IP Library › Granted Patent US 8,906,933

Granted Patent B2

US 8,906,933 · App. 13/814,316 · Granted Dec 9, 2014

Dihydropyrimidin-2(1H)-one compounds as neurokinin-3 receptor antagonists

Inventors: Xicheng Sun (Broomfield, CO); Jian Qiu (Longmont, CO)

Assignee: N30 Pharmaceuticals, Inc.

C07D239/22 C07D409/14 C07D413/10 C07D409/04 A61K31/505

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Quick Facts

Patent No.: US 8,906,933
App. No.: 13/814,316
Granted: Dec 9, 2014
Kind: B2

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Abstract

The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as Neurokinin-3 (NK3) receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of making and using the same.

Claims (243)

1. A method of attenuating at least one deleterious symptom or effect of schizophrenia characterized by overstimulation of NK3 which comprises administering to a patient in need thereof a therapeutically effective amount of an NK3 receptor antagonist of formula I:

wherein

X is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, each having 6 members or less in the ring;

Y is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;

Z is selected from the group consisting of O, S and NR 7 ;

R 1 , R 2 and R 7 are independently selected from the group consisting of hydrogen, and C 1 -C 6 alkyl;

R 3 is selected from the group consisting of hydrogen, nitro, cyano, carboxyl, carbamoyl, methylsulfonamido, fluoro, chloro, bromo, hydroxy, methylsulfonyl, and methylsulfinyl, isoxazol-4-yl, C 1 -C 6 alkoxy, —C(NH)NHOH, sulfonic acid, and acetyl;

R 4 is selected from the group consisting of hydrogen, hydroxy, methoxy, carboxyl, and tetrazol-5-yl;

or optionally R 3 and R 4 , taken together can form a heterocycle;

R 5 is selected from the group consisting of hydrogen, hydroxyl, carboxy, chloro, fluoro, cyano, —O(CH 2 ) 1-6 NMe 2 , C 1 -C 6 alkyl, —O(CH 2 ) 1-6 OCH 3 , —O(CH 2 ) 1-6 OH, acetyl, CF 3 , and C 1 -C 6 alkoxy;

or optionally R 4 and R 5 , taken together can form a heterocycle; and

R 6 is selected from the group consisting of hydrogen and hydroxyl.

2. The method of claim 1 wherein R 1 , R 2 and R 7 are independently selected from the group consisting of hydrogen and methyl;

R 3 is selected from the group consisting of hydrogen, nitro, cyano, carboxyl, carbamoyl, methylsulfonamido, fluoro, chloro, bromo, methylsulfonyl, and methylsulfinyl, isoxazol-4-yl, C 1 -C 6 alkoxy, —C(NH)NHOH, sulfonic acid, and acetyl;

R 4 is selected from the group consisting of hydroxy, carboxyl, and tetrazol-5-yl;

R 5 is selected from the group consisting of hydrogen, hydroxyl, carboxy, chloro, fluoro, cyano, —O(CH 2 ) 2 NMe 2 , C 1 -C 6 alkyl, —O(CH 2 ) 2 OCH 3 , —O(CH 2 ) 2 OH, acetyl, CF 3 , methoxy, ethoxy, isopropoxy, and n-propoxy; and

R 6 is hydrogen.

3. The method of claim 1 wherein X is selected from the group consisting of phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, thiazol-yl, substituted thiazol-yl, pyrazin-yl, substituted pyrazin-yl, pyridin-yl, and substituted pyridin-yl, cyclohexyl, and substituted cyclohexyl.

4. The method of claim 1 wherein X is selected from the group consisting of phenyl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, 2-fluorophenyl, p-tolyl, m-tolyl, biphenyl-4-yl, 4-methoxyphenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 4-bromophenyl, o-tolyl, 4-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3,4-difluorophenyl, 4-cyanophenyl, 3-carbamoylphenyl, pyrazin-2-yl, biphenyl-3-yl, 2-cyanophenyl, pyridin-4-yl, and pyridin-3-yl, 4-(dimethylamino)phenyl, 3-fluorophenyl, 3-ethylphenyl, and cyclohexyl.

5. The method of claim 1 wherein Y is selected from phenyl, substituted phenyl, thiophen-yl, substituted thiophen-yl, thiazol-yl, substituted thiazol-yl, pyrazin-yl, substituted pyrazin-yl, pyridin-yl, substituted pyridin-yl, furan-yl, substituted furan-yl, benzo[d][1,3]dioxol-yl, substituted benzo[d][1,3]dioxol-yl, imidazol-yl, substituted imidazol-yl, naphthalen-yl, substituted naphthalen-yl, pyrrol-yl, substituted pyrrol-yl, pyrazol-yl, substituted pyrazol-yl, tetrahydrofuran-yl, substituted tetrahydrofuran-yl, cyclopentyl, substituted cyclopentyl, cyclohexyl, and substituted cyclohexyl.

6. The method of claim 1 wherein Y is selected from the group consisting of phenyl, 3-methoxyphenyl, p-tolyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 3-fluorophenyl, 4-bromophenyl, biphenyl-4-yl, 4-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3,4-dichlorophenyl, 4-hydroxyphenyl, 2,4-difluorophenyl, furan-3-yl, 2-chlorophenyl, 3-cyanophenyl, 4-(dimethylamino)phenyl, 2-fluorophenyl, 4-morpholinophenyl, 4-aminophenyl, naphthal-2-yl, benzo[d][1,3]dioxol-5-yl, 4-cyanophenyl, naphthal-3-yl, naphthal-4-yl, 4-acetamidophenyl, thiophen-2-yl, thiophen-3-yl, 1-methyl-1H-imidazol-4-yl, naphthalene-1-yl, methyl phenylcarbamate, and naphthalene-2-yl, 4-(methanesulfonamido)phenyl, 1H-pyrrol-3-yl, 1-(phenylsulfonyl)-1H-pyrrol-3-yl, furan-2-yl, 4-(trifluoromethyl)phenyl, o-tolyl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 3-chloro-5-fluorophenyl, 3-hydroxyphenyl, pyrazin-2-yl, quinolin-6-yl, isoquinolin-6-yl, 1-methyl-1H-pyrazol-5-yl, tetrahydrofuran-2-yl, cyclopentyl, tetrahydrofuran-3-yl, and cyclohexyl.

7. The method of claim 1 wherein the NK3 receptor antagonist is selected from the group consisting of

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione;

4-(4-hydroxy-3-methoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3,4-dihydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(2-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-p-tolyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-p-tolyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-m-tolyl-3,4-dihydropyrimidin-2(1H)-one;

5-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(4-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

5-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

5-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

5-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

5-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-o-tolyl-3,4-dihydropyrimidin-2(1H)-one;

5-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

5-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;

5-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(3,5-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(4-bromophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(biphenyl-4-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(4-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(3-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(3,4-dimethoxyphenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-fluoro-4-methoxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-fluoro-5-hydroxy-4-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-1,3-dimethyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;

6-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(3-chloro-4-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(3,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(3,5-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(3,4-dichlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(2,4-difluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-3-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(2-chlorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

3-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzamide;

3-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile;

6-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(2-fluorophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-morpholinophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(4-aminophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyrazin-2-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-2-yl)-3,4-dihydropyrimidin-2(1H)-one;

5-(biphenyl-3-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(benzo[d][1,3]dioxol-5-yl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-3-methyl-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)benzonitrile;

4-(3-ethoxy-5-fluoro-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-fluoro-4-hydroxy-5-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;

2-(4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)benzonitrile;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one;

7-ethoxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one;

N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)acetamide;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one;

N-(3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;

N-(2-hydroxy-3-methoxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;

3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-2-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-imidazol-4-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-1-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

3-ethoxy-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzamide;

methyl 4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenylcarbamate;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-5-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(naphthalen-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(4-hydroxy-3-methoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

5-(4-(dimethylamino)phenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(3-(isoxazol-4-yl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

1,1′-(2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-1,3-phenylene)diethanone;

3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

2-hydroxy-3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;

4-(4-hydroxy-3-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;

2-ethoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzamide;

N-hydroxy-3-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzimidamide;

4-(3-bromo-5-ethoxy-4-hydroxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

N-(4-(6-(3-ethoxy-4-hydroxy-5-nitrophenyl)-2-oxo-5-phenyl-1,2,3,6-tetrahydropyrimidin-4-yl)phenyl)methanesulfonamide;

4-(4-hydroxy-3-isopropoxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-(methylsulfonyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-(methylsulfinyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

3-ethoxy-2-hydroxy-5-(2-oxo-6-phenyl-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(3-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(furan-2-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

2-ethoxy-4-(2-imino-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-o-tolyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-fluorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

(Z)-2-ethoxy-4-(2-(methylimino)-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-6-nitrophenol;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-chloro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

6-(3-chloro-5-fluorophenyl)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

2-hydroxy-3-nitro-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;

2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzenesulfonic acid;

(R)-3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(3-fluoro-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

3-ethoxy-2-hydroxy-5-(2-oxo-6-(pyridin-3-yl)-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzonitrile;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(3-hydroxyphenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(4-hydroxy-3-nitro-5-propoxyphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyrazin-2-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(quinolin-6-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(isoquinolin-6-yl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-methoxyphenyl)-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

3-ethoxy-2-hydroxy-5-(5-(3-methoxyphenyl)-2-oxo-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-4-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(4-hydroxy-3-(2-hydroxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

2-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-5-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

2-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(3-ethylphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one;

3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

2-chloro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

(R)-3-ethoxy-2-hydroxy-5-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

(R)-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(1-methyl-1H-pyrazol-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-ethoxy-6-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one;

3-fluoro-2-hydroxy-5-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

2-fluoro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

2-ethoxy-6-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(4-hydroxy-3-nitro-5-(trifluoromethyl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(4-hydroxy-3-(2-methoxyethoxy)-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(4-hydroxy-3-nitro-5-propylphenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-2-(trifluoromethyl)benzoic acid;

2-fluoro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

2-hydroxy-4-(2-oxo-5-phenyl-6-(pyridin-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

2-ethoxy-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(4-(2H-tetrazol-5-yl)phenyl)-5-phenyl-6-(pyridin-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

2-chloro-6-hydroxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(4-(2H-tetrazol-5-yl)phenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

2-hydroxy-6-methoxy-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(4-(2H-tetrazol-5-yl)phenyl)-6-(pyridin-3-yl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-phenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

(R)-2-hydroxy-4-(6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-5-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimidin-4-yl)benzoic acid;

4-(3-(2-(dimethylamino)ethoxy)-4-hydroxy-5-nitrophenyl)-5,6-diphenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;

6-cyclopentyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-(tetrahydrofuran-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

6-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-(thiophen-3-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((S)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one;

4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-5-phenyl-6-((R)-tetrahydrofuran-2-yl)-3,4-dihydropyrimidin-2(1H)-one; and

5-cyclohexyl-4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one.

8. The method of claim 1 wherein the NK3 receptor antagonist is selected from an R enantiomer of the compound of formula I or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 wherein the NK3 receptor antagonist is selected from the group consisting of: