 MHz, DMSO-d6) 1-(2- 6 ppm 12.73 (br. s., 1 H), 7.62 hydroxyethyl)—6- (d, J=7.56 Hz, 1 H), 6.97 (d, (2-methoxy J=7.33 Hz, 1 1 21 H), 5.76 (s, H), methylpyridin 294.1 4.69 (t, J=5.38 Hz, 1 H), 4.43 - y|)—2-thioxo—2,3- 4.55 (m, 1 H), 3.86 (s, 3 H), dihydropyrimidin 3.44 - 3.60 (m, 3 H), 2.43 (s, 3 -4(1H)—one 1H NMR Spectral Data or HPLC Retention Time and Conditions 1H NMR (400 MHz, 1-(2— FORM-d) 5 ppm 7.33 yethyl)—6- (d, J=8.47 Hz, 1 H), 7.29 (d, (3-methoxy J=8.47 Hz, 1 H), 5.93 (s, 1 H), methylpyridin-Z- 4.18 - 4.35 (m, 2 H), 3.91 - 3.98 y|)—2—thioxo—2,3- (m, 2 H), 3.84 (s, 3 H), 2.54 (s, opyrimidin 3 H) -4(1H)—one 1H NMR (400 MHz, 1-(2— CHLOROFORM-d) 5 ppm 9.76 methoxyethyl)— (br. s, 1 H), 8.32 (dd, J=5.04, 6—(2— 1.83 Hz, 1 H), 7.56 (dd, J=7.33, methoxypyridin- 1.83 Hz, 1 H), 7.03 (dd, J=7.33, 3-y|)thioxo- 5.04 Hz, 1 H), 5.80 (s, 1 H), 2,3- 4.76 (dt, 4, 3.43 Hz, 1 opyrimidin H), 3.99 (s, 3 H), 3.69 - 3.86 (m, -4(1H)—one 2 H), 3.40 (dt, J=10.00, 4.20 Hz,1H,3.15 s,3H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.54 1-(2— (br. s, 1 H), 7.44 - 7.52 (m, 1 hydroxyethyl)—6- H), 7.30 (d, J=8.01 Hz, 1 H), 7.25 - 7.27 (m, 2 H), 5.85 (s, 1 (methylthio)phe H), 4.71 (dt, J=13.74, 5.38 Hz, nyl]—2-thioxo- 1 H), 3.88 (td, J=11.28, 5.38 2,3- Hz, 1 H), 3.80 (dt, J=13.74, dihydropyrimidin .95 Hz, 1 H), 3.70 (td, -4(1H)—one J=11.05, 5.15 Hz, 1 H), 2.49 (s, 3 H), 1.87 (t, J=5.72 Hz, 1 H) 1H NMR (400 MHz, DMSO-d6) 1-(2— ppm 12.89 (s, 1 H), 7.80 (br. aminoethyl)—6- s., 3 H), 7.44 (dd, J=8.39, 6.64 (4-fluoro-2— Hz, 1 H), 7.18 (dd, J=11.22, methoxyphenyl) 2.24 Hz, 1 H), 6.97 (ddd, thioxo-2,3- J=8.40, 8.40, 2.20 Hz, 1 H), dihydropyrimidin .82 (s, 1 H), 4.54 — 4.66 (m, 1 -4(1H)—one H), 3.86 (s, 3 H), 3.79 - 3.85 (m, hydrochloride 1H,2.88 br.s,2H 1H NMR (400 MHz, DMSO-d6) 1-(2— ppm 12.91 (s, 1 H), 7.88 (br. aminoethyl)—6- s., 3 H), 7.42 (td, J=8.78, 3.12 (5-fluoro-2— Hz, 1 H), 7.34 (dd, J=8.20, 3.12 methoxyphenyl) Hz, 1 H), 7.23 (dd, J=9.27, 4.20 thioxo-2,3- Hz, 1 H), 5.88 (d, J=1.95 Hz, 1 dihydropyrimidin H), 4.53 — 4.63 (m, 1 H), 3.85 - -4(1H)—one 3.93 (m, 1 H), 3.83 (s, 3 H), hydrochloride 2.85-2.99 m, 2 H Ex- 1H NMR Spectral Data or Compound ample HPLC ion Time and Name Conditions 1H NMR (400 MHz, 6-(4-fluoro METHANOL-d4) 5 ppm 7.33 methoxyphenyl) (dd, J=8.39, 6.44 Hz, 1 H), 6.95 _1_(2_ (dd, J=10.83, 2.24 Hz, 1 H), 27 hydroxyethyl)—2- 297.0 6.82 (ddd, J=8.40, 8.40, 2.30 —2,3- Hz, 1 H), 5.73 (s, 1 H), 4.57 - dihydropyrimidin 4.69 (m, 1 H), 3.87 (s, 3 H), -4(1H)—one 3.67 - 3.83 (m, 2 H), 3.55 - 3.62 1H NMR (500 MHz, DMSO-d6) 6-(5-fluoro 6 ppm 12.77 (br. s., 1 H), 7.37 yphenyl) (ddd, J=8.70, 8.70, 2.90 Hz, 1 -1 _(2_ H), 7.26 (dd, J=8.42, 3.05 Hz, 1 28 hydroxyethyl)—2- 297.3 H), d, J=9.03, 4.15 Hz,1 thioxo-2,3- H), 5.82 (d, J=1.71 Hz, 1 H), dihydropyrimidin 4.45 - 4.54 (m, 1 H), 3.82 (s, 3 -4(1H)—one H), 3.50 - 3.64 (m, 2 H), 3.40 - 3.47 m, 1 H 1H NMR (400 MHz, DMSO-d6) ppm 12.81 (br. s., 1 H), 11.49 2-[6-(1H-indoI (br. s, 1 H), 7.54 (d, J=8.31 Hz, y|)oxo 1 H), 7.49 (br. s., 1 H), 7.27 (br. thioxo-3,4- 29 301.0 s., 1 H), 7.17 (t, J=7.83 Hz, 1 dihydropyrimidin H), 6.99 (d, J=7.34 Hz, 1 H), -1(2H)- 6.96 (br. s., 1 H), 6.36 (br. s., 1 y|]acetamide H), 5.84 (s, 1 H), 5.16 - 5.34 (m, 1H,3.77-3.96 m, 1 H 1H NMR (300 MHz, METHANOL-d4) 5 ppm 7.60 (d, 1_(3_ J=8.36 Hz, 1 H), 7.43 (d, aminopropyl)—6- J—3.14 Hz,_ 1 _ H H), 7.28 (t, J—7.66 % I .. (1H-indoIy|)- NH Hz 1 H) 7.12(d J=6.97 Hz 1 2-thloxo-2,3-. 301.1 ’ ’ ’ ’ I H), 6.37 (d, J=2.09 Hz, 1 H), dihydropyrimidin .92 (s, 1 H), 4.49 - 4.63 (m, 1 _4(1H)_One H H), 3.94 -4.09 (m, 1 H), 2.63 (t, trifluoroacetate J=7.84 Hz, 2 H), 1.79 - 2.05 (m, 2 H) o benzzigllgp-r 1H NMR (300 MHz, H OL-d4) 5 ppm 7.88 (d, H), 7.80-7.84 (m, \ y|)_4_0x0_2_ 31 8% I J=2.09 Hz, 1 thioxo_3 4_ 3019 1 H), 7.34-7.38 (m, 2 H), 6.99 0V dihydropyri’midin (d, J=2.26 Hz, 1 H), 5.98 (s, 1 _1(2H)_ y|]acetamide Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name ions 1.36 min Waters Atlantis dC18 1-(3- 5um 4.6x50mm, aminopropyl)—6- 95%H20/5%MeCN linearto (1 H-indazoI 5%H20/95% MeCN over 4.0 y|)thioxo—2,3- min, HOLD at dihydropyrimidin 5%H20/95%MeCN to 5.0min. -4(1H)-one (0.05% TFA). Flow rate: 2 mL/min 1H NMR (400 MHz, 6-(1H-indoI METHANOL-d3) 6 ppm 7.63 (s, 1 H), 7.45 (t, J=8.01 Hz, 2 H), methoxyethyl)— 7.22 (t, J=7.79 Hz, 1 H), 7.16 (t, 2-thioxo-2,3- J=7.33 Hz, 1 H), 5.92 (s, 1 H), dihydropyrimidin 4.64 (br. s., 2 H), 3.60 (t, -4(1H)-one J=5.72 Hz, 2 H , 3.03 s, 3 H 1H NMR (400 MHz, 1-(3— METHANOL-d4) 6 ppm 7.91 (d, aminopropyl)—6- J=1.96 Hz, 1 H), 7.88 (dd, (1 furan- , 2.45 Hz, 1 H), 7.41 - 7-y|)thioxo- 7.46 (m, 2 H), 7.03 (d, J=1.96 2,3- Hz, 1 H), 5.98 (s, 1 H), 4.48 - dihydropyrimidin 4.60 (m, 1 H), 3.87 - 4.00 (m, 1 -4(1H)-one H), 2.67 (t, J=7.83 Hz, 2 H), hydrochloride 1.83- 1.98 m, 2 H 1-(2- 1H NMR (400 MHz, DMSO-d6) methoxyethyl)— 6 ppm 12.30 (br. s., 1 H), 8.30 6-(1H- (dd, J=4.81, 1.60 Hz, 1 H), 7.94 pyrro|o[2,3- (dd, J=8.01, 1.60 Hz, 1 H), 7.89 b]pyridinyl)—2- (s, 1 H), 7.17 (dd, J=7.79, 4.58 thioxo-2,3- Hz, 1 H), 5.87 (s, 1 H), 4.44 (br. dihydropyrimidin s., 2 H), 3.45 (t, J=5.95 Hz, 2 -one 1-(2- 1H NMR (400 MHz, D20) 5 aminoethyl)—6- ppm 7.92-7.94 (m, 1H), 7.82 (s, (1 -benzothien 1H), .48 (m, 1H), 7.39- y|)thioxo—2,3- 7.37 (m, 2H), 5.99 (s, 1H), 4.72- dihydropyrimidin 4.71 (m, 1H), 4.05-3.99 (m, -4(1H)-one h 1H), 3.01-2.94 (m, 2H) drochloride 2-[6-(2,3- 1H NMR (300 MHz, DMSO-d6) dihydro 6 ppm 12.74 (br. s., 1 H), 7.45 benzofu ran (br. s., 1 H), 7.29 (br. s, 1 H), y|)oxo 7.09 - 7.17 (m, 2 H), 6.85 (d, thioxo-3,4- J=8.36 Hz, 1 H), 5.75 (s, 1 H), dihydropyrimidin 4.59 (t, J=8.62 Hz, 1 H), 3.20 (t, -1(2H)— J=8.88 Hz, 2 H) | acetamide Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1H NMR (300 MHz, DMSO-d6) 1-(3- 6 ppm 12.74 (s, 1 H), 7.81 (br. aminopropyl)—6- s., 3 H), 7.37 (s, 1 H), 7.23 (dd, (2,3-dihydro J=8.36, 2.09 Hz, 1 H), 6.88 (d, benzofu ran J=8.36 Hz, 1 H), 5.76 (d, y|)thioxo—2,3- J=2.79 Hz, 1 H), 4.61 (t, J=8.71 dihydropyrimidin Hz, 2 H), 4.10 (t, J=6.97 Hz, 2 -4(1H)—one H), 3.25 (t, J=8.71 Hz, 2 H), hydrochloride 2.53 - 2.61 (m, 2 H), 1.79 - 1.93 1H NMR (400MHz, enzothien- METHANOL-d4) 7.97 (d, 1H), 3-y|)(2- 7.92 (s, 1H), 7.61 (dd, 1H), hydroxyethyl)—2- 39 7.46-7.45 (m, 2H), 5.92 (s, 1H), thioxo-2,3- 4.65-4.63 (m, 1H), 3.90-3.85 dihydropyrimidin (m, 1H), .80 (m, 1H), -4(1H)—one 3.62-3.61 m, 1H 1H NMR (400 MHz, DMSO-d6) 6-(1-benzothien- 6 ppm 12.82 (br. s., 1 H), 8.02 - 2-y|)(2- 8.06 (m, 1 H), 7.89 - 7.94 (m, 1 hydroxyethyl)—2- H), 7.74 (s, 1 H), 7.41 - 7.47 (m, thioxo-2,3- 2 H), 6.06 (d, J=2.29 Hz, 1 H), dihydropyrimidin 4.86 (t, J=6.18 Hz, 1 H), 4.31 (t, -4(1H)—one J=6.18 Hz, 2 H), 3.63 (td, J=6.40, 6.40 Hz, 2 H 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.89 6-(2,3-dihydro— (br. s., 1 H), 7.31 (d, J=7.33 Hz, 1-benzofuran 1 H), 7.03 (d, J=7.56 Hz, 1 H), y|)(2- 6.93 (t, J=7.56 Hz, 1 H), 5.84 4 methoxyethyl)— (s, 1 H), 4.68 -4.81 (m, 1 H), 2-thioxo-2,3- 4.63 (t, J=8.70 Hz, 2 H), 3.95 - dihydropyrimidin 4.05 (m, 1 H), 3.67 (br. s., 1 H), -4(1H)—one 3.48 (br. s, 1 H), 3.28 (t, J=8.70 3.14 s,3H 1H NMR (400 MHz, DMSO-d6) 6-(1,3- 6 ppm 12.91 (s, 1 H) 9.50 (s, 1 benzothiazoI H) 8.24 (d, J=7.34 Hz, 1 H) (2- 7.71 1 H) 42 (dd, J=7.83, 7.34 Hz, hydroxyethyl)—2- 7.65 (d, J=7.83 Hz, 1 H) 6.03 thioxo-2,3- (s, 1 H) 4.72 (t, J=5.62 Hz, 1 H) opyrimidin 4.22 - 4.31 (m, 1 H) 3.86 - 3.96 -4(1H)—one m, 1 H 3.43- 3.56 m, 2 H WO 68875 1H NMR Spectral Data or HPLC Retention Time and Conditions H NMR (500 MHz, DMSO-d6) 1-(3- 6 ppm 12.79 (s, 1 H), 7.92 (br. aminopropyl)—6- s., 3 H), 7.34 (dd, J=8.29, 1.22 (2-methoxy Hz, 1 H), 7.19 (d, J=1.46 Hz,1 methylpheny|)- H), 7.08 (d, J=8.54 Hz, 1 H), 2-thioxo-2,3- 5.78 (d, J=1.46 Hz, 1 H), 4.38 dihydropyrimidin (br. s., 1 H), 3.62 (br. s., 1 H), -4(1H)-one 3.34 (s, 3 H), 2.47 - 2.56 (m, 2 hydrochloride H), 2.30 (s, 3 H), 1.84 (s, 1 H), 1.69- 1.79 m, 1 H 2-[6-(2- methoxy 1H NMR (400 MHz, DMSO-d6): methylpyridin 612.82(br.s., 1H), 8.14 (s, 1H), y|)oxo 7.71 (s, 1H), 7.44 (s, 1H), 7.31 thioxo-3,4- (s, 1H), 7.02 (s, 1H), 5.88 (s, dihydropyrimidin 1H), 5.50 (br.s., 1H), 3.87 (s, -1(2H)- 4H), 2.20 (s, 3H). | acetamide 1-(3- 1H NMR (400 MHz, DMSO-d6): aminopropyl)—6- 6 12.82 (s, 1H), 8.20 (s, 1H), (2-methoxy 7.71 (s, 1H), 7.80 (br.s., 2H), methylpyridin .90 (s, 1H), 4.35-4.45 (m, 1H), thioxo—2,3- 3.97 (s, 3H), 3.58-3.85 (m, 1H), dihydropyrimidin 2.50-2.85 (m, 2H), 2.30 (s, 3H), -one 1.90-1.85 (m, 2H). trifluoroacetate 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.44 (br. s., 1 H), 7.44 - 7.52 (m, 1 OH 6-[2-(2- H), 7.41 (d, J=7.10 Hz, 1 H), hyd roxyethyl)ph 7.34 (dd, J=7.79, 8.87 Hz, 1 H), eny|](2- 7.23-7.25 (m, 1 H), 5.84 (s, 1 46 methoxyethy|)- 307.1 H), 4.48 (dt, 8, 5.07 Hz, 2-thioxo-2,3- 1 H), 3.81 - 3.99 (m, 3 H), 3.85 dihydropyrimidin (ddd, J=10.25, 8.93, 5.27 Hz, 1 -4(1H)-one H), 3.58 (dt, J=10.36, 5.24 Hz, 1 H), 3.18 (s, 3 H), 2.83 (dt, , 8.98 Hz, 1 H), 2.72 (dt, J=14.20, 7.00 Hz, 1 H) Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.57 6-(2,3-dihydro- (br. s, 1 H), 7.02 (dd, J=8.24, 1,4- 1.37 Hz, 1 H), 6.94 (dd, J=7.90, benzodioxin 7.90 Hz, 1 H), 6.80 (dd, J=7.56, y|)(2- 7 1.37 Hz, 1 H), 5.87 (s, 1 H), hydroxyethyl)—2- 4.73 (dt, 4, 5.52 Hz, 1 thioxo-2,3- H), 4.30 (s, 4 H), 3.97 (dt, opyrimidin J=14.31, 5.78 Hz, 1 H), 3.83 - -4(1H)—one 3.92 (m, 1 H), 3.67 - 3.78 (m, 1 1-(2- 3.442 min Column: XBRIDGE- aminoethyl)—6- C18 4.6X75mm 3.50m; Mobile (3,5- phase— A=0.1% TFA IN ACN, dimethoxypheny B=0.1% TFA IN WATER; |)thioxo-2,3- Time(min)/% B: 0/90, 0.8/90 , opyrimidin 1.8/55, 3/5, 6.5/5 ,7/90; Flow -4(1H)—one :0.8mL/min, Column h oride Temp=40°C; Diluent: CAN 1-(2- 1H NMR (400 MHz, methoxyethyl)— CHLOROFORM-d) 5 ppm 9.41 6-(3-methoxy—6- (br. s., 1 H), 7.25 - 7.27 (m, 2 9 methylpyridin H), 5.90 (s, 1 H), 4.22 - 4.38 (m, y|)—2-thioxo—2,3- 2 H), 3.84 (s, 3 H), 3.57 (t, dihydropyrimidin J=6.41 Hz, 2 H), 3.15 (s, 3 H), -4(1H)—one 2.53 (s, 3 H) 1H NMR (400 MHz, 1-(2- METHANOL-d3) 5 ppm 7.56 (d, methoxyethyl)— J=7.56 Hz, 1 H), 6.94 (d, 6-(2-methoxy—6- J=7.33 Hz, 1 1 50 H), 5.74 (s, H), methylpyridin 4.72 (dt, J=13.57, 3.86 Hz, 1 y|)—2-thioxo—2,3- H), 3.95 (s, 3 H), 3.67 - 3.83 (m, dihydropyrimidin 2 H), 3.35 - 3.43 (m, 1 H), 3.11 -4(1H)—one 1-(2- 1H NMR (400 MHz, methoxyethyl)— METHANOL-d3) 5ppm 8.11 (s, 6-(2-methoxy—5- 1 H), 7.56 (d, J=2.06 Hz, 1 H), 1 pyridin 5.76 (s, 1 H), 4.84 - 4.78 (m, 1 y|)—2-thioxo—2,3- H), 3.94 (s, 3 H), 3.88 - 3.82 (m, dihydropyrimidin 2 H), 3.35 - 3.44 (m, 1 H), 3.10 -4(1H)—one (s, 3 H), 2.30 (s, 3 H) 1H NMR Spectral Data or HPLC Retention Time and Conditions 6-[2-(2- 2.14 min Waters Atlantis dC18 aminoethoxy)ph 5um 4.6x50mm, eny|](2- /5%MeCN linearto hydroxyethyl)—2- 5%H20/95% MeCN over 4.0 thioxo-2,3- min, HOLD at dihydropyrimidin 5%H20/95%MeCN to 5.0min. -4(1H)-one (0.05% TFA). Flow rate: 2 formate mL/min 1H NMR (400 MHz, CD3OD) 6 3.09 (ddd, J=12.9, 7.6, 6.1 Hz, 1-(2- 1 H), 3.19 (ddd, J=12.9, 7.6, 6.5 aminoethyl)—6- Hz, 1 H), 3.81-3.91 (m, 2 H), [2-(2- 4.16 (ddd, J=10.6, 4.7, 3.5 Hz, hydroxyethoxy)p 1 H), 4.22 (ddd, J=10.8, 6.1, 3.9 —2-thioxo— Hz, 1 H), 4.26-4.37 (m, 1 H), 2,3- 4.60-4.74 (m, 1 H), 5.84 (s, 1 dihydropyrimidin H), 7.15 (td, J=7.5, 1.0 Hz, 1 -4(1H)-one H), 7.23 (dd, J=8.4, 0.6 Hz, 1 hloride H), 7.36 (dd, J=7.4, 1.6 Hz, 1 H), 7.57 (ddd, J=8.5, 7.5, 1.8 1H NMR (300 MHz, DMSO-d6) 6-(3,5- ppm 12.72 (br. s, 1 H), 6.67 oxypheny (d, J=2.26 Hz, 2 H), 6.62 (t, |)(2- J=2.30 Hz, 1 H), 5.76 (d, hydroxyethyl)—2- J=2.26 Hz, 1 H), 4.77 (t, J=5.57 thioxo-2,3- Hz, 1 H), 4.14 (t, J=6.45 Hz, 2 dihydropyrimidin H), 3.78 (s, 6 H), 3.57 (td, -4(1H)-one J=5.90 Hz, 2 H) 1H NMR (400 MHz, 1-(2- CHLOROFORM-d) 5 ppm 9.66 methoxyethyl)— (br. s, 1 H), 7.40 - 7.50 (m, 1 6-[2- H), 7.28 (d, J=8.01 Hz, 1 H), (methylthio)phe 7.24 (d, J=6.64 Hz, 2 H), 5.82 nyl]—2-thioxo- (s, 1 H), 4.59 -4.71 (m, 1 H), 2,3- 3.68 - 3.81 (m, 2 H), 3.41 - 3.51 dihydropyrimidin (m, 1 H), 3.15 (s, 3 H), 2.48 (s, -one 1H NMR (400 MHz, DMSO-d6) 2-[6-(4-fluoro ppm 12.78 (s, 1 H), 7.27 (br. methoxyphenyl) s., 1 H), 7.17 (dd, J=8.30, 6.93 oxothioxo- Hz, 1 H), 7.08 (dd, J=11.13, 3,4- 2.15 Hz, 1 H), 6.97 (br. s., 1 H), dihydropyrimidin 6.86 (td, J=8.44, 2.24 Hz, 1 H), -1(2H)— .78 (d, J=2.15 Hz, 1 H), 5.36 y|]acetamide br. s., 2 H , 3.28 s, 3 H Ex- 1H NMR Spectral Data or Com ound ample Napme HPLC Retention Time and Conditions 1H NMR (400 MHz, 1-(3- METHANOL-d4) 5ppm 7.36 ropyl)—6- (dd, J=8.39, 6.44 Hz, 1 H), 7.01 (4-fluoro (dd, J=10.83, 2.24 Hz, 1 H), methoxyphenyl) 6.85 (td, J=8.30, 2.34 Hz, 1 H), thioxo—2,3- 5.79 (s, 1 H), 4.51 - 4.63 (m, 1 dihydropyrimidin H), 3.89 (s, 3 H), 3.69 - 3.81 (m, -4(1H)—one 1 H), 2.76 (t, J=7.81 Hz, 2 H), hydrochloride 1.93 - 2.07 (m, 1 H), 1.74 - 1.88 1-(3- 1H NMR (400 MHz, aminopropyl)—6- METHANOL-d4) 6 ppm 7.31 (5-fluoro (td, , 3.12 Hz, 1 H), 7.14 yphenyl) - 7.23 (m, 2 H), 5.81 (s, 1 H), 58 310 0 thioxo—2,3- 4.51 - 4.64 (m, 1 H), 3.87 (s, 3 opyrimidin H), 3.73 - 3.83 (m, 1 H), 2.77 (t, -4(1H)-one J=7.71 Hz, 2 H), 1.95 - 2.09 (m, h drochloride 1.77 - 1.91 , m, 1 H 1H NMR (500 MHz, DMSO-d6) 2'[6'(5'fl”°r°'2' 2 5 ppm 3.35 (br. s., 2 H) 3.83 (s, methoxyphenyl) 3 H) 5.85 - 5.90 (m, 1 H) 7.03 _4_OXO_2_thiOXO_ (d, J=7.56 Hz, 1 H) 7.07 (br. s., 59 3 4_ 310 0 1 H) 7.19 (dd, J=9.15, 4.27 Hz, dihydropyrimidin 1 H) 7.33 (br. S., 1 H) 7.38 (td, -1(2H)- J=8.72, 3.05 Hz, 1 H) 12.85 (br. y|]acetamide 1H NMR (400 MHz, CHLOROFORM-d)5ppm miffofluofir?_ _ _ _ .08 (br. s., 1 H), 7.44 (ddd, _1_V(F2’_ yI) J=8.30, 8.30, 6.80 Hz, 1 H), 8.82 (t, J=8.47 Hz, 1 H), 8.77 methF’Xyethy')‘ 3“ 1 (d J=8.47 Hz 1 H) 5.88 (s 1 .Z'th'oxo'2’3'. H), 4.49 -4.65 (m, 1 H), 3.88 - d'hydroi’yr'm'd'“ 3.97 (m 1 H) 3.85 (s 3 H) '4(1H)'°“e 3.56 - 3.66 (m, 1 H), 3.45 - 3.54 (m, 1 H), 3.16 (s, 3 H) 1H NMR (300 MHz, DMSO-d6) 1_(2_ ppm 12.99 (br. s., 1 H), 7.74 @1315??? (br. s., 3 H), 7.55 (d, J=8.36 Hz, 1 H), 7.30 (d, J=2.09 Hz, 1 H), methox_2_thi03)’(%_2 33:hen I) 311.9 7.12 (dd, J=8.36, 2.09 Hz, 1 H), . . a . 5.91 (d, J=2.09 Hz, 1 H), 4.53- oi’yr'm'd'“ 4.71 (m 1 H) 3.85 (s 3 H) '4(1H)'°“.e 3.73 - 3.84 (m, 1 H), 2.92 - 3.08 hydrOCh'or'de m 1H 2.77-2.90 m 1H Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1-(2— 1H NMR (400 MHz, aminoethyl)—6- METHANOL-d3) 6 ppm 7.34 (d, (4-chloro-2— J=8.24 Hz, 1 H), 7.27 (d, methoxyphenyl) J=1.60 Hz, 1 H), 7.16 (dd, thioxo-2,3- J=8.13, 1.72 Hz, 1 H), 5.83 (s, dihydropyrimidin 1 H), 4.68 - 4.81 (m, 1 H), 4.01 -4(1H)—one - 4.12 (m, 1 H), 3.91 (s, 3 H), h drochloride 2.97 - 3.16 m, 2 H 1-(2— 1.67 min Waters Atlantis dC18 aminoethyl)—6- 5um 4.6x50mm, oro 95%H20/5%MeCN linearto methoxyphenyl) 5%H20/95% MeCN over 4.0 63 3122 thioxo-2,3- min, HOLD at dihydropyrimidin 5%H20/95%MeCN to 5.0min. -4(1H)—one (0.05% TFA). Flow rate: 2 h drochloride mL/min 1H NMR (500 MHz, DMSO-d6) 6 ppm 12.76 (br. s., 1 H) 7.57 6-(5-chloro (dd, J=8.78, 2.68 Hz, 1 H) 7.42 methoxyphenyl) (d, J=2.68 Hz, 1 H) 7.19 (d, -1 _(2_ J=9.03 Hz, 1 H) 5.83 (d, J=2.20 hydroxyethyl)—2- 313.2 Hz, 1 H) 5.18 (br. s., 1 H)4.44- thioxo-2,3- 4.52 (m, 1 H) 3.83 (s, 3 H) 3.56 opyrimidin - 3.62 (m, 1 H) 3.53 (dt, -4(1H)—one J=13.66, 6.83 Hz, 1 H) 3.42 (ddd, J=10.12, 6.46, 3.90 Hz, 1 6-(5-chloro 1H NMR (400 MHz, DMSO-d6) methoxypyridin- 6 ppm 12.80 (br. s., 1 H), 8.38 3-y|)(2- (d, J=2.75 Hz, 1 H), 7.89 (d, 65 hydroxyethyl)—2- 314.0 J=2.75 Hz, 1 H), 5.93 (d, -2,3- J=2.06 Hz, 1 H), 4.45 - 4.54 (m, dihydropyrimidin 1 H), 3.89 (s, 3 H), 3.55 - 3.65 -4(1H)—one (m, 1 H), 3.36 - 3.51 (m, 2 H) 1H NMR (400 MHz, CHLOROFORM-d) d ppm 9.90 1-(2— (br. s, 1 H), 7.67 (d, J=7.79 Hz, methoxyethyl)— 1 H), 7.31 - 7.42 (m, 2 H), 7.21 6-(1-methyI-1H- (dd, J=7.10, 7.10 Hz, 1 H), 6.65 2-y|) 316.0 (s, 1 H), 5.98 (s, 1 H), 4.71 (br. -2,3- s, 1 H), 4.34 (br. s, 1 H), 3.72 - dihydropyrimidin 3.84 (m, 1 H), 3.69 (s, 3 H), -4(1H)—one 3.43 - 3.58 (m, 1 H), 3.11 (s, 3 Ex- 1H NMR Spectral Data or ample HPLC Retention Time and Name ions 1H NMR (400 MHz, 1-(2- CHLOROFORM-d) 5 ppm 9.70 methoxyethyl)— (br. s., 1 H), 7.50 (d, J=7.79 Hz, 6-(1-methyI-1H- 1 H), 7.36 - 7.43 (m, 2 H), 7.33 indoIy|) (t, J=7.44 Hz, 1 H), 7.19 - 7.26 thioxo-2,3- (m, 1 H), 5.99 (s, 1 H), 4.61 (br. dihydropyrimidin s., 2 H), 3.88 (s, 3 H), 3.68 (t, -4(1H)—one J=5.50 Hz, 2 H , 3.18 s, 3 H 2-[6-(1- 1H NMR (400 MHz, benzothien METHANOL-d3) 5ppm 7.99 - y|)oxo 8.12 (m, 1 H), 7.92 (s, 1 H), thioxo-3,4- 7.77 (d, J=6.18 Hz, 1 H), 7.42 - dihydropyrimidin 7.57 (m, 2 H), 6.02 (s, 1 H), -1(2H)— 5.17 - 5.68 (m, 1 H), 3.77 - 4.25 | acetamide 2-[6-(1- 1H NMR (400 MHz, DMSO-d6) benzothien 6 ppm 12.63 (br. s, 1 H), 7.97 - y|)oxo 8.04 (m, 1 H), 7.86 - 7.93 (m, 1 thioxo-3,4- H), 7.61 (s, 1 H), 7.40 - 7.48 (m, dihydropyrimidin 2 H), 7.34 (br. s, 1 H), 6.97 (br. -1(2H)— s., 1 H), 6.03 - 6.11 (m, 1 H), I]acetamide 4.53 - 5.06 m, 2 H 1H NMR (400 MHz, oxy—4-[3- CHLOROFORM-d) 5 ppm 9.46 (2- (br. s, 1 H), 7.32 - 7.42 (m, 2 methoxyethyl)— H), 7.20 (s, 1 H), 5.75 (s, 1 H), 6-oxothioxo- 4.71 (dt, J=14.20, 3.43 Hz, 1 1,2,3,6- H), 3.90 (s, 3 H), 3.80 (td, yd ropyrimi J=9.79, 3.78 Hz, 1 H), 3.64 din (ddd, 0, 9.39, 4.35 Hz, 1 yl]benzonitrile H), 3.36 (ddd, J=10.30, 4.35, 3.21 Hz, 1 H , 3.14 s, 3 H 1H NMR (300 MHz, DMSO-d6) 1-(3- 6 ppm 12.90 (br. s., 1 H), 8.06 - aminopropyl)—6- 8.11 (m, 1 H), 7.95 - 8.01 (m, 1 (1-benzothien H), 7.80 (s, 1 H), 7.73 (br. s., 3 y|)—2-thioxo—2,3- H), 7.47 - 7.54 (m, 2 H), 6.16 (s, dihydropyrimidin 1 H), 4.22 - 4.33 (m, 2 H), 2.60 -4(1H)—one - 2.70 (m, 2 H), 1.94 - 2.06 (m, hydrochloride 1-(3- 1H NMR (400 MHz, DMSO-d6) aminopropyl)—6- 5 ppm 12.98 (s, 1 H), 9.54 (s, 1 (1 ,3- H), 8.29 (d, J=7.34 Hz, 1 H), benzothiazoI 7.72 (m, J=9.78 Hz, 2 H), 7.52 y|)—2-thioxo—2,3- (br. s., 3 H), 6.10 (d, J=1.96 Hz, dihydropyrimidin 1 H), 4.21 -4.31 (m, 1 H), 3.49 -4(1H)—one - 3.82 (m, 3 H), 1.68 - 1.87 (m, trifluoroacetate 1H NMR Spectral Data or Compound HPLC Retention Time and Name ions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.72 (br. s, 1 H), 7.94 (dd, J=8.01, 0.69 Hz, 1 H), 7.53 (d, J=5.50 6-(1-benzothien- Hz, 1 H), 7.49 (t, J=7.67 Hz, 1 7-y|)(2- H), 7.42 (d, J=5.50 Hz, 1 H), yethyl)— 7.33 (d, J=7.33 Hz, 1 H), 6.02 2-thioxo-2,3- (s, 1 H), 4.55 (dt, J=14.03, 4.89 dihydropyrimidin Hz, 1 H), 4.06 (dt, J=13.40, -4(1H)—one 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 , 3.07 s, 3 H 1H NMR (301 MHz, DMSO-d6) 6 ppm 12.85 (br. s., 1 H), 8.16 6-(1-benzothien- (t, J=4.48 Hz, 1 H), 7.90 (d, 4-y|)(2- J=5.51 Hz, 1 H), 7.47 (d, methoxyethyl)— J=4.36 Hz, 2 H), 7.37 (d, 2-thioxo-2,3- J=5.51 Hz, 1 H), 5.87 (s, 1 H), dihydropyrimidin 4.31 (ddd, J=13.31, 7.57, 5.74 -4(1H)—one Hz, 1 H), 3.84 (dt, J=13.37, 6.74 Hz, 1 H), 3.32 - 3.45 (m, 2 , 2.82 s, 3 H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.91 6-(1,3- (br. s., 1 H), 8.14 (d, J=8.01 Hz, benzothiazoI 1 H), 7.98 (d, J=7.79 Hz, 1 H), y|)(2- 7.61 (ddd,J=8.01,7.10, 1.15 methoxyethyl)— Hz, 1 H), 7.54 (ddd, J=7.80, 2-thioxo-2,3- 7.80, 0.90 Hz, 1 H), 6.27 (s, 1 dihydropyrimidin H), 5.04 (t, J=5.27 Hz, 2 H), -4(1H)—one 3.63 (t, J=5.27 Hz, 2 H), 3.09 1-(3- aminopropyl)—6- 1H NMR (300 MHz, DMSO-d6) (2,3-dihyd ro- 6 ppm 12.76 (br. s., 1 H), 7.71 1,4- (br. s., 3 H), 7.07 (s, 1 H), 6.93 - 76 ioxin 320.0 7.02 (m, 2 H), 5.77 (d, J=2.09 y|)thioxo—2,3- Hz, 1 H), 4.30 (s, 4 H), 4.03 - opyrimidin 4.18 (m, 2 H), 2.53 - 2.66 (m, 2 -4(1H)-one H), 1.76 - 1.93 (m, 2 H) hydrochloride 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (500 MHz, DMSO-d6) 6 ppm 12.85 (s, 1 H), 7.65 (br. 2-{2-[6-(2- t, J=6.10, 6.10 Hz, 1 H), 7.53 methoxyphenyl) (td, J=7.93, 1.46 Hz, 1 H), 7.32 oxothioxo- (dd, J=7.56, 1.46 Hz, 1 H), 7.17 3,4- (d, J=8.29 Hz, 1 H), 7.07 (t, dihydropyrimidin J=7.44 Hz, 2 H), 6.97 (br. s., 4 -1(2H)— H), 5.80 (d, J=2.20 Hz, 1 H), y|}guanidin 4.54 (br. d, J=13.70 Hz, 1 H), e hydrochloride 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 m, 1 H , 3.17-3.22 1H NMR (301 MHz, 6-(1,3- CHLOROFORM-d) 6 ppm 9.97 hiazol (br. s., 1 H), 9.10 (s, 1 H), 8.27 yl)(2- (d, J=8.26 Hz, 1 H), 7.66 (t, methoxyethyl)— J=7.80 Hz, 1 H), 7.44 (d, 2-thioxo—2,3- J=7.34 Hz, 1 H), 6.01 (s, 1 H), dihydropyrimidin 4.48 (dt, 0, 4.82 Hz, 1 -4(1H)-one H), 4.11 - 4.32 (m, 1 H), 3.45 - 3.69 m, 2 H , 3.06 s, 3 H 1H NMR (400 MHz, 1-(2- METHANOL-d4) 6ppm 7.57 (t, aminoethyl)—6- J=7.42 Hz, 1 H), 7.40 (d, [2-(3- J=6.83 Hz, 1 H), 7.22 (d, aminopropoxy)p J=8.59 Hz, 1 H), 7.15 (t, J=7.03 henyl]—2-thioxo— Hz, 1 H), 5.83 (s, 1 H), 4.90 - 2,3- .00 (m, 1 H), 4.26 -4.35 (m, 1 dihydropyrimidin H), 4.17 - 4.25 (m, 1 H), 4.02 - -4(1H)-one 4.13 (m, 1 H), 2.97 - 3.18 (m, 4 hydrochloride H , 2.08 -2.20 m, 2 H 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.79 -dihydro— (br. s., 1 H), 7.00 (dd, J=8.24, 1,4- 1.60 Hz, 1 H), 6.92 (t, J=7.90 benzodioxin Hz, 1 H), 6.79 (dd, J=7.56, 1.60 yl)(2- Hz, 1 H), 5.84 (s, 1 H), 4.70 (dt, 80 321.2 methoxyethyl)— 1, 4.84 Hz, 1 H), 4.29 (s, 2-thioxo—2,3- 4 H), 3.94 (dt, J=14.08, 6.93 dihydropyrimidin Hz, 1 H), 3.70 (ddd, J=10.19, -4(1H)-one 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) WO 68875 1H NMR Spectral Data or HPLC Retention Time and Name Conditions 1-(2- aminoethyl)—6- 1H NMR (400 MHz, DMSO-d6): (2,4-dimethoxy- 5 12.85 (s, 1 H), 7.80 (br.s., 3 - H), 7.11 (s, 1 H), 6.76 (s, 1 H), methylphenyl)— 5.75 (s, 1 H), 4.58-4.69 (m, 1 2-thioxo-2,3- H), 3.88-3.95 (m, 1H), 3.89 (s, 4 dihydropyrimidin H), 3.86 (s, 3 H), 2.82-2.95 (m, -4(1H)-one 2 H), 2.10 (s, 3 H): h drochloride 1-(3- 1H NMR (400 MHz, DMSO-d6) aminopropyl)—6- 6 ppm 12.76 (br. s., 1 H), 7.71 (3,4- (br. s., 3 H), 7.13 (d, J=1.96 Hz, dimethoxypheny 1 H), 7.05 (d, J=5.38 Hz, 2 H), |)thioxo-2,3- 5.81 (d, J=1.96 Hz, 1 H), 4.09 - dihydropyrimidin 4.20 (m, 2 H), 3.82 (s, 3 H), -4(1H)-one 3.80 (s, 3 H), 2.53 - 2.62 (m, 2 h drochloride ,1.79- 1.90 m, 2 H 2-[6-(3,4- 1H NMR (300 MHz, 6) oxypheny 6 ppm 12.75 (br. s., 1 H), 7.46 |)oxo (br. s., 1 H), 7.16 (br. s., 1 H), thioxo-3,4- 7.00 - 7.09 (m, 2 H), 6.91 - 6.99 dihydropyrimidin (m, 1 H), 5.81 (s, 1 H), 4.98 - -1(2H)- 5.44 (m, 1 H), 3.94 - 4.29 (m, 1 | acetamide 1-(2- aminoethyl)—6- 1H NMR (400 MHz, (2,5-dimethoxy- METHANOL-d4): 5 6.95 (s, 4- 1H), 6.81 (s, 1H), 5.75 (s, 1H), methylphenyl)— 4.58-4.47 (m, 1H), 4.11-4.20 2-thioxo-2,3- (m, 1H), 3.75 (s, 3H), 3.30 (s, dihydropyrimidin 3H), 2.95-3.08 (m, 2H), 2.18 (s, -4(1H)-one 3H). hydrochloride 1-(3- 3.567 min (Column: E- aminopropyl)—6- C18 4.6X75mm 3.5pm; Mobile (3,5- phase— A=0.1% TFA IN ACN, dimethoxypheny B=0.1% TFA IN WATER; |)thioxo-2,3- Time(min)/% B: 0/90, 0.8/90 , dihydropyrimidin 1.8/55, 3/5, 6.5/5 ,7/90 Flow -4(1H)-one :0.8mL/min, Column hydrochloride Temp=40°C; Diluent: CAN) 2-[6-(3,5- 1H NMR (300 MHz, 6) dimethoxypheny 6 ppm 12.79 (br. s., 1 H), 7.46 |)oxo (br. s., 1 H), 7.17 (br. s., 1 H), thioxo-3,4- 6.62 (d, J=1.74 Hz, 1 H), 6.60 dihydropyrimidin (s, 2 H), 5.83 (d, J=1.92 Hz, 1 -1(2H)- H), 5.17 (br. s, 1 H), 4.08 (br. s, | acetamide 1H NMR Spectral Data or HPLC Retention Time and Conditions 1-(3- 1H NMR (400 MHz, aminopropyl)—6- METHANOL-d4) 5 ppm 7.08 - (2,5- 7.12 (m, 2 H), 6.93 (s, 1 H), dimethoxypheny 5.79 (s, 1 - 4.62 (m, 1 322 1 H), 4.47 l)thioxo-2,3- H), 3.84 - 3.87 (m, 1 H), 3.83 (s, dihydropyrimidin 3 H), 3.78 (s, 3 H), 2.76 (t, -4(1H)-one J=7.71 Hz, 2 H), 1.95 - 2.09 (m, h drochloride ,1.78- 1.93 m, 1 H 1H NMR (500 MHz, CD30D) 6 1.81-1.92 (m, 1 H), 2.05 (dqd, 1-(3- J=13.4, 8.1, 5.6 Hz, 1 H), 2.76 aminopropyl)—6- (t, J=7.8 Hz, 2 H), 3.82-3.90 (m, [2-(2- 2 H), .02 (m, 1 H), 4.16 hydroxyethoxy)p (ddd, J=11.0, 4.6, 3.7 Hz, 1 H), —2-thioxo— 4.20 (ddd, J=10.7, 5.9, 4.1 Hz, 2,3- 1 H), 4.45-4.59 (m, 1 H), 5.82 dihydropyrimidin (s, 1 H), 7.13 (t, J=7.4 Hz, 1 H), -4(1H)-one 7.21 (d, J=8.5 Hz, 1 H), 7.35 hloride (dd, J=7.4, 1.6 Hz, 1 H), 7.55 ddd, J=8.4, 7.6, 1.3 Hz, 1 H 2.09 min Waters Atlantis dC18 5um 4.6x50mm, dimethoxypheny 95%H20/5%MeCN linearto |)oxo %H20/95% MeCN over 4.0 thioxo—3,4- min, HOLD at dihydropyrimidin 5%H20/95%MeCN to 5.0min. -1(2H)-yl]acetic (0.05% TFA). Flow rate: 2 acid mL/min 1-(2- 1H NMR (400 MHz, DMSO-d6): aminoethyl)—6- 12.88 (s, 1 H), 7.87 (br.s., 3 oro-2,4- H), 7.32 (d, 1 H), 6.97 (d, 1 H), dimethoxypheny .82 (s, 1 H), 4.55-4.66 (m, 1 l)thioxo-2,3- H), 3.95 (s, 3 H), 3.87 (s, 3 H), dihydropyrimidin 3.83-3.92 (m, 1H), 2.87-2.98 -one (m, 2 H). hydrochloride 1H NMR (400 MHz, DMSO-d6) 1-(3- 5 ppm 12.88 (s, 1 H), 7.88 (br. aminopropyl)—6- s, 3 H), 7.55 (d, J=8.80 Hz, 1 (2-chloro—4- H), 7.27 (d, J=2.45 Hz, 1 H), methoxyphenyl) 7.09 (dd, J=8.80, 2.45 Hz, 1 H), thioxo-2,3- 5.89 (d, J=1.96 Hz, 1 H), 4.38 - dihydropyrimidin 4.48 (m, 1 H), 3.85 (s, 3 H), -4(1H)-one 3.57 - 3.63 (m, 1 H), 2.53 - 2.64 hydrochloride (m, 2 H), 1.86 - 1.95 (m, 1 H), 1.87-1.78 m, 1 H 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions H NMR (500 MHz, 1-(3- METHANOL-d4) 6 ppm 7.57 aminopropyl)—6- (dd, J=9.03, 2.68 Hz, 1 H), 7.44 (5-Chloro (d, J=2.44 Hz, 1 H), 7.19 (d, methoxyphenyl) J=9.03 Hz, 1 H), 5.83 (s, 1 H), thioxo-2,3- 4.53 - 4.63 (m, 1 H), 3.91 (s, 3 dihydropyrimidin H), 3.75 - 3.84 (m, 1 H), 2.80 (t, -4(1H)—one J=7.81 Hz, 2 H), 1.98 - 2.08 (m, hydrochloride ,1.80- 1.90 m, 1 H 1-(3- 1H NMR (400 MHz, ropyl)—6- METHANOL-d4) 5 ppm 8.37 (d, (5-Chloro J=2.45 Hz, 1 H), 7.92 (d, methoxypyridin- J=2.45 Hz, 1 H), 5.90 (s, 1 H), 3-y|)thioxo- 4.52 - 4.52 (m, 1 H), 4.02 (s, 3 2,3- H), 3.74 - 3.85 (m, 1 H), 2.84 (t, dihydropyrimidin J=7.83 Hz, 2 H), 1.98 - 2.09 (m, -4(1H)—one 1 H), 1.81 - 1.94 (m, 1 H) h drochloride 1H NMR (400 MHz, METHANOL-d3) 5 ppm 7.51 6-(5-chloro (dd, J=8.93, 2.52 Hz, 1 H), 7.39 methoxyphenyl) (d, J=2.29 Hz, 1 H), 7.14 (d, -1 _(3_ J=8.93 Hz, 1 H), 5.77 (s, 1 H), hyd opyl)— 4.52 (ddd, J=13.91, 9.79, 4.59 2-thioxo-2,3- Hz, 1 H), 3.88 (s, 3 H), 3.78 dihydropyrimidin (ddd, J=14.43, 10.08, 5.27 Hz, -4(1H)—one 1 H), 3.35 (t, J=6.18 Hz, 2 H), 1.82- 1.95 (m, 1 H), 1.52- 1.75 (m, 1 H) 1H NMR (400 MHz, DMSO-d6) 1-(2— ppm 12.92 (d, J=1.83 Hz, 1 aminoethyl)—6- H), 7.97 (s, 1 H), 7.90 (t, J=7.33 (3-methoxy Hz, 2 H), 7.73 (br. s., 3 H), 7.53 naphthy|) - 7.59 (m, 2 H), 7.40 - 7.45 (m, thioxo-2,3- 1 H), 5.92 (d, J=2.29 Hz, 1 H), dihydropyrimidin 4.58 - 4.59 (m, 1 H), 3.92 (s, 3 —one H), 3.77 - 3.87 (m, 1 H), 2.79 - hydrochloride 2.99 m, 2 H 1H NMR (400 MHz, FORM-d) 5 ppm 9.79 6-(5-chloro (br. s., 1 H), 8.24 (d, J=2.52 Hz, ypyridin- 1 H), 7.54 (d, J=2.52 Hz, 1 H), 3-y|)(2- 5.78 (d, J=2.29 Hz, 1 H), 4.75 methoxyethyl)— (dt, J=14.37, 2.89 Hz, 1 H), 2-thioxo-2,3- 3.95 (s, 3 H), 3.85 (td, J=9.96, dihydropyrimidin 3.43 Hz, 1 H), 3.55 (ddd, -4(1H)—one J=14.20, 9.85, 3.89 Hz, 1 H), 3.35 (dt, J=10.36, 3.52 Hz, 1 Ex- 1H NMR Spectral Data or ample HPLC Retention Time and Name # Conditions 1-(2- thyl)—6- 1H NMR (400 MHz, DMSO-d6): (2- 6 12.92 (br.s., 1 H), 8.20 (s, 1 methoxyquinolin H), 7.83-7.65 (m, 6 H), 7.38 (t, 97 y|)thioxo- 328.8 1 H), 6.01 (s, 1 H), 4.52-4.61 2,3- (m, 1 H), 3.70-3.80 (m, 1H), dihydropyrimidin 3.68 (s, 3 H), 2.98-3.18 (m, 2 -4(1H)-one H). trifluoroacetate 1-(3- ngE/(gfi: 0.893 min Column: LCMS—Q Supelco 3x30 mm; Mobile 1 2 3-triazol yi)phenyl]-2 3_ phase: from 0% CH3CN 328 9 dihydropyrimidin ' (0.1%TFA) in water (0.1%TFA) to 60% CH3CN (0.1%TFA) in -4(1H)-one water (0.1%TFA) hydrochloride thigj::6)-)E2):(22_H- 1H NMR (400 MHz, DMSO-d6): 6 12.76 (s, 1H), 8.11 (s, 2H), 1,2,3-triazol 7.98 (d, 1H), 7.72 (t, 1H), 7.55 yl)phenyl]—3,4- 329.0 (t, 1H), 7.45 (d, 1H), 7.35 (s, dihydropyrimidin 1H), 7.04 (s, 1H), 5.68 (s, 1H), -1(2H)- .22 (d, 1H), 3.79 (d, 1H).: tamide 1H NMR (400 MHz, DMSO-d6) 6 ppm 12.80 (d, J=1.37 Hz, 1 0 1_(2_ H), 7.92 (s, 1 H), 7.88 (d, hydroxyethyl)—6- . « 3% 1 1251121411;= z, 100 . . . 0 Egg): 32‘“ , , , 7.49 (s, 1 H H), 7.41 (ddd, J=8.24, O dihydropyrimidin 6.87, 0.92 Hz, 1 H), 5.87 (d, OH J=2.29 Hz, 1 H), 4.68 (br. s., 1 -4(1H)—one H), 4.47 - 4.58 (m, 1 H), 3.91 (s, 3 H), 3.44 - 3.54 (m, 2 H) 1-(2- 1H NMR (300 MHz, DMSO-d6) O //_\\ methoxyethyl)— 6 ppm 12.77 (br. s., 1 H), 8.14 H N\N/N 2-thioxo[2- (s, 2 H), 8.05 (d, J=7.67 Hz, 1 101 3% I (2H-1,2,3- H), 7.77 (td, J=7.67, 2.09 Hz, 1 3301 triazol ' H H), 7.60 - 7.71 (m, 2 H), 5.79 (s, yl)phenyl]—2,3- 1 H), 4.32 - 4.44 (m, 1 H), 3.47 /o dihydropyrimidin - 3.62 (m, 1 H), 3.36 - 3.46 (m, -4(1H)—one 1 H), 2.99 (s, 3 H) 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm .25 - 10.39 (m, 1 H) 7.39 - 6-(2— 7.50 (m, 1 H)7.30 - 7.36 (m, 1 ethoxypheny|)- H) 7.00 - 7.07 (m, 1 H) 6.88 - 1- 6.99 (m, 1 H)5.81- 5.88 (m, 1 (tetrahyd rofu ran H) 4.68 - 4.77 (m, 1 H) 4.56 - y|methy|)—2- 4.65 (m, 1 H) 4.05 - 4.14 (m, 2 thioxo-2,3- H) 3.49 - 3.57 (m, 1 H) 3.34 - dihydropyrimidin 3.44 (m, 1 H)3.05 - 3.13 (m, 1 —one H) 1.90 - 2.01 (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 - 2-{3-[6-(2- 1.31 min Waters Atlantis dC18 yphenyl) 5um 4.6x50mm, thioxo- 95%H20/5%MeCN linearto 3,4- 5%H20/95% MeCN over 4.0 dihydropyrimidin min, HOLD at -1(2H)— 5%H20/95%MeCN to 5.0min. y|]propy|}guanidi (0.05% TFA). Flow rate: 2 ne mL/min 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm .15 (br. s., 1 H) 7.45 (ddd, J=8.29, 7.51, 1.76 Hz, 1 H) 6-(2— 7.24 (dd, J=7.51, 1.66 Hz, 1 H) ethoxypheny|)- 7.03 (ddd, J=7.41, 0.78 Hz, 1 1-(2- H) 6.94 (d, J=8.39 Hz, 1 H) isopropoxyethyl) 5.83 (d, J=2.34 Hz, 1 H) 4.69 thioxo-2,3- (ddd, J=13.46, 5.66, 4.10 Hz, 1 dihydropyrimidin H) 4.10 (q, J=6.89 Hz, 2 H) -4(1H)—one 3.68 - 3.85 (m, 2 H) 3.50 (ddd, , 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, , 1.76 Hz, 6 H 1-(3- aminopropyl)—6- 1H NMR (400 MHz, DMSO-d6): (2,4-dimethoxy- 5 12.76 (s, 1H), 7.68 (br.s., 3H), - 7.11 (s, 1H), 6.74 (s, 1H), 5.73 methylphenyl)— (s, 1H), 4.35-4.45 (m, 1H), 3.88 2-thioxo-2,3- (s, 3H), 3.85 (s, 3H), 3.59-3.68 dihydropyrimidin (m, 1H), 2.52-2.51 (m, 2H), -4(1H)—one 2.09 (s, 3H), 1.81-1.71 (m, 2H).: h drochloride Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1-(3- 1H NMR (400 MHz, aminopropyl)—6- METHANOL-d4): 6 6.91 (s, (2,5-dimethoxy- 4- 1H), 6.79 (s, 1H), 5.72 (s, 1H), 4.40-4.50 (m, 1H), 3.78-3.88 methylphenyl)- (m, 1H), 3.74 (s, 3H), 3.72 (s, 2-thioxo-2,3- 3H), 2.68 (t, 2H), 2.17 (s, 3H), dihydropyrimidin 1.89-1.94 (m, 1H), .88 -4(1H)-one h (m, 1H). drochloride 2-[6-(5-fluoro— 2,4- 1H NMR (400 MHz, DMSO-d6): oxypheny 67.11 (br.s., 1 H), 6.94 (d, 1 H), |)oxo 6.87 (d, 1 H), 6.83 (br.s., 1 H), 339 9 thioxo-3,4- 5.72 (br.s., 1 H), 5.41 (s, 1 H), dihydropyrimidin 3.91 (s, 3 H), 3.83 (s, 3 H), - 3.72-3.82 (m, 1 H). | acetamide 1-(3- aminopropyl)—6- 1H NMR (400 MHz, DMSO-d6): (5-fluoro-2,4- 6 7.36 (d, 1H), 6.95 (d, 1H), oxypheny 5.80 (s, 1H), 4.38-4.48 (m, 1H), 339 9 |)thioxo-2,3- 3.95 (s, 3H), 3.86 (s, 3H), 3.59- dihydropyrimidin 3.67 (m, 1H), 2.45-2.61 (m, -4(1H)-one 2H), 1.67-1.78 (m, 2H).: h drochloride 1H NMR (400 MHz, 1-(2- FORM-d) d ppm methoxyethyl)- .70 (br. s., 1 H), 8.08 (d, 6—[3- J=7.79 Hz, 1 H), 8.03 (s, 1 H), (methylsulfonyl) 341.0 7.72 (dd, J=7.80, 7.80 Hz, 1 H), phenyl]—2- 7.65 (d, J=7.33 Hz, 1 H), 5.87 thioxo-2,3- (s, 1 H), 4.30 (br. s., 2 H), 3.67 dihydropyrimidin (br. s., 2 H), 3.22 (s, 3 H), 3.12 -4(1H)-one (s, 3 H) 1-(2- 1H NMR (400 MHz, methoxyethyl)- CHLOROFORM-d) 6 ppm 8.08 6—[4- (d, J=8.24 Hz, 2 H), 7.59 (d, (methylsulfonyl) 341.1 J=8.24 Hz, 2 H), 5.81 (s, 1 H), phenyl]—2- 4.31 (br. s., 2 H), 3.66 (t, thioxo-2,3- J=5.04 Hz, 2 H), 3.21 (s, 3 H), dihydropyrimidin 3.14 (s, 3 H) -one 1H NMR Spectral Data or HPLC Retention Time and Name Conditions 1-(2— 1H NMR (400 MHz, DMSO-d6) aminoethyl)—6- ppm 12.87 (br. s, 1 H), 7.80 (5-Chloro-2,4- (br. s, 3 H), 7.48 (s, 1 H), 6.94 dimethoxypheny (s, 1 H), 5.84 (d, J=1.96 Hz, 1 |)thioxo-2,3- H), 4.55 - 4.65 (m, 1 H), 3.97 (s, dihydropyrimidin 3 H), 3.90 (s, 3 H), 3.71 - 3.80 -4(1H)—one 1 h (m, H), 2.86 - 2.99 (m, 2 H) drochloride 1H NMR (400 MHz, 2-[6-(3- OL-d3) 5 ppm 7.84 (d, methoxy J=8.24 Hz, 1 H), 7.81 (d, naphthyl)—4-oxo— J=7.79 Hz, 1 H), 7.79 (s, 1 H), 2-thioxo-3,4- 7.52 (ddd, J=8.24, 7.10, 1.14 dihydropyrimidin Hz, 1 H), 7.35 - 7.44 (m, 2 H), -1(2H)— 5.89 (s, 1 H), 5.42 - 5.70 (m, 1 y|]acetamide H), 4.05 - 4.28 (m, 1 H), 3.98 (s, 1H NMR (300 MHz, DMSO-d6) 1-[(2S)—3-amino- ppm 12.84 (s, 1 H), 7.89 (br. s, 3 H), 7.58 (dd, J=9.06, 2.79 hyd roxypropyl]— Hz, 1 H), 7.29 (d, J=2.79 Hz, 1 6-(5-chloro H), 7.18 (d, J=9.06 Hz, 1 H), yphenyl) .87 (d, J=2.09 Hz, 1 H), 5.74 thioxo-2,3- (d, J=5.57 Hz, 1 H), 4.55 - 4.85 dihydropyrimidin (m, 1 H), 4.21 -4.34 (m, 1 H), -4(1H)—one 3.83 (s, 3 H), 3.13 - 3.23 (m, 1 trifluoroacetate , 2.75-2.88 m, 2 H 1H NMR (300 MHz, DMSO-d6) 1-[(2R)—3- ppm 12.84 (s, 1 H), 7.89 (br. s, 3 H), 7.58 (dd, J=9.06, 2.79 hyd opyl]— Hz, 1 H), 7.29 (d, J=2.79 Hz, 1 6-(5-chloro H), 7.18 (d, J=9.06 Hz, 1 H), methoxyphenyl) .87 (d, J=2.09 Hz, 1 H), 5.74 thioxo-2,3- (d, J=5.57 Hz, 1 H), 4.55 - 4.85 dihydropyrimidin (m, 1 H), 4.21 -4.34 (m, 1 H), -4(1H)—one 3.83 (s, 3 H), 3.13 - 3.23 (m, 1 trifluoroacetate H), 2.75 - 2.88 (m, 2 H) 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.54 (br. s., 1 H), 8.11 -8.19 (m, 1 1-(2- H), 7.88 - 7.95 (m, 1 H), 7.71 methoxyethyl)— (d, J=8.47 Hz, 1 H), 7.61 (dd, 6-(1-methoxy—2- J=6.30, 3.09 Hz, 2 H), 7.28 (d, naphthyl)—2- J=8.47 Hz, 1 H), 5.98 (s, 1 H), thioxo-2,3- 4.87 - 4.81 (m, 1 H), 4.02 (ddd, dihydropyrimidin J=14.03, 8.30, 5.38 Hz, 1 H), -4(1H)—one 3.90 (s, 3 H), 3.88 - 3.78 (m, 1 H), 3.38 (dt, J=9.90, 4.78 Hz, 1 Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1.942 min (Column:AQU|TY 6-(5-chloro BEH C-18,2.1x50mm,1.7pm; methoxyphenyl) Mobile Phase:A—0.1%FA IN [(2R)—2,3- ACN, B-0.1%FA IN WATER; dihyd roxypropyl] T/%B(min):0/90, 0.7/90, 2/55, thioxo-2,3- 3/55, 3.8/5, 5.8/5, 6/90; dihydropyrimidin FIow:0.5mL/min, Diluent:CAN) -4(1H)—one 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.76 1-(2— (br. s., 1 H), 7.80 (t, J=8.36 Hz, methoxyethyl)— 2 H), 7.74 (s, 1 H), 7.55 (ddd, ethoxy—2- ,7.10, 1.03 Hz, 1 H), naphthyl)—2- 343 4 7.43 (ddd, J=8.07, 6.93, 1.03 thioxo-2,3- Hz, 1 H), 7.21 (s, 1 H), 5.90 (d, dihydropyrimidin J=2.06 Hz, 1 H), 4.67 - 4.77 (m, -4(1H)—one 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 1-(2— 1H NMR (400 MHz, methoxyethyl)— CHLOROFORM-d) 5 ppm 9.79 2-thioxo[2- (br. s., 1 H), 7.54 - 7.63 (m, 1 (trifluoromethox 347.1 H), 7.35 - 7.48 (m, 3 H), 5.86 (s, y)pheny|]—2,3- 1 H), 4.57 - 4.73 (m, 1 H), 3.71 dihydropyrimidin - 3.94 (m, 2 H), 3.38 - 3.49 (m, -one 6-(2- 1.37 min Waters XBridge C18 methoxy mm, 5um 95%H20/ methylphenyl)— 5%MeCN linear to 5%H20/ 4-oxo-2—thioxo- 95%MeCN over 4.0min, HOLD 3,4- 348.2 at 5%H20 / 95%MeCN to dihydropyrimidin .0min. Flow: -1(2H)- 2.0mL/min.NH4OH 0.03%. y|]propy|}guanidi Flow rate: 2 mL/min N-{2—[6-(2— methoxy methylphenyl)— 1H NMR (500 MHz, CD30D) d 2—thioxo- ppm 7.37 (d, 1 H), 7.22 (s, 1 H), 3,4- 7.06 (d, 1 H), 5.78 (s, 1 H), 4.81 349.2 dihydropyrimidin (m, 1 H), 3.88 (s, 3 H), 3.86 (br. -1(2H)- s., 0 H), 3.55 (m, 2 H), 3.45 (m, y|]ethy|}g|ycina 2 H), 2.36 (s, 3 H) mide h drochloride 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, DMSO-d6) 2-{2-[6-(2,5- 6 ppm 12.85 (s, 1 H), 7.61 (br. dimethoxypheny t, J=6.10, 6.10 Hz, 1 H), 7.07 - l)oxo 7.12 (m, 2 H), 6.98 (br. s., 3 H), thioxo—3,4- 6.93 (d, J=1.56 Hz, 1 H), 5.85 dihydropyrimidin (d, J=2.15 Hz, 1 H), 4.54 (br. d, -1(2H)— J=14.30 Hz, 1 H), 3.78 (s, 3 H), y|]ethy|}guanidin 3.76 (s, 3 H), 3.66 - 3.75 (m, 1 e hydrochloride H), 3.47 - 3.60 (m, 1 H), 3.15 - 6-(5-chloro 3.641 min Column: XBRIDGE- methoxyphenyl) C18 4.6X75mm 3.5pm; Mobile phase— A=0.1% FA IN ACN, pyrrolidin B=0.1% FA IN WATER; y|methyl] in)/% B: 0/90, 0.8/90 thioxo—2,3- , , 3/5, 6.5/5 ,7/90; Flow dihydropyrimidin :0.8mL/min, Column -4(1H)—one Temp=40°C; Diluent: CAN h oride 1H NMR (400 MHz, DMSO-d6) 6-(5-chloro 6 ppm 12.99 (br. s., 1 H), 9.08 methoxyphenyl) (br. s., 1 H), 8.14 - 8.52 (m, 1 [(28)- H), 7.61 - 7.67 (m, 1 H), 7.50 - pyrrolidin 7.58 (m, 1 H), 7.23 - 7.28 (m, 1 y|methyl] H), 5.92 - 6.00 (m, 1 H), 4.90 - thioxo—2,3- .04 (m, 1 H), 3.83 - 3.88 (m, 3 opyrimidin H), 3.63 - 3.77 (m, 1 H), 2.98 - -4(1H)—one 3.20 (m, 3 H), 1.76 - 1.89 (m, 2 hydrochloride H), 1.62 - 1.75 (m, 2 H) 1.23 min Waters Atlantis dC18 2-[4-oxo—2- 5um 4.6x50mm, thioxo—6-(2,4,5- 95%H20/5%MeCN linearto trimethoxypheny 5%H20/95% MeCN over 4.0 |)-3,4- min, HOLD at dihydropyrimidin %H20/95%MeCN to 5.0min. -1(2H)— (0.05% TFA). Flow rate: 2 y|]acetamide mL/min 1H NMR (500 MHz, 6) 1-(3- ppm 1.70 - 1.91 (m, 2 H) 2.53 aminopropyl)—2- - 2.50 (m, 2 H) 3.57 (s, 2 H) thioxo—6-(2,4,5- 3.69 (d, J=7.07 Hz, 1 H) 3.75 trimethoxypheny 352 1 (s, 3 H) 3.83 (s, 3 H) 3.87 (s, 3 |)-2,3- H) 4.42 (br. s., 1 H) 5.79 (d, dihydropyrimidin J=1.95 Hz, 1 H)6.82 (s, 1 H) -4(1H)—one 7.00 (s, 1 H) 7.86 (br. s., 2 H) hydrochloride 1H NMR al Data or HPLC Retention Time and Conditions 2-{3-[6-(5-fluoro- 1.22 min Waters XBridge C18 4.6x50mm, 5um; 95%H20/ yphenyl) %MeCN linear to 5%H20/ oxothioxo- 95%MeCN over 4.0min, HOLD 3,4- at 5%H20 / 95%MeCN to dihydropyrimidin .0min. Flow: -1(2H)— 2.0mL/min.NH4OH 0.03% y|]propy|}guanidi Flow rate: 2 mL/min 6-(5- fluoro methoxyphenyl) 1H NMR (500 MHz, CD30D) d oxothioxo- ppm 7.30 (td, 1 H), 7.25 (dd, 1 3,4- H), 7.16 (dd, 1 H), 5.81 (s, 1 H), dihydropyrimidin 4.79 (m, 1 H), 3.89 (s, 3 H), -1(2H)— 3.82 (m, 1 H), 3.54 (m, 2 H), y|]ethy|}g|ycina 3.45 (m, 2 H) mide h drochloride 1H NMR (500 MHz, DMSO-d6) 2-{2-[6-(5- ppm 12.88 (s, 1 H), 7.63 (br. chloro s., 1 H), 7.58 (dd, J=9.03, 2.68 methoxyphenyl) Hz, 1 H), 7.39- 7.41 (m, 1 H), oxothioxo- 7.20 (d, J=9.03 Hz, 1 H), 7.00 3,4- (br. s., 4 H), 5.91 (d, J=2.20 Hz, dihydropyrimidin 1 H), 4.54 (br. d, J=13.40 Hz, 1 -1(2H)— H), 3.84 (s, 3 H), 3.59 - 3.67 (m, y|]ethy|}guanidin 1 H), 3.55 (dt, J=9.33, 4.97 Hz, e hydrochloride 1 H), 3.17- 3.25 (m, 1 H) 1-(3- 1H NMR (400 MHz, DMSO-d6) aminopropyl)—6- 6 ppm 12.78 (s, 1 H), 7.75 (br. (5-Chloro-2,4- s., 3 H), 7.49 (s, 1 H), 6.92 (s, 1 dimethoxypheny H), 5.83 (d, J=2.45 Hz, 1 H), |)thioxo-2,3- 4.32 - 4.45 (m, 1 H), 3.97 (s, 3 dihydropyrimidin H), 3.90 (s, 3 H), 3.59 - 3.70 (m, -4(1H)—one 1 H), 2.53 - 2.65 (m, 2 H), 1.66 hydrochloride - 1.88 (m, 2 H) 1-(2-{4-oxo thioxo[2-(2H- 1H NMR (400 MHz, 1,2,3-triazoI METHANOL-d4): 5 8.12 (d, y|)pheny|]—3,4- 1H), 7.91 (s, 2H), 7.75 (t, 1H), opyrimidin 7.55-7.59 (m, 2H), 5.74 (s, 1H), -1(2H)— 4.40 (m, 1H), 3.75 (m, 1H), 3.55 y|}ethy|)guanidin (m, 1H), 3.35 (m, 1H). e h drochloride Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 2-{3-[6-(2,5- 2.44 min Waters Atlantis dC18 dimethoxypheny 5um 4.6x50mm, |)oxo 95%H20/5%MeCN linearto thioxo-3,4- %H20/95% MeCN over 4.0 dihydropyrimidin min, HOLD at -1(2H)— 5%H20/95%MeCN to 5.0min. y|]propy|}guanidi (0.05% TFA). Flow rate: 2 mL/min trifluoroacetate 6-(5-chloro 3.639 min Column: XBRIDGE- methoxyphenyl) C18 4.6X75mm 3.5um Mobile (piperidin phase— A=0.1% FA IN ACN, ylmethyl) B=0.1% FA IN WATER 366 0 thioxo-2,3- Time(min)/% B: 0/90, 0.8/90 , dihydropyrimidin , 3/5, 6.5/5 ,7/90 Flow -4(1H)—one :0.8mL/min, Column h drochloride Temo=40°C; Diluent: MEOH 2-{3-[6-(5- 1.38 min Waters XBridge C18 4.6x50mm, 5um 95%H20/ methoxyphenyl) 5%MeCN linear to 5%H20/ oxothioxo- 95%MeCN over 4.0min, HOLD 3,4- 368 1 at 5%H20 / 95%MeCN to dihydropyrimidin .0min. Flow: 2.0mL/min.NH4OH 0.03% py|}guanidi Flow rate: 2 mL/min 1H NMR (400 MHz, DMSO-d6) N-{3-[6-(5- d ppm 12.73 (s, 1 H), 7.62 (t, chloro J=6.0 Hz, 1 H), 7.58 (dd, J=9.0, methoxyphenyl) 2.7 Hz, 1 H), 7.50 (d, J=2.7 Hz, oxothioxo- 1 H), 7.21 (s, 0 H), 5.83 (d, 3,4- 368.1 J=2.1 Hz, 1 H), 4.12 - 4.27 (m, dihydropyrimidin 1 H), 3.85 (s, 3 H), 3.58 - 3.70 -1(2H)— (m, 1 H), 2.78 (q, J=6.2 Hz, 2 y|]propy|}acetam H), 1.85 - 1.75 (m, 0 H), 1.81 (s, 3 H), 1.48 - 1.58 (m, 1 H) N-{2-[6-(5- chloro yphenyl) 1H NMR (400 MHz, 00300) d oxothioxo- ppm 7.54 (dd, 1 H), 7.48 (d, 1 3,4- H), 7.17 (d, 1 H), 5.81 (s, 1 H), 369.2 dihydropyrimidin 4.78 (m, 1 H), 3.91 (s, 3 H), -1(2H)— 3.80 (m, 1 H), 3.55 (m, 2 H), y|]ethyl}glycina 3.48 (t, 2 H) mide h drochloride Ex- 1H NMR Spectral Data or am#ple HPLC Retention Time and Name Conditions 1-cyano—3-{2-[6- (2,4- 1H NMR (400 MHz, DMSO-d6): dimethoxypheny 5 7.17 (d, 1 H), 6.70-6.88 (br, 1 |)oxo H), 6.55-6.65 (m, 4 H), 5.69 (s, thioxo-3,4- 1 H), 4.43-4.45 (m, 1 H), 3.88 dihydropyrimidin (s, 3 H), 3.84 (s, 3 H), 3.59-3.68 -1(2H)- (m, 1 H), 3.30-3.40 (m, 1H), y|]ethy|}guanidin 3.16-3.17 (m, 1 H). tert-butyl [6- 2.59 min Waters XBridge C18 (2,4- 4.6x50mm, 5um 95%H20/ dimethoxypheny 5%MeCN linear to 5%H20/ xo 95%MeCN over 4.0min, HOLD 379 1 thioxo-3,4- at 5%H20 / N to dihydropyrimidin 5.0min. Flow: -1(2H)- 2.0mL/min.NH4OH 0.03% Flow rate: 2 mL/min 1H NMR (500 MHz, DMSO-d6) 6 ppm 12.80 (d, J=1.71 Hz, 1 2-{2-[4-oxo H), 7.59 (t, J=6.10 Hz, 1 H), thioxo—6-(2,4,5- 6.98 (br. s., 4 H), 6.89 (s, 1 H), trimethoxypheny 6.80 (s, 1 H), 5.81 (d, J=2.20 380 1 Hz, 1 H), 4.54 (br. d, J=14.15 dihydropyrimidin Hz, 1 H), 3.86 (s, 3 H), 3.82 (s, -1(2H)- 3 H), 3.77 - 3.81 (m, 1 H), 3.75 y|]ethy|}guanidin (s, 3 H), 3.53 (ddt, J=14.45, e hydrochloride 8.72, 5.49, 5.49 Hz, 1 H), 3.15 - 3.25 m, 1 H 1H NMR (400 MHz, ethyl CHLOROFORM-d) 6 ppm 9.60 thioxo—6-(2,4,5- (br. s., 1 H), 6.71 (s, 1 H), 6.52 trimethoxypheny (s, 1 H), 5.86 (s, 1 H), 5.39 (br. - 381 1 d, J=17.40 Hz, 1 H), 4.24 (br. d, dihydropyrimidin J=17.80 Hz, 1 H), 4.02 - 4.18 -1(2H)- (m, 2 H), 3.93 (s, 3 H), 3.81 (s, y|]acetate 3 H), 3.79 (s, 3 H), 1.18 (t, J=7.13 Hz, 3 H) 1-(2-{2-[6-(2,4- 1H NMR (400 MHz, dimethoxypheny METHANOL-d4): 5 8.38 (br.s., |)oxo 1H), 7.21 (d, 1H), 6.66-6.62 (m, thioxo-3,4- 2H), 5.73 (s, 1H), 4.82-4.76 (m, dihydropyrimidin 393.8 1H), 3.93-3.81 (m, 7H), 3.77- -1(2H)- 3.71 (m, 1H), 3.57-3.51 (m, y|]ethoxy}ethy|)g 1H), 3.44-3.40 (m, 2H), 3.27- uanidine 3.22 (m, 2H). formate Ex- 1H NMR Spectral Data or Compound am#ple HPLC ion Time and Name Conditions 2-{3-[4-oxo 1.60 min Waters Atlantis dC18 thioxo—6-(2,4,5- 5um 4.6x50mm, trimethoxypheny 95%H20/5%MeCN linearto |)-3,4- 5%H20/95% MeCN over 4.0 dihydropyrimidin min, HOLD at - 5%H20/95%MeCN to 5.0min. y|]propy|}guanidi (0.05% TFA). Flow rate: 2 mL/min trifluoroacetate 1H NMR (300 MHz, METHANOL-d4) 5 ppm 11.13 1-(2— (br. s., 1 H), 7.62 (d, J=8.01 Hz, aminoethyl)—6- 1 H), 7.44 (d, J=3.14 Hz, 1 H), (1 H-indoIy|)- 7.29 (t, J=7.66 Hz, 1 H), 7.13 2-thioxo-2,3- (d, J=7.32 Hz, 1 H), 6.40 (d, dihydropyrimidin J=2.44 Hz, 1 H), 5.93 (s, 1 H), -4(1H)-one 4.70 - 4.81 (m, 1 H), 4.32 (dt, trifluoroacetate J=14.28, 7.14 Hz, 1 H), 2.91 - 3.11 m, 2 H 1H NMR (400 MHz, DMSO-d6) 1-(2— . 5 ppm 13.01 (br. s, 1 H), 8.13 aflgflflga: (d, J=1.96 Hz, 1 H), 7.90 (dd, J=7.34, 1.96 Hz, 1 H), 7.67 (br. 7-y|)thioxo- s, 3 H), 7.42 - 7.49 (m, 2 H), 2 3_ opyrimidin 7.14 (d, J=2.45 Hz, 1 H), 6.04 (s, 1 H), 4.57 - 4.73 (m, 1 H), -4(1H)—one 3.85 - 4.02 (m, 1 H), 3.03 - 3.09 hloride m, 1 H ,2.83-2.91 m, 1 H 1-(2— //—\\ aminoethyl)—2- 1H NMR (400 MHz, H ”\N/N thioxo—6-[2-(2H- 297.9 METHANOL-d4): 5 8.11 (d, 144 A I 1,2,3-triazoI [M- 1H), 7.90 (s, 2H), 7.74 (t, 1H), 8 NH3+ 7.60 (d, 2H), 5.62 (s, H y|)pheny|]-2,3- 1H), 4.67 dihydropyrimidin 1]+ (m, 1H), 4.10 (m, 1H), 3.28 (m, NH, -4(1H)—one 1H), 3.05 (s, 1H).: hydrochloride 2-[6-(5-chloro O methoxypyridin- 1H NMR (400 MHz, H 0/ 3-y|)oxo A l METHANOL-d4) 5 ppm 8.31 (s, -3 4_’ 325 0 145 ' s \N 1 H), 7.72 (s, 1 H), 5.88 (s, 1 OE) |/ d'hydmpyr'm'd'“ [M'H]' H), 5.56-5.72 (m,1H), 4.06- -1(2H)- 4'21 (m, 1 H), 3-95 (S, 3 H) NH Cl y|]acetamide Ex- 1H NMR al Data or Com ound ample Napme HPLC Retention Time and # Conditions 2-[6-(2,4- 1H NMR (400 MHz, DMSO-d6): dimethoxy—5- 512.55(br, 1 H), 7.31 (s, 1 H), methylphenyl)— 7.02 (s, 1 H), 6.92 (s, 1 H), 6.72 4-oxo-2—thioxo- (s, 1 H), 5.72 (s, 1 H), 5.35 3,4- (br.s., 1 H), 3.93 (br.s., 1 H), dihydropyrimidin 3.88 (s, 3 H), 3.85 (s, 3 H), 2.05 -1(2H)— (s, 3 H).
I]acetamide 2-[6-(2,5- dimethoxy—4- 1H NMR (400 MHz, methylphenyl)— METHANOL-d4): 6 6.86 (s, 2—thioxo- 1H), 6.69 (s, 1H), 5.72 (s, 1H), 3,4- 4.57 (m, 1H), 4.10 (m, 1H), 3.74 dihydropyrimidin (s, 3H), 3.68 (s, 3H), 2.16 (s, -1(2H)— 3H). | acetamide 1H NMR (500 MHz, DMSO-d6) 1-{3—[6-(5- d ppm 12.72 (br. s, 1 H), 7.57 chloro (dd, J=9.0, 2.7 Hz, 1 H), 7.52 methoxyphenyl) (d, J=2.7 Hz, 1 H), 7.19 (d, oxothioxo- J=9.0 Hz, 1 H), 5.84 (s, 1 H), 3,4- 5.75 (m, 1 H), 5.26 (s, 2 H), dihydropyrimidin 4.26 (m, 1 H), 3.84 (s, 3 H), -1(2H)— 3.61 (m, J=10.0 Hz, 1 H), 2.72 pyl}urea (m, 2 H), 1.65 (m, 1 H), 1.49 dd, J=11.6, 5.7 Hz, 1 H 1H NMR (500 MHz, DMSO-d6) N-{3-[6-(5- d ppm 8.29 (t, J=5.6 Hz, 1 H), chloro 7.87 - 8.16 (m, 2 H), 7.60 (dd, methoxyphenyl) J=9.0, 2.7 Hz, 1 H), 7.53 (d, oxothioxo- J=2.7 Hz, 1 H), 7.23 (d, J=9.0 3,4- Hz, 1 H), 5.87 (s, 1 H), 4.17 - dihydropyrimidin 4.32 (m, 1 H), 3.84 (s, 3 H), -1(2H)— 3.56 - 3.73 (m, 1 H), 3.34 - 3.42 yl]propyl}glycina (m, 2 H), 2.80 - 3.00 (m, 2 H), mide 1.74 (d, J=6.6 Hz, 1 H), 1.55 - hydrochloride 1.64 (m, 1 H) 1-(2— hydroxyethyl)—6- 1H NMR (400 MHz, CD30D) d hoxy ppm 8.14 (m, 1 H), 7.59 (d, 1 methylpyridin H), 5.78 (d, 1 H), 4.71 (m, 1 H), yl)—2-thioxo—2,3- 3.96 (d, 3 H), 3.85 (dt, 1 H), dihydropyrimidin 3.70 (dt, 1 H), 3.59 (m, 1 H), -4(1H)—one 2.32 (s, 3 H) The following Examples of Table 3 were prepared from the corresponding methyl ketone to afford the intermediate beta-keto-ester as described above for the Preparations in the Methyl Ketone Route section followed by ing other methods bed in the |. Beta Ketone Ester Route Section as well as standard methods and techniques known to those skilled in the art.
Table 3. es from Methyl Ketone Route - 1H NMR Spectral Data or Com ound HPLC Retention Time and # Conditions 6-(2,4- 3.653 min Column: XBRIDGE- dimethoxypheny C18 4.6X75mm 3.5um Mobile |)[(3R)- phase- A=0.1% FA IN ACN, din B=0.1% FA IN WATER ylmethyl]—2- Time(min)/% B: 0/90, 0.8/90 -2,3- , 1.8/55, 3/5, 6.5/5 ,7/90 Flow dihydropyrimidin :0.8mL/min, Column -4(1 H)-one Temp=40°C; Diluent: CAN h drochloride 1HNMR (400 MHz, 6-(2,4- METHANOL-d4): 5 7.26 (d, dimethoxypheny 1H), 6.70 (d, 1H), 6.67 (dd, 1H), l)(2-piperidin- .76 (s, 1H), .67 (m, 1H), 4-ylethyl) 3.88 (s, 3H), 3.8 (s, 3H), 3.72- thioxo-2,3- 3.80 (m, 1H), 3.22-3.25 (m, dihydropyrimidin 2H), 2.82-2.89 (t, 2H), 1.63- -4(1 H)-one 1.75 (m, 3H), 1.341.48 (m, 2H), hydrochloride 1.08-1.29 (m, 2H). 1HNMR (400 MHz, 1-[2-(1- METHANOL-d4): 5 7.25 (d, acetylpiperidin- 1H), 6.71 (d, 1H), 6.68 (dd, 1H), 4-yl)ethyl]—6- 5.75 (s, 1H), 4.52-4.65 (m, 1H), (2,4- 4.27-4.35 (m, 1H), 3.88 (s, 6H), dimethoxypheny 3.70-3.80 (m, 2H), 2.92-3.03 l)thioxo-2,3- (m, 1H), 2.49-2.56 (m, 1H), dihydropyrimidin 2.05 (s, 3H), 1.71-1.74 (m, 1H), -4(1H)-one 1.33-1.57 (m, 4H), 0.68-1.10 (m, 2H). 1H NMR (400 MHz, 6-(1H-imidazol- METHANOL-d3) 5 ppm 7.26 2-y|)(2- (br. s., 2 H), 6.04 (s, 1 H), 4.84 methoxyethyl)- (br. s., 2 H), 3.63 (t, J=5.27 Hz, 2-thioxo—2,3- 2 H), 3.13 (s, 3 H) dihydropyrimidin -4(1H)-one 1H NMR Spectral Data or Compound HPLC Retention Time and Name ions 1H NMR (400 MHz, 1-(2- METHANOL-d3) 6 ppm 7.43 hyd roxyethyl)—6- (dd, J=7.80, 7.80 Hz, 1 H), 7.08 (3- (ddd, J=8.47, 2.52, 0.92 Hz, 1 methoxyphenyl) H), 7.04 (dd, J=2.29, 2.29 Hz, 1 thioxo-2,3- H), 7.00 (ddd, J=7.80, 2.30, dihydropyrimidin 0.92 Hz, 1 H), 5.79 (s, 1 H), -4(1H)-one 4.26 - 4.39 (m, 2 H), 3.84 (s, 3 , 3.77 t, J=6.18 Hz, 2 H 1H NMR (400 MHz, 1-(2- FORM-d) 6 ppm 7.51 hyd roxyethyl)—6- (ddd, J=8.24, 7.30, 1.80 Hz, 1 (2- H), 7.25 (dd, J=7.56, 1.60 Hz, 1 methoxyphenyl) H), 7.08 (ddd, J=7.60, 7.60, thioxo-2,3- 0.90 Hz, 1 H), 7.00 (d, J=8.24 dihydropyrimidin Hz, 1 H), 5.86 (s, 1 H), 4.70 - -one 4.79 (m, 1 H), 3.83 - 3.91 (m, 5 H m, 1 H , 3.64- 3.72 1H NMR (400 MHz, 6-(2,6- CHLOROFORM-d) 5 ppm dimethoxypheny .00 (br. s., 1 H), 7.40 (t, |)methy|—2- J=7.79 Hz, 1 H), 6.62 (d, thioxo-2,3- J=8.24 Hz, 2 H), 5.85 (s, 1 H), dihydropyrimidin 3.80 (s, 6 H), 3.45 (s, 3 H) -4(1H)-one 1H NMR (400 MHz, METHANOL-d3) 5 ppm 7.54 - 7.63 (m, 1 H), 7.47 (ddd, 6-(2- , 7.60, 1.80 Hz, 1 H), fluorophenyl)—1 - 7.35 (ddd, J=7.80, 7.80, 1.40 Hz, 1 H), 7.29 (ddd, J=9.85, methoxyethyl)— 8.47, 0.92 Hz, 1 H), 5.86 (s, 1 2-thioxo-2,3- H), 4.64 (dt, J=14.08, 4.64 Hz, dihydropyrimidin 1 H), 3.99 - 4.12 (m, 1 H), 3.70 -4(1H)-one (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) 1H NMR (500 MHz, DMSO-d6) 1-(2- 6 ppm 12.80 - 12.90 (m, 1 H) aminoethyl)—6- 7.95 (br. s., 3 H) 7.36 (dd, (2-methoxy J=8.42, 1.83 Hz, 1 H) 7.18 (d, methylphenyl)— J=1.95 Hz, 1 H) 7.10 (d, J=8.54 2-thioxo-2,3- Hz, 1 H) 5.78 (d, J=2.20 Hz, 1 opyrimidin H) 4.54 - 4.65 (m, 1 H) 3.86 - -4(1 H)-one 3.96 (m, 1 H) 3.81 (s, 3 H) 2.82 hydrochloride 1H NMR Spectral Data or HPLC Retention Time and Conditions 1H NMR (400 MHz, METHANOL-d3) d ppm 7.53 (ddd, J=8.00, 8.00, 1.80 Hz, 1 1-(2- H), 7.32 (dd, J=7.33, 1.83 Hz, 1 methoxyethyl)— H), 7.14 (d, J=8.70 Hz, 1 H), 6-(2- 7.09 (ddd, J=7.60, 7.60, 0.90 methoxyphenyl) Hz, 1 H), 5.75 (s, 1 H), 4.71 thioxo-2,3- (ddd, J=13.74, 5.95, 4.12 Hz, 1 dihydropyrimidin H), 3.89 (s, 3 H), 3.80 - 3.88 (m, -4(1H)-one 1 H), 3.68 (ddd, J=10.53, 7.79, .95 Hz, 1 H), 3.43 (ddd, J=10.42, 6.53, 4.12 Hz, 1 H), 3.08 s, 3 H 1H NMR (400 MHz, DMSO-d6) 6 ppm 12.71 (br. s, 1 H) 7.32 1-(2- (ddd, J=8.39, 2.15, 0.59 Hz, 1 hyd roxyethyl)—6- H) 7.14 (d, J=2.15 Hz, 1 H) (2-methoxy 7.06 (d, J=8.39 Hz, 1 H) 5.72 phenyl)— (d, J=2.15 Hz, 1 H)4.70 (t, 2-thioxo-2,3- J=5.56 Hz, 1 H) 4.43 - 4.51 (m, dihydropyrimidin 1 H) 3.79 (s, 3 H) 3.55 - 3.64 -4(1H)-one (m, 1 H) 3.47 - 3.55 (m, 1 H) 3.38 - 3.46 (m, 1 H) 2.28 (s, 3 1H NMR (400 MHz, DMSO-d6) 1-(2- 6 ppm 12.82 (br. s., 1 H), 7.99 - hyd roxyethyl)—6- 8.13 (m, 2 H), 7.67 - 7.73 (m, 1 (1-naphthyl)—2— H), 7.52 - 7.66 (m, 4 H), 5.87 thioxo-2,3- (d, J=1.76 Hz, 1 H), 4.61 (br. s., opyrimidin 1 H), 4.23 - 4.37 (m, 1 H), 3.34 -4(1H)-one - 3.51 m, 3 H 2- 1H NMR (500 MHz, DMSO-d6) hyd roxyethyl ) 5 ppm 12.80 (s, 1 H) 8.03 (dd, oxothioxo— J=8.78, 1.95 Hz, 1 H) 7.82 (d, 1 ,2,3,6- J=2.20 Hz, 1 H) 7.36 (d, J=8.78 tetra hyd mi Hz, 1 H) 5.87 (d, J=2.20 Hz, 1 diny|] H) 4.46 - 4.54 (m, 1 H) 3.92 (s, methoxybenzoni 3 H) 3.57 - 3.64 (m, 1 H) 3.38 - trile 3.49 (m, 2 H) 2-[6-(2- 1.44 min Waters Atlantis dC18 methoxy—5- 5um 4.6x50mm, methylphenyl)— 95%H20/5%MeCN linear to 4-oxothioxo- 95% MeCN over 4.0 3,4- min, HOLD at dihydropyrimidin 5%H20/95%MeCN to 5.0min. -1(2H)— (0.05% TFA). Flow rate: 2 | acetamide mL/min Ex- 1H NMR Spectral Data or Com ound ample mee HPLC Retention Time and # Conditions 6-[6- 1H NMR (400 MHz, (dimethylamino) OL-d3) 6 ppm 8.07 (d, pyridinyl]—1 - J=1.83 Hz, 1 H), 7.99 (dd, (2- J=9.62, 2.29 Hz, 1 H), 7.28 (d, methoxyethyl)— J=9.62 Hz, 1 H), 5.90 (s, 1 H), 2-thioxo-2,3- 4.40 (br. s., 2 H), 3.71 (t, dihydropyrimidin J=5.04 Hz, 2 H), 3.33 (s, 6 H), 3.26 s, 3 H 1H NMR (400 MHz, DMSO-d6) aminoethyl)—6- 6 ppm 12.87 (s, 1 H) 7.93 (br. (2,5- s., 3 H) 7.09 - 7.16 (m, 2 H) dimethoxypheny 7.03 (d, J=2.73 Hz, 1 H) 5.82 |)thioxo-2,3- (d, J=1.95 Hz, 1 H) 4.54 - 4.64 dihydropyrimidin (m, 1 H) 3.86 - 3.98 (m, 1 H) -4(1H)—one 3.79 (s, 3 H) 3.75 (s, 3 H) 2.85 - h drochloride 2.97 m, 2 H 1H NMR (400 MHz, DMSO-d6) 6-(2,6- 6 ppm 12.72 (br. s., 1 H), 7.45 dimethoxypheny (t, J=8.36 Hz, 1 H), 6.79 (d, J=8.47 Hz, 2 H), 5.71 (d, hyd roxyethyl)—2- J=2.06 Hz, 1 H), 3.94 (t, J=7.21 thioxo-2,3- Hz, 2 H), 3.76 (s, 6 H), 3.35 (t, dihydropyrimidin J=7.56 Hz, 2 H) -4(1H)-one 1.57 min Waters Atlantis dC18 6-[2-(2- 5um mm, hyd roxyethoxy)p 95%H20/5%MeCN linear to henyl]—1-(2- 5%H20/95% MeCN over 4.0 hyd roxyethyl)—2- min, HOLD at thioxo-2,3- %H20/95%MeCN to 5.0min. opyrimidin (0.05% TFA). Flow rate: 2 -4(1H)-one mL/min 1H NMR (500 MHz, DMSO-d6) 6-(2,5- 6 ppm 12.72 (s, 1 H) 7.06 - 7.11 dimethoxypheny (m, 2 H) 6.95 (d, J=2.44 Hz, 1 |)(2- H) 5.77 (d, J=2.20 Hz, 1 H) hyd roxyethyl)—2- 4.72 (t, J=5.61 Hz, 1 H) 4.44 - thioxo-2,3- 4.50 (m, 1 H) 3.77 (s, 3 H) 3.74 dihydropyrimidin (s, 3 H) 3.51 - 3.64 (m, 2 H) -4(1H)-one 3.40 - 3.46 m, 1 H 1H NMR (500 MHz, DMSO-d6) 2-[6-(5-cyano—2- 6 ppm 3.76 - 3.94 (m, 2 H), methoxyphenyl) 3.93 (s, 3 H), 5.92 (d, J=1.7 Hz, oxothioxo- 1 H), 7.10 (br. s., 1 H), 7.31 (br. 3,4- s., 1 H), 7.37 (d, J=8.8 Hz, 1 H), dihydropyrimidin 7.61 (s, 1 H), 8.03 (dd, J=8.7, -1(2H)— 1.6 Hz, 1 H), 12.88 (br. s., 1 H) yl]acetamide 1H NMR Spectral Data or HPLC Retention Time and ions 4-methoxy[3- 2.34 min Waters is dC18 (2- 5um 4.6x50mm, methoxyethyl)— 95%H20/5%MeCN linear to 6-oxo—2-thioxo- 5%H20/95% MeCN over 4.0 1,2,3,6- min, HOLD at tetrahydropyrimi 5%H20/95%MeCN to 5.0min. din (0.05% TFA). Flow rate: 2 |]benzonitri|e mL/min 1H NMR (400 MHz, 1-(2- FORM-d) 6 ppm isopropoxyethyl) 10.19 (br. s., 1 H) 7.29 (d, (4- J=8.78 Hz, 2 H) 6.97 (d, J=8.97 methoxyphenyl) 321.1 Hz, 2 H) 5.84 (d, J=2.15 Hz, 1 thioxo-2,3- H) 4.37 (t, J=5.46 Hz, 2 H) 3.87 dihydropyrimidin (s, 3 H) 3.68 (t, J=5.66 Hz, 2 H) -4(1H)—one 3.47 (spt, J=6.08 Hz, 1 H) 1.06 d, J=6.05 Hz, 6 H 1H NMR (400 MHz, OL-d4) 5 ppm 7.53 (ddd, J=8.39, 7.61, 1.76 Hz, 1 H) 7.33 (dd, J=7.41, 1.76 Hz, 1 1_(2_ H) 7.13 (d, J=8.58 Hz, 1 H) isopropoxyethyl) 7.08 (ddd, J=7.51, 7.51, 0.98 _6_(2_ Hz, 1 H) 5.75 (s, 1 H)4.69 methqupheny') 321'5 (ddd, J=13.51, 6.58, 3.90 Hz, 1 'Z'th'oxo'2’3' H) 3.88 (s, 3 H) 3.78 (dt, d'hygqoggggdm 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 1H NMR (500 MHz, DMSO-d6) 2-[6-(2 4_ dimethoxypheny 6 ppm 12.75 (s, 1 H) 7.31 (br. s., 1 H) 7.08 (d, J=8.54 Hz, 1 H) |)oxo 6.98 (br. s., 1 H) 6.69 (d, thioxo-3 4_ 322 2 dihydropyrimidin ' J=2.20 Hz, 1 H) 6.61 (dd, J=8.54, 2.20 Hz, 1 H) 5.74 (s, 1 -1(2H)— H) 5.38 (br. s., 1 H) 3.87 (br. s., y|]acetamide 1 H) 3.82 (s, 3 H) 3.81 (s, 3 H) METHANOL-d(3) 5 ppm 7.211H NMR 400 MHz, -1_[(2R)_2_ - aminopropy|] 7.31 (m, 1 H), 6.71 (d, J=1.83 (2 4_ dimetho’x Hz, 1 H), 6.68 (dd, , 2.29 I)_2_thiox3g§2 3_yhen 322.1 Hz, 1 H), 5.77 - 5.85 (m, 1 H), d'hydmpyr'm'd'“. . z . 5.10-5.24 (m, 1 H), 3.87-3.90 (m 3 H) 3.83-3.86 (m 3 H) '4(1H)'°“.e 3.61 - 3.73 (m, 1 H), 3.47 - 3.59 hydrOCh'or'de m 1H 0.90-1.15 m 3H Ex- 1H NMR Spectral Data or Com ound ample mee HPLC Retention Time and # Conditions amgngsgxwfl 1H NMR (400 MHz, METHANOL-d3) 5 ppm 7.24 - (2 4_ dimetho’xypheny 7.33 (m, 1 H), 6.67 - 6.76 (m, 2 H), 5.80 - 5.85 (m, 1 H), 5.13 - I)_2_thioxo_2 3_ . . z . 5.25 (m, 1 H), 3.87-3.92 (m,6 d'hydmpyr'm'd'“ H), 3.51 - 3.76 (m, 2 H), 0.95 - -4(1H)—one 1'16 (m, 3 H) h drochloride éicpheny 1H NMR (400 MHz, METHANOL-d3) 5 ppm 7.27 (d, I)_1_[2_ J=8.24 Hz, 1 H), 6.73 (d, (methylamino)et J=2.29 Hz, 1 H), 6.70 (dd, hyl]_2_thioxo_ 322 1 J=8.47, 2.52 Hz, 1 H), 5.81 (s, 2 3- . . . 1 H), 4.06 — 4.17 (m, 2 H), 3.90 194120;;22‘?”. (s, 3 H), 3.87 (s, 3 H), 2.99 - 3.16 (m, 2 H), 2.55 (s, 3 H) formate 1H NMR (400 MHz, DMSO-d6) 1_(3_ ppm 8-29 (S, 1 H). 7.25 (d, amino(2 4?)!ro |) J=8.70 HZ, 1 H), 6.68 (d, dimethoxypheny J=2-29 Hz, 1 H), 5.62 (dd, 322'1 J=8'24’ 2'29 Hz, 1 H), 5-72 (S, hioxo-2,3- 1 H), 4.31 - 4.45 (m, 2 H), 3.80 dihydropyrimidin (s, 3 H), 3.79 (s, 3 H), 3.16 - -4(1H)—one 3.62 (m, 3 H), 2.39 - 2.44 (m, 2 formate ,1.52-1.81 m,2H 1H NMR (400 MHz, - CHLOROFORM-d) 6 ppm 9.57 dimethoxypheny - 9.72 (m, 1 H), 7.11 - 7.21 (m, |)(2- 1 H), 6.45 - 6.60 (m, 2 H), 5.82 hydroxypropyl)— 323 1 (dd, J=13.05, 2.52 Hz, 1 H), xo-2,3- 4.41 - 4.93 (m, 1 H), 4.27 - 4.41 dihydropyrimidin (m, 1 H), 3.86 (s, 3 H), 3.82 (m, -4(1H)—one 3 H), 3.53 - 3.69 (m, 1 H), 0.94 - 1 05 m 3 H 2.50 min Waters Atlantis dC18 6-(2 6- dimethoxypheny 5um 4.6x50mm, 95%H20/5%MeCN linear to |)_1_(2_ 5%H20/95% MeCN over 4.0 yethyl)— 323.1 min HOLD at Z-th'0X0'2a3' %H20/95%MeCN to 5.0min. “3120:;2:13” (0.05% TFA). Flow rate: 2 mL/min 1H NMR Spectral Data or Compound HPLC Retention Time and Name Condltlons_ _ 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.46 6-(2,4- (br. s., 1 H), 7.11 (d, J=8.24 Hz, dimethoxypheny 1 H), 6.56 (dd, J=8.24, 2.29 Hz, I)_1_(3_ 1 H), 6.52 (d, J=2.29 Hz, 1 H), hydroxypropyl)_ .82 (d, J=2.75 Hz, 1 H), 4.64 - 2_thioxo_2 3_ dihydropyrmgidin 4.75 (m, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), .89 (m, 2H), _4(1H)_0ne 3.49 (t, J=5.72 Hz, 1 H), 1.56 - 1 83 m 2 H 1H NMR (300MHz, CDCI3) 6-(2,4- 9.80 (bs, 1H), 7.13 (d, J=8.4 dimethoxypheny Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), |)(2- 6.50 (s, 1H), 5.80 (d, J=2.1Hz, methoxyethy|)- 323.2 1H), 4.70 (dt, J=13.5, 4.5 Hz, 2-thioxo—2,3- 1H), 3.86 (s, 3H), 3.83-3.91 (m, dihydropyrimidin 1H) 3.82 (s, 3H), 3.66-3.74 (m, —one 1H), .47 (m, 1H), 3.16 (s, 1-(2- aminoethyl)—6- 1H NMR (500 MHz, DMSO-d6) (3- d ppm 12.88 (br. s., 1 H), 7.86 bromophenyl)—2- (br. s., 2 H), 7.82 (s, 1 H), 7.77 thioxo—2,3- (d, J=7.8 Hz, 1 H), 7.56 (m, 1 dihydropyrimidin H), 7.51 (m, 1 H), 5.87 (s, 1 H), -4(1H)—one 4.26 (br. s., 2 H), 2.94 (m, 2 H) h drochloride 6-(5-fluoro—2,4- 1H NMR (400 MHz, 00300) d dimethoxypheny ppm 7.12 (dd, 1 H), 6.85 (d, 1 H), 5.75 (d, 1 H), 4.60 - 4.73 hydroxyethy|) (m, 1 H), 3.97 (s, 3 H), 3.90 (s, thioxo—2,3- 3 H), 3.76 - 3.86 (m, 2 H), 3.56 dihydropyrimidin - 3.65 (m, 1 H) -4(1H)—one 1H NMR (400 MHz, DMSO-d6) ppm 12.92 (br. s, 1 H), 8.24 1-(2- (dd, J=7.44, 1.95 Hz, 1 H), 7.73 aminoethyl)—6- (d, J=7.33 Hz, 1 H), 7.49 - 7.65 (4-methoxy (m, 6 H), 7.08 (d, J=8.01 Hz, 1 naphthyl)—2- H), 5.89 (s, 1 H), 4.47 (ddd, thioxo—2,3- J=13.91, 8.87, 5.15 Hz, 1 H), dihydropyrimidin 4.01 (s, 3 H), 3.66 - 3.77 (m, 1 -4(1 H)-one H), 2.82 - 2.91 (m, 1 H), 2.77 hydrochloride (ddd, J=12.31, 8.87, 6.30 Hz, 1 1H NMR al Data or HPLC Retention Time and Conditions 1-(2- 1H NMR (400 MHz, CDCI3): 5 hydroxyethyl)—2- 9.89 (br.s., 1H), 7.63-7.58 (m, thioxo—6-[2- 1H), 7.45-7.40 (m, 3H), 5.89 (d, (trifluoromethox 1H), 4.74-4.67 (m, 1H), 4.01- y)pheny|]—2,3- 3.95 (m, 1H), 3.82-3.75 (m, dihydropyrimidin 1H), .66 (m, 1H), 1.83 (s, 1H NMR (400 MHz, 2 4_ dimethoxypheny OL-d4) 5 ppm 7.23 (d, J=8.22 Hz, 1 H), 6.71 (d, I)_4_OXO_2_ J=2.15 Hz, 1 H), 6.68 (dd, thioxo_3 4_ dihydropyri’midin , 2.15 Hz, 1 H), 5.78 (s, 3351 -1 2H H), 4.97 (dt, J=14.57, 5.72 y|]propénir3fldam- 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 trifluoroacetate , 2.62-2.72 m, 1 H 1H NMR (400 MHz, 2_[6_(2 4_ dimethoxypheny CHLOROFORM-d) 5 ppm 9.79 (br. s., 1 H), 7.11 - 7.25 (m, 1 I)_4_OXO_2_ thioxo_3 4_ 336 1 H), 6.48 - 6.64 (m, 2 H), 5.85 - ’ ' 5.91 (m, 1 H), 5.42-5.75 (m, 2 dihydropyrimidin H), 4.35 — 4.76 (m, 1 H), 3.85 - -1(2H)— 3.90 (m, 3 H), 3.81 - 3.85 (m, 3 y|]propanamide , 1.85 m, J=6.87 Hz, 3 H 1H NMR (400 MHz, DMSO-d6) 3-[6-(2 4_ dimethoxypheny 5 ppm 12.66 (br. s, 1 H), 7.23 (d, J=8.70 Hz, 1 H), 7.21 (br. s., |)oxo 1 H), 6.72 (br. s., 1 1 H), 6.67 (d, thioxo-3 4_ 336 dro rimidin J=2.29 Hz, 1 H), 6.60 (dd, dihy_1(ng)_ J=8.24, 2.29 Hz, 1 H), 5.69 (s, H), 4.31 - 4.44 (m, 2 H), 3.79 y|]propanamide. (s, 3 H), 3.78 (s, 3 H) 1H NMR (400 MHz, DMSO-d6) 2-[6-(2,4- 6 ppm 12.77 (br. s., 1 H), 7.75 dimethoxypheny (d, J=4.58 Hz, 1 H), 7.07 (d, |)oxo J=8.24 Hz, 1 H), 6.67 (d, thioxo-3,4- J=2.29 Hz, 1 H), 6.60 (dd, 336.2 dihydropyrimidin J=8.47, 2.06 Hz, 1 H), 5.75 (s, -1(2H)-y|]-N- 1 H), 5.24 - 5.43 (m, 1 H), 3.87 methylacetamid - 3.99 (m, 1 H), 3.81 (s, 3 H), e 3.78 - 3.81 (m, 3 H), 2.45 (d, J=4.58 Hz, 3 H 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (300 MHz, 6) 6 ppm 12.73 (br. s., 1 H), 7.85 1-(4- (br. s., 3 H), 7.31 (d, J=8.36 Hz, aminobutyl)—6- 1 H), 6.72 (d, J=2.09 Hz, 1 H), (2,4- 6.66 (dd, J=8.36, 2.79 Hz, 1 H), dimethoxypheny .75 (d, J=2.09 Hz, 1 H), 4.29 - |)thioxo-2,3- 4.48 (m, 1 H), 3.84 (s, 3 H), dihydropyrimidin 3.83 (s, 3 H), 3.45 - 3.50 (m, 1 -4(1 H)-one H), 2.53 - 2.62 (m, 2 H), 1.38 - hydrochloride 1.66 (m, 2 H), 1.21 - 1.37 (m, 2 1H NMR (400 MHz, DMSO-d6) 6-(2,4- 6 ppm 12.75 (br. s., 1 H), 8.38 dimethoxypheny (br. s., 2 H), 7.28 (d, J=8.24 Hz, |)[3- 1 H), 6.69 (d, J=2.06 Hz, 1 H), lamino)pr 6.63 (dd, J=8.47, 2.29 Hz, 1 H), opyl]—2-thioxo— .73 (d, J=2.06 Hz, 1 H), 4.32 - 2,3- 4.44 (m, 1 H), 3.80 (s, 6 H), dihydropyrimidin 3.52 - 3.63 (m, 1 H), 3.28 (s, 3 -4(1 H)-one H), 2.39 (t, J=4.92 Hz, 2 H), hydrochloride 1.63 - 1.92 m, 2 H 1H NMR (400 MHz, 6) 3-[6-(2,4- 6 ppm 12.76 (br. s., 1 H), 7.30 dimethoxypheny (d, J=8.70 Hz, 1 H), 6.70 (d, xo J=2.29 Hz, 1 H), 6.65 (dd, thioxo-3,4- J=8.70, 2.29 Hz, 1 H), 5.74 (s, dihydropyrimidin 1 H), 4.38 - 4.51 (m, 1 H), 3.82 -1(2H)— (s, 3 H), 3.82 - 3.87 (m, 1 H), y|]propanoic 3.82 (s, 3 H), 2.53 - 2.63 (m, 1 acid , 2.40-2.48 m, 1 H 1H NMR (400 MHz, 6-(2,4- CHLOROFORM-d) 6 ppm 9.89 dimethoxypheny (br. s, 1 H), 7.21 (d, J=8.24 Hz, H o/ |)(2-hydroxy- 1 H), 6.58 (dd, J=8.70, 1.83 Hz, 3% | 194 2-methylpropyl)— 337.1 1 H), 6.51 (d, J=1.83 Hz, 1 H), )2 2-thioxo—2,3- 5.87 (s, 1 H), 5.11 - 5.30 (m, 1 dihydropyrimidin H), 3.87 (s, 3 H), 3.84 (s, 3 H), 0H | -4(1H)—one 3.46 - 3.64 (m, 1 H), 1.11 (br. s., 3 H), 0.96 (br. s., 3 H) 1H NMR Spectral Data or HPLC Retention Time and Name Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 6-(2,4- 10.07 (br. s., 1 H), 7.13 (d, oxypheny J=8.70 Hz, 1 H), 6.57 (dd, |)(3-hydroxy- J=8.70, 2.29 Hz, 1 H), 6.52 (d, 2-methylpropyl)— J=2.29 Hz, 1 H), 5.87 (s, 1 H), 2-thioxo—2,3- 4.95 (br. s., 2 H), 3.88 (s, 3 H), dihydropyrimidin 3.85 (s, 3 H), 3.54 (dd, J=11.91, -4(1H)-one 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 H NMR (400 MHz, METHANOL-d4) 5 ppm 7.20 (d, 6-(2,4- J=8.20 Hz, 1 H), 6.66 (d, dimethoxypheny J=2.15 Hz, 1 H), 6.64 (dd, |)(4- J=8.20, 2.34 Hz, 1 H), 5.71 (s, hyd roxybutyl)—2- 1 H), 4.44 - 4.56 (m, 1 H), 3.85 thioxo-2,3- (s, 6 H), 3.62 - 3.75 (m, 1 H), opyrimidin 3.32 (t, J=6.64 Hz, 2 H), 1.66 - -4(1H)-one 1.81 (m, 1 H), 1.40 - 1.56 (m, 1 ,1.16- 1.32 m, 2 H 1-[(2R)—3- 1H NMR (400 MHZ, DMSO-d6) amino ppm 12.72 - 12.82 (m, 1 H), hyd roxypropyl]— 7.61- 7.74 (m, 3 H), 7.16 - 7.28 6-(2,4- (m, 1 H), 6.59 - 6.75 (m, 2 H), dimethoxypheny .70 - 5.79 (m, 1 H), 5.60 - 5.65 |)thioxo-2,3- (m, 1 H), 4.53 - 4.63 (m, 1 H), dihydropyrimidin 4.21 - 4.31 (m, 1 H), 3.77 - 3.86 -4(1 H)-one (m, 6 H), 2.72 - 2.85 (m, 2 H) trifluoroacetate 1H NMR (400 MHz, 6) 1-(2- 6 ppm 12.79 (s, 1 H), 7.92 (br. aminoethyl)—2- s., 3 H), 6.99 (s, 1 H), 6.80 (s, 1 thioxo(2,4,5- H), 5.76 (d, J=1.76 Hz, 1 H), trimethoxypheny 4.55 (dt, 6, 6.88 Hz, 1 |)-2,3- H), 3.93 (dt, J=14.06, 7.03 Hz, dihydropyrimidin 1 H), 3.84 (s, 3 H), 3.80 (s, 3 -4(1 H)-one H), 3.70 (s, 3 H), 2.80 - 2.97 (m, hydrochloride 2 H) 1H NMR (400 MHz, DMSO-d6) 1-(3-amino—2- 6 ppm 12.69 - 12.76 (m, 1 H), hyd roxypropyl)— 7.61 - 8.08 (m, 3 H), 7.13 - 7.26 6-(2,4- (m, 1 H), 6.56 - 6.71 (m, 2 H), dimethoxypheny .65 - 5.76 (m, 1 H), 5.60 (m, |)thioxo-2,3- J=4.90 Hz, 1 H), 4.55 (s, 1 H), dihydropyrimidin 4.15 - 4.30 (m, 1 H), 3.74 - 3.84 -4(1 H)-one (m, 6 H), 3.54 - 3.63 (m, 1 H), hydrochloride 2.61 - 2.95 m, 2 H 2012/055949 Ex- 1H NMR Spectral Data or Com ound ample mee HPLC Retention Time and # ions 1-[(2S)amino- 1H NMR (300 MHz, DMSO-d6) 2- 5 ppm 12.78 (m, 1 H), 7.63 (br. hydroxypropyl]— s, 3 H), 7.18-7.28 (m, 1 H), 6-(2,4- 6.60-6.75 (m, 2 H), 5.71- dimethoxypheny 5.80(m, 1H), 5.58-5.66 (m, |)thioxo-2,3- 1H), 4.54-4.62 (m, 1H), 4.08- dihydropyrimidin 4.23 (m, 1H), 3.78-3.85 (m, -4(1H)—one 6H), 3.23-3.41 (m, 1H), 2.71- trifluoroacetate 2.83 m, 1H , 2.38-2.45 m, 1H 1H NMR (400 MHz, 1-(2,3- CHLOROFORM-d) 5 ppm oxypropyl) 10.33 (br. s., 1 H) 7.17 (br. s., 1 (2,4- H) 6.58 (br. s., 1 H) 6.52 (d, dimethoxypheny J=7.22 Hz, 1 H) 5.88 (d, J=7.22 |)thioxo-2,3- Hz, 1 H) 4.80 - 4.95 (m, 1 H) dihydropyrimidin 4.60 - 4.73 (m, 1 H) 3.99 - 4.14 -4(1H)-one (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H 3.23 - 3.68 m, 4 H 1H NMR (500 MHz, DMSO-d6) 1-(2- 6 ppm 12.68 (s, 1 H), 6.95 (s, 1 hyd roxyethyl)—2- H), 6.80 (s, 1 H), 5.74 (s, 1 H), thioxo(2,4,5- 4.43 - 4.51 (m, 1 H), 3.86 (s, 3 trimethoxypheny H), 3.82 (s, 3 H), 3.71 (s, 3 H), 3.64 - 3.70 (m, 1 H), 3.49 - 3.56 dihydropyrimidin (m, 1 H), 3.40 - 3.46 (m, 1 H) -4(1H)-one 1H NMR (400 MHz, 1-[(2S)-2,3- CHLOROFORM-d) 5 ppm dihydroxypropyl] 10.33 (br. s., 1 H) 7.17 (br. s., 1 (2,4- H) 6.58 (br. s., 1 H) 6.52 (d, oxypheny J=7.22 Hz, 1 H) 5.88 (d, J=7.22 |)thioxo-2,3- Hz, 1 H) 4.80 - 4.95 (m, 1 H) dihydropyrimidin 4.60 - 4.73 (m, 1 H) 3.99 - 4.14 -4(1H)-one (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H 3.23 - 3.68 m, 4 H 1H NMR (400 MHz, ABS 1-[(2R)-2,3- CHLOROFORM-d) 6 ppm OH dihydroxypropyl] 10.33 (br. s., 1 H) 7.17 (br. s., 1 (2,4- H) 6.58 (br. s., 1 H) 6.52 (d, 204 \O tsNJNW dimethoxypheny 339.2 J=7.22 Hz, 1 H) 5.88 (d, J=7.22 yo |)thioxo-2,3- Hz, 1 H) 4.80 - 4.95 (m, 1 H) \ dihydropyrimidin 4.60 - 4.73 (m, 1 H) 3.99 - 4.14 -4(1H)-one (m, 1 H) 3.87 (s, 3 H) 3.83 (s, 3 H) 3.23 - 3.68 (m, 4 H) Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1H NMR (400 MHz, DMSO-d6) 2-[6-(4- 6 ppm 12.90 (br. s, 1 H), 8.25 methoxy—1 - (d, J=7.33 Hz, 1 H), 7.69 - 7.77 naphthyl)—4-oxo— (m, 1 H), 7.56 - 7.68 (m, 2 H), 2-thioxo-3,4- 7.38 - 7.47 (m, 1 H), 7.23 (s, 1 dihydropyrimidin H), 7.06 (d, J=8.24 Hz, 1 H), - 6.98 (br. s., 1 H), 5.92 (d, yl]acetamide J=1.83 Hz, 1 H), 5.10 - 5.35 (m, , 4.02 s, 3 H 1H NMR (400 MHz, 6-(4-chloro—2,5- CHLOROFORM-d) 6 ppm 9.88 dimethoxypheny (br. s., 1 H), 7.03 (s, 1 H), 6.85 |)(2- (s, 1 H), 5.84 (s, 1 H), 4.73 (dt, hyd roxyethyl)—2- J=14.20, 5.15 Hz, 1 H), 3.91 - thioxo-2,3- 4.00 (m, 1 H), 3.87 - 3.90 (m, 1 dihydropyrimidin H), 3.86 (s, 3 H), 3.81 (s, 3 H), -4(1H)-one 3.59 - 3.73 (m, 1 H), 1.95 (br. 1H NMR (500 MHz, 6-(2,4- METHANOL-d4) 5 ppm 7.48 dimethoxypheny (br. s., 1 H), 6.90 (d, J=8.05 Hz, |)(1H-pyrazo|— 1 H), 6.62 (d, J=2.20 Hz, 1 H), -ylmethyl)—2- 345.1 6.46 (d, J=5.12 Hz, 1 H), 5.95 - thioxo-2,3- 6.13 (m, 2 H), 5.77 (s, 1 H), dihydropyrimidin 4.88 - 5.01 (m, 1 H), 3.82 (s, 3 -4(1H)-one 2-{4-oxo thioxo—6-[2- 1H NMR (400 MHz, Methoanol- (trifluorom ethox d3) d ppm 7.67 (ddd, J=7.7, y)pheny|]—3,4- 345.9 7.6, 2.0 Hz, 1 H), 7.46-7.52 (m, dihydropyrimidin 3 H), 5.89 (s, 1 H), 5.50 , 1 -1(2H)- H), 4.01 , 1H) y|}acetamide 6-(2,4- 1.84 min Waters Atlantis dC18 dimethoxypheny 5um 4.6x50mm, |)thioxo-1 - /5%MeCN linear to (1 H-1,2,4- 5%H20/95% MeCN over 4.0 346.0 I min, HOLD at ylmethy|)-2,3- 5%H20/95%MeCN to 5.0min. dihydropyrimidin (0.05% TFA). Flow rate: 2 mL/min Ex- 1H NMR al Data or Com ound ample mee HPLC Retention Time and # Conditions 1-(2- 1H NMR (400 MHz, methoxyethyl)— CHLOROFORM-d) 5 ppm 9.53 2-thioxo[4- (br. s., 1 H), 7.42 (d, J=8.70 Hz, 210 (trifluoromethox 347.1 2 H), 7.34 (d, J=8.24 Hz, 2 H), y)pheny|]—2,3- 5.82 (d, J=2.29 Hz, 1 H), 4.34 dihydropyrimidin (br. s., 2 H), 3.67 (t, J=5.27 Hz, , 3.20 s, 3 H 1H NMR (400 MHz, DMSO-d6) ppm 12.89 (s, 1 H), 9.25 (br. s, 1 H), 8.08 - 8.71 (br. m., 1 H), dimethoxypheny 7.24 - 7.42 (m, 1 H), 8.74 (d, I)_1_(pyrr0”din_ J=2.33 Hz, 1 H), 8.89 (dd, 2_ylmethyl)_2_ 211 348.4 J=8.61, 2.09 Hz, 1 H), 5.80 (m, thioxo_2 3_ . .1 . . 1 H), 4.97- 5.07 (m, 1 H), 3.81 d'hydr0pyr'm'd'“ - 3.88 (m, 6 H), 3.61 - 3.78 (m, h;:(r1)':r)l'lggge 2 H), 2.98 - 3.17 (m, 2 H), 1.73 - 1.90 (m, 1 H), 1.85 (m, 2 H), 1.13-1.26 m, 1 H 1H NMR (300 MHz, DMSO-d6) 6 ppm 12.80 (s, 1 H), 8.77 (br. 6-(2,4- s., 2 H), 7.27 - 7.38 (m, 1 H), dimethoxypheny 6.73 (d, J=2.09 Hz, 1 H), 6.67 |)(pyrro|idin- (dd, J=8.36, 2.09 Hz, 1 H), 5.78 3-y|methy|)—2- - 5.79 (m, 1 212 H), 4.80 - 4.75 (m, 3484 thioxo-2,3- 1 H), 3.84 (br. s., 4 H), 3.57 (s, dihydropyrimidin 3 H), 3.13 - 3.24 (m, 1 H), 3.01 -4(1H)—one -3.13 (m, 1 H), .97 (m, hydrochloride 1 H), 2.70 - 2.83 (m, 1 H), 2.55 -2.89 (m, 1 H), 1.81 - 1.95 (m, 1.79 m, 1 H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.59 (br. s, 1 H), 7.12 - 7.24 (m, 1 H), 8.58 (dd, , 1.83 Hz, 1 6_(2 4_1 . H), 8.43 - 8.51 (m, 1 H), 5.75 - d'methoxypheny .82 (m, 1 H), 4.87 (dd, J=13.74, 2.29 Hz, 1 H 0/ tetr2h1yéfi§3ram H), 4.53 - 213 5% I 349.1 4.82 (m, 1 H), 3.85 (s, 3 H), Ztfi'methggz_ _ _ 3.79 - 3.83 (m, 3 H), 3.54 (q, Q) o/ 'OXO' : T . J=7.20 Hz, 1 H), 3.39 (dd, d.Ihydropyrlmldln J=13.28, 10.08 Hz, 1 H), 3.15 -4(1H)—one (q, J=7.17 Hz, 1 H), 1.89 - 2.02 (m, 1 H), 1.84 - 1.80 (m, 1 H), 1.45- 1.54 (m, 1 H), 1.23- 1.35 (m, 1 H) Ex- 1H NMR Spectral Data or Com ound ample mee HPLC Retention Time and # Conditions 1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.20 - 7.28 (m, 1 H) 6.63 - 6.68 (m, 2 6-(2,4- H)5.70-5.74 (m, 1 H) 4.71 dimethoxypheny (dd, J=14.07, 2.74 Hz, 1 H) |)[(2R)- 4.56 - 4.65 (m, 1 H) 3.84 - 3.88 tetrahyd rofuran- (m, 6 H) 3.50 - 3.57 (m, 1 H) 2-y|methy|]—2- 3.43 - 3.50 (m, 1 H) 3.22 (dt, thioxo-2,3- , 6.72 Hz, 1 H) 1.93 (m, opyrimidin J=12.46, 7.89, 7.89, 6.16 Hz, 1 -4(1H)-one H) 1.64- 1.77 (m, 1 H) 1.43 - 1.55 (m, 1 H) 1.31 - 1.40 (m, 1 1H NMR (400 MHz, DMSO-d6) N-{2-[6-(2,4- 6 ppm 12.70 (br. s., 1 H), 7.77 dimethoxypheny (t, J=5.95 Hz, 1 H), 7.20 (d, |)oxo J=8.24 Hz, 1 H), 6.61 - 6.70 (m, thioxo-3,4- 2 H), 5.70 (s, 1 H), 4.50 (dt, opyrimidin J=13.40, 5.21 Hz, 1 H), 3.82 (s, -1(2H)— 3 H), 3.79 (s, 3 H), 3.59 (dt, y|]ethy|}acetami J=13.62, 6.70 Hz, 1 H), 3.15 - 3.28 m,2 H, 1.67 s, 3 H 3-[6-(2,4— 1H NMR (400 MHz, DMSO-d6) dimethoxypheny 6 ppm 12.63 (br. s., 1 H), 7.71 |)oxo (br. s., 1 H), 7.25 (d, J=7.79 Hz, thioxo-3,4- 1 H), 6.70 (s, 1 H), 6.64 (d, dihydropyrimidin J=8.70 Hz, 1 H), 5.72 (s, 1 H), -1(2H)-y|]-N- 4.37 - 4.53 (m, 2 H), 3.83 (s, 3 methylpropana H), 3.82 (s, 3 H), 3.35 - 3.44 (m, mide 2 H , 2.45 d, J=4.58 Hz, 3 H 3-[6-(2,4— 1H NMR (500 MHz, DMSO-d6) dimethoxypheny 6 ppm 12.50 - 12.85 (m, 1 H) |)oxo 7.15 - 7.34 (m, 2 H) 6.55 - 6.83 thioxo-3,4- (m, 3 H) 5.64 - 5.77 (m, 1 H) dihydropyrimidin 4.34 - 4.67 (m, 1 H) 3.75 - 3.89 -1(2H)-y|] (m, 6 H) 3.46 - 3.71 (m, 1 H) methylpropana 2.75 - 3.13 (m, 1 H) 0.66 - 0.90 mide H NMR (400 MHz, OL-d4) 5 ppm 7.24 (d, aminopentyl)—6- J=7.81 Hz, 1 H), 6.69 (s, 1 H), (2,4- 6.66 (d, J=8.00 Hz, 1 H), 5.75 oxypheny (s, 1 H), 4.46 - 4.60 (m, 1 H), |)thioxo-2,3- 3.87 (s, 6 H), 3.62 - 3.75 (m, 1 dihydropyrimidin H), 2.83 (br. s, 2 H), 1.69 - 1.83 -4(1H)—one (m, 1 H), 1.41 - 1.57 (m, 3 H), hydrochloride 1.05-1.24 m,2H 1H NMR al Data or Compound HPLC Retention Time and Name Conditions 1-(3-amino 1H NMR (400 MHz, DMSO-d6): methylbutyl)—6- 5 7.28 (d, 1 H), 6.71 (s, 1 H), (2,4- 6.65 (d, 1 H), 5.76 (s, 1 H), 4.49 dimethoxypheny (br.s., 1 H), 3.84 (s, 3 H), 3.82 |)thioxo-2,3- (s, 3 H), 3.50-3.60 (br.s., 1H), dihydropyrimidin .95 (m, 1 H), 1.42-1.55 -4(1 H)-one (m, 1 H), 0.89 (s, 3 H), 0.80 (s, h drochloride 3 H : 1H NMR (400 MHz, DMSO-d6) 6 ppm 12.76 (br. s., 1 H), 7.29 6-(2,4- (d, J=8.47 Hz, 1 H), 6.70 (d, dimethoxypheny J=2.06 Hz, 1 H), 6.64 (dd, |)[3- J=8.47, 2.06 Hz, 1 H), 5.74 (s, (dimethylamino) 1 H), 4.29 - 4.47 (m, 1 H), 3.80 propyl]—2-thioxo- (s, 6 H), 3.50 - 3.68 (m, 1 H), 2,3- 3.41 - 3.51 (m, 1 H), 2.74 (br. dihydropyrimidin s., 1 H), 2.55 (br. s., 6 H), 1.79 - -4(1H)—one 1.94 (m, 1 H), 1.63 - 1.78 (m, 1 1H NMR (400 MHz, DMSO-d6) ppm 12.94 (s, 1 H), 7.11 (d, ethyl [6-(2,4- J=8.70 Hz, 1 H), 6.70 (d, oxypheny J=2.29 Hz, 1 H), 6.63 (dd, |)oxo J=8.24, 2.29 Hz, 1 H), 5.83 (s, thioxo-3,4- 1 H), 5.18-5.40 (m, 1 H), 4.16 dihydropyrimidin -4.31 (m, 1 H), 4.02 (dtt, -1(2H)— J=10.88, 7.16, 7.16, 3.66, 3.66 y|]acetate Hz, 2 H), 3.82 (s, 6 H), 1.08 (t, J=7.10 Hz, 3 H) 1H NMR (500 MHz, DMSO-d6) 6 ppm 12.78 (br. s., 1 H) 7.28 2,4— (d, J=8.54 Hz, 1 H) 6.70 (d, oxypheny J=2.20 Hz, 1 H) 6.67 (dd, |)oxo J=8.29, 2.20 Hz, 1 H) 5.75 (s, 1 thioxo-3,4- H) 4.70 (dt, J=14.70, 4.36 Hz, 1 dihydropyrimidin H) 4.29 (ddd, J=11.95, 7.81, -1(2H)-y|]ethy| 4.39 Hz, 1 H) 4.02 (dt, J=11.71, acetate 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) 1.80 min Waters Atlantis dC18 1-{2-[6-(2,4- 5um 4.6x50mm, dimethoxypheny 95%H20/5%MeCN linear to |)oxo %H20/95% MeCN over 4.0 thioxo-3,4- min, HOLD at opyrimidin 5%H20/95%MeCN to 5.0min. -1(2H)— (0.05% TFA). Flow rate: 2 y|]ethy|}urea mL/min 1H NMR Spectral Data or Comszmeound HPLC Retention Time and Conditions 1H NMR (400 MHz, 6_(2 4_ dimethoxypheny METHANOL-d3) 5 ppm 7.31 (d, J=8.24 Hz, 1 H), 6.63 - 6.69 (m, |)(3-hydroxy- 2 H), 5.76 (s, 1 2 2_ H), 5.19 (d, glpmpw J=15.11 Hz, 1 H), 3.87 (s, 3 H), 3.87 (s, 3 H), 3.50 (d, J=14.66 2_thioxo_2 3_ dihydropyrirnidin HZ’ 1 H), 3-29 (d, J=10-53 HZ, 1 H), 3.05 (d, J=10.99 Hz, 1 H), _4(1H)_One 0.83 s 3H 066 s,3H H NMR (500 MHz, METHANOL-d4) 6 ppm 7.22 (d, 6-(2,4- J=8.29 Hz, 1 H), 6.68 (d, dimethoxypheny J=1.95 Hz, 1 H), 6.66 (dd, - J=8.29, 2.20 Hz, 1 H), 5.73 (s, hydroxypentyl)— 351.1 1 H), 4.44 - 4.57 (m, 1 H), 3.87 2-thioxo-2,3- (s, 6 H), 3.61 - 3.71 (m, 1 H), opyrimidin 3.40 (t, J=6.46 Hz, 2 H), 1.68 - -4(1H)—one 1.79 (m, 1 H), .51 (m, 1 H), 1.25 - 1.36 (m, 2 H), 1.03 - 1 20 m 2 H 1H NMR (400 MHz, FORM-d) 5 ppm 9.58 (br. s., 1 H)7.15 (d, J=8.40 Hz, 6_(2 4_ dimethoxypheny 1 H) 6.55 (dd, J=8.40, 2.35 Hz, 1 H)6.50 (d, J=2.35 Hz, 1 H) 1)—1—(2— . 5.79 (d, J=2.35 Hz, 1 H) 4.64 — 'SOprOpoxyethy') 35“ 4.71 (m, 1 H) 3.87 (s, 3 H) 3.82 thioxo-2,3- (s, 3 H) 3.69 - 3.81 (m, 2 H) dihydropyrimidin 3.49 (ddd, J=9.58, 5.86, 3.13 -4(1H)—one Hz, 1 H) 3.46 (dt, J=12.31, 6.25 Hz, 1 H) 1.04 (dd, J=6.06, 1.37 1H NMR (400 MHz, DMSO-d6) 6-(2,4- d ppm 7.32 (d, J=8.4 Hz, 1 H), dimethoxypheny 6.73 (d, J=2.0 Hz, 1 H), 6.68 |)[3- (dd, J=8.4, 2.0 Hz, 1 H), 5.76 (methylthio)prop 353.1 (d, J=2.0 Hz, 1 H), 4.45 (br.s., 1 y|]thioxo—2,3- H), 3.84 (s, 6H), 3.70 (br.s., 1 dihydropyrimidin H), 2.22 (tt, d=6.4, 6.4 Hz, 2 H), -4(1H)—one 1.85-1.91 (m, 1 H), 1.83 (s, 3 ,1.59-1.65 m, 1 H 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, FORM-d) 6 ppm 9.84 (br. s., 1 H), 7.14 - 7.22 (m, 3 1-benzyI(2,4- H), 6.84 - 6.93 (m, 2 H), 6.72 dimethoxypheny (d, J=8.24 Hz, 1 H), 6.44 (d, |)thioxo-2,3- J=1.83 Hz, 1 H), 6.34 (dd, dihydropyrimidin , 2.06 Hz, 1 H), 5.96 (d, -4(1H)—one J=16.03 Hz, 1 H), 5.84 (s, 1 H), 4.94 (d, J=15.11 Hz, 1 H), 3.82 2-[6-(4-chloro- 2,5- 1H NMR (400 MHz, dimethoxypheny METHANOL-d3) 5 ppm 7.20 (s, |)oxo 1 H), 6.96 (s, 1 H), 5.84 (s, 1 -3,4- H), 4.65 (br. s, 2 H), 3.83 (s, 3 dihydropyrimidin H), 3.81 (s, 3 H) -1(2H)— | acetamide 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.57 (br. s., 1 H), 8.43 (dd, J=4.58, 6-(2,4- 0.90 Hz, 1 H), 7.57 (ddd, dimethoxypheny , 7.60, 1.80 Hz, 1 H), |)(pyridin 7.11 (ddd, J=7.79, 5.04, 0.92 ylmethy|) Hz, 1 H), 7.00 (d, J=7.79 Hz, 1 thioxo-2,3- H), 6.88 (d, J=8.24 Hz, 1 H), dihydropyrimidin 6.43 (d, J=2.29 Hz, 1 H), 6.32 -4(1H)—one (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, 3H , 3.75 s, 3H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.56 (br. s., 1 H), 8.46 (dd, J=4.81, 6-(2,4- 1.60 Hz, 1 H), 7.97 (d, J=1.83 dimethoxypheny Hz, 1 H), 7.51 (ddd, J=8.00, |)(pyridin 1.80, 1.80 Hz, 1 H), 7.18 (ddd, ylmethy|) , 4.81, 0.92 Hz, 1 H), thioxo-2,3- 6.79 (d, J=8.24 Hz, 1 H), 6.46 dihydropyrimidin (d, J=2.29 Hz, 1 H), 6.42 (dd, -4(1H)—one J=8.24, 2.29 Hz, 1 H), 5.88 (d, J=15.11 Hz, 1 H), 5.84 (s, 1 H), .06 (d, J=15.57 Hz, 1 H), 3.84 Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 6-(2,4- 11.02 (br. s, 1 H), 8.48 (d, dimethoxypheny J=5.95 Hz, 2 H), 6.87 (d, |)(pyridin J=5.95 Hz, 2 H), 6.77 (d, 232 ylmethyl)—2- 356.1 J=8.24 Hz, 1 H), 6.42 (d, thioxo-2,3- J=2.29 Hz, 1 H), 6.36 (dd, dihydropyrimidin J=8.24, 2.29 Hz, 1 H), 5.88 - -4(1H)-one 5.90 (m, 1 H), 5.87 (s, 1 H), 4.93 - 5.08 (m, 1 H), 3.81 (s, 3 , 3.66 s, 3 H 1H NMR (400 MHz, DMSO-d6) (imitfiggghzegy 6 ppm 12.81 (br. s., 1 H), 7.27 0-112— 877JFJ‘S’11T2’2'3??? 233 293%???) 357-1 1 H), 3.79 (s, 3 H), 3.77 (s, 3 dihydropyrimidin H), 3.66 - 3.75 (m, 1 H), 3.52 (dt, , 6.93 Hz, 1 H), 3.33 -4(1H)-one -3.39 m, 1 H,3.01 s,3H 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.81 6-(2 4_ (br. s., 1 H), 8.59 (d, J=4.81 Hz, O dimethox,ypheny . « 011919992- 357(2'15—9’55‘L'SEHS; 16211 234 s)\ I Wig/2032. 35”) (d, J=1.83 Hz, 1 H), 6.28 (dd, / ' -4(1H)-one ' _Z’ )’ ' (S’ )’ 4.94 (d, J—17.17 Hz, 1 H), 3.81 (s, 3 H), 3.76 (s, 3 H) 1H NMR (400 MHz, DMSO-d6) 6 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 dimethoxypheny Hz, 1 H), 6.71 (d, J=2.33 Hz, 1 |)(piperidin H), 6.67 (dd, J=8.37, 2.33 Hz, 1 H 0/ ylmethyl)—2- H), 5.76 (d, J=2.33 Hz, 1 H), 235 3% I 362'1 thioxo-2,3- 4.51 - 4.77 (m, 1 H), 3.84 (s, 3 dihydropyrimidin H), 3.83 (s, 3 H), 3.67 - 3.79 (m, H0) I -4(1H)-one 1 H), 3.03 - 3.20 (m, 2 H), 2.57 hydrochloride - 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) Ex- 1H NMR Spectral Data or Com ound ample mee HPLC Retention Time and # ions [amino(imino)m 1H NMR (400 MHz, ethyl]—2-[6-(2,4- METHANOL-d4) 5 ppm 7.19 (d, dimethoxypheny J=8.41 Hz, 1 H), 6.68 (d, |)oxo J=2.15 Hz, 1 H), 6.63 (dd, thioxo-3,4- J=8.41, 2.35 Hz, 1 H), 5.84 (s, dihydropyrimidin 1 H), 5.44 (br. d, J=15.10 Hz, 1 -1(2H)— H), 4.55 (br. d, J=17.40 Hz, 1 yl]acetamide H), 3.88 (s, 3 H), 3.85 (s, 3 H) trifluoroacetate 3-[6-(2,4- 1H NMR (400 MHz, DMSO-d6) dimethoxypheny 6 ppm 12.71 (br. s, 1 H), 7.30 xo (d, J=8.24 Hz, 1 H), 6.70 (d, thioxo-3,4- J=1.83 Hz, 1 364 1 H), 6.65 (dd, dihydropyrimidin J=8.24, 2.29 Hz, 1 H), 5.74 (s, -1(2H)-yl]-N,N- 1 H), 4.39 - 4.55 (m, 2 H), 3.82 dimethylpropan (s, 6 H), 2.81 (s, 3 H), 2.69 (s, 3 amide 1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.19 (d, - J=8.39 Hz, 1 H), 6.57 - 6.69 (m, dimethoxypheny 2 H), 5.73 (s, 1 H), 4.74 (dd, |)(morpholin- J=14.45, 2.15 Hz, 1 H), 4.33 2-ylmethyl)—2- (ddt, J=11.18, 8.44, 2.39 Hz, 1 364 2 thioxo-2,3- ' H), 3.93 (dd, J=12.98, 3.61 Hz, opyrimidin 1 H), 3.84 (d, J=1.17 Hz, 8 H), -4(1H)-one 3.54 - 3.88 (m, 3 H), 3.13 (d, hydrochloride 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 1H NMR (400 MHz, DMSO-d6) d?mgth0)[<$p§h8nyth |2- - 2 4- ppm 12.89 - 12.78 (m, 1 H), 7.09 - 7.31 (m, 1 H), 8.81 - 8.73 I)_4_OXO_2_ (m, 2 H), 5.75 - 5.83 (m, 1 H), thioxo_3 4_ 3651 4.44 - 4.57 (m, 1 H), 3.91 - 4.18 dihydropyrimidin (m, 2 H), 3.75 - 3.85 (m, 8 H), _1(2H)_ 1.87 (d, J=6.90 Hz, 3 H), 1.09 - yl]propanoate 1 24 m 3 H 1H NMR (400 MHz, DMSO-d6) ppm 12.78 (s, 1 H), 7.29 (d, ethyl 3-[6-(2,4- J=8.24 Hz, 1 H), 6.71 (d, dimethoxypheny J=1.83 Hz, 1 H), 6.66 (dd, |)oxo J=8.24, 2.29 Hz, 1 H), 5.75 (d, thioxo-3,4- 365.1 J=2.29 Hz, 1 H), 4.43 - 4.58 (m, opyrimidin 1 H), 3.94 (q, J=6.87 Hz, 2 H), -1(2H)— 3.83 - 3.89 (m, 1 H), 3.82 (s, 3 yl]propanoate 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 Ex- 1H NMR Spectral Data or Com ound ample mee HPLC Retention Time and # Conditions amin6e(tiyl) 1HNMR (400 MHZ, METHANOL—d4): 5 8.28 (m, [6-(2 4_ OXS/pheny 1H), 7.15 (d, 1H), 6.66 (d, 1H), 6.62 (dd, 1H), 5.79 (s, 1H), I)_4_OXO_2_ .42-5.40 (m, 1H), 4.37-4.23 thiOX0-3 4_ dihydropyriinidin (m, 1H), 3'90 (3’ 3H), 3-80 (S, 3H), 3.20-3.15 (m, 1H), 3.05- -1(2H)- . 3.12 (m, 1H), 2.95-2.85 (m, tamlde 2H). h drochloride N~2~-{2-[6-(2,4- dimethoxypheny 1HNMR (400 MHz, |)oxo METHANOL-d4): 5 7.14 (d, thioxo-3,4- 1H), .60 (m, 2H), 5.65 (s, dihydropyrimidin 1H), 4.55-4.62 (m, 1H), 4.51 (s, -1(2H)- 1H), 3.77 (s, 6H), 3.00 (s, 2H), y|]ethy|}g|ycina 2.64-2.79 (m, 2H). mide N-{2-[6-(2,4- l dimethoxypheny 1H NMR (400MHz, DMSO-d6): |)oxo 512.88(br, 1H), 7.26 (d, 1H), -3,4- 6.66-6.74 (m, 2H), 5.78 (s,1 H), dihydropyrimidin 4.76 (m,1H) ,392 (m, 1H), 3.83 -1(2H)- (s, 6H), 3.70 (s, 2H), 3.02 (m, y|]ethy|}g|ycine 2H). h drochloride 1H NMR (400 MHz, CD30D) 6 2.37 (s, 3 H), 3.71 (d, J=17.2 2-[6-(2,4- Hz, 1 H), 3.79 (d, J=17.2 Hz, 1 dimethoxypheny H), 3.87 (s, 3 H), 3.88 (s, 3 H), |)oxo 4.04 (ddd, J=14.8, 6.8, 5.5 Hz, thioxo-3,4- 1 H), 4.28 (dt, J=11.7, 5.3 Hz, 1 366 2 dihydropyrimidin ' H), 4.51 (ddd, J=11.6, 6.7, 5.1 -1(2H)-yl]ethyl Hz, 1 H), 4.97 (dt, J=14.5, 5.0 ate Hz, 1 H), 5.78 (s, 1 H), 6.65- tosylate 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 6-(2,4- 1.58 min Waters Atlantis dC18 dimethoxypheny 5um 4.6x50mm, |){3-[(2- 95%H20/5%MeCN linear to hydroxyethyl)am 5%H20/95% MeCN over 4.0 365 9 ino]propyl} min, HOLD at thioxo-2,3- 5%H20/95%MeCN to 5.0min. dihydropyrimidin (0.05% TFA). Flow rate: 2 mL/min Ex- 1H NMR Spectral Data or Compound ample HPLC ion Time and Name # Conditions {2-[6-(2,4- dimethoxypheny 1HNMR (400 MHz, |)oxo METHANOL-d4): 5 7.25 (d, thioxo-3,4- 1H), 6.64 (m, 2H), 5.73 (s, 1H), dihydropyrimidin 4.74 (m, 1H), 3.92 (m, 1H), 3.87 -1(2H)— (s, 3H), 3.86 (s, 3H), 3.75 (m, y|]ethoxy}acetic 3H), 3.61 (m, 1H). acid 1H NMR (400 MHz, DMSO-d6) 6-(2,4- 5 ppm 12.81 (br. s., 1 H), 8.34 dimethoxypheny (s, 1 H), 8.19 (s, 1 H), 6.98 (d, |)[(5- J=8.24 Hz, 1 H), 6.58 (d, methylpyrazin- J=2.06 Hz, 1 H), 8.42 (dd, 2-y|)methy|]—2- J=8.36, 2.18 Hz, 1 H), 5.81 (d, thioxo-2,3- J=16.26 Hz, 1 H), 5.78 (s, 1 H), dihydropyrimidin 4.88 (d, J=16.72 Hz, 1 H), 3.72 -4(1H)—one (s, 3 H), 3.71 (br. s., 3 H), 2.39 1H NMR (400 MHz, DMSO-d6) 2-[6-(2 4_ dimethoxypheny 6 ppm 12.76 (br. s., 1 H), 7.26 (d, J=8.24 Hz, 1 H), 6.92 (s, 2 xo H), 6.66 (d, J=2.06 Hz, 1 H), thioxo-3 4_ dihydropyrimidin 6.61 (dd, J=8.47, 2.06 Hz, 1 H), .72 (d, J=1.60 Hz, 1 H), 4.57 -1(2H)— (br. s., 1 H), 3.92 - 4.06 (m, 1 y|]ethanesulfona H), 3.79 (s, 3 H), 3.78 (s, 3 H), mide 3.08 - 3.29 m, 2 H 6-(2,4- 1H NMR (500 MHz, dimethoxypheny METHANOL-d4) 6 ppm 7.05 (d, |)[2-(1H- J=8.29 Hz, 1 H) 6.71 (s, 2 H) oI 6.62 (d, J=2.20 Hz, 1 H) 6.43 y|amino)ethy|]— (dd, J=8.42, 2.07 Hz, 1 H) 5.77 2-thioxo-2,3- (s, 1 H) 4.84 (br. s., 1 H) 3.90- dihydropyrimidin 3.93 (m, 1 H) 3.88 (s, 3 H) 3.84 s, 3 H 3.26 - 3.33 m, 2 H ng 1H NMR (400 MHz, 0 METHANOL-d4) 6 ppm 7.21 (d, imidazoI H o/ J=8.00 Hz, 1 H), 6.68 - 6.73 (m, 52\ I y|amino)ethy|]— 2 H), 5.79 (s, 1 H), 4.72 - 4.84 250 6-(2 4_ 3761 H ' O ox,ypheny (m, 2 H), 3.89 (s, 6 H), 3.69 - <Nj‘N/NH 3.81 (m, 1 H), 3.57 - 3.67 (m, 2 |)thioxo-2 3_ dihydropyrimidin H), 3.43 - 3.57 (m, 2 H), 3.23 (d, J—15.23 Hz, 1 H) -4(1H)—one Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # ions 6-(2,4- 1HNMR (400 MHz, CDCI3): 6 dimethoxypheny 9.89 (br.s., 1H), 7.13 (d, 1H), |)(2- 6.56 (dd, 1H), 6.53 (s, 1H), 5.80 morpholin (s, 1H), 4.68 (br.s., 1H), 3.81- ylethy|) 3.85 (m, 1H), 3.84 (s, 3H), 3.80 thioxo-2,3- (s, 3H), 3.58-3.65 (m, 4H), dihydropyrimidin 2.52-2.66 (m, 2H), 2.28-2.38 1H NMR (500 MHz, DMSO-d6) 6 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), dimethoxypheny 6.63 (d, J=8.29 Hz, 1 H), 5.74 |)[(4- (d, J=1.46 Hz, 1 H), 5.24 (d, hydroxypiperidin J=14.64 Hz, 1 H), 4.82 (br. s., 1 y|)methy|]—2- H), 3.82 (s, 3 H), 3.81 (s, 3 H), thioxo-2,3- 3.47 - 3.53 (m, 1 H), 3.05 (d, dihydropyrimidin J=11.95 Hz, 1 H), 2.97 (d, -4(1 H)-one J=11.22 Hz, 1 H), 2.86 (q, hydrochloride 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 6-(2,4- 1HNMR (400 MHz, dimethoxypheny METHANOL-d4): 6 8.57 (br, |)oxo 1H), 7.25 (d, 1H), 6.71 (d, 1H), thioxo-3,4- 6.68 (dd, 1H), 5.77 (s, 1H), dihydropyrimidin .61 (m, 1H), .72 -1(2H)— (m, 1H), 3.02-3.06 (t, 2H), 1.76- yl]buty|}guanidin 1.78 (m, 1H), 1.52-1.55 (m, e , 1.33-1.40 m, 2H . 1H NMR (400 MHz, CD30D) 6 N~2~-{[6-(2,4- 3.69 (d, J=17.0 Hz, 1 H), 3.79 dimethoxypheny 305.1 (d, J=17.0 Hz, 1 H), 3.85 (s, 3 |)oxo [M- H), 3.86 (s, 3 H), 4.34 (br. d, thioxo-3,4- NHC 254 J=16.2 Hz, 1 H), 5.33 (br. d, dihydropyrimidin H2CO J=14.9 Hz, 1 H), 5.81 (s, 1 H), -1(2H)— NH2] 6.61 (dd, J=8.5, 2.2 Hz, 1 H), yl]acetyl}g|ycina 6.66 (d, J=2.3 Hz, 1 H), 7.18 (d, mide J=8.4 Hz, 1 H) 1H NMR al Data or HPLC Retention Time and Conditions N-{2-[6-(2,4- dimethoxypheny 7.51 min Chiralcel OD-H |)oxo 25cm, thioxo-3,4- 75%CO2/25%MeOH dihydropyrimidin (0.2% iPrN H2). -1(2H)—yl]ethyl}- Flow rate: 2.5 mL/min D-alaninamide trifluoroacetate N-{2-[6-(2,4- dimethoxypheny 6.32 min Chiralcel OD-H |)oxo 4.6mmx25cm, thioxo-3,4- 75%CO2/25%MeOH dihydropyrimidin (0.2% iPrN H2). -1(2H)—yl]ethyl}- Flow rate: 2.5 mL/min L-alaninamide trifluoroacetate 1H NMR (400 MHz, N-{2-[6-(2,4- CHLOROFORM-d) 5 ppm 9.48 dimethoxypheny (br. s., 1 H), 7.21 (d, J=8.70 Hz, |)oxo 1 H), 6.61 (dd, J=8.24, 2.29 Hz, thioxo-3,4- 1 H), 6.54 (d, J=2.29 Hz, 1 H), dihydropyrimidin .85 (d, J=2.29 Hz, 1 H), 4.62 -1(2H)— (t, J=6.64 Hz, 2 H), 3.88 (s, 3 y|]ethy|}methane H), 3.85 (s, 3 H), 3.27 - 3.47 (m, sulfonamide 2-{[6-(2,4- dimethoxypheny 1.72 min Waters Atlantis dC18 |)oxo 5um 4.6x50mm, thioxo-3,4- 95%H20/5%MeCN linear to dihydropyrimidin %H20/95% MeCN over 4.0 -1(2H)— min, HOLD at y|]methyl}pyrroli 5%H20/95%MeCN to 5.0min. dine (0.05% TFA). Flow rate: 2 carboximidamid mL/min trifluoroacetate 3-{[6-(2,4- dimethoxypheny 1.69 min Waters Atlantis dC18 |)oxo 5um mm, thioxo-3,4- /5%MeCN linear to dihydropyrimidin 5%H20/95% MeCN over 4.0 -1(2H)— min, HOLD at y|]methyl}pyrroli 5%H20/95%MeCN to 5.0min. (0.05% TFA). Flow rate: 2 carboximidamid mL/min trifluoroacetate 1H NMR Spectral Data or Compound HPLC Retention Time and Name CondItIons_ _ 1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.23 (d, 6-[6-(2,4- J=8.20 Hz, 1 H), 6.68 (d, dimethoxypheny J=2.15 Hz, 1 H), 6.66 (dd, |)oxo J=8.39, 2.54 Hz, 1 H), 5.75 (s, thioxo-3,4- 1 H), 4.48 - 4.59 (m, 1 H), 3.87 dihydropyrimidin (s, 6 H), 3.75 - 3.81 (m, 1 H), -1(2H)— 3.65 - 3.74 (m, 1 H), 1.73 - 1.83 yl]nor|eucinamid (m, 1 H), 1.63 - 1.73 (m, 2 H), e hloride 1.45 - 1.57 (m, 1 H), 1.14 - 1.25 1H NMR (500 MHz, DMSO-d6) ppm 12.81 (d, J=1.71 Hz, 1 ’flgggjofiieny H)’ 9'86 (S’ 1 H), 9-11 (S, 1 H), 8.47 (d, J=2.93 Hz, 1 H), 7.20 |)_4_OXO_2_ (d, J=8.54 Hz, 1 H), 6.63 (d, thioxo_3 4_ dihydropyrimidin J=2-20 Hz, 1 H), 6-51 (dd, 404 2 J=8.29, 2.20 Hz, 1 H), 6.32 (d, -1(2H)— J—2.93_ Hz, 1 H), 5.80 (d, ylimgtggllijlj- J=2.20 Hz, 1 H), 5.77 (d, cafgothioamide 8 Hz, 1 H), 4.78 (d, J=16.34 Hz, 1 H), 3.77 (s, 3 H), 6-(2,4- dimethoxypheny 0.83 min Column: Xtimate C18, |)[(1- 2.1x30mm, 3pm; Mobile phase: pyrrolidin- from 10% MeCN (0.06% TFA) 2-yl)methyl]—2- 405.1 in water (0.06% TFA) to 80% thioxo-2,3- MeCN (0.06% TFA) in water dihydropyrimidin (0.06% TFA); wavelength; 220 -4(1H)—one nm h drochloride disji-ggg/(Shtny 5.74 min Column: XBRIDGEC18 4.6mmX150mm 5pm |)oxo Mobile phase— A=0.1% TFA IN thioxo-3 4_ dihydropyrimidin 407 3 MeCN, B=0.1% TFA IN WATER: Phase A = 5% to 1.5 -1(2H)-yl]ethy|}- min, linear to 100% to 10 min.
L-valinamide Flow rate = 1.5 mL/min. trifluoroacetate. 1-(2- 1H NMR (300 MHz, 6) aminoethyl)—6- 6 ppm 12.87 (br. s., 1 H), 7.81 (3- (br. s., 3 H), 7.46 (t, J=7.67 Hz, methoxyphenyl) 1 H), 7.10 - 7.17 (m, 2 H), 7.07 278.1 thioxo-2,3- (d, J=7.67 Hz, 1 H), 5.82 (s, 1 dihydropyrimidin H), 4.31 (t, J=6.62 Hz, 2 H), -4(1H)—one 3.81 (s, 3 H), 2.90 - 3.01 (m, 2 h drochloride 1H NMR Spectral Data or HPLC Retention Time and Name Conditions 1H NMR (400 MHz, DMSO-d6) 1-(3- 6 ppm 12.80 (s, 1 H), 7.73 (br. aminopropyl)—6- s, 3 H), 7.45 (dd, J=9.05, 7.58 Hz, 1 H), 7.09 - 7.13 (m, 2 H), methoxyphenyl) 7.07 (d, J=7.83 Hz, 1 H), 5.82 thioxo-2,3- (d, J=1.96 Hz, 1 H), 4.02 - 4.14 dihydropyrimidin (m, 2 H), 3.81 (s, 3 H), 2.53 - -4(1 H)-one 2.59 (m, 2 H), 1.79 - 1.90 (m, 2 hydrochloride 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm .35 (br. s., 1 H), 7.04 (d, J=8.19 Hz, 1 H), 6.52 (d, 1-allyl(2,4- J=2.34 Hz, 1 H), 6.47 - 6.50 (m, oxypheny 1 H), 5.82 (d, J=2.15 Hz, 1 H), |)thioxo-2,3- 5.72 (ddt, J=16.78, 10.93, 5.46, dihydropyrimidin 5.46 Hz, 1 H), 5.21 (dd, -4(1H)-one 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, 1H,3.84 s,3H,3.79 s,3H 1H NMR (500 MHz, DMSO-d6) 6 ppm 12.89 (br. s., 1 H), 9.25 - 6-(2,4- 9.43 (m, 1 H), 8.74 (br. s., 1 H), dimethoxypheny 7.25 - 7.43 (m, 1 H), 6.73 (d, |)[(2R)- J=1.46 Hz, 1 H), 6.68 (dd, pyrrolidin J=8.42, 1.83 Hz, 1 H), 5.73 - y|methyl] .85 (m, 1 H), 4.96 - 5.08 (m, 1 thioxo-2,3- H), 3.80 - 3.88 (m, 6 H), 3.61 - dihydropyrimidin 3.77 (m, 1 H), 3.42 - 3.53 (m, 1 -4(1 H)-one H), 2.93 - 3.15 (m, 2 H), 1.73 - hydrochloride 1.90 (m, 1 H), 1.50 - 1.73 (m, 2 ,1.14- 1.25 m, 1 H 1H NMR (500 MHz, DMSO-d6) 6-(2,4- 6 ppm 12.89 (br. s., 1 H), 9.25 - oxypheny 9.43 (m, 1 H), 8.74 (br. s., 1 H), |)[(28)- 7.25 - 7.43 (m, 1 H), 6.73 (d, pyrrolidin J=1.46 Hz, 1 H), 6.68 (dd, y|methyl] J=8.42, 1.83 Hz, 1 H), 5.73 - -2,3- .85 (m, 1 H), 4.96 - 5.08 (m, 1 dihydropyrimidin H), 3.80 - 3.88 (m, 6 H), 3.61 - -4(1 H)-one 3.77 (m, 1 H), 3.42 - 3.53 (m, 1 hydrochloride H), 2.93 - 3.15 (m, 2 H), 1.73 - hydrochloride 1.90 (m, 1 H), 1.50 - 1.73 (m, 2 hydrochloride ,1.14-1.25 m, 1 H Ex- 1H NMR Spectral Data or Com ound ample mee HPLC Retention Time and # Conditions 1H NMR (300 MHz, DMSO-d6) 1-[2-(2- 5 ppm 12.78 (br. s, 1 H), 7.73 aminoethoxy)et (br. s, 3 H), 7.29 (d, J=8.36 Hz, hy|](2,4- 1 H), 6.72 (s, 1 H), 6.66 (dd, dimethoxypheny J=8.36, 2.09 Hz, 1 H), 5.76 (d, 352 3 |)thioxo-2,3- ' J=2.09 Hz, 1 H), 4.55 - 4.68 (m, dihydropyrimidin 1 H), 3.83 (s, 6 H), 3.70 - 3.79 -4(1H)—one (m, 1 H), 3.47 - 3.56 (m, 2 H), hydrochloride 3.34 - 3.41 (m, 2 H), 2.80 - 2.90 m, 2 H 2-{3-[6-(2,4- 1H NMR (400 MHz, dimethoxypheny OL-d4) 6 ppm 7.22 (d, |)oxo J=8.41 Hz, 1 H), 6.68 (d, thioxo-3,4- J=1.96 Hz, 1 H), 6.65 (dd, dihydropyrimidin , 2.15 Hz, 1 H), 5.76 (s, -1(2H)— 1 H), 4.51 - 4.63 (m, 1 H), 3.86 y|]propy|}guanidi (s, 6 H), 3.75 - 3.83 (m, 1 H), ne 2.98 - 3.09 (m, 2 H), 1.86 - 2.00 trifluoroacetate m, 1 H - 1.79 m, 1 H , 1.67 The following Examples of Table 4 were prepared from the corresponding aryl halide to afford the intermediate beta-keto—ester as described above for the Preparations in the Aryl Halide Route n followed by employing the methods described in the |. Beta Keto Ester Route n as well as standard methods and techniques known to those skilled in the art.
Table 4. Examples from Aryl Halide Route 1H NMR Spectral Data Compound Name HPLC Retention Time and Conditions 1H NMR (500 MHz, CHLOROFORM-d) 5 ppm .31 (br. s., 1 H), 7.48 (dd, J=7.80, 7.80 Hz, 1 H), 7.42 (d, J=7.81 Hz, 1 1-(2-hyd roxyethyl)—6- H), 7.35 (dd, J=7.60 Hz, 1 [2-(2- H), 7.25 (d, J=7.81 Hz, 1 methoxyethyl)phenyl] H), 5.88 (s, 1 H), 4.57 (dt, thioxo—2,3- J=13.80, 5.80 Hz, 1 H), dihydropyrimidin- 3.92 (dt, J=14.00, 5.90 4(1H)—one 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, , 7.04 Hz, 1 H), 2.73 (dt, J=14.45, 5.95 1H NMR (500 MHz, METHANOL-d4) 6 ppm 3.11 - 3.20 (m, 1 H) 3.26 - 2-{2-[3-(2- 3.33 (m, 1 H)4.46 (dt, aminoethyl)—6-oxo J=13.72, 6.92 Hz, 1 H) thioxo—1,2,3,6- 4.65 (d, J=6.10 Hz, 1 H) tetrahyd midin- 4.70 - 4.81 (m, 2 H) 5.89 4- (s, 1 H) 7.08 (d, J=8.54 y|]phenoxy}acetamid Hz, 1 H) 7.19 (t, J=7.56 e oroacetate Hz, 1 H) 7.40 (dd, J=7.32, 1.22 Hz, 1 H) 7.54 - 7.60 (m, 1 H) 1H NMR (500 MHz, METHANOL-d4) 6 ppm 6-(2,5-dimethoxy 6.97 (s, 1 H), 6.88 (s, 1 methylphenyl)—1-(2- H), 5.78 (s, 1 H), 4.61 - hydroxyethyl)—2- 4.71 (m, 1 H), 3.85 - 3.91 thioxo-2,3- (m, 1 H), 3.84 (s, 3 H), dihydropyrimidin- 3.82 (s, 3 H), 3.79 - 3.81 4(1H)—one (m, 1 H), 3.59 - 3.67 (m, 1 , 2.28 s, 3 H 2.53 min Waters Atlantis dC18 5um 4.6x50mm, 1-(2-hyd roxyethyl)—6- 95%H20/5%MeCN linear (4-methoxy to 5%H20/95% MeCN naphthyl)—2-thioxo— over 4.0 min, HOLD at 2,3-dihydropyrimidin- 95%MeCN to 4(1H)—one .0min. (0.05% TFA).
Flow rate: 2 mL/min 1H NMR al Data Compound Name HPLC Retention Time and Conditions 2.79 min Waters Atlantis 6-(2,5-dimethoxy dC18 5um 4.6x50mm, methylphenyl)—1-(2- 95%H20/5%MeCN linear methoxyethyl)—2- to 5%H20/95% MeCN thioxo-2,3- over 4.0 min, HOLD at dihydropyrimidin- 5%H20/95%MeCN to 4(1H)-one 5.0min. (0.05% TFA).
Flow rate: 2 mL/min The following es of Table 5 were prepared from 6-iodo(2-methoxyethyl)—2- (methylthio)pyrimidin-4(1H)-one and the appropriate aryl boronate as described above for the Preparations and ures in the Suzuki Route section as well as standard methods and techniques known to those skilled in the art.
Table 5. Examples from Suzuki Route 1H NMR Spectral Data or HPLC Retention Time and Conditions 1H NMR (400 MHz, 1-(2- METHANOL-d3) 6 ppm 7.93 - methoxyethyl)— 8.05 (m, 4 H), 7.58 - 7.65 (m, 2 aphthyl)— H), 7.52 (dd, J=8.24, 1.83 Hz, 1 2-thioxo-2,3- H), 5.90 (s, 1 H), 4.40 - 4.52 dihydropyrimidin (m, 2 H), 3.59 - 3.68 (m, 2 H), -4(1H)-one 3.07 s, 3 H 1H NMR (400 MHz, METHANOL-d3) 6 ppm 7.80 6-(2-furyl)(2- (dd, J=1.83, 0.92 Hz, 1 H), 7.06 methoxyethyl)— (dd, J=3.66, 0.92 Hz, 1 H), 6.66 2-thioxo-2,3- (dd, J=3.21, 1.83 Hz, 1 H), 6.10 dihydropyrimidin (s, 1 H), 4.66 (t, J=5.04 Hz, 2 -4(1H)-one H), 3.73 (t, J=6.18 Hz, 2 H), 1-(2- 1H NMR (400 MHz, methoxyethyl)— METHANOL-d3) 6 ppm 7.81 6-(1H-pyrazol (br. s., 1 H), 6.66 (d, J=2.29 Hz, yl)—2-thioxo—2,3- 1 H), 5.99 (s, 1 H), 4.76 (br. s., dihydropyrimidin 2 H), 3.66 (t, J=6.18 Hz, 2 H), -4(1H)-one 3.17 (s, 3 H) Ex- 1H NMR Spectral Data or Compound ample HPLC Retention Time and Name # Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.76 1-(2- (br. s., 1 H), 8.76 (dd, J=4.81, methoxyethyl)— 1.60 Hz, 1 H), 8.64 (d, J=1.83 dinyI Hz, 1 H), 7.72 (ddd, J=7.80, 279 264 thioxo-2,3- ' 1 2.10, 2.10 Hz, 1 H), 7.45 (ddd, opyrimidin J=7.79, 4.58, 0.92 Hz, 1 H), -4(1H)—one 5.85 (s, 1 H), 4.34 (br. s., 2 H), 3.67 (t, J=5.04 Hz, 2 H), 3.21 3-(2- 1H NMR (400 MHz, methoxyethyl)— METHANOL-d3) 6 ppm 9.26 (s, 2-thioxo-2,3- 1 H), 8.90 (s, 2 H), 5.94 (s, 1 280 dihydro-4,5'- 265.1 H), 4.35 (br. s., 2 H), 3.67 (t, bipyrimidin- J=4.81 Hz, 2 H), 3.20 (s, 3 H) 6(1H)—one 1H NMR (400 MHz, 1_(2_ METHANOL-d3) 5 ppm 6.87 methoxyethyl)_ (dd, , 1.80 Hz, 1 H), 6.32 6_(1_methyl_1H_ (dd, J=3.66, 1.83 Hz, 1 H), 6.19 281 pyrrol_2_yl)_2_ 266 ' 1 (dd, J=3.66, 2.75 Hz, 1 H), 5.86 thiomz 3_ dihydropyri’midin (s, 1 H), 4.50 (br. s., 2 H), 3.62 (t, J=5.27 Hz, 2 H), 3.58 (s, 3 '4(1H)'°“e H , 3.12 s, 3 H 1H NMR (400 MHz, 0 CHLOROFORM-d) 5 ppm 9.54 1_(2_ (br. s., 1 H), 7.53 (dd, J=5.04, “N methox | .yethVI)_ /6 1.37 Hz, 1 H), 7.33 (dd, J=3.66, S 6-(2-th1enyl)—2- 282 _ N 269.1 0.92 Hz, 1 H), 7.13 (dd, J—5.04, H \ thiomz 3_ / 3.66 Hz, 1 H), 6.02 (d, J=2.29 dih dro ri’midin Xi(1I-FI))¥one Hz, 1 H), 4.53 (t, J=5.72 Hz, 2 /O H), 3.74 (t, J=5.72 Hz, 2 H), 3.28 (s, 3 H) 1H NMR (400 MHz, 0 1_(2_ CHLOROFORM-d) 5 ppm 9.55 methoxyethyl)_ H (br. s., 1 H), .41 (m, 2 | 6_(3_ 283 32\ methylphenyl)— 277.1 “(21 3222757 I1: (1mHi 29538;” H difiytg‘r'gxrizmfim J=5.27 Hz, 2 H), 3.63 (t, J=5.50 /o Hz, 2 H), 3.18 (s, 3 H), 2.42 (s, _4(1H)_one 2012/055949 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.65 (br. s., 1 H), 7.41 (ddd, J=7.80, 1-(2- 7.80, 1.80 Hz, 1 H), 7.28 - 7.34 methoxyethyl)— (m, 2 H), 7.23 (dd, J=6.87, 1.83 6-(2- Hz, 1 H), 5.82 (d, J=2.29 Hz, 1 methylphenyl)— H), 4.57 (dt, J=13.74, 5.04 Hz, xo-2,3- 1 H), 3.89 (dt, J=13.28, 6.87 dihydropyrimidin Hz, 1 H), 3.67 (ddd, J=10.53, -4(1H)—one 7.33, 5.04 Hz, 1 H), 3.56 (dt, J=1053 5.04 Hz, 1 H) 3.16 (s, 1H NMR (400 MHz, 1-(2- CHLOROFORM--d) 5 ppm 9.71 methoxyethyl)— (br. s., 1 H), 7.29 (d, J=7.79 Hz, 6-(4- 2 H), 7.23 (d, J=8.24 Hz, 2 H), methylphenyl)— .83 (s, 1 H), 4.39 (t, J=5.04 2-thioxo-2,3- Hz, 2 H), 3.63 (t, J=5.72 Hz, 2 dihydropyrimidin H), 3.19 (s, 3 H), 2.43 (s, 3 H) -4(1H)—one 6-(4- 1H NMR (400 MHz, DMSO-d6) hydroxyphenyl)— d ppm 12.73 (br. s., 1 H), 9.97 1-(2- (s, 1 H), 7.29 (d, J=8.24 Hz, 2 methoxyethyl)— H), 6.85 (d, J=8.24 Hz, 2 H), 2-thioxo-2, 3- 5.72 (s, 1 H), 4.29 (t, J=5.95 dihydropyrimidin Hz, 2H), 3.46(t, J=6.41 Hz, 2 6-(3- 1H NMR (301 MHz, DMSO-d—6) hyd roxyphenyl)— 6ppm12.75(br. s., 1 H) 9.85 1-(2- (s, 1 H), 7.27 (dd, J=7.80, 7.80 methoxyethyl)— Hz, 1 H), 6.82 - 6.90 (m, 2 H), xo-2,3- 6.79 (br. s., 1 H), 5.72 (s, 1 H), dihydropyrimidin 4.20 (t, J=6.54 Hz, 1 H), 3.45 (t, -4(1H)—one J=6.08 Hz, 2 H), 3.00 (s, 3 H) 1H NMR (400 MHz, OL-d3) 5 ppm 7.34 (td, J=7.90, 1.60 Hz, 1 H), 7.23 6-(2- (dd, J=7.67, 1.49 Hz, 1 H), 6.94 hyd roxyphenyl)— (t, J=7.44 Hz, 1 H), 6.90 (d, 1-(2- J=8.24 Hz, 1 H), 5.73 (s, 1 H), methoxyethyl)— 4.76 (ddd, J=13.51, 5.72, 4.58 2-thioxo-2,3- Hz, 1 H), 3.97 (dt, 1, dihydropyrimidin 7.13 Hz, 1 H), 3.65 (ddd, -4(1H)—one J=10.25, 7.38, 6.64 Hz, 1 H), 3.45 (ddd, J=10.42, 6.41, 4.24 Hz,1H,3.06 s,3H WO 68875 Ex- 1H NMR Spectral Data or Com ound ample Napme HPLC Retention Time and # Conditions 1H NMR (400 MHz, 6-(3- CHLOROFORM-d) 5 ppm fluorophenyl)—1- 10.00 (br. s., 1 H), 7.47 (ddd, (2- J=8.10, 8.10, 5.70 Hz, 1 H), methoxyethyl)— 7.22 (ddd, J=8.10, 8.10, 2.10 xo-2,3- Hz, 1 H), 7.07 - 7.16 (m, 2 H), dihydropyrimidin 5.85 (d, J=1.37 Hz, 1 H), 4.36 —one (br. s., 2 H), 3.66 (br. s., 2 H), 3.21 s, 3 H 1H NMR (400 MHz, 6-(4— CHLOROFORM-d) 5 ppm 9.57 fluorophenyl)—1- (br. s, 1 H), 7.35 (dd, J=8.93, .27 Hz, 2 H), 7.18 (dd, J=8.20 methoxyethyl)— Hz, 2 H), 5.82 (s, 1 H), 4.35 (t, 2-thioxo-2,3- J=5.04 Hz, 2 H), 3.65 (t, J=5.50 dihydropyrimidin Hz, 2 H), 3.20 (s, 3 H) -4(1H)—one 3-[3-(2- 1H NMR (400 MHz, methoxyethyl)— FORM-d) 5 ppm 9.70 6-oxothioxo- (br. s., 1 H), 7.81 (d, J=7.33 Hz, 1,2,3,6- 1 H), 7.71 (s, 1 H), 7.55 - 7.66 tetrahyd ropyrimi (m, 2 H), 5.82 (d, J=1.83 Hz, 1 din H), 4.29 (br. s., 2 H), 3.67 (br. | benzonitrile s.,2H,3.23 s,3H 1H NMR (400 MHz, DMSO-d6) 6-[2- 6 ppm 12.77 (br. s., 1 H), 7.43 - (hyd roxymethyl) 7.56 (m, 2 H), 7.30 - 7.41 (m, 2 pheny|](2- H), 5.76 (s, 1 H), 5.27 (t, J=5.38 methoxyethyl)— Hz, 1 H), 4.38 (d, J=5.27 Hz, 2 2-thioxo-2,3- H), 4.26 - 4.35 (m, 1 H), 3.69 - dihydropyrimidin 3.82 (m, 1 H), 3.45 - 3.55 (m, 1 -4(1H)—one H), 3.39 (dt, J=9.85, 6.75 Hz, 1 H), 2.97 (s, 3 H) 1H NMR (400 MHz, METHANOL-d3) 5 ppm 7.42 (t, 1-(2- J=8.24, 8.24 Hz, 1 H), 7.08 methoxyethyl)— (ddd, J=8.24, 2.75, 0.92 Hz, 1 6-(3- H), 7.03 (dd, J=2.75, 1.37 Hz, 1 methoxyphenyl) H), 6.99 (ddd, J=7.79, 1.83, thioxo-2,3- 0.92 Hz, 2 H), 5.79 (s, 1 H), dihydropyrimidin 4.39 (t, J=5.50 Hz, 2 H), 3.84 -4(1H)—one (s, 3 H), 3.64 (t, J=5.72 Hz, 2 2012/055949 1H NMR Spectral Data or HPLC Retention Time and Conditions 1H NMR (400 MHz, 1-(2- CHLOROFORM-d) 5 ppm 9.62 methoxyethyl)— (br. s., 1 H), 7.28 (d, J=8.70 Hz, 6—(4— 2 H), 6.99 (d, J=8.70 Hz, 2 H), methoxyphenyl) .83 (d, J=1.37 Hz, 1 H), 4.41 thioxo-2,3- (t, J=5.50 Hz, 2 H), 3.87 (s, 3 dihydropyrimidin H), 3.64 (t, J=5.72 Hz, 2 H), -4(1H)—one 3.20 s, 3 H 1H NMR (400 MHz, 1-(2- CHLOROFORM-d) 5 ppm 9.53 methoxyethyl)— (br. s., 1 H), 8.16 (d, J=1.83 Hz, 6—(6— 1 H), 7.58 (dd, J=8.70, 2.29 Hz, methoxypyridin- 1 H), 6.85 (dd, J=8.70, 0.92 Hz, 2-thioxo- 1 H), 5.84 (d, J=2.29 Hz, 1 H), 2,3- 4.37 (br. s., 2 H), 4.01 (s, 3 H), dihydropyrimidin 3.68 (t, J=5.27 Hz, 3 H), 3.23 -4(1H)—one s, 3 H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.61 1-(2- (br. s., 1 H), 8.42 (s, 1 H), 8.40 methoxyethyl)— (d, J=4.81 Hz, 1 H), 7.18 (d, 6—(3— J=4.81 Hz, 1 H), 5.77 (d, methoxypyridin- J=2.29 Hz, 1 H), 4.73 (dt, 4-y|)thioxo- 7, 3.43 Hz, 1 H), 3.97 (s, 2,3- 3 H), 3.80 (td, J=9.62, 3.89 Hz, dihydropyrimidin 1 H), 3.68 (ddd, J=13.80, 9.33, -4(1H)—one 4.58 Hz, 1 H), 3.36 (dt, J=10.08, 3.89 Hz, 1 H), 3.14 (s, 3 H) 1H NMR (400 MHz, 1-(2- CHLOROFORM-d) 5 ppm 9.59 methoxyethyl)— (br. s., 1 H), 8.29 (dd, J=5.04, 6—(2— 0.92 Hz, 1 H), 6.85 (dd, J=5.27, methoxypyridin- 1.60 Hz, 1 H), 6.74 (d, J=1.37 4-y|)thioxo- Hz, 1 H), 5.81 (d, J=2.29 Hz, 1 2,3- H), 4.35 (br. s., 2 H), 4.00 (s, 3 dihydropyrimidin H), 3.66 (t, J=5.27 Hz, 2 H), -4(1H)—one 6-(4— 1H NMR (400 MHz, chlorophenyl)—1 - METHANOL-d3) 5 ppm 7.53 (d, J=7.79 Hz, 2 H), 7.45 (d, methoxyethyl)— J=8.24 Hz, 2 H), 5.79 (s, 1 H), xo-2,3- 4.38 (t, J=5.04 Hz, 2 H), 3.62 (t, dihydropyrimidin J=5.72 Hz, 2 H), 3.16 (s, 3 H) -one 1H NMR Spectral Data or HPLC Retention Time and Conditions 1H NMR (400 MHz, 6-(2— CHLOROFORM-d) 5 ppm 9.57 chlorophenyl)—1 - (br. s., 1 H), 7.44 - 7.52 (m, 2 H), 7.39 - 7.44 (m, 1 H), 7.34 - methoxyethyl)— 7.39 (m, 1 H), 5.83 (d, J=1.37 2—thioxo-2,3- Hz, 1 H), 4.66 - 4.76 (m, 1 H), dihydropyrimidin 3.73 - 3.86 (m, 2 H), 3.41 - 3.47 -4(1H)—one .17 s,3H 6-(3- chlorophenyl)—1 - 1H NMR (400 MHz, (2- METHANOL-d3) 5 ppm 7.47 - methoxyethyl)— 7.57 (m, 3 H), 7.39 (ddd, xo-2,3- , 1.40 Hz, 1 H), 5.80 (s, dihydropyrimidin 1 H), 4.36 (br. s., 2 H), 3.64 (t, -4(1H)—one J=5.50 Hz, 2 H), 3.16 (s, 3 H) 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.55 6-(1H-indoI (br. s., 1 H), 8.44 (br. s., 1 H), y|)(2- 7.73 (d, J=8.24 Hz, 1 H), 7.41 methoxyethyl)— (s, 1 H), 7.38 (dd, J=3.43, 2.52 xo-2,3- Hz, 1 H), 7.05 (dd, J=8.24, 1.37 dihydropyrimidin Hz, 1 H), 8.85 (ddd, J=3.09, -4(1H)—one 1.95, 0.92 Hz, 1 H), 5.91 (s, 1 H), 4.48 (br. s., 2 H), 3.83 (br. s.,2H,3.15 s,3H 1H NMR (400 MHz, DMSO-d6) d ppm 12.81 (s, 1 H), 11.88 (br. 6-(1H-indoI s., 1 H), 7.59 (d, J=7.79 Hz, 1 y|)(2- H), 7.41 (d, J=8.24 Hz, 1 H), methoxyethyl)— 7.18 (t, J=7.67 Hz, 1 H), 7.05 (t, 2—thioxo-2,3- J=7.44 Hz, 1 H), 8.84 (s, 1 H), dihydropyrimidin 6.03 (s, 1 H), 4.55 (t, J=5.84 -4(1H)—one Hz, 2 H), 3.52 (t, J=5.84 Hz, 2 , 3.01 s, 3 H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.54 6-(1H-indoI (br. s., 1 H), 8.39 (br. s., 1 H), y|)(2- 7.81 (s, 1 H), 7.48 (d, J=8.24 methoxyethyl)— Hz, 1 H), 7.34 (t, J=2.75 Hz, 1 2—thioxo-2,3- H), 7.12 (dd, J=8.36, 1.49 Hz, 1 dihydropyrimidin H), 8.83 (d, J=2.06 Hz, 1 H), -4(1H)—one 5.90 (d, J=2.52 Hz, 1 H), 4.45 (br. s., 2 H), 3.80 (t, J=5.84 Hz, 2H,3.08-3.18 m,3H 1H NMR Spectral Data or HPLC Retention Time and Name Conditions 1H NMR (400 MHz, OL-d3) 5ppm 7.55 (d, J=8.01 Hz, 1 H), 7.39 (d, 6-(1H-indoI J=3.21 Hz, 1 H), 7.23 (t, J=7.79 (2- Hz, 1 H), 7.09 (d, J=7.10 Hz, 1 methoxyethyl)— H), 6.31 (d, J=2.98 Hz, 1 H), 2-thioxo-2,3- 5.86 (s, 1 H), 4.57 - 4.70 (m, 1 dihydropyrimidin H), 4.15 (dt, J=13.34, 6.50 Hz, -4(1H)-one 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 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.69 6-(1- (br. s., 1 H), 7.94 (s, 1 H), 7.59 benzofu ran (d, J=8.24 Hz, 1 H), 7.47 (d, y|)(2- J=7.79 Hz, 1 H), 7.42 (td, methoxyethyl)— J=7.67, 1.14 Hz, 1 H), 7.36 (t, 2-thioxo-2,3- J=6.87 Hz, 1 H), 6.02 (d, dihydropyrimidin J=2.52 Hz, 1 H), 4.49 (br. s., 2 -4(1H)-one H), 3.63 - 3.72 (m, 2 H), 3.19 s, 3 H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.54 benzofu ran (br. s., 1 H), 7.68 (d, J=7.56 Hz, y|)(2- 1 H), 7.55 (d, J=8.24 Hz, 1 H), methoxyethyl)— 7.44 (t, J=7.67 Hz, 1 H), 7.34 (t, 2-thioxo-2,3- J=7.44 Hz, 1 H), 7.23 (s, 1 H), dihydropyrimidin 6.25 (d, J=2.29 Hz, 1 H), 4.66 -4(1H)-one (br. s., 2 H), 3.78 (t, J=5.84 Hz, , 3.25 s, 3 H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm .48 (br. s., 1 H), 7.75 (dd, o 6-(1- J=7.79, 1.37 Hz, 1 H), 7.67 (d, benzofu ran J=2.29 Hz, 1 H), 7.35 (dd, | \ yI)(2- J=7.30, 7.30 Hz, 1 H), 7.27 (dd, 307 1 s methoxyethyl)— 303.4 H J=7.56, 1.15 Hz, 1 H), 6.87 (d, 2-thioxo-2,3- J=2.29 Hz, 1 H), 5.98 (s, 1 H), opyrimidin O 4.57 - 4.76 (m, 1 / H), 3.93 - 4.10 -4(1H)-one (m, 1 H), 3.59 - 3.75 (m, 1 H), 3.33 - 3.50 (m, 1 H), 3.03 (s, 3 Ex- 1H NMR Spectral Data or Com ound ample Napme HPLC Retention Time and # Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.97 6-(2,3-dihydro- (br. s., 1 H), 7.15 (d, J=1.37 Hz, 1-benzofuran 1 H), 7.08 (dd, J=8.01, 2.06 Hz, y|)(2- 1 H), 6.85 (d, J=8.24 Hz, 1 H), methoxyethyl)— .84 (d, J=2.75 Hz, 1 H), 4.67 2-thioxo-2,3- (t, J=8.70 Hz, 2 H), 4.43 (t, dihydropyrimidin J=5.50 Hz, 1 H), 3.64 (t, J=5.50 -4(1H)-one Hz, 2 H), 3.28 (t, J=8.93 Hz, 2 , 3.20 s, 3 H 6-(1,3- 1H NMR (400 MHz, benzodioon METHANOL-d3) 6 ppm 6.96 (d, y|)(2- J=1.83 Hz, 1 H), 6.94 (s, 1 H), methoxyethyl)— 6.92 (d, J=1.83 Hz, 1 H), 6.05 xo-2,3- (s, 2 H), 5.78 (s, 1 H), 4.43 (t, dihydropyrimidin J=5.72 Hz, 2 H), 3.63 (t, J=5.72 -one Hz,2H,3.17 s,3H 1H NMR (400 MHz, METHANOL-d3) 5 ppm 7.51 (ddd, J=8.36, 7.44, 1.60 Hz, 1 6-(2- H), 7.32 (dd, , 1.60 Hz, 1 ethoxypheny|)- H), 7.11 (d, J=8.70 Hz, 1 H), 1-(2- 7.08 (t, J=7.30 Hz, 1 H), 5.75 methoxyethyl)— (s, 1 H), 4.70 - 4.79 (m, 1 H), 2-thioxo-2,3- 4.15 (q, J=7.20 Hz, 2 H), 3.82 - dihydropyrimidin 3.92 (m, 1 H), 3.69 (ddd, -4(1H)-one 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 1H NMR (400 MHz, 6-(4- METHANOL-d3) 5 ppm 7.36 (d, ethoxypheny|)- J=8.70 Hz, 2 H), 7.03 (d, 1-(2- J=8.70 Hz, 2 H), 5.76 (s, 1 H), methoxyethyl)— 4.44 (t, J=5.50 Hz, 2 H), 4.10 2-thioxo-2,3- (q, J=6.87 Hz, 2 H), 3.61 (t, opyrimidin J=5.95 Hz, 2 H), 3.14 (s, 3 H), -4(1H)-one 1.42 t, J=7.10 Hz, 3 H 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, FORM-d) 6 ppm 9.46 (br. s, 1 H), 7.27 - 7.31 (m, 1 1-(2- H), 7.03 (d, J=1.83 Hz, 1 H), methoxyethyl)— 6.86 (d, J=8.20 Hz, 1 H), 5.81 6-(2-methoxy—5- (d, J=2.29 Hz, 1 H), 4.62 - 4.72 methylphenyl)— (m, 1 H), 3.84 - 3.93 (m, 1 H), xo-2,3- 3.82 (s, 3 H), 3.72 (ddd, dihydropyrimidin J=10.19, 7.90, 5.72 Hz, 1 H), -4(1H)—one 3.44 (ddd, J=10.19, 6.30, 4.12 Hz, 1 H), 3.14 (s, 3 H), 2.34 (s, 1H NMR (400 MHz, 6-(6- CHLOROFORM-d) 6 ppm 9.60 ethoxypyridin (br. s., 1 H), 8.13 (d, J=2.29 Hz, (2- 1 H), 7.57 (dd, J=8.47, 2.06 Hz, methoxyethyl)— 1 H), 6.82 (d, J=8.70 Hz, 1 H), 2-thioxo-2,3- 5.84 (s, 1 H), 4.42 (q, J=7.02 dihydropyrimidin Hz, 2 H), 4.37 (br. s, 2 H), 3.68 -4(1H)—one (t, J=5.04 Hz, 2 H), 3.23 (s, 3 , 1.43 t, J=6.87 Hz, 3 H (dimethylamino) 1H NMR (400 MHz, _3_(2_ CHLOROFORM-d) 6 ppm 9.83 methoxyethyl)— (br. s., 1 H), 8.30 (s, 2 H), 5.83 2-thioxo-2,3- (d, J=2.75 Hz, 1 H), 4.43 (br. s., o—4,5'- 2 H), 3.72 (t, J=5.04 Hz, 2 H), bipyrimidin- 3.26 (s, 3 H), 3.26 (s, 6 H) 6(1H)—one 1H NMR (400 MHz, 6-(3-fluoro CHLOROFORM-d) 6 ppm 9.58 methoxyphenyl) (br. s., 1 H), 7.13 (dd, J=11.22, -1 _(2_ 2.06 Hz, 1 H), 7.07 (dd, J=8.70, methoxyethyl)— 1.83 Hz, 1 H), 7.03 (dd, J=7.80, 2-thioxo-2,3- 7.80 Hz, 1 H), 5.81 (d, J=2.29 dihydropyrimidin Hz, 1 H), 4.37 (br. s., 2 H), 3.95 -4(1H)—one (s, 3 H), 3.65 (t, J=5.27 Hz, 1 , 3.21 s, 3 H 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.49 6-(2-fluoro (br. s., 1 H), 7.22 (t, J=8.47 Hz, methoxyphenyl) 1 H), 6.81 (dd, J=8.24, 2.29 Hz, -1 _(2_ 1 H), 6.72 (dd, J=11.68, 2.06 methoxyethyl)— Hz, 1 H), 5.86 (d, J=2.75 Hz, 1 xo-2,3- H), 4.60 - 4.70 (m, 1 H), 4.02 - dihydropyrimidin 4.12 (m, 1 H), 3.87 (s, 3 H), -4(1H)—one 3.71 - 3.81 (m, 1 H), 3.48 (dd, J=9.85, 4.81 Hz, 1 H), 3.18 (s, Ex- 1H NMR al Data or Com ound ample Napme HPLC ion Time and # Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.58 6-(5-fluoro (br. s, 1 H), 7.17 (ddd, J=9.05, methoxyphenyl) 7.90, 3.21 Hz, 1 -1 _(2_ H), 6.98 (dd, J=7.79, 3.21 Hz, 1 H), 6.89 (dd, methoxyethyl)— J=9.16, 4.12 Hz, 1 H), 5.79 (d, 2-thioxo-2,3- J=2.29 Hz, 1 H), 4.85 - 4.75 (m, opyrimidin 1 H), 3.82 (s, 3 H), 3.72 - 3.80 -4(1H)—one (m, 2 H), 3.37 - 3.43 (m, 1 H), 3.18 s, 3 H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.58 6-(4-fluoro (br. s., 1 H), 7.21 (dd, J=8.24, methoxyphenyl) 8.41 Hz, 1 -1 _(2_ H), 8.78 (ddd, J=8.20, 8.20, 2.30 Hz, 1 H), methoxyethyl)— 8.71 (dd, J=10.53, 2.29 Hz, 1 2-thioxo-2,3- H), 5.79 (s, 1 H), 4.85 - 4.75 dihydropyrimidin (m, 1 H), 3.85 (s, 3 H), 3.89 - -4(1H)—one 3.83 (m, 2 H), 3.38 - 3.47 (m, 1 , 3.18 s, 2 H 1H NMR (400 MHz, METHANOL-d3) 5 ppm 8.07 1-(2— (dd, J=6.87, 2.75 Hz, 1 H), 7.98 methoxyethyl)— - 8.04 (m, 1 H), 7.88 - 7.71 (m, aphthyl)— 1 H), 7.58 - 7.88 (m, 4 H), 5.92 2-thioxo-2,3- (s, 1 H), 4.50 -4.80 (m, 1 H), dihydropyrimidin 3.70 - 3.80 (m, 1 H), 3.59 - 3.87 -4(1H)—one (m, 1 H), 3.43 (ddd, J=10.42, 8.07, 4.58 Hz, 1 H), 2.98 (s, 3 1H NMR (400 MHZ, CHLOROFORM-d) 6 ppm 9.99 (br. 3., 1 H), 8.89 (d, J=2.29 Hz, 1-(2— 1 H), 8.17 - 8.23 (m, 2 H), 7.91 methoxyethyl)— (dd, J=8.01, 1.14 Hz, 1 H), 7.87 6-quinolinyl- (ddd, J=8.59, 6.98, 1.37 Hz, 1 2-thioxo-2,3- H), 7.69 (ddd, J=8.24, 6.87, dihydropyrimidin 1.37 Hz, 1 H), 5.95 (d, J=0.92 -4(1H)—one Hz, 1 H), 4.36 - 4.46 (m, 2 H), 3.68 (t, J=4.81 Hz, 2 H), 3.21 Ex- 1H NMR Spectral Data or Com ound ample Napme HPLC Retention Time and # Conditions 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm .50 (br. s., 1 H), 9.02 (dd, J=4.12, 1.80 Hz, 1 H), 8.28 (d, J=8.47 Hz, 1 H), 8.02 (d, 1-(2- J=8.47 Hz, 1 H), 7.81 (dd, methoxyethyl)— J 8.47, 7.33 Hz, 1 H), 7.58 (dd, 6-quinolinyl- J 7.10, 0.89 Hz, 1 H), 7.51 (dd, xo-2,3- J=8.59, 4.24 Hz, 1 H), 5.98 (d, dihydropyrimidin J=1.37 Hz, 1 H), 4.45 (dt, -4(1H)—one J=14.14, 4.84 Hz, 1 H), 3.83 - 3.98 (m, 1 H), 3.80 (ddd, J=10.48, 8.35, 4.89 Hz, 1 H), 3.49 (dt, J=10.30, 4.92 Hz, 1 , 3.02 s, 3 H 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.82 (br. s., 1 H), 8.95 (dd, J=4.12, 1.83 Hz, 1 H), 8.25 (dd, J=8.47, 1.80 Hz, 1 H), 8.01 (dd, J=8.24, 1-(2- 1.37 Hz, 1 H), 7.74 (dd, J=6.87, methoxyethyl)— 1.37 Hz, 1 H), 7.88 (dd, J=8.24, 6-quinolinyl- 8.87 Hz, 1 H), 7.52 (dd, J=8.24, 2-thioxo-2,3- 4.12 Hz, 1 H), 5.93 (d, J=2.29 dihydropyrimidin Hz, 1 H), 4.85 (ddd, J=13.74, -4(1H)—one 5.04, 3.88 Hz, 1 H), 3.75 (ddd, J=10.30, 8.24, 5.50 Hz, 1 H), 3.85 (ddd, 7, 8.24, 5.72 Hz, 1 H), 3.38 (ddd, J=10.30, .50, 3.88 Hz, 1 H), 3.07 (s, 3 1H NMR (400 MHz, 6-(1-benzothien- CHLOROFORM-d) 6 ppm 9.81 2-y|)(2- (br. s., 1 H), 7.80 - 7.92 (m, 2 methoxyethyl)— H), 7.51 (s, 1 H), 7.42 - 7.48 2-thioxo-2,3- (m, 2 H), 6.10 (d, J=2.29 Hz, 1 dihydropyrimidin H), 4.57 (t, J=5.50 Hz, 2 H), —one 3.74 (t, J=5.50 Hz, 2 H), 3.26 (s, 3 H) 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.88 6-(1-benzothien- (br. s., 1 H), 7.87 - 7.98 (m, 1 1-(2- H), 7.87 (s, 1 H), 7.52 - 7.80 methoxyethyl)— (m, 1 H), 7.41 - 7.51 (m, 2 H), 2-thioxo-2,3- 5.98 (d, J=2.29 Hz, 1 H), 4.88 dihydropyrimidin (dt, J=13.97, 4.10 Hz, 1 H), -4(1H)—one 3.92 - 4.07 (m, 1 H), 3.89 - 3.82 (m, 1 H), 3.41 - 3.50 (m, 1 H), Ex- 1H NMR Spectral Data or Compound am#p|e HPLC Retention Time and Name Conditions ygthyly 1H NMR (400 MHz, METHANOL-d3) 5 ppm 7.89 - 6-oxo—2—thioxo- 7.99 (m, 1 1 2 3 6- H), 7.86 (s, 1 H), 325 tetrah,ydropyrimi 320.1 7.54 - 7.65 (m, 2 H), 5.81 (s, 1 H), 4.36 (br. s., 2 H), 3.60 (t, diny|]-N- J=5.50 Hz, 2 H), 3.11 (s, 3 H), methylbenzamid 2.92 (s, 3 H) . 1H NMR (400 MHz, 6'(2’31'd£‘ydr°' CHLOROFORM-d) 5 ppm 9.49 benzodioxin (br. s., 1 H), 6.94 (d, J=8.24 Hz, 1 H), 6.87 (d, J=2.29 Hz, 1 H), y|)(2- 326 321.1 6.80 (dd, J=8.24, 2.29 Hz, 1 H), methoxyethyl)— .82 (d, J=2.29 Hz, 1 H), 4.42 2-thioxo—2 3_ dihydropyrimidin (t, J=5.27 Hz, 2 H), 4.27 - 4.35 (m, 4 H), 3.65 (t, J=5.72 Hz, 2 -4(1H)—one H , 3.22 s, 3 H 1H NMR (400 MHz, 6-(4- CHLOROFORM-d) 5 ppm 9.59 poxyphen (br. s., 1 H), 7.25 (d, J=9.16 Hz, (2- 2 H), 6.95 (d, J=8.70 Hz, 2 H), 327 methoxyethyl)— 321.2 5.83 (d, J=2.29 Hz, 1 H), 4.62 2-thioxo—2,3- (spt, J=6.00 Hz, 1 H), 4.42 (t, dihydropyrimidin J=5.50 Hz, 2 H), 3.64 (t, J=5.72 -4(1H)—one Hz, 2 H), 3.18 - 3.21 (m, 3 H), 1.38 d, J=6.41 Hz, 6 H 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm .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), O 6-(2- 7.02 (ddd, J=7.80, 7.70, 0.92 %0* poxyphen Hz, 1 H), 6.95 (d, J=8.24 Hz, 1 | y|)(2- H), 5.82 (s, 1 H), 4.74 (ddd, 328 52\ methoxyethyl)— 321.2 J=13.74, 5.04, 3.66 Hz, 1 H), 2-thioxo—2,3- 4.62 (spt, J=6.00 Hz, 1 H), 3.86 dihydropyrimidin (ddd, J=13.85, 7.90, 6.18 Hz, 1 / -4(1H)—one H), 3.71 (ddd, J=10.08, 8.24, .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 1H NMR al Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.48 (br. s., 1 H), 7.15 (dd, J=8.20 6-(2,3- Hz, 1 H), 7.06 (dd, J=8.24, 1.37 dimethoxypheny Hz, 1 H), 6.83 (dd, J=7.79, 1.37 |)(2- Hz, 1 H), 5.85 (d, J=2.75 Hz, 1 methoxyethyl)— H), 4.67 (dt, 4, 4.58 Hz, 2-thioxo-2,3- 1 H), 3.92 (s, 3 H), 3.86 - 4.00 opyrimidin (m, 1 H), 3.82 (s, 3 H), 3.72 -4(1H)-one (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 1H NMR (300 MHz, 6-(3,5- CHLOROFORM-d) 5 ppm dimethoxypheny .17 (br. s., 1 H), 6.55 (t, J=2.30 Hz, 1 H), 6.48 (d, methoxyethyl)— J=2.30 Hz, 2 H), 5.88 (d, 2-thioxo-2,3- J=1.84 Hz, 1 H), 4.39 (t, J=5.51 dihydropyrimidin Hz, 2 H), 3.82 (s, 6 H), 3.68 (t, -4(1H)-one J=5.51 Hz, 2 H , 3.22 s, 3 H 1H NMR (400 MHz, 6-(3,4- CHLOROFORM-d) 5 ppm dimethoxypheny .27 (br. s., 1 H), 6.85 - 6.98 |)(2- (m, 3 H), 5.88 (s, 1 H), 4.33 - methoxyethyl)— 4.49 (m, 2 H), 3.94 (s, 3 H), 2-thioxo-2,3- 3.91 (s, 3 H), 3.63 - 3.75 (m, 2 opyrimidin H), 3.22 (s, 3 H) -4(1H)-one 1H NMR (400 MHz, CHLOROFORM-d) d ppm 9.77 (br. s., 1 H), 7.43 (d, J=7.79 Hz, 6-(2,6- 1 H), 6.42 (d, J=8.24 Hz, 1 H), dimethoxypyridi .79 (s, 1 H), 4.75 (ddd, ny|)(2- J=13.60, 3.50, 3.50 Hz, 1 H), methoxyethyl)— 3.98 (s, 3 H), 3.97 (s, 3 H), 3.85 2-thioxo-2,3- (ddd, J=13.74, 8.70, 5.50 Hz, 1 dihydropyrimidin H), 3.77 (ddd, J=9.20, 9.20, -4(1H)-one 4.10 Hz, 1 H), 3.43 (ddd, J=9.60, 4.60, 4.60 Hz, 1 H), 3.18 (s, 3 H) 1H NMR (400 MHz, 6-(5-Chloro METHANOL-d3) 5 ppm 7.51 methoxyphenyl) -1 _(2_ (dd, J=8.70, 2.75 Hz, H), 7.35 (d, J=2.75 Hz, 1 H), 7.13 (d, methoxyethyl)— J=9.16 Hz, 1 H), 5.77 (s, 1 H), 2-thioxo-2,3- 4.67 - 4.76 (m, 1 H), 3.89 (s, 3 dihydropyrimidin H), 3.73 - 3.81 (m, 2 H), 3.38 - -4(1H)-one 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 6-(2-chloro .18 (br. s., 1 H), 7.26 (d, methoxyphenyl) J=8.70 Hz, 1 -1 _(2_ H), 7.00 (d, J=2.29 Hz, 1 H), 6.92 (dd, methoxyethyl)— J=8.93, 2.06 Hz, 1 H), 5.84 (s, xo-2,3- 1 H), 4.64 - 4.78 (m, 1 H), 3.87 dihydropyrimidin (s, 3 H), 3.76 - 3.85 (m, 2 H), -4(1H)—one 3.39 - 3.52 (m, 1 H), 3.19 (s, 3 1H NMR (400 MHz, 6-(4-chloro CHLOROFORM-d) 5 ppm 9.96 methoxyphenyl) (br. s., 1 H), 7.17 (d, J=7.79 Hz, -1 _(2_ 1 H), 7.06 (dd, J=8.24, 1.83 Hz, methoxyethyl)— 1 H), 6.97 (d, J=1.37 Hz, 1 H), 2-thioxo-2,3- 5.79 (s, 1 H), 4.64 - 4.77 (m, 1 opyrimidin H), 3.86 (s, 1 H), 3.72 - 3.82 -4(1H)—one (m, 2 H), 3.36 - 3.47 (m, 1 H), 4-[3-(2- methoxyethyl)— 1H NMR (400 MHz, 6-oxothioxo- METHANOL-d3) 5 ppm 7.53 - 1,2,3,6- 7.60 (m, 4 H), 5.82 (s, 1 H), tetrahyd ropyrimi 4.40 (t, J=5.27 Hz, 2 H), 3.62 (t, diny|]-N, N- J=5.50 Hz, 2 H), 3.14 (s, 3 H), dimethylbenzam 3.13 (s, 3 H), 3.03 (s, 3 H) 1H NMR (400 MHz, OL-d3) 5 ppm 7.37 (dd, J=8.59, 2.18 Hz, 1 H), 7.16 6-(5-isopropyI (d, J=2.29 Hz, 1 H), 7.03 (d, methoxyphenyl) J=8.70 Hz, 1 H), 5.72 (s, 1 H), -1 _(2_ 4.69 (dt, J=13.80, 4.89 Hz, 1 methoxyethyl)— H), 3.83 (s, 3 H), 3.76 - 3.82 2-thioxo-2,3- (m, 1 H), 3.66 (ddd, J=10.19, opyrimidin 7.79, 6.07 Hz, 1 H), 3.41 (ddd, -4(1H)—one 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) 6-[6- 1H NMR (400 MHz, (dimethylamino) CHLOROFORM-d) 5 ppm 9.61 (br. s., 1 H), 7.90 (s, 1 H), 7.27 methoxypyridin- (s, 1 H), 5.91 (s, 1 H), 4.78 (dt, 3-y|](2- J=14.08, 3.72 Hz, 1 H), 3.87 (s, methoxyethyl)— 3 H), 3.82 (dt, 4, 6.41 2-thioxo-2,3- Hz, 1 H), 3.67-3.76 (m, 1 H), dihydropyrimidin 3.42- 3.51 (m, 1 H), 3.21 (s, 3 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, 1-(2- CHLOROFORM-d) 9.58 (s, methoxyethyl)— 1H), 8.02 (d, 1H), 7.82 (d, 1H), ethoxy—1 - 7.50-7.58 (m, 2H), 7.39-7.43 naphthy|) (dd, 1H), 7.31 (d, 1H), 5.89 (s, thioxo-2,3- 1H), 4.26-4.33 (m, 1H), 4.02- dihydropyrimidin 4.11 (m, 1H), 3.97 (s, 3H), -4(1H)—one 3.51-3.57 (m, 1H), 3.31-3.39 m, 1H , 2.88 s, 3H 1H NMR (400 MHz, 1-(2— CHLOROFORM-d) 6 ppm 9.56 methoxyethyl)— (br. s., 0 H), 7.53 (dd, J=7.80, 2-thioxo—6-[3- 7.80 Hz, 1 H), 7.37 (d, J=9.16 (trifluoromethox Hz, 1 H), 7.25 - 7.31 (m, 2 H), y)pheny|]—2,3- .84 (d, J=2.29 Hz, 1 H), 4.34 dihydropyrimidin (br. s, 2 H), 3.66 (br. s, 2 H), -4(1H)—one 3.20 s, 3 H 1H NMR (400 MHz, 1-(2- METHANOL-d3) 6 ppm 6.96 (s, yethyl)— 1 H), 6.78 (s, 1 H), 5.70 (s, 1 6-(3-methoxy— H), 4.60 - 4.72 (m, 1 H), 3.86 ,6,7,8- (dt, J=14.03, 7.30 Hz, 1 H), tetrahyd ronapht 3.81 (s, 3 H), 3.67 (ddd, haleny|) J=10.30, 7.56, 6.41 Hz, 1 H), thioxo-2,3- 3.41 (ddd, J=10.36, 6.35, 4.12 dihydropyrimidin Hz, 1 H), 3.07 (s, 3 H), 2.82 (br. -4(1H)—one s., 2 H), 2.72 (br. s., 2 H), 1.75 1-(2— 1H NMR (400 MHz, methoxyethyl)— CHLOROFORM-d) 5 ppm 9.91 2-thioxo (br. s., 1 H), 6.59 (s, 2 H), 5.88 (d, J=2.29 Hz, 1 H), 4.39 (t, trimethoxypheny J=5.50 Hz, 2 H), 3.92 (s, 3 H), 3.88 (s, 6 H), 3.73 (t, J=5.27 dihydropyrimidin Hz, 2 H), 3.24 (s, 3 H) -4(1H)—one 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 9.49 1-(2— (br. s., 1 H), 6.92 (d, J=8.70 Hz, methoxyethyl)— 1 H), 6.73 (d, J=8.70 Hz, 1 H), 2-thioxo .83 (d, J=2.29 Hz, 1 H), 4.62 - (2,3,4- 4.71 (m, 1 H), 3.93 - 3.98 (m, 1 trimethoxypheny H), 3.92 (s, 3 H), 3.90 (s, 3 H), |)-2,3- 3.89 (s, 3 H), 3.73 (ddd, dihydropyrimidin J=10.08, 8.01, 5.72 Hz, 1 H), -4(1H)—one 3.46 (ddd, J=10.08, 6.18, 3.89 Hz,1H,3.17 s,3H 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions 1H NMR (400 MHz, 6-(4-fluoro METHANOL-d3) 6 ppm 7.23 (d, isopropyI J=8.24 Hz, 1 H), 6.87 (d, methoxyphenyl) J=12.14 Hz, 1 H), 5.72 (s, 1 H), -1 _(2_ 4.69 (dt, J=13.45, 4.15 Hz, 1 methoxyethyl)— H), 3.84 (s, 3 H), 3.64 - 3.81 2-thioxo-2,3- (m, 2 H), 3.40 (ddd, J=9.79, dihydropyrimidin 5.55, 3.66 Hz, 1 H), 3.19 (spt, -4(1H)—one J=7.10 Hz, 1 H), 3.10 (s, 3 H), 1.24 d, J=6.87 Hz, 6 H 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.86 1-(2- (br. s., 1 H), 7.84 (d, J=8.70 Hz, methoxyethyl)— 1 H), 7.42 (d, J=8.70 Hz, 2 H), 6-(8-methoxy—2- 7.10 (d, J=8.24 Hz, 1 H), 5.95 uinolin- (d, J=2.29 Hz, 1 H), 4.49 (dt, -y|)thioxo- J=14.08, 5.09 Hz, 1 H), 4.15 (s, 2,3- 3 H), 3.85 - 4.00 (m, 1 H), 3.61 opyrimidin (ddd, 9, 6.87, 4.58 Hz, 1 -4(1H)—one H), 3.49 (dt, J=10.30, 5.38 Hz, 1H,3.04 s,3H,2.84 s,3H 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 9.58 6-[5-fluoro (br. s., 1 H), 7.31 - 7.39 (m, 1 (trifluoromethox H), 7.26 - 7.29 (m, 1 H), 7.15 y)pheny|](2- (dd, J=7.90, 3.09 Hz, 1 H), 5.83 methoxyethyl)— (d, J=2.52 Hz, 1 H), 4.68 (dt, 2-thioxo-2,3- J=14.20, 3.32 Hz, 1 H), 3.88 dihydropyrimidin (td, J=9.85, 3.66 Hz, 1 H), 3.72 -4(1H)—one (ddd, J=13.91, 9.45, 3.89 Hz, 1 H), 3.39 (dt, J=10.36, 3.75 Hz, 4-[3-(2- 1H NMR (400 MHz, methoxyethyl)— CHLOROFORM-d) 6 ppm 9.84 6-oxothioxo- (br. s., 1 H), 7.90 (d, J=6.87 Hz, 347 370.1 2 H), 7.56 (d, J=6.87 Hz, 2 H), tetrahyd ropyrimi .84 (s, 1 H), 4.32 (br. s., 2 H), y|]-N, N- 3.66 (t, J=4.35 Hz, 2 H), 3.20 dimethylbenzen (s, 3 H), 2.81 (s, 6 H) esulfonamide Ex- 1H NMR Spectral Data or ample Napmeound HPLC Retention Time and # Conditions 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm .14 (br. s., 1 H), 7.91 (ddd, methoxyethyl)— J=8.24, 1.80, 1.50 Hz, 1 H), 6-oxo—2—thioxo- 7.84 (dd, J=1.60, 1.60 Hz, 1 H), 1,2,3,6- 7.69 (dd, , 7.80 Hz, 1 H), tetrahyd ropyrimi 7.59 (ddd, J=7.80, 1.40, 1.40 yl]-N, N- Hz, 1 H), 5.85 (d, J=1.83 Hz, 1 dimethylbenzen H), 4.31 (br. s, 2 H), 3.87 (br. esulfonamide s., 2 H), 3.21 (s, 3 H), 2.77 (s, 8 Additions to |. Beta Keto Ester Route Section E. Ester Route Section Preparation 19 BUCK tert-Butyl 3-(2-(2-hydroxyethoxy)pheny/)—3—oxopropanoate To a solution of tert—butyl acetate (7.96 g, 68.5 mmol) in anhydrous THF (100 mL) was added freshly prepared lithium diisopropyl amine (37 mL, 1.85 M in THF) dropwise over min at -78 °C min. 2H- , and the mixture was stirred at -78 °C for 30 benzo[e][1,4]dioxepin-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. Saturated NaHCOB on was added and the mixture was extracted with EtOAc. The organic layer was dried (NazSO4), and concentrated under reduced pressure to give the title compound (6.0 g, 77.9%) as a yellow oil, which was used directly in the next step without further cation.
MS (ES+) 303.2 [M+Na]+. 1H NMR (500 MHz, CDCI3) 5 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) 8.97 (d, J=8.4 Hz, 1 H) 4.18-4.20 (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).
Preparation 20 Ethyl 3-(2—(2-hydroxyethoxy)pheny/)—3-oxopropanoate tert—Butyl 3-(2-(2-hydroxyethoxy)phenyl)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 trated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography (30-40% EtOAc: petroleum ether) to give the title nd as a yellow solid.
Preparation 21 (Z)-Ethyl 3-((2-amino-2—oxoethyl)amino)(2-(2—hydroxyethoxy)pheny/)acrylate To a solution of ethyl 3-(2-(2-hydroxyethoxy)phenyl)—3-oxopropanoate (2 g, 7.94 mmol) and glycinamide hloride (3.5 g, 31.7 mmol) in methanol (20 mL) was added triethylamine (3.21 g, 31.7 mmol) at room temperature. The mixture was stirred at 40 0C for 20 min. Acetic acid (1.9 g, 31.7 mmol) was added, and the mixture was d at 80 °C for 18 hours. The reaction mixture was cooled to room temperature and saturated sodium bicarbonate (200mL) was added. The organic layer was separated, dried (Na2804) and trated to give a yellow solid. The solid was washed with EtOAc (20 mL), and the residue was dried under reduced pressure to give the title compound as a white solid. This material was used without further purification.
Example 349 HN o/\/OH 2—(6-(2-(2-Hydroxyethoxy)phenyl)oxothioxo-3, 4-dihydropyrimidin- 1 (2H)- y/)acetamide To a solution of (Z)—ethyl 3-((2-aminooxoethyl)amino)—3-(2-(2- hydroxyethoxy)phenyl)acrylate (1.0 g, 3.25 mmol) in tetrahydrofuran (15 mL) was added trimethylsilyl isothiocyanate (1.7 g, 12.9 mmol), and the mixture was stirred at 80 °C for 18 hours. The reaction e was cooled to room temperature, poured into a flask containing water and extracted with CH20|2 (3 x 100 mL). The combined organic layers were dried and concentrated under reduced pressure to give a yellow solid, which was purified by flash chromatography (2-5% H20I2) to give the title compound (330 mg, 31.7%) as a yellow solid.
MS (ES+) 343.9 [M+Na]. 1H NMR (DMSO-d6) d: 12.77 (s, 1H), .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), .34 (br. s., 1H), 4.84 (br. s., 1H), 4.00-4.15 (m, 2H), 3.93 (br. s., 1H), 3.55 (q, J=4.4 Hz, |||. Amide Coupling Route n Preparation 22 08‘) OMe (Z)-Methyl 3-(2, 4-dimethoxyphenyI)((2—ethoxy—2—oxoethyl)amino)acry/ate To a solution of methyl 3-(2,4-dimethoxyphenyl)oxopropanoate (5.0 g, 21 mmol) in EtOH (30 mL) was added glycine methyl ester hydrochloride (10.5 g, 83.9 mmol) followed by acetic acid (1.20 mL, 21 mmol) and ylamine (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 EtOAc and saturated aqueous ammonium chloride.
The organic layer was washed with brine, dried over sodium e and concentrated in vacuo. The crude product was dissolved in CH2CI2 (10 mL) filtered through a plug of silica gel, eluting with 15-35% EtOAc in heptanes and dried under vacuum to give the title compound (4.7 g, 69%) as a yellow solid. This material was used in the next step without further purification.
MS(ES+)324.3[M+1]+.1H NMR (500 MHz, CDCI3) 6 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 0%) OMe OEt Ethyl 2-(6- (2, 4-dimethoxypheny/)oxothioxo—3, 4-dihydropyrimidin— 1 (2H)-yl)acetate To a solution of (Z)-methyl 3-(2,4-dimethoxyphenyl)((2-ethoxy oxoethyl)amino)acrylate (4.68 g, 15.1 mmol) in 2-methyltetrahydrofuran (38 mL) was added (trimethylsilyl)isothiocyanate (12.9 mL, 90.8 mmol). The ing solution was purged with nitrogen gas for 3 times, and the mixture was heated at 110 0C for 18 hours. The mixture was cooled down to room temperature and the solvent was removed under reduced pressure to give a red solid. This residue was ded in a mixture of 3:1 heptane/EtOAc (200 mL), and it was stirred at room temperature for 1 hour. The solid was filtered, and triturated with CH2CI2 (100 mL), concentrated under d pressure and dried under vacuum the title compound (4.42 g, 87%) as a pink solid. This material was used t further purification in the next step.
MS(ES+)351.5[M+1]+.1H NMR (500 MHz, CDCI3) 6 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) 4.25- 4.20 (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 0V OMe 2, thoxyphenyl)oxothioxo—3, 4-dihydropyrimidin- 1 (2H)-y/)acetic acid To a solution of ethyl 2—(6-(2,4-dimethoxyphenyl)—4-oxo—2—thioxo-3,4-dihydropyrimidin- 1(2H)—yl)acetate (6.8 g, 20.3 mmol) in methanol (34 mL) was added 6N aqueous NaOH (16.9 mL), and the solution was stirred at 35 °C for 3 hours. The mixture was concentrated under reduced pressure, and water (100 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 200 mL), and acidified with concentrated HCI to pH ~ 2. The resultant acidic aqueous solution was extracted with EtOAc (3 x 200 mL), and the combined organic layers were dried with sodium sulfate, and concentrated under reduced pressure to give the title compound 6.53 g (99%) as a white solid.
MS (ES+) 323.2 [M+1]+. 1H NMR (500 MHz, CD30D) 6 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 HN OMe s N X 0 OMe OJKMNNH tert-Butyl (6-(2, 4-dimethoxyphenyl)oxo—2—thioxo—3, 4-dihydropyrimidin-1(2H)- y/)acetamido)ethyl)carbamate To a solution of 2-(6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- yl)acetic acid (40 g, 124 mmol) in DMF (300 mL) was added utyl (2- aminoethyl)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 it was purged with nitrogen gas for 3 times. After 10 s, a 50% solution of T3P in DMF (109 mL) was added drop-wise at 0 °C, and stirring was continued for 1 hour, whereupon the water/ice bath was removed and stirring was continued for 4 hours. The reaction solution was slowly poured into a stirring on of aqueous HCI solution (2500 mL, 0.5 M), and the suspension was stirred at room temperature for 1 hour. The formed solid was filtered, and the filter cake was washed with 0.5M HCI solution (500 mL) followed by water (500 mL). The solid was dried in the vacuum oven at 50 °C for 20 hours to give 54.6 g of light beige powder. This solid was suspended in EtOAc (500 mL), heated to 70 °C under a stream of nitrogen gas with stirring for 1 hour, and then at room temperature for 18 h. The suspension was cooled down to 0 °C, and the solid was ed, the filter cake washed with cold (0 °C) EtOAc (100 mL) and dried in the vacuum oven at 50 °C for 9 hours to give 49.0 g of off-white solid. This solid was suspended in itrile (300 mL), and stirred at 70 °C under a stream of nitrogen for 18 h. The mixture was cooled to 0 °C, and the resultant solid was filtered, washed with cold acetonitrile (50 mL) and dried in the vacuum oven at 50 °C for 8 hours to give 46.5 g of off-white solid. This solid was suspended in EtOAc (350 mL), heated to 70 °C under a stream of en gas with stirring for 1 hour, and then at room temperature for 18 h.
The suspension was cooled down to 0 °C, and the solid was filtered, the filter cake washed with cold (0 °C) EtOAc (50 mL) and dried in the vacuum oven at 50 °C for 9 hours to give the title compound (45.4 g, 78.8%) as an off-white powder.
MS(ES+)465.3[M+1]+.1H NMR (500 MHz, CD30D) 6 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) 4.22- 4.14 (m, 1 H) 3.87 (s, 3 H) 3.85 (s, 3 H) 3.19-3.11 (m, 2 H) 3.06-3.00 (m, 2 H) 1.42 (s, 9 Example 241 0%) OMe H2N/\/NH N-(2-aminoethyI)(6-(2,4-dimethoxyphenyI)oxothioxo-3,4-dihydropyrimidin- 1 (2H)-y/)acetamide hydrochloride To cold (0 °C) ethanol (21.5 mL) under nitrogen was added acetyl de (1.55 mL) dropwise over 5 minutes, and the reaction mixture was then heated at 50 °C for 30 minutes. The reaction mixture was cooled to room ature and tert-butyl (2-(2-(6- (2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- yl)acetamido)ethyl)carbamate was added (1.0 g, 2.15 mmol), followed by heating to 50 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in ethanol (10 mL), heated to 75 °C for minutes, and EtOAc (20 mL) was added and heating was continued for r 20 minutes. The mixture was allowed to slowly cool to down to room temperature with stirring during 18 hours. The resultant precipitate was filtered and dried in a vacuum oven at 70 °C for 20 hours to give the title compound (751 mg, 87%) as a white solid.
MS (ES+) 365.2 [M+1]+. 1H NMR (500 MHz, DMSO-De) 6 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) .78 (s, 1 H) 5.41-5.35 (m, 1 H) 4.07-4.02 (m, 1 H) 3.84 (s, 3 H) 3.83 (s, 3 H) 3.20-3.16 (m, 2 H) 2.74-2.64 (m, 2 H).
IV. Guanidine Route Section Example 350 HN O J\\Jj\/ H2N N 0 Methyl ({3-[6—(5—chloro—2-methoxyphenyl)oxo-2—thioxo—3, 4-dihydropyrimidin- 1(2H)-y/]propyl}amino)methy/idenejcarbamate To a on of 1-(3-aminopropyl)—6-(5-chloromethoxyphenyl)thioxo-2,3- dihydropyrimidin-4(1H)-one (prepared in an analogous manner to Example 6; 50 mg, 0.14 mmol) and methyl [amino(1H-pyrazoly|)methylidene]carbamate (28 mg, 0.16 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine (0.024 mL, 0.14 mmol) at room temperature, and the mixture was stirred for 72 hours. The t was removed under reduced pressure, the residue was dissolved in DMSO (0.9 mL) and ed using mass-triggered automatic purification to give the title compound (4.9 mg) 2012/055949 MS (ES+) 425.9 . Retention time: 1.54 min; Method: XBridge C18 5um 4.6x50mm, 95%H20/5%MeCN linearto 5%H20/95% MeCN over 4.0 min, HOLD at %H20/95%MeCN to 5.0min. (0.03% NH4OH). Flow rate: 2 mL/min.
Preparation 26 ///N F7C/N 3, 3-Dif/uoroazetidinecarbonitrile A suspension of 3,3-difluoroazetidine hydrochloride (600 mg, 4.63 mmol) in DCM (15.4 mL) was treated with triethylamine (1.48 mL). The reaction mixture was cooled to 0 °C, treated with cyanogen bromide (3M in DCM, 2.01 mL, 6.02 mmol) and the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and saturated sodium bicarbonate (5 mL), and extracted with ethyl acetate (3 x 50 mL) and DCM (2 x 50 mL). The combined cs were dried over sodium sulfate, ed and concentrated in vacuo. The crude product was dissolved in dichlormethane (30 mL) and washed with saturated aqueous ammonium chloride (2 x 15 mL). The organic layer was dried over sodium sulfate, filtered and trated in vacuo to give the title compound as a light brown solid (490 mg, 89%). 1H NMR (500 MHz, CDCI3) 6 4.52 (t, 4H).
Preparation 27 Q”,‘N F7C/N/KNH F 1-(1H-Benzotriazoly/)(3,3—dif/uoroazetidiny/)methanimine A mixture of fluoroazetidinecarbonitrile (135 mg, 1.14 mmol) and benzotriazole (136 mg, 1.14 mmol) in 1,2-dichloroethane (0.2 mL) was heated to 80 °C under nitrogen for 30 min. A needle was inserted to facilitate evaporation of the solvent and the mixture was heated at 80 °C for 45 min. The ing solids were washed with ether (2 x 3 mL) and dried under reduced pressure to give the title compound as an off-white solid (160 mg, 51%). 1H NMR (500 MHz, DMSO-d6) 6 8.35 (d, 1H, J = 8.4 Hz), 8.15 (d, 1H, 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).
WO 68875 Example 351 3, 3-Dif/uoro—N-{3-[6-(5-f/uoromethoxyphenyl)oxothioxo—3, dropyrimidin- 1(2H)-yl]propy/}azetidinecarboximidamide To a mixture of 1-(3-aminopropyl)(5-f|uoromethoxyphenyl)—2-thioxo-2,3- dihydropyrimidin-4(1H)-one (prepared in an analogous manner to e 6; 50 mg, 0.14 mmol) and 1-(1H-benzotriazolyl)—1-(3,3-difluoroazetidiny|)methanimine (47.5 mg, 0.174 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) under nitrogen and heated at 60 °C under nitrogen for 1 h. The reaction mixture was cooled to room temperature, and treated with 4N HCI in dioxane (0.25 mL).
The mixture was stirred at room temperature for 10 min, then concentrated in vacuo and azeotroped with es (3 x 10 mL). The residue was dissolved in water (1 mL) and purified using medium pressure reverse-phase (C18) chromatography (100:0 to 70:30 water/acetonitrile) to give the title compound as a white solid (22 mg, 33%).
MS(ES+) 428.2 [M+H]+. 1H NMR (500 MHz, CD3OD) 6 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, 1H), 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 of Table 6 (additions to Table 2) were prepared from the corresponding carboxylic acid to afford the ediate beta-keto-ester as described above for the Preparations in the Carboxylic Acid Route section followed by employing other the methods bed in the |. Beta Keto Ester Route Section as well as standard methods and techniques known to those skilled in the art.
Table 6. Examples from Carboxylic Acid Route 1H NMR Spectral Data or Structure COL"pound HPLC Retention Time and Conditions N-{2-[6-(2,5- 0.32 min Waters Acqity HSS o/ dimethoxyph T3, 2.1x50mm, C18, 1.7pm; eny|)oxo- A: 0.1% formic acid in water; 2-thioxo-3,4- Mobile phase B: 0.1% formic \ dihydropyrim acid in MeCN A: 0.1% idin-1(2H)— ammonia in water; Mobile y|]ethy|}g|yci phase B: 0.1% a in namide MeCN Flow 1.25mI/min 1H NMR (400 MHz, “Effiggj CHLOROFORM-d) 6 ppm 7.59 (dd, J=8.8, 2.7 Hz, 1H) yphe 7.54 (d, J=2.7 Hz, 1H) 7.22 ny|)oxo CI (d, J=9.0 Hz, 1H) 6.86 (t, J = -3 4-di hydropyr,imid 6.2 Hz, 1H), 5.86 (d, J=2.2 Hz, 1H) 4.28 (br. s., 1H) 3.84 in-1(2H)— (s, 3H) 3.65 (br. s., 1H) 2.75- pyl} 2.78 (m, 3H) 2.71 (tt, J=12.7, methanesulf 6.3 Hz, 2H) 1.71-1.81 (m, onamide 1H 1.56-1.66 m, 1H 1-(2-amino ethy|)(1- 1H NMR (400 MHz, DMSO- benzothioph d6) 5 ppm 8.09 (br. s., 1H), eny|) 8.01 (br. s., 3H), 7.98 (br. s., thioxo—2,3- 1H), 7.79 (s, 1H), 7.49 (br. s., dihydro 2H), 6.12 (s, 1H), 4.50 (br. s., din- 2H), 3.12 (br. s., 2H) 27:31:11}; 1H NMR (400 MHz, DMSO- d6) 6 ppm 7.12 (d, J=1.8 Hz, pheny|)(2- h 1H), 7.05 (d, J=8.3 Hz, 1H), 3’2 mydrox ethV| 7.01 (dd, J=8.1, 1.9 Hz, 1H), )' '2 g?“ .74 (s, 1H), 4.72 (t, J=5.7 dihydr,opyrim Hz, 1H), 4.19 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 3.78 (s, 'd'' 'n_4 1H)—( 3H), 3.57 (q, J=6.1 Hz, 2H) 356 o 6-(2,3- H dihydro-1,4- 1H NMR (400 MHz, DMSO- % | benzo d6) 5 ppm 7.02 (d, J=1.8 Hz, H O dioxiny|)- 1H), 6.94-6.97 (m, 1H), 6.92 OH 0Q 1-(2-hydroxy (dd, J=8.3, 1.8 Hz, 1H), 5.70 307 1 ethy|) ' (s, 1H), 4.72 (t, J=5.7 Hz, thioxo—2,3- 1H), 4.25-4.33 (m, 4H), 4.17 dihydro (t, J=6.4 Hz, 2H), 3.55 (q, pyrimidin- J=6.1 Hz, 2H) 4(1H)—one Ex- 1H NMR Spectral Data or Compound Obs ample HPLC Retention Time and Name Mass # Conditions 1-(2- thyl)— 6-(2,3- 1H NMR (400 MHz, DMSO- dihydro-1,4- d6) 6 ppm 7.89-8.01 (m, 3H), benzo 7.07 (d, J=1.8 Hz, 1H), 8.92- dioxinyl)— 7.02 (m, 2H), 5.75 (s, 1H), 2-thioxo-2,3- 4.34 (br. s., 2H), 4.30 (br. s., dihydropyrim 4H), 2.91-2.98 (m, 2H) idin-4(1H)- 2-[6-(2,3- 2.039 min Symmetry-C18 dihydro-1,4- 2.1X50mm 3.50m Mobile benzodioxin- phase- A: 0.1 % FA in 6-yl)—4-oxo— MeCN IN water; , FA 2-thioxo-3,4- Time(min)/% B=0/90,0.5/90, dihydropyrim 2/55,3/55,3.5/10,6.5/10,7/90; idin-1(2H)— Flow :0.5mL/min, Column | acetamide Temo=40°C; Diluent: ACN 6-(5-chloro— 2.018 min AQUITY BEH C- methoxyphe 18,2.1x50mm,1.7pm Mobile nyl)—1-[(2S)— Phase:A-0.1%FA IN 2,3- MeCN,B-0.1%FA IN water dihydroxypro T/%B(min):0/90,0.7/90,2/55, pyl]—2-thioxo— .8/5,5.8/5,6/90 2,3- .5mL/min, dihydropyrim Diluent:ACN, Temp - 40°C idin-4(1H)- 1-(2-amino 1H NMR (600MHz, DMSO- ethyl)—6-(3,4- d6) 6 ppm 8.44 (br. s., 4H), dimethoxy 7.17 (d, J=1.3 Hz, 1H), 7.09 - phenyl)—2- 7.05 (m, 1H), 7.05 - 6.96 (m, thioxo—2,3- 1H), 5.78 (s, 1H), 4.38 (br. s., opyrim 2H), 3.81 (s, 3H), 3.79 (s, idin-4(1H)- 3H), 2.97 (t, J=7.2 Hz, 2H) 1-[(2S) aminopropyl] 4.82 min XBridge C-18 (5-chloro— 4.6x150mm, 3.5um M phase: A=MeCN; B = 5mM methoxyphe ammonium acetate in water; -thioxo- TIME (min) %OF B: 0/95, 2,3- 1/95 dihydropyrim , 3/5, 10/5, 10.05/95 flow: 0.8mI/min, Diluent: ACN idin-4(1H)- W0 2013/068875 Ex- 1H NMR Spectral Data or Compound Obs ample HPLC Retention Time and Name Mass # Conditions 1-(2- 1H NMR (DMSO-d6) 5 ppm aminoethyl)- 9.53 (s, 1H), 8.28 (dd, J=7.5, 6-(1,3-benzo 1.3 Hz, 1H), 7.80-8.10 (m, thiazoIyl)- 3H), 7.68-7.77 (m, 2H), 8.07 2-thioxo-2,3- (s, 1H), 4.44-4.54 (m, 1H), dihydropyrim 4.02 (br. s., 1H), 2.92-2.98 idin-4(1H)- (m, 1H), .91 (m, 1H) 1H NMR (400 MHz, DMSO- 2,3- d6) 5 ppm 12.84 (br. s., 1H), dihydro-1,4- 7.32 (s, 1H), 7.02 (dd, J=8.5, benzodioxin- 1.5 Hz, 2H), 8.91 (t, J=7.8 -y|)oxo- Hz, 1H), 8.70-8.78 (m, J=1.5 2-thioxo-3,4- Hz, 1H), 5.83 (s, 1H), 5.42 dihydropyrim (br. s, 1H), 4.28-4.38 (m, idin-1(2H)-y|] 4H), 3.93-4.07 (m, J=7.0 Hz, acetamide 2-[6-(2,3- 1H NMR (400 MHz, DMSO- dihydro d6) 5 ppm 12.80 (br. s., 1H), benzofuran- 7.38 (d, J=7.5 Hz, 2H), 7.00 7-y|)oxo- (d, J=8.5 Hz, 2H), .95 2-thioxo-3,4- (m, 1H), 5.81 (s, 1H), 5.38- dihydropyrim 5.53 (m, 1H), 4.81 (t, J=8.8 idin-1(2H)-y|] Hz, 2H), 3.98-4.11 (m, 1H), acetamide 3.24 t, J=9.0 Hz, 3H 2-{6-[2- (methyl 1H NMR (400 MHz, sulfanyl)phe METHANOL-d4) 5 ppm 7.48- nyl]—4-oxo 7.55 (m, 1H), 7.43 (d, J=8.0 thioxo -3,4- Hz, 1H), 7.22-7.32 (m, 2H), dihyd ro 5.81 (s, 1H), 5.54 (d, J=17.1 pyrimidin- Hz, 1H), 3.97 (d, J=18.1 Hz, 1 (2H) 1H), 2.54 (s, 3H) amide 1H NMR (400 MHz, DMSO- yd roxy d6) 5 ppm 12.71 (br. s., 1H), ethyI)(2- .25 (s, 1H), 7.30-7.42 (m, hydroxyphen 1H), 7.25 (d, J=7.5 Hz, 1H), y|)thioxo- 8.88-7.00 (m, 2H), 5.71 (s, 2,3- 1H), 4.72 (t, J=5.5 Hz, 1H), dihydropyrim 4.51-4.63 (m, 1H), 3.80-3.74 idin-4(1H)- (m, 1H), 3.43-3.55 (m, J=6.0 Ex- 1H NMR Spectral Data or Compound Obs am#ple HPLC Retention Time and Name Mass ions 367 1H NMR (400 MHz, DMSO- 2-[4-oxo d6) 6 ppm 13.08 (m, (quinolin 1H), 9.00 (d, J=2.5 Hz, 1H), y|)thioxo- 8.35 (d, J=8.0 Hz, 1H), 8.18 3,4- (d, J=8.5 Hz, 1H), 7.82-7.91 dihydropyrim (m, 1H), 7.62 (br. s., 2H), idin-1(2H)— 7.22 (s, 1H), 6.98 (br. s., 1H), y|]acetamide 6.00 s, 1H 1H NMR (400 MHz, DMSO- d6) 6 ppm 10.37 (br. s., 1H), 2-[6-(2- 7.37 (br. s., 1H), 7.30-7.36 hydroxyphen (m, J=7.8, 7.8 Hz, 1H), 7.09 y|)oxo (dd, J=7.8, 1.8 Hz, 1H), 6.98 —3,4- (br. s., 1H), 6.96 (d, J=8.5 dihydropyrim Hz, 1H), 6.84-6.90 (m, 1H), idin-1(2H)— .76 (s, 1H), 5.43 (br. s., 1H), y|]acetamide 3.94 (br. s., 1H), 3.16 (d, J=5.0 Hz, 1H N-(2- 1H NMR z, DMSO- o/ aminoethyl)— d6) 5 ppm 12.93 (br. s., 1H), 2-[6-(5- 8.24 (br. s., 1H), 7.88 (br. s., chloro 3H), 7.57 (d, J=9.0 Hz, 1H), c1 methoxyphe 7.28 - 7.10 (m, 2H), 5.93 (s, nyl)—4-oxo—2- 1H), 5.43 (d, J=14.1 Hz, 1H), thioxo—3,4- 4.05 - 3.92 (m, 1H), 3.85 (s, dihydropyrim 3H), 3.16 (d, J=4.5 Hz, 2H), idin-1(2H)— 2.76 - 2.61 (m, 2H) I]acetamide 1H NMR (400 MHz, DMSO- N-(2- d6) 6 ppm 12.89 (s, 1H), aminoethyl)— 8.18 (t, J=5.5 Hz, 1H), 7.82 2-[6-(2,5- (br. s., 3H), 7.01-7.16 (m, dimethoxyph 2H), 6.75 (s, 1H), 5.86 (d, enyl)—4-oxo- J=2.0 Hz, 1H), 5.25-5.53 (m, 2-thioxo-3,4- 1H), 4.02 (d, J=17.1 Hz, 1H), dihydropyrim 3.78 (s, 3H), 3.73 (br. s., 3H), (2H)— 3.10-3.20 (m, 2H), 2.59-2.75 y|]acetamide N-(2-amino [6- 0.849 min LCMS—C(4#-302) (5-fluoro Ultimate XB-C18 2.1x30mm metho Mobile phase: from 0 MeCN xyphenyl)—4- (0.1%TFA) in water oxothioxo- (0.1%TFA) to 60 %MeCN 3,4-dihydro (0.1%TFA) in water pyrimidin- (0.1%TFA) 1(2H) | acetamide Ex- 1H NMR Spectral Data or Compound Obs am#p|e HPLC Retention Time and Name Mass Conditions H NMR (400 MHz, / N-(2-amino METHANOL-d4) 6 ppm 8.28 ethy|)[6- (t, J=5.5 Hz, 1H), 7.51-7.59 (2- (m, 1H), 7.27 (dd, J=7.5, 1.5 methoxyphe Hz, 1H), 7.16 (d, J=8.5 Hz, nyl)oxo 1H), 7.01-7.10 (m, 1H), 5.84 thioxo—3,4- (s, 1H), 5.45 (d, J=15.1 Hz, dihydropyrim 1H), 4.23 (d, J=16.1 Hz, 1H), idin-1(2H)- 3.90 (s, 3H), 3.35-3.45 (m, y|]acetamide 1H), 3.23-3.29 (m, 1H), 2.87- N-(2- 1H NMR (400 MHz, o/ aminoethy|)- METHANOL-d4) 5 ppm 7.34 2-[6-(2- (dd, J=8.5, 1.5 Hz, 1H), 7.07 y—5- (d, J=2.0 Hz, 1H), 7.03 (d, methyl J=8.5 Hz, 1H), 5.81 (s, 1H), phenyl)—4- .44 (d, J=14.1 Hz, 1H), 4.26 oxothioxo- (d, J=17.1 Hz, 1H), 3.86 (s, 3,4- 3H), .43 (m, 1H), 3.24- dihydropyrim 3.29 (m, 1H), 2.85-3.00 (m, idin-1(2H)- 2H), 2.30 (s, 3H) I]acetamide 6-(5-fluoro—2- 1H NMR (400 MHz, methoxyphe ol-d3): 6 ppm 7.33 nyl)[3- (td, J=8.03, 3.01 Hz, 1H), 7.26-7.17 (m, 2H), 5.84 (s, amino)propyl 1H), 4.66-4.50 (br s, 1H), ]thioxo- 3.89 (s, 3H), 3.85-3.73 (br m, 2,3- 1H), 2.86 (t, J=7.53 Hz, 2H), dihydropyrim 2.62 (s, 3H), 2.15-2.00 (m, idin-4(1H)- 1H), 1.96-1.81 (m, 1H) 1-{3-[6-(5- fluoro—2- 1H NMR (400 MHz, DMSO- meth d6): 5 ppm 12.82 (s, 1H), oxypheny|)- .35 (m, 2H), 7.23-7.17 4-oxo—2- (m, 1H), 7.17-7.06 (br m, thioxo—3,4- 4H), 5.86 (d, J=2.01 Hz, 1H), dihyd ro 4.45-4.31 (br s, 1H), 3.82 (s, pyrimidin- 3H), 3.67-3.54 (br m, 1H), 1 (2H) 3.19-3.12 (br m, 2H), 2.75- ylipropy|} 2.65 (m 3H), 1.91-1.73 (m, methyl 1H), 1.72-1.56 (m, 1H) 0 uanidine 1H NMR Spectral Data or HPLC Retention Time and Mass Conditions N-carbam imidoyl[6- 1H NMR (400 MHz, DMSO- (5-chloro—2- d6) 6 ppm 13.08 (s, 1 H), methoxy 11.64 (br s, 1 H), 8.19 (br s, phenyl)—4- 4 H), 7.61 (dd, J=9.03, 2.51 oxothioxo- Hz, 1 H), 7.34-7.30 (m, 1 H), 3,4- 7.22 (d, J=9.03 Hz, 1H), 6.00 dihydropyrim (s, 1 H), 5.15 (brs, 1 H), 4.45 idin-1(2H)-yl] (br s, 1 H), 3.83 (s, 3 H) acetamide chloro 1H NMR (400 MHz, DMSO- hydroxy d6) 6 ppm 12.80 (br. s., 1H), phenyl)—4- 10.64 (br. s., 1H), 7.34-7.42 thioxo- (m, 2H), 7.10 (d, J=9.5 Hz, 3,4- 2H), 6.95 (d, J=8.5 Hz, 1H), opyrim 5.86 (s, 1H), 5.47 (br. s., 1H), idin-1(2H)— 3.92 (br. s., 1H) |]acetamide The following Examples of Table 7 (additions to Table 3) were prepared from the corresponding methyl ketone to afford the intermediate beta-keto—ester as described above for the Preparations in the Methyl Ketone Route section followed by employing other methods described in the |. Beta Ketone Ester Route Section as well as standard methods and techniques known to those skilled in the art.
Table 7. Examples from Methyl Ketone Route am 1H NMR Spectral Data or Compound Obs HPLC Retention Time and Name Mass Conditions 378 N-(-2amino SLfiuiC:(3on ethyl)--{-6[2- roxy 1.10min Xtimate C18, ethoxy)—5— 2.1*30mm Mobile phase: yphenyl 395.1 from 0% MeCN in water ]oxo (0.1% TFA in water) to 30% thioxo-3,4- MeCN in water (0.1% TFA in dihydropyrimidi water) n-1(2H)- yl}acetamide e# 1H NMR Spectral Data or Compound Obs HPLC Retention Time and Name Mass Conditions 379 o 2- 1H NMR (400 MHz, o/\/OH yethoxy) methanol-d4): 6 ppm 7.11- methoxy 7.04 (m, 2H), 6.94-6.91 (m, phenyl]—1-(2- 1H), 5.79 (s, 1H), 4.74-4.59 hydroxyethyl)— 2-thioxo-2, 3- (m, 2H), 4.12-4.06 (m, 2H), 3.95-3.83 (m, 1H), 3.83-3.76 dihydropyrimidi (m, 6H), 3.68-3.60 (m, 1H) 1H NMR (400 MHz, DMSO- 2-{6-[2-(2— d6) 6 ppm 12.79 (s, 1H), hyd h oxy) 7.35 (br. s., 1H), 6.99-7.15 methoxy (m, 3H), 6.76 (br. s., 1H), phenyl]—4-oxo- .81 2-th ioxo-3,4- (s, 1H), 5.24-5.43 (m, 1H), 4.73-4.92 (m, 1H), 4.01 dihydropyrimidi n-1 (2 H )- (d, J=5.5 Hz, 2H), 3.84-3.95 (m, 1H), 3.70 (s, 3H), 3.62 (t, yl}acetamide J=5.0 Hz, 2H 1-{2-[(2- 0.77 min Waters Acqity HSS aminoethyl)ami T3, 2.1x50mm, C18, 1.7pm; no]ethyl}- A: 0.1% formic acid in water; o(2,4-d—imethoxy Mobile phase B: 0.1% formic phenyl)— acid in MeCN A: 0.1% thioxo-2, 3- ammonia in water; Mobile dihydropyrimidi phase B: 0.1% ammonia in MeCN Flow 1.25ml/min 1-(-2amino ethyl)—2-thioxo- 3.41 min Waters symmetry trifluoro 2.1x50 mm 5 um Mobile methoxy)pheny phase: from 0% MeCN in |]-2,3-dihydro water (0.1% TFA) to 30% din- MeCN in water (0.1% TFA) H NMR (400 MHz, DMSO- d6) 6 ppm 8.68 (br. s., 2H), 7.30 (d, J=8.8 Hz, 1H), 7.10- dimethoxyphen ° 7.21 (m, 1H), 6.70-6.75 (m, y|){2-[(2- 1H), 6.63-6.69 (m, 1H), 5.76 hyd roxyethyl)a (s, 1H), 5.18 (br. s., 1H), 4.69 mino]ethyl} (br. s., 1H), 3.99 (br. s., 1H), thioxo-2,3- 3.85-3.81 (m, 6H), 3.70-3.78 dihydropyrimidi (m, 1H), 3.55 (t, J=5.0 Hz, n-4(1 H)-one 1H), 3.06 (br. s., 1H), 2.97- 3.01 m, 1H 2.84 br. s., 2H 1H NMR Spectral Data or Compound Obs HPLC Retention Time and Name Mass Conditions 3.661 min XBRIDGE-C18 2-[6-(3- 4.6X75mm 3.50m Mobile methoxyphenyl phase- A: 0.1% FA IN )oxo 292.0 MeCN, B=0.1% FA IN water thioxo-3,4- Time(min)/% B: 0/90, 0.8/90, dihydropyrimidi 1.8/55, 3/5, 6.5/5 ,7/90 Flow: n-1(2H)— 0.8mL/min, Column y|]acetamide Temp=40°C; t: ACN 0 2,4- 1H NMR (400 MHz, dimethoxyphen METHANOL-d4) 5 ppm 7.98 (br. 5% 03)%\ y|)oxo s., 1H) 7.15 (d, J=8.5 Hz, o -3,4- 1H) 6.65 (d, J=2.0 Hz, 1H) INH opyrimidi 365.4 6.60 (dd, J=8.5, 2.0 Hz, 1H) n-1(2H)-y|]-N- 5.77 (s, 1H) 5.50 (br. s., 1H) (2- 4.20 (d, J=15.1 Hz, 1H) 3.87 hydroxyethyl)a (s, 3H) 3.85 (s, 3H) 3.41-3.53 cetamide m, 2H 3.14-3.22 m, 2H 2464216' . 1H NMR (400 MHz DMSO- 0/ d'methoxyphe“ d6) 5 ppm 12.75 (br. s., 1H) y|)oxo 321.8 7.45 (t, J=8.5 Hz, 1H) 7.13 thioxo-3,4- (br. s., 1H) 6.92 (s, 1H) 6.77 dihydropyrimidi (d, J=8.0 Hz, 2H) 5.76 (s,1H) n-1(2H)- 4.33-4.80 (m, 2H) 3.74(s,1H) | acetamide 0 H NMR (400 MHZ, DMSO- Aiifil 2-{6-[4-(2- H o/ d6) 5 ppm 12.76 (s, 1H), 7.31 yfhoxy) (br. s., 1H), 7.06 (d, J=8.5 oT: N01 Hz, 1H), 6.98 (s, 1H), 6.68 f‘z‘iny' (d, J=2.0 Hz, 1H), 6.60 (dd, J=8.5, 2.0 Hz, 1H), 5.74 (d, thioxo_3 4_ dihydropyrimidi J=2.5 Hz, 1H), 5.37 (br. s., 1H), 4.04 (t, J=5.0 Hz, 2H), n_1(2H)_ 3.89 (br. s., 1H), 3.82 (s, 3H), y|}acetamide 3.72 (t, J=4.8 Hz, 2H) 2-[6-(2,4- dimethoxyphen 0.965 min LCMS—AI(4#-302) y|)oxo Ultimate XB-C18 2.1x30mm Mobile phase from 0 MeCN thioxo-3,4- ‘1’ dihydropyrimidi (OJZMFA) '” wet? n-1(2H)-y|]-N- (0.10A)TFA) to 60 AMeCN [(3R)-pyrro|idin- (0.10A)TFA) In water (0'1 ATFA) 3- | acetamide 1H NMR Spectral Data or Compound am#p|e HPLC Retention Time and Name Conditions 389 ABS 1--{2-[(3R)—3—- 0.972 min LCMS—AI(4#-302) aminopyrrolidin Ultimate XB-C18 mm |]--2oxoet Mobile phase: from 0 MeCN hy|}---6 (2, 4- i (0.1 %TFA) in water dimethoxyphen (0.1%TFA) to 60 % MeCN y|)-thioxo-2, 3 (0.1%TFA) in water -dihydropyrimi (0.1%TFA) din-4 1H -one 1H NMR (400 MHz, N-(2- METHANOL-d4) 6 ppm 7.17 aminoethyl)—2- (d, J=8.5 Hz, 1H), 6.68 (s, [6-(2,4-dimeth 1H), 6.60 (d, J=7.5 Hz, 1H), oxyphenyl)—4- .80 (s, 1H), 5.65 (d, J=17.1 oxothioxo- Hz, 1H), 4.33 (d, J=16.6 Hz, 3,4-dihyd ropyr 1H), 3.88 (s, 3H), 3.85 (s, imidin-1(2H)— 3H), 3.59-3.70 (m, 1H), 3.36- y|]-N-methy| 3.49 (m, 1H), 3.02 (br. s., acetamide 391 0 H NMR (400 MHz, 2-[6-(2,4- METHANOL--d4) 6 ppm 8.34 8’ N dimethoxyphen (t, J=5.8 Hz, 1H), 7.17 (d, 05H11%6 y|)oxo J=8.5 Hz, 1H), 6.67 (d, J=2.0 N” thioxo—3,4- Hz, 1H), 6.62 (dd, J=8.5, 2.0 379 2 \u opyrimidi ' Hz, 1H), 5.81 (s, 1H), 5.42 n-1(2H)-y|]-N- (d, J=16.6 Hz, 1H), 4.28 (d, [2- J=16.6 Hz, 1H), 3.88 (s, 3H), lamino)e 3.85 (s, 3H), 3.40-3.48 (m, thyl]acetamide 1H), 3.33-3.38 (m, 1H), 3.00- 3.07 (m, 2H), 2.69 (s, 3H) 392 1H NMR (400 MHz, DMSO- 2-[6-(2 4_ HN o/ d6) 6 ppm 12'82 (S’ 1H)’ 2»l dimethox, I)_4_OX3C’)F_’2_hen 10.19 (br. s., 1H), 8.28 (br.
Os) ‘1’ Bihioxo-3 4_ s., 1H), 7.09 (d, J=8.0 Hz, jNH dihydropyrimidi 1H)’ 6'69 (d’ J=2'0 HZ’ 1H)’ 393 2' \N 6.62 (dd, J=8.5, 2.0 Hz, 1H), ' n-1(2H)-y|]-N- .79 (d, J=2.0 Hz, 1H), 5.37 (d, J=12.5 Hz, 1H), 4.02 (d, (dimethylamino J=16.6 Hz, 1H), 3.83 (s, 3H), )ethyl]acetamid 3.81 (s, 3H), 2.95 (d, J=18.1 Hz, 2H), 2.70 (br. s., 6H) Ex- 1H NMR Spectral Data or Com ound Obs ample Napme HPLC Retention Time and Mass # Conditions H NMR (400 MHz, HN o/ METHANOL-d4) 5 ppm 7.16 1 2,4- (SD/HM (dd, J=8.3, 5.3 Hz, 1H), 6.67 dimethoxyphen (s, 1H), 6.61 (dt, J=8.5, 2.3 H y|)oxo (N) Hz, 1H), 5.79 (s, 1H), 5.39- thioxo-3,4- .62 (m, 1H), 4.16-4.34 (m, dihydropyrimidi 2H), 3.88 (d, J=3.5 Hz, 3H), n-1(2H)—y|]-N- 3.85 (s, 3H), 3.49-3.37 (m, [(3S)-pyrro|idin- 2H), 3.09-3.17 (m, 1H), 2.95- 3-yl]acetamide 3.02 (m, 1H), 2.14-2.32 (m, , .98 m, 1H H NMR (400MHz, METHANOL-d4, rotameric mixture) 6 ppm 7.20 (d, J=8.0 Hz, 0.4H) 7.14 (d, N-[(2S)—1- J=8.5 Hz, 0.6H) 6.67 (d, aminopropan- J=2.0 Hz, 1H) 6.61 (td, 2-y|][6-(2,4- J=2.3, 8.5 Hz, 1H) 5.81 (s, dimethoxyphen 0.6H), 5.79 (s, 0.4H) 5.63 (d, oxo J=15.6 Hz, 1H) 5.35-5.27 (m, thioxo-3,4- 1H) 4.35 - 4.27 (m, 0.4H) dihydropyrimidi 4.20 (d, J=16.6 Hz, 0.6H) )— 4.05-3.94 (m, 1H) 3.89 (s, y|]acetamide 2H), 3.87 (s, 1H) 3.85 (d, J=1.5 Hz, 3H) 3.04 - 2.92 (m, 0.7H) 2.89 - 2.77 (m, 1.3H) 1.19 (d, J=6.5 Hz, 1H) 1.05 (d, J=7.0 Hz, 2H) N-[(2R)—2- 1H NMR (400 MHz, aminopropyl]—2- METHANOL-d4) 5 ppm 7.22 [6-(2,4- (t, J=8.3 Hz, 1H), 6.72 (s, dimethoxyphen 1H), 6.66 (d, J=8.5 Hz, 1H), y|)oxo 5.86 (s, 1H), 5.37-5.64 (m, thioxo-3,4- 1H), 4.35 (d, J=15.1 Hz, 1H), dihydropyrimidi 3.93 (d, J=2.5 Hz, 3H), 3.90 n-1(2H)— (s, 3H), 3.34-3.47 (m, 3H), y|]acetamide 1.25 (dd, J=13.3, 5.8 Hz, 3H) Compound 1H NMR Spectral Data or am:p |e HPLC Retention Time and Name Conditions 396 ABS H NMR (400 MHz, DMSO- d6) 6 ppm 12.81 (br. s., 1H), N-[(2S)—2- 8.24 (d, J=3.0 Hz, 1H), 7.97 aminopropyl]—2- (br. s., 3H), 7.07 (dd, J=11.8, [6-(2,4- 8.3 Hz, 1H), 6.65-6.73 (m, dimethoxyphen 1H), 6.59 (ddd, J=8.4, 4.1, y|)oxo 2.0 Hz, 1H), 5.78 (d, J=2.0 thioxo-3,4- Hz, 1H), 5.28-5.50 (m, 1H), dihydropyrimidi 4.06 (d, J=15.6 Hz, 1H), 3.83 n-1(2H)- (d, J=2.5 Hz, 3H), 3.81 (s, y|]acetamide 2H), 3.21 (d, J=6.5 Hz, 1H), 2.93-3.09 (m, 2H), 0.93-1.06 6-(2,4- 0.879 min Xtimate dimethoxyphen C18, 2.1x30mm,3um Mobile y|)[2-oxo phase. from 0% MeCN in (piperazin 391 .2 water (0.0685% TFA'In y|)ethy|] water) to 60% n thioxo-2, 3- water (0.0685% TFA in dihydropyrimidi water) 1---{2[(38)- aminopyrrolidin 0.988 min LCMS—AI(4#—302) y|] Xtimate C18,2.1x30mm,3um oxoethyI} Mobile phase: from 0% (2,4- 413.0 MeCN (0.1%TFA) in water dimethoxyphen (0.1%TFA) to 60% MeCN y|)thioxo- (0.1 %TFA) in water 2, 3- (0.1%TFA) opyrimidi 399 ABS H NMR (400 MHz, DMSO- {[6-(2,4- d6) 6 ppm 8.33 (s, 1H) 8.12 oxyphen (br. s., 1H) 8.06 (br. s., 1H) y|)oxo 7.07 (d, J=8.5 Hz, 1H) 6.68 thioxo-3,4- (d, J=2.5 Hz, 1H) 6.56-6.63 opyrimidi 436.0 (m, 1H) 5.77 (s, 1H), 5.38 n-1(2H)- (br. s., 1H) 4.22 (br., 3H) y|]acety|}amino 3.97 (d, J=13.6 Hz, 1H) 3.82- )ethy|]-L- 3.88 (m, 3H) 3.81 (s, 3H) alaninamide 3.37-3.48 (m, 1H) 2.99 (br. s., 4H) 1.17 (d, J=7.0 Hz, 3H) 1H NMR Spectral Data or Compound Obs HPLC Retention Time and Name Mass Conditions H NMR (METHANOL-d4, rotameric mixture) 5 ppm 7.18 (d, J=8.5 Hz, 0.6H) 7.13 0 2-[6-(2,4- ‘ (d, J=8.5 Hz, 0.4H) 6.67 (d, dimethoxyphen J=2.0 Hz, 1H) .63 (m, y|)oxo 1H) 5.74-5.81 (m, 1H) 5.66 thioxo-3,4- (d, J=16.6 Hz, 1H) 4.23-4.38 dihydropyrimidi (m, 1H) 3.87-4.00 (m, 3H) n-1(2H)-y|]-N- 3.80 (s, 3H) 3.53 (dt, J=13.6, methyl-N-[2- 6.8 Hz, 0.6H) 3.34-3.40 (m, (methylamino)e 0.4H) 3.14-3.27 (m, 1H) 2.93 cetamide (s, 2H) 2.84 (s, 1H) 2.57-2.73 (m, 2H) 2.38 (s, 2H) 2.33 (s, 401 ABS H NMR (400MHz, METHANOL-d4, rotameric H o/ 52‘» | mixture) 5 ppm 7.20 (d, 03) J=8.0 Hz, 0.4H) 7.14 (d, NH N-[(2R) J=8.5 Hz, 0.6H) 6.67 (d, j/ aminopropan- J=2.0 Hz, 1H) 6.61 (td, H2” 2-y|][6-(2,4- J=2.3, 8.5 Hz, 1H) 5.81 (s, dimethoxyphen 0.6H) 5.79 (s, 0.4H) 5.63 (d, y|)oxo 379.1 J=15.6 Hz, 1H) 5.35-5.27 (m, thioxo—3,4- 1H) .27 (m, 0.4H) 4.20 dihydropyrimidi (d, J=16.6 Hz, 0.6H) 4.05- )- 3.94 (m, 1H) 3.89 (s, 2H) y|]acetamide 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) 402 0 1H NMR (400 MHz, DMSO- 323%HN o/\/OH d6) 6 ppm 12.75 (S, 1H), aminL-éfépyly 7.73 (br s, 3 H), 7.28 (d, J) / J=8.03 Hz, 1H), 6.72 (d, 6_[2_(2_ J=2.51 H»: Hz, 1H), 6.64 (dd, hydrox ethox31- y) J=8.53, 2.51 Hz, 1H), 5.77- 352 2' .73 (m, 1H), 4.40 ( br s, yphenyl 1H), 4.10 (t, J=5.02 Hz, 2H), ]thioxo-2 3_ dihydropyrimidi 3.82 (s, 3H), 3.75-3.66 (br s, 1H), 3.64 (t, J—5.02 Hz, 2H), n-4(1H)-one 2.50-2.51 (m, 2H), 1.90-1.78 (m, 1H), 1.78-1.66 (m, 1H) Ex- 1H NMR Spectral Data or Com ound Obs ample Napme HPLC Retention Time and Mass # Conditions 0 1H NMR (400 MHZ, DMSO- 52:51:»H N” I 1- 3- 6- 2- 2- d6) 6 ppm 12.70 (s hydfioiyeflhéxy) ’ 1H) ’ 7.35 (t, J=6.02 Hz, 1H), 7.25 M ‘ _4_ (d, J=8.53 Hz, 1H), 7.22-6.74 H (br s, 4H), 6.71 (d, J=2.51 yphenyl Hz, 1H), 6.62 (dd, , ]oxo 2.51 Hz, 1H), 5.73 (d, J=2.01 thioxo-3,4- . . Hz, 1H), 4.87 (brs, 1H), 4.39 d'hflczgmn'd'. . (br s, 1H), 4.15-4.02 (m, 2H), 3.82 (s, 3H) ynpropybguani , 3.60-3.74 (m, 3H), 2.98-2.93 (m, 2H), 1.85- dine 1.68 (m, 1H), 1.66-1.51 (m, N-(2- 1H NMR (400 MHz, aminoethyl)—2- Methanol-d4) 6 ppm 8.35- {6-[2-(2- 8.26 (m, 0.3H), 7.18 (d, hydroxyethoxy) J=8.53 Hz, 1H), 6.68 (d, J=2.01 Hz, 1H), 6.62 (dd, methoxyphenyl 395.12 J=8.53, 2.01 Hz, 1H), 5.82 ]oxo (s, 1H), 5.52-5.37 (br m, 1H), thioxo-3,4- 4.42-4.29 ( br m, 1H), 4.20- opyrimidi 4.09 (m, 2H), 3.90-3.79 (m, n-1(2H)- 5H), 3.43-3.33 (m, 2H), 3.00- | acetamide 2.90 m, 2H 0 N-(2- 1H NMR (400 MHz, k i aminoethyl)—2- Methanol-d4)6ppm 7.27(td, 8% N , 3.01 Hz, 1H), 7.16 V {6-[5-fluoro (2- (dd, , 4.02 Hz, 1H), hydroxyethoxy) 7.08 (dd, J=8.03, 2.51 Hz, phenyl]—4-oxo- 1H), 5.88 (s, 1H), 5.50-5.38 2-thioxo-3,4- (br m, 1H), 4.36-4.26 (br m, dihydropyrimidi 1H), 4.20-4.10 (m, 2H), 3.84 n-1(2H)- (t, J=4.02 Hz, 2H), 3.44-3.33 | acetamide m, 2H , 3.00-2.93 m, 2H 1H NMR (400 MHz, 1-(3- Methanol-d4) 6 ppm 7.31 (td, aminopropyl)— J=9.03, 3.01 Hz, 1H), 7.25- 6-[5-fluoro—2- 7.18 (m, 2H), 5.85 (s, 1 H), 4.57-4.44 ( br s, 1H), 4.03- hyd roxyeth oxy) 3.90 ( br m, 2H), 3.97-3.96 pheny|] (m, 1H), 3.84 (t, J=4.02 Hz, thioxo-2,3- 2H), 2.79 (t, J=8.03 Hz, 2H), dihydropyrimidi 2.13-2.00 (m, 1H), 1.95-1.82 n-4(1 H)-one 1H NMR Spectral Data or Compound am#p|e HPLC Retention Time and Name Conditions 407 1--(-3{6-[5- 1H NMR (400 MHz, fluoro-(2- Methanol-d4) 6 ppm 7.30 (td, % yethoxy) J=9.03, 3.01 Hz, 1H), 7.25- phenyl]—4-oxo- 7.15 (m, 2H), 5.84 (s, 1H), 2-thioxo-3,4- 4.60-4.46 (br m, 1H), 4.19- opyrimidi 4.10 (m, 2H), 3.96-3.79 (m, n-1(2H)- 3H), 3.10-3.01 (m, 2H), 2.06- y|}propy|)guani 1.93 (m, 1H), .68 (m, dine 1H NMR (400 MHz, 3-[6-(2,4- form-d) 6 ppm 6 9.57 dimethoxyphen (br s, 1H), 7.22 (d, J: 8.53 y|)oxo Hz, 1H), 6.62 (dd, J: 8.53, thioxo-3,4- 2.51 Hz, 1H), 6.55 (d, J=2.51 dihydropyrimidi Hz, 1H), 5.85 (d, J: 2.51 Hz, n-1(2H)- 1H), 4.67-4.53 (br m, 1H), y|]propanenitri| 4,19-4.05 (br m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.19-3.06 m, 1H , 2.71-2.63 m, 1H 6-[2-(2- 1H NMR (400 MHz, DMSO- NO” hydroxyethoxy) d6) 6 ppm 12.65 (s, 1 H), 7.22 ( br s, 1 H), 6.78-6.53 methoxyphenyl (br m, 2 H), 5.68 ( brs, 1H), ](2- 338.9 4.90-4.78 ( br m, 1H), 4.72- hydroxyethyl)— 4.62 (br m, 1H), 4.59-4.42 (br 2-thioxo-2, 3- m, 1H), 4.19-3.97 (br m, 2H), dihydropyrimidi 3.81 (br S, 3H), 3.64 (br S, 2--[-6(4- 0.905 min LCMS—C (4#-302) methoxyphenyl Ultimate XB-C18 2.1x30mm )oxo Mobile phase: from 0 MeCN thioxo-3,4- (0.1%TFA) in water | dihydropyrimidi (0.1%TFA) to 60 % MeCN n-1(2H)- FA) in water | acetamide 0.1%TFA 6-[5-fluoro—2- 1H NMR (400 MHz, O/\/OH (2_ methanol-d4) 6 ppm 7.25 (td, hydroxyethoxy) , 3.01 Hz, 1H), 7.19- pheny|](2- 7.13 (m, 2H), 5.80 (s, 1H), hydroxyethyl)— 4.76-4.65 (m, 1H), 4.61 (br s, 2-thioxo-2, 3- 1H), 4.16-4.09 (m, 2H), 3.88- dihydropyrimidi 3.78 (m, 3H), 3.66-3.60 (m, arix-le 1H NMR Spectral Data or Compound Obs #p HPLC Retention Time and Name Mass Conditions 1H NMR (400 MHz, 0H 2-{6-[5-fluoro— O/\/ methanol-d4) 6 ppm 7.25 (td, 2-(2- J= 9.03, 3.01, 1H), 7.15 (dd, hyd roxyeth oxy) J=9.03, 4.02 Hz, 1H), 7.06 ]—4-oxo- (dd, J: 8.03, 3.01 Hz, 1H), 2-thioxo-3,4- .84 (s, 3H), 5.67-5.42 (br s, dihydropyrimidi 1H), 4.37-4.18 (br s, 1H), n-1(2H)- 4.14 (t, J=4.52 Hz, 2H), 3.83 yl}acetamide t, J=4.02 Hz, 2H 1H NMR (400 MHz, DMSO- O/\/OH d6) 6 ppm 12.71 (s, 1H), 6-[4-fluoro 7.39-7.33 (m, 1H), 7.12 (dd, J: 11.54, 2.01 Hz, 1H), 6.90 hyd roxyeth oxy) (td, J=8.53, 2.51 Hz, 1H), pheny|](2- .75 (s, 1H), 5.73 (d, J=2.01 hydroxyethyl)- Hz, 1H), 4.97-4.79 (br s, 1H), 2-thioxo-2,3- 4.77-4.62 (br s, 1H), 4.53- dihydropyrimidi 4.43 (m, 1H), 4.16-4.04 (m, n-4(1 H)-one 2H), 3.64 (br t, J=4.52 Hz, , 3.61-3.49 m, 2H 1H NMR (400 MHz, DMSO- O/\/OH 2-{6-[4-fluoro— d6) 6 ppm 12.80 (s, 1H), 2-(2- 7.33 (brs, 1H), 7.24-7.17 (m, hyd roxyeth oxy) 1H), 7.12 (d, J=11.54 Hz, phenyl]—4-oxo- 1H), 7.01 (br s,1H),6.91- 2-thioxo-3,4- 6.83 (m, 1H), 5.79 (s, 1H), dihydropyrimidi 5.52-5.22 (br s, 1H), 4.97- n-1(2H)- 4.81 (br m, 1H), 4.17-4.05 (br yl}acetamide m, 2H), .85 (brs, 1H), 3.69-3.60 br m, 2H 1H NMR (400 MHz, N-(2- methanol-d4) 6 ppm 8.33- aminoethyI) 8.24 (m, 1H), .27 (m, {6-[4-fluoro 1H), 7.00 (dd, J: 10.90, 1.71 Hz, 1H), 6.81 (td, J=8.03, hyd roxyeth oxy) 383.2 2.01 Hz, 1H), 5.85 (s, 1H), phenyl]—4-oxo- .52-5.39 (br m, 1H), 4.37- xo-3,4- 4.26 (br m, 1H), 4.23-4.12 opyrimidi (m, 2H), 3.85 (brt, J=4.02 n-1(2H)- Hz, 2H), 3.47-3.35 (m, 2H), yl}acetamide 3.00-2.91 m, 2H 1H NMR Spectral Data or Compound Obs HPLC Retention Time and Name Mass Conditions 1H NMR (400 MHz, DMSO- 511 0/ 2-[6-(2,3- d6) 6 ppm 12.77 (br. s., 1H), 0\ dimethoxyphen 7.26 (br. s., 1H), 7.17-7.23 09 y|)oxo (m, 1H), .17 (m, 1H), NH2 thioxo-3,4- 6.93 (br. s., 1H), 6.75 (d, dihydropyrimidi J=7.5 Hz, 1H), 5.75 (br. s., n-1(2H)- 1H), 5.42 (br. s., 1H), 4.11 tamide (br. s., 1H), 3.85 (s, 3H), 3.72 4-chloro- 1H NMR (400 MHz, DMSO- d6) 5 ppm 12.81 (br.s.,1H), methoxyphenyl 7.34 (br. s., 1H), 7.28 (s, 1H), )oxo 326.2 7.15-7.20 (m, 1H), 7.10-7.14 thioxo-3,4- (m, 1H), 7.04 (br. s., 1H), dihydropyrimidi .83 (s, 1H), 5.43 (br. s., 1H), n-1(2H)— 3.86 (s, 4H) | acetamide 2-[6-(2- 1H NMR (400 MHz, DMSO- methoxy—4- d6) 5 ppm 12.78 (br. s., 1H), methylphenyl)— 7.04 (d, J=7.5 Hz, 1H), 7.00 4-oxothioxo- (s, 2H), 8.85 (d, J=7.5 Hz, 3,4- 1H), 5.75 (s, 1H), 5.35 (br. s., dihydropyrimidi 1H), 3.88-3.94 (m, 1H), 3.82 n-1(2H)— (s, 3H), 2.38 (s, 3H) I]acetamide 1-{2-[6-(5- fluoro 1H NMR (400 MHz, methoxyphenyl METHANOL-d4) 5 ppm 8.45 )oxo (br. s., 1H), 7.30 (td, J=8.5, F thioxo-3,4- 354.2 3.0 Hz, 1H), .24 (m, dihydropyrimidi 2H), 5.83 (s, 1H), 4.73-4.83 n-1(2H)— (m, 1H), .16 (m, 3H), ‘ y|]ethoxy}guanidine 3.89 (S, 3H) 1H NMR (400 MHz, DMSO- 2-{6-[2-(2— A“18?“ d6) 5 ppm 12.72 (br. s., 1H), hyd roxyeth oxy) 7.32 (br. s., 1H), 7.09 (d, 0%) J=8.0 Hz, 1H), 8.97 (br. s., NH2 methoxyphenyl 1H), 8.89 (br. s., 1H), 8.80 ]oxo (d, J=9.0 Hz, 1H), 5.74 (d, thioxo-3,4- J=11.0 Hz, 1H), 5.32 (br. s., dihydropyrimidi 1H), 4.84 (br. s., 1H), 4.08 n-1(2H)— (d, J=4.0 Hz, 2H), 3.97 (br. y|}acetamide s., 1H), 3.80 (s, 3H), 3.84 (br. arix-le 1H NMR Spectral Data or Compound Obs #p HPLC Retention Time and Name Mass Conditions 0 1H NMR (400 MHz, 3-(2— METHANOL-d4) 6 ppm 8.09 .4 | o/\/O\[( 0 amino (s, 0.6H), 7.57 (br. s., 0.2H), yl)—6- 7.27 (td, J=8.5, 3.0 Hz, 1H), oxothioxo- 7.14 (dd, J=9.0, 4.5 Hz, 1H), 1,2,3,6- 7.07 (dd, J=8.3, 3.3 Hz, 1H), tetrahyd ropyrim 6.99 (br. s., 0.2H), 5.83 (s, idinyl]—4- 1H), 5.67 (d, J=14.1 Hz, 1H), fluorophenoxy} 4.30-4.46 (m, 2H), 4.22-4.30 ethyl acetate (m, 2H), 4.12 (d, J=17.1 Hz, The following Examples of Table 8 (additions to Table 4) were prepared from the corresponding aryl halide to afford the intermediate beta-keto-ester as described above for the ations in the Aryl Halide Route section followed by employing the methods described in the |. Beta Keto Ester Route Section as well as rd methods and techniques known to those skilled in the art.
Table 8. Examples from Aryl Halide Route Ex- 1H NMR Spectral Data or Compound Obs ample HPLC Retention Time and Name Mass # Conditions 2-{6-[5-(2— 1H NMR (400 MHz, O hyd h oxy) METHANOL-d4) 6 ppm 7.09- methoxy 7.18 (m, 1H), 7.03-7.09 (m, phenyl]—4-oxo- 1H), 6.88 (d, J=3.0 Hz, 1H), 2—thioxo-3,4- 5.81 (s, 1H), 5.46-5.63 (m, O\/\OH dihydropyrimidi 1H), 4.17 (br. s., 1H), 4.00 )— (d, J=3.5 Hz, 2H), 3.84 (s, | acetamide 1H NMR (400 MHz, DMSO- 2-{4-[3-(2— d6) 5 ppm 12.85 (s, 1H) 8.06 aminoethyl)—6- (br s, 3H) 7.69 (s, 1H) 7.48 2 oxothioxo- (s, 1H) 7.30 (d, J=8.53 Hz, 1,2,3,6- 351.2 1H) 6.82 (d, J=2.01 Hz) 1H) tetrahyd ropyrim 8.87 (dd, J=8.53, 2.01 Hz, idinyl]—3- 1H) 5.75 (s, 1H) 4.71-4.60 methoxypheno (brs, 1H) 4.51 (s, 2H) 3.94- xy}acetamide 3.81 (m, 4H) 2.95-2.80 (m, The following Examples of Table 9 were prepared from the corresponding aryl ester or lactone to afford the intermediate eto—ester as described above for the Preparations in the Ester Route section followed by employing the methods described in the |. Beta Keto Ester Route Section as well as rd methods and techniques known to those skilled in the art.
Table 9. es from Ester Route 1H NMR Spectral Data or Compound am#ple HPLC Retention Time and Name Conditions 424 N--(2- 1H NMR (400 MHz, OH aminoethy|)- Methanol-d4) 5 ppm 7.50 {6-[5--c-h|oro2- (dd, J=9.03, 3.01 Hz, 1 H), c. (2-hydroxy 7.30 (d, J=2.51 Hz, 1 H), ethoxy)phenyl]- 7.17 (d, J=9.03 Hz, 1 H), 4-oxothioxo- 5.88 (s, 1H), 5.56-5.43 (br m, 3,4-dihydropyr 1H), .06 (m, 4H), 3.84 imidin-1(2H)- (t, J: 4.52 Hz,2H), 3.44-3.33 yl}acetamide (m, 2H), 3.03-2.89 (m, 2H) 6-[5-ch |oro 1H NMR (400 MHz, DMSO- o/VOH (2_ d6) 5 ppm 12.73 (br s, 1H), hyd roxyeth oxy) 7.52 (br s, 1H), 7.40 (br s, phenyl]—1-(2- 1H), 7.28-7.15 (br m, 1H), hydroxyethy|)- 5.88-5.72 (br m, 1H), 4.92 (br 2-th , 3- s, 1H), 4.78 (br s, 1H), 4.48 dihydropyrimidi (br s, 1H), 4.08 (br s, 2H), n-4(1H)-one 3.73-3.52 (br m, 4H) 1H NMR (400 MHz, DMSO- 2-{6-[5-chloro- O/\/OH d6) 5 ppm 12.84 (br. s, 1H), 2-(2- 7.54 (dd, J=9.0, 3.0 Hz, 1H), hyd roxyeth oxy) 7.35 (s, 1H), 7.21 (d, J=8.5 phenyl]—4-oxo— Hz, 2H), 7.09 (s, 1H), 5.87 2-thioxo-3,4- (s, 1H), 5.37 (br. s., 1H), 4.86 dihydropyrimidi (t, J=5.3 Hz, 1H), 4.04-4.13 (m, 2H), 3.95 (br. s., 1H), yl}acetamide 3.58-3.70 m, 2H 1H NMR (400 MHz, 1-(2- O/\/OH METHANOL-d4) 5 ppm 8.49 aminoethyl) (br. s., 1H) 7.56 (dd, J=9.3, [5-chloro—2-(2- 2.3 Hz, 1H) 7.45 (d, J=2.5 hyd roxyeth oxy) Hz, 1H) 7.22 (d, J=9.0 Hz, pheny|] 1H) 5.87 (s, 1H) 4.62 (br. s., thioxo—2,3- 2H) 4.12-4.30 (m, 3H) 3.85 dihydropyrimidi (br. s., 2H) 3.14-3.25 (m, 1H) n-4(1 H)-one 3.04-3.13 m, J=8.0 Hz, 1H 1H NMR Spectral Data or Compound am#ple HPLC Retention Time and Name Conditions 428 H NMR (400 MHz, Afi©O/\/OH N--(2- METHANOL-d4) 6 ppm 8.28 (t, J=5.8 Hz, 1H) 7.48-7.55 aminoethyl)- (m, 1H) 7.27 (dd, J=7.5, 1.5 {6-[2-(2- Hz, 1H) 7.16 (d, J=8.0 Hz, hyd roxyeth oxy) 1H) 7.06 (td, J=7.5, 1.0 Hz, phenyl]—4-oxo- 1H) 5.85 (s, 1H), 5.44 (br. s., 2-thioxo-3,4- 1H)4.31 (d, J=15.1 Hz, 1H) dihydropyrimidi 4.13-4.20 (m, 2H) 3.85 (ddd, n-1(2H)- J=5.4, 3.9, 2.3 Hz, 2H) 3.33- yl}acetamide 3.40 (m, 2H) 2.92 (t, J=5.8 The following Examples of Table 10 were prepared from the ponding acil carboxylic acid as described above for the ations in the III. Amide Coupling Route section and by employing the s described in the |. Beta Keto Ester Route Section as well as standard methods and techniques known to those skilled in the art.
Table 10. Examples from Amide Coupling Route 1H NMR Spectral Data or Compound Obs HPLC ion Time and Name Mass Conditions H NMR (400 MHz, METHANOL-d4) 5 ppm 8.42 N-(2-amino (t, J=6.3 Hz, 1H), 7.17 (d, methylpropyl)- J=8.0 Hz, 1H), 6.68 (d, J=2.0 2-[6-(2,4- Hz, 1H), 6.62 (d, J=2.0 Hz, dimethoxyphen 1H), 5.82 (s, 1H), 5.41 (d, yl)oxo J=13.6 Hz, 1H), 4.31 (d, thioxo-3,4- J=15.6 Hz, 1H), 3.88 (s, 3H), dihydropyrimidi 3.85 (s, 3H), 3.34-3.40 (m, n-1(2H)- 1H), 3.09-3.17 (m, 1H), 1.22- yl}acetamide 1.29 (m, 5H), 1.26 (d, J=5.5 H NMR (400 MHz, N-(cis METHANOL-d4) 5 ppm 8.31 aminocyclobuty (d, J=6.5 Hz, 1H), 7.15 (d, |)[6-(2,4- J=8.5 Hz, 1H), 6.67 (d, J=2.0 dimethoxyphen Hz, 1H), 6.60 (dd, J=8.3, 2.3 yl)oxo Hz, 1H), 5.79 (s, 1H), 5.53 thioxo-3,4- (br. s., 1H), 4.20 (br. s., 1H), dihydropyrimidi 3.90-3.98 (m, 1H), 3.88 (s, n-1(2H)- 3H), 3.86 (s, 3H), 3.43-3.52 yl}acetamide (m, 1H), 2.57-2.76 (m, 2H), 1.93-2.14 m, 2H Ex- 1H NMR Spectral Data or Compound Obs ample HPLC Retention Time and Name Mass # ions 1-[2-(3- 1H NMR (400 MHz, Sb aminoazetidin- METHANOL-d4) 5 ppm 7.21 1-y|) (dd,J=14.05, 8.53 Hz, 1 H), oxoethyl]—6- 6.70-6.58 (m, 2 H), 5.80 (s, 1 (2,4-dimethoxy H), .28 (br m, 1H), pheny|) 5.18-5.09 (br m, 1H), 4.44- thioxo-2,3- 4.25 (m, 5H), 4.23-4.11 (m, dihydropyrimidi 2H), 4.11-3.92 (m, 1H), 3.86 n-4 1 H -one s, 6H 1H NMR (400 MHz, DMSO- $6»H O/ N-(1-amino—2- | d6) 6 ppm 12.81 (brs, 1H), methylpropan- 7.81 (s, 1H),7.79-7.63 (brs, 2-y|)[6-(2,4- 'dimethoxyphen 3H), 7.08 (d, J=8.03 Hz, 1H), 392.9 6.70 (s, 1H), 6.61 (d, J: 8.50 y|)oxo Hz, 1H), 5.77 (s, 1H), 5.42 thioxo-3,4- (br s, 1H), 4.05 (br s, 1H), opyrimidi 3.83 (s, 3H), 3.81 (s, 3H), n-1(2H)— 2.94 (s, 2H), 1.13 (s, 3H), y|]acetamide 0 N-[(2R,3R)—3- H O/ aminobutan 0.931 min Xtimate C18 8/ y|][6-(2,4- 2.1x30mm 3um Mobile dimethoxyphen 1W phase: from 0% MeCN (0.1% oxo HZN TFA) in water (0.1% TFA) to thioxo-3,4- 60% MeCN (0.1% TFA) in dihydropyrimidi water (0.1% TFA) n-1(2H)- I]acetamide 434 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 2-[6-(2,4- 9.75 (br, 1H), 7.20 (d, J=8.53 dimethoxyphen Hz, 1H), 5.55 (dd, J: 8.53, y|)oxo 2.51 Hz, 1H), 5.49 (d, J=2.51 349.9 thioxo-3,4- Hz, 1H),5.87 (s, 1H), 5.52 dihydropyrimidi (br, 1H), 5.12 (br, 1H), 4.25 n-1(2H)-y|]-N- (br, 1H), 3.85(s, 3 1 (s, ethylacetamide 3H), 3.35-3.24 (m, 1 H), 3.24-3.14 (m, 1H), 1.10 (t, J=7.53 Hz, 3H) WO 68875 1H NMR Spectral Data or Compound Obs HPLC Retention Time and Name Mass ions 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 2-[6-(2,4- 9.61 (br, 1H), 7.21 (d,J=8.53 dimethoxyphen Hz, 1H), 6.54 (dd, J=8.53, y|)oxo 2.51 Hz, 1 H), 6.49 (d, thioxo-3,4- J=2.51 Hz, 1H), 5.87 (s, 1H), dihydropyrimidi 5.64 (br, 1H), 5.15 (br, 1H), n-1(2H)—y|]-N- 4.26 (br, 1H), 3.85 (s, 3 propylacetamid H),3.81 (s, 3H), 3.30-3.18 (m, 1 5-3.04 (m, 1H), 1.48 (q, J=7.03, 2 H), 0.88 (t, J=7.03 Hz, 3 H 1H NMR (400 MHz, 2-[6-(2,4- CHLOROFORM-d) 6 ppm dimethoxyphen 9.59 (br, 1H), 7.22 (d, J=8.53 y|)oxo Hz, 1H), 6.54 (dd,J=8.53, thioxo-3,4- 2.51, 1H), 6.49 (d, J=2.51 dihydropyrimidi Hz, 1H), 5.99 (br s, 1H), 5.86 n-1(2H)—y|]-N- (s, 1H), 5.18 (brs, 1H), 4.22 (brs, 1H), 3.85 (s, 3H), 3.82 methoxyethyl)a (s, 3H) 3.51-3.38 (m, 3 H), cetamide 3.36-3.28 m, 4H 1H NMR (400 MHz, N-(trans—3- METHANOL-d4) 6 ppm 7.13 aminocyclobuty (d, J=8.53 Hz, 1H), 6.67 (d, |)[6-(2,4- J=2.01 Hz, 1H), 6.59 (dd, J: oxyphen 8.53, 2.01 Hz, 1H), 5.78 (s, y|)oxo 1H), 5.68-5.43 (br s, 1H), thioxo-3,4- 4.38-4.27 (m, 1H), 4.27-4.13 dihydropyrimidi (br m, 1H), 3.88 (s, 3H), 3.85 n-1(2H)— (s, 3H), 3.83-3.73 (m, 1H), y|]acetamide .33 (m, 3H), 2.32-2.22 m, 1H . 438 0 1H NMR (400 MHz, N-(azetidin METHANOL-d4) 6 ppm 8.71 y|)[6-(2,4- (d, J=6.02 Hz, 1H), 7.15 (d, dimethoxyphen J=8.53 Hz, 1H), 6.69-6.65 y|)oxo 377.1 (m, 1H), 6.60 (dd, J=8.53, thioxo-3,4- 2.01 Hz, 1H), 5.80 (s, 1H), dihydropyrimidi 5.54 (br s, 1H), 4.59-4.48 (m, n-1(2H)— 1H), .15 (m, 3H), 4.13- y|]acetamide 3.98 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H). a“439 1H NMR Spectral Data or Compound HPLC Retention Time and Name Conditions N--[(18, 28)-2—- aminocyclobuty 0.903 min Xtimate C18 |][6-(2,4- 2.1x30mm 3um Mobile dimethoxyphen phase: from 0% MeCN in y|)oxo water (0.0685% TFA in thioxo-3,4- water) to 60% MeCN in dihydropyrimidi water 5% TFA in n-1(2H)- water) | acetamide 1H NMR (400 MHz, DMSO- N-{2-[6-(2,4- d6) 6 ppm 12.90 (s, 0.33H) dimethoxyphen ,12.75 (s, 0.66H), 8.02 (br s, y|)oxo 3H), 7.33 (d, J=8.53 Hz, thioxo-3,4- 0.33H),7.30 (d, J=8.53 Hz, dihydropyrimidi 0.66H), 6.72-6.66 (m, 2H), n-1(2H)- 5.83 (s, 0.33H),5.73 (s, y|]ethy|}-N- 0.66H), 4.66-4.44 (br m, 1H), methylglycinam .81 (m, 6H), 3.79-3.64 ide (m, 3H),3.62-3.51 (m, 1H), N-[(1R,2R) aminocyclobuty 0.897 min Xtimate C18, |][6-(2,4- 2.1x30mm 3um Mobile dimethoxyphen 391.2 phase: from 0% MeCN (0.1% y|)oxo TFA) in water (0.1% TFA) to thioxo-3,4- 60% MeCN (0.1% TFA) in dihydropyrimidi water (0.1 % TFA) n-1(2H)- y|]acetamide 1H NMR (400 MHz, N-(3- METHANOL-d4) 6 ppm 8.25 aminopropyl)— (t, 0.5H), 7.17 .53 Hz, 2-[6-(2,4- 1 H), 6.66 (d, J=2.01 Hz, 1 dimethoxyphen H), 6.61 (dd,J=8.53, 2.01 Hz, y|)oxo 1H), 5.80 (s, 1H), 5.36 (br s, thioxo-3,4- 1H), 4.19-4.35 (m, 1H), 3.89 opyrimidi (s, 3H),3.87 (s, 3H), 3.21- 3.05 (m, 2H), 2.98-2.90 (m, y|]acetamide 2H), .75 (m, 2H).
N-(3-amino— 2,2- difluoropropyl)— 0.888 min Xtimate C18 2-[6-(2,4- 2.1x30mm 3 um Mobile dimethoxyphen phase: from 0% MeCN in y|)oxo water (0.1% TFA in water) to -3,4- 60% MeCN in water (0.1% dihydropyrimidi TFA in water) n-1(2H)- l]acetamide 1H NMR Spectral Data or am#ple HPLC Retention Time and Name Conditions 444 1H NMR (400 MHz, 31% N--(2- METHANOL-d4) 5 ppm 7.23 aminoethyl)—3-- (d, J=8.53 Hz, 1H), 6.68 (d, [6- (2, 4- J=2.01 Hz, 1H), 6.65 (dd, J: dimethoxyphen 8.53, 2.01 Hz, 1H), 5.75 (s, y|)oxo 1H), 4.81-4.70 (br s, 1H), thioxo-3,4- 4.07-3.95 (br m, 1H), 3.88 (s, dihydropyrimidi 3H), 3.87 (s, 1H), 3.93-3.32 n-1(2H)- (m, 2H), 3.01-2.95 (m, 2H), panamide 2.70-2.48 (m, 2H), 1.40-1.35 1H NMR (400 MHz, METHANOL--d4) 5 ppm 8.42- N-{2- 8.35 (m, 1H), 7.52-7.45 (m, ‘1’ [(cyclopropylm 0.5 H), 7.30-7.33 (m, 0.5H), ethyl)amino]eth 7.18 (d, J=8.53 Hz, 1H), yl}[6-(2,4- 6.69-6.66 (m, 1H), 6.64-6.60 dimethoxyphen (m, 1H), 5.82 (s, 1H), 5.49 (s, y|)oxo 1H), .28 (br s, 1H), -3,4- 4.35-4.22 (br m, 1H), 3.88 (s, dihydropyrimidi 3H), 3.85 (s, 1H), 3.54-3.42 n-1(2H)- (m, 1H), 3.15-2.99 (m, 2H), y|]acetamide 2.95-2.86 (m, 2H), 1.12-1.01 (m, 1H), 0.73-0.66 (m, 2H), 0.43-0.37 m, 2H . 1H NMR (400 MHz, DMSO- d6) 5 ppm 12.81 (s, 1H), carbamimidoyl- 11.82 (br s, 1H) 8.51-7.95 (br 3-[6-(2,4- ' m, 4H) 7.27 (d, J=8.53 Hz, dimethoxyphen 1H) 6.69 (d, J=2.01 Hz, 1H) y|)oxo 6.63 (dd, J=8.53, 2.01 Hz, thioxo-3,4- 1H) 5.76 (d, J=2.01 Hz, 1H) dihydropyrimidi 4.57-4.41 (br m, 1H) 4.03- n-1(2H)- 3.90 (br m ,1H) 3.86-3.78 (m, y|]propanamide 6H .71 m, 2H .
The ing Examples of Table 11 were prepared from the corresponding thiouracil amines as bed above for the Preparations in the IV. Guanidine Route section and by employing the methods described in the |. Beta Keto Ester Route Section as well as standard methods and techniques known to those skilled in the art.
WO 68875 Table 11. es from Guanidine Route 1H NMR Spectral Data or Compound Structure HPLC Retention Time and Name Conditions 1-cyano—3-{3- 1H NMR (400 MHz, DMSO- [6-(5-fluoro d6) 6 ppm 12.78 (s, 1H), yphenyl 7.41-7.34 (m, 2H), 7.16 (dd, )oxo ,4.02 Hz, 1H), 6.94- -3,4- 6.31 (brs, 3H), 5.85 (s, 1H), dihydropyrimidi 4.26 (br s, 1H), 3.82 (s, 3H), n-1(2H)- 3.72-3.58 (br m, 1H), 2.91- y|]propy|}guani 2.75 (m, 2H), 1.77-1.66 (br dine ,1.61-1.46 br m, 1H . 1-(2-{6-[5- 1.31 min Atlantis dC18 5um chloro(2- 4.6x50mm, /5% hyd roxyeth oxy) MeCN linear to 5%H20/95% phenyl]—4-oxo- MeCN over 4.0 min, HOLD 2-thioxo-3,4- at 5%H20/95%MeCN to dihydropyrimidi 5.0min. (0.05% formic acid). )-yl}ethyl Flow rate: 2 mL/min. o uanidine 1-{3-[6-(5- 1.62 min is dC18 5um chlorometh 4.6x50mm, 95%H20/5% oxyphenyl)—4- MeCN linear to 5%H20/95% oxothioxo- MeCN over 4.0 min, HOLD 3,4-dihyd ropyr at 5%H20/95%MeCN to imidin-1(2H)- 5.0min. (0.05% trifluoroacetic y|]propy|} acid). Flow rate: 2 mL/min. eth lo uanidine N-{3-[6-(5- chlorometh 2.02 min Atlantis dC18 5um oxyphenyl)—4- 4.6x50mm, 95%H20/5% oxothioxo- MeCN linear to 5%H20/95% 3,4-dihyd ropyr MeCN over 4.0 min, HOLD imidin-1(2H)- at 5%H20/95%MeCN to y|]propy|}pyrroli 5.0min. (0.05% trifluoroacetic dinecarbox acid). Flow rate: 2 mL/min. imidamide 1H NMR (500 MHz, 1-{3-[6-(5- METHANOL—d4) 5 ppm 7.58 chlorometh (m, 2H), 7.43 (m, 2H), 7.31 oxyphenyl)—4- (br s, 1H), 7.20 (d, J = 8.8 oxothioxo- Hz, 1H), 5.84 (s, 2H), 4.56 3,4-dihyd ropyr (br s, 1H), 3.92 (s, 3H), 3.81 imidin-1(2H)- (br s, 1H), 3.62 (td, J = 14.0, y|]propy|} 8.4 Hz, 2H), 3.15 (q, J = 6.8 (2,2-difluoro Hz, 2H), 1.95-2.03 (m, 1H), propyl) 1.75-1.85 (m, 1H), 1.87 (t, J guanidine = 18.2 Hz, 3H Ex- 1H NMR Spectral Data or Compound Obs ample Structure HPLC Retention Time and Name Mass # Conditions 452 O 1- NH O car bamimidoyl- 1.002 min Xtimate C18 S N 3 -{2-[6-(2,4- 2.1x30mm,3um Mobile O dim ethoxyphen O NH phase: from 0% MeCN (0.1% y l)oxo 393.1 H2N NH TFA) in water (0.1% TFA) to t hioxo-3,4- NH 60% MeCN (0.1% TFA) in dihydropyrimidi water (0.1% TFA) n-1(2H)- yl]ethyl}urea 453 O 1H NMR (400 MHz, DMSO{3-[6-(2,4- NH O d6) δ ppm 12.96 (s, 1 H), dim ethoxyphen S N 7.81-7.72 (m, 1 H), 7.59-7.24 F y l)oxo O (br s, 4H), 7.23-7.16 (m, 2H), F t hioxo-3,4- N 400.1 6.70-6.67 (m, 1 H), 6.64 (dd, dih ydropyrimidi H2N NH2 J=8.53,2.01 Hz, 1H), 5.82 (d, n-1(2H)-yl]-2,2- J=1.51 Hz, 1 H), 5.79-5.61 difluoropropyl}g (m, 1 H), 3.89-3.80 (m, 6 H), uanidine 3.75-3.62 (m, 2 H) All publications, including but not d to, issued patents, patent applications, and journal articles, cited in this application are each herein orated by reference in their entirety.
Although the invention has been described above with nce to the disclosed ments, those skilled in the art will readily appreciate that the specific experiments ed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the scope of the invention.
What is claimed:

Claims (30)

1. A compound having Formula | 8%N R1 Formula | or a pharmaceutically acceptable salt or g thereof wherein 10 R1 is a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully rated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from en, sulfur and oxygen; and 15 said R1 is optionally mono-, di-, ortri-substituted independently with cyano, halo, hydroxyl, amino, (C1-C4)alkyl, )alkoxy, )alkoxy(C1-C4)alkyl, hydroxy(Cg- C4)alkoxy, carbamoyl(C1-C4)alkoxy, amino(Cg-C4)alkoxy, cyano(C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylamino, aminocarbonyl, mono-N- or di-N,N(C1-C4)alkylaminocarbonyl, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, or - or 20 di-N,N(C1-C4)alkylaminosulfonyl, wherein any of the (C1-C4)alkyl or (C1-C4)alkoxy may be optionally mono-, di- or tri-substituted with fluoro; or wherein R1 is ally substituted with a five to six membered aromatic ring optionally having one to three heteroatoms selected independently from nitrogen, sulfur and oxygen; R2 is a fully ted, partially unsaturated or fully unsaturated one to fourteen 25 membered straight carbon chain n the carbons, other than the connecting carbon, a. may be branched b. may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur is optionally 30 mono- or di-substituted with oxo, c. may optionally be mono-, di- or tri-substituted independently with halo, d. may optionally be ubstituted with hydroxy, and e. may optionally be mono-substituted with oxo, and wherein the carbon chain is optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully rated five to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Z is optionally mono-, di- or tri-substituted independently with halo, (C1-C6)alkyl, (C1-C6)alkylcarbonyl, aminothioxo, amino(C1-C6)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or (C1-C6)alkoxy and wherein said (C1- C6)alkyl or (C1-C6)alkoxy substituent is also optionally substituted with one to three halo, and wherein said (C1-C6)alkyl or (C2-C6)alkoxy tuent is also optionally substituted with one to three hydroxy; with the proviso that R1 is not tituted phenyl, and R2 is not unsubstituted (C1- C6)alkyl.
2. The compound of claim 1 wherein R1 is phenyl, naphthyl, furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, lyl, imidazolinyl, cyclopentyl, cyclohexyl, pyrrolyl, l, benzo[b]thiophenyl, benzothiazolyl, b]furanyl or thiophenyl; and wherein said R1 is mono-, di-, or tri-substituted ndently with cyano, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C2-C4)alkoxy, trifluoro(C1- C4)alkyl, trifluoro(C1-C4)alkoxy or halo.
3. The compound of claim 2 n R2 is a fully saturated, partially unsaturated or fully unsaturated one to fourteen membered straight carbon chain wherein the s, other than the connecting carbon, a. may be branched b. may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said sulfur is optionally mono- or di-substituted with oxo, c. may optionally be mono-, di- or tri-substituted independently with halo, d. may optionally be mono-substituted with hydroxy, and e. may optionally be mono-substituted with oxo; or R2 is l(C1-C4)alkyl, triazolyl(C1-C4)alkyl, pyridinyl(C1-C4)alkyl, pyrazinyl(C1- 5 C4)alkyl, pyridazinyl(C1-C4)alkyl, pyrimidinyl(C1-C4)alkyl, imidazolyl(C1-C4)alkyl or pyrrolidinyl(C 2 rings optionally mono-, di- or bstituted 1-C4)alkyl, said R independently with (C1-C4)alkyl, (C1-C4)alkoxy or halo.
4. The nd of claim 3 wherein 10 R1 is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl; wherein said R1 is mono-, di-, or tri-substituted independently with (C 1-C4)alkyl, (C1-C4)alkoxy, y(C2- C4)alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and 15 R2 is (C1-C4)alkoxy(C 1-C4)alkyl, carboxy(C1-C4)alkyl, mono-or roxy(C2-C6)alkyl, amino(C 2-C4)alkyl, diaminomethyleneamino(C2-C4)alkyl, mono-N- or di-N,N(C1- C4)alkylamino(C lkyl, (C1-C4)alkylcarbonyloxy(C 1-C4)alkyl,, (C1- C4)alkoxycarbonyl(C 1-C4)alkyl, carbamoyl(C1-C4)alkyl, carbamoylamino(C2-C4)alkyl, - or di-N,N(C1-C4)alkylcarbamoyl(C 1-C4)alkyl, amino(C2-C4)alkylcarbamoyl(C 1- 20 C4)alkyl, (C1-C4)alkylcarbonylamino(C 2-C4)alkyl, C1-C4)alkylcarbonylamino(C 2- C4)alkyl, (C1-C4)alkoxycarbonylamino(C 2-C4)alkyl, (C1-C4)alkylsulfonylamino(C 2- C4)alkyl, (C1-C4)alkylaminosulfonyl(C 1-C4)alkyl, aminosulfonyl(C1-C4)alkyl, amino(C3- C4)hydroxyalkyl or )alkylthioalkyl(C 1-C4). 25
5. The compound of claim 4 wherein R1 is phenyl and said R1 is mono-, di-, or bstituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro; and R2 is diaminomethyleneamino(C2-C4)alkyl, carbamoyl(C1-C4)alkyl, hydroxy(C2-C4)alkyl, amino(C lkylcarbamoyl(C 1-C4)alkyl, (C1-C4)alkylcarbonylamino(C 2-C4)alkyl, 30 amino(C 1-C4)alkylcarbonylamino(C 2-C4)alkyl, amino(C3-C4)hydroxyalkyl or amino(C2- C4)alkyl.
6. The compound of claim 3 wherein R1 is phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrimidinyl, 35 pyridazinyl, pyrazinyl, imidazolinyl, furanyl, cyclopentyl, cyclohexyl, pyrrolyl, indolyl, benzo[b]thiophenyl, hiazolyl, benzo[b]furanyl or thiophenyl; n said R1 is mono-, di-, or tri-substituted independently with (C 1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C2- C4)alkoxy, cyano, trifluoromethyl, trifluoromethoxy or halo; and R2 is triazolyl(C1-C4)alkyl, pyridinyl(C1-C4)alkyl, pyrazinyl(C1-C4)alkyl, pyridazinyl(C1- 5 C4)alkyl, pyrimidinyl(C1-C4)alkyl, imidazolyl(C1-C4)alkyl or pyrrolidinyl(C1-C4)alkyl, said R2 rings optionally mono-, di- or tri-substituted independently with (C1-C4)alkyl, (C1- oxy or halo.
7. The compound of claim 1 wherein R1 is phenyl and said R1 is mono-, di-, tri- 10 substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro.
8. The compound of claim 1 wherein R2 is hydroxy(C2-C4)alkyl, diaminomethyleneamino(C 2-C4)alkyl, carbamoyl(C1-C4)alkyl, amino(C3-C4)hydroxyalkyl, amino(C 2-C4)alkylcarbamoyl(C 1-C4)alkyl, (C1-C4)alkylcarbonylamino(C 2-C4)alkyl, 15 amino(C 1-C4)alkylcarbonylamino(C 2-C4)alkyl or amino(C2-C4)alkyl.
9. The compound of claim 1 wherein R2 is (C1-C4)alkyl mono- or di-substituted independently with amino, carbamoyl, yl, (C1-C4)alkoxy, C1- C4)alkylcarbonylamino, amino(C2-C4)alkylcarbamoyl, (C1-C4)alkylcarbonylamino or 20 diaminomethyleneamino.
10. The compound or a pharmaceutically acceptable salt thereof n the compound is 6-(2,4-dimethoxyphenyl)(2-hydroxyethyl)thioxo-2,3-dihydropyrimidin-4(1H)-one; 25 1-(2-aminoethyl)(2,4-dimethoxyphenyl)thioxo-2,3-dihydropyrimidin-4(1H)-one; 2-[6-(2,5-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide; 5-chloromethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- yl]acetamide; 1-(2-aminoethyl)thioxo(2,4,5-trimethoxyphenyl)-2,3-dihydropyrimidin-4(1H)-one; 30 1-(3-aminopropyl)(2-methoxymethylphenyl)thioxo-2,3-dihydropyrimidin-4(1H)- one; N-{2-[6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- yl]ethyl}glycinamide; 6-(2-methoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- 35 yl]propyl}guanidine; 1-[(2S)aminohydroxypropyl](5-chloromethoxyphenyl)thioxo-2,3- dihydropyrimidin-4(1H)-one; 1-[(2R)aminohydroxypropyl](5-chloromethoxyphenyl)thioxo-2,3- dihydropyrimidin-4(1H)-one; 5 N-(2-aminoethyl)[6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- yl]acetamide; or 1-(2-aminoethyl)[2-(2-hydroxyethoxy)phenyl]thioxo-2,3-dihydropyrimidin-4(1H)-one or a pharmaceutically acceptable salt thereof. 10
11. The compound 2-(6-(2,5-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide or a pharmaceutically acceptable salt thereof.
12. The compound 15 5-chloromethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- tamide or a pharmaceutically acceptable salt thereof.
13. The compound having the Formula NH OMe S N NH2 OMe .
14. The compound having the Formula NH OMe S N NH2 Cl .
15. Use of a therapeutically effective amount of a compound of claim 1 or a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug in the manufacture of a medicament for treating cardiovascular ions in a mammal. 10
16. A use as d in claim 15 n the cardiovascular condition is heart e, congestive heart failure, peripheral arterial disease, pulmonary hypertension or vasculitis.
17. A use as recited in claim 15 wherein the mammal has unstable angina or has 15 experienced myocardial infarction.
18. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or a g thereof or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or 20 diluent.
19. A pharmaceutical combination composition comprising: a therapeutically ive amount of a composition comprising: a first compound, said first compound being a compound of claim 1, a prodrug 25 thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; WO 68875 a second nd, said second compound being an angiotensin converting enzyme inhibitor, a HMG-CoA reductase inhibitor, a non-steroidal anti-inflammatory agent, a Factor Xa inhibitor or in; and a pharmaceutical carrier, vehicle or ts.
20. The compound of claim 4 wherein R1 is naphthyl, quinolinyl, isoquinolinyl, indolyl, benzo[b]thiophenyl, benzothiazolyl, benzo[b]furanyl or thiophenyl and said R1 is mono-, di-, or tri-substituted independently with hydroxyethoxy, methyl, methoxy, fluoro or chloro; and R2 is diaminomethyleneamino(Cg-C4)alkyl, carbamoyl(C1-C4)alkyl, hydroxy(Cg-C4)alkyl, 10 amino(Cg-C4)alkylcarbamoyl(C1-C4)alkyl, (C1-C4)alkylcarbonylamino(Cg-C4)alkyl, amino(C1-C4)alkylcarbonylamino(Cg-C4)alkyl, amino(Cg-C4)hydroxyalkyl or amino(Cg- C4)alkyl.
21. The compound or a pharmaceutically acceptable salt thereof wherein the compound is 2-[6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)-yl]acetamide; 2-[6-(2-methoxymethylphenyl)—4-oxothioxo-3,4-dihydropyrimidin-1(2H)- yl]acetamide; 1-[(2R)—2-aminopropyl]—6-(2,4-dimethoxyphenyl)—2-thioxo—2,3-dihyd ropyrimidin-4(1 H)- 20 one; 2-[6-(3-methoxynaphthyl)oxothioxo-3,4-dihydropyrimidin-1(2H)—yl]acetamide; or 2-[6-(1H-indolyl)oxothioxo-3,4-dihydropyrimidin-1(2H)—yl]acetamide.
22. The compound or a pharmaceutically acceptable salt f wherein the 25 compound is 2-{6-[2-(2-hydroxyethoxy)—5-methoxyphenyl]—4-oxo—2-thioxo—3,4-dihyd midin-1 (2H)- yl}acetamide; N-(2-aminoethyl)—2-{6-[2-(2-hydroxyethoxy)—4-methoxyphenyl]—4-oxo—2-thioxo—3,4- opyrimidin-1(2H)—yl}acetamide; 3O 6-[2-(2-hydroxyethoxy)—4-methoxyphenyl]—1-(2-hydroxyethyl)thioxo-2,3- dihydropyrimidin-4(1H)—one; 6-[5-fluoro(2-hydroxyethoxy)phenyl](2-hydroxyethyl)—2-thioxo—2,3-dihydropyrimidin- 4(1H)—one; or 2-{6-[2-(2-hydroxyethoxy)—4-methoxyphenyl]—4-oxo—2-thioxo—3,4-dihyd ropyrimidin-1 (2H)- 35 yl}acetamide.
23. The compound N-(2-aminoethyl)[6-(2,4-dimethoxyphenyl)oxothioxo-3,4-dihydropyrimidin-1(2H)- yl]acetamide or a pharmaceutically able salt thereof. 5
24. The compound having the Formula HN OMe S N H2N .
25. A compound having Formula I A S N R1 10 R2 Formula I A or a ceutically acceptable salt or prodrug thereof wherein R1 is a five to six membered aromatic ring optionally having one to three heteroatoms 15 selected independently from nitrogen, sulfur and oxygen or a bicyclic ring consisting of two fused partially saturated, fully ted or fully unsaturated five to six membered rings, taken ndently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and said R1 is optionally mono-, di-, or tri-substituted independently with cyano, halo, 20 hydroxyl, amino, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, hydroxy(C2- C4)alkoxy, oyl(C1-C4)alkoxy, amino(C2-C4)alkoxy, cyano(C1-C4)alkyl, (C1- C4)alkylcarbonyloxy(C1-C4)alkyl, amino(C1-C4)alkylcarbonyloxy(C1-C4)alkyl, (C1- C4)alkylcarbonyloxy(C1-C4)alkoxy, C1-C4)alkylcarbonyloxy(C1-C4)alkoxy, mono- N- or di-N,N-(C1-C4)alkylamino, aminocarbonyl, mono-N- or di-N,N(C1- 25 C4)alkylaminocarbonyl, (C1-C4)alkylthio, aminosulfonyl, (C1-C4)alkylsulfinyl, (C1- C4)alkylsulfonyl, or mono-N- or di-N,N(C1-C4)alkylaminosulfonyl, wherein any of the (C1- C4)alkyl or )alkoxy may be optionally mono-, di- or tri-substituted with fluoro; or wherein R1 is ally substituted with a five to six membered aromatic ring optionally having one to three heteroatoms ed independently from nitrogen, sulfur and 5 oxygen; R2 is a fully saturated, partially unsaturated or fully unsaturated one to fourteen ed straight carbon chain wherein the carbons, other than the connecting carbon, a. may be branched 10 b. may optionally be replaced with one or two heteroatoms ed independently from oxygen and sulfur and may optionally be replaced with one to four nitrogens, n said sulfur is optionally mono- or di-substituted with oxo, c. may optionally be mono-, di- or tri-substituted independently with halo, d. may optionally be mono-substituted with hydroxy, and 15 e. may optionally be mono-substituted with oxo, and wherein the carbon chain is optionally mono-substituted with Z; wherein Z is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of 20 two fused partially saturated, fully saturated or fully unsaturated five to six membered rings, taken ndently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Z is optionally mono-, di- or tri-substituted independently with amino, halo, (C1-C6)alkyl, (C1-C6)alkylcarbonyl, aminothioxo, amino(C1- 25 C6)alkylcarbonyl, hydroxyl, diaminomethylene, carbamoyl or (C1-C6)alkoxy and wherein said (C1-C6)alkyl or )alkoxy substituent is also optionally tuted with one to three halo, and n said (C1-C6)alkyl or (C2-C6)alkoxy substituent is also optionally substituted with one to three hydroxy; with the proviso that R1 is not unsubstituted phenyl, and R2 is not unsubstituted(C1- 30 yl.
26. The use of a therapeutically effective amount of a compound of claim 25 or a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug in the manufacture of a medicament for treating cardiovascular events and conditions wherein the cardiovascular condition or event is heart failure, congestive heart failure, peripheral arterial e, pulmonary hypertension, itis, a primary or secondary myocardial tion, ischemia, ischemia reperfusion injury, atrial fibrillation or coronary artery bypass graft surgery.
27. The use of a therapeutically effective amount of a compound of claim 25 or a prodrug thereof or a pharmaceutically acceptable salt of said compound of said prodrug in the manufacture of a medicament for treating a condition selected from dialysis, delayed graft function, transplant organ rejection or nephropathy caused by contrasting 10 agents.
28. A ceutical composition which comprises a therapeutically effective amount of a compound of claim 25 or a prodrug thereof or a pharmaceutically acceptable salt of said nd or of said prodrug and a pharmaceutically acceptable carrier, vehicle or 15 diluent.
29. A pharmaceutical combination composition comprising: a eutically ive amount of a composition comprising: a first compound, said first compound being a compound of claim 25, a prodrug 20 thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; a second compound, said second compound being an angiotensin converting enzyme inhibitor, a HMG-CoA reductase inhibitor, a non-steroidal anti-inflammatory agent, a Factor Xa inhibitor or in; and a pharmaceutical r, vehicle or diluents.
30. The compound of any one of claims 1, 10 to 14, or 21 to 25, substantially as herein described with reference to any one of the Examples and/or
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