Claims for Patent: 8,324,208

Summary for Patent: 8,324,208

Title:	Prolyl hydroxylase inhibitors
Abstract:	The invention described herein relates to certain pyrimidinetrione N-substituted glycine derivatives of formula (I) which are antagonists of HIF prolyl hydroxylases and are useful for treating diseases benefiting from the inhibition of this enzyme, anemia being one example.
Inventor(s):	Kevin J. Duffy, Duke M. FITCH, Jian Jin, Ronggang Liu, Antony N. Shaw, Kenneth Wiggall
Assignee:	GlaxoSmithKline LLC
Application Number:	US12/305,675
Patent Claims:	1. A compound according to formula (I): wherein: R1 and R4 are each independently selected from the group consisting of hydrogen, —NR5R6, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C10alkyl, C5-C8cycloalkenyl, C5-C8cycloalkenyl-C1-C10alkyl, C3-C8heterocycloalkyl, C3-C8heterocycloalkyl-C1-C10alkyl, aryl, aryl-C1-C10alkyl, heteroaryl and heteroaryl-C1-C10alkyl; R2 is —NR7R8 or —OR9; R3 is H or C1-C4alkyl; where R5 and R6 are each independently selected from the group consisting of hydrogen, C1-C10alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C10alkyl, C3-C8heterocycloalkyl, C3-C8heterocycloalkyl-C1-C10alkyl, aryl, aryl-C1-C10alkyl, heteroaryl, heteroaryl-C1-C10alkyl, —C(O)C1-C4alkyl, —C(O)C3-C6cycloalkyl, —C(O)C3-C6heterocycloalkyl, —C(O)aryl, —C(O)heteroaryl and —S(O)2C1-C4alkyl, or, when R5 and R6 are attached to the same nitrogen, R5 and R6 taken together with the nitrogen to which they are attached form a 5- or 6- or 7-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen and sulphur, R7 and R8 are each independently selected from the group consisting of hydrogen, C1-C10alkyl, C2-C10 alkenyl, C2-C10alkynyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl and heteroaryl, and R9 is H or a cation, or C1-C10alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C3-C6cycloalkyl, heterocycloalkyl, aryl and heteroaryl; X is O or S; and Y is O or S; where any carbon or heteroatom of R1, R2, R3, R4, R5, R6, R7, R8, R9 is unsubstituted or is substituted with one or more substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen, —OR10, —NR5R6, oxo, cyano, nitro, —C(O)R10, —C(O)OR10, —SR10, —S(O)R10, —S(O)2R10, —NR5R6, —CONR5R6, —N(R5)C(O)R10, —N(R5)C(O)OR10, —OC(O)NR5R6, —N(R5)C(O)NR5R6, —SO2NR5R6, —N(R5)SO2R10, C2-C10alkenyl, C2-C10alkynyl, C3-C6cycloalkyl, C3-C6heterocycloalkyl, aryl, C1-C6alkyl-aryl, heteroaryl and C1-C6alkyl-heteroaryl, wherein R5 and R6 are the same as defined above and R10is selected from hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, —C(O)C1-C4alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)C3-C6cycloalkyl, —C(O)C3-C6heterocycloalkyl, —S(O)2C1-C4alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C14aryl, aryl-C1-C10alkyl, heteroaryl and heteroaryl-C1-C10alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 wherein: X is O; Y is O; R1 and R4 are each independently selected from the group consisting of hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl- C1-C10alkyl, C5-C8cycloalkenyl, C5-C8cycloalkenyl-C1-C10alkyl, C3-C8heterocycloalkyl, C3-C8heterocycloalkyl-C1-C10alkyl, aryl, aryl-C1-C10alkyl, heteroaryl and heteroaryl-C1-C10alkyl; R2 is —NR7R8 or —OR9; R3 is H or C1-C4alkyl; where R7 and R8 are each independently selected from the group consisting of hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, aryl and heteroaryl, and R9 is H or a cation, or C1-C10alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C3-C6cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where any carbon or heteroatom of R1, R2, R3, R4, R7, R8, R9 is unsubstituted or is substituted with one or more substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen, —OR10, —NR5R6, oxo, cyano, nitro, —C(O)R10, —C(O)OR10, —SR10, —S(O)R10, —S(O)2R10, —NR5R6, —CONR5R6, —N(R5)C(O)R10, —N(R6)C(O)OR10, —OC(O)NR5R6, —N(R5)C(O)NR5R6, —SO2NR5R6, —N(R5)SO2R10, C2-C10alkenyl, C2-C10alkynyl, C3-C6cycloalkyl, C3-C6heterocycloalkyl, aryl, C1-C6alkyl-aryl, heteroaryl and C1-C6alkyl-heteroaryl, wherein R5, and R6 are as defined in claim 1 and R10is selected from hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, —C(O)C1-C4 alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)C3-C6cycloalkyl, —C(O)C3-C6heterocycloalkyl, —S(O)2C1-C4 alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C14aryl, aryl-C1-C10alkyl, heteroaryl and heteroaryl-C1-C10alkyl; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1 wherein: X is O; Y is O; R1 and R4 are each independently selected from the group consisting of hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C10alkyl, C5-C8cycloalkenyl, C5-C8cycloalkenyl-C1-C10alkyl, C3-C8heterocycloalkyl, C3-C8heterocycloalkyl-C1-C10alkyl, aryl, aryl-C1-C10alkyl, heteroaryl and heteroaryl-C1-C10alkyl; R2 is —OR9; R3 is H or C1-C4alkyl; R9 is H or a cation, or C1-C10alkyl which is unsubstituted or is substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where any carbon or heteroatom of R1, R2, R3, R4, R9 is unsubstituted or is substituted with one or more substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen, —OR10, —NR5R6, oxo, cyano, nitro, —C(O)R10, —C(O)OR10, —SR10, —S(O)R10, —S(O)2R10, —NR5R6, —CONR5R6, —N(R5)C(O)R10, —N(R5)—C(O)OR10, —OC(O)NR5R6, —N(R5)C(O)NR5R6, —SO2NR5R6, —N(R5)SO2R10, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6cycloalkyl, C3-C6heterocycloalkyl, aryl, C1-Colkyl-aryl, heteroaryl and C1-C6 alkyl-heteroaryl, wherein R5, and R6 are the same as defined in claim 1 and R10is selected from hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, —C(O)C1-C4alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)C3-C6cycloalkyl, —C(O)C3-C6heterocycloalkyl, —S(O)2C1-C4alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, C6-C14aryl, aryl-C1-C10alkyl, heteroaryl and heteroaryl-C1-C10alkyl; or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 1 wherein: X is O; Y is O; R1 and R4 are each independently selected from the group consisting of hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-C10alkyl, C5-C8cycloalkenyl, C5-C8cycloalkenyl-C1-C10alkyl, C3-C8heterocycloalkyl, C3-C8heterocycloalkyl-C1-C10alkyl, aryl, aryl-C1-C10alkyl, heteroaryl and heteroaryl-C1-C10alkyl; R2 is —OR9; R3 is H; R9 is H or a cation; where any carbon or heteroatom of R1, R2, R3, R4 is unsubstituted or is substituted with one or more substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, halogen, —OR10, —NR5R6, oxo, cyano, nitro, —C(O)R10, —C(O)OR10, —SR10, —S(O)R10, —S(O)2R10, —NR5R6, —CONR5R6, —N(R5)C(O)R10, —N(R5)—C(O)OR10, —OC(O)NR5R6, —N(R5)C(O)NR5R6, —SO2NR5R6, —N(R5)SO2R10, C2-C10alkenyl, C2-C10alkynyl, C3-C6cycloalkyl, C3-C6heterocycloalkyl, aryl, C1-C6alkyl-aryl, heteroaryl and C1-C6 alkyl-heteroaryl, wherein R5, and R6 are the same as defined in claim 1 and R10is selected from hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, —C(O)C1-C4alkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)C3-C6cycloalkyl, —C(O)C3-C6heterocycloalkyl, —S(O)2C1-C4 alkyl, C3-C8 cycloalkyl, C3-C8heterocycloalkyl, C6-C14 aryl, aryl-C1-C10alkyl, heteroaryl and heteroaryl-C1-C10alkyl; or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition which comprises a compound as described in claim 1 and one or more of pharmaceutically acceptable carriers, diluents and excipients. 6. A compound according to claim 1 which is: N-{[1,3-bis(2,6-dichlorophenyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1,3-bis[(2-chlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(6-hydroxy-1,3-bis{[2-(methyloxy)phenyl]methyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(1,3-bis{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(1-(2-biphenylyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(1-(2-bromophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(1-(2,4-dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(1-(2,6-dichlorophenyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[6-hydroxy-2,4-dioxo-1-(2-phenylethyl)-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-(4-chlorophenyl)-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-{[2,4-bis(methyloxy)phenyl]methyl}-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-(4-chlorophenyl)-6-hydroxy-4-oxo-3-(phenylmethyl)-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-{[6-hydroxy-2,4-dioxo-1-phenyl-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[6-hydroxy-1-(2-nitrophenyl)-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-[(3-cyanophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4- tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-[(6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[1-[(3,4-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[6-hydroxy-1-{[3-(methyloxy)phenyl]methyl}-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; or N-{[1-[(2,6-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 1 which is: N-{[1-(1-acetyl-3-piperidinyl)-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(1-{[(phenylmethy)oxy]carbonyl}-3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(4-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1-cyclohexyl-6-hydroxy-3-[3-(4-morpholinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; or N-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(tetrahydro-2h-pyran-4-yl)-1,2,3,4-tetrahydro-5- pyrimidinyl]carbonyl}glycine; or a pharmaceutically acceptable salt thereof. 8. A compound which is N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine, or a salt thereof. 9. A compound which is N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine. 10. A compound according to claim 8 which is N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine, or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 12. A compound according to claim 1 which is: N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(tetrahydro-2h-pyran-4-yl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1-cyclohexyl-6-hydroxy-3-[(2-methylphenyl)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(3-{[2-bromo-4-(1,1-dimethylethyl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-({3-[(2-bromo-5-fluorophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(3-{[2,4-bis(trifluoromethyl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(3-{[2-bromo-5-(methyloxy)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-({3-(2-cyclopropylethyl)-1-[4-(2-furanyl)phenyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({3-(2-cyclopropylethyl)-6-hydroxy-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({3-(2-cyclopropylethyl)-6-hydroxy-1-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-3-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-({3-(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1-[4-(2-thienyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-{[3-(2-cyclopropylethyl)-6-hydroxy-1-(3-nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({3-(2-cyclopropylethyl)-6-hydroxy-1-[4-(methyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[(3,4-difluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[(2,6-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({3-[(2-bromophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(1-cyclohexyl-3-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-6-hydroxy-2,4- dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-({1-cyclohexyl-3-[(3,4-difluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({3-(2-cyclopropylethyl)-6-hydroxy-1-[3-(methyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[(3,4-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[(2,3-difluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[4-(1,1-dimethylethyl)phenyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[3-cyclohexyl-6-hydroxy-1-(1-naphthalenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1-cyclohexyl-3-[(2,6-dichlorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-{[1-cyclohexyl-6-hydroxy-3-(2-naphthalenyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1-cyclohexyl-6-hydroxy-2,4-dioxo-3-[(2,4,6-trimethylphenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[(4-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[(2-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(1-cyclohexyl-6-hydroxy-3-{[4-(1-methylethyl)phenyl]methyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-({1-cyclohexyl-6-hydroxy-2,4-dioxo-3-[(2,4,6-trifluorophenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[(2,4-dimethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-6-hydroxy-2,4-dioxo-3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({3-[(2-chlorophenyl)methyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3-[(2-fluorophenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(1-cyclohexyl-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[1-cyclohexyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-[(3-{[3,5-bis(methyloxy)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[1-cyclohexyl-6-hydroxy-3-(2-naphthalenylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1-cyclohexyl-6-hydroxy-3-[(4-methylphenyl)methyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-{[3-(4-biphenylylmethyl)-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-[(3-{[4-(1,3-benzoxazol-2-yl)phenyl]methyl}-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; or N-({3-[2-(4-biphenylyl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 1 which is: N-{[3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1-(3-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4-dioxo-1-(2-thienyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(2-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-[(1-(1,1-dimethylethyl)-3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-2,4- dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; n-{[3-[(2-bromophenyl)methyl]-1-(1,1-dimethylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[3-{[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-1-(1-methylethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[6-hydroxy-1-methyl-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-hexyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-ethyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-propyl-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-butyl-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-cyclohexyl-3-(1,1-dimethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(1-cyclohexyl-3-hexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; 6-[5-{[(carboxymethyl)amino]carbonyl}-3-cyclohexyl-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]hexanoic acid; or 6-[5-{[(carboxymethyl)amino]carbonothioyl}-3-cyclohexyl-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]hexanoic acid; or a pharmaceutically acceptable salt thereof. 14. A compound according to claim 1 which is: N-{[1-cyclohexyl-3-(3,3-dimethyl-2-oxobutyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({3-[2-(1-benzofuran-2-yl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({3-[2-(4-cyanophenyl)-2-oxoethyl]-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-3[2-(4-fluorophenyl)-2-oxoethyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({1-cyclohexyl-6-hydroxy-3-[2-(4-methylphenyl)-2-oxoethyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(1-cyclohexyl-6-hydroxy-3-{2-[4-(methyloxy)phenyl]-2-oxoethyl}-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; or N-{[1-cyclohexyl-6-hydroxy-2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 1 which is: N-{[1,3-bis(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[3-cyclohexyl-6-hydroxy-2,4-dioxo-1-(4-phenylcyclohexyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1-[1,1′-bi(cyclohexyl)-4-yl]-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-({3-cyclohexyl-6-hydroxy-1-[trans-4-(methyloxy)cyclohexyl]-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-{[3-cyclohexyl-1-(4,4-dimethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; 3-[5-{[(carboxymethyl)amino]carbonyl}-3-cyclohexyl-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2h)-pyrimidinyl]cyclohexanecarboxylic acid; N-{[1-cyclohexyl-6-hydroxy-3-(1-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; cis-4-[3-cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2h)-pyrimidinyl]cyclohexanecarboxylic acid; N-{[1-cyclohexyl-3-(4-ethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; 4-[5-{[(carboxymethyl)amino]carbonyl}-3-cyclohexyl-4-hydroxy-2,6-dioxo-3,6-dihydro-1(2h)-pyrimidinyl]cyclohexanecarboxylic acid; N-{[1-cyclohexyl-3-(2,3-dimethylcyclohexyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-[(1,3-dicyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(1,3-dicycloheptyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[1-cyclohexyl-6-hydroxy-3-(2-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-[(3-cyclohexyl-1-cyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(1-cyclobutyl-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(3-cyclohexyl-1-cyclopropyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[1-cyclohexyl-6-hydroxy-3-(3-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1-[(1r,2r,4s)-bicyclo[2.2.1]hept-2-yl]-3-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-[(3-cyclohexyl-6-hydroxy-2,4-dioxo-1-tricyclo[3.3.1.13,7]dec-1-yl-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-[(3-cycloheptyl-1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[1-cyclohexyl-3-(cyclohexylmethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-({1-cyclohexyl-3-[4-(1,1-dimethylethyl)cyclohexyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycine; N-{[1-cyclohexyl-6-hydroxy-3-(4-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-cyclohexyl-3-(2-cyclohexylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1-cyclohexyl-3-(2-cyclopropylethyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; ethyl n-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonothioyl]glycinate; or N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonothioyl]glycine; or a pharmaceutically acceptable salt thereof. 16. A compound according to claim 1 which is: N-{[1,3-bis(1,1-dimethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-[(1,3-dibutyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[6-hydroxy-1,3-bis(2-methylpropyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1,3-bis(1-ethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine; N-{[1,3-bis(1-ethylpropyl)-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5- pyrimidinyl]carbonyl}glycine; N-{[6-hydroxy-2,4-dioxo-1,3-bis(1-propylbutyl)-1,2,3,4-tetrahydro-5- pyrimidinyl]carbonyl}glycine; N-[(1,3-dihexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine; N-{[6-hydroxy-1,3-bis(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydro-5- pyrimidinyl]carbonyl}glycine; or N-{[6-hydroxy-1,3-bis(1-methylethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5- pyrimidinyl]carbonyl}glycine; or a pharmaceutically acceptable salt thereof.