Small molecule modulators of human sting

Abstract

The present invention relates to compounds of formula (I). The compounds maybe used to modulate the Stimulator of Interferon Genes (STING) protein and thereby treat diseases such as cancer and microbial infections. ##STR00001##

Claims

1. A compound of formula (I): ##STR00487## wherein X.sup.1 is CR.sup.1 or N; X.sup.2 is CR.sup.2 or N; X.sup.3 is CR.sup.3 or N; Q is C═O or; L is optionally substituted C.sub.1-C.sub.6 alkyl, C═O, S═O, SO.sub.2, or —CH.sub.2C(O)—; R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, CONR.sup.1R.sup.2, NR.sup.1R.sup.2, NHCOR.sup.1, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, and optionally substituted C.sub.1-C.sub.6 alkoxy R.sup.6 is a ring optionally substituted with one or more R.sup.12 groups, wherein the ring is selected from the group consisting of phenyl, pyridyl, thiazole, isoxazole, oxazole, pyrazole, and pyridone; Y is an optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.7 is H, or optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.8 is an optionally substituted ring selected from phenyl, furan, benzofuran and cyclohexyl; R.sup.9 and R.sup.10 are each independently selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, halogen, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, and mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, or R.sup.9 and R.sup.10 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; R.sup.11 is selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 alkoxy, mono and bicyclic optionally substituted 5 to 10 membered heteroaryl; each R.sup.12 group is independently selected from the group consisting of halogen, OH, OP(O)(OH).sub.2, NR.sup.13R.sup.14, CONR.sup.13R.sup.14, CN, COOR.sup.13, NO.sub.2, azido, SO.sub.2R.sup.13, OSO.sub.2R.sup.13, NR.sup.13SO.sub.2R.sup.14, NR.sup.13C(O)R.sup.14, O(CH.sub.2).sub.nOC(O)R.sup.13, NR.sup.13(CH.sub.2).sub.nOC(O)R.sup.14, OC(O)R.sup.13, OC(O)OR.sup.13, OC(O)NR.sup.13R.sup.14, OC(O)O(CH.sub.2).sub.nCOOR.sup.14, OC(O)NR.sup.13(CH.sub.2).sub.nCOOR.sup.14, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, an optionally substituted mono or bicyclic C.sub.5-C.sub.10 aryl, an optionally substituted mono or bicyclic 5 to 10 membered heteroaryl, an optionally substituted C.sub.3-C.sub.6 cycloalkyl and an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R.sup.13 and R.sup.14 are each independently selected from the group consisting of H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, and optionally substituted mono or bicyclic 3 to 8 membered heterocycle; and n is an integer between 0 and 6; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein X.sup.1 is CR.sup.1, X.sup.2 is CR.sup.2 and X.sup.3 is CR.sup.3.

3. A compound according to claim 1, wherein one or two of X.sup.1, X.sup.2 and X.sup.3 is N.

4. A compound according to any preceding claim, wherein R.sup.1, R.sup.2 and R.sup.3 are each H.

5. A compound according to claim 1, wherein R.sup.9 is different to R.sup.10 such the compound of formula (I) defines the carbon atom to which R.sup.9 and R.sup.10 are covalently bonded is a first stereogenic centre and defines an S enantiomer.

6. A compound according to claim 5, wherein the compound is a compound of formula (I)-ent 1: ##STR00488## R.sup.9 is H and R.sup.10 is an optionally substituted C.sub.1-C.sub.6 alkyl, halogen, or a C.sub.3-C.sub.6 cycloalkyl.

7. A compound according to claim 6, wherein R.sup.10 is methyl.

8. A compound according to claim 1, wherein R.sup.11 is selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy and optionally substituted C.sub.2-C.sub.6 alkenyl.

9. A compound according to claim 8, wherein R.sup.11 is methyl.

10. A compound according to claim 1, wherein Q is C═O.

11. A compound according to claim 1, wherein L is an optionally substituted C.sub.1-C.sub.6 alkyl, or —CH.sub.2C(O)—.

12. A compound according to claim 1, wherein R.sup.6 comprises a ring substituted with between 1 and 5 R.sup.12 groups, and each R.sup.12 group is independently selected from the list consisting of halogen, C.sub.1-C.sub.6 alkyl, CN, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 polyfluoroalkyl, azido, NR.sup.1R.sup.2, CONR.sup.1R.sup.2, OR.sup.1, OH and OP(O)(OH).sub.2.

13. A compound according to claim 12, wherein R.sup.6 is a phenyl substituted by 1 or 2 halogens.

14. A compound according to claim 12, wherein R.sup.6 is a phenyl further substituted with a hydroxyl.

15. A compound according to claim 1, wherein R.sup.8 comprises between 1 and 5 substituents, and each substituent is independently selected from the list consisting of C.sub.1-C.sub.6 alkyl, halogen, OH, C.sub.1-C.sub.6 alkoxy, CONR.sup.1R.sup.2, CN, azido, NO.sub.2, NH.sub.2, OCH.sub.2CH.sub.2OH, OCH.sub.2C(O)OH, OP(O)(OH).sub.2 and an optionally substituted mono or bicyclic 3 to 8 membered heterocycle.

16. A compound according to claim 1, wherein: X.sup.1 is CR.sup.1; X.sup.2 is CR.sup.2; X.sup.3 is CR.sup.3; Q is C═O; L is optionally substituted C.sub.1-C.sub.3 alkyl; Y is an optionally substituted C.sub.1-C.sub.6 alkyl; R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, halogen, CN, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl; R.sup.6 is a ring optionally substituted with one or more R.sup.12 groups, wherein the ring is selected from the group consisting of phenyl, pyridyl, thiazole, isoxazole, oxazole, pyrazole, and pyridone; R.sup.7 is H; R.sup.8 is an optionally substituted ring selected from phenyl, furan, benzofuran and cyclohexyl; R.sup.9 and R.sup.10 are each independently selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, halogen, optionally substituted C.sub.3-C.sub.6 cycloalkyl, and optionally substituted C.sub.2-C.sub.6 alkenyl; and R.sup.11 is selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy and optionally substituted C.sub.2-C.sub.6 alkenyl.

17. A compound according to claim 16, wherein: X.sup.1 is CH; X.sup.2 is CH; X.sup.3 is CH; Q is C═O; L is a C.sub.1-C.sub.2 alkyl; Y is a C.sub.1-C.sub.2 alkyl; R.sup.6 is a ring optionally substituted with one or more R.sup.12 groups, wherein the ring is selected from the group consisting of phenyl, pyridyl, thiazole, isoxazole, oxazole, pyrazole, and pyridone; R.sup.8 is an optionally substituted ring selected from phenyl, furan, benzofuran and cyclohexyl; R.sup.9 and R.sup.10 are each independently selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.4 alkenyl, H and halogen; and R.sup.11 is selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.4 alkenyl and H.

18. A compound according to claim 16, wherein: L is —CH.sub.2—; Y is —CH.sub.2—; R.sup.6 is a phenyl or a pyridinyl optionally substituted with one or more R.sup.2 groups; R.sup.8 is an optionally substituted phenyl ring; R.sup.9 and R.sup.10 are each independently selected from the group consisting of C.sub.1-C.sub.3 alkyl and H; and R.sup.11 is selected from the group consisting of C.sub.1-C.sub.3 alkyl and H.

19. A compound according to claim 18, wherein: R.sup.6 is a ring optionally substituted with at least one R.sup.2 group, wherein each R.sup.2 group is independently substituent selected from the group consisting of a halogen, —OH, optionally substituted C.sub.1-C.sub.4 alkoxy, amino, optionally substituted C.sub.1-C.sub.3 alkyl and C(O)NH.sub.2; R.sup.8 is substituted with at least one halogen; R.sup.9 and R.sup.10 are each independently selected from the group consisting of CH.sub.3 and H; and R.sup.11 is selected from the group consisting of CH.sub.3 and H.

20. A compound according to claim 19, wherein: R.sup.6 is substituted with one or two halogens, and each halogen is independently chlorine or fluorine; and R.sup.8 is substituted 2 or 3 halogens, and each halogen is fluorine.

21. A compound according to claim 20, wherein R.sup.6 is further substituted with a hydroxyl.

22. A compound, wherein the compound is: 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-cyclopropyl-1-(3,5-difluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(2,4-difluorobenzyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(4-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(3,5-difluorobenzyl)-3-ethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2,4-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-methylbenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-methoxybenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-bromo-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-3-methylbenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(3-carbamoylbenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(3,5-difluorobenzyl)-3-isopropyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-4-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(3,5-difluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chlorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((2-methylthiazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-2-oxo-3-(pyrimidin-2-yl)-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((6-methoxybenzofuran-2-yl)methyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((6-fluorobenzofuran-2-yl)methyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((5-fluorobenzofuran-2-yl)methyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-N-(3-(oxazol-2-yl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((5-hydroxybenzofuran-2-yl)methyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-N-(3-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-N-(3-(1-methyl-1H-pyrazol-5-yl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(2-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-N-(3-(4-methylpiperazin-1-yl)benzyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(benzofuran-5-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-(1-methyl-1H-imidazol-4-yl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((1,2,5-thiadiazol-3-yl)methyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((2-methyloxazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((1-methyl-1H-imidazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((5-methyl-2-(m-tolyl)oxazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-cyano-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((5-methyl-2-(p-tolyl)oxazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(2-fluoro-6-methoxybenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((2-(4-fluorophenyl)-5-methyloxazol-4-yl)methyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(benzo[d][1,3]dioxol-4-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(4-fluoro-2-methoxybenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((7-methoxybenzofuran-2-yl)methyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-N-((5-nitrobenzofuran-2-yl)methyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methoxy-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(benzofuran-4-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-N-((1-methyl-1H-indazol-6-yl)methyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(benzofuran-6-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((1-methyl-1H-pyrazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((3-methylisoxazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-methyl-1-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-(trifluoromethyl)benzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-((5-aminobenzofuran-2-yl)methyl)-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-((2-oxoindolin-5-yl)methyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(2,6-difluoro-4-methoxybenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(4-fluoro-2-methoxybenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2,6-dichlorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-3-methoxybenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((3-cyclopropylisoxazol-5-yl)methyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(6-chloro-2-fluoro-3-methylbenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3-(benzyloxy)-1-(2-chloro-6-fluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7-carboxamide 2,2-dioxide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide; N-(benzofuran-2-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (R)-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((5-chloro-3-fluoro-2-methylpyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-Difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-4-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-4-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-3-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)propyl dihydrogen phosphate; (S)-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)methyl dihydrogen phosphate; (S)-4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl dihydrogen phosphate; (S)-4-Acetamidobenzyl-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl) carbonate; (S)-Benzyl-3-(((4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)carbonyl)(methyl)amino)propanoate; (S)-1-(2-Chloro-6-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-Chloro-6-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenyl dihydrogen phosphate; (S)-(2-Chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)methyl dihydrogen phosphate; (S)-2-(2-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,4-difluorophenoxy)ethyl dihydrogen phosphate; (S)-4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3-fluorophenyl dihydrogen phosphate; (S)-2-((1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamido)methyl)-5-fluorophenyl dihydrogen phosphate; (S)-3-(2-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)propyl dihydrogen phosphate; (S)-2-(2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)ethyl dihydrogen phosphate; (S)-3-(2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)propyl dihydrogen phosphate; (S)-2-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)ethyl dihydrogen phosphate; (S)-3-chloro-4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-5-fluorophenyl dihydrogen phosphate; (S)-2-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,4-difluorophenyl dihydrogen phosphate; (S)-2-((1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamido)methyl)-3-fluorophenyl dihydrogen phosphate; (S)-4-((1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamido)methyl)-3,5-difluorophenyl dihydrogen phosphate; (S)-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4-difluorophenyl dihydrogen phosphate; (S)-2-(3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4-difluorophenoxy)ethyl dihydrogen phosphate; (S)-3-(3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4-difluorophenoxy)propyl dihydrogen phosphate; (S)-2-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl dihydrogen phosphate; (S)-1-(2-Chloro-6-fluoro-3-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-Chloro-6-fluoro-3-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-4-Acetamidobenzyl-(2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenyl) carbonate; (S)-Benzyl 3-(((2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)carbonyl)(methyl)amino)propanoate; (S)-1-(3-Carbamoyl-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-3-((3,4-Dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4-difluorobenzoic acid; (S)-1-(2,6-Difluoro-3-((2-hydroxyethyl)carbamoyl)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-(Allyloxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (4S)-1-(4-(2,3-Dihydroxypropoxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-((R)-2,3-Dihydroxypropoxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-((S)-2,3-Dihydroxypropoxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide; (S)—N,1-bis(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)—N,1-bis(2,6-Difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-Chloro-6-fluorobenzyl)-N-(2-hydroxyethyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(3,5-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-bromo-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-methylbenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(6-chloro-2-fluoro-3-methylbenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-3-methylbenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-5-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(5-carbamoyl-2-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-3-methylbenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(6-chloro-2-fluoro-3-methylbenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-4-methylbenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-amino-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-(methylamino)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-(dimethylamino)-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((5-chloro-3-fluoro-2-methylpyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(6-chloro-2,3-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2,3-difluoro-6-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-3,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((3-fluoro-2-methylpyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-amino-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-5-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((5-chloro-3-fluoro-2-methoxypyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-methyl 2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorobenzoate; (S)-1-(3-carbamoyl-2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-2-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)ethyl 2-aminoacetate; (S)-1-(3-amino-2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-4-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-benzyl-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-(trifluoromethyl)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3,4-dimethyl-1-((2-methylpyridin-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3,4-dimethyl-1-((3-methylisoxazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 3,4-dimethyl-1-((5-methylisoxazol-3-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 2-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3-fluorophenyl methanesulfonate; 1-(2,4-difluoro-6-(trifluoromethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((3-fluoropyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N-(benzofuran-2-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; N,1-dibenzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2,6-dimethylbenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-(difluoromethoxy)-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(4-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(4-chloro-2-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-bromo-6-fluoro-3-methylbenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-chloro-4-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(4-chloro-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-N-((5-fluorobenzofuran-2-yl)methyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((4-fluoro-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-N-((5-fluorobenzofuran-2-yl)methyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-(methylsulfonamido)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide 1-(2-acetamido-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((3-fluoropyridin-2-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 2-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3-fluorophenoxy)acetic acid; 2-(3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)acetic acid; 1-(2-fluoro-4-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-5-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((3-bromo-5-fluoropyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-5-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 2-(2-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3-fluorophenoxy)acetic acid; 1-(2-chloro-6-fluorobenzyl)-N-(4-hydroxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-(2-fluoro-6-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((5-fluoro-2-methylpyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 1-((3-fluoro-6-methylpyridin-2-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-azidobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; 2-(4-((1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamido)methyl)phenoxy)acetic acid; (S)-1-(2,3-difluoro-6-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,3-difluoro-6-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-aminobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-2-(2-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,4-difluorophenoxy)acetic acid; (S)-1-(2-chloro-6-fluorobenzyl)-N-(2-fluoro-6-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(4-fluoro-2-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(3-fluoro-5-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(2-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(3-fluoro-5-hydroxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(2-fluoro-6-hydroxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(4-fluoro-2-hydroxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,3-difluoro-6-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-3-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-3-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,4-difluoro-6-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,4-difluoro-6-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((3-fluoro-2-methylpyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-5-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-5-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-6-((2-hydroxyethyl)amino)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide hydrochloride; (S)-1-(2-fluoro-4,5-dimethoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(3-fluoro-5-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(2-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; -(2-fluoro-5-(hydroxymethyl)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-3-(hydroxymethyl)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,3-difluoro-5-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-5-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-(2-aminoacetamido)-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide dihydrochloride; (S)-1-(5-amino-2-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-4,5-dihydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,4-difluoro-6-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(2-fluoro-3-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (S)-2-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)acetic acid; (S)-1-(2-fluoro-6-((3-hydroxypropyl)amino)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-(3-aminopropoxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,3-difluoro-5-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,3-difluoro-5-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,3-difluoro-5-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluorobenzyl)-N-(4-fluoro-2-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(6-amino-2,3-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-amino-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((5-chloro-3-fluoro-2-oxo-1,2-dihydropyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((5-chloro-3-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (4S)-1-(2,6-difluoro-3-(1-hydroxyethyl)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-4-(2-(methylsulfonamido)ethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2,6-difluoro-4-(2-morpholinoethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-(2-aminoethoxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide hydrochloride; (S)-1-(2-chloro-6-fluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-4-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)butanoic acid; (S)-1-((3,5-difluoropyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((3-fluoro-5-methoxy-2-methylpyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-((5-chloro-3-fluoro-1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(2-chloro-6-fluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide; (S)-1-(4-(2-aminoethoxy)-2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide hydrochloride; or (S)-2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenyl methyl(2-(methylamino)ethyl)carbamate hydrochloride.

23. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.

24. A method of activating Stimulator of Interferon Genes (STING) protein in a subject, the method comprising administering to the subject a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

25. A method of treating a disease selected from cancer or viral infection, comprising administering to a subject a compound, according to claim 1, or a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein the disease is a cancer selected from the group consisting of colorectal cancer, aero-digestive squamous cancer, lung cancer, brain cancer, liver cancer, stomach cancer, sarcoma, leukaemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic carcinoma or renal carcinoma.

27. A compound according to claim 1, wherein the compound has the formula of: ##STR00489##

28. A compound according to claim 1, wherein the compound has the formula of: ##STR00490##

29. A compound according to claim 1, wherein the compound has the formula of: ##STR00491##

30. A method of treating a disease selected from cancer or viral infection, comprising administering to a subject a pharmaceutical composition according to claim 23.

31. A compound according to claim 1, wherein Y is CH.sub.2.

32. A compound according to claim 31, wherein L is C.sub.1-C.sub.6 alkyl.

33. A compound according to claim 31, wherein L is CH.sub.2.

34. The method of claim 25, wherein the method comprises treating a disease selected from cancer, comprising administering to a subject a compound, according to claim 1, or a pharmaceutically acceptable salt thereof.

35. The method of claim 30, wherein the method comprises treating a disease selected from cancer, comprising administering to a subject a pharmaceutical composition according to claim 23.

Description

(1) For a better understanding of the invention, and to show embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which:—

(2) FIG. 1 shows allele frequency of the major polymorphisms of human STING derived from the 1000 Genome Project database;

(3) FIG. 2 are Western blots of human STING proteins combined with compounds of the invention or a vehicle control (VC) and incubated with antibodies specific for phosphorylated STING (pSTING), phosphorylated IRF3 (pIRF3), ACTIN, total STING (STING), and IRF3;

(4) FIG. 3 shows the results of cytokines measured by an ELISA assay of human PBMCs stimulated with compounds of the invention compared to an unstimulated control (Unstm); and

(5) FIG. 4 shows tumour growth against time (in days) in mice dosed intra-tumorally with compounds of the invention or a VC.

GENERAL SCHEMES

(6) General Scheme 1

(7) Compounds of formula (I) may be prepared from compounds of formula (II) and (III) using an amide bond forming reaction, as shown below.

(8) ##STR00058##

(9) Typical conditions employ activation of the carboxylic acid of the compound of formula (II) using a suitable organic base and a suitable coupling agent. Preferred coupling agents are either EDCI with HOBt, T.sub.3P, HATU, HBTU or BOP. Preferred organic bases comprise either DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction may be shaken or stirred at room temperature.

(10) Compounds of formula (II) and (III) are commercially available or may be synthesized by those skilled in the art. In particular, methods of synthesising compounds of formula (II) are described in General Schemes 2 to 4 (below).

(11) General Scheme 2

(12) Compounds of formula (II) may be synthesized from esters of formula (IV), where R is methyl, ethyl, benzyl or tert-butyl, by a hydrolysis reaction.

(13) ##STR00059##

(14) The compound of Formula (IV) may be reacted with a suitable alkali or base to cause it to undergo hydrolysis and provide a compound of formula (II). The suitable alkali or base may be LiOH, KOH, NaOH or K.sub.2CO.sub.3, and the reaction may be conducted in an aqueous solution.

(15) General Scheme 3

(16) Alternatively, compounds of formula (II) can be obtained from a halide of formula (V) as shown in the general scheme below.

(17) ##STR00060##

(18) First the compound of formula (V) undergoes a cyanation reaction to give a compound of formula (VI). This could be conducted in the using CuCN or ZnCN.sub.2 in a polar solvent at elevated temperatures with a suitable catalyst. The polar solvent could be NMP, DMF, DMA or MeCN and catalyst could be tetrakistriphenylphosphine palladium(0). The compound of formula (VI) may then undergo hydrolysis to give the compound of formula (II). In particular, the compound of formula (II) may be hydrolysed using an aqueous solution of an alkali, such as NaOH, LiOH and KOH, or an acid, such as HCl, at an elevated temperature.

(19) General Scheme 4

(20) In a further alternative process, the compound of formula (V) may undergo a direct carbonylation reaction to produce a compound of formula (II), as shown below.

(21) ##STR00061##

(22) The reaction could be conducted using CO gas in the presence of a suitable catalyst in an appropriate polar solvent. The catalyst may be aPd, Rh, Ir or Fe catalyst, and the solvent may be NMP, DMF, DMA or MeCN with the reaction carried out in the presence of a suitable nucleophile such as water or alcohols (to prepare the corresponding esters).

(23) General Scheme 5

(24) Compounds of formulae (IV), (V) and (VI) may be synthesized by those skilled in the art via an alkylation/acylation/sulfonylation reaction with a compound of formula (VII), where G is a leaving group such as an optionally substituted alkylaryl(het), alkyl, aryl(het), cycloalkyl, alkylcycloalkyl halide, triflate or tosylate.

(25) ##STR00062##

(26) General Scheme 6

(27) A compound of formula (IX) may be prepared in a seven-step process, as shown below, from a compound of formula (XVI), where R is methyl, ethyl, benzyl or tert-butyl.

(28) ##STR00063## ##STR00064##

(29) First, the compound of formula (XVI) can be brominated, using either Br.sub.2 or a bromine source, such as NBS, to give a compound of formula (XV). This compound can then be aminated, using NH.sub.2R.sup.9, to provide a compound of formula (XIV). The nitro group on the compound of formula (XV) can then be reduced by suitable reducing agents to provide a compound of formula (XIII). The compound of formula (XIII) may then be reacted with a suitable carbonyl source to provide a compound of formula (XII). The carbonyl source may be 1,1-carbonyl-diimidazole, phosgene or triphosgene.

(30) The compound of formula (XII) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XI). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (X). Finally, this compound may be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (IX).

(31) It will be appreciated that the compound of formula (IX) is a compound of formula (I) where Q is C═O.

(32) General Scheme 7

(33) A compound of formula (XVII) may be prepared in an eight-step process, as shown below, from a compound of formula (XXV), where R is methyl, ethyl, benzyl or tert-butyl.

(34) ##STR00065## ##STR00066##

(35) First, the compound of formula (XXV) can be protected by acetylating groups using reagents such as TFAA, BOC-anhydride and acetic anhydride to give a compound of formula (XXIV). This compound may be alkylated using a suitable alkyl halide (R.sup.11-G) in the presence of a suitable base such as NaH, K.sub.2CO.sub.3, KHCO.sub.3, Cs.sub.2CO.sub.3 or .sup.tBuCOOK/Na to give a compound of formula (XXIII). A subsequent nitration reaction may be performed on compounds of formula (XXIII) with a nitrating mixture to give a compound of formula (XXII). The nitro group on compounds of formula (XXII) can then be reduced either by Pd-catalyzed hydrogenation methods or by using the sodium dithionite and TBASH method as described in General Procedure 11 to give the corresponding amino derivative which on further reaction with ethyl chloroformate in the presence of a suitable organic or inorganic base such as pyridine or K.sub.2CO.sub.3 to provide a compound of formula (XXI). This compound may undergo a cyclization process to give a compound of formula (XX) by using a suitable base and solvent combination such as K.sub.2CO.sub.3 and methanol.

(36) The compound of formula (XX) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XIX). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (XVIII). Finally, this compound may then be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XVII).

(37) It will be appreciated that the compound of formula (XVII) is a compound of formula (I) where Q is C═O.

(38) General Scheme 8

(39) A compound of formula (XXX) may be converted into compound of formulas (XXIX) which may be further derivatized into (XXVIII), (XXVII) and (XXVI) as described below.

(40) ##STR00067##

(41) First, the compound of formula (XXX) may undergo a de-methylation reaction with suitable reagents such as BBr.sub.3, BCl.sub.3, AlCl.sub.3, or HBr in appropriate solvents such as DCM, DCE, toluene or water to produce the corresponding phenolic compounds of formula (XXIX). Secondly, these compounds may then be used under different conditions to obtain different products. An extended chain alcohol or amine can be formed by the reaction of (XXIX) with a suitable halo substituted alcohol/amine or ester to give a compound of formula (XXVIII). Finally, the compounds of formula (XXIX) may also be transformed into their corresponding phosphate prodrugs such as a compound of formulas (XXVII) and (XXVI) using appropriate phosphorylating reagents.

(42) General Scheme 9

(43) A compound of formula (XXXV) can be translated into many prodrug forms of their parent as described below.

(44) ##STR00068##

(45) First, the compound of formula (XXXVI) may undergo a de-methylation reaction to form a compound of formula (XXXV) as described in General Scheme 9. The compound of formula (XXXV) may then be derivatized into various prodrugs e.g. carbonate (XXXI), carbamate (XXXIV) and phosphates (XXXIII) and (XXXII) with appropriate phosphorylating reagents as described in General Procedures 15-19.

(46) General Scheme 10

(47) A compound of formula (XXIX) can be further converted into dihydroxy derivatives of compound of formula (XXXVII), (XXXVIII) and (XXXIX) as described below.

(48) ##STR00069##

(49) First, the compound of formula (XXIX) may be converted into an allyl derivative of formula (XL) by treatment with allyl bromide in the presence of a mild base such as NaH, K.sub.2CO.sub.3, NaHCO.sub.3, tBuCOOK or organic base such as TEA or DIPEA. Secondly, this compound may undergo a dihydroxylation reaction with osmium tetroxide or KMnO.sub.4 to provide a compound of formula (XXXIX) as a racemic mixture. The compound of formula (XL) may also undergo an asymmetric dihydroxylation reaction with a chiral auxiliary AD-mix-α and AD-mix-β to yield the corresponding R-enantiomer (XXXVIII) and S-enantiomer (XXXVII) respectively.

(50) General Scheme 11

(51) A compound of formula (XLII) may be prepared in a six-step process, as shown below, from a compound of formula (XLVI) and 2,4-difluoro-3-methylbenzoic acid, where R is H, methyl, ethyl, ethanol, benzyl or tert-butyl.

(52) ##STR00070##

(53) First, commercially available 2,4-difluoro-3-methylbenzoic acid is converted into the corresponding methyl ester which may be treated with NBS in a bromination step resulting in the formation of methyl 3-(bromomethyl)-2,4-difluorobenzoate. Secondly, a compound of formula (XLVI) which can be prepared according to methods described in General Scheme 7 may undergo an amidation reaction with an appropriate amine to yield a compound of formula (XLV). This compound may then be subject to an alkylation reaction with methyl 3-(bromomethyl)-2,4-difluorobenzoate in the presence of a mild base as described in General Scheme 7 to provide a compound of formula (XLIV) which upon basic hydrolysis may give a compound of formula (XLIII). Finally, the compound of formula (XLIII) may undergo an amide coupling reaction with an appropriate amine in the presence of a suitable amide coupling reagent (such as HATU, HBTU, CDI, HOBT, EDCI or TPP) to provide compounds of formula (XLII).

(54) General Synthetic Procedures

(55) General Procedure 1

(56) ##STR00071##

(57) To a stirred solution of a carboxylic acid (II) (1.28 mmol) in a suitable solvent, such as DCM, DMF, DMA or MeCN, (to mL) was added amine (III) (1.2 eq.) and a coupling reagent, such as T.sub.3P, HATU, EDCI, HOBT, BOP or HBTU, (1.5 eq.), followed by addition of an organic base, such as DIPEA or TEA, (2.0 eq.) drop wise to the solution and the mixture allowed to stir at RT for 2-3 h. When UPLC or TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO.sub.3 solution followed by dilute aqueous HCl and finally with brine, and then dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to obtain the crude material which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (I) (70-80% yield) as a pale yellow solid. A similar procedure can be followed to synthesize all amides of formula (I).

(58) General Purification and Analytical Methods

(59) All final compounds were purified by either Combi-flash or prep-HPLC purification, and analysed for purity and product identity by UPLC or LCMS according to one of the below conditions.

(60) Prep-HPLC

(61) Preparative HPLC was carried out on a Waters auto purification instrument using either a YMC Triart C18 column (250×20 mm, 5 μm) or a Phenyl Hexyl column (250×21.2 mm, 5 μm) operating at between ambient temperature and 50° C. with a flow rate of 16.0-50.0 mL/min.

(62) Mobile phase 1: A=20 mM Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 60% A and 40% B after 3 min., then to 30% A and 70% B after 20 min., then to 5% A and 95% B after 21 min., held at this composition for 1 min. for column washing, then returned to initial composition for 3 min.

(63) Mobile phase 2: A=10 mM Ammonium Acetate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 90% A and 10% B, then to 70% A and 30% B after 2 min., then to 20% A and 80% B after 20 min., then to 5% A and 95% B after 21 min., held at this composition for 1 min. for column washing, then returned to initial composition for 3 min.

(64) LCMS Method

(65) General 5 min method: Zorbax Extend C18 column (50×4.6 mm, 5 μm) operating at ambient temperature and a flow rate of 1.2 mL/min. Mobile phase: A=10 mM Ammonium Acetate in water, B=Acetonitrile; Gradient profile: from 90% A and 10% B to 70% A and 30 B in 1.5 min, and then to 1 to % A and 90% B in 3.0 min, held at this composition for 1.0 min, and finally back to initial composition for 2.0 min.

(66) UPLC Method

(67) UPLC was carried out on a Waters auto purification instrument using a Zorbax Extend C18 column (50×4.6 mm, 5 μm) at ambient temperature and a flow rate of 1.5 ml/min. Mobile phase 1: A=5 mM Ammonium Acetate in water, B=5 mM Ammonium Acetate in 90:10 Acetonitrile/water; Gradient profile from 95% A and 5% B to 65% A and 35% B in 2 min., then to 10% A and 90% B in 3.0 min., held at this composition for 4.0 min. and finally back to the initial composition for 5.0 min.

(68) Mobile phase 2: A=0.05% formic acid in water, B=Acetonitrile; Gradient profile from 98% A and 2% B over 1 min., then 90% A and 10% B for 1 min., then 2% A and 98% B for 2 min. and then back to the initial composition for 3 min.

(69) General Procedure 2

(70) ##STR00072##

(71) To a stirred solution of ester (IV) (1.49 mmol) in a mixture of MeOH or THF (10 mL) and water (5 mL) was added LiOH, NaOH or KOH (2.0 eq.) at RT and the resulting reaction mixture was stirred at RT for 2-16 h. TLC showed complete consumption of the ester (IV), upon which the solvent was evaporated under reduced pressure and the resulting residue was washed with ether. The residue was then acidified with 1N HCl to pH 2-4, which resulted in the formation of a precipitate, which was filtered and washed with water and then dried under reduced pressure at 50-60° C. to afford the desired carboxylic acid of formula (II) (70-85% yield) as an off white solid.

(72) General Procedure 3

(73) ##STR00073##

(74) Option A

(75) To a stirred solution of a compound of formula (VIII) (2.7 mmol, 1.0 eq.) in DMF or THF (4 mL/mmol) was added K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3, NaOH or NaH (2.0 eq.)—in the case where NaOH was used, TBAB (0.1 eq.) was also added as a phase transfer catalyst—followed by addition of a compound of formula (VII) (1.5 eq.) and the mixture allowed to stir at RT for 0.5-1 h. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was diluted with water, extracted with EtOAc, and the organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organics were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford compounds of formula (IV) (80-90% yield) as colourless oil.

(76) Option B

(77) Alternatively, to a stirred solution of a compound of formula (VIII) (2.7 mmol) in DCM or MeCN or THF (4 mL/mmol) was added TEA or DIPEA (2.0 eq.) followed by addition of a compound of formula (VII) (1.5 eq.) and the whole allowed to stir at RT for 0.5 to 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organic layers were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (IV) (80-90% yield) as colourless oil.

(78) General Procedure 4

(79) ##STR00074##

(80) To a stirred solution of a compound of formula (XLIII) (1.0 eq.) in a suitable solvent such as carbon tetrachloride or trifluoromethylbenzene (100 mL) was added NBS (1.2 eq.) and AIBN or benzoyl peroxide (0.1 eq.). The reaction mixture was heated at 70-100° C. for 12-16 h. After complete consumption of starting material, the reaction mixture was quenched with a saturated solution of Na.sub.2S.sub.2O.sub.3 and extracted with EtOAc. The combined organic layers were washed with brine and then dried over anhydrous Na.sub.2SO.sub.4. The crude product obtained after concentration of the organic layer under reduced pressure was purified by column chromatography to afford a compound of formula (XLII) in 30-40% yield.

(81) General Procedure 5

(82) ##STR00075##

(83) To a stirred solution of a compound of formula (XLII) (9.124 mmol, 1.0 eq.) in a suitable solvent such as THF was added an appropriate amine, such as MeNH.sub.2, (25 mL, 2M solution in THF) at RT for 10-16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with a saturated brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford a compound of formula (XLI) (60-70% yield) as a red gummy solid.

(84) General Procedure 6

(85) ##STR00076##

(86) Option A: (Reduction by Sodium Dithionate)

(87) To a stirred solution of a compound of formula (XIV) (1.0 mmol, 1.0 eq.) in a mixture of either MeCN:H.sub.2O or THF:H.sub.2O (12 mL/mmol, 2:1) was added sodium hydrosulphite (8.0 eq.), tetra butyl ammonium hydrosulphate (0.5 eq.) and potassium carbonate (6.0 eq.) at RT and then the mixture was stirred for 1 h. Progress of the reaction was monitored by TLC and or LCMS. After completion of the reaction, solvents were evaporated under reduced pressure to give an oily liquid which was dissolved in 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organics were filtered and evaporated under reduced pressure to give a compound of formula (XIII) (90-95% yield) as a yellowish solid.

(88) Option B: (Reduction by Pd/C/H.sub.2)

(89) To a stirred solution of a compound of formula (XIV) (12.85 mmol, 1.0 eq.) in EtOAc, MeOH or EtOH (9.4 mL/mmol, 120 mL) was added 10% Pd—C(50% w/w in water) (77.8 mg/mmol) under an inert atmosphere at room temperature. The reaction mixture was purged with H.sub.2 gas using balloon pressure and then allowed to further stir for 3-5 h at room temperature. The course of the reaction was monitored by TLC and/or LCMS. After completion of the reaction the reaction mass was diluted with EtOAc, filtered carefully through a bed of celite and washed with EtOAc 4-5 times until the mother liquor showed no compound remaining by TLC. Then the collected organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a compound of formula (XIII) (80-85% yield) as a yellow semi solid. The product was pure enough to use in the next step without any further purification.

(90) General Procedure 7

(91) ##STR00077##

(92) To a stirred solution of a compound of formula (XL) (3.61 mmol, 1.0 eq.) in a suitable solvent, such as DCM or THF (5 mL/mmol) was added a suitable carbonyl source equipped with suitable leaving groups, such as 1,1-carbonyl-diimidazole, phosgene or triphosgene (1.1 eq.) followed by a suitable base, such as TEA or DIPEA (3.0 eq.) at 0-5° C. and the reaction mixture was stirred at room temperature under an inert atmosphere for 2-4 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO.sub.3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to provide a crude residue which was purified by silica gel column chromatography and eluted with 1% MeOH in DCM to afford a compound of formula (XXXIX) (20-30% yield) as an off white solid.

(93) General Procedure 8

(94) ##STR00078##

(95) To a stirred solution of a compound of formula (XXV) (0.279 mol, 1.0 eq.) in toluene (1.8 mL/mmol) was added TFAA (2.0 eq.) at 10-15° C. dropwise over 20-30 min., and the resulting reaction mixture was stirred at 25-30° C. for 1-5 h. The progress of the reaction was monitored by UPLC-MS. The reaction mixture was poured into crushed ice and extracted with EtOAc. The combined organic layers were washed successively with a saturated solution of NaHCO.sub.3, brine and then dried over anhydrous Na.sub.2SO.sub.4. The filtered organics were evaporated under reduced pressure to afford the compound of formula (XXIV) (90-96% yield) as a white solid. The product was pure enough to use in the next step without any further purification.

(96) General Procedure 9

(97) ##STR00079##

(98) To a stirred solution of NaH (1.2 eq, 60% suspension in oil) in DMF (1.65 mL/mmol) was added a mixture of a compound of formula (XXIV) (0.272 mol, 1.0 eq.) and an alkyl or aryl halide (R.sup.11-G) (2.0 eq.) in DMF (1.1 mL/mmol) dropwise using a dropping funnel over 20-30 min. at 10-15° C. and the resulting reaction mixture then stirred for 2 h at 20-25° C. Completion of the reaction was confirmed by UPLC-MS. The reaction mixture was poured into an ice-water mixture and extracted with EtOAc. The combined organics were washed with 1N hydrochloric acid, a saturated solution of NaHCO.sub.3 and then brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford a compound of formula (XXIII) (90-96% yield) as an off white solid. The product was pure enough to use in the next step without any further purification.

(99) General Procedure 10

(100) ##STR00080##

(101) A compound of formula (XXIII) (0.262 mol, 1.0 eq.) was added into a pre-prepared nitrating mixture of concentrated sulfuric acid (2.17 mL/mmol) and fuming nitric acid (0.73 mL/mmol) portionwise whilst maintaining the internal temperature between 0-5 OC over a period of 30 min. The resulting mixture was stirred at 20-25° C. for 1-2 h. Completion of the reaction was confirmed by UPLC-MS and after consumption of the starting material the reaction mixture was poured into an ice-water mixture and extracted with EtOAc. The combined organics were washed with a saturated solution of NaHCO.sub.3 followed by a saturated brine solution, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford a compound of formula (XXII) (yield 92-98%) as a thick brown oil. The product was pure enough to use in the next step without any further purification.

(102) General Procedure 11

(103) ##STR00081##

(104) Option A:

(105) To a stirred solution of a compound of formula (XXII) (59.8 mmol, 1.0 eq.) in 14-dioxane (3.34 mL/mmol, degassed with nitrogen) was added 10% Pd—C(0.167 g/mmol, 50% w/w in water) under an inert atmosphere and the resulting reaction mixture was stirred under H.sub.2 gas balloon pressure at RT for overnight. Progress of the reaction was monitored by TLC and UPLC-MS which showed complete conversion of the nitro group into its corresponding amino group. Then the H.sub.2 gas balloon was removed and solid K.sub.2CO.sub.3 (1.66 eq.) was added into the reaction vessel followed by dropwise addition of ethyl chloroformate (1.34 eq.) at RT. The resulting reaction mixture was further stirred for overnight. UPLC-MS showed completion of the reaction; then the reaction mixture was filtered through a celite bed and the bed was washed with DCM. The filtrate was evaporated under reduced pressure to give a crude product which was dissolved in EtOAc, washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford crude product as a thick oil which was purified by trituration with n-hexane and dried to afford a compound of formula (XXI) (80-85% yield) as a white solid.

(106) Option B:

(107) To a stirred solution of a compound of formula (XXII) (251.47 mmol, 1.0 eq.) in THF (6.68 mL/mmol) was added a solution of K.sub.2CO.sub.3 (6.0 eq.) in water (3 mL/mmol) at 10-15° C. followed by portionwise addition of sodium dithionite (8.0 eq.), TBASH (0.5 eq.) and water (0.4 mL/mmol). The resulting reaction mixture was stirred at RT (20-25° C.) for a further 2-3 h. The reaction was monitored by UPLC-MS and after completion; the reaction mixture was left to settle to allow separation of the organic and aqueous layers. The aqueous layer was then extracted with THF. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and then pyridine (0.8 mL/mmol) was added. The organic mixture was then evaporated at ˜40° C. under reduced pressure to afford the crude product which was dissolved in DCM (6.7 mL/mmol) and another portion of pyridine (0.8 mL/mmol) was added followed by dropwise addition of ethyl chloroformate (5.0 eq.) at 10-15° C. The resulting reaction mixture was further stirred at RT for 2-3 h. UPLC-MS showed completion of the reaction. The reaction mixture was diluted with water and allowed to settle for separation of the layers. The aqueous layer was washed with DCM and the combined organics were washed with 0.5N HCl, a saturated solution of NaHCO.sub.3 and finally with brine. The obtained organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product as yellowish thick oil. The oil was purified by trituration with hexane to give a compound of formula (XXI) (90-94% yield) as a faint yellow sticky solid.

(108) General Procedure 12

(109) ##STR00082##

(110) To a stirred solution of a compound of formula (XXI) (146.0 mmol, 1.0 eq.) in methanol (3.8 mL/mmol) was added K.sub.2CO.sub.3 (2.0 eq.) at RT and the resulting reaction mixture was heated to 60-65° C. for 2-3 h. The progress of the reaction was monitored by UPLC-MS and after completion, the reaction mass was cooled to 5-10° C. and neutralized with 2N HCl to obtain a pH ˜3-4. The solvents were evaporated under reduced pressure at 40-45° C. to give the crude product which was dissolved in EtOAc, washed successively with a saturated brine solution, 2N HCl, NaHCO.sub.3 solution and finally again with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford crude compound as a brownish solid. This was purified by trituration with hexane to afford a compound of formula (XX) (80-85% yield) as an off white to pale yellow solid.

(111) General Procedure 13

(112) ##STR00083##

(113) To a stirred solution of a compound of formula (XXX) (0.96 mmol, 1.0 eq.) in DCM (26 mL/mmol) was added BBr.sub.3 (5 mL/mmol, 1.0M solution in DCM) and the mixture was stirred at RT for 1-2 h. The progress of reaction was monitored by UPLC-MS and after completion of reaction the mixture was diluted with DCM and water. The organic layer was separated and washed with NaHCO.sub.3 solution followed by brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by Combi-flash to give a compound of formula (XXIX) (80-85% yield) as a white solid.

(114) General Procedure 14

(115) ##STR00084##

(116) To a stirred solution of a compound of formula (XXIX) (0.099 mmol, 1.0 eq.) in DMF (20 mL/mmol) was added K.sub.2CO.sub.3 (3.0 eq.) followed by addition of a substituted alkyl halide [X—(CH.sub.2).sub.m-GH]; where X is halogen, G is O, NH, COO and GH is COOR) (2.0 eq.) and the whole reaction mixture was heated at 60° C. for overnight. After completion of the reaction the mixture was diluted with water and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to provide crude product which was purified by Combi-flash using a mixture of EtOAc in hexane as eluent to give a compound of formula (XXVIII) (30-35% yield) as a white solid.

(117) General Procedure 15

(118) ##STR00085##

(119) A compound of formula (XXVIII) (where m is >1) (0.56 mmol, 1.0 eq.) was dissolved in neat POCl.sub.3 (9.0 eq.) at 0-5° C. and the reaction mixture was slowly allowed to warm up to RT over 1 h. After complete conversion of the starting material, the reaction mixture was dissolved in MeCN (2.5 mL/mmol) and a mixture of silver nitrate (0.35 eq.) in water (5 mL/mmol) was added dropwise at 0-5° C. The resulting reaction mixture was further stirred for 1-2 h at the same temperature and then kept in the refrigerator for 18-20 h to afford a solid which was filtered and the filtrate evaporated under reduced pressure to afford the crude product which was purified by prep-HPLC to give a compound of formula (XXVII) (40-45% yield) as a pale yellow solid.

(120) General Procedure 16

(121) ##STR00086##

(122) To a stirred solution of a compound of formula (XXIX) (0.30 mmol, 1.0 eq.) in dry DMF (6 mL/mmol) was added K.sub.2CO.sub.3 (1.5 eq.) and after 15 min. dibenzyl (chloromethyl) phosphate (1.1 eq.) was added under a N.sub.2 atmosphere. The reaction mixture was stirred at 55-60° C. for 2-3 h. After completion of the reaction the mixture was diluted with EtOAc and washed with water followed by brine solution. The organic layer was then dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness under reduced pressure to give the crude product which was purified by Prep-HPLC to afford a benzyl protected intermediate which was dissolved in THF (6 mL/mmol) and added 10% Pd—C (0.009 g/mmol, 50% w/w in water) at RT under an inert atmosphere. The resulting reaction mixture was stirred at RT for 15-30 min. under a H.sub.2 gas balloon pressure and after completion of the reaction the mixture was diluted with EtOAc and passed through a short bed of celite. The filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by Prep-HPLC to afford a compound of formula (XXVII) (50-60% yield) as a white solid.

(123) General Procedure 17

(124) ##STR00087##

(125) To a stirred solution of a compound of formula (XXIX) (0.30 mmol, 1.0 eq.) in dry acetonitrile (15 mL/mmol) was added tetrazole (1.0 eq.) followed by dibenzyl-diisopropylphosphoramidite (1.4 eq.) under an inert atmosphere and the mixture was allowed to stir at RT for 2-3 h. The course of the reaction was monitored by TLC and LCMS and after completion; the reaction mixture was evaporated under reduced pressure to give the crude product which was dissolved in DCM (20 mL/mmol) and added m-CPBA (1.5 eq.) at 0-5° C. under an inert atmosphere. The reaction mixture was then stirred at 0-5° C. for 1-2 h. The course of the reaction was monitored by TLC and LCMS and after completion; the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the oxidized compound (90-95% yield) as crude. The de-protection of the benzyl groups was performed by the method described in General Procedure 16 to give the final product of formula (XXVI).

(126) General Procedure 18

(127) ##STR00088##

(128) To a stirred solution of a compound of formula (XXXV) (0.096 mmol, 1.0 eq.) in DMF (20 mL/mmol) was added NaH (0.03 g/mmol, 60% w/w in mineral oil) at 0-5° C. and the reaction mixture was stirred for 15-20 min. at the same temperature. Then, separately synthesized R.sup.12O-substituted 4-nitrophenyl-carbonate (for example as described in US 1996/5585397) (3.0 eq.) was dissolved in DMF (20 mL/mmol) and added into the reaction mixture and the whole stirred at RT for overnight. Progress of the reaction was monitored by TLC and LCMS and after completion of the reaction the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude compound which was purified by either column chromatography or prep-HPLC to afford a compound of formula (XXXI) (20-30% yield) as a white solid.

(129) General Procedure 19

(130) ##STR00089##

(131) To a stirred solution of a compound of formula (XXXV) (0.08 mmol, 1.0 eq.) in DMF (25 mL/mmol) was added NaH (0.125 g/mmol, 60% w/w in mineral oil) at 0-5° C. and the reaction mixture was stirred for 15 min. at the same temperature. Then, separately synthesized R.sup.12R.sup.13N-substituted 4-nitrophenyl carbamate (for example as described in Syn. Comm., 2007, 37, 1927) (1.2 eq.) in DMF (to mL/mmol) was added into the reaction mixture and the whole heated at 75-80° C. for 2-3 days. Progress of the reaction was monitored by TLC and LCMS and after 2-3 days the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with NaHCO.sub.3 and brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to afford a compound of formula (XXXIV) (20-30% yield) as a white solid.

(132) General Procedure 20

(133) ##STR00090##

(134) To a stirred solution of a compound of formula (XXIX) (0.30 mmol, 1.0 eq.) in DMF (15 mL/mmol) was added K.sub.2CO.sub.3 (2.5 eq.) and then allyl bromide (1.2 eq.) at RT. The whole reaction mixture was further stirred at RT for 1-2 h. The course of the reaction was monitored by TLC and LCMS and after completion; the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography to afford a compound of formula (XL) (80-90% yield) as a white solid.

(135) General Procedure 21

(136) ##STR00091##

(137) To a stirred solution of a compound of formula (XL) (0.11 mmol, 1.0 eq.) in acetone (9 mL/mmol) was added osmium tetroxide (1.0 eq), NMO (1.2 eq.) and water (0.1 mL/mmol) at RT and the resulting reaction mixture was stirred at RT for 20-30 min. After completion of the reaction (monitored by TLC); the reaction mixture was poured into a saturated solution of Na.sub.2SO.sub.3 and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography or prep-HPLC to afford a compound of formula (XXXIX) (30-35% yield) as a white solid.

(138) General Procedure 22

(139) ##STR00092##

(140) To a stirred solution of a compound of formula (XL) (0.14 mmol, 1.0 eq.) in tert-butanol (7 mL/mmol) and water (7 mL/mmol) at 0-5° C. was added AD-mix-α (1.8 g/mmol) and the reaction mixture was stirred at 0-5° C. for overnight. The course of the reaction was monitored by TLC and LCMS and after completion; the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give crude product which was purified by column chromatography or prep-HPLC to afford a compound of formula (XXXVIII) (44-50% yield) as a white solid.

(141) General Procedure 23

(142) ##STR00093##

(143) To a stirred solution of a compound of formula (0.14 mmol, 1.0 eq.) in tert-butanol (7 mL/mmol) and water (7 mL/mmol) at 0-5° C. was added AD-mix-β (1.8 g/mmol) and the reaction mixture was stirred at 0-5° C. overnight. The reaction was processed as for General Procedure 22 and the crude product purified by column chromatography or prep-HPLC to afford a compound of formula (XXXVII) (40-50% yield) as a white solid.

(144) General Procedure 24

(145) ##STR00094##

(146) To a stirred solution of a compound of formula (XLIII) (0.26 mmol, 1.0 eq.) in THF (20 mL/mmol) was added HATU (1.2 eq.) followed by TEA (2.0 eq.) and the reaction mixture was stirred at RT for 15 min., then an optionally substituted alkyl/aryl amine (R—NH.sub.2) (10.0 eq.) was added. The resulting reaction mixture was further stirred at RT for 2 h. Further aliquots of HATU, TEA and the amine may be required for complete consumption of the starting material. After completion of the reaction the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography to provide a compound of formula (XLII) (20-30% yield) as a yellow solid.

EXAMPLES

(147) Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (6) are given in parts-per-million downfield from tetramethylsilane (for .sup.1H-NMR) and upfield from trichloro-fluoro-methane (for .sup.19F NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl.sub.3, deuterochloroform; d.sub.6-DMSO, deuterodimethylsulphoxide; and CD.sub.3OD, deuteromethanol.

(148) Mass spectra, MS (m/z), were recorded using electrospray ionisation (ESI). Where relevant and unless otherwise stated the m/z data provided are for isotopes .sup.19F, .sup.35Cl, .sup.79Br and .sup.127I.

(149) All chemicals, reagents and solvents were purchased from commercial sources and used without further purification. All reactions were performed under an atmosphere of nitrogen unless otherwise noted.

(150) Flash column chromatography was carried out using pre-packed silica gel cartridges in a Combi-Flash platform. Prep-HPLC purification was carried out according to the General purification and analytical methods described above. Thin layer chromatography (TLC) was carried out on Merck silica gel 60 plates (5729). All final compounds were >95% pure as judged by the LCMS or UPLC analysis methods described in the General purification and analytical methods above unless otherwise stated.

Example 1: 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(151) ##STR00095##

(152) Example 1 was prepared according to the methods described in General Procedures 1-3, and the methods described below.

Preparation 1: Methyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(153) ##STR00096##

Step 1: Methyl-4-(bromomethyl)-3-nitrobenzoate

(154) ##STR00097##

(155) To a stirred solution of methyl-4-methyl-3-nitrobenzoate (4.0 g, 20.51 mmol) in trifluoro toluene (85 mL) was added NBS (5.477 g, 30.77 mmol) and benzoyl peroxide (0.746 g, 3.08 mmol) at RT. The resulting reaction mixture was heated at 100° C. for 16 h. After completion, the reaction mixture was quenched with a saturated solution of Na.sub.2S.sub.2O.sub.3 (100 mL) and extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to give the crude product which was purified by column chromatography using 2% EtOAc in hexanes as eluent to afford titled compound (2.5 g, 44% yield) as a brown gummy solid. .sup.1H NMR (400 MHz; CDCl.sub.3): δ 3.97 (s, 3H), 4.83 (s, 2H), 7.66 (d, J=7.32 Hz, 1H), 8.24 (d, J=6.64 Hz, 1H), 8.65 (s, 1H).

Step 2: Methyl-4-((methylamino)methyl)-3-nitrobenzoate

(156) ##STR00098##

(157) MeNH.sub.2 (25 mL, 1M solution in THF) was added to methyl-4-(bromomethyl)-3-nitrobenzoate (Step 1) (2.5 g, 9.12 mmol) at RT and the resulting reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and after completion, the reaction mixture was diluted with water (80 mL) and extracted with EtOAc. The combined organics were washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford titled compound (1.4 g, 68% yield) as a red gummy solid. LCMS m/z: 225 [M+H].

Step 3: Methyl-3-amino-4-((methylamino)methyl)benzoate

(158) ##STR00099##

(159) To a stirred solution of methyl-4-((methylamino)methyl)-3-nitrobenzoate (Step 2) (1.4 g, 6.25 mmol) in EtOAc (25 mL) was added 10% Pd/C (0.5 g, 10% w/w on carbon) under a N.sub.2 gas atmosphere. The resulting reaction mixture was stirred at RT for 3 h under a H.sub.2 gas balloon pressure. The reaction was monitored by TLC and after completion; the reaction mixture was filtered through a celite bed and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the crude product which was purified by column chromatography to afford titled compound (1.2 g, 99% yield) as a brownish gum. LCMS m/z: 195 [M+H].

Step 4: Methyl-3-methyl-2-oxo-1,2,34-tetrahydroquinazoline-7-carboxylate

(160) ##STR00100##

(161) To a stirred solution of methyl-3-amino-4-((methylamino)methyl)benzoate (Step 3) (0.7 g, 3.61 mmol) in DCM (15 mL) was added triphosgene (1.07 g, 3.61 mmol) followed by TEA (1.26 mL, 9.02 mmol) at 0-5° C. and the reaction mixture was stirred at RT under an inert atmosphere for 3 h. After completion of the reaction (monitored by TLC/LCMS), the reaction mixture was quenched with saturated NaHCO.sub.3 solution (30 mL) and extracted with DCM. The combined organics were washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel using 1% MeOH in DCM as eluent to afford titled compound (0.19 g, 24% yield) as an off white solid. LCMS m/z: 221 [M+H].

Preparation 2: Methyl 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(162) ##STR00101##

(163) To a stirred solution of 3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (Preparation 1) (0.19 g, 0.86 mmol) in DMF (5 mL) was added NaH (0.038 g, 0.95 mmol, 60% suspension in mineral oil) at 0-5° C. and the whole stirred for 15 min. then, 3,5-difluorobenzylbromide (0.134 mL, 1.04 mmol) was added and the reaction mixture was allowed to stir at RT for 1 h. The progress of the reaction was monitored by TLC and after completion the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude product which was purified by Combi-flash eluting with 28% EtOAc in hexane as eluent to afford titled compound (0.13 g, 43.5% yield) as an off white solid. LCMS m/z: 347 [M+H].

Preparation 3: 1-(3,5-Difluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

(164) ##STR00102##

(165) To a stirred solution of 1-(3,5-difluoro-benzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (Preparation 2) (0.13 g, 0.38 mmol) in THF-H.sub.2O (1:1, 2 mL) was added LiOH.H.sub.2O (0.0174 g, 0.41 mmol) at 0-5° C. The reaction mixture was stirred at RT for 6 h. After completion of the reaction (monitored by TLC and LCMS); the reaction mixture was diluted with water (20 mL) and washed with EtOAc. The aqueous layer was acidified with N HCl solution and extracted with EtOAc (3×30 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford titled compound (0.1 g, 80.1% yield) as an off white solid. LCMS m/z: 333 [M+H].

Preparation 4: 1-(3,5-Difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 1)

(166) ##STR00103##

(167) To a stirred solution of 1-(3,5-difluoro-benzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid (Preparation 3) (0.04 g, 0.12 mmol) in DCM (3 mL) was added TEA (0.0034 mL, 0.24 mmol) and HATU (0.0687 g, 0.18 mmol) at 0-5° C. and the whole was stirred for 15 min. Then 2,4,6-trifluoro benzyl amine (0.016 mL, 0.13 mmol) was added and the reaction mixture was stirred at RT for 16 h. The course of the reaction was monitored by TLC and or LCMS and after completion the reaction; mixture was diluted with DCM and washed with water, 1N HCl, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to obtain a crude material which was purified by prep-TLC using 70% EtOAc-hexane as eluent to afford titled compound (Example 1) (0.0178 g, 31.1% yield and purity 96.6%) as a white solid. LCMS m/z: 476.3 [M+H]; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.95 (s, 3H), 4.38 (s, 2H), 4.52 (s, 2H), 5.11 (s, 2H), 6.93 (d, J=6.64 Hz, 2H), 7.11-7.16 (m, 4H), 7.23 (d, J=7.52 Hz, 1H), 7.42 (d, J=7.08 Hz, 1H), 8.81 (bs, 1H).

(168) Examples 2-13 were made in an analogous manner to Example 1 starting from the appropriate quinazoline and using the appropriate benzyl halides and amines as described for General Procedures 1-3.

(169) TABLE-US-00001 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 2 04 1-(3,5- difluorobenzyl)- 3-methyl-N-((5- methylfuran-2- yl)methyl)-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.20 (s, 3H), 2.96 (s, 3H), 4.34 (d, J = 4.96 Hz, 2H), 4.53 (s, 2H), 5.12 (s, 2H), 5.96 (s, 1H), 6.05 (s, 1H), 6.95 (d, J = 6.88 Hz, 2H), 7.09 (t, J = 8.96 Hz, 1H), 7.16 (s, 1H), 7.24 (d, J = 7.84 Hz, 1H), 7.47 (d, J = 8.32 Hz, 1H), 8.84 (bs, 1H). 426.1 3 05 3-cyclopropyl-1-(3.5- difluorobenzyl)- 2-oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 0.60 (bs, 2H), 0.75 (bs, 2H), 2.66 (bs, 1H), 4.38 (s, 2H), 4.48 (s, 2H), 5.11 (bs, 2H), 6.92 (bs, 2H), 7.11-7.13 (m, 4H), 7.27 (d, J = 6.48 Hz, 1H), 7.40-7.41 (m, 1H), 8.79 (bs, 1H). 502.3 4 06 N-(2,4- difluorobenzyl)- 1-(3,5- difluorobenzyl)- 3-methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.96 (s, 3H), 4.41 (d, J = 5.6 Hz, 2H), 4.54 (s, 2H), 5.12 (s, 2H), 6.94-6.96 (m, 2H), 6.98-7.03 (m, 1H), 7.08-7.12 (m, 1H), 7.16-7.22 (m, 2H), 7.25- 7.35 (m, 2H), 7.48 (d, J = 3.88 Hz, 1H), 8.94 (t, J = 5.64 Hz, 1H). 458.0 5 07 1-(2-chloro-6- fluorobenzyl)-3- methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.91 (s, 3H), 4.37 (s, 2H), 4.42 (d, J = 4.88 Hz, 2H), 5.22 (s, 2H), 7.09- 7.21 (m, 4H), 7.26-7.31 (m, 2H), 7.36-7.40 (m, 2H) ,8.75 (t, J = 4.88 Hz, 1H). 492.3 6 08 1-(4- fluorobenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.95 (s, 3H), 4.38 (d J = 3.96 Hz, 2H), 4.50 (s, 2H), 5.07 (bs, 2H), 7.10- 7.21 (m, 6H), 7.24-7.26 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 8.80 (bs, 1H). 458.2 7 09 1-(3,5- difluorobenzyl)- 3-ethyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 1.14 (t, J = 6.64 Hz, 3H), 3.43 (d, J = 6.68 Hz, 2H), 4.39 (d, J = 3.52 Hz, 2H), 4.54 (s, 2H), 5.10 (s, 2H), 6.92 (d, J = 5.68 Hz, 2H), 7.11-7.15 (m, 4H), 7.24 (d, J = 7.56 Hz, 1H), 7.42 (d, J = 8.36 Hz, 1H), 8.80 (bs, 1H). 490.2 8 0 1-(2,4- difluorobenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.94 (s, 3H), 4.38 (d, J = 4.88 Hz, 2H), 4.50 (s, 2H), 5.08 (s, 2H), 6.94- 7.07 (m, 2H), 7.14-7.17 (m, 3H), 7.22-7.30 (m, 2H), 7.42 (d, J = 7.68 (m, 1H), 8.82 (t, J = 4.94 Hz, 1H). 476.2 9 1-(2-fluoro-6- methylbenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.31 (s, 3H), 2.92 (s, 3H), 4.37 (s, 2H), 4.41 (d, J = 4.76 Hz, 2H), 5.14 (s, 2H), 6.88-6.97 (m, 2H), 7.11-7.20 (m, 4H), 7.36 (s, 1H), 7.38 (s, 1H), 8.74 (s, 1H). 472.0 10 1-(2-fluoro-6- methoxybenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.86 (s, 3H), 3.80 (s, 3H), 4.33 (s, 2H), 4.41 (s, 2H), 5.14 (s, 2H), 6.65 (t, J = 9.38 Hz, 1H), 6.80 (d, J = 7.84 Hz, 1H), 7.13- 7.19 (m, 4H), 7.33 (d ,J = 6.6 Hz, 1H), 7.41 (s, 1H), 8.72 (s, 1H). 488.0 11 1-(2-bromo-6- fluorobenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.91 (s, 3H), 4.37 (s, 2H), 4.41 (d, J = 4.88 Hz, 2H), 5.17 (s, 2H), 7.13-7.24 (m, 5H), 7.34 (s, 1H), 7.39 (d, J = 7.76 Hz, 1H), 7.44 (d, J = 7.84 Hz, 1H), 8.75 (t, J = 5.04 Hz, 1H). 536.44 12 1-(2-fluorobenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.94 (s, 3H), 4.37 (d, J = 4.12 Hz, 2H), 4.51 (s, 2H), 5.12 (s, 2H), 7.00 (t, J = 4.64 Hz, 1H), 7.07 (t, J = 6.04 Hz, 1H), 7.14- 7.16 (m, 3H), 7.20-7.27 (m, 3H), 7.42 (d, J = 8.6 Hz, 1H), 8.81 (bs, 1H). 458.31 13 1-(2-fluoro-3- methylbenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.25 (s, 3H), 2.93 (s, 3H), 4.37 (d, J = 3.72 Hz, 2H), 4.51 (s, 2H), 5.10 (s, 2H), 6.77 (bs, 1H), 6.95 (t, J = 7.56 Hz, 1H), 7.14-7.16 (m, 4H), 7.23 (d, J = 7 8 Hz, 1H), 7.42 (d, J = 7.52 Hz, 1H), 8.82 (bs, 1H). 472.43

(170) Examples 14-72 were made in an analogous manner to Example 1 starting from the appropriate quinazoline and using the appropriate benzyl halides and amines as described in General Procedures 1-3.

(171) TABLE-US-00002 LCMS Example Structure IUPAC Name 1H-NMR [M + H] 14 1-(3- carbamoylbenzyl)- 3-methyl-2-oxo- N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.96 S, 3H), 4.36 (s, 2H), 4.52 (s, 2H), 5.13 (s, 2H), 7.12-7.14 (m, 3H), 7.22 (d, J = 764 Hz, 1H), 7.34-7.41 (m, 4H), 7.70 (s, 1H), 7.73 (s, 1H), 7.94 (s, 1H), 8.79 (bs, 1H). 483.4 15 1-(3,5- difluorobenzyl)- 3-isopropyl-2-oxo- N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.76 Hz, 6H), 4.39 (d, J = 5.08 Hz, 4H), 4.54-4.57 (m, 1H), 5.10 (s, 2H), 6.91 (d, J = 6.68 Hz, 2H), 7.07-7.16 (m, 4H), 7.30 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.84 Hz, 1H), 8.79 (bs, 1H). 504.2 16 N-(benzofuran-2- ylmethyl)-1-(3.5- difluorobenzyl)- 3-methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.96 (s, 3H), 4.54-4.58 (m, 4H), 5.13 (s, 2H), 6.65 (s, 1H), 6.96 (d, J = 5.92 Hz, 2H), 7.10 (t, 9.12 Hz, 1H), 7.20-7-28 (m, 4H), 7.49-7.56 (m, 3H), 9.05 (bs, 1H). 459.9 17 1-(2-chloro-4- fluorobenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.94 (s, 3H), 4.37 (d, J = 5.04 Hz, 2H), 4.53 (s, 2H), 5.05 (s, 2H), 6.94- 6.98 (m, 1H), 7.00 (s, 1H), 7.09-7.16 (m, 3H), 7.25 (d, J = 7.88 Hz, 1H), 7.43 (d, J = 7.76 Hz, 1H), 7.51 (dd, J.sub.1 = 2.60 Hz, J.sub.2 = 8.60 Hz, 1H), 8.83 (t, J = 4.88 Hz, 1H). 491.9 18 0 1-(3,5- difluorobenzyl)- 2-oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 4.39 (d, J = 4.96 Hz, 3H), 4.42 (s, 1H), 5.08 (s, 2H), 6.93 (d, J = 6.76 Hz, 2H), 7.07-7.16 (m, 4H), 7.22 (d, J = 7.84 Hz, 1H), 7.35 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 8.80 (t, J = 5.0 Hz, 1H). 462.1 19 l-(2-chlorobenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.94 (s, 3H), 4.36 (s, 2H), 4.54 (s, 2H), 5.09 (s, 2H), 6.93 (d, J = 6.52 Hz, 1H), 7.01 (s, 1H), 7.14 (t, J = 8.16 Hz, 2H), 7.21-7.26 (m, 3H), 7.43 (d, J = 7.32 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 8.81 (s, 1H). 474.1 20 3-methyl-1-((2- methylthiazol- 5-yl)methyl)- 2-oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.54 (s, 3H), 2.92 (s, 3H), 4.43-4.46 (m, 4H), 5.19 (s, 2H), 7.16-7.21 (m, 3H), 7.43 (d, J = 7.88 Hz, 1H), 7.49 (s, 1H), 7.60 (s, 1H), 8.88 (s, 1H). 461.2 21 1-(2-chloro-6- fluorobenzyl)- 2-oxo-3- (pyrimidin-2-yl)-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 4.37 (s, 2H), 4.90 (s, 2H), 5.34 (s, 2H), 7.08-7.38 (m, 7 H), 7.47 (d, J = 7.24 Hz, 1H), 7.64 (s, 1H), 8.72 (d, J = 3.32 Hz, 2H), 8.83 (s, 1H), 555.6 22 1-(2-chloro-6- fluorobenzyl)-N-((6- methoxybenzofuran- 2-yl)methyl)-3- methyl-2-oxo-1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.77 (s, 3H), 4.39 (s, 2H), 4.55 (d, J = 5.52 Hz, 2H), 5.23 (s, 2H), 6.62 (s, 1H), 6.84 (dd, J.sub.1 = 2.08 Hz, J.sub.2 = 9.08 Hz, 1H), 7.08-7.11 (m, 1H), 7.13 (s, 1H), 7.23-7.31 (m, 3H), 7.43- 7.49 (m, 3H), 8.98 (t, J = 5.6 Hz, 1H). 508.3 23 1-(2-chloro-6- fluorobenzyl)-N-((6- fluorobenzofuran- 2-yl)methyl)-3- methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.39 (s, 2H), 4.58 (d, J = 5.48 Hz, 2H), 5.23 (s, 2H), 6.73 (s, 1H), 7.08-7.14 (m, 2H), 7.23- 7.31 (m, 3H), 7.44 (s, 1H), 7.47-7.50 (m, 2H), 7.57-7.60 (m, 1H), 9.02 (t, J = 5.24 Hz, 1H). 496.3 24 1-(2-chloro-6- fluorobenzyl)- N-((5- fluorobenzofuran- 2-yl)methyl)-3- methyl-2-oxo-1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s,3H), 4.39 (s, 2H), 4.59 (d, J = 5.12 Hz, 2H), 5.23 (s,2H), 6.72 (s, 1H), 7.10-7.14 (m, 2H), 7.24- 7.31 (m, 3H), 7.39 (d, J = 6.52 Hz, 1H), 7.45-7.49 (m, 2H), 7.55 (dd, J.sub.1 = 4.16 Hz, J.sub.2 = 8.68 Hz, 1H), 9.05 (bs, 1H). 496.48 25 1-(2-chloro-6- fluorobenzyl)-3- methyl-N-(3- (oxazol-2- yl)benzyl)-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s,3H), 4.39 (s, 2H), 4.51 (d, J = 5.8 Hz, 2H), 5.24 s, 2H), 7.11-7.13 (m, 1H), 7.24-7.30 (m, 3H), 7.37 (s, 1H), 7.42-7.51 (m, 4H), 7.86 (d, J = 7.56 Hz, 1H), 7.92 (s, 1H), 8.21 (s, 1H), 9.05 (t, J = 5.6 Hz, 1H). 519.3 26 N-(2-(1H- 1,2,4-triazol-l- yl)ethyl)-1-(2- chloro-6- fluorobenzyl)-3- methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.60 (q, J = 5.78 Hz, 2H), 4.33 (t, J = 5.98 Hz, 2H), 4.37 (s, 2H), 5.21 (s, 2H), 7.13- 7.16 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.28-7.35 (m, 4H), 7.94 (s, 1H), 8.44 (s, 1H), 8.51 (t, J = 5.4 Hz, 1H). 443.4 27 1-(2-chloro-6- fluorobenzyl)- N-((5- hydroxybenzof uran-2- yl)methyl)-3- methyl-2-oxo- 1.2,3,4- tetrahydroquin azoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.39 (s, 2H), 4.53 (s, 2H), 5.23 (s, 2H), 6.55 (s, 1H), 6.67 (d, J = 8.08 Hz, 1H), 6.86 (s, 1H), 7.11-7.13 (m, 1H), 7.23- 7.29 (m, 4H), 7.44-7.48 (m, 2H), 8.99 (s, 1H), 9.10 (s, 1H). 494.47 28 0 1-(2-chloro-6- fluorobenzyl)- 3-methyl-N-(3-(1- methyl-1H-pyrazol-3- yl)benzyl)-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.86 (s, 3H), 4.39 (s, 2H), 4.47 (d, J = 5.88 Hz, 2H), 5.24 (s, 2H), 6.62 (d, J = 2.16 Hz, 1H), 7.08-7.13 (m, 1H), 7.19 (d, J = 7.52 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.27-7.35 (m, 3H), 7.45 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.76 Hz, 1H), 7.71-7.73 (m, 2H), 8.98 (t, J = 5.68 Hz, 1H). 518.49 29 1-(2-chloro-6- fluorobenzyl)- 3-methyl-N-(3-(1- methyl-1H-pyrazol- 5-yl)benzyl)-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.81 (s,3H), 4.38 (s, 2H), 4.50 (d, J = 5.2 Hz, 2H), 5.23 (s, 2H), 6.35 (s, 1H), 7.05-7.12 (m, 1H), 7.21-7.30 (m, 2H), 7.34 (d, J = 7.48 Hz, 1H), 7.42-7.46 (m, 7H), 8.99 (bs, 1H). 518.49 30 1-(2-chloro-6- fluorobenzyl)-N-(2- fluorobenzyl)- 3-methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.93 (s,3H), 4.39 (s, 2H), 4.47 (d, J = 5.64 Hz, 2H), 5.24 (s, 2H), 7.10-7.20 (m, 3H), 7.24 (d, J = 7.8 Hz, 1H), 7.27-7.33 (m, 4H), 7.43 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 8.92 (t, J = 5.48 Hz, 1H). 356.39 31 l-(2-chloro-6- fluorobenzy])- 3-methyl-N-(3-(4- methylpiperazin-1- yl)benzyl)-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.20 (s, 3H), 2.42 (t, J = 4.72 Hz, 4H), 2.92 (s, 3H), 3.09 (t, J = 4.64 Hz, 4H), 4.37 (d, J = 6.12 Hz, 4H), 5.23 (s, 2H), 6.68 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 8.48 Hz, 1H), 6.86 (s, 1H), 7.10-7.16 (m, 2H), 7.23 (d, J = 7.76 Hz, 1H), 7.27-7.31 (m, 2H), 7.43-7.46 (m, 2H), 8.86 (t, J = 5.88 Hz, 1H). 536.56 32 N-(benzofuran-5- ylmethyl)-1-(2- chloro-6- fluorobenzyl)- 3-methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.38 (s, 2H), 4.52 (d, J = 5.8 Hz, 2H), 5.23 (s, 2H), 6.92 (s, 1H), 7.09-7.14 (m, 1H), 7.22-7.31 (m, 4H), 7.44 (s, 1H), 7.47 (d, J = 7.84 Hz, 1H), 7.52-7.55 (m, 2H), 7.96-7.97 (m, 1H), 8.97 (t, J = 5.8 Hz, 1H). 478.41 33 3-methyl-1- ((5-methylisoxazol- 3-yl)methyl)-2-oxo- N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.33 (s, 3H), 2.92 (s, 3H), 4.41-4.46 (m, 4H), 5.05 (s, 2H), 6.04 (s, 1H), 7.14- 7.22 (m, 3H), 7.34 (s, 1H), 7.43 (d, J = 7.0 Hz, 1H), 8.83 (bs, 1H). 445.39 34 1-(2-chloro-6- fluorobenzyl)- 3-(1-methyl-1H- imidazol-4-yl)-2- oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 3.62 (s, 3H), 4.44 (d, J = 4.92 Hz, 2H), 4.97 (s, 2H), 5.27 (s, 2H), 7.13- 7.22 (m, 4H), 7.27-7.33 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.44-7.46 (m, 2H), 7.50 (s, 1H), 8.80 (t, J = 4.96 Hz, 1H). 558.53 35 l-((l,2,5-thiadiazol- 3-yl)methyl)-3- methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.40 (s, 2H), 4,49 (s, 2H), 5.35 (s, 2H), 7.16 (t, J = 8.48 Hz, 2H), 7.23 (d,J = 7.68 Hz, 1H), 7.44 (d, J = 7.56 Hz, 1H), 8.73 (s, 1H), 8.81 (bs, 1H). 448.33 36 3-methyl-1-((2- methyloxazol- 4-yl)methyl)-2-oxo- N-(2,4,6- trifluorobenzyl)- l,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.33 (s, 3H), 2.90 (s, 3H), 4.43 (s, 4H), 4.91 (s, 2H), 7.14-7.20 (m, 3H), 7.41- 7.43 (m, 2H), 7.64 (s, 1H), 8.81 (t, J = 5.32 Hz, 1H). 445.35 37 3-methyl-1-((1- methyl-1H- imidazol-4- yl)methyl)-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.90 (s, 3H), 3.53 (s, 3H), 4.42 (d, J = 6.04 Hz, 4H), 4.88 (s, 2H), 6.79 (s, 1H), 7.15-7.19 (m, 3H), 7.37 (d, J = 7.56 Hz, 1H), 7.43 (s, 1H), 7.53 (s, 1H), 8.77 (bs, 1H). 444.38 38 0 3-methyl-1-((5- methyl-2-(m- tolyl)oxazol-4- yl)methyl)-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.34 (s, 6H), 2.93 (s, 3H), 4.45 (s, 4H), 4.97 (s, 2H), 7.13 (t, J = 8.28 Hz, 2H), 7.19 (d, J = 6.96 Hz, 1H), 7.19 (s, 1H), 7.34-7.36 (m, 2H), 7.42 (d, J = 7.2 Hz, 1H), 7.65-7.69 (m, 3H). 534.8 39 1-(2-cyano-6- fluorobenzyl)-3- methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz ; DMSO-d.sub.6): δ 2.91 (s, 3H), 4.40-4.44 (m, 4H), 5.29 (s, 2H), 7.17 (t ,J = 8.68 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.27 (s, 1H), 7.42 (d, J = 7.88 Hz, 1H), 7.48-7.51 (m, 1H), 7.56-7.58 (m, 1H), 7.60-7.63 (m, 1H), 8.79 (t, J = 4.92 Hz, 1H). 483.42 40 3-methyl-1-((5- methyl-2-(p- tolyl)oxazol-4- yl)methyl)-2-oxo- N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.33 (d, J = 6.56 Hz, 6H), 2.92 (s, 3H), 4.44 (s, 4H), 4.96 (s, 2H), 7.14 (t, J = 8.48 Hz, 2H), 7.19 (d, J = 7.92 Hz, 1H), 7.28 (d, J = 7.72 Hz, 2H), 7.42 (d, J = 7.56 Hz, 1H), 7.64 (s, 1H), 7.73 (d, J = 7.8 Hz, 2H), 8.82 (bs, 1H). 535.52 41 1-(2-chloro-6- fluorobenzyl)- N-(2-fluoro-6- methoxybenzyl)- 3-methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2,91 (s, 3H), 3.79 (s, 3H), 4.36 (s, 2H), 4.42 (s, 2H), 5.22 (s, 2H), 6.79 (t, J = 9.12 Hz, 1H), 6.86 (d, J = 8.28 Hz, 1H), 7.11 (t, J = 9.24 Hz, 1H), 7.18 (d, J = 7.72 Hz, 1H), 7.28- 7.31 (m, 3H), 7.37 (s, 1H), 7.40 (d, J = 7.68 Hz, 1H), 8.36 (bs, 1H). 486.40 42 l-((2-(4- fluorophenyl)- 5-methyloxazol-4- yl)methyl)-3-methyl- 2-oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.34 (s, 3H), 2.92 (s, 3H), 4.44 (s, 4H), 4.97 (s, 2H), 7.14 (t, J = 8.44 Hz, 2H), 7.19 (d, J = 7.92 Hz, 1H), 7.31 (t, J = 8.6 Hz, 2H), 7.42 (d, J = 7.12 Hz, 1H), 7.63 (s, 1H), 7.86-7.89 (m, 2H), 8.81 (bs, 1H). 539.50 43 N-(benzo[d][1,3] dioxol-4-ylmethyl)- 1-(2-chloro-6- fluorobenzyl)- 3-methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.39 (d, J = 6.04 Hz, 4H), 5.23 (s, 2H), 6.00 (s, 2H), 6.73- 6.82 (m, 3H), 7.10-7.15 (m, 1H), 7.23 (d, J = 7.76 Hz, 1H), 7.27-7.32 (m, 2H), 7.42 (s, 1H), 7.46 (d, J = 7.84 Hz, 1H), 8.87 (t, J = 5.64 Hz, 1H). 482.36 44 l-(2-chloro-6- fluorobenzyl)- N-((2,3- dihydrobenzo[ b][1,4]dioxin- 5-yl)methyl)-3- methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.93 (s, 3H), 4.25 (dd, J.sub.1 = 4.6 Hz, J.sub.2 = 16.88 Hz, 4H), 4.38 (d, J = 7.56 Hz, 4H), 5.24 (s, 2H), 6.58- 6.70 (m, 1H), 6.73-6.75 (m, 2H), 7.10-7.15 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.27-7.32 (m, 2H), 7.43 (s, 1H), 7.47 (d, J = 7.76 Hz, 1H), 8.75 (t, J = 5.44 Hz, 1H). 496.45 45 1-((6- fluoroimidazo[1,2- a]pyridin-2- yl)methyl)-3- methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- l,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.93 (s, 3H), 4.38 (d, J = 4.96 Hz, 2H), 4.48 (s, 2H), 5.15 (s, 2H), 7.13 (t, J = 8.72 Hz, 2H), 7.21 (d, J = 7.88 Hz, 1H), 7.25- 7.30 (m, 1H), 7.39 (s, 1H), 7.41 (s, 1H), 7.52- 7.56 (m, 1H), 7.64 (s, 1H), 8.63-8.64 (m, 1H), 8.79 (t,J = 4.96 Hz, 1H). 498.43 46 l-(4-fluoro-2- methoxybenzyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.93 (s, 3H), 3.88 (s, 3H), 4.37 (d, J = 4.92 Hz, 2H), 4.50 (s, 2H), 4.94 (s, 2H), 6.59-6.64 (m, 1H), 6.79 (t, J = 7.92 Hz, 1H), 6.93-6.96 (m, 1H), 7.06 (s, 1H), 7.14 (t, J = 8.64 Hz, 2H), 7.21 (d, J = 7.88 Hz, 1H), 7.40 (d, J = 7.68 Hz, 1H), 8.78 (t, J = 4.8 Hz, 1H). 488.38 47 1-(2-chloro-6- fluorobenzyl)- N-((7- methoxybenzofuran- 2-yl)methyl)-3- methyl-2-oxo-1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.90 (s, 3H), 4.39 (s, 2H), 4.58 (d, J = 5.32 Hz, 2H), 5.23 (s, 2H), 6.69 (s, 1H), 6.88 (s, 1H), 7.11-7.14 (m, 3H), 7.23-7.31 (m, 3H), 7.45 (s, 1H), 7.48 (d, J = 7.44 Hz, 1H), 9.03 (bs, 1H). 508.40 48 0 1-(2-chloro-6- fluorobenzyl)-3- methyl-N-((5- nitrobenzofuran- 2-yl)methyl)-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.39 (s, 2H), 4.65 (d, J = 4.76 Hz, 2H), 5.23 (s,2H), 6.97 (s,1H), 7.12 (t, J = 8.0 Hz, 1H), 7.24-7.31 (m, 3H), 7.45 (s, 1H), 7.49 (d, J = 7.84 Hz, 1H), 7.79 (d, J = 8.92 Hz, 1H), 8.16-8.19 (m, 1H), 8.57 (d, J = 2.2 Hz, 1H), 9.10 (bs, 1H). 523.38 49 1-(2-chloro-6- fluorobenzyl)-3- methoxy-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 3.67 (s, 3H), 4.42 (d, J = 4.76 Hz, 2H), 4.56 (s, 2H), 5.25 (s, 2H), 7.12- 7.21 (m, 3H), 7.27-7.35 (m, 3H), 7.40 (s, 1H), 7.45 (d, J = 7.92 Hz, 1H), 8.78 (t,J = 4.84 Hz, 1H). 508.2 50 N-(benzofuran-4- ylmethyl)-1-(2- chloro-6- fluorobenzyl)- 3-methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.38 (s, 2H), 4.68 (d, J = 4.84 Hz, 2H), 5.23 (s, 2H), 7.05 (s, 1H), 7.11-7.16 (m, 2H), 7.22- 7.28 (m, 4H), 7.43-7.50 (m, 2H), 7.97 (s, 1H), 8.99 (bs, 1H). 478.2 51 1-(2-chloro-6- fluorobenzyl)- 3-methyl-N-((1- methyl-1H-indazol- 6-yl)methyl)-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.99 (s,3H), 4.39 (s, 2H), 4.58 (d, J = 5.8 Hz, 2H), 5.24 (s, 2H), 7.08-7.14 (m, 2H), 7.23- 7.31 (m, 3H), 7.45 (s, 1H), 7.48-7.50 (m, 2H), 7.69 (d, J = 8.32 Hz, 1H), 7.99 (s, 1H), 8.99 (t, J = 5.8 Hz, 1H). 492.45 52 N-(benzofuran-6- ylmethyl)-1-(2- chloro-6- fluorobenzyl)-3- methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.39 (s, 2H), 4.54 (d, J = 5.36 Hz, 2H), 5.24 (s, 2H), 6.92 (s, 1H), 7.12 (t, J = 8.52 Hz, 1H), 7.19- 7.31 (m, 4H), 7.44- 7.48 (m, 3H), 7.59 (d, J = 7.96 Hz, 1H), 7.95 (s, 1H), 8.99 (bs, 1H). 478.2 53 3-methyl-1-((1- methyl-1H-pyrazol- 5-yl)methyl)-2-oxo- N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.83 (s, 3H), 4.43 (d, J = 4.84 Hz, 2H), 4.46 (s, 2H), 5.14 (s, 2H), 5.92 (s, 1H), 7.15-7.21 (m, 3H), 7.23 (s, 1H), 7.34 (s, 1H), 7.44 (d, J = 7.84 Hz, 1H), 8.83 (bs, 1H). 444.2 54 3-methyl-1-((3- methylisoxazol- 5-yl)methyl)-2-oxo- N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.15 (s, 3H), 2.92 (s, 3H), 4.43 (d, J = 4.40 Hz, 2H), 4.47 (s, 2H), 5.17 (s, 2H), 6.09 (s, 1H), 7.17 (t, J = 9.04 Hz, 2H), 7.23 (d, J = 7.76 Hz, 1H), 7.34 (s, 1H), 7.47 (d, J = 7.28 Hz, 1H), 8.86 (bs, 1H). 445.46 55 3-methyl-1-((1- methyl-1H-1,2,3- triazol-4-yl)methyl)- 2-oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.91 (s,3H), 3.96 (s, 3H), 4.42 (d, J = 5.56 Hz, 4H), 5.06 (s, 2H), 7.14-7.20 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.79 (s, 1H), 8.82 (t, J = 5.16 Hz, 1H). 445.2 56 1-(2-fluoro-6- (trifluoromethyl)benzyl)- 3-methyl-2-oxo-N- (2,4,6-trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline- 7-carboxamide (400 MHz; DMSO-d.sub.6): δ 2.90 (s, 3H), 4.38-4.41 (m, 4H), 5.27 (s, 2H), 7.17 (t, J = 8.72 Hz, 2H), 7.22 (d, J = 7.84 Hz, 1H), 7.30 (s, 1H), 7.40-7.46 (m, 2H), 7.49-7.53 (m, 1H), 7.60 (d ,J = 7.72 Hz, 1H), 8.74 (t ,J = 4.92 Hz, 1H). 526.45 57 l-((l,5-dimethyl-1H- pyrazol-3-yl)methyl)-3- methyl-2-oxo-N-(2,4,6- trifluorobenzyl)-1,2,3,4- tetrahydroquinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 2.13 (s, 3H), 2.91 (s, 3H), 3.61 (s, 3H), 4.42 (s, 4H), 4.90 (s, 2H), 5.75 (s, 1H), 7.16-7.19 (m, 3H), 7.37 (d, J = 7.92 Hz, 1H), 7.43 (s, 1H), 8.78 (bs, 1H). 458.2 58 0 N-((5- aminobenzofuran-2- yl)methyl)-1-(2- chloro-6-fluorobenzyl)- 3-methyl-2-oxo-1,2,3,4- tetrahydroquinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 4.39 (s, 2H), 4.50 (d, J = 5.36 Hz, 2H), 4.77 (s, 2H), 5.24 (s, 2H), 6.44 (s, 1H), 6.53 (dd, J.sub.1 = 1.72 8.76 Hz, J.sub.2 = Hz, 1H), 6.65 (s, 1H), 7.11- 7.16 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.26-7.31 (m, 2H), 7.44 (s, 1H), 7.47 (d, J = 7.68 Hz, 1H), 8.96 (t, J = 5.36 Hz, 1H). 493.4 59 1-(2-chloro-6- fluorobenzyl)-3- methyl-2-oxo-N-((2- oxoindolin-5- yl)methyl)-1,2,3,4- tetrahydroquinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.44 (s, 2H), 4.35-4.38 (m, 4H), 5.23 (s, 2H), 6.74 (d, J = 7.8 Hz, 1H), 7.08-7.15 (m, 3H), 7.22 (d, J = 7.6 Hz, 1H), 7.28-7.31 (m, 2H), 7.43-7.46 (m, 2H), 8.88 (bs, 1H), 10.32 (s, 1H). 493.3 60 1-(2-chloro-6- fluorobenzyl)- N-(2,6-difluoro-4- methoxybenzyl)-3- methyl-2-oxo-1,2,3,4- tetrahydroquinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 2.92 (s, 3H), 3.78 (s, 3H), 4.37 (m, 4H), 5.22 (s, 2H), 6.74 (d, J = 9.7 Hz, 2H), 7.13 (t, J = 9.2 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.27-7.33 (m, 2H), 7.38-7.42 (m, 2H), 8.68 (t, J = 4.85 Hz, 1H). 504.23 61 1-(2-chloro-6- fluorobenzyl)- N-(4-flnoro-2- methoxybenzyl)- 3-methyl-2-oxo- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 2.93 (s, 3H), 3.82 (s, 3H), 4.36 (d, J = 5.7 Hz, 2H), 4.40 (s, 2H), 5.25 (s, 2H), 6.71-6.71 (m, 1H), 6.89- 6.92 (dd, J.sub.1 = 2.4 Hz, J.sub.2 = 11.35 Hz, 1H), 7.12- 7.17 (m, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.28- 7.38 (m, 2H), 7.43 (s, 1H), 7.48 (d, J = 7.85 Hz, 1H), 8.77 (t, J = 5.8 Hz, 1H). 486.26 62 l-(2,6- dichlorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 2.91 (s, 3H), 4.35 (s, 2H), 4.44 (d, J = 4.95 Hz, 2H), 5.29 (s, 2H), 7.19-7.22 (m, 3H), 7.27 (t, J = 7.95 Hz, 1H), 7.38-7.46 (m, 4H), 8.72 (t, J = 5. Hz, 1H). 508.21 63 1-(2-fluoro-3- methoxybenzyl)-3- methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 2.94 (s, 3H), 3.85 (s, 3H), 4.39 (d, J = 4.95 Hz, 2H), 4.51 (bs, 2H), 5.12 (s, 2H), 6.52 (t, J = 6.95 Hz, 1H), 6.99 (t, J = 7.9 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 7.15 (t, J = 8.65 Hz, 3H), 7.24 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 4H), 8.40 (bs, 1H). 488.26 64 1-((3- cyclopropylisoxazol- 5-yl)methyl)-3- methyl-2-oxo-N- (2,4,6-trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 0.67-0.68 (m, 2H), 0.94- 0.95 (m, 2H), 1.93-1.98 (m, 1H), 2.91 (s, 3H), 4.43-4.47 (m, 4H), 5.14 (s, 2H), 6.01 (s, 1H), 7.16 (t, J = 8.6 Hz, 2H), 7.23 (d, J = 7.96 Hz, 1H), 7.33 (s, 1H), 7.46 (d, J = 7.28 Hz, 1H), 8.85 (bs, 1H). 471.0 65 1-(imidazo[1,2- a]pyridin-2-ylmethyl)- 3-methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 2.94 (s, 3H), 4.38 (d, J = 4.88 Hz, 2H), 4.48 (s, 2H), 5.16 (s, 2H), 6.82 (t. J = 6.8 Hz, 1H), 7.10-7.22 (m, 4H), 7.39-7.47 (m, 3H), 7.61 (s, 1H), 8.42 (d, J = 6.64 Hz, 1H), 8.78 (t, J = 4.84 Hz, 1H). 480.43 66 1-(6-chloro-2-fluoro-3- methylbenzyl)-3-methyl- 2-oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 2.13 (d, J = 1.5 Hz, 3H), 2.92 (s,3H) 4.37 (s, 2H), 4.43 (d, J = 4.9 Hz, 2H), 5.21 (s, 2H), 7.15-7.21 (m, 5H), 6.37-6.40 (m, 2H), 8.78 (t, J = 5.05 Hz, 1H). 506.16 67 1-((4-bromo-1,3- dimethyl-1H-pyrazol- 5-yl)methyl)-3- methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 2.00 (s, 3H), 2.94 (s, 3H), 3.78 (s, 3H), 4.44 (d, J = 5.0 Hz, 4H), 5.16 (s, 2H), 7.19-7.24 (m, 3H), 7.32 (s, 1H), 7.43 (d, J = 8.38 Hz, 1H), 8.78 (t, J = 5.0 Hz, 1H). 536.14 68 0 3-(benzyloxy)-1-(2- chloro-6- fluorobenzyl)-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 4.42 (s, 2H), 4.51 (s, 2H), 4.90 (s, 2H), 5.28 (s, 2H), 7.19-7.52 (m, 13H), 8.78 (bs, 1H). 584.3 69 1-(2-chloro-6- fluorobenzyl)-3- hydroxy-2-oxo-N- (2,4,6-trifluorobenzyl)- 1,2,3,4- tetrahydroquinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 4.41 (s, 2H), 4.50 (s, 2H), 5.25 (s, 2H), 7.13-7.21 (m, 3H), 7.29 (d, J = 5.08 Hz, 3H), 7.38-7.42 (m, 2H), 8.78 (s, 1H), 9.63 (s, 1H). 494.0

Example 70: 1-(3,5-difluorobenzyl)-3-methyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7-carboxamide 2,2-dioxide

(172) ##STR00172##

(173) Example 70 was prepared according to the methods described in General Procedures 1-3, and the methods described below.

Preparation 5: Methyl-3-methyl-3,4-dihydro-H-benzo[c][1,2,6]thiadiazine-7-carboxylate 2,2-dioxide

(174) ##STR00173##

(175) To a stirred solution of methyl-3-amino-4-((methylamino)methyl)benzoate (Preparation 1) (0.6 g, 3.09 mmol) in pyridine (20 mL) was added sulfamide (0.89 g, 9.28 mmol) at 0-5° C. The resulting reaction mixture was warmed up to RT and then heated at reflux for 4 h. After completion of the reaction, the mixture was quenched with 2N HCl and extracted with EtOAc. The collected organic layer was washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude compound which was purified by Combi-flash using 30% EtOAc/hexane as eluent to afford the titled compound (0.22 g, 28% yield and purity>95%) as a yellow solid. LCMS m/z: 257.6 [M+H].

Preparation 6: Methyl-1-(3,5-difluorobenzyl)-3-methyl-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7-carboxylate 2,2-dioxide

(176) ##STR00174##

(177) To a stirred solution of methyl-3-methyl-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7-carboxylate 2,2-dioxide (Preparation 5) (0.17 g, 0.66 mmol) in DMF (5 mL) at 0-5° C., was added potassium tert-butoxide (0.081 g, 0.73 mmol) and the whole stirred for another 10-15 min. at the same temperature. Then, 3,5-difluorobenzyl bromide (0.137 g, 0.66 mmol) was added and the reaction mixture was stirred at RT for 1 h. Progress of the reaction was monitored by TLC and after completion, the reaction mixture was diluted with water and extracted with EtOAc. The collected organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by Combi-flash using 15% EtOAc/hexane as eluent to afford the titled compound (0.22 g, 86.7% yield and purity>85%) as a yellow solid. LCMS m/z: 383 [M+H].

Preparation 7: 1-(3,5-difluorobenzyl)-3-meth-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7-carboxylic acid 2,2-dioxide

(178) ##STR00175##

(179) To a stirred solution of methyl-1-(3,5-difluorobenzyl)-3-methyl-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7-carboxylate 2,2-dioxide (Preparation 6) (0.22 g, 0.68 mmol) in a mixture of THF:MeOH:H.sub.2O (4.5 mL, 1:1:1) was added LiOH.H.sub.2O (0.114 g, 2.71 mmol) at RT and the reaction mixture was further stirred at the same temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS and after completion, the solvents were evaporated under reduced pressure and the residue was dissolved in water and acidified with 1N HCl to pH 3-5. The resulting aqueous solution was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the titled compound (0.18 g, 85% yield and purity>97%) as a pale yellow solid. LCMS m/z: 367 [M+H].

Preparation 8: 1-(3,5-difluorobenzyl)-3-methyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7-carboxamide 2,2-dioxide (Example 70)

(180) ##STR00176##

(181) To a stirred solution of 1-(3,5-difluorobenzyl)-3-methyl-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine-7-carboxylic acid 2,2-dioxide (Preparation 7) (0.06 g, 0.16 mmol) in DCM (2 mL) was added TEA (0.045 mL, 0.33 mmol) at 0-5° C. followed by HBTU (0.074 g, 0.20 mmol) and the mixture allowed to stir for 5 min at the same temperature. Then, 2,4,6-trifluorobenzylamine (0.028 g, 0.18 mmol) was added and the reaction mixture was brought to RT and stirred for 3 h. Completion of the reaction was monitored by TLC and LC. After completion of the reaction; the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the crude product which was purified by Combi-flash using 30% EtOAc/hexane as eluent to give the titled compound (0.015 g, 18% yield and purity 96.8%) as an off white solid. LCMS m/z: 512 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 2.75 (s, 3H), 4.41 (s, 2H), 4.78 (s, 2H), 5.12 (s, 2H), 7.10-7.20 (m, 6H), 7.31 (d, J=5.52 Hz, 1H), 7.50 (d, J=5.84 Hz, 1H), 8.88 (s, 1H).

Example 71: 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide

(182) ##STR00177##

(183) Example 71 was prepared according to the methods described in General Procedures 1-3 and 6-7, and the methods described below.

Preparation 9: Methyl-3-oxo-1,2,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxylate

(184) ##STR00178##

Step 1: Methyl-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-nitronicotinate

(185) ##STR00179##

(186) To a stirred solution of methyl-6-formyl-5-nitronicotinate (0.9 g, 4.28 mmol) in MeOH (30 mL) was added methylamine hydrochloride (0.32 g, 4.71 mmol) followed by sodium triacetoxyborohydride (1.82 g, 8.57 mmol) at RT and the resulting reaction mixture was stirred at the same temperature for 2 min. Then a saturated solution of NH.sub.4Cl was added into the reaction mixture to quench the excess sodium triacetoxyborohydride. Then BOC anhydride (1.4 g, 6.42 mmol) was added into the mixture and the whole was stirred at RT for 30 min. Completion of the reaction was confirmed by TLC and LCMS after which the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography to afford the titled compound (0.52 g, 37% yield and purity>60%) as a white solid. LCMS m/z: 326 [M+H].

Step 2: Methyl-5-amino-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)nicotinate

(187) ##STR00180##

(188) To a stirred solution of methyl-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-nitronicotinate (Step 1) (0.52 g, 1.60 mmol) in methanol (20 mL) was added 10% Pd—C (0.15 g, 50% w/w in water) at RT under a N.sub.2 gas atmosphere and the whole further stirred at RT for 2 h under a H.sub.2 gas balloon pressure. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was filtered through a celite bed and washed carefully with methanol under a N.sub.2 gas atmosphere. The collected filtrate was evaporated under reduced pressure to give the title compound (0.6 g, purity>83%) as crude which was used in the next step without further purification. LCMS m/z: 296 [M+H].

Step 3: Methyl-6-(((tert-butoxycarbonyl(methyl)amino)methyl)-5-((phenoxycarbonyl)amino)nicotinate

(189) ##STR00181##

(190) To a stirred solution of methyl-5-amino-6-(((tert-butoxycarbonyl)(methyl)amino)-methyl)nicotinate (Step 2) (0.6 g, 2.03 mmol) in THF (20 mL) was added phenyl chloroformate (0.48 g, 3.05 mmol) at RT and the resulting reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS and after completion the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the titled compound (0.95 g, purity>67%) as crude which was used in the next step without further purification. LCMS m/z: 416 [M+H].

Step 4: Methyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxylate

(191) ##STR00182##

(192) To a stirred solution of methyl-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-((phenoxycarbonyl)amino)nicotinate (Step 3) (0.95 g, 2.29 mmol) in DCM (20 mL) was added TFA (2.8 mL) at 0-5° C. and the reaction mixture was then stirred at RT for 2 h. After complete consumption of the starting materials the solvents were evaporated under reduced pressure to give a residue which was dissolved in DMF and neutralized with TEA. The resulting neutralised reaction mass was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography to give the titled compound (0.165 g, 33% yield and purity>99%) as a white solid. LCMS m/z: 222.63 [M+H].

Example 71: 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide

(193) ##STR00183##

(194) 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide (Example 71) was prepared from methyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxylate (Preparation 9) according to methods described in Preparations 2, 3 and 4 and General Procedures 1-3. Purity 97.56%; LCMS m/z: 493.41 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 2.95 (s, 3H), 4.46 (s, 2H), 4.52 (s, 2H), 5.21 (s, 2H), 7.15-7.22 (m, 3H), 7.32 (m, 2H), 7.67 (s, 1H), 8.52 (s, 1H), 9.00 (bs, 1H).

(195) Examples 72 and 73 were made in an analogous manner to Example 71 starting from the appropriate substituted pyridine and using the appropriate benzyl halides and amines as described for General Procedures 1-3 and 6-7.

(196) TABLE-US-00003 Exam- LCMS ple Structure IUPAC Name .sup.1H-NMR [M + H] 72 1-(3,5- difluorobenzyl)-3- methyl-2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydropyrido[3,2- d]pyrimidine- 7-carboxamide (500 MHz; DMSO- d.sub.6): δ 2.99 (s, 3H), 4.43 (s, 2H), 4.65 (s, 2H), 5.10 (s, 2H), 6.99 (d, J = 5.6 Hz, 2H), 7.12-7.17 (m, 3H), 7.37 (s, 1H), 8.53 (s, 1H), 9.04 (s, 1H). 477.39 73 N-(benzofuran-2- ylmethyl)-1-(2- chloro-6- fluorobenzyl)-3- methyl-2-oxo- 1,2,3,4- tetrahydropyrido[3,2- d]pyrimidine- 7-carboxamide (500 MHz; DMSO d.sub.6): δ 2.96 (s, 3H), 4.55 (s, 2H), 4.65 (s, 2H), 5.22 (s, 2H), 6.77 (s, 1H), 7.06 (m, 1H), 7.15-7.31 (m, 4H), 7.53-7.59 (m, 2H), 7.75 (s, 1H), 8.62 (s, 1H), 9.26 (s, 1H). 479.44

Example 74: 1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(197) ##STR00186##

(198) Example 74 was prepared according to the methods described in General Procedures 1-3 and 4-7, and the methods described below.

Preparation 10: Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(199) ##STR00187##

Step 1: Methyl-4-ethyl-3-nitrobenzoate

(200) ##STR00188##

(201) To a stirred solution of commercially available 4-ethyl-3-nitro-benzoic acid (2.0 g, 10.25 mmol) in MeOH (30 mL) was added thionylchloride (1.12 mL, 15.37 mmol) at 0-5° C. and the reaction mixture was stirred at 50° C. for 16 h under a N.sub.2 gas atmosphere. The reaction mixture was concentrated and NaHCO.sub.3 solution (50 mL) was added and the mixture extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the titled compound (1.8 g, 84.0% yield) as a pale yellow liquid. .sup.1H NMR (400 MHz; CDCl3): δ 1.29 (t, J=7.44 Hz, 3H), 2.95 (q, J=7.44 Hz, 2H), 3.94 (s, 3H), 7.45 (d, J=8.0 Hz, 1H), 8.15 (d, J=7.92 Hz, 1H), 8.50 (s, 1H).

Step 2: Methyl-4-(1-bromoethyl)-3-nitrobenzoate

(202) ##STR00189##

(203) To a stirred solution of 4-ethyl-3-nitro-benzoic acid methyl ester (Step 1) (2.5 g, 11.96 mmol) in trifluoro toluene (50 mL) were added NBS (3.194 g, 17.94 mmol) and benzoyl peroxide (0.435 g, 1.79 mmol) and the reaction mixture was heated at 100° C. for 16 h. The progress of reaction was monitored by TLC and after completion the reaction mixture was quenched with a saturated solution of Na.sub.2S.sub.2O.sub.3 (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude material which was purified by column chromatography using 5-6% EtOAc in hexane as eluent to afford the titled compound (2.0 g, 58.0% yield) as a brown gummy liquid. .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.05 (d, J=6.6 Hz, 3H), 3.91 (s, 3H), 5.82 (q, J=6.6 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.26 (d, J=7.96 Hz, 1H), 8.37 (s, 1H).

Step 3: Methyl-4-(1-(methylamino)ethyl)-3-nitrobenzoate

(204) ##STR00190##

(205) To a stirred solution of 4-(1-bromo-ethyl)-3-nitro-benzoic acid methyl ester (Step 2) (2.5 g, 8.68 mmol) in THF (15 mL) was added methylamine (15 mL, 2M solution in THF) and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC and after completion of the reaction the mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the titled compound (2.0 g, 96.7% yield) as a brown gummy liquid. LCMS m/z: 239.3 [M+H].

Step 4: Methyl-3-amino-4-(1-(methylamino)ethyl)benzoate

(206) ##STR00191##

(207) A stirred solution of 4-(1-methylamino-ethyl)-3-nitro-benzoic acid methyl ester (Step 3) (2.0 g, 8.40 mmol) in EtOAc (30 mL) was purged with nitrogen gas for 10 min. and then 10% Pd—C(1.0 g, 50% w/w in water) was added. The mixture was hydrogenated under a H.sub.2 gas balloon pressure for 16 h at RT. After completion of the reaction the mixture was filtered through a celite bed and washed with 5% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford the titled compound (1.5 g, 85.7% yield) as a pale yellow gum. LCMS m/z: 209.3 [M+H].

Step 5: Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(208) ##STR00192##

(209) To a stirred solution of 3-amino-4-(1-methylamino-ethyl)-benzoic acid methyl ester (Step 4) (2.0 g, 9.62 mmol) in THF (30.0 mL) was added triphosgene (1.712 mg, 5.77 mmol) at 0-5° C. and the whole stirred for 10 min. TEA (2.67 ml, 19.23 mmol) was added and the reaction mixture was allowed to further stir at RT for 16 h. The reaction mixture was quenched by adding NaHCO.sub.3 solution and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and concentrated under reduced pressure. The crude material was purified by Combi-flash eluting with 70% EtOAc in hexane as eluent to afford the titled compound (0.5 g, 22.2% yield) as a brown solid. LCMS m/z: 235.3 [M+H].

Preparation 11: Methyl-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(210) ##STR00193##

(211) To a stirred solution of 3,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (Preparation 10) (0.38 g, 1.62 mmol) in DMF (5 mL) was added NaH (72 mg, 1.79 mmol, 60% dispersion in mineral oil) at 0-5° C. and the mixture stirred for 15 min. 2-Bromomethyl-1-chloro-3-fluoro-benzene (0.28 mL, 1.95 mmol) was added and the reaction mixture was further stirred at RT for 1 h. The progress of reaction was monitored by TLC and LCMS and after completion the mixture was quenched by adding water and extracted with EtOAc. The organic layer was washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford crude material which was purified by Combi-flash eluting with 15% EtOAc in hexane to afford the titled compound (0.45 g, 73.5% yield) as an off white solid. LCMS m/z: 376.9 [M+H].

Preparation 12: 1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

(212) ##STR00194##

(213) To a stirred solution of 1-(2-chloro-6-fluoro-benzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (Preparation 11) (0.4 g, 1.06 mmol) in THF:H.sub.2O (6 mL, 1:1) was added LiOH.H.sub.2O (49.15 mg, 1.17 mmol) and the reaction mixture was stirred at RT for 4 h. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was acidified with 1N HCl solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the titled compound (0.25 g, 64.8% yield) as an off white solid. LCMS m/z: 362.9 [M+H].

Preparation 13: 1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 74)

(214) ##STR00195##

(215) To a stirred solution of 1-(2-chloro-6-fluoro-benzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid (Preparation 12) (0.25 g, 0.69 mmol) in DCM (5 mL) was added TEA (0.192 ml, 1.38 mmol) and HATU (0.394 g, 1.04 mmol) at 0-5° C. and the whole was stirred for 10 min. Then 2,4,6-trifluorobenzylamine (0.101 mL, 0.83 mmol) was added and the reaction mixture was allowed to stir at RT for 16 h. The progress of reaction was monitored by TLC and LCMS and after completion the mixture was diluted with water (15 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with 1N HCl (10 mL), saturated sodium bicarbonate solution (10 mL) and finally with water. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude material which was purified by prep-HPLC to afford the titled compound (0.15 g, 42.9% yield and purity 99.57%) as a white solid. LCMS m/z: 506.1 [M+H]; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 1.22 (d, J=6.08 Hz, 3H), 2.93 (s, 3H), 4.41-4.53 (m, 3H), 4-90 (d, J=15.6 Hz, 1H), 5.54 (d, J=16.08 Hz, 1H), 7.14-7.19 (m, 4H), 7.24-7.32 (m 2H), 7.39 (d, J=7.64 Hz, 1H), 7.44 (s, 1H), 8.75 (bs, 1H).

(216) Chiral Separation of Example 74:

(217) Racemic 1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 74) (0.15 g) was subjected to chiral separation to afford two enantiomers;

(218) Enantiomer 1, Example 75 (26.2 mg, purity 99.72%, chiral purity 100% ee)

(219) Enantiomer 2, Example 76 (24.7 mg, purity 99.36%, chiral purity 97.86% ee)

(220) Chiral Separation Methods:

(221) Chiral separation was carried out using an Agilent HPLC (1200 series) under the following conditions;

(222) TABLE-US-00004 Column Chiralpak ID (21 × 250 mm), 5 μm Mobile phase Hexane/Ethanol: 70/30 Flow rate 21.0 mL/min. Run time 30 min. Wave length 220 nm Solubility Methanol

(223) Both enantiomers were subsequently synthesized individually from chiral starting materials to confirm the absolute configuration of each enantiomer, as described below.

Example 76: (S)-1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(224) ##STR00196##

(225) Example 76 was prepared according to the methods described in General Procedures 1-3 and 8-12, and the methods described below.

Preparation 14: (S)-Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(226) ##STR00197##

Step 1: (S)-Methyl-4-(1-(2,2,2-trifluoroacetamido)ethyl)benzoate

(227) ##STR00198##

(228) To a stirred solution of commercially available (S)-methyl-4-(1-aminoethyl)benzoate (50.0 g, 0.28 mol) in toluene (500 mL) was added TFAA (79 mL, 0.56 mol) at 10-15° C. dropwise over 20-30 min., and the resulting reaction mixture was stirred at 25° C. for 1 h. The progress of the reaction was monitored by UPLC-MS. The reaction mixture was poured into crushed ice (1000 g) and extracted with EtOAc (2×1000 mL). The combined organic layers were washed successively with saturated NaHCO.sub.3 solution (1000 mL) and a saturated brine solution (1000 mL) and then dried over anhydrous Na.sub.2SO.sub.4. The filtered organics were evaporated under reduced pressure to afford the titled compound (75.0 g, yield 96.5%, purity 99.6%) as a white solid. LCMS m/z: 274.01 [M−H].

Step 2: (S)-Methyl-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate

(229) ##STR00199##

(230) To a stirred solution of sodium hydride (13.0 g, 0.327 mol, 60% suspension in oil) in DMF (450 mL) was added a mixture of (S)-methyl-4-(1-(2,2,2-trifluoro-acetamido)ethyl)benzoate (Step 1) (75.0 g, 0.27 mol) and methyl iodide (34.1 mL, 0.54 mol) in DMF (300 mL) dropwise using a dropping funnel over 20-30 min. at 10-15° C. and the resulting mixture then stirred for 2 h at 25° C. Completion of the reaction was confirmed by UPLC-MS. The reaction mixture was poured into an ice-water mixture (3500 mL) and extracted with EtOAc (3×1000 mL). The organic layer was washed with 1N HCl (500 mL), saturated NaHCO.sub.3 solution (500 mL) and a saturated brine solution (1000 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the titled compound on overnight freezing (76.0 g, yield 96.4%, purity 99.3%) as an off white solid. .sup.1H NMR (50 MHz; DMSO-d.sub.6): δ 1.58 (d, J=7.05 Hz, 3H), 1.67 (d, J=6.75 Hz, 1H), 2.84 (s, 2H), 3.86 (s, 3H), 5.71-5.75 (q, J=6.95 Hz, 1H), 7.45-7.49 (m, 2H), 7.97-8.01 (m, 2H).

Step 3: (S)-Methyl 3-nitro-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate

(231) ##STR00200##

(232) Concentrated sulfuric acid (570 mL) was charged to a 2 L round bottomed flask equipped with guard tube and thermo pocket and cooled to 0-5° C. with an external ice-salt bath. Fuming nitric acid (190 mL) was added dropwise through a dropping funnel to maintain the internal temperature between 0-10° C. over a period of 20 min. Then (S)-methyl-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate (Step 2) (76.0 g, 0.26 mol) was added portionwise maintaining the internal temperature between 0-5° C. over a period of 30 min. The resulting mixture was stirred at 25° C. for 1 h. Completion of the reaction was confirmed by UPLC-MS. The reaction mixture was poured into an ice-water mixture (3500 mL) and extracted with EtOAc (3×1000 mL). The combined organic layers were washed with a saturated NaHCO.sub.3 solution (6×1500 mL) followed by a saturated brine solution (2×1000 mL) and dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the titled compound (85.85 g, yield 97.7%, purity 99.3%) as a thick brown oil. .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.62 (d, J=6.95 Hz, 3H), 2.92 (s, 3H), 3.91 (s, 3H), 5.76-5.80 (q, J=6.8 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 8.26 (d, J=8.15 Hz, 1H), 8.36 (s, 1H).

Step 4: (S)-Methyl-3-((ethoxycarbonyl)amino)-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate

(233) ##STR00201##

(234) Option A:

(235) To a stirred solution of (S)-methyl-3-nitro-4-(1-(2,2,2-trifluoro-N-methylacetamido)-ethyl)benzoate (Step 3) (20.0 g, 59.8 mmol) in 1,4-dioxane (200 ml, degassed with nitrogen) was added 10% Pd—C(4.0 g, 50% w/w in water) under an inert atmosphere and the resulting reaction mixture was stirred under a H.sub.2 gas balloon pressure at RT for overnight. Progress of the reaction was monitored by TLC and UPLC-MS which showed in-complete conversion of starting material. Then the reaction mixture was filtered and washed with 1,4-dioxane carefully and equally divided into three parts and again added 10% Pd—C(3×2.0 g, 50% w/w in water) into each part, individually stirred under a H.sub.2 gas balloon at RT for 8 h. UPLC-MS showed completion of the reactions in all three reaction vessels. Then the hydrogen gas balloon was removed from each vessels and added solid K.sub.2CO.sub.3 (3×13.77 g, 99.78 mmol) into each vessel followed by dropwise addition of ethyl chloroformate (3×7.6 mL, 79.85 mmol) at RT. The resulting reaction mixture was further stirred at RT for overnight. UPLC-MS showed completion of the reaction, all three reactions were filtered through a celite bed into one filtration flask, and the bed was washed with DCM. The filtrate was evaporated under reduced pressure to give a crude product which was dissolved in EtOAc (500 mL), washed with water (2×250 mL) followed by brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product (25.0 g) as a thick oil which was purified by trituration with n-hexane (2×75 mL) and dried to afford the titled compound (18.11 g, 80% yield, purity>96%) as a white solid. LCMS m/z: 375.20 [M−H].

(236) Option B:

(237) To a stirred solution of (S)-methyl-3-nitro-4-(1-(2,2,2-trifluoro-N-methylacetamido)-ethyl)benzoate (Step 3) (84.0 g 251.47 mmol) in THF (1680 mL) was added a solution of K.sub.2CO.sub.3 (208.0 g, 1.508 mmol) in water (740 mL) at 10-15° C. followed by portionwise addition of sodium dithionite (350.0 g, 2011.9 mmol), TBASH (42.62 g, 125.7 mmol) and water (100 mL); after 10 min. an exotherm was observed and the internal temperature reached ˜30° C. The resulting reaction mixture was stirred at RT (20-25° C.) for 3 h. The reaction was monitored by UPLC-MS and after completion; the reaction mixture was left to allow separation of the organic and aqueous layers. The aqueous layer was then extracted with THF (1000 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and then pyridine (202 mL) was added to the filtered organics. The mixture was then evaporated at ˜40° C. under reduced pressure to afford the crude product which was dissolved in DCM (1680 mL) and another portion of pyridine added (202 mL) followed by dropwise addition of ethyl chloroformate (119.7 mL, 1257 mmol) at 10-15° C. The resulting reaction mixture was further stirred at RT for 3 h. UPLC-MS showed completion of the reaction. The reaction mixture was diluted with water (1500 mL), and the layers were separated. The aqueous layer was washed with DCM (1000 mL), and the combined organic layers were washed with 0.5N HCl (2×2000 mL), a saturated solution of NaHCO.sub.3 (1000 mL) and finally with brine (1000 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product (150.0 g) as a yellowish thick oil. The oil was purified by hexane (3×200 mL) to give titled compound (90.0 g, 94% yield, purity>63%) as a faint yellow sticky solid. LCMS m/z: 377.18 [M+H].

Step 5: (S-Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(238) ##STR00202##

(239) To a stirred solution of (S)-methyl-3-((ethoxycarbonyl)amino)-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate (Step 4) (55.0 g 146.0 mmol) in methanol (550 ml) was added K.sub.2CO.sub.3 (40.0 g, 292.0 mmol) at RT and the resulting reaction mixture was heated to 60° C. for 2 h. The progress of the reaction was monitored by UPLC-MS and after completion, the reaction mass was cooled to 5-10° C. and neutralized with 2N HCl (300 mL) to maintain a pH ˜3-4. The solvents were evaporated under reduced pressure at 45° C. to give the crude product which was dissolved in EtOAc (1000 mL), washed successively with a saturated brine solution (50 mL), 2N HCl (500 mL) and NaHCO.sub.3 solution (500 mL), and finally again with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford crude compound (29.1 g) as a brownish solid which was purified by trituration with hexane (3×200 mL) to afford the titled compound (28.9 g, 84% yield, purity>97%) as an off white to pale yellow solid. LCMS m/z: 235.07 [M+H].

Preparation 15: (S)-Methyl-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(240) ##STR00203##

(241) To a stirred solution of (S)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7 carboxylate (Preparation 14) (28.7 g, 122.64 mmol) in DMF (200 ml) was added NaH (5.4 g, 1349 mmol, 60% suspension in oil) followed by 2-chloro-6-fluoro benzyl bromide (18.5 mL, 134.9 mmol) portionwise at 15-20° C. and the whole further stirred at RT for 30 min. UPLC-MS showed completion of the reaction, then the reaction mixture was quenched with crushed ice-water and stirred for 1 h. A solid precipitated, which was filtered and washed with water (500 mL) and hexane (3×400 mL) to obtain the wet product (90.0 g) which was dried in a vacuum oven at 60° C. for overnight to afford the titled compound (40.0 g, 86.7% yield, purity>97.8%) as an off white to pale yellow solid. LCMS m/z: 377.11 [M+H].

Preparation 16: (S)-1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

(242) ##STR00204##

(243) To a stirred solution of (S)-methyl-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 15) (40.0 g, 406.38 mmol) in a mixture of solvents THF:MeOH:water (2:1:1) (800 mL) was added LiOH.H2O (35.7 g, 851 mmol) and the temperature maintained at RT for 3-4 h. The reaction was monitored by UPLC-MS and after completion of the reaction, the solvents ware evaporated under reduced pressure to give the crude product which was diluted with water (3500 mL) and washed with EtOAc (2×500 mL). The aqueous layer was acidified with 6N HCl to maintain a pH ˜2-3. The resulting solid precipitate was faltered and washed with water (500 mL) followed by hexane (1000 mL). The obtained solid was dried in a vacuum oven at 60° C. for overnight to give the titled compound (35.2 g, 91% yield and purity 99.9%) as an off white solid. LCMS m/z: 363.07 [M+H].

Preparation 17: (S)-1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 76)

(244) ##STR00205##

(245) To a stirred solution of (S)-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 16) (35.2 g, 97.23 mmol) in DCM (1400 mL) was added HBTU (44.2 g, 116.6 mmol) followed by TEA (35 mL, 243.0 mmol) at 10-15° C. and stirring was continued for some 5-10 min. 2,4,6-Trifluorobenzylamine (15.6 mL, 106.9 mmol) was added and the reaction maintained at RT for 1 h. The reaction was monitored by UPLC-MS and after completion of the reaction the mixture was diluted with water (1000 mL) and the organic layer was separated, washed with 2N HCl (2×500 mL), NaHCO.sub.3 solution (4×2000 mL) and finally with brine (500 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the crude product (48.0 g) as an off white solid which was purified by crystallization by dissolving in acetone (960 mL) at 40-45° C. to obtain a clear yellowish solution and then activated charcoal (2.4 g) was added and the whole was stirred at 45° C. for 30 min. The resulting mixture was filtered through a G-2 sintered funnel with a celite bed. The bed was washed with acetone (240 mL) to give a clear pale yellowish filtrate, to which n-hexane (3600 mL) was added to give white slurry which was stirred at RT for 1.5 h. The slurry mass was filtered through a Buchner funnel and washed with hexane (500 mL) to afford the wet product as a white solid (41.0 g) which was dried in a vacuum oven at 70° C. for overnight to give titled compound (42.5 g, 88.5% yield, purity 99.9% and chiral purity 100%) as a white solid. LCMS m/z: 506.20 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J=6.55 Hz, 3H), 2.94 (s, 3H), 4.38-4.42 (dd, J, =4.85 Hz, J.sub.2=14.4 Hz, 1H), 4.46-4.50 (dd, J, =5.35 Hz, J.sub.2=14.55 Hz, 1H), 4.51-4.55 (q, J=6.4 Hz, 1H), 4.91 (d, J=15.75 Hz, 1H), 5.55 (d, J=15.8 Hz, 1H), 7.13-7.19 (m, 1H), 7.21 (t, J=7.9 Hz, 3H), 7.28-7.35 (m, 2H), 7.41 (d, J=7.85 Hz, 1H), 7.46 (s, 1H), 8.78 (t, J=5.0 Hz, 1H); Specific rotation [α].sub.D: [−24.27° ] at 25° C.

Example 75: (R)-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,4-tetrahydroquinazoline-7-carboxamide

(246) ##STR00206##

(247) Example 75 was prepared according to the methods described for Example 76, and the methods described below.

Preparation 18: (R)-Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(248) ##STR00207##

Step 1: (R)-methyl-4-(1-(2,2,2-trifluoroacetamido)ethyl)benzoate

(249) ##STR00208##

(250) To a stirred solution of commercially available (R)-methyl-4-(1-aminoethyl)benzoate (1.0 g, 5.58 mmol) in CHCl.sub.3 (10 mL) was added TFAA (2.35 g, 11.17 mmol) at 10-15° C. dropwise and the resulting reaction mixture was stirred at 25° C. for 40 min. The progress of the reaction was monitored by UPLC-MS. The reaction mixture was poured into crushed ice-water and extracted with EtOAc. The combined organic layers were washed successively with saturated NaHCO.sub.3 solution and brine solution and then dried over anhydrous Na.sub.2SO.sub.4. The filtered organics were evaporated under reduced pressure to afford the titled compound (1.4 g, yield 91% and purity>98%) as a white solid. LCMS m/z: 274.05 [M+H].

Step 2: (R)-methyl 3-nitro-4-(1-(2,2,2-trifluoroacetamido)ethyl)benzoate

(251) ##STR00209##

(252) Concentrated sulfuric acid (10 mL) was cooled to 0-5° C. and then added fuming nitric acid (5 mL) dropwise through a dropping funnel to maintain the internal temperature between 0-10° C. over a period of 20 min. Then (R)-methyl-4-(1-(2,2,2-trifluoroacetamido)ethyl)benzoate (Step 1) (1.4 g, 5.09 mmol) was added portionwise over a period of 30 min., maintaining the internal temperature between 0-5 CC. The resulting mixture was stirred at 25° C. for 1 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was poured into an ice-water mixture and extracted with DCM. The combined organic layers were washed with a saturated NaHCO.sub.3 solution followed by a saturated brine solution, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the titled compound (1.5 g, yield 92% and purity>98%) as a white solid. LCMS m/z: 319.05 [M+H].

Step 3: (R)-Methyl-3-nitro-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate

(253) ##STR00210##

(254) To a stirred solution of (R)-methyl-3-nitro-4-(1-(2,2,2-trifluoroacetamido)-ethyl)benzoate (Step 2) (1.4 g, 4.38 mmol) in DMF (15 mL) was added NaH (0.217 g, 60% suspension in oil) portionwise at 0-5° C. The resulting mixture was stirred at RT for 3 h. Completion of the reaction was confirmed by TLC and UPLC-MS and after completion; the mixture was poured into an ice-water mixture and extracted with EtOAc. The organic layer was washed with 1N hydrochloric acid, saturated NaHCO.sub.3 solution and brine solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford titled compound (0.9 g, yield 55% and purity>96%) as crude which was used in the next step without any further purification. LCMS m/z: 335.12 [M+H].

Step 4: (R)-Methyl-R-amino-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate

(255) ##STR00211##

(256) To a stirred solution of (R)-methyl 3-nitro-4-(1-(2,2,2-trifluoro-N-methylacetamido)-ethyl)benzoate (Step 3) (0.9 g, 2.70 mmol) in EtOAc (10 mL) was added 10% Pd—C(0.1 g, 50% w/w in water) under an inert atmosphere. The reaction mixture was stirred for overnight under a H.sub.2 gas balloon pressure. The progress of reaction was monitored by TLC and LCMS and after completion the reaction mixture was filtered through a celite bed under a N.sub.2 atmosphere. The filtrate was dried over sodium sulphate and concentrated under reduced pressure to give the crude compound which was purified by Combi-flash using 30% EtOAc in hexane as eluent to afford titled compound (0.8 g, 97.5% yield and purity>71%) as a white solid. LCMS m/z: 305.09 [M+H].

Step 5: (R)-Methyl-3-((ethoxycarbonyl)amino)-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate

(257) ##STR00212##

(258) To a stirred solution of (R)-methyl 3-amino-4-(1-(2,2,2-trifluoro-N-methylacetamido)-ethyl)benzoate (Step 4) (0.6 g, 1.97 mmol) in DCE (10 mL) was added dry pyridine (0.807 g, 10.22 mmol) at RT under an inert atmosphere. The resulting reaction mixture was stirred at RT for 10 min. then ethyl chloroformate (0.255 g, 2.37 mmol) was added and the whole was further stirred at RT for 1 h. Completion of the reaction was monitored by TLC and LCMS and after completion the mixture was diluted with water and the layer was separated. The aqueous layer was washed with DCM and the combined organic layers were washed with 0.5N HCl, a saturated solution of NaHCO.sub.3 and finally with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by column chromatography to give titled compound (0.4 g, 54% yield and purity>94%) as a white solid. LCMS m/z: 377.24 [M+H].

Step 6: (R)-Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(259) ##STR00213##

(260) To a stirred solution of (R)-methyl 3-((ethoxycarbonyl)amino)-4-(1-(2,2,2-trifluoro-N-methylacetamido)ethyl)benzoate (Step 5) (0.17 g, 0.45 mmol) in a mixture of solvents MeOH and water (6 mL, 2:1) was added K.sub.2CO.sub.3 (0.125 g, 0.90 mmol) at RT and the resulting reaction mixture was heated at 60° C. for 20 min. The reaction mixture was cooled to RT and diluted with a saturated solution of NaHCO.sub.3 and extracted with EtOAc. The organic layer was washed with 1N HCl followed by brine. The organic layer was then dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give titled compound (0.07 g, 66.6% yield and purity>97%) as a white solid.

Example 75: (R)-1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(261) ##STR00214##

(262) Example 75 was prepared from (R)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 18) according to methods described in Preparations 15-17 and General Procedure 1-3. Yield 46%; Purity 98.4%; Chiral purity 99.4%; LCMS m/z: 506.22 [M+H]; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 1.23 (d, J=6.2 Hz, 3H), 2.93 (s, 3H), 4.42-4.46 (m, 2H), 4.50-4.53 (m, 1H), 4.91 (d, J=15.96 Hz, 1H), 5.54 (d, J=15.48, 1H), 7.12-7.20 (m, 4H), 7.29-7.32 (m, 2H), 7.39 (d, J=7.6 Hz, 1H), 7.44 (s, 1H), 8.74 (bs, 1H); Specific rotation [α].sub.D: [+21.170] at 25° C.

Example 77: (S)-1-((5-chloro-3-fluoro-2-methylpyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(263) ##STR00215##

(264) Example 77 was prepared according to the methods described in General Procedures 1-3, and the methods described below.

Preparation 19: 5-Chloro-3-fluoro-2-methylisonicotinic acid

(265) ##STR00216##

(266) To a stirred solution of commercially available 5-chloro-3-fluoro-2-methylpyridine (1.0 g, 6.87 mmol) in dry THF (10 mL) was added n-BuLi (4.12 mL, 8.24 mmol, 2M solution in hexane) dropwise at −78° C. and stirring was continued for further 2 h. The reaction mixture was quenched by the addition of excess dry ice pellets and stirred well for a further 1 h. The reaction mixture was concentrated under reduced pressure to a semi-solid mass, which was dissolved in water (10 mL) and washed with EtOAc (25 mL). The aqueous layer was acidified with N HCl to maintain the pH ˜1 and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give titled compound (1.06 g, 81% yield and purity>96%) as a yellowish solid which was used in the next step without any further purification. LCMS m/z: 189.95 [M+H].

Preparation 20: Methyl-5-chloro-3-fluoro-2-methylisonicotinate

(267) ##STR00217##

(268) To a stirred solution of 5-chloro-3-fluoro-2-methylisonicotinic acid (Preparation 19) (1.05 g, 5.54 mmol) in DMF (11 mL) was added K.sub.2CO.sub.3 (1.531 g, 11.08 mmol) followed by Me.sub.2SO.sub.4 (0.838 g, 6.65 mmol) at 0-5° C. and then the reaction mixture was stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with cold water, extracted with EtOAc and washed with brine. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give titled compound (0.95 g, 84% yield and purity>96%) as a reddish brown liquid which was used in the next step without any further purification. LCMS m/z: 203.98 [M+H].

Preparation 21: (5-Chloro-3-fluoro-2-methylpyridin-4-yl)methanol

(269) ##STR00218##

(270) To a stirred solution of methyl-5-chloro-3-fluoro-2-methylisonicotinate (Preparation 20) (0.85 g, 4.18 mmol) in dry THF (12 mL) was added DIBAL-H (16.67 mL, 1M solution in hexane) dropwise at 0-5° C. and the whole reaction mixture was stirred at room temperature for 6 h. After completion of the reaction, it was quenched with a solution of sodium potassium tartrate. The quenched reaction mixture was extracted with EtOAc, washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to give the crude product which was purified by prep-HPLC to afford titled compound (0.25 g, 34% yield and purity>99%) as a white solid. LCMS m/z: 175.98 [M+H].

Preparation 22: 4-(Bromomethyl)-5-chloro-3-fluoro-2-methylpyridine

(271) ##STR00219##

(272) To a stirred solution of (5-chloro-3-fluoro-2-methylpyridin-4-yl)methanol (Preparation 21) (0.06 g, 0.34 mmol) in dry THF (2 mL) was added PBr.sub.3 (0.081 mL, 0.85 mmol) at −10° C. The whole was stirred at RT for 2 h. After completion of the reaction the mixture was poured into ice water and extracted with EtOAC. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give titled compound (0.075 g, 81.5% yield and purity>92%) as a yellowish liquid which was used in the next step without any further purification. LCMS m/z: 237.89 [M+H].

Preparation 23: 4-(Chloromethyl)-3-fluoro-5-methoxy-2-methylpyridine

(273) ##STR00220##

(274) To a stirred solution of (3-fluoro-5-methoxy-2-methylpyridin-4-yl)methanol (Preparation 21) (0.080 g, 0.47 mmol) in dry DCM (1 mL) was added TEA (0.195 mL, 0.14 mmol) followed by MeSO.sub.2Cl (0.0831 g, 0.70 mmol) at 0-5° C. and the mixture then stirred for overnight at RT. The reaction was monitored by TLC and LCMS and after consumption of the starting material; the reaction mixture was diluted with DCM and washed with cold water and then brine. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give titled compound (0.08 g, 90% yield, purity>77%) as a light yellow liquid which was used in the next step without any further purification. LCMS m/z: 189.99 [M+H].

(275) The following intermediates were synthesized according to similar methods to those described above in Preparations 19-23) starting from the appropriate substituted pyridine.

(276) TABLE-US-00005 Structure IUPAC Name 4-(bromomethyl)-3- fluoro-2-methylpyridine 4-(bromomethyl)-3,5- difluoropyridine 4-(bromomethyl)-5- fluoro-2-methylpyridine 4-(chloromethyl)-3- fluoro-5-methoxy-2- methylpyridine 5-chloro-4- (chloromethyl)-3-fluoro- 2-methoxypyridine 2-(chloromethyl)-3- fluoro-6-methylpyridine

Example 77: (S)-1-((5-chloro-3-fluoro-2-methylpyridin-4-yl)methyl)-2,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,34-tetrahydroquinazoline-7-carboxamide

(277) ##STR00227##

(278) (S)-1-((5-chloro-3-fluor-2-methylpyridin-4-yl)methyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 77) was prepared from (S)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 14, Step 5) and 4-(bromomethyl)-5-chloro-3-fluoro-2-methylpyridine (Preparation 22) according to the methods described in Preparations 2, 3 and 4 and General Procedures 1-3. LCMS m/z: 521.13 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.24 (d, J=6.5 Hz, 3H), 2.35 (d, J=2.9 Hz, 3H), 2.93 (s, 3H), 4.44-4.45 (m, 2H), 4.56-4.57 (m, 1H), 5.0 (d, J=16.15 Hz, 1H), 5.45 (d, J=16.25 Hz, 1H), 7.18-7.24 (m, 3H), 7.40-7.45 (m, 2H), 8.37 (s, 1H), 8.81 (t, J=4.8 Hz, 1H).

Example 78: (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(279) ##STR00228##

(280) Example 78 was prepared according to the methods described in General Procedures 1-3 and 13, and the methods described below.

Preparation 24: (S)-1-(2,6-Difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 79)

(281) ##STR00229##

(282) To a stirred solution of (S)-1-(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 52) (0.7 g, 1.86 mmol) in DCM (70 mL) was added HBTU (0.846 g, 2.23 mmol) followed by addition of TEA (0.67 mL, 4.65 mmol) at 10-15° C. and stirring was continued for a further 15 min. 2,4,6-Trifluorobenzylamine (0.299 mL, 2.04 mmol) was added at RT and the whole was stirred at RT for 1 h. The reaction was monitored by UPLC-MS and after completion of the reaction, the mixture was diluted with water (50 mL), the organic layer was separated, washed with 2N HCl (2×25 mL), followed by NaHCO.sub.3 solution (4×5 mL) and finally with brine (25 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by Combi-flash to afford titled compound (0.07 g, 82% yield and purity 99.6%) as an off white solid. LCMS m/z: 520.17 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.15 Hz, 3H), 2.94 (bs, 3H), 3.73 (bs, 3H), 4.39-4.43 (m, 1H), 4.47-4.51 (m, 2H), 4.73 (d, J=15.7 Hz, 1H), 5.55 (d, J=15.7 Hz, 1H), 6.67 (d, J=9.9 Hz, 2H), 7.18-7.23 (m, 3H), 7.40 (d, J=7.55 Hz, 1H), 7.44 (s, 1H), 8.81 (bs, 1H).

Preparation 25: (S)-1-(2,6-Difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 78)

(283) ##STR00230##

(284) To a stirred solution of (S)-1-(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 79) (0.5 g, 0.96 mmol) in DCM (25 mL) was added BBr.sub.3 (5 mL, 1.0M solution in DCM) and the mixture stirred at RT for 2 h. The reaction was monitored by UPLC-MS and after completion of the reaction the mixture was diluted with DCM (100 mL) and water (100 mL). The organic layer was separated and washed with NaHCO.sub.3 solution (50 mL) followed by brine (50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by Combi-flash to give titled compound (0.4 g, 82% yield and purity 99.6%) as a white solid. LCMS m/z: 5006.18 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.15 (d, J=5.9 Hz, 3H), 2.93 (bs, 3H), 4.39-4.42 (m, 1H), 4.48-4.51 (m, 2H), 4.67 (d, J=15.7 Hz, 1H), 5.51 (d, J=15.3 Hz, 1H), 6.38 (d, J=9.65 Hz, 2H), 7.17-7.22 (m, 3H), 7.39 (d, J=7.45 Hz, 1H), 7.43 (s, 1H), 8.79 (bs, 1H), 10.34 (s, 1H).

(285) Examples 80 and 81 were prepared according to the methods described in General Procedures 14, and the methods described below.

Example 80: (S)-1-(2,6-difluoro-4-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,4-tetrahydroquinazoline-7-carboxamide

(286) ##STR00231##

Preparation 26: (S)-Ethyl-2-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)acetate

(287) ##STR00232##

(288) To a stirred solution of (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 78) (0.05 g, 0.099 mmol) in DMF (2 mL) was added NaH (0.0047 g, 0.12 mmol, 50% suspension in oil) at 0-5° C. and the resulting mixture was stirred at the same temperature for 10 min., then ethyl bromoacetate (0.0198 g, 0.12 mmol) was added at 0-5° C. and the reaction mixture was further stirred for 40 min. The course of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with a saturated solution of NH.sub.4Cl, extracted with EtOAc and washed with brine. The collected organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give titled compound (0.05 g, 85% yield and purity 98.8%) as an off white solid which was used in the next step without any further purification. LCMS m/z: 592.17 [M+H].

Preparation 27: (S)-1-(2,6-Difluoro-4-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 80)

(289) ##STR00233##

(290) To a stirred solution of (S)-ethyl-2-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)acetate (Preparation 26) (0.06 g, 0.10 mmol) in ethanol (2 mL) was added NaBH.sub.4 (0.0306 g, 0.81 mmol) at 0-5° C. The reaction mixture was then stirred at RT for 3 h. The course of the reaction was monitored by TLC and LCMS and after completion of the reaction the mixture was quenched with a saturated solution of NH.sub.4Cl, extracted with EtOAc and washed with brine. The organic layer was concentrated under reduced pressure to give the crude product which was purified by column chromatography to afford titled compound (0.024 g, 43% yield and purity 96.8%) as a white solid. LCMS m/z: 550.16 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.45 Hz, 3H), 2.94 (s, 3H), 3.64-3.67 (q, J=5.05 Hz, 2H), 3.96 (t, J=4.7 Hz, 2H), 4.39-4.52 (m, 3H), 4.74 (d, J=15.6 Hz, 1H), 4.88 (t, J=5.45 Hz, 1H), 5.52 (d, J=15.65 Hz, 1H), 6.66 (d, J=10.05 Hz, 2H), 7.18-7.23 (m, 3H), 7.40 (d, J=7.75 Hz, 1H), 7.45 (s, 1H), 8.80 (t, J=4.75 Hz, 1H).

Example 81: (S)-1-(2,6-difluoro-4-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(291) ##STR00234##

(292) To a stirred solution of (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 78) (0.050 g, 0.099 mmol) in DMF (2 mL) was added K.sub.2CO.sub.3 (0.041 g, 0.29 mmol) followed by addition of 3-bromopropanol (0.018 mL, 0.198 mmol) and the whole heated at 60° C. for overnight. After completion of the reaction the mixture was diluted with water and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to provide the crude product which was purified by Combi-flash (4.0 g column) using 90% EtOAc in hexane as eluent to give titled compound (0.017 g, 30.9% yield and purity 99.5%) as a white solid. LCMS m/z: 564.19 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.15 (d, J=4.7 Hz, 3H), 1.80 (bs, 2H), 2.94 (s, 3H), 3.50-3.51 (m, 2H), 3.99 (bs, 2H), 4.39-4.42 (m, 1H), 4.48-4.56 (m, 3H), 4.73 (d, J=15.6 Hz, 1H), 5.53 (d, J=15.45 Hz, 1H), 6.65 (d, J=9.45 Hz, 2H), 7.19-7.21 (m, 3H), 7.39-7.45 (m, 2H), 8.80 (bs, 1H).

(293) Example 82 was prepared according to the methods described in General Procedure 15, and the methods described below.

Example 82: (S)-3-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)propyl dihydrogen phosphate

(294) ##STR00235##

(295) (S)-1-(2,6-difluoro-4-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 81) (0.32 g, 0.56 mmol) was taken up in neat POCl.sub.3 (0.48 mL, 5.11 mmol) at 0° C. and then the reaction mixture was slowly allowed to come to RT over 1 h. Completion of the reaction was monitored by TLC and after complete conversion of the starting material, the reaction mixture was dissolved in MeCN (1.5 mL) and a mixture of silver nitrate (0.192 g, 1.13 mmol) in water (3 mL) was added dropwise at 0-5° C. The resulting reaction mixture was further stirred for 1 h at the same temperature and then kept in the refrigerator for 18 h to afford a solid which was filtered and the filtrate evaporated under reduced pressure to afford the crude product which was purified by prep-HPLC to give titled compound (0.15 g, 41% yield and purity 99.3%) as a pale yellow solid. LCMS m/z: 644.11 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.3 Hz, 3H), 1.97 (t, J=5.9 Hz, 2H), 2.93 (s, 3H), 4.02-3.92 (m, 5H), 4.52-4.38 (m, 4H), 4.74 (d, J=15.7 Hz, 1H), 5.53 (d, J=15.7 Hz, 1H), 6.67 (d, J=9.9 Hz, 2H), 7.24-7.18 (m, 3H), 7.40 (d, J=7.7 Hz, 1H), 7.45 (s, 1H), 8.81 (bs, 1H).

(296) Example 83 was prepared according to the methods described in General Procedure 16, and the methods described below.

Example 83: (S)-(4-(((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)methyl dihydrogen phosphate

(297) ##STR00236##

Preparation 28: (S)-Dibenzyl-((4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)methyl) phosphate

(298) ##STR00237##

(299) To a stirred solution of (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 78) (0.15 g, 0.30 mmol) in dry DMF (2 mL) was added K.sub.2CO.sub.3 (0.0615 g, 00.44 mmol) and after 15 min. dibenzyl (chloromethyl) phosphate (0.106 g, 0.327 mmol) was added under a N.sub.2 atmosphere. The reaction mixture was stirred at 60° C. for 3 h. After completion of the reaction the mixture was diluted with EtOAc and washed with water followed by brine solution. The organic layer was then dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness under reduced pressure to give the crude product which was purified by Prep-HPLC to afford titled compound (0.09 g, 38% yield and purity>99%) as a white solid. LCMS m/z: 796.24 [M+H].

Preparation 29: (S)-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)methyl dihydrogen phosphate (Example 83)

(300) ##STR00238##

(301) To a stirred solution of (S)-dibenzyl ((4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)methyl) phosphate (Preparation 28) (0.07 g, 0.14 mmol) in THF (2 mL) was added 10% Pd—C(0.03 g, 50% w/w in water) at RT under an inert atmosphere. The resulting mixture was stirred at RT for 15 min. under H.sub.2 gas balloon pressure and after completion of the reaction the mixture was diluted with EtOAc and passed through a short bed of celite. The filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by Prep-HPLC to afford titled compound (0.028 g, 51.8% yield and purity>99%) as a white solid. LCMS m/z: 616.14 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.0 Hz, 3H), 2.93 (s, 3H), 4.51-4.39 (m, 3H), 4.74 (d, J=15.9 Hz, 1H), 5.32 (t, J=7.1 Hz, 2H), 5.52 (d, J=15.5 Hz, 1H), 6.80 (d, J=10 Hz, 2H), 7.25-7.17 (m, 3H), 7.38 (d, J=7.7 Hz, 1H), 7.46 (s, 1H), 8.81 (bs, 1H).

Example 84: (S)-4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl dihydrogen phosphate

(302) ##STR00239##

(303) Example 84 was prepared according to the methods described in General Procedure 17, and the methods described below.

Preparation 30: (S)-Dibenzyl (4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl) phosphite

(304) ##STR00240##

(305) To a stirred solution of (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 78) (0.15 g, 0.30 mmol) in dry acetonitrile (5 mL) was added tetrazole (0.026 mL, 0.30 mmol) followed by dibenzyl-diisopropylphosphoramidite (0.20 mL, 0.71 mmol) under an inert atmosphere and the mixture allowed to stir at RT for 3 h. The course of the reaction was monitored by TLC and LCMS and after completion, the reaction mixture was evaporated under reduced pressure to dryness to give titled compound (0.21 g, 95% yield and purity>66%) as crude which was used in the next step without any further purification. LCMS m/z: 750.21 [M+H].

Preparation 31: (S)-Dibenzyl-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl) phosphate

(306) ##STR00241##

(307) To a stirred solution of (S)-dibenzyl-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl) phosphite (Preparation 30) (0.21 g, 0.28 mmol) in DCM (8 mL) was added m-CPBA (0.077 g, 0.45 mmol) at 0-5° C. under an inert atmosphere and the reaction mixture was then stirred at 0-5° C. for 1 h. The course of the reaction was monitored by TLC and LCMS and after completion; the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give titled compound (0.1 g, 93% yield and purity>98%) as crude which was used in the next step without any further purification. LCMS m/z: 766.20 [M+H].

Preparation 32: (S)-4-((3,4-Dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl dihydrogen phosphate (Example 84)

(308) ##STR00242##

(309) To a stirred solution of (S)-dibenzyl-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl) phosphate (Preparation 31) (0.1 g, 0.13 mmol) in dry THF (4 mL) was added 10% Pd—C(0.001 g, 50% w/w in water) under an inert atmosphere and the resulting reaction mixture was stirred at RT overnight under a H.sub.2 gas balloon pressure. The course of the reaction was monitored by TLC and LCMS and after completion, the reaction mixture was diluted with EtOAc and filtered carefully through a celite bed and washed twice with EtOAc under an inert atmosphere. The collected organic were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by prep-HPLC to provide titled compound (0.04 g, 40% yield and purity 99.36%) as a white solid. LCMS m/z: 586.12 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=5.2 Hz, 3H), 2.93 (s, 3H), 4.50-4.40 (m, 3H), 4.72 (d, J=15.6 Hz, 1H), 5.52 (d, J=15.4 Hz, 1H), 6.80 (d, J=10.4 Hz, 2H), 7.23-7.16 (m, 3H), 7.38 (d, J=7.3 Hz, 1H), 7.47 (s, 1H), 8.78 (s, 1H).

(310) Example 85 was prepared according to the methods described in General Procedure 18, and the methods described below.

Example 85: (S)-4-Acetamidobenzyl-(4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenyl) carbonate

(311) ##STR00243##

(312) To a stirred solution of (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 78) (0.05 g, 0.099 mmol) in DMF (2 mL) was added NaH (0.003 g, 60% w/w in mineral oil) at 0-5° C. and the reaction mixture was stirred for 15 min. at the same temperature. Then, separately synthesized 4-acetamidobenzyl-(4-nitrophenyl)-carbonate (preparation described in US 1996/5585397) (0.1 g, 0.30 mmol) was dissolved in DMF (2 mL) and added to the reaction mixture and the whole stirred at RT for 30 min. Progress of the reaction was monitored by TLC and LCMS and after completion of the reaction the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude compound which was purified by prep-HPLC to afford titled compound (0.015 g, 21.7% yield and purity 99.75%) as a white solid. LCMS m/z: 697.19 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J=6.0 Hz, 3H), 2.05 (s, 3H), 2.93 (s, 3H), 4.43-4.39 (m, 1H), 4.55-447 (m, 2H), 4.86 (d, J=15.8 Hz, 1H), 5.19 (s, 2H), 5.52 (d, J=15.8 Hz, 1H), 7.22-7.15 (m, 5H), 7.37-7.30 (m, 2H), 7.42 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.60 (d, J=7.9 Hz, 2H), 8.82 (bs, 1H), 10.05 (s, 1H).

(313) Example 86 was prepared according to the methods described in General Procedure 19, and the methods described below.

Example 86: (S)-Benzyl-3-(((4-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-3,5-difluorophenoxy)carbonyl)(methyl)amino)propanoate

(314) ##STR00244##

(315) To a stirred solution of (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 78) (0.040 g, 0.079 mmol) in DMF (0.4 mL) was added NaH (0.0095 g, 60% w/w in mineral oil) at 0-5° C. and the reaction mixture was stirred for 15 min. at the same temperature. Then, separately synthesized benzyl-3-(methyl((4-nitrophenoxy)carbonyl)amino)-propanoate (Syn. Comm. 2007, 37, 1927) (0.034 g, 0.095 mmol) in DMF (0.2 mL) was added into the reaction mixture and the whole heated at 80° C. for 20 h. Progress of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with NaHCO.sub.3 and brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude compound which was purified by prep-HPLC to afford titled compound (0.022 g, 38% yield and purity 99.78%) as a white solid. LCMS m/z: 725.19 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J=6.2 Hz, 3H), 2.67 (t, J=6.8 Hz, 1H), 2.75 (t, J=6.7 Hz, 1H), 2.88 (s, 1H), 2.93 (s, 3H), 2.97 (s, 2H), 3.52 (t, J=6.9 Hz, 1H), 3.62 (t, J=6.7 Hz, 1H), 4.42-4.38 (m, 1H), 4.53-4.46 (m, 2H), 4.83 (d, J=15.7 Hz, 1H), 5.09 (d, J=5.7 Hz, 2H), 5.54 (d, J=15.9 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.22-7.18 (m, 3H), 7.37-7.33 (m, 5H), 7.42 (d, J=7.6 Hz, 1H), 7.47 (bs, 1H), 8.82 (s, 1H).

Example 87: (S)-1-(2-Chloro-6-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(316) ##STR00245##

(317) Example 87 was prepared according to the methods described in General Procedures 1-2 and 13, and the methods described below.

Preparation 33: (S)-Methyl-1-(2-chloro-6-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(318) ##STR00246##

(319) A stirred solution of (S)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 14, Step 5) (0.28 g, 1.19 mmol) in DMF (5 ml) was cooled to 15-20° C. with a cold water bath and NaH (0.053 g, 1.31 mmol) was then added portionwise. After the addition was complete, 2-chloro-6-fluoro-3-methoxy-benzyl bromide (0.331 g, 1.31 mmol) was then added. The resulting mixture was maintained at 20-25° C. for 30 min. Progress of the reaction was monitored by UPLC-MS and after completion the mixture was quenched by pouring into a crushed ice/water mixture (100 mL) and the whole stirred for 30 min. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give the crude product which was purified by Combi-flash (24.0 g column) and eluted with 74% EtOAc in hexane as eluent to afford titled compound (0.448 g, 92% yield and purity>95%) as a white solid. LCMS m/z: 407 [M+H].

Preparation 34: (S)-1-(2-Chloro-6-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

(320) ##STR00247##

(321) To a stirred solution of(S)-methyl 1-(2-chloro-6-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 33) (0.448 g, 1.10 mmol) in THF/MeOH/water (10 mL, 2:1:1) was added LiOH (0.37 g, 8.82 mmol) at RT and the whole maintained at the same temperature for another 3 h. The reaction was monitored by UPLC-MS and after completion, the solvents ware evaporated under reduced pressure to give the crude which was diluted with water and washed with diethyl ether (2×20 mL). The aqueous layer was cooled in ice water to ˜10-15 OC and acidified with 6N HCl to pH-2-3. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford titled compound (0.4 g, 92.5% yield and purity>95%) as an off white solid which was used in the next step without any further purification. LCMS m/z: 393 [M+H].

Preparation 35: (S)-1-(2-Chloro-6-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 88)

(322) ##STR00248##

(323) To a stirred solution of (S)-1-(2-chloro-6-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 34) (0.4 g, 1.02 mmol) in DCM (20 mL) was added HBTU (0.464 g, 1.22 mmol) followed by TEA (0.368 mL, 2.55 mmol) at 10-15° C. and the whole was stirred for 5 min. 2,4,6-trifluorobenzylamine (0.164 mL, 1.12 mmol) was then added and the temperature maintained at RT for 1 h. The progress of the reaction was monitored by UPLC-MS and after completion the reaction mixture was diluted with water (100 mL) and the separated organic layer was washed with 2N HCl, followed by saturated NaHCO.sub.3 solution and finally with brine solution. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford titled compound (0.52 g, 98% yield and purity 99.8%) as an off white solid which was used in the next step without any further purification. LCMS m/z: 536.13 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J=6.4 Hz, 3H), 2.94 (s, 3H), 3.81 (s, 3H), 4.38-4.49 (m, 2H), 4.50-4.53 (m, 1H), 4.90 (d, J=15.75 Hz, 1H), 5.54 (d, J=15.7 Hz, 1H), 7.05-7.07 (m, 1H), 7.10-7.14 (m, 1H), 7.19-7.22 (m, 3H), 7.40 (d, J=7.8 Hz, 1H), 7.44 (s, 1H), 8.77 (bs, 1H).

Preparation 36: (S)-1-(2-Chloro-6-fluoro-3-hydroxybenzyl)-4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,4-tetrahydroquinazoline-7-carboxamide (Example 87)

(324) ##STR00249##

(325) To a stirred solution of (S)-1-(2-chloro-6-fluoro-3-methoxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 88) (2.0 g, 3.74 mmol) in DCM (20 mL) was added BBr.sub.3 (9.345 mL, 9.35 mmol, 1M solution in DCM) at 0-25° C. and the reaction mixture was stirred for 1 h. Progress of the reaction was monitored by TLC and LCMS and after completion of the reaction the mixture was quenched with a saturated solution of NaHCO.sub.3 and extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCO.sub.3, brine and dried over anhydrous Na.sub.2SO.sub.4. The solvent was concentrated under reduced pressure to afford the crude product which was purified by prep-HPLC to give titled compound (1.1 g, 56.45% yield and purity 99.5%) as a white solid. LCMS m/z: 522.15 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J=6.55 Hz, 3H), 2.94 (s, 3H), 4.38-4.41 (m, 1H), 4.46-4.54 (m, 2H), 4.86 (d, J=15.75 Hz, 1H), 5.52 (d, J=15.75 Hz, 1H), 6.84-6.87 (m, 1H), 6.95 (t, J=9.45 Hz, 1H), 7.18-7.22 (m, 3H), 7.39 (d, J=7.75 Hz, 1H), 7.43 (s, 1H), 8.77 (t, J=4.8 Hz, 1H), 10.15 (bs, 1H).

Example 89: (S)-2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-ylmethyl-4-fluorophenyl dihydrogen phosphate

(326) ##STR00250##

(327) Example 89 was prepared according to the methods described in General Procedure 17, and the methods described below.

Preparation 37: (S)-Dibenzyl-(2-chloro-3-((3,4-dimethyl-2-oxo-7-(2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl-4-fluorophenyl) phosphate

(328) ##STR00251##

(329) To a stirred solution of (S)-1-(2-chloro-6-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 87) (0.15 g, 0.28 mmol) in acetonitrile (10 mL) was added DMAP (0.004 g, 0.031 mmol) followed by CCl.sub.4 (0.22 mL, 1.43 mmol) and DIPEA (0.11 mL, 0.60 mmol) under an inert atmosphere at 0-10° C. The resulting reaction mixture was stirred at the same temperature for 15 min., then diphenyl phosphite (0.144 mL, 0.414 mmol) was added and the mixture maintained at 0-10° C. for 2 h. UPLC-MS showed completion of the reaction, which was quenched with an aqueous solution of dipotassium hydrogen phosphate and extracted with EtOAc, dried and evaporated under reduced pressure to afford the crude product which was purified by Combi-flash (20 g column, pre-neutralized with EtOAc:hexane:TEA (50:50:1) using 70% EtOAc in hexane as eluant to afford titled compound (0.2 g, 89% yield and purity>94%) as a white solid. LCMS m/z: 782 [M+H].

Preparation 38: (S)-2-Chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl-4-fluorophenyl dihydrogen phosphate (Example 89)

(330) ##STR00252##

(331) To a stirred solution of (S)-dibenzyl-(2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenyl) phosphate (Preparation 37) (0.18 g, 0.23 mmol) in THF (10 mL) was added 10% Pd—C (0.05 g, 50% w/w in water) under an inert atmosphere at RT and the whole was stirred under H.sub.2 gas balloon pressure for 1 h. After completion of the reaction (monitored by LCMS or TLC) the mixture was filtered through a celite bed and washed carefully with THF under a N.sub.2 gas atmosphere. The solvent was evaporated under reduced pressure to give the crude product which was purified by prep-HPLC using ammonium acetate buffer to afford titled compound (0.055 g, 40% yield and purity 99.8%) as a white solid. LCMS m/z: 602.2 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6+D2O): δ 1.22 (s, 3H), 2.94 (s, 3H), 4.50-4.42 (m, 3H), 4.87 (d, J=14.9 Hz, 1H), 5.52 (d, J=15.3 Hz, 1H), 6.98 (s, 1H), 7.52-7.19 (m, 7H), 8.78 (s, 1H).

Example 90: (S)-(2-Chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl-4-fluorophenoxy)methyl dihydrogen phosphate

(332) ##STR00253##

(333) Example 90 was prepared according to the methods described in General Procedure 16, and the methods described below.

Preparation 39: (S)-dibenzyl ((2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)methyl) phosphate

(334) ##STR00254##

(335) To a stirred solution of (S)-1-(2-chloro-6-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 87) (0.15 g, 0.29 mmol) in dry DMF (3 mL) was added K.sub.2CO.sub.3 (0.079 g, 0.58 mmol) at 0-5° C. under a N.sub.2 gas atmosphere in a sealed tube. Then after 15 min. dibenzyl (chloromethyl) phosphate (0.113 g, 0.35 mmol) was added and the resulting reaction mixture was stirred at 60° C. for 5 h. After completion of the reaction (monitored by TLC and LCMS) it was cooled to RT and poured into cold water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness to give titled compound (0.165 g, 70% yield and purity 95%) as a yellowish solid which was used in the next step without any further purification. LCMS m/z: 812.21 [M+H].

Preparation 40: (S)-(2-Chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)methyl dihydrogen phosphate (Example 90)

(336) ##STR00255##

(337) To a stirred solution of (S)-dibenzyl ((2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)-methyl) phosphate (Preparation 39) (0.165 g, 0.20 mmol) in THF (3 mL) was added 10% Pd/C (80 mg, 50% w/w in water) under a N.sub.2 gas atmosphere. The resulting reaction mixture was stirred under H.sub.2 gas balloon pressure at RT for another 15 min. After completion of the reaction (monitored by UPLC-MS) the mixture was diluted with EtOAc and passed through a celite bed. The collected filtrate was evaporated under reduced pressure to give the crude product which was purified by prep-HPLC to give titled compound (0.028 g, 22% yield and purity>98%) as a white solid. LCMS m/z: 632.04 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.22 (s, 3H), 2.93 (s, 3H), 4.51-4.39 (m, 3H), 4.90 (d, J=15.3 Hz, 1H), 5.38 (d, J=6.6 Hz, 2H), 5.51 (d, J=15.6 Hz, 1H), 7.08 (t, J=9.0 Hz, 2H), 7.20 (bs, 3H), 7.38 (bs, 2H), 7.47 (s, 1H), 8.79 (s, 1H).

(338) Following the same procedures described in Preparations 37-40, several phosphate-containing Examples were synthesised as shown in the following tables. The Examples from which the phosphates were derived are indicated in the tables.

(339) TABLE-US-00006 Ex. (de- rived LCMS from) Structure IUPAC name NMR [M + H] Ex 91(Ex. 242) (S)-2-(2-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-3,4- difluorophenoxy) ethyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.16 (d, J = 5.85 Hz, 3H), 2.95 (s, 3H), 3.95 (s, 1H), 4.02-4.07 (m, 2H), 4.12 (s, 1H), 4.42 (s, 2H), 4.50 (s, J = 6.2 Hz, 1H), 4.92 (d, J = 15.65 Hz, 1H), 5.53 (d, J = 16.2 Hz, 1H), 6.80 (d, J = 8.55 Hz, 1H), 7.12-7.15 (m, 3H), 7.19-7.24 (m, 1H), 7.34 (d, J = 7.75 Hz, 1H), 7.49 (s, 1H), 9.13 (bs, 1H) 628.12 [M −H] Ex 92(Ex. 181) (S)-4-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-3- fluorophenyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.25 (d, J = 6.25 Hz, 3H), 2.96 (s, 3H), 4.41 (s, 2H), 4.60 (d, J = 6.35 Hz, 1H), 4.97 (d, J = 16.55 Hz, 1H), 5.22 (d, J = 16.7 Hz, 1H), 6.87 (d, J = 5.55 Hz, 1H), 6.97-7.00 (m, 1H), 7.05 (d, J = 10.45 Hz, 1H), 7.17-7.19 (m, 2H), 7.23 (d, J = 7.75 Hz, 1H), 7.28 (s, 1H), 7.43 (d, J = 7.75 Hz, 566.16 [M −H] 1H), 8.84 bs, 1H). Ex 93(Ex 253) (S)-2-((1-(2- chloro-6- fluorobenzyl)- 3,4-dimethyl-2- oxo-1,2,3,4- tetrahydroquin- azoline-7-carboxa- mido)methyl)-5- fluorophenyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.23 (d, J = 5.8 Hz, 3H), 2.95 (s, 3H), 4.39 (s, 2H), 4.51 (s, 1H), 4.97 (d, J = 16.00 Hz, 1H), 5.49 (d, J = 15.10 Hz, 1H), 6.80 (s, 1H), 6.98-7.30 (m, 6H), 7.59 (s, 1H), 7.66 (s, 1H), 10.08 (s, 1H). 566.12 Ex 94(Ex 275) (S)-3-(2-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-3,5- difluorophenoxy) propyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.22 (d, J = 6.45 Hz, 3H), 1.86 (t, J = 6.05 Hz, 2H), 2.97 (s, 3H), 3.73 (d, J = 6.65 Hz, 2H), 3.95-3.99 (m, 2H), 4.44 (s, 2H), 4.56 (t, J = 6.45 Hz, 1H), 4.93 (d, J = 16.05 Hz, 1H), 5.40 (d, J = 16.55 Hz, 1H), 7.12-7.25 (m, 5H), 7.43 (t, J = 11.7 Hz, 2H), 9.24 (s, 1H) 644.16 Ex 95(Ex 137) 0 (S)-2-(2-chloro- 3-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-4- fluorophenoxy) ethyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6 + D.sub.2O): δ 1.21 (s, 3H), 2.91 (s, 3H), 3.95 (d, J = 8.0 Hz, 2H), 4.07 (d, J = 4.8 Hz, 2H), 4.37 (d, J = 14.4 Hz, 1H), 4.45-4.50 (m, 2H), 4.87 (d, J = 15.8 Hz, 1H), 5.51 (d, J = 15.85 Hz, 1H), 7.02- 7.12 (m, 4H), 7.18 (d, J = 7.85 Hz, 1H), 7.34- 7.36 (m, 1H), 7.40 (s, 1H), 646.05 Ex 96(Ex 138) (S)-3-(2-chloro- 3-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-4- fluorophenoxy) propyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.21 (d, J = 6.5 Hz, 3H), 1.92-1.97 (m, 2H), 2.93 (s, 3H), 3.83 (dd, J′ = 6.2 Hz, J″ = 12.95 Hz, 2H), 4.04 (dd, J′ = 5.95 Hz, J″ = 9.8 Hz, 2H), 4.38-4.41 (m, 1H), 4.46-4.53 (m, 2H), 4.91 (d, J = 15.65 Hz, 1H), 5.51 (d, J = 15.75 Hz, 1H), 7.04- 7.08 (m, 2H), 7.17- 7.20 (m, 3H), 7.39 (d, J = 7.75 Hz, 1H), 7.46 (s, 1H), 8.72 (d, J = 4.95 Hz, 1H). 660.08 Ex 97(Ex 80) (S)-2-(4-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-3,5- difluorophenoxy) ethyl dihydrogen phosphate (400 MHz; DMSO- d.sub.6): δ 1.16 (d, J = 6.2 Hz, 3H), 2.93 (s, 3H), 4.09 (d, J = 22.8 Hz, 3H), 4.43 (bs, 2H), 4.52-4.39 (m, 3H), 4.75 (d, J = 15.7 Hz, 1H), 5.51 (d, J = 15.6 Hz, 1H), 6.69 (d, J = 9.8 Hz, 2H), 7.46-7.17 (m, 5H), 8.76 (s, 1H) 630.07 Ex 98(Ex 298) (S)-3-chloro-4- ((3,4-dimethyl- 2-oxo-7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-5- fluorophenyl dihydrogen phosphate (500 MHz; DMSO- d6): δ 1.22 (d, J = 5.8 Hz, 3H), 2.93 (s, 3H), 4.41 (d, J = 10.25 Hz, 1H), 4.50-4.51 (m, 2H), 4.79 (d, J = 15.45 Hz, 1H), 5.49 (d, J = 15.5 Hz, 1H), 6.91 (d, J = 12.3 Hz, 1H), 7.07 (s, 1H), 7.17-7.23 (m, 3H), 7.38 (d, J = 7.35 Hz, 1H), 7.50 (s, 1H), 8.76 (s, 1H). 600 [M −H] Ex 99(Ex 242) (S)-2-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-3,4- difluorophenyl dihydrogen phosphate (500 MHz; DMSO- d6): δ 1.24 (d, J = 5.75 Hz, 3H), 2.97 (s, 3H), 4.35 (s, 2H), 4.58 (s, 1H), 5.17 (d, J = 17.3 Hz, 1H), 5.54 (d, J = 17.0 Hz, 1H), 7.05-7.19 (m, 5H), 7.43 (d, J = 7.5 Hz, 1H), 7.74 (s, 1H), 9.87 (s, 1H). 584.19 [M − H] Ex 100(Ex 251) (S)-2-((1-(2- chloro-6- fluorobenzyl)- 3,4-dimethyl-2- oxo-1,2,3,4- tetrahydroquin- azoline-7-carboxa- mido)methyl)-3- fluorophenyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.22 (d, J = 6.4 Hz, 3H), 2.95 (s, 3H), 4.49-4.55 (m, 3H), 4.94 (d, J = 15.5 Hz, 1H), 5.51 (d, J = 15.5 Hz, 1H), 6.98 (d, J = 8.55 Hz, 1H), 6.99- 7.16 (m, 3H), 7.28- 7.34 (m, 3H), 7.47 (d, J = 6.75 Hz, 1H), 7.56 (s, 1H), 9.29 (bh, 1H). 566.16 Ex 101(Ex 252) (S)-4-((1-(2- chloro-6- fluorobenzyl)- 3,4-dimethyl-2- oxo-1,2,3,4- tetrahydroqin- azoline-7- carboxamido) methyl)-3,5- difluorophenyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.23 (d, J = 6.5 Hz, 3H), 2.93 (s, 3H), 4.34-4.45 (m, 2H), 4.52 (d, J = 6.45 Hz, 1H), 4.92 (d, J = 15.6 Hz, 1H), 5.54 (d, J = 15.85 Hz, 1H), 6.87 (d, J = 9.8 Hz, 1H), 7.13- 7.19 (m, 3H), 7.28- 7.33 (m, 2H), 7.42 (d, J = 7.75 Hz, 1H), 7.47 (s, 1H), 8.63 (d, J = 584.13 4.75 Hz, 1H) Ex 102(Ex 255) (S)-3-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-2,4- difluorophenyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.17 (d, J = 6.2 Hz, 3H), 2.94 (s, 3H), 4.39-4.51 (m, 3H), 4.81 (d, J = 15.7 Hz, 1H), 5.57 (d, J= 16.0 Hz, 1H), 6.86 (d, J = 18.15 Hz, 1H), 7.18- 7.22 (m, 5H), 7.37 (d, J = 7.5 Hz, 2H), 7.45 (s, 1H), 8.85 (s, 1H). 586.13 Ex 103(Ex 256) (S)-2-(3-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-2,4- difluorophenoxy) ethyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.17 (s, 3H), 2.93 (d, J = 3.35 Hz, 3H), 3.89 (s, 2H), 4.07 (s, 2H), 4.39-4.52 (m, 3H), 4.89 (d, J = 14.65 Hz, 1H), 5.52 (d, J = 15.3 Hz, 1H), 6.90- 6.94 (m, 1H), 7.08 (s, 1H), 7.19 (t, J = 3.35 Hz, 3H), 7.40-7.46 (m, 2H), 8.81 (s, 1H) 630.06 Ex 104(Ex 257) (S)-3-(3-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-2,4- difluorophenoxy) propyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.16 (s, 3H), 1.91-1.94 (m, 2H), 2.93 (s, 3H), 3.83 (d, J = 6.60 Hz, 2H), 4.01 (d, J = 2.15 Hz, 2H), 4.39-4.52 (m, 3H), 4.87 (d, J = 15.9 Hz, 1H), 5.52 (d, J= 15.95 Hz, 1H), 6.90-6.93 (m, 1H), 7.03-7.07 (m, 1H), 7.17-7.20 (m, 3H), 7.18-7.45 (m, 2H), 8.80 (d, J = 4.45 Hz, 1H). 644.10 Ex 105(Ex 260) 0 (S)-2-((3,4- dimethyl-2-oxo- 7-((2,4,6- trifluorobenzyl) carbamoyl)-3,4- dihydroquinazo- lin-1(2H)- yl)methyl)-3,5- difluorophenyl dihydrogen phosphate (500 MHz; DMSO- d.sub.6): δ 1.27 (d, J = 6.1 Hz, 3H), 2.96 (s, 3H), 4.41 (s, 2H), 4.56 (d, J = 4.65 Hz, 1H), 4.81 (d, J = 16.4 Hz, 1H), 5.31 (d, J = 17.2 Hz, 1H), 7.14-7.21 (m, 7H), 7.36 (d, J = 6.1 Hz, 2H), 9.04 (s, 1H) 586.16

(340) TABLE-US-00007 Derived from Ex. Structure Example 106 1 107 188 108 5 109 242 110 18 111 250 112 27 113 251 114 27 115 0 252 116 58 117 253 118 69 119 254 120 71 121 255 122 77 123 260 124 87 125 0 267 126 235 127 269 128 143 129 285 130 150 131 273 132 148 133 286 134 171 135 00 298 136 01 182

(341) Examples 137, 138, 139 and 140 were prepared according to the methods described in General Procedures 14, 14, 18 and 19 respectively and the methods described below.

Example 137: (S)-1-(2-Chloro-6-fluoro-3-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(342) ##STR00302##

Preparation 41: (S)-Ethyl-2-(2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)acetate

(343) ##STR00303##

(344) To a stirred solution of (S)-1-(2-chloro-6-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,34-tetrahydroquinazoline-7-carboxamide (Example 87) (0.06 g, 0.12 mmol) in dry DMF (2 mL) under an inert atmosphere was added NaH (0.005 g, 0.13 mmol, 60% suspension in mineral oil) at 0-5° C. and the whole stirred for 10 min. Ethyl bromoacetate (0.029 g, 0.17 mmol) was then added to the reaction mixture and stirring continued for 5 min. at the same temperature. The reaction mixture was allowed to warm to RT and further stirred for 2 h. Completion of the reaction was monitored by TLC and LCMS and after completion the mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na—SO.sub.4 and concentrated under reduced pressure to afford titled compound (0.08 g, purity>80%) as a yellow viscous oil which was used in the next step without any further purification. LCMS m/z: 608.15 [M+H].

Preparation 42: (S)-1-(2-Chloro-6-fluoro-3-(2-hydroxyethoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 137)

(345) ##STR00304##

(346) To a stirred solution of (S)-ethyl-2-(2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)-acetate (Preparation 41) (0.075 g, 0.13 mmol) in methanol (3 mL) was added NaBH.sub.4 (0.078 g, 1.27 mmol) and LiCl (0.054 g, 1.27 mmol) at 0-5° C. and the reaction mixture was stirred at RT for 30 min. After consumption of the starting material the solvents were evaporated under reduced pressure to give a residue which was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the crude product which was purified by prep-HPLC to give titled compound (0.02 g, 28.7% yield and purity 98.46%) as an off white solid. LCMS m/z: 566.12 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.23 (bs, 3H), 2.94 (s, 3H), 3.72 (bs, 2H), 4.02 (bs, 2H), 4.41-4.52 (m, 3H), 4.90 (bs, 2H), 5.54 (d, J=14.55 Hz, 1H), 7.08-7.20 (m, 5H), 7.40-7.45 (m, 2H), 8.78 (bs, 1H).

Example 138: (S)-1-(2-Chloro-6-fluoro-3-(3-hydroxypropoxy)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(347) ##STR00305##

(348) To a stirred solution of (S)-1-(2-chloro-6-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 87) (0.04 g, 0.077 mmol) in dry DMF (2 mL) at room temperature under an inert atmosphere was added K.sub.2CO.sub.3 (0.053 g, 0.23 mmol) and KI (1.0 mg) at RT and stirring continued for 10 min. 3-Bromopropanol (0.0159 g, 0.12 mmol) was added to the reaction mixture and the whole stirred at RT overnight. Progress of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was quenched with H.sub.2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the crude product which was purified by prep-HPLC to give titled compound (0.02 g, 45% yield and purity 98.94%) as a white solid. LCMS m/z: 580.14 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J=6.6 Hz, 3H), 1.85 (t, J=6.1 Hz, 2H), 2.94 (s, 3H), 3.55-3.58 (m, 2H), 4.06 (d, J=3.1 Hz, 2H), 4.41-4.37 (m, 1H), 4.66-4.46 (m, 3H), 4.91 (d, J=15.7 Hz, 1H), 5.54 (d, J=15.7 Hz, 1H), 7.11-7.05 (m, 2H), 7.22-7.18 (m, 3H), 7.44-7.39 (m, 2H), 8.78 (bs, 1H).

Example 139: (S)-4-Acetamidobenzyl-(2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenyl) carbonate

(349) ##STR00306##

(350) To a stirred solution of (S)-1-(2-chloro-6-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,34-tetrahydroquinazoline-7-carboxamide (Example 87) (0.05 g, 0.0959 mmol) in DMF (2 mL) was added NaH (0.003 g, 60% w/w in mineral oil) at 0-5° C. and the reaction mixture was stirred for 15 min. at the same temperature. Then the separately synthesized 4-acetamidobenzyl (4-nitrophenyl) carbonate (US 1996/5585397) (0.1 g, 0.303 mmol) was dissolved in DMF (2 mL) and added to the reaction mixture and stirred at RT for overnight. Progress of the reaction was monitored by TLC and LCMS and after completion of the reaction the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude compound which was purified by prep-HPLC to afford titled compound (0.015 g, 21.9% yield and purity 99.38%) as a white solid. LCMS m/z: 713.14 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.20 (d, J=6.3 Hz, 3H), 2.05 (s, 3H), 2.92 (s, 3H), 4.53-4.39 (m, 3H), 4.96 (d, J=15.6 Hz, 1H), 5.21 (s, 2H), 5.50 (d, J=15.8 Hz, 1H), 7.22-7.17 (m, 3H), 7.27 (t, J=9.4 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.46-7.42 (m, 2H), 7.48 (s, 1H), 7.61 (d, J=8.1 Hz, 2H), 8.79 (bs, 1H), 10.06 (s, 1H).

Example 140: (S)-Benzyl 3-((2-chloro-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-4-fluorophenoxy)carbonyl)(methylamino)propanoate

(351) ##STR00307##

(352) To a stirred solution of (S)-1-(2-chloro-6-fluoro-3-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 87) (0.042 g, 0.08 mmol) in DMF (2 mL) was added NaH (0.01 g, 60% w/w in mineral oil) at 0-5° C. and the reaction mixture was stirred for 15 min. at the same temperature. Then, separately synthesized benzyl 3-(methyl((4-nitrophenoxy)carbonyl)amino)-propanoate (Syn. Comm., 2007, 37, 1927) (0.035 g, 0.098 mmol) in DMF (1 mL) was added into the reaction mixture and the whole heated at 80° C. for 3 days. Progress of the reaction was monitored by TLC and LCMS and after 3 days the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with NaHCO.sub.3 and brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude compound which was purified by column chromatography to afford titled compound (0.012 g, 20% yield and purity>99%) as a white solid. LCMS m/z: 741.2 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.21 (d, J=5.3 Hz, 3H), 2.67 (t, J=6.3 Hz, 1H), 2.81 (t, J=6.9 Hz, 1H), 2.90 (s, 2H), 2.92 (s, 3H), 3.04 (s, 1H), 3.53 (s, 1H), 3.68 (s, 1H), 4.46-4.40 (m, 2H), 4.52 (d, J=6.1 Hz, 1H), 4.95 (d, J=15.7 Hz, 1H), 5.10 (s, 2H), 5.48 (d, J=15.3 Hz, 1H), 7.22-7.17 (m, 5H), 7.35 (d, J=10.2 Hz, 5H), 7.43 (d, J=7.5 Hz, 1H), 7.49 (s, 1H), 8.78 (s, 1H).

Example 141: (S)-1-(3-Carbamoyl-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(353) ##STR00308##

(354) Example 141 was prepared according to the methods described in General Procedures 1-3 and 24, and the methods described below.

Preparation 43: Methyl-3-(bromomethyl)-2,4-difluorobenzoate

(355) ##STR00309##

(356) To a stirred solution of commercially available methyl-2,4-difluoro-3-methylbenzoate (0.136 g, 0.73 mmol) in CCl.sub.4 (5 mL) was added NBS (0.143 g, 0.80 mmol) followed by AIBN (0.01 g, 0.06 mmol) at RT. The resulting reaction mixture was refluxed for 3 h. Completion of the reaction was monitored by TLC and LCMS after which the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography to afford titled compound (0.18 g, 92% yield and purity 99%) as an off white sticky solid.

Preparation 44: (S)-3,4-Dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

(357) ##STR00310##

(358) To a stirred solution of (S)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 14) (0.25 g, 1.0672 mmol) in a mixture of solvents THF:H.sub.2O:MeOH (12 mL, 2:1:1) was added LiOH.H.sub.2O (0.358 g, 8.532 mmol) at RT and the resulting reaction mixture was further stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS and after completion of the reaction the mixture was acidified with 1N HCl to pH ˜3-4. The solution was further diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford titled compound (0.25 g, purity 92%) as a yellow solid which was pure enough to use in the next step without any further purification. LCMS m/z: 221 [M+H].

Preparation 45: (S)-3,4-Dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(359) ##STR00311##

(360) To a stirred solution of (S)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 44) (0.25 g, 1.14 mmol) in THF (5 mL) was added HATU (0.52 g, 1.36 mmol) followed by TEA (0.17 g, 1.70 mmol). The resulting reaction mixture was stirred at RT for 1 h and then 2, 4, 6-trifluorobenzyl amine (0.219 g, 1.36 mmol) added and the whole further stirred at RT for 2 h. Completion of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the crude product which was purified by column chromatography to give titled compound (0.28 g, 68% yield and purity 99%) as a white solid. LCMS m/z: 364 [M+H].

Preparation 46: (S)-Methyl-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4-difluorobenzoate

(361) ##STR00312##

(362) To a stirred solution of (S)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Preparation 45) (0.12 g, 0.34 mmol) in DMF (5 mL) was added NaH (0.00 g, 60% w/w in mineral oil) at 0-5° C. and stirring continued for 15 min. Into this mixture was added methyl-3-(bromomethyl)-2,4-difluorobenzoate (Preparation 43) (0.1 g, 0.38 mmol) and then the reaction mixture was further stirred for 30 min. at 0-5° C. After completion of the reaction (monitored by TLC and LCMS) the mixture was quenched with a saturated solution of NH.sub.4Cl and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give titled compound (0.2 g, purity 91%) as a white solid which was used in the next step without any further purification. LCMS m/z: 548 [M+H].

Preparation 47: (S)-3-((3,4-Dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4-difluorobenzoic acid (Example 142)

(363) ##STR00313##

(364) To a stirred solution of (S)-methyl-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4-difluorobenzoate (Preparation 46) (0.2 g, 0.37 mmol) in a mixture of solvents THF:H.sub.2O:MeOH (8 mL, 2:1:1) was added LiOH.H.sub.2O (0.036 g, 0.73 mmol) at RT and the resulting reaction mixture was further stirred at RT for 2 h. Progress of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was acidified with 1N HCl to pH ˜3-4. The quenched solution was further diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of brine, dried over anhydrous Na—SO.sub.4 and concentrated under reduced pressure to afford the crude product which was purified by prep-HPLC to give titled compound (0.14 g, 72% yield and purity 99.9%) as a yellow solid. LCMS m/z: 534 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J=6.4 Hz, 3H), 2.93 (s, 3H), 4.55-4.39 (m, 3H), 4.92 (d, J=15.7 Hz, 1H), 5.51 (d, J=15.7 Hz, 1H), 7.11 (t, J=8.8 Hz, 1H), 7.22-7.08 (m, 3H), 7.42 (d, J=7.7 Hz, 1H), 7.47 (s, 1H), 7.76 (d, J=6.7 Hz, 1H), 8.82 (t, J=4.7 Hz, 1H), 13.46 (bs, 1H).

Preparation 48: (S)-1-(3-Carbamoyl-2,6-difluorobenzyl)-4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 141)

(365) ##STR00314##

(366) To a stirred solution of (S)-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)-carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4 difluorobenzoic acid (Example 142) (0.14 g, 0.26 mmol) in THF (6 mL) was added HATU (0.119 g, 0.31 mmol) followed by TEA (0.053 g, 0.52 mmol) and the reaction mixture was stirred at RT for 15 min., then ammonium formate (0.165 g, 2.63 mmol) was added and the resulting reaction mixture was further stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS which showed incomplete conversion of starting material. The same amount of HATU, TEA and ammonium format was further added into the reaction mixture and stirring was continued at RT for 2 h. After completion of the reaction; the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give crude product which was purified by column chromatography to afford titled compound (0.06 g, 22.9% yield and purity 99.7%) as a yellow solid. LCMS m/z: 533.19 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.18 (d, J=6.35 Hz, 3H), 2.94 (s, 3H), 4.40-4.43 (m, 1H), 4.46-4.50 (m, 1H), 4.52-4.55 (m, 1H), 4.90 (d, J=15.75 Hz, 1H), 556 (d, J=15.9 Hz, 1H), 7.11 (t, J=9.05 Hz, 1H), 7.19-7.21 (m, 3H), 7.41 (d, J=7.7 Hz, 1H), 7.47 (bs, 1H), 7.54-7.57 (m, 1H), 7.65 (bs, 1H), 7.69 (bs, 1H), 8.84 (t, J=4.85 Hz, 1H).

Example 143: (S)-1-(2,6-Difluoro-3-(2-hydroxyethyl)carbamoyl)benzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(367) ##STR00315##

(368) To a stirred solution of (S)-3-((3,4-dimethyl-2-oxo-7-((2,4,6-trifluorobenzyl)-carbamoyl)-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2,4 difluorobenzoic acid (Example 142) (0.16 g, 0.30 mmol) in THF (5 mL) was added HATU (0.137 g, 0.36 mmol) followed by TEA (0.046 g, 0.45 mmol) and the reaction mixture was stirred at RT for 1 h, then 2-aminoethanol (0.022 g, 0.36 mmol) was added and the resulting mixture was further stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS and after completion; the reaction mass was diluted with water and extracted with EtOAc. The combined organics were washed with NaHCO.sub.3 solution followed by brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography to give the titled compound (0.065 g, 37.5% yield and purity 99.8%) as a yellow solid. LCMS m/z: 577.17 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J=6.4 Hz, 3H), 2.93 (s, 3H), 3.31-3.27 (m, 2H), 3.49-3.45 (m, 2H), 4.55-4.40 (m, 3H), 4.74 (t, J=5.5 Hz, 1H), 4-91 (d, J=15.8 Hz, 1H), 5.55 (d, J=15.9 Hz, 1H), 7.12 (t, J=8.9 Hz, 1H), 7.22-7.19 (m, 3H), 7.42 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.56-7.51 (m, 1H), 8.23 (bs, 1H), 8.85 (t, J=5.0 Hz, 1H).

(369) Examples 144-147 were prepared according to the methods described in General Procedures 20-23, and the methods described below.

Example 144: (S)-4-(4-(Allyloxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(370) ##STR00316##

(371) To a stirred solution of (S)-1-(2,6-difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 78) (0.15 g, 0.30 mmol) in DMF (5 mL) was added K.sub.2CO.sub.3 (0.171 g, 0.74 mmol) and then allyl bromide (0.043 g, 0.36 mmol) at RT. The whole reaction mixture was further stirred at RT for 1 h. The course of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography to afford titled compound (0.14 g, 86.5% yield and purity 96.27%) as a white solid. LCMS m/z: 546.24 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.1 Hz, 3H), 2.94 (s, 3H), 4.42-4.39 (m, 1H), 4.55-4.46 (m, 4H), 4.74 (d, J=15.7 Hz, 1H), 5.25 (d, J=10.4 Hz, 1H), 5.38 (d, J=16.9 Hz, 1H), 5.52 (d, J=15.4 Hz, 1H), 6.00-5.95 (m, 1H), 6.69 (d, J=10.1 Hz, 2H), 7.23-7.18 (m, 3H), 7.40 (d, J=7.5 Hz, 1H), 7.45 (s, 1H), 8.80 (s, 1H).

Example 145: (4S)-1-(4-(2,3-Dihydroxypropoxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(372) ##STR00317##

(373) To a stirred solution of (S)-1-(4-(allyloxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 144) (0.06 g, 0.11 mmol) in acetone (1 mL) was added osmium tetroxide (0.0028 g, 0.011 mmol), NMO (0.0154 g, 0.13 mmol) and water (0.1 mL) at RT and the resulting reaction mixture was stirred at RT for 30 min. After completion of the reaction; the reaction mixture was poured into a saturated solution of Na.sub.2SO.sub.3 and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give crude product which was purified by prep-HPLC to afford titled compound (0.020 g, 31.5% yield and purity 99.3%) as a white solid. LCMS m/z: 580.2 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.1 Hz, 3H), 2.93 (s, 3H), 3.40-3.38 (m, 2H), 3.73 (d, J=4.6 Hz, 1H), 3.84 (bs, 1H), 3.96 (d, J=9.8 Hz, 1H), 4.52-4.39 (m, 3H), 4.75-4.70 (m, 2H), 4.99 (d, J=4.4 Hz, 1H), 5.52 (d, J=15.7 Hz, 1H), 6.65 (d, J=24.9 Hz, 2H), 7.23-7.18 (m, 3H), 7.39 (d, J=7.7 Hz, 1H), 7.45 (s, 1H), 8.80 (bs, 1H).

Example 146: (S)-1-(4-((R)-2,3-Dihydroxypropoxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(374) ##STR00318##

(375) To a stirred solution of (S)-1-(4-(allyloxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 144) (0.075 g, 0.14 mmol) in tert-butanol (1 mL) and water (1 mL) at 0-5° C. was added AD-mix-α (0.258 g) and the reaction mixture was stirred at 0° C. for overnight. The course of the reaction was monitored by TLC and LCMS and after completion; the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give crude product which was purified by prep-HPLC to afford titled compound (0.037 g, 46.4% yield and purity 99.7%) as a white solid. LCMS m/z: 580.2 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.0 Hz, 3H), 2.93 (s, 3H), 3.40-3.38 (t, J=5.3 Hz, 2H), 3.74-3.71 (m, 1H), 3.85-3.82 (m, 1H), 3.97 (d, J=7.2 Hz, 1H), 4.43-4.39 (m, 1H), 4.52-4.47 (m, 2H), 4.68 (t, J=5.2 Hz, 1H), 4.74 (d, J=15.9 Hz, 1H), 4.98 (d, J=4.7 Hz, 1H), 5.52 (d, J=15.6 Hz, 1H), 6.65 (d, J=9.9 Hz, 2H), 7.23-7.18 (m, 3H), 7.40 (d, J=7.7 Hz, 1H), 7.45 (s, 1H), 8.79 (s, 1H).

Example 147: (S)-1-(4-((S)-2,3-Dihydroxypropoxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(376) ##STR00319##

(377) To a stirred solution of (S)-1-(4-(allyloxy)-2,6-difluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 144) (0.075 g, 0.14 mmol) in tert-butanol (1 mL) and water (1 mL) at 0-5° C. was added AD-mix-β (0.258 g) and the reaction mixture was stirred at 0-5° C. for overnight. The course of the reaction was monitored with TLC and LCMS and after completion the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by prep-HPLC to afford titled compound (0.033 g, 41.4% yield and purity 99.0%) as a white solid. LCMS m/z: 580.19 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.1 Hz, 3H), 2.93 (s, 3H), 3.40-3.38 (t, J=10.5 Hz, 2H), 3.74-3.71 (m, 1H), 3.85 (t, J=7.7 Hz, 1H), 3.98-3.95 (m, 1H), 4.42-4.39 (m, 1H), 4.52-4.47 (m, 2H), 4.75-4.68 (m, 2H), 4.98 (d, J=4.7 Hz, 1H), 5.52 (d, J=15.7 Hz, 1H), 6.65 (d, J=10 Hz, 2H), 7.23-7.18 (m, 3H), 7.40 (d, J=7.7 Hz, 1H), 7.45 (s, 1H), 8.79 (s, 1H).

Example 148: 1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide

(378) ##STR00320##

(379) Example 148 was prepared according to the methods described in General Procedures 1-3, and the methods described below.

Preparation 49: Methyl-3,4-dimethyl-2-oxo-1,2,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxylate

(380) ##STR00321##

Step 1: Methyl-5-nitro-6-((trimethylsilyl)ethynyl)nicotinate

(381) ##STR00322##

(382) A stirred solution of commercially available methyl 6-chloro-5-nitronicotinate (1.0 g, 4.62 mmol) in THF (20 mL) was degassed with N.sub.2, and then ethynyltrimethylsilane (0.544 g, 5.54 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.324 g, 0.46 mmol), CuI (0.017 g, 0.089 mmol) and triethylamine (10 mL) were added sequentially. The resulting reaction mixture was heated at 80° C. for 3 h. Completion of the reaction was monitored by TLC and LCMS after which the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography to provide titled compound (0.6 g, 46.6% yield and purity 98%) as an oily liquid. LCMS m/z: 279 [M+H].

Step 2: Methyl-6-ethynyl-5-nitronicotinate

(383) ##STR00323##

(384) To a stirred solution of methyl 5-nitro-6-((trimethylsilyl)ethynyl)nicotinate (Step 1) (0.65 g, 2.34 mmol) in anhydrous DCM (25 mL) and MeOH (25 mL) was added 3 drops of acetic acid followed by KF (0.069 g, 1.18 mmol) at 0-5° C. and the whole stirred at the same temperature for 10 min. The reaction was monitored by TLC and after completion the reaction mixture was quenched with NaHCO.sub.3 solution and extracted with EtOAc. The combined organic layer was dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to give titled compound (0.54 g, 100% yield and purity>85%) as a pale yellow gum which was used in the next step without any further purification. LCMS m/z: 205.78 [M.sup.+].

Step 3: Methyl-5-amino-6-ethylnicotinate

(385) ##STR00324##

(386) To a stirred solution of methyl-6-ethynyl-5-nitronicotinate (Step 2) (0.48 g, 2.32 mmol) in anhydrous EtOAc (15 mL) was added 10% Pd—C(0.0272 g, 0.26 mmol, 10% w/w on carbon) under a N.sub.2 gas atmosphere and the resulting mixture then purged twice with N.sub.2 gas followed by H.sub.2 gas. The reaction mixture was stirred at RT under a H.sub.2 gas balloon pressure for 3 h. After completion of the reaction the mixture was filtered through a short celite bed and the bed was washed with EtOAc×3 under an inert atmosphere. The combined filtrate was evaporated to dryness under reduced pressure to give titled compound (0.39 g, 95% yield and purity>92%) as a brown gum. LCMS m/z: 18.02 [M+H].

Step 4: Methyl-5-((ethoxycarbonyl)amino)-6-ethylnicotinate

(387) ##STR00325##

(388) To a solution of methyl-5-amino-6-ethylnicotinate (Step 3) (0.39 g, 2.16 mmol) in anhydrous DCE (15 mL) and pyridine (0.37 g, 4.67 mmol) was added ethylchloroformate (0.28 g, 2.58 mmol) dropwise under a nitrogen atmosphere at 0-5° C. The resulting reaction mixture was stirred at RT for 3 h and after completion of the reaction the reaction mass was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give the crude compound which was purified by column chromatography to afford titled compound (0.34 g, 63% yield and purity>91%) as an off white solid. LCMS m/z: 253.01 [M+H].

Step 5: Methyl-6-(1-bromoethyl)-5-((ethoxycarbonyl)aminonicotinate

(389) ##STR00326##

(390) To a solution of methyl-5-((ethoxycarbonyl)amino)-6-ethylnicotinate (Step 4) (0.2 g, 0.79 mmol) in CCl.sub.4 (20 mL) was added NBS (0.155 g, 0.87 mmol) and AIBN (0.013 g, 0.079 mmol) under a nitrogen atmosphere and the reaction was refluxed at 75-80° C. overnight. The progress of the reaction was monitored by TLC and or LCMS and after consumption of starting materials the reaction mass was quenched with a saturated aqueous solution of sodium thiosulphate and extracted with EtOAc. The combined organics ware washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give the crude compound which was purified by column chromatography to provide titled compound (0.2 g, 76% yield and purity>88%) as an off white solid. LCMS m/z: 253.01 [M+H].

Step 6: Methyl-5-((ethoxycarbonyl)amino)-6-(1-(methylamino)ethyl)nicotinate

(391) ##STR00327##

(392) To a stirred solution of methyl-6-(1-bromoethyl)-5-((ethoxycarbonyl)amino)nicotinate (Step 5) (0.2 g, 0.60 mmol) in acetonitrile (5 mL) was added K.sub.2CO.sub.3 (0.417 g, 3.01 mmol) and MeNH.sub.2.HCl (0.061 g, 0.90 mmol) under a nitrogen atmosphere and the combined reaction mixture was stirred at RT for 14 h. After this time, the solvent was evaporated under reduced pressure to give a residue which was dissolved in water and extracted twice with DCM. The combined organics were dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to give titled compound (0.18 g, 106% yield and purity>70%) as a brown solid which was used in the next step without any further purification. LCMS m/z: 282.2 [M+H].

Step 7: Methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxylate

(393) ##STR00328##

(394) To a stirred solution of methyl-5-((ethoxycarbonyl)amino)-6-(1-(methylamino)ethyl)-nicotinate (Step 6) (0.18 g, 0.64 mmol) in MeOH (5 mL) was added K.sub.2CO.sub.3 (0.09 g, 1.33 mmol) and the reaction was stirred at 60° C. for 2 h. The reaction was monitored by TLC and after completion the solvent was evaporated under reduced pressure to give a residue which was dissolved in water and extracted twice with DCM. The organics were dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by column chromatography over silica gel using 52% EtOAc in hexane mixture as eluent to provide titled compound (0.07 g, yield 46.6% yield and purity>87%) as a white solid. LCMS m/z: 236.02 [M+H].

Preparation 50: 1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxamide (Example 148)

(395) ##STR00329##

(396) To a stirred solution of 1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-7-carboxylic acid (prepared from the product of Preparation 49 according to the methods described in General Procedures 2 and 3) (0.04 g, 0.11 mmol) in anhydrous DMF (2 mL) was added TEA (0.034 g, 0.34 mmol) and HATU (0.05 g, 0.13 mmol) under a N.sub.2 gas atmosphere at RT. After stirring for 10-15 min., 2,4,6-trifluorobenzyl amine (0.018 g, 0.11 mmol) was added into the reaction mixture and stirring was continued for a further 1 h. Reaction progress was monitored by TLC or LCMS and after completion the mixture was quenched with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to give the crude compound which was purified by prep-HPLC to afford titled compound (0.005 g, 10% yield and purity 99.0%) as a white solid. LCMS m/z: 507.10 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.28 (d, J=6.6 Hz, 3H), 2.97 (s, 3H), 4.42-4.52 (m, 2H), 4.57-4.61 (q, J=6.6 Hz, 1H), 4.92 (d, J=15.75 Hz, 1H), 5.49 (d, J=15.7 Hz, 1H), 7.16-7.24 (m, 3H), 7.30-7.37 (m, 2H), 7.76 (s, 1H), 8.52 (s, 1H), 9.01 (bs, 1H).

Example 149: (S)—N,1-bis(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(397) ##STR00330##

(398) Example 149 was prepared according to the methods described in General Procedures 1-3, and the methods described below.

Preparation 51: (S)-Methyl 1-(2,6-difluoro-4-methoxybenzyl)-4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

(399) ##STR00331##

(400) To a stirred solution of (S)-methyl 3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 14) (0.1 g, 0.43 mmol) in DMF (3 mL) was added NaH (0.014 g, 60% suspension in mineral oil) at 0-5° C. under an inert atmosphere and the whole allowed to stir for 15 min. Then, 2-(bromomethyl)-1,3-difluoro-5-methoxybenzene (0.119 g, 0.47 mmol) was added into the reaction mixture which was allowed to further stir at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS and after completion the mixture was quenched with a saturated solution of NH.sub.4Cl and extracted with EtOAc. The organics were washed with cold water followed by brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give titled compound (0.166 g, 100% yield and purity>95%) as a white solid. LCMS m/z: 391.14 [M+H].

Preparation 52: (S′)-1-(2,6-Difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

(401) ##STR00332##

(402) To a stirred solution of(S)-methyl 1-(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 51) (0.166 g, 0.43 mmol) in a mixture of solvents THF:H.sub.2O:MeOH (4 mL, 2:1:1) was added LiOH.H.sub.2O (0.071 g, 1.70 mmol) at RT and the whole allowed to stir at RT for 2 h. After completion of the reaction (monitored by LCMS and TLC) the reaction mass was washed with EtOAc. The aqueous layer was acidified with N HCl to pH 2-3 and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford titled compound (0.15 g, 94% yield) as a white solid which was used in the next step without any further purification. LCMS m/z: 377.12 [M+H].

Preparation 53: (S)—N,1-bis(2,6-Difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 149)

(403) ##STR00333##

(404) To a stirred solution of (S)-1-(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 52) (0.05 g, 0.13 mmol) in DMF (3 mL) was added HATU (0.076 g, 0.20 mmol) and TEA (0.037 mL, 0.27 mmol) at RT and the whole allowed to stir for 15-20 min. Then, (2,6-difluoro-4-methoxyphenyl)methanamine (0.020 mL, 0.13 mmol) was added and the mixture further stirred at RT for 2 h. The course of the reaction was monitored by TLC and LCMS and after completion the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with a saturated solution of K.sub.2CO.sub.3, 1N HCl and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to obtain the crude product which was purified by prep-HPLC to afford titled compound (0.04 g, 57% yield and purity 99.9%) as an off white solid. LCMS m/z: 532.22 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J=6.3 Hz, 3H), 2.94 (s, 3H), 3.73 (s, 3H), 3.78 (s, 3H), 4.36-4.39 (m, 1H), 4.42-4.46 (m, 1H), 4.50-4.52 (m, 1H), 4.74 (d, J=15.65 Hz, 1H), 5.53 (d, J=15.5 Hz, 1H), 6.67 (d, J=9.95 Hz, 2H), 6.75 (d, J=9.35 Hz, 2H), 7.18 (d, J=7.85 Hz, 1H), 7.41 (d, J=7.75 Hz, 1H), 7.46 (bs, 1H), 8.70 (bs, 1H).

Example 150: (S)—N,1-bis(2,6-Difluoro-4-hydroxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(405) ##STR00334##

(406) To a stirred solution of (S)—N,1-bis(2,6-difluoro-4-methoxybenzyl)-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 149) (0.11 g, 0.21 mmol) in DCM (4 mL) was added BBr.sub.3 (0.41 mL, 0.41 mmol, 1M solution in DCM) at 0-5° C. and the reaction mixture stirred at room temperature for 30 min. The course of the reaction was monitored by TLC and LCMS which showed incomplete conversion of starting material. Another portion of BBr.sub.3 (1.2 mL, 1.22 mmol) was added and after consumption of the starting material was confirmed by TLC, the reaction mixture was quenched with a saturated solution of NaHCO.sub.3 and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain the crude compound which was purified by prep-HPLC to give titled compound (0.06 g, 57% yield and purity 99.6%) as a white solid. LCMS m/z: 504.19 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.15 (d, J=6.6 Hz, 3H), 2.93 (s, 3H), 4.31-4.52 (m, 3H), 4.68 (d, J=15.70 Hz, 1H), 5.50 (d, J=15.65 Hz, 1H), 6.37 (d, J=9.85 Hz, 2H), 6.46 (d, J=9.25 Hz, 2H), 7.17 (d, J=7.75 Hz, 1H), 7.40 (d, J=7.80 Hz, 1H), 7.44 (bs, 1H), 8.62 (bs, 1H), 10.38 (bs, 2H).

Example 151: (S)-1-(2-Chloro-6-fluorobenzyl)-N-(2-hydroxyethyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(407) ##STR00335##

Preparation 54: (4S)-1-(2-Chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide

(408) ##STR00336##

(409) To a stirred solution of (S)-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 76) (0.1 g, 0.20 mmol) in DMF (3 mL) was added NaH (5.7 g, 60% suspension on mineral oil) at 0-5° C. and the reaction mixture was stirred at the same temperature for 15 min. Into this reaction mixture 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.05 g, 0.24 mmol) was added and the whole further stirred overnight. The following day, the reaction mixture was heated at 60-65° C. for 2 h and a 2.sup.nd identical portion of both NaH and 2-(2-bromoethoxy)tetrahydro-2H-pyran were added and stirring continued at 60-65° C. for 2 h. The progress of the reaction was monitored by TLC and LCMS which showed in-complete conversion of the starting material. A 3.sup.rd identical portion of both NaH and 2-(2-bromoethoxy)tetrahydro-2H-pyran were added and the mixture heated for 2 h. After the starting material had been consumed, the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give titled compound (0.095 g, 75% yield and purity>65%) as crude which was used in the next step without any further purification. LCMS m/z: 634 [M+H].

Preparation 55: (S)-1-(2-Chloro-6-fluorobenzyl)-N-(2-hydroxyethyl)-3,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Example 151)

(410) ##STR00337##

(411) To a stirred solution of (4S)-1-(2-chloro-6-fluorobenzyl)-3,4-dimethyl-2-oxo-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (Preparation 54) (0.095 g, 0.19 mmol) in 14-dioxane (3 mL) was added aqueous HCl (0.3 mL, 35% in water) dropwise at 0-5° C. The reaction mixture was stirred at RT for 4 h. Completion of the reaction was confirmed by TLC and LC. The solvents were evaporated under reduced pressure to give a residue which was purified by prep-HPLC to afford titled compound (0.018 g, 21.8% yield and purity>90%) as a white solid. LCMS m/z: 550 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 1.25 (bs, 3H), 2.83 (s, 2H), 2.97 (bs, 3H), 3.76 (bs, 2H), 4.26 (bs, 2H), 4.60 (bs, 1H), 4.88 (bs, 1H), 5.72 (bs, 1H), 7.17-7.29 (m, 6H), 7.54 (bs, 2H).

Examples 152-300

(412) Examples 152-300 were made in an analogous manner to Examples 74-76 starting from the appropriate quinazoline and using the appropriate benzyl halides and amines as described for General Procedures 1-14.

(413) TABLE-US-00008 Ex- am- IUPAC LCMS ple Structure Name .sup.1H-NMR [M + H] 152 1-(3,5- difluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 6.48 Hz, 3H), 2.98 (s, 3H), 4.40 (s, 2H), 4.63 (q, J = 6.50 Hz, 1H), 5.12 (s, 2H), 6.88 (d, J = 6.8 Hz, 2H), 7.08- 7.15 (m, 4H), 7.24 (d, J = 7.84 Hz, 1H), 7.44 (d, J = 7.76 Hz, 1H), 8.81 (t, J = 5.02 Hz, 1H). 490.3 153 1-(2-fluoro- 6- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.14 (d, J = 6.12 Hz, 3H), 2.94 (s, 3H), 3.79 (s, 3H), 4.40-4.48 (m, 3H), 4.74 (d, J = 15.6 Hz, 1H), 5.58 (d, J = 15.36 Hz, 1H), 6.68 (t, J = 9.36 Hz, 1H), 6.80 (d, J = 8.32 Hz, 1H), 7.12-7.20 (m, 4H), 7.33 (d, J = 7.48 Hz, 1H), 7.49 (s, 1H), 8.70 (bs, 1H). 501.8 154 0 1-(2-fluoro- 6- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.14 (d, J = 6.48 Hz, 3H), 2.94 (s, 3H), 3.79 (s, 3H), 4.43 (d, J = 4.56 Hz, 2H), 4.48 (q, J = 6.48 Hz, 1H), 4.74 (d, J = 15.44 Hz, 1H), 5.58 (d, J = 15.48 Hz, 1H), 6.68 (t, J = 9.28 Hz, 1H), 6.80 (d, J = 8.44 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.15-7.24 (m, 3H), 7.33 (d, J = 7.76 Hz, 1H), 7.49 (s, 1H), 8.70 (t, J = 4.96 Hz, 1H). 502.3 155 1-(2-fluoro- 6- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.14 (d, J = 6.52 Hz, 3H), 2.94 (s, 3H), 3.79 (s, 3H), 4.42-4.45 (m, 2H), 4.48 (q, J = 6.36 Hz, 1H), 4.74 (d, J = 15.44 Hz, 1H), 5.58 (d, J = 15.44 Hz, 1H), 6.68 (t, J = 9.28 Hz, 1H), 6.80 (d, J = 8.44 Hz, 1H), 7.13 (d, J= 7.8 Hz, 1H), 7.16-7.24 (m, 3H), 7.33 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 8.70 (t, J = 4.92 Hz, 1H). 502.2 156 1-(3,5- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 6.4 Hz, 3H), 2.98 (s, 3H), 4.40 (s, 2H), 4.63 (q, J = 6.4 Hz, 1H), 5.12 (s, 2H), 6.88 (d, J = 6.76 Hz, 2H), 7.08- 7.15 (m, 4H), 7.24 (d, J = 7.84 Hz, 1H), 7.44 (d, J = 7.64 Hz, 1H), 8.80 (bs, 1H). 490.3 157 1-(3,5- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 6.36 Hz, 3H), 2.98 (s, 3H), 4.40 (s, 2H), 4.63 (q, J = 6.44 Hz, 1H), 5.12 (s, 2H), 6.88 (d, J = 6.88 Hz, 2H), 7.07- 7.15 (m, 4H), 7.23 (d, J = 7.80 Hz, 1H), 7.44 (d, J = 7.76 Hz, 1H), 8.80 (bs, 1H). 490.3 158 1-(2-bromo- 6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.24 (d, J = 6.48 Hz, 3H), 2.92 (s, 3H), 4.38-4.49 (m, 2H), 4.53 (q, J = 6.48 Hz, 1H), 4.91 (d, J = 15.76 Hz, 1H), 5.46 (d, J = 15.72 Hz, 1H), 7.13-7.27 (m, 5H), 7.39-7.46 (m, 3H), 8.73 (t, J = 4.96 Hz, 1H). 550.1 159 1-(2-bromo- 6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.24 (d, J = 6.32 Hz, 3H), 2.92 (s, 3H), 4.39-4.45 (m, 2H), 4.53 (q, J = 6.64 Hz, 1H), 4.91 (d, J = 15.68 Hz, 1H), 5.14-7.25 (m, 5H), 7.39-7.46 (m, 3H), 8.74 (bs, 1H). 550.2 160 1-(2-fluoro- 6- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.18 (d, J = 6.4 Hz, 3H), 2.94 (s, 3H), 4.37-4.45 (m, 2H), 4.48 (q, J = 6.36 Hz, 1H), 4.74 (d, J = 15.48 Hz, 1H), 5.49 (d, J = 15.4 Hz, 1H), 6.49 (t, J = 9.92 Hz, 1H), 6.63 (d, J = 8.24 Hz, 1H), 7.02 (dd, J.sub.1 = 8.24 Hz, J.sub.2 = 15.12 Hz, 1H), 7.15-7.20 (m, 3H), 7.34 (d, J = 7.52 Hz, 1H), 7.56 (s, 1H), 8.68 (t, 488.2 J = Hz, 1H), 10.24 (s, 1H). 161 1-(2-fluoro- 6- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.20 (d, J = 6.48 Hz, 3H), 2.39 (s, 3H), 2.93 (s, 3H), 4.41-4.45 (m, 2H), 4.53 (q, J = 6.52 Hz, 1H), 4.83 (d, J = 15.72 Hz, 1H), 5.44 (d, J = 15.72 Hz, 1H), 6.92 (t, J = 10.44 Hz, 1H), 6.98 (d, J = 7.48 Hz, 1H), 7.13-7.21 (m, 4H), 7.39 (d, J = 7.84 Hz, 1H), 7.42 (s, 1H), 8.75 (bs, 1H). 485.7 162 1-(2-fluoro- 6- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.20 (d, J = 6.52 Hz, 3H), 2.39 (s, 3H), 2.93 (s, 3H), 4.41-4.45 (m, 2H), 4.53 (q, J = 6.52 Hz, 1H), 4.83 (d, J = 15.72 Hz, 1H), 5.44 (d, J = 15.72 Hz, 1H), 6.92 (t, J = 10.44 Hz, 1H), 6.98 (d, J = 7.52 Hz, 1H), 7.13-7.21 (m, 4H), 7.39 (d, J = 7.80 Hz, 1H), 7.42 (s, 1H), 8.75 (bs, 1H). 485.8 163 1-(6-chloro- 2-fluoro-3- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J = 6.55 Hz, 3H), 2.13 (s, 3H), 2.94 (s, 3H), 4.42-4.49 (3, 2H), 4.54 (q, J = 6.15 Hz, 1H), 4.88 (d, J = 15.65 Hz, 1H), 5.57 (d, J = 15.65 Hz, 1H), 7.16-7.22 (m, 5H), 7.39 (d, J = 7.85 Hz, 1H), 7.46 (s, 1H), 8.76 (t, J = 4.85 Hz, 1H). 520.4 164 0 1-(2-fluoro- 3- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.5 Hz, 3H), 2.24 (s, 3H), 2.96 (s, 3H), 4.39 (t, J= 4.5 Hz, 2H), 4.61-4.65 (q, J = 6.35 Hz, 1H), 5.03 (d, J = 19.95 Hz, 1H), 5.23 (d, J = 17 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.14-7.18 (m, 3H), 7.21 (s, 1H), 7.24 (d, J = 7.85 Hz, 1H), 7.43- 7.44 (dd, J.sub.1 = 1.1 Hz, J.sub.2 = 7.75 Hz, 1H), 8.84 (t, J = 5.1 Hz, 1H). 486.24 165 1-(2,6- difluoro-4- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 6.5 Hz, 3H), 2.94 (s, 3H), 3.73 (s, 3H), 4.38-4.42 (m, 1H), 4.47- 4.53 (m, 2H), 4.73 (d, J = 15.7 Hz, 1H), 5.54 (d, J = 15.65 Hz, 1H), 6.67 (d, J = 10 Hz, 2H), 7.18-7.23 (m, 3H), 7.40 (d, J = 8.05 Hz, 1H), 7.45 (s, 1H), 8.80 (t, J = 4.95 Hz, 1H). 520.18 166 1-(2-fluoro- 5- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.5 Hz, 3H), 2.97 (s, 3H), 3.62 (s, 3H), 4.40 (d, J = 5 Hz, 2H), 4.61-4.65 (q, J = 6.35 Hz, 1H), 4.98 (d, J = 16.85 Hz, 1H), 5.26 (d, J = 16.65 Hz, 1H), 6.53-6.55 (m, 1H), 6.81-6.84 (m, 1H), 7.13-7.19 (m, 3H), 7.24-7.25 (m, 2H), 7.44- 7.46 (dd, J.sub.1 = 1.0 Hz, J.sub.2 = 7.8 Hz 1.0 H), 8.85 (t, J = 502.17 5.1 Hz, 1H). 167 1-(5- carbamoyl-2- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.48 Hz, 3H), 2.95 (s, 3H), 4.37 (s, 2H), 4.62 (q, J = 5.6 Hz, 1H), 5.06 (d, J = 17.52 Hz, 1H), 16.28 Hz, 1H), 7.10- 7.16 (m, 3H), 7.21-7.28 (m, 3H), 7.41 (d, J = 7.36 Hz, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 7.91 (s, 1H), 8.78 (s, 1H). 515.3 168 (S)-1-(2- fluoro-3- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.5 Hz, 3H), 2.24 (s, 3H), 2.96 (s, 3H), 4.39 (t, J = 4.55 Hz, 2H), 4.61-4.65 (q, J = 6.30 Hz, 1H), 5.03 (d, J = 16.95 Hz, 1H), 5.22 (d, J = 16.95 Hz, 1H), 6.80 (t, J = 7.3 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.14-7.25 (m, 5H), 7.44 (d, J = 7.95 Hz, 1H), 8.84 (t, J = 6.55 Hz, 1H). 486.18 169 (S)-1-(6- chloro-2- fluoro-3- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J = 5.05 Hz, 3H), 2.13 (s, 3H), 2.94 (s, 3H), 4.39-4.49 (m, 2H), 4.51- 4.55 (q, J = 6.55 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H), 5.57 (d, J = 15.65 Hz, 1H), 7.16-7.22 (m, 5H), 7.39 (d, J = 7.75 Hz, 1H), 7.46 (s, 1H), 8.76 (t, J = 4.95 Hz, 1H). 520.14 170 (S)-1-(2- fluoro-4- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.26 (d, J = 6.5 Hz, 3H), 2.26 (s, 3H), 2.97 (s, 3H), 4.36-4.44 (m, 2H), 4.59- 4.63 (q, J = 6.25 Hz, 1H), 4.98 (d, J = 16.65 Hz, 1H), 5.22 (d, J = 16.6 Hz, 1H), 6.88-6.93 (m, 2H), 7.04 (d, J = 11.4 Hz, 1H), 7.16-7.24 (m, 4H), 7.43 (d, J = 7.8 Hz, 1H), 8.84 (t, J = 4.9 Hz, 1H). 486.18 171 1-(2-fluoro- 6- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.18 (d, J = 5.92 Hz, 3H), 2.94 (s, 3H), 4.42-4.49 (m, 3H), 4.74 (d, J = 15.4 Hz, 1H), 5.49 (d, J = 15.48 Hz, 1H), 6.49 (t, J = 9.22 Hz, 1H), 6.63 (d, J = 7.68 Hz, 1H), 7.01 (q, J = 7.68 Hz, 1H), 7.13-7.20 (m, 3H), 7.34 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 8.69 (bs, 1H), 10.25 (s, 1H). 488.0 172 (R)-1-(2- fluoro-6- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.18 (d, J= 5.92 Hz, 3H), 2.94 (s, 3H), 4.41-4.49 (m, 3H), 4.74 (d, J = 15.8 Hz, 1H), 5.49 (d, J = 15.76 Hz, 1H), 6.49 (t, J = 8.92 Hz, 1H), 6.63 (d, J = 7.92 Hz, 1H), 7.01 (q, J = 7.72 Hz, 1H), 7.13-7.20 (m, 3H), 7.34 (d, J = 8.12 Hz, 1H), 7.56 (s, 1H), 8.69 (bs, 1H), 10.25 (s, 1H). 487.8 173 1-(2-amino- 6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 6.35 Hz, 3H), 2.95 (s, 3H), 4.40-4.52 (m, 3H), 4.81 (d, J = 15.75 Hz, 1H), 5.36 (d, J = 16.15 Hz, 1H), 5.42 (s, 2H), 6.24 (t, J = 9.3 Hz, 1H), 6.44 (d, J = 8.05 Hz, 1H), 6.89-6.94 (q, J = 7.25 Hz, 1H), 7.17-7.23 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.64 (s, 1H), 8.73 (bs, 1H). 487.20 174 0 1-(2-fluoro- 6- (methylamino) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.12 (d, J = 6.45 Hz, 3H), 2.7 (d, J = 4.7 Hz, 3H), 2.96 (s, 3H), 4.44-4.52 (m, 3H), 4.84 (d, J = 15.9 Hz, 1H), 5.33 (d, J = 16.0 Hz, 1H), 5.58 (d, J = 4.75 Hz, 1H), 6.28-6.34 (m, 2H), 7.04-7.08 (q, J = 7.85 Hz, 1H), 7.16-7.23 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 8.72 (t, J = 5.05 Hz, 1H). 501.27 175 1-(2- (dimethylami- no)-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.18 (d, J = 6.4 Hz, 3H), 2.69 (s, 6H), 2.97 (s, 3H), 4.23-4.35 (m, 1H), 4.44- 4.50 (m, 2H), 4.78 (d, J = 15.35 Hz, 1H), 5.75 (d, J = 15.85 Hz, 1H), 6.72 (t, J = 8.9 Hz, 1H), 6.90 (d, J = 8.05 Hz, 1H), 7.08- 7.24 (m, 5H), 7.39 (s, 1H), 8.65 (bs, 1H). 515.25 176 1-((5-chloro- 3-fluoro-2- methylpyridin- 4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.24 (d, J = 5.75 Hz, 3H), 2.35 (s, 3H), 2.93 (s, 3H), 4.44 (bs, 2H), 4.56-4.57 (m, 1H), 5.0 (d, J = 15.9 Hz, 1H), 5.45 (d, J = 15.95 Hz, 1H), 7.18-7.24 (m, 3H), 7.40-7.45 (m, 2H), 8.36 (s, 1H), 8.81 (bs, 1H). 521.18 177 (S)-1-(6- chloro-2,3- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J = 5.55 Hz, 3H), 2.93 (s, 3H), 4.41-4.49 (m, 2H), 4.54-4.56 (m, 1H), 4.96 (d, J = 15.5 Hz, 1H), 5.48 (d, J = 15.65 Hz, 1H), 7.18-7.24 (m, 3H), 7.35 (bs, 1H), 7.40- 7.45 (m, 3H), 8.81 (bs, 1H). 524.13 178 1-(2,3- difluoro-6- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 6.5 Hz, 3H), 2.95 (s, 3H), 3.78 (s, 3H), 4.40-4.44 (m, 2H), 4.49- 4.53 (q, J = 6.45 Hz, 1H), 4.80 (d, J = 15.65 Hz, 1H), 5.56 (d, J = 15.7 Hz, 1H), 6.69-6.81 (m, 1H), 7.16-7.21 (m, 3H), 7.24- 7.30 (m, 1H), 7.37 (d, J = 7.75 Hz, 1H), 7.47 (bs, 1H), 8.76 (t, J = 5 Hz, 1H). 520.17 179 (S)-1-(2- chloro-3,6- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J = 6.6 Hz, 3H), 2.93 (s, 3H), 4.39-4.50 (m, 2H), 4.52-4.56 (q, J = 6.4 Hz, 1H), 4.96 (d, J = 15.75 Hz, 1H), 5.53 (d, J = 15.8 Hz, 1H), 7.19- 7.26 (m, 4H), 7.38-7.45 (m, 3H), 8.79 (t, J = 4.9 Hz, 1H). 524.13 180 1-((3-fluoro- 2- methylpyridin- 4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.5 Hz, 3H), 2.46 (d, J = 2.85 Hz, 3H), 2.97 (s, 3H), 4.39 (d, J = 5.05 Hz, 2H), 4.63-4.67 (q, J = 6.4 Hz, 1H), 5.13 (d, J = 17.7 Hz, 1H), 5.20 (d, J = 17.65 Hz, 1H), 6.80 (t, J = 5.1 Hz, 1H), 7.14-7.18 (m, 3H), 7.28 (d, J = 7.9 Hz, 1H), 7.46- 7.48 (m, 1H), 8.16 (d, J = 4.9 Hz, 1H), 8.86 (t, J = 5.1 Hz, 1H). 487.19 181 1-(2-fluoro- 4- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.24 (d, J = 6.3 Hz, 3H), 2.96 (s, 3H), 4.45-4.40 (m, 2H), 4.61-4.57 (m, 1H), 4.88 (d, J = 16.3 Hz, 1H), 5.18 (d, J = 16.5 Hz, 1H), 6.56-6.48 (m, 2H), 6.87 (t, J = 8.7 Hz, 1H), 7.22-7.16 (m, 3H), 7.26 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 8.83 (t, J = 4.8 Hz, 1H), 9.81 (s, 1H). 488.13 182 (S)-1-(2- amino-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 11.6 (bs, 3H), 2.95 (bs, 3H), 4.44-4.50 (m, 3H), 4.82 (d, J = 15.4 Hz, 1H), 5.35-5.42 (m, 3H), 6.24 (bs, 1H), 6.44 (bs, 1H), 6.92 (bs, 1H), 7.17- 7.21 (m, 3H), 7.41 (bs, 1H), 7.65 (bs, 1H), 8.73 (bs, 1H). 487.23 183 (S)-1-(2- fluoro-5- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.5 Hz, 3H), 2.97 (s, 3H), 3.62 (s, 3H), 4.40 (d, J = 4.85 Hz, 2H), 4.61-4.65 (q, J = 6.3 Hz, 1H), 4.98 (d, J = 16.8 Hz, 1H), 5.24 (d, J = 16.65 Hz, 1H), 6.53-6.54 (m, 1H), 6.81-6.84 (m, 1H), 7.13-7.25 (m, 5H), 7.45 (d, J = 7.85 Hz, 1H), 8.85 (t, J = 4.85 Hz, 1H). 502.17 184 0 (S)-1-((5- chloro-3- fluoro-2- methoxypyri- din-4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.24 (d, J = 6.5 Hz, 3H), 2.92 (s, 3H), 3.90 (s, 3H), 4.48-4.39 (m, 2H), 4.59-4.55 (m, 1H), 5.00 (d, J = 16.2 Hz, 1H), 5.39 (d, J = 16.1 Hz, 1H), 7.25- 7.18 (m, 3H), 7.38 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H), 8.83 (t, J = 4.8 Hz, 1H). 537.13 185 (S)-methyl 2- chloro-3- ((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)-4- fluorobenzoate (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J = 5.9 Hz, 3H), 2.92 (s, 3H), 3.84 (s, 3H), 4.54-4.41 (m, 3H), 4.99 (d, J = 15.5 Hz, 1H), 5.47 (d, J = 15.6 Hz, 1H), 7.23-7.18 (m, 3H), 7.29 (t, J = 9.0 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.49 (s, 1H), 7.73 (t, J = 6.5 Hz, 1H), 8.81 (s, 1H). 564.14 186 (S)-1-(3- carbamoyl-2- chloro-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J = 6.1 Hz, 3H), 2.94 (d, 3H), 4.42-4.39 (m, 1H), 4.54-4.47 (m, 2H), 4.94 (d, J = 15.9 Hz, 1H), 5.51 (d, J = 15.8 Hz, 1H), 7.22-7.19 (m, 4H), 7.36 (t, J = 6.6 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.60 (s, 1H), 7.90 (s, 1H), 8.81 (s, 1H). 549.16 187 (S)-2-(4- ((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)- 3,5- difluorophen- 500 MHz; DMSO-d.sub.6): δ 1.13 (d, J = 23.8 Hz, 3H), 2.94 (s, 3H), 3.70 (d, J = 21.8 Hz, 1H), 3.86 (s, 2H), 4.21 (bs, 2H), 4.53- 4.39 (m, 5H), 4.75 (d, J = 15.6 Hz, 1H), 5.54 (d, J = 15.4 Hz, 1H), 6.72 (d, J = 10 Hz, 2H), 7.24-7.19 (m, 3H), 7.40 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 8.82 (bs, 1H). 607.16 oxy)ethyl 2- aminoacetate 188 (S)-1-(3- amino-2- chloro-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J = 6.2 Hz, 3H), 2.94 (s, 3H), 4.41-4.37 (m, 1H), 4.53-4.46 (m, 2H), 4.82 (d, J = 15.9 Hz, 1H), 5.22 (s, 2H), 5.52 (d, J = 15.7 Hz, 1H), 6.70- 6.68 (m, 1H), 6.85 (t, J = 9.5 Hz, 1H), 7.22-7.18 (m, 3H), 7.38 (d, J = 7.7 Hz, 1H), 7.43 (s, 1H), 8.75 (s, 1H). 521.17 189 1-(2-chloro- 6- fluorobenzyl)- 4-methyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.29 (d, J = 6.2 Hz, 3H), 4.43 (s, 3H), 5.02 (d, J = 15.88 Hz, 1H), 5.42 (d, J = 16.00 Hz, 1H), 7.14- 7.21 (m, 4H), 7.29-7.43 (m, 5H), 8.72 (bs, 1H). 492.2 190 1-benzyl-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.4 Hz, 3H), 2.98 (s, 3H), 4.38 (d, J = 5.0 Hz, 2H), 4.61 (q, J = 6.4 Hz, 1H), 5.04 (d, J = 16.48 Hz, 1H), 5.16 (d, J = 16.48 Hz, 1H), 7.14- 7.23 (m, 7H), 7.28-7.31 (m, 2H), 7.40 (d, J = 7.72 Hz, 1H), 8.79 (t, J = 4.72 Hz, 1H). 454.2 191 1-benzyl-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 5.92 Hz, 3H), 2.97 (s, 3H), 4.39 (d, J = 5.92 Hz, 2H), 4.61 (q, J = 6.4 Hz, 1H), 5.04 (d, J = 16.96 Hz, 1H), 5.18 (d, J = 16.44 Hz, 1H), 7.14- 7.29 (m, 8H), 7.40 (d, J = 7.52 Hz, 2H), 8.79 (bs, 1H). 454.3 192 1-benzyl-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 5.8 Hz, 3H), 2.97 (s, 3H), 4.38 (d, J = 5.92 Hz, 2H), 4.62 (q, J = 6.0 Hz, 1H), 5.04 (d, J = 15.68 Hz, 1H), 5.18 (d, J = 16.24 Hz, 1H), 7.14- 7.22 (m, 7H), 7.28 (d, J = 6.84 Hz, 2H), 7.39 (d, J = 7.0 Hz, 1H), 8.79 (bs, 1H). 454.1 193 1-(2-bromo- 6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.12 Hz, 3H), 2.92 (s, 3H), 4.39-4.49 (m, 2H), 4.53 (d, J = 6.32 Hz, 1H), 4.91 (d, J = 15.56 Hz, 1H), 5.47 (d, J = 15.84 Hz, 1H), 7.16- 7.25 (m, 5H), 7.39-7.46 (m, 3H), 8.75 (bs, 1H). 550.2 194 0 1-(2- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 5.36 Hz, 3H), 2.96 (s, 3H), 4.39 (s, 2H), 4.62 (q, J = 4.48 Hz, 1H), 5.05 (d, J = 16.72 Hz, 1H), 5.25 (d, J = 17.12 Hz, 1H), 7.02- 7.27 (m, 8H), 7.42 (d, J = 6.44 Hz, 1H), 8.81 (bs, 1H). 472.3 195 1-(2,6- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.44 Hz, 3H), 2.93 (s, 3H), 4.37-4.54 (m, 3H), 4.85 (d, J = 15.88 Hz, 1H), 5.57 (d, J = 15.92 Hz, 1H), 7.09 (t, J = 8.16 Hz, 2H), 7.17- 7.23 (m, 3H), 7.31 (t, J = 7.92 Hz, 1H), 7.37 (d, J = 9.32 Hz, 1H), 7.44 (s, 1H), 8.77 (t, J = 5.0 Hz, 1H). 490.1 196 1-(2-fluoro- 6- (trifluorometh- yl)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.26 (d, J = 6.52 Hz, 3H), 2.91 (s, 3H), 4.40 (d, J = 4.56 Hz, 2H), 4.58 (q, J = 6.56 Hz, 1H), 5.15 (d, J = 16.64 Hz, 1H), 5.41 (d, J = 16.72 Hz, 1H), 7.16 (t, J = 8.64 Hz, 2H), 7.22 (d, J = 7.84 Hz, 1H), 7.31 (s, 1H), 7.39-7.44 (m, 2H), 7.49-7.54 (m, 1H), 7.63 (d, J = 7.76 Hz, 1H), 8.74 (t, J = 5.24 Hz, 1H). 540.1 197 N-(2,4- difluoroben- zyl)-1-(2- fluorobenzyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 5.88 Hz, 3H), 2.97 (s, 3H), 4.40 (d, J = 4.04 Hz, 2H), 4.64 (q, J = 5.8 Hz, 1H), 5.07 (d, J = 17.2 Hz, 1H), 5.25 (d, J = 17.16 Hz, 1H), 7.02- 7.09 (m, 3H), 7.21-7.31 (m, 6H), 7.49 (d, J = 7.04 Hz, 1H), 8.95 (bs, 1H). 454.2 198 3,4- dimethyl-1- ((2- methylpyridin- 4- yl)methyl)-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.31 (d, J = 6.16 Hz, 3H), 2.46 (s, 3H), 2.98 (s, 3H), 4.37 (d, J = 3.64 Hz, 2H), 4.66 (q, J = 6.16 Hz, 1H), 5.13 (s, 2H), 7.10 (s, 2H), 7.15 (t, J = 8.52 Hz, 2H), 7.21 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.72 Hz, 1H), 8.41 (d, J = 5.12 Hz, 1H), 8.82 (bs, 1H). 469.41 199 3,4- dimethyl-1- ((3- methylisoxa- zol-5- yl)methyl)-2- oxo-N- (2,4,6- trifluroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.48 Hz, 3H), 2.15 (s, 3H), 2.94 (s, 3H), 4.43 (d, J = 5.04 Hz, 2H), 4.59 (q, J = 6.6 Hz, 1H), 5.18-5.24 (m, 2H), 6.07 (s, 1H), 7.17 (t, J = 8.72 Hz, 2H), 7.24 (d, J = 7.84 Hz, 1H), 7.37 (s, 1H), 7.47 (d, J = 7.72 Hz, 1H), 8.85 (bs, 1H). 459.1 200 3,4- dimethyl-1- ((5- methylisoxa- zol-3- yl)methyl)-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.23-1.26 (m, 3H), 2.33 (s, 3H), 2.95 (s, 3H), 4.42 (d, J = 3.25 Hz, 2H), 4.57 (q, J = 6.88 Hz, 1H), 5.08 (s, 2H), 6.05 (s, 1H), 7.16 (t, J = 8.36 Hz, 2H), 7.22 (d, J = 6.6 Hz, 1H), 7.37 (s, 1H), 7.44 (d, J = 6.6 Hz, 1H), 8.82 (bs, 1H). 459.4 201 1-(2- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.26 (d, J = 6.32 Hz, 3H), 2.96 (s, 3H), 4.39 (s, 2H), 4.62 (q, J = 6.44 Hz, 1H), 5.04 (d, J = 16.68 Hz, 1H), 5.24 (d, J = 16.96 Hz, 1H), 7.00-7.02 (m, 1H), 7.08 (t, J = 6.4 Hz, 1H), 7.13-7.27 (m, 6H), 7.42 (d, J = 6.88 Hz, 1H), 8.81 (s, 1H). 472.2 202 1-(2- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.26 (d, J = 6.16 Hz, 3H), 2.96 (s, 3H), 4.39 (s, 2H), 4.62 (q, J = 6.48 Hz, 1H), 5.04 (d, J = 17.6 Hz, 1H), 5.24 (d, J = 16.48 Hz, 1H), 7.01-7.27 (m, 8H), 7.42 (d, J = 7.76 Hz, 1H), 8.81 (s, 1H). 472.2 203 1-(2-fluoro- 6- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.20 (d, J = 6.24 Hz, 3H), 2.40 (s, 3H), 2.93 (s, 3H), 4.38-4.54 (m, 3H), 4.83 (d, J = 16.04 Hz, 1H), 5.45 (d, J = 16.4 Hz, 1H), 6.90 (t, J = 9.56 Hz, 1H), 6.98 (d, J = 7.24 Hz, 1H), 7.12-7.19 (m, 4H), 7.38-7.42 (m, 2H), 8.74 (bs, 1H). 486.3 204 0 2-((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)-3- fluorophenyl methanesulfo- nate (400 MHz; DMSO-d.sub.6): δ 1.08 (d, J = 6.44 Hz, 3H), 2.94 (s, 3H), 3.53 (s, 3H), 4.44 (bs, 2H), 4.52 (q, J = 6.76 Hz, 1), 4.84 (d, J = 16.36 Hz, 1H), 5.65 (d, J = 17.0 Hz, 1H), 7.12-7.28 (m, 5H), 7.37-7.42 (m, 3H), 8.72 (bs, 1H). 566.1 205 1-(2,6- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.48 Hz, 3H), 2.93 (s, 3H), 4.40-4.46 (m, 2H), 4.50 (q, J = 6.52 Hz, 1H), 4.86 (d, J = 15.84 Hz, 1H), 5.57 (d, J = 15.92 Hz, 1H), 7.02 (t, J = 8.2 Hz, 2H), 7.16-7.21 (m, 3H), 7.29-7.35 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 8.76 (t, J = 5.04 Hz, 1H). 490.2 206 1-(2,6- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.52 Hz, 3H), 2.93 (s, 3H), 4.37-4.49 (m, 2H), 4.52 (q, J = 6.40 Hz, 1H), 4.85 (d, J = 15.84 Hz, 1H), 5.57 (d, J = 15.92 Hz, 1H), 7.02 (t, J = 8.2 Hz, 2H), 7.16-7.21 (m, 3H), 7.29-7.35 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 8.76 (t, J = 5.0 Hz, 1H). 490.2 207 3,4- dimethyl-1- ((2- methylpyridin- 4- yl)methyl)-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.44 Hz, 3H), 2.40 (s, 3H), 2.98 (s, 3H), 4.37 (s, 2H), 4.65 (q, J = 5.4 Hz, 1H), 5.08 (s, 2H), 6.95 (d, J = 5.12 Hz, 1H), 7.05 (s, 1H), 7.11-7.17 (m, 3H), 7.24 (d, J = 7.56 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 8.34 (d, J = 4.52 Hz, 1H), 8.80 (bs, 1H). 469.0 208 3,4- dimethyl-1- ((2- methylpyridin- 4- yl)methyl)-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.40 Hz, 3H), 2.40 (s, 3H), 2.98 (s, 3H), 4.37 (d, J = 4.24 Hz, 2H), 4.65 (q, J = 6.08 Hz, 1H), 5.08 (s, 2H), 6.95 (d, J = 5.10 Hz, 1H), 7.05 (s, 1H), 7.11-7.17 (m, 3H), 7.24 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.64 Hz, 1H), 8.34 (d, J = 4.68 Hz, 1H), 8.80 (bs, 1H). 469.0 209 1-(2-fluoro- 6- (trifluorometh- yl)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (400 MHz; DMSO-d.sub.6): δ 1.26 (d, J = 6.72 Hz, 3H), 2.91 (s, 3H), 4.40 (d, J = 4.36 Hz, 2H), 4.57 (q, J = 6.52 Hz, 1H), 5.15 (d, J = 16.64 Hz, 1H), 5.41 (d, J = 16.68 Hz, 1H), 7.16 (t, J = 8.64 Hz, 2H), 7.22 (d, J = 7.84 Hz, 1H), 7.31 (s, 1H), 7.39-7.43 (m, 2H), 7.48-7.54 (m, 1H), 7.63 (d, J = 7.84 Hz, 1H), 8.74 (t, J = 5.0 Hz, 1H). 540.0 210 1-(2,4- difluoro-6- (trifluorometh- oxy)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.29 (d, J = 6.5 Hz, 3H), 2.97 (s, 3H), 4.40 (d, J = 5.0 Hz, 2H), 4.62-4.66 (q, J = 6.3 Hz, 1H), 5.06 (d, J = 17.05 Hz, 1H), 5.18 (d, J = 17.2 Hz, 1H), 7.08-7.10 (m, 2H), 7.15- 7.26 (m, 4H), 7.43 (t, J = 8.95 Hz, 2H), 8.80 (t, J = 4.9 Hz, 1H). 556.23 211 1-((3- fluoropyridin- 4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.31 (d, J = 6.55 Hz, 3H), 2.97 (s, 3H), 4.39 (d, J = 5.0 Hz, 2H), 4.66 (d, J = 6.5 Hz, 1H), 5.15 (d, J = 17.55 Hz, 1H), 5.24 (d, J = 17.55 Hz, 1H), 7.00 (t, J = 5.65 Hz, 1H), 7.18-7.18 (m, 3H), 7.28 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 8.31 (d, J = 4.75 Hz, 1H), 8.58 (s, 1H), 8.85 (t, J = 4.95 Hz, 1H). 473.24 212 1-(2-chloro- 6- fluorobenzyl)- 3,4- dimethyl-N- ((5- methylfuran- 2-yl)methyl)- 2-oxo- 1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.24 (d, J = 6.55 Hz, 3H), 2.23 (s, 3H), 2.94 (s, 3H), 4.33-4.43 (m, 2H), 4.53- 4.57 (q, J = 6.5 Hz, 1H), 4.95 (d, J = 15.75 Hz, 1H), 5.54 (d, J = 15.75 Hz, 1H), 5.99 (d, J = 2.2 Hz, 1H), 6.12 (d, J = 2.9 Hz, 1H), 7.13-7.17 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.29-7.33 (m, 2H), 7.46 (d, J = 7.9 Hz, 1H), 456.24 7.52 (s, 1H), 8.84 (t, J = 5.65 Hz, 1H). 213 N- (benzofuran- 2-ylmethyl)- 1-(2-chloro- 6- fluorobenzyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.3 Hz, 3H), 2.94 (s, 3H), 4.55-4.65 (m, 3H), 4.95 (d, J = 15.6 Hz, 1H), 5.55 (d, J = 16.05 Hz, 1H), 6.73 (s, 1H), 7.14 (t, J = 8.25 Hz, 1H), 7.20-7.32 (m, 5H), 7.49-7.60 (m, 4H), 9.05 (bs, 1H). 492.56 214 00 N,1-dibenzyl- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.45 Hz, 3H), 3.00 (s, 3H), 4.42 (d, J = 5.7 Hz, 2H), 4.63-4.67 (q, J = 6.3 Hz, 1H), 5.07-5.21 (m, 2H), 7.23-7.49 (m, 13H), 8.98 (t, J = 6.05 Hz, 1H). 400.25 215 01 1-(2,6- dimethylben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): 1.26 (d, J = 6.55 Hz, 3H), 2.32 (s, 6H), 2.92 (s, 3H), 4.39-4.49 (m, 2H), 4.55- 4.59 (q, J = 6.4 Hz, 1H), 4.79 (d, J = 15.4 Hz, 1H), 5.32 (d, J = 16.8 Hz, 1H), 6.94-7.02 (m, 3H), 7.19- 7.22 (m, 3H), 7.40-7.43 (m, 2H), 8.77 (t, J = 5.05 Hz, 1H). 482.25 216 02 1-(2- (difluorometh- oxy)-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide 500 MHz; DMSO-d.sub.6): 1.19 (d, J = 6.5 Hz, 3H), 2.93 (s, 3H), 4.39-4.54 (m, 3H), 4.82 (d, J = 15.75 Hz, 1H), 5.56 (d, J = 15.75 Hz, 1H), 7.00- 7.08 (m, 2H), 7.17-7.27 (m, 3H), 7.33-7.53 (m, 4H), 8.76 (t, J = 4.9 Hz, 1H). 538.18 217 03 1-(2-fluoro- 4- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.6 Hz, 3H), 2.97 (s, 3H), 3.72 (s, 3H), 4.40-4.42 (m, 2H), 4.60- 4.61 (m, 1H), 4.93 (d, J = 16.45 Hz, 1H), 5.21 (d, J = 16.45 Hz, 1H), 6.67- 6.69 (dd, J.sub.1 = 2.3 Hz, J.sub.2 = 8.6 Hz, 1H), 6.82-6.85 (dd, J.sub.1 = 2.3 Hz, J.sub.2 = 12.35 Hz, 1H), 6.97 (t, J = 8.7 Hz, 1H), 7.17-7.26 (m, 4H), 7.42 (d, J.sub.1 = 1 Hz, 502.21 1H), 8.84 (t, J = 5.1 Hz, 1H). 218 04 1-(4- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.5 Hz, 3H), 2.98 (s, 3H), 4.40 (d, J = 4.8 Hz, 2H), 4.61-4.64 (q, J = 6.35 Hz, 1H), 5.05-5.15 (m, 2H), 7.12- 7.27 (m, 8H), 7.42 (d, J = 7.7 Hz, 1H), 8.84 (t, J = 5.0 Hz, 1H). 472.18 219 05 1-(4-chloro- 2- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.45 Hz, 3H), 2.97 (s, 3H), 4.40 (d, J = 4.85 Hz, 2H), 4.61-4.65 (q, J = 7.56 Hz, 1H), 5.05 (d, J = 17 Hz, 1H), 5.19 (d, J = 17.2 Hz, 1H), 7.02 (t, J = 8.2 Hz, 1H), 7.16- 7.21 (m, 4H), 7.25 (d, J = 7.8 Hz, 1H), 7.44-7.49 (m, 2H), 8.85 (t, J = 4.9 Hz, 1H). 506.17 220 06 1-(2-bromo- 6-fluoro-3- methylbenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.6 Hz, 3H), 2.32 (s, 3H), 2.93 (s, 3H), 4.38-4.49 (m, 2H), 4.52- 4.56 (q, J = 6.2 Hz, 1H), 4.97 (d, J = 15.55 Hz, 1H), 5.47 (d, J = 15.8 Hz, 1H), 7.08 (t, J = 10.25 Hz, 1H), 7.19-7.22 (m, 3H), 7.30-7.32 (m, 1H), 7.39-7.41 (m, 2H), 8.76 (t, J = 5.05 Hz, 1H). 564.12 221 07 1-(2-chloro- 4- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.32 (d, J = 5.05 Hz, 3H), 2.97 (s, 3H), 4.39 (d, J = 5.05 Hz, 2H), 4.64-4.68 (q, J = 6.35 Hz, 1H), 5.08 (s, 2H), 6.93-6.95 (m, 1H), 7.06 (s, 1H), 7.12- 7.18 (m, 3H), 7.27 (d, J = 7.9 Hz, 1H), 7.45-7.47 (dd, J.sub.1 = 1.05 Hz, J.sub.2 = 7.85 Hz, 1H), 7.51-7.54 (dd, J.sub.1 = 2.6 Hz, J.sub.2 = 8.5 Hz, 1H), 8.84 (t, J = 5.10 506.17 Hz, 1H). 222 08 1-(4-chloro- 2,6- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.18 (d, J = 6.5 Hz, 3H), 2.93 (s, 3H), 4.39-4.50 (m, 2H), 4.51-4.55 (q, J = 6.3 Hz, 1H), 4.86 (d, J = 15.9 Hz, 1H), 5.50 (d, J = 16 Hz, 1H), 7.17-7.23 (m, 3H), 7.33 (d, J = 7.8 Hz, 2H), 7.42-7.43 (m, 2H), 8.82 (t, J = 5 Hz, 1H). 524.17 223 09 1-((1,3- dimethyl-1H- pyrazol-5- yl)methyl)- N-((5- fluorobenzo- furan-2- yl)methyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.26 (d, J = 5.45 Hz, 3H), 1.99 (s, 3H), 2.96 (s, 3H), 3.77 (s, 3H), 4.63 (bs, 3H), 4.98 (d, J = 16.55 Hz, 1H), 5.26 (d, J = 16.65 Hz, 1H), 5.67 (s, 1H), 6.72 (s, 1H), 7.11 (t, J = 9.4 Hz, 1H), 7.29 (d, J = 7.45 Hz, 1H), 7.39- 7.42 (m, 2H), 7.54-7.57 (m, 2H), 9.13 (bs, 1H). 476.25 224 0 1-((4-fluoro- 1,3-dimethyl- 1H-pyrazol- 5-yl)methyl)- N-((5- fluorobenzo- furan-2- yl)methyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSOd.sub.6): δ 1.23 (d, J = 4.25 Hz, 3H), 1.99 (s, 3H), 2.96 (s, 3H), 3.73 (s, 3H), 4.60-4.66 (m, 3H), 4.95 (d, J = 16.75 Hz, 1H), 5.44 (d, J = 16.85 Hz, 1H), 6.74 (s, 1H), 7.11 (t, J = 9.05 Hz, 1H), 7.27 (d, J = 6.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.47 (s, 1H), 7.53- 7.57 (m, 2H), 9.10 (bs, 1H). 494.25 225 1-(2-fluoro- 6- (methylsulfona- mido)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.15 (d, J = 5.05 Hz, 3H), 2.94 (s, 3H), 3.08 (s, 3H), 4.46-4.54 (m, 3H), 5.07 (d, J = 17.1 Hz, 1H), 5.33 (d, J = 16 Hz, 1H), 7.01 (bs, 1H), 7.20-7.23 (m, 4H), 7.3 (bs, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.54 (bs, 1H), 8.82 (bs, 1H), 9.47 (bs, 1H). 565.22 226 1-(2- acetamido-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.11 (d, J = 5.45 Hz, 3H), 2.06 (s, 3H), 2.95 (s, 3H), 4.46-4.53 (m, 3H), 4.91 (d, J = 15.95 Hz, 1H), 5.39 (d, J = 15.3 Hz, 1H), 6.91 (t, J = 8.9 Hz, 1H), 7.19-7.25 (m, 4H), 7.41-7.47 (m, 2H), 7.56 (s, 1H), 8.73 (bs, 1H), 9.59 (s, 1H). 529.21 227 (S)-1-((3- fluoropyridin- 2- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.45 Hz, 3H), 2.92 (s, 3H), 4.38 (d, J = 4.8 Hz, 2H), 4.57-4.61 (q, J = 6.1 Hz, 1H), 5.22 (d, J = 17.15 Hz, 1H), 5.32 (d, J = 17.05 Hz, 1H), 7.15- 7.18 (m, 2H), 7.21-7.24 (m, 2H), 7.33-7.37 (m, 1H), 7.41 (d, J = 7.65 Hz, 1H), 7.71 (t, J = 9.3 Hz, 1H), 8.23 (d, J = 4.45 Hz, 1H), 8.80 (t, J = 4.9 Hz, 473.15 1H). 228 2-(4-((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)-3- fluorophenoxy) acetic acid (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.4 Hz, 3H), 2.96 (s,, 3H), 4.37-4.45 (m, 2H), 4.59-4.63 (q, J = 6.35 Hz, 1H), 4.67 (s, 2H), 4.94 (d, J = 16.5 Hz, 1H), 5.20 (d, J = 16.55 Hz, 1H), 6.66-6.68 (m, 1H), 6.82-6.84 (m, 1H), 6.93-6.97 (m, 1H), 7.18-7.26 (m, 4H), 7.43 (d, J = 7.35 Hz, 1H), 8.84 (t, J = 5 Hz, 1H), 13.06 (bs, 1H). 546.13 229 2-(3-((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)-4- fluorophenoxy) acetic acid (500 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 6.35 Hz, 3H), 2.98 (s, 3H), 4.40 (d, J = 4.45 Hz, 2H), 4.53 (s, 2H), 4.63-4.64 (m, 1H), 5.02 (d, J = 16.75 Hz, 1H), 5.19 (d, J = 17.4 Hz, 1H), 6.50 (bs, 1H), 6.77- 6.79 (m, 1H), 7.13-7.18 (m, 3H), 7.22-7.26 (m, 2H), 7.45 (d, J = 7.5 Hz, 1H), 8.85 (bs, 1H), 13.01 (bs, 1H). 546.16 230 1-(2-fluoro- 4-(2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 4.9 Hz, 3H), 2.97 (s, 3H), 3.68 (s, 2H), 3.95 (s, 2H), 4.41 (s, 2H), 4.61 (d, J = 4.75 Hz, 1H), 4.81-4.96 (m, 2H), 5.19 (d, J = 16.4 Hz, 1H), 6.68 (d, J = 6.9 Hz, 1H), 6.83 (d, J = 11.85 Hz, 1H), 6.95 (m, 1H), 7.182-7.25 (m, 4H), 7.42 (d, J = 6.9 Hz, 1H), 8.84 (bs, 1H). 532.17 231 1-(2-fluoro- 5- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.45 Hz, 3H), 2.97 (s, 3H), 4.40 (d, J = 4.7 Hz, 2H), 4.63-4.66 (q, J = 6.15 Hz, 1H), 5.0 (d, J = 17.15 Hz, 1H), 5.10 (d, J = 17.45 Hz, 1H), 6.34 (m, 1H), 6.59-6.60 (m, 1H), 7.01 (t, J = 9.2 Hz, 1H), 7.15-7.18 (m, 3H), 7.25 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 8.85 (t, J = 4.95 Hz, 488.15 1H), 9.29 (s, 1H). 232 (S)-1-((3- bromo-5- fluoropyridin- 4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 5.4 Hz, 3H), 2.92 (s, 3H), 4.42 (bs, 2H), 5.58 (d, J = 5.7 Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H), 5.35 (d, J = 16.1 Hz, 1H), 7.18-7.47 (m, 5H), 8.49 (s, 1H), 8.62 (s, 1H), 8.83 (bs, 1H). 551.06 carboxamide 233 1-(2-fluoro- 5-(2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 6.45 Hz, 3H), 2.97 (s, 3H), 3.59-3.62 (q, J = 5.15 Hz, 2H), 3.82 (t, J = 4.75 Hz, 2H), 4.40 (d, J = 4.85 Hz, 2H), 4.62-4.66 (q, J = 6.2 Hz, 1H), 4.82 (t, J = 5.65 Hz, 1H), 5.03 (d, J = 17.05 Hz, 1H), 5.16 (d, J = 17.2 Hz, 1H), 6.48 (bs, 1H), 6.82-6.84 (m, 1H), 7.13-7.26 (m, 5H), 7.45 532.18 (d, J = 7.6 Hz, 1H), 8.85 (t, J = 4.85 Hz, 1H). 234 0 2-(2-((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)-3- fluorophenoxy) acetic acid (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.45 Hz, 3H), 2.95 (s, 3H), 3.39-3.51 (m, 3H), 4.70-4.85 (m, 3H), 5.62 (d, J = 15.65 Hz, 1H), 6.70-6.74 (m, 2H), 7.13-7.22 (m, 4H), 7.35 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 8.70 (t, J = 4.6 Hz, 1H), 13.09 (bs, 1H). 546.17 235 1-(2-chloro- 6- fluorobenzyl)- N-(4- hydroxybenzyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.24 (d, J = 6.45 Hz, 3H), 2.94 (s, 3H), 4.29-4.38 (m, 2H), 4.54-4.55 (m, 1H), 4.94 (d, J= 2.3 Hz, 1H), 5.55 (d, J = 15.75 Hz, 1H), 6.71 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 7.14-7.17 (m, 1H), 7.22 (d, J = 7.75 Hz, 1H), 7.30-7.33 (m, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.51 (bs, 1H), 8.84 (t, J = 468.15 5.75 Hz, 1H), 9.29 (bs, 1H). 236 1-(2-fluoro- 6-(2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.14 (d, J = 6.1 Hz, 3H), 2.97 (s, 3H), 3.70-3.75 (m, 2H), 3.91 (bs, 1H), 4.03-4.04 (m, 1H), 4.44- 4.45 (m, 2H), 4.50-4.52 (m, 1H), 4.81 (d, J = 16.05 Hz, 2H), 5.62 (d, J = 15.3 Hz, 1H), 6.70 (t, J = 9.05 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 7.65 Hz, 1H), 7.19-7.20 (m, 3H), 7.36 (d, J = 7.15 532.20 Hz, 1H), 7.53 (bs, 1H), 8.74 (bs, 1H). 237 1-((5-fluoro- 2- methylpyridin- 4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- (500 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.5 Hz, 3H), 2.33 (bs, 3H), 2.97 (bs, 3H), 4.40 (d, J = 4.9 Hz, 2H), 4.63-4.67 (q, J = 6.3 Hz, 1H), 5.10 (d, J = 17.5 Hz, 1H), 5.19 (d, J = 17.6 Hz, 1H), 6.85 (d, J = 5.75 Hz, 1H), 7.16-7.19 (m, 3H), 7.27 (d, J = 7.85 Hz, 1H), 7.47 (d, J = 7.95 Hz, 1H), 8.41 (s, 1H), 8.86 (t, J = 4.85 Hz, 1H). 487.18 carboxamide 238 1-((3-fluoro- 6- methylpyridin- 2- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- (500 MHz; DMSO-d.sub.6): δ 1.32 (d, J = 6.3 Hz, 3H), 2.28 (s, 3H), 2.93 (s, 3H), 4.41 (d, J = 4.45 Hz, 2H), 4.56-4.57 (m, 1H), 5.05 (d, J = 16.85 Hz, 1H), 5.46 (d, J = 16.95 Hz, 1H), 7.15-7.21 (m, 4H), 7.35 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.95 Hz, 1H), 8.80 (bs, 1H). 487.19 carboxamide 239 (S)-1-(4- azidobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.4 Hz, 3H), 2.98 (s, 3H), 4.39 (d, J = 4.85 Hz, 2H), 4.61-4.64 (q, J = 6.15 Hz, 1H), 5.04-5.16 (m, 2H), 7.07 (d, J = 8.2 Hz, 2H), 7.17- 7.26 (m, 6H), 7.41 (d, J = 7.8 Hz, 1H), 8.84 (t, J = 4.9 Hz, 1H). 495.16 240 2-(4-((1-(2- chloro-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamido) methyl)phen- oxy)acetic acid (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.4 Hz, 3H), 2.94 (bs, 3H), 4.36-4.39 (m, 2H), 4.54-4.55 (m, 1H), 4.65 (s, 2H), 4.94 (d, J = 15.75 Hz, 1H), 5.55 (d, J = 15.75 Hz, 1H), 6.87 (d, J = 8.45 Hz, 2H), 7.14-7.33 (m, 6H), 7.46 (d, J = 7.75 Hz, 1H), 7.52 (s, 1H), 8.90 (bs, 1H), 13.02 (bs, 1H). 526.19 241 (S)-1-(2,3- difluoro-6- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 6.45 Hz, 3H), 2.95 (s, 3H), 3.78 (s, 3H), 4.43-4.45 (m, 2H), 4.49-4.53 (q, J = 6.1 Hz, 1H), 4.80 (d, J = 15.75 Hz, 1H), 5.57 (d, J = 15.75 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.16-7.21 (m, 3H), 7.24-7.30 (q, J = 9.70 Hz, 1H), 7.37 (d, J = 7.70 Hz, 1H), 7.47 (s, 1H), 8.76 (t, J = 4.6 Hz, 1H). 520.17 242 (S)-1-(2,3- difluoro-6- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.20 (d, J = 6.4 Hz, 3H), 2.95 (s, 3H), 4.39-4.48 (m, 2H), 4.50-4.54 (q, J = 6.05 Hz, 1H), 4.79 (d, J = 15.70 Hz, 1H), 5.48 (d, J = 15.75 Hz, 1H), 6.59-6.60 (m, 1H), 7.05- 7.11 (m, 1H), 7.17-7.20 (m, 3H), 7.38 (d, J = 7.8 Hz, 2H), 7.53 (bs, 1H), 8.76 (t, J = 4.75 Hz, 1H). 506.16 243 (S)-1-(4- aminobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J = 6.45 Hz, 3H), 2.96 (s, 3H), 4.41-4.42 (m, 2H), 4.56-4.60 (m, 1H), 4.81-4.84 (m, 1H), 4.96 (bs, 2H), 5.01-5.06 (m, 1H), 6.46 (d, J = 8.15 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H), 7.17-7.21 (m, 3H), 7.32 (s, 1H), 7.39 (d, J = 775 Hz, 1H), 8.84 (t, J = 5 Hz,1H). 469.21 244 0 (S)-2-(2- ((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)- 3,4- difluorophen- oxy)acetic acid (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J = 6.3 Hz, 3H), 1.24 (m, 1H), 2.94 (s, 3H), 4.37-4.42 (m, 4H), 4.54-4.55 (m, 1H), 5.04 (d, J = 16.7 Hz, 1H), 5.64 (d, J = 16.4 Hz, 1H), 6.73 (d, J = 7 Hz, 1H), 7.10 (t, J = 8.3 Hz, 2H), 7.16- 7.23 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.68 (bs, 1H), 9.72 (s, 1H). 564.15 245 (S)-1-(2- chloro-6- fluorobenzyl)- N-(2-fluoro- 6- methoxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J = 6.45 Hz, 3H), 2.943 (s, 3H), 3.81 (s, 3H), 4.40-4.49 (m, 2H), 4.51-4.55 (m, 1H), 4.92 (d, J = 15.7 Hz, 1H), 5.54 (d, J = 15.7 Hz, 1H), 6.81 (t, J = 8.8 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 7.13- 7.19 (m, 2H), 7.28-7.35 (m, 3H), 7.41-7.46 (m, 2H), 8.390 (bs, 1H). 500.20 246 (S)-1-(2- chloro-6- fluorobenzyl)- N-(2,6- difluoro-4- methoxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J = 6.5 Hz, 3H), 2.93 (s, 3H), 3.78 (s, 3H), 4.35-4.38 (m, 1H), 4.42-4.46 (m, 1H), 4.50- 4.52 (q, J = 6.3 Hz, 1H), 4.91 (d, J = 15.05 Hz, 1H), 5.54 (d, J = 15.6 Hz, 1H), 6.75 (d, J = 9.5 Hz, 2H), 7.13-7.20 (m, 2H), 7.29-7.35 (m, 2H), 7.41 (d, J = 8.15 Hz, 1H), 7.47 (bs, 1H), 8.68 (t, J = 4.8 518.18 Hz, 1H). 247 (S)-1-(2- chloro-6- fluorobenzyl)- N-(4-fluoro- 2- methoxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.5 Hz, 3H), 2.95 (s, 3H), 3.83 (s, 3H), 4.32-4.41 (m, 2H), 4.54-4.57 (q, J = 6.25 Hz, 1H), 4.95 (d, J = 15.8 Hz, 1H), 5.56 (d, J = 15.85 Hz, 1H), 6.72-6.75 (m, 1H), 6.90-6.93 (m, 1H), 7.13-7.18 (q, J = 9.25 Hz, 2H), 7.24 (d, J = 7.75 Hz, 1H), 7.30-7.36 (m, 2H), 7.49 (d, J = 7.75 Hz, 500.18 1H), 7.52 (s, 1H), 8.77 (t, J = 5.65 Hz, 1H). 248 (S)-1-(2- chloro-6- fluorobenzyl)- N-(3-fluoro- 5- methoxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.5 Hz, 3H), 2.95 (s, 3H), 3.75 (s, 3H), 4.37-4.47 (m, 2H), 4.54-4.58 (q, J = 5.95 Hz, 1H), 4.94 (d, J = 15.65 Hz, 1H), 5.58 (d, J = 15.65 Hz, 1H), 6.66-6.72 (m, 3H), 7.15 (t, J = 9.3 Hz, 1H), 7.25 (d, J = 7.7 Hz, 2H), 7.29-7.34 (m, 2H), 7.47 (d, J = 7.75 Hz, 1H), 7.52 (s, 1H), 8.98 (t, J = 5.45 Hz, 1H). 500.15 249 (S)-1-(2- chloro-6- fluorobenzyl)- N-(2-fluoro- 3- methoxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.7 Hz, 3H), 2.95 (s, 3H), 3.83 (s, 3H), 4.43-4.52 (m, 2H), 4.53-4.57 (q, J = 6.6 Hz, 1H), 4.94 (d, J = 15.8 Hz, 1H), 5.56 (d, J = 15.7 Hz, 1H), 6.85-6.88 (m, 1H), 7.05-7.11 (m, 2H), 7.16 (t, J = 9.35 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.29-7.35 (m, 2H), 7.47 (d, J = 7.85 Hz, 1H), 7.51 (s, 1H), 500.15 8.93 (t, J = 5.5 Hz, 1H). 250 (S)-1-(2- chloro-6- fluorobenzyl)- N-(3-fluoro- 5- hydroxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.45 Hz, 3H), 2.95 (s, 3H), 4.32-4.42 (m, 2H), 4.54-4.57 (m, 1H), 4.94 (d, J = 15.75 Hz, 1H), 5.57 (d, J = 15.65 Hz, 1H), 6.42 (d, J = 9.45 Hz, 1H), 6.51-6.55 (m, 2H), 7.16 (t, J = 8.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.29-7.35 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 8.96 (t, J = 6.2 Hz, 1H), 486.15 9.89 (s, 1H). 251 (S)-1-(2- chloro-6- fluorobenzyl)- N-(2-fluoro- 6- hydroxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J = 6.5 Hz, 3H), 2.93 (s, 3H), 4.38-4.46 (m, 2H), 4.51-4.55 (q, J = 6.2 Hz, 1H), 4.94 (d, J = 15.7 Hz, 1H), 5.53 (d, J= 15.6 Hz, 1H), 6.63-6.70 (m, 2H), 7.13-7.16 (m, 2H), 7.20 (d, J = 7.8 Hz, 1H), 7.28-7.34 (m, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 8.71 (bs, 1H), 10.18 (bs, 1H). 486.12 252 (S)-1-(2- chloro-6- fluorobenzyl)- N-(2,6- difluoro-4- hydroxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23 (d, J = 6.5 Hz, 3H), 2.93 (s, 3H), 4.31-4.35 (m, 1H), 4.38-4.42 (m, 1H), 4.51-4.55 (m, 1H), 4.92 (d, J = 15.7 Hz, 1H), 5.54 (d, J = 15.7 Hz, 1H), 6.46 (d, J = 9.25 Hz, 2H), 7.13-7.20 (m, 2H), 7.28- 7.35 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 8.62 (t, J = 4.65 Hz, 1H), 10.34 (bs, 1H). 504.14 253 (S)-1-(2- chloro-6- fluorobenzyl)- N-(4-fluoro- 2- hydroxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.5 Hz, 3H), 2.95 (s, 3H), 4.30-4.39 (m, 2H), 4.53-4.57 (q, J = 6.25 Hz, 1H), 4.95 (d, J = 15.75 Hz, 1H), 5.56 (d, J = 15.8 Hz, 1H), 6.57- 6.62 (m, 2H), 7.10 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 8.9 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.30-7.35 (m, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H), 486.15 8.84 (t, J = 5.55 Hz, 1H), 10.13 (s, 1H). 254 0 (S)-1-(2,3- difluoro-6- (2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- (500 MHz; DMSO-d.sub.6): δ 1.15 (d, J = 6.45 Hz, 3H), 2.97 (s, 3H), 3.62-3.74 (m, 2H), 3.88-3.92 (m, 1H), 4.01-4.05 (m, 1H), 4.40-4.47 (m, 2H), 4.51- 4.55 (q, J = 6.35 Hz, 1H), 4.79 (t, J = 6.05 Hz, 1H), 4.88 (d, J = 15.65 Hz, 1H), 5.60 (d, J = 15.65 Hz, 1H), 6.78-6.79 (m, 1H), 7.17-7.28 (m, 4H), 7.38 (d, J = 7.7 Hz, 1H), 550.16 carboxamide 7.49 (s, 1H), 8.77 (t, J = 6.45 Hz, 1H). 255 (S)-1-(2,6- difluoro-3- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.18 (d, J = 6.4 Hz, 3H), 2.94 (s, 3H), 4.38-4.55 (m, 3H), 4.84 (d, J = 15.95 Hz, 1H), 5.54 (d, J = 15.9 Hz, 1H), 6.80-6.82 (m, 2H), 7.18-7.21 (m, 3H), 7.41 (d, J = 7.7 Hz, 1H), 7.44 (s, 1H), 8.80 (t, J = 4.9 Hz, 1H), 9.80 (bs, 1H). 506.20 256 (S)-1-(2,6- difluoro-3- (2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.18 (d, J = 6.35 Hz, 3H), 2.94 (s, 3H), 3.66-3.68 (m, 2H), 3.97-3.99 (m, 2H), 4.38-4.55 (m, 3H), 4.86-4.91 (m, 2H), 5.53 (d, J = 16 Hz, 1H), 6.95 (t, J = 9.35 Hz, 1H), 7.05-7.08 (m, 1H), 7.18- 7.22 (m, 3H), 7.41 (d, J = 7.75 Hz, 1H), 7.45 (s, 1H), 8.82 (t, J = 4.5 Hz, 1H). 550.18 257 (S)-1-(2,6- difluoro-3- (3- hydroxyprop- oxy)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.4 Hz, 3H), 1.79-1.84 (m, 2H), 2.94 (s, 3H), 3.49-3.53 (m, 2H), 4.03 (bs, 2H), 4.38- 4.57 (m, 4H), 4.87 (d, J = 15.8 Hz, 1H), 5.54 (d, J = 15.85 Hz, 1H), 6.95 (t, J = 9.5 Hz, 1H), 7.04-7.08 (m, 1H), 7.18-7.21 (m, 3H), 7.41 (d, J = 7.95 Hz, 1H), 7.44 (s, 1H), 8.81 (t, J = 4.75 Hz, 1H). 564.19 258 (S)-1-(2,6- difluoro-3- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.25 Hz, 3H), 2.94 (s, 3H), 3.77 (s, 3H), 4.38-4.53 (m, 3H), 4.85 (d, J = 16.3 Hz, 1H), 5.57 (d, J = 15.9 Hz, 1H), 6.95-7.21 (m, 5H), 7.41 (d, J = 7.75 Hz, 1H), 7.44 (s, 1H), 8.81 (bs, 1H). 520.21 259 (S)-1-(2,4- difluoro-6- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): 1.15 (d, J = 6.35 Hz, 3H), 2.94 (s, 3H), 3.81 (s, 3H), 4.44-4.50 (m, 3H), 4.70 (d, J = 15.55 Hz, 1H), 5.53 (d, J = 15.6 Hz, 1H), 6.72 (t, J = 9.2 Hz, 1H), 6.79 (d, J = 10.45 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.19-7.22 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 8.75 (bs, 1H). 520.18 260 (S)-1-(2,4- difluoro-6- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.18 (d, J = 6.35 Hz, 3H), 2.94 (s, 3H), 4.40-4.50 (m, 3H), 4.69 (d, J = 15.55 Hz, 1H), 5.46 (d, J = 15.6 Hz, 1H), 6.45 (d, J = 10.35 Hz, 1H), 6.52 (t, J = 9.35 Hz, 1H), 7.15- 7.22 (m, 3H), 7.37 (d, J = 7.65 Hz, 1H), 7.55 (s, 1H), 8.76 (bs, 1H), 10.85 (bs, 1H). 506.17 261 (S)-1-((3- fluoro-2- methylpyridin- 4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.4 Hz, 3H), 2.47 (bs, 3H), 2.97 (s, 3H), 4.390-4.398 (m, 2H), 4.66-4.66 (m, 1H), 5.11-5.22 (m, 2H), 6.79 (bs, 1H), 7.14-7.21 (m, 3H), 7.27-7.32 (m, 1H), 7.47 (d, J = 7.75 Hz, 1H), 8.15 (d, J = 4.8 Hz, 1H), 8.85 (bs, 1H). 487.20 262 (S)-1-(2- fluoro-5- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.4 Hz, 3H), 2.97 (s, 3H), 4.4 (d, J = 4.75 Hz, 2H), 4.63-4.66 (q, J = 6.2 Hz, 1H), 4.98- 5.12 (m, 2H), 6.33-6.34 (m, 1H), 6.59-6.60 (m, 1H), 7.01 (t, J = 9.7 Hz, 1H), 7.15-7.18 (m, 3H), 7.25 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.65 Hz, Hz, 1H), 8.85 (t, J = 4.8 Hz, 1H), 9.29 (s, 1H). 488.16 263 (S)-1-(2- fluoro-5-(2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 6.4 Hz, 3H), 2.97 (s, 3H), 3.59-3.62 (m, 2H), 3.82 (t, J = 4.4 Hz, 2H), 4.40 (d, J = 4.75 Hz, 2H), 4.62-4.65 (m, 1H), 4.81-4.83 (m, 1H), 5.02-5.17 (m, 2H), 6.48- 6.57 (m, 1H), 6.82-6.84 (m, 1H), 7.13-7.26 (m, 5H), 7.45 (d, J = 7.45 Hz, 1H), 8.86 (t, J = 4.75 Hz, 1H). 532.19 264 0 (S)-1-(2- fluoro-6-((2- hydroxyethyl) amino)ben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide hydrochloride (500 MHz; DMSO-d.sub.6): δ 1.11 (d, J = 6.5 Hz, 3H), 2.96 (s, 3H), 3.09-3.13 (m, 2H), 3.55-3.60 (m, 2H), 4.40-4.44 (m, 1H), 4.47-4.51 (m, 2H), 4.87 (d, J = 15.85 Hz, 1H), 5.39 (d, J = 16.1 Hz, 1H), 6.32 (t, J = 9.35 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 7.02-7.06 (m, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.20- 7.23 (m, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 531.23 8.75 (t, J = 4.65 Hz, 1H). 265 (S)-1-(2- fluoro-4,5- dimethoxy- benzyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J = 6.5 Hz, 3H), 2.97 (s, 3H), 3.58 (s, 3H), 3,.72 (s, 3H), 4.43 (d, J = 4.25 Hz, 2H), 4.56-4.59 (q, J = 6.35 Hz, 1H), 4.80 (d, J = 16.05 Hz, 1H), 5.41 (d, J = 15.9 Hz, 1H), 6.79 (d, J = 7.15 Hz, 1H), 6.86 (d, J = 11.75 Hz, 1H), 7.18-7.21 (m, 3H), 7.40 (s, 1H), 7.43 (d, J = 7.85 Hz, 1H), 532.20 8.84 (t, J = 5 Hz, 1H). 266 (S)-1-(2- chloro-6- fluorobenzyl)- N-(3-fluoro- 5-(2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.3 Hz, 3H), 2.95 (s, 3H), 3.70 (d, J = 4.2 Hz, 2H), 3.97 (bs, 2H), 4.38-4.45 (m, 2H), 4.55-4.57 (m, 1H), 4.90- 4.95 (m, 2H), 5.58 (d, J = 15.75 Hz, 1H), 6.66-6.71 (m, 3H), 7.17-7.18 (m, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.31-7.40 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H), 8.99 (bs, 1H). 530.19 267 (S)-1-(2- chloro-6- fluorobenzyl)- N-(2-fluoro- 3- hydroxyben- zyl)-3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.5 Hz, 3H), 2.95 (s, 3H), 4.41-4.51 (m, 2H), 4.53-4.57 (q, J = 5.8 Hz, 1H), 4.94 (d, J = 15.75 Hz, 1H), 5.55 (d, J = 15.85 Hz, 1H), 6.70 (t, J = 6.5 Hz, 1H), 6.84 (t, J = 7.75 Hz, 1H), 6.92 (t, J = 7.9 Hz, 1H), 7.16 (t, J = 8.9 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.30-7.35 (m, 2H), 7.48 (d, J = 7.75 486.16 Hz, 1H), 7.52 (s, 1H), 8.89 (t, J = 5.6 Hz, 1H), 9.80 (bs, 1H). 268 1-(2-fluoro- 5- (hydroxymeth- yl)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.29 (d, J = 6.3 Hz, 3H), 2.98 (s, 3H), 4.34 (d, J = 5 Hz, 2H), 4.40-4.409 (m, 2H), 4.63-4.64 (m, 1H), 5.04 (d, J = 16.9 Hz, 1H), 5.17 (d, J = 5.45 Hz, 1H), 5.26 (d, J = 16.75 Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 7.15-7.19 (m, 4H), 7.23-7.25 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H), 8.85 (bs, 1H). 502.17 269 (S)-1-(2,6- difluoro-3- (hydroxymeth- yl)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.4 Hz, 3H), 2.94 (s, 3H), 4.44-4.39 (m, 3H), 4.54-4.49 (m, 2H), 4.86 (d, J = 15.8 Hz, 1H), 5.26 (t, J = 5.6 Hz, 1H), 5.57 (d, J = 15.8 Hz, 1H), 7.02 (t, J = 9.0 Hz, 1H), 7.20 (t, J = 9.2 Hz, 3H), 7.40-7.33 (m, 2H), 7.45 (s, 1H), 8.79 (t, J = 4.9 Hz, 1H). 520.18 270 (S)-1-(2,3- difluoro-5- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.5 Hz, 3H), 2.97 (s, 3H), 3.64 (s, 3H), 4.41 (d, J = 4.6 Hz, 2H), 4.63 (d, J = 6.3 Hz, 1H), 5.04 (d, J = 16.9 Hz, 1H), 5.28 (d, J = 16.9 Hz, 1H), 6.36 (bs, 1H), 6.99 (bs, 1H), 7.26-7.15 (m, 4H), 7.46 (d, J = 7.7 Hz, 1H), 8.86 (bs, 1H). 520.16 271 (S)-1-(2- fluoro-5-(3- hydroxyprop- oxy)benzyl)- 3,4- dimethyl-2- oxo-N-(2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.3 Hz, 3H), 1.78-1.73 (m, 2H), 2.97 (s, 3H), 3.46 (d, J = 4.5 Hz, 2H), 3.88 (t, J = 6.2 Hz, 2H), 4.40 (d, J = 4.4 Hz, 2H), 4.51 (s, 1H), 4.65-4.62 (m, 1H), 5.01 (d, J = 16.8 Hz, 1H), 5.20 (d, J = 17 Hz, 1H), 6.50 (bs, 1H), 6.82 (t, J = 4.5 Hz, 1H), 7.26-7.14 (m, 5H), 7.45 (d, J = 7.7 Hz, 1H), 8.86 (bs, 1H). 546.19 272 (S)-1-(2-(2- aminoaceta- mido)-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide dihydrochloride (500 MHz; DMSO-d.sub.6): δ 1.14 (d, J = 5.7 Hz, 3H), 1.75 (s, 1H), 2.94 (s, 3H), 3.50-3.46 (m, 1H), 3.72- 3.66 (m, 1H), 3.94-3.89 (m, 1H), 4.45 (s, 1H), 4.52 (d, J = 6.1 Hz, 2H), 4.96 (d, J = 15.9 Hz, 1H), 5.39 (d, J = 16 Hz, 1H), 6.98 (t, J = 8.5 Hz, 1H), 7.37-7.15 (m, 7H), 7.43 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H), 8.28 (s, 1H), 8.94 (bs, 1H). 544.19 273 (S)-1-(5- amino-2- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.30 (d, J = 6.3 Hz, 3H), 2.97 (s, 3H), 4.40 (d, J = 4.4 Hz, 2H), 4.63 (d, J = 6.3 Hz, 1H), 4.96 (d, J = 15.9 Hz, 1H), 5.06-4.90 (m, 4H), 6.14 (d, J = 4.1 Hz, 1H), 6.39-6.38 (m, 1H), 6.86 (t, J = 9.3 Hz, 1H), 7.24-7.15 (m, 4H), 7.43 (d, J = 7.7 Hz, 1H), 8.84 (bs, 1H). 487.17 274 0 (S)-1-(2- fluoro-4,5- dihydroxy- benzyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.4 Hz, 3H), 2.97 (s, 3H), 4.41 (d, J = 4.6 Hz, 2H), 4.63-4.59 (m, 1H), 4.88 (d, J = 16.2 Hz, 1H), 5.05 (d, J = 16.6 Hz, 1H), 6.38 (d, J = 7.5 Hz, 1H), 6.55 (d, J = 11.2 Hz, 1H), 7.25-7.15 (m, 4H), 7.42 (d, J = 7.8 Hz, 1H), 8.83 (s, 2H), 9.25 (s, 1H). 504.17 275 (S)-1-(2,4- difluoro-6- (3- hydroxyprop- oxy)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- (500 MHz; DMSO-d.sub.6): δ 1.13 (d, J = 5.1 Hz, 3H), 1.78 (bs, 2H), 2.93 (s, 3H), 3.52 (s, 2H), 4.04- 4.00 (m, 2H), 4.48-4.45 (m, 4H, 4.71 (d, J = 15.1 Hz, 1H), 5.49 (d, J = 15.2 Hz, 1H), 6.77-6.68 (m, 2H), 7.21-7.14 (m, 3H), 7.37 (d, J = 7.1 Hz, 1H), 7.49 (s, 1H), 8.79 (s, 1H). 564.19 carboxamide 276 (S)-1-(2- chloro-6- fluorobenzyl)- N-(2-fluoro- 3-(2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.6 Hz, 3H), 2.95 (s, 3H), 3.75-3.72 (m, 2H), 4.04 (t, J = 4.65 Hz, 2H), 4.43-4.39 (m, 2H), 4.58-4.54 (m, 1H), 4.96-4.,92 (m, 2H), 5.57 (d, J = 15.6 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 9.5 Hz, 1H), 7.18- 7.13 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.36-7.30 (m, 2H), 7.47 (d, J = 7,.6 Hz, 1H), 7.51 (s, 1H), 8.73 (t, J = 5.7 Hz, 1H). 530.18 277 (S)-2-(4- ((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)- 3,5- difluorophen- oxy)acetic acid (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 6.3 Hz, 3H), 2.93 (s, 3H), 4.42-4.38 (m, 1H), 4.53-4.47 (m, 2H), 4.65 (s, 2H), 4.74 (d, J = 15.7 Hz, 1H), 5.51 (d, J = 15.7 Hz, 1H), 6.65 (d, J = 19.9 Hz, 2H), 7.23-7.18 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 8.80 (bs, 1H). 564.16 278 (S)-1-(2- fluoro-6-((3- hydroxyprop- yl)amino)ben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluorobenz- yl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.11 (bs, 3H), 1.72 (bs, 2H), 2.97 (s, 3H), 3.06 (bs, 2H), 3.53 (bs, 2H), 4.54-4.43 (m, 4H), 4.89 (d, J = 15.5 Hz, 2H), 5.57 (d, J = 15.6 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 9.5 Hz, 1H), 7.18- 7.13 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.36-7.30 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 8.73 (t, J = 5.7 Hz, 1H). 545.23 279 (S)-1-(2- fluoro-3- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.27 (d, J = 6.4 Hz, 3H), 2.96 (s, 3H), 3.83 (s, 3H), 4.44-4.35 (m, 2H), 4.64-4.60 (m, 1H), 5.03 (d, J = 16.7 Hz, 1H), 5.25 (d, J = 16.9 Hz), 6.54 (t, J = 6.2 Hz, 1H), 7.06-6.99 (m, 2H), 7.25-7.15 (m, 4H), 7.43 (d, J = 7.7 Hz, 1H), 8.86 (bs, 1H). 502.18 280 (S)-1-(4-(3- aminopropoxy)- 2,6- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 6.5 Hz, 3H), 2.09-1.94 (m, 2H), 2.94- 2.89 (m, 4H), 4.02 (t, J = 5.7 Hz, 2H), 4.54-4.38 (m, 3H), 4.74 (d, J = 15.6 Hz, 1H), 5.55 (d, J = 15.6 Hz, 1H), 6.69 (d, J = 9.9 Hz, 2H), 7.24-7.18 (m, 3H), 7.4 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.71 (bs, 2H), 8.83 (t, J = 4.9 Hz, 1H). 563.20 281 (S)-1-(2,3- difluoro-5- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.29 (d, J = 6.0 Hz, 3H), 2.97 (s, 3H), 4.40 (d, J = 3.8 Hz, 2H), 4.65 (d, J = 6.0 Hz, 1H), 5.16-5.03 (m, 2H), 6.17 (s, 1H), 6.63 (bs, 2H), 7.27-7.14 (m, 3H), 7.46 (d, J = 7.6 Hz, 1H), 8.87 (s, 1H), 9.76 (s, 1H). 506.17 282 (S)-1-(2,3- difluoro-5- (2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 6.4 Hz, 3H), 2.97 (s, 3H), 3.62-3.59 (m, 2H), 3.85 (s, 2H), 4.40 (d, J = 4.7 Hz, 2H), 4.66-4.62 (m, 1H), 4.85 (t, J = 5.4 Hz, 1H), 5.20- 5.08 (m, 2H), 6.17 (s, 1H), 6.29 (s, 1H), 7.01- 6.99 (m, 1H), 7.27-7.14 (m, 4H), 7.46 (d, J = 7.8 Hz, 1H), 8.87 (t, J = 4.9 Hz, 1H). 550.17 283 (S)-1-(2,3- difluoro-5- (3- hydroxyprop- oxy)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.28 (d, J = 6.6 Hz, 3H), 1.77-1.72 (m, 2H), 2.97 (s, 3H), 3.46-3.43 (m, 2H), 3.90 (t, J = 6.2 Hz, 2H), 4.41 (d, J = 3.9 Hz, 2H), 4.53 (t, J = 5 Hz, 1H), 4.65-4.62 (m, 1H), 5.07 (d, J = 16.9 Hz, 1H), 5.23 (d, J = 16.8 Hz, 1H), 6.32 (s, 1H), 7.0-6.99 (m, 1H), 7.16 (t, J = 8.5 Hz, 2H), 7.27-7.23 (m, 2H), 7.46 (d, J = 7.8 Hz, 1H), 8.87 (bs, 1H). 564.23 284 0 (S)-1-(2- chloro-6- fluorobenzyl)- N-(4-fluoro- 2-(2- hydroxyethoxy) benzyl)- 3,4- dimethyl-2- oxo-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 3.6 Hz, 3H), 2.95 (s, 3H), 3.74 (s, 2H), 4.03 (s, 2H), 4.41 (bs, 2H), 4.56 (bs, 1H), 4.97- 4.92 (m, 2H), 5.57 (d, J = 15.5 Hz, 1H), 6.72 (bs, 1H), 6.91 (d, J = 10.5 Hz, 1H), 7.31-7.15 (m, 5H), 7.51-7.47 (m, 2H), 8.75 (bs, 1H). 530.18 285 (S)-1-(6- amino-2,3- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.17 (d, J = 6.4 Hz, 3H), 2.95 (s, 3H), 4.55-4.41 (m, 3H), 4.85 (d, J = 16 Hz, 1H), 5.28 (s, 2H), 5.34 (d, J = 16.1 Hz, 1H), 6.42-6.41 (m, 1H), 7.01- 6.99 (m, 1H), 7.20-7.17 (m, 3H), 7.42 (d, J = 7.7 Hz, 1H), 7.58 (s, 1H), 8.77 (t, J = 4.8 Hz, 1H). 505.22 286 (S)-1-(4- amino-2,6- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.15 (d, J = 6.3 Hz, 3H), 2.93 (s, 3H), 4.57-4.38 (m, 4H), 5.48 (d, J = 15.4 Hz, 1H), 5.68 (s, 2H), 6.09 (d, J = 10.3 Hz, 2H), 7.22-7.16 (m, 3H), 7.38 (d, J = 7.7 Hz, 1H), 7.43 (s, 1H), 8.76 (t, J = 4.5 Hz, 1H). 505.20 287 (S)-1-((5- chloro-3- fluoro-2-oxo- 1,2- dihydropyridin- 4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.4 Hz, 3H), 2.93 (s, 3H), 4.48-4.40 (m, 2H), 4.59-4.55 (m, 1H), 4.89 (d, J = 16.4 Hz, 1H), 5.25 (d, J = 16.3 Hz, 1H), 7.25-7.17 (m, 3H), 7.35 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 8.85 (t, J = 4.8 Hz, 1H), 12.47 (s, 1H). 523.16 carboxamide 288 (S)-1-((5- chloro-3- fluoro-1- methyl-2- oxo-1,2- dihydropyridin- 4- yl)methyl) 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 5.7 Hz, 3H), 2.93 (s, 3H), 3.44 (s, 3H), 4.48-4.41 (m, 2H), 4.57 (d, J = 6 Hz, 1H), 4.87 (d, J = 16.3 Hz, 1H), 5.27 (d, J = 16.4 Hz, 1H), 7.25- 7.18 (m, 3H), 7.36 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.84 (s, 1H). 537.16 quinazoline-7- carboxamide 289 (4S)-1-(2,6- difluoro-3-(1- hydroxyethyl) benzyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.23-1.15 (m, 6H), 2.95 (s, 3H), 4.52-4.39 (m, 3H), 4.86-4.77 (m, 2H), 5.33-5.30 (m, 1H), 5.63 (t, J = 16.2 Hz, 1H), 7.08- 7.01 (m, 1H), 7.19 (d, J = 6.6 Hz, 3H), 7.51-7.39 (m, 3H), 8.80 (d, J = 5.2 Hz, 1H). 534.18 290 (S)-1-(2,6- difluoro-4- (2- (methylsulfon- amido)ethoxy) benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 5.9 Hz, 3H), 2.93 (d, J = 4.9 Hz, 6H), 3.30-3.27 (m, 2H), 4.03- 3.99 (m, 2H), 4.42-4.38 (m, 1H), 4.52-4.47 (m, 2H), 4.74 (d, J = 15.7 Hz, 1H), 5.53 (d, J = 15.7 Hz, 1H), 6.69 (d, J = 9.8 Hz, 2H), 7.28-7.18 (m, 4H), 7.40 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 8.81 (bs, 1H). 627.10 quinazoline-7- carboxamide 291 (S)-1-(2,6- difluoro-4- (2- morpholino- ethoxy)benzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 6.1 Hz, 3H), 2.42 (s, 4H), 2.62 (t, J = 5.0 Hz, 2H), 2.93 (s, 3H), 3.54 (bs, 4H), 4.05 (t, J = 5.5 Hz, 2H), 4.42-4.38 (m, 1H), 4.52-4.46 (m, 2H), 4.73 (d, J = 15.6 Hz, 1H), 5.53 (d, J = 15.8 Hz, 1H), 6.68 (d, J = 9.9 Hz, 2H), 7.24-7.18 (m, 3H), 7.40 (d, J = 7.6 Hz, 1H), 619.16 quinazoline-7- 7.44 (s, 1H), 8.81 (bs, carboxamide 1H). 292 (S)-1-(4-(2- aminoethoxy)- 2,6- difluoroben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- (500 MHz; DMSO-d.sub.6): δ 1.16 (d, J = 5.7 Hz, 3H), 2.93 (s, 3H), 3.15 (bs, 2H), 3.56 (s, 1H), 4.16 (s, 2H), 4.52-4.38 (m, 3H), 4.75 (d, J = 15.6 Hz, 1H), 5.53 (d, J = 15.7 Hz, 1H), 6.71 (d, J = 9.5 Hz, 2H), 7.23-7.18 (m, 3H), 7.40 (d, J = 7.3 Hz, 1H), 7.45 (s, 1H), 8.12 (s, 2H), 8.81 (bs, 1H). 549.23 carboxamide hydrochloride 293 (S)-1-(2- chloro-6- fluoro-4- methoxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J = 6.0 Hz, 3H), 2.94 (s, 3H), 3.74 (s, 3H), 4.52-4.39 (m, 3H), 4.79 (d, J = 15.7 Hz, 1H), 5.52 (d, J = 15.6 Hz, 1H), 6.80 (d, J = 12.3 Hz, 1H), 6.89 (s, 1H), 7.23-7.19 (m, 3H), 7.39 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 8.77 (s, 1H). 536.17 294 0 (S)-4-(4- ((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)- 3,5- difluorophen- oxy)butanoic (500 MHz; DMSO-d.sub.6): δ 1.16 (s, 3H), 1.88 (s, 2H), 2.33 (s, 2H), 2.94 (s, 3H), 3.95 (s, 2H), 4.75-4.42 (m, 4H), 4.53 (d, J = 12.3 Hz, 1H), 6.66 (s, 2H), 7.20 (s, 3H), 7.43 (d, J = 23.8 Hz, 2H), 8.80 (s, 1H), 12.23 (bs, 1H). 592.21 acid 295 (S)-1-((3,5- difluoro- pyridin-4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- triflurooben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.21 (d, J = 9.3 Hz, 3H), 2.93 (s, 3H), 4.48-4.39 (m, 2H), 4.57 (d, J = 6.1 Hz, 1H), 5.05 (d, J = 16.5 Hz, 1H), 5.49 (d, J = 16.3 Hz, 1H), 7.22-7.19 (m, 3H), 7.40 (s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 8.47 (s, 2H), 8.75 (s, 1H). 491.19 296 (S)-1-((3- fluoro-5- methoxy-2- methylpyridin- 4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.18 (d, J = 6.2 Hz, 3H), 2.26 (s, 3H), 2.95 (s, 3H), 3.89 (s, 3H), 4.48-4.40 (m, 2H), 4.55-4.51 (m, 1H), 4.82 (d, J = 16.0 Hz, 1H), 5.52 (d, J = 15.9 Hz, 1H), 7.21-7.17 (m, 3H), 7.37 (d, J = 7.7 Hz, 1H), 7.40 (s, 1H), 8.08 (s, 1H), 8.77 (s, 1H). 517.21 297 (S)-1-((5- chloro-3- fluoro-1-(2- hydroxyethyl)- 2-oxo-1,2- dihydro- pyridin-4- yl)methyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- (500 MHz; DMSO-d.sub.6): δ 1.25 (d, J = 6.2 Hz, 3H), 2.94 (s, 3H), 3.61 (d, J = 3.7 Hz, 2H), 3.99-3.93 (m, 2H), 4.48-4.41 (m, 2H), 4.57 (d, J = 6.5 Hz, 1H), 4.89 (d, J = 16.4 Hz, 1H), 4.96 (s, 1H), 5.25 (d, J = 16.3 Hz, 1H), 7.25- 7.18 (m, 3H), 7.37 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.77 (s, 1H), 8.85 (s, 1H). 567.11 carboxamide 298 (S)-1-(2- chloro-6- fluoro-4- hydroxyben- zyl)-3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.21 (d, J = 6.1 Hz, 3H), 2.93 (s, 3H), 4.42-4.38 (m, 1H), 4.51-4.47 (m, 2H), 4.73 (d, J = 15.6 Hz, 1H), 5.50 (d, J = 15.5 Hz, 1H), 6.50 (d, J = 12.2 Hz, 1H), 6.65 (s, 1H), 7.22- 7.18 (m, 3H), 7.38 ( d, J = 7.7 Hz, 1H), 7.44 (s, 1H), 8.75 (s, 1H), 10.34 (s, 1H). 522.15 299 (S)-1-(4-(2- aminoethoxy)- 2-chloro-6- fluorobenzyl)- 3,4- dimethyl-2- oxo-N- (2,4,6- trifluoroben- zyl)-1,2,3,4- tetrahydro- quinazoline-7- carboxamide (500 MHz; DMSO-d.sub.6): δ 1.24 (s, 3H), 2.94 (s, 3H), 3.22 (s, 2H), 4.23 (s, 2H), 4.55-4.96 (m, 3H), 4.95 (d, J = 15.8 Hz, 1H), 5.53 (d, J = 15.8 Hz, 1H), 7.16- 7.19 (m, 5H), 7.44 (s, 2H), 8.22 (bs, 3H), 8.79 (s, 1H). 565.22 hydrochloride 300 (S)-2-chloro- 3-((3,4- dimethyl-2- oxo-7- ((2,4,6- trifluoroben- zyl)carbamoyl)- 3,4- dihydroquina- zolin-1(2H)- yl)methyl)-4- fluorophenyl- methyl(2- (methylamino) ethyl)carbamate hydrochloride (500 MHz; DMSO-d.sub.6): δ 1.22 (d, J = 6.1 Hz, 3H), 2.61 (s, 3H), 2.94 (s, 3H), 2.96 (s, 1H), 3.10 (s, 3H), 3.20 (s, 1H), 5.45 (s, 1H), 3.74 (s, 1H), 4.41-4.49 (m, 2H), 4.54 (d, J = 6.15 Hz, 1H), 4.99 (d, J = 15.45 Hz, 1H), 5.50 (d, J = 15.75 Hz, 1H), 7.16- 7.23 (m, 4H), 7.39-7.44 (m, 1H), 7.48 (s, 2H), 8.76 (s, 1H), 8.81 (bs, 2H). 636.25

(414) Biological Assays

(415) Stable Cell Line Generation a) Stable STING expressing cells—Stable HEK293T STING-expressing cell lines were generated using plasmids purchased from Invivogen, CA, USA, that contain STING cDNA cloned into the pUNO-1 vector under hEF.sub.1-HTLV promoter and containing the Blasticidin selection cassette. The plasmids hSTING(R232), hSTING(H232), hSTING(HAQ) were directly procured from Invivogen while hSTING (AQ) and hSTING (Q) were derived from hSTING(HAQ) and hSTING (R232) plasmids respectively by using a PCR based site directed mutagenesis method. These vectors were individually transfected into HEK293T cells using Lipofectamine (Invitrogen) and transfected cells were selected under Blasticidin selection. These transfected cells were further subjected to clonal selection using the limiting dilution method to obtain clonally pure populations of HEK cells transfected with each of the above mentioned human STING variants. Only those clones were selected in which ligand independent activation of STING was minimal. b) Stable Luciferase reporter gene expressing cells—Stable HEK293T Luciferase reporter gene expressing cell lines were generated using pCDNA4 plasmids under an IRF-inducible promoter. This promoter is comprised of five tandem interferon-stimulated response elements (ISRE) fused to an ISG54 minimal promoter. This vector was transfected into HEK293T cells using Lipofectamine (Invitrogen) and transfected cells were selected under Zeocin selection. These transfected cells were further subjected to clonal selection using the limiting dilution method to obtain clonally pure populations of HEK cells transfected the Luciferase reporter construct. Only those clones were selected in which ligand independent induction of luciferase was minimal.

(416) Luciferase Assay

(417) 5×10.sup.5 clonally selected HEK293T-hSTING-Luciferase cells were seeded in 384-well plates in growth medium and stimulated with novel compounds. After 20 hr of stimulation supernatant were removed and secretary reporter gene activity were measured using the Quanti-Luc detection system (Invivogen) on a Spectramax i3X luminometer.

(418) In the tables below, EC.sub.50 value ranges for exemplary compounds are given. The EC.sub.50 ranges are indicated as “A” for values less than or equal to 1 μM, “B” for values greater than 1 μM and less than or equal to 10 μM, and “C” for values greater than 10 μM.

(419) All compounds were first tested in a primary screen to obtain a ‘fold-induction’ over baseline levels of protein activity. Only those compounds that had a fold induction>1 have been included in the table and all are considered ‘active’.

(420) TABLE-US-00009 R232 human activity Ex. Activity 1 A 2 C 3 C 4 A 5 A 6 A 7 B 8 A 9 A 10 A 11 A 12 A 13 A 14 B 15 B 16 B 17 B 18 B 19 B 20 B 21 C 22 C 23 B 24 B 25 C 26 C 27 B 28 C 29 C 30 B 31 C 32 B 33 B 34 C 35 C 36 C 37 C 38 A 39 B 40 C 41 C 42 B 43 C 44 C 45 C 46 B 47 C 48 C 49 B 50 C 51 C 52 B 53 C 54 B 55 C 56 B 57 C 58 C 59 C 60 B 61 C 62 B 63 B 64 C 65 C 66 A 67 B 68 C 69 C 70 B 71 B 72 B 73 C 74 A 75 B 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 B 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 A 96 A 97 A 99 B 101 B 102 A 103 A 104 A 105 A 137 A 138 A 139 A 140 C 141 A 142 C 143 A 144 A 145 A 146 A 147 A 148 A 149 A 150 A 151 C 152 A 153 A 154 A 155 B 156 A 157 A 158 A 159 A 160 A 161 B 162 A 163 A 164 A 165 A 166 A 167 A 168 A 169 A 170 A 171 A 172 B 173 A 174 A 175 B 176 A 177 A 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A 189 B 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 C 200 C 201 A 202 A 203 A 204 A 205 A 206 A 207 B 208 A 209 A 210 A 211 A 212 A 213 A 214 B 215 A 216 A 217 A 218 A 219 A 220 A 221 A 222 A 223 B 224 A 225 B 226 B 227 A 228 C 229 C 230 A 231 A 232 A 233 A 234 C 235 B 236 A 237 A 238 A 239 A 240 C 241 A 242 A 243 B 244 A 245 B 246 A 247 B 248 B 249 B 250 A 251 B 252 A 253 B 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262 A 263 A 264 A 265 A 266 C 267 A 268 A 269 A 270 A 271 A 272 B 273 A 274 B 275 A 276 C 277 C 278 A 279 A 280 A 281 A 282 A 283 A 284 C 285 A 286 A 287 C 288 B 289 A 290 A 291 A 292 A 293 A 294 A 295 A 296 A 297 C 298 A 299 A 300 A

(421) Selected compounds were further tested against cynomolgus monkey STING protein overexpressed in HEK293T cells.

(422) TABLE-US-00010 Cynomolgus monkey STING activity Ex. Activity 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 B 87 A 88 A 89 A 90 A 94 C 95 C 96 C 97 A 101 B 102 A 103 A 105 A 137 A 138 A 139 A 141 A 144 A 145 A 146 A 147 A 149 A 154 A 162 A 164 A 165 A 166 B 168 A 169 A 171 A 176 A 177 A 178 A 179 A 180 A 182 A 183 A 184 A 187 A 188 A 202 A 206 A 209 A 231 A 232 A 241 A 242 A 254 B 255 A 256 B 257 B 258 A 259 A 260 A 261 A 262 A 263 B 265 A 269 A 270 A 271 B 273 B 275 C 281 A 282 B 283 B 286 A 289 B 290 A 291 A 294 A 295 A 296 A 298 A 299 C 300 A

(423) STING Polymorphisms

(424) Single nucleotide polymorphisms of human STING have been described, which can affect the functional potency of compounds that modulate the activity of the STING protein (see Yi et. al., PLoS One, October 2013, 8(10), e77846). The 5 major polymorphisms of human STING are shown in FIG. 1, with their prevalence in human populations indicated.

(425) The tables below show the potency of selected compounds of the invention against the most common polymorphisms.

(426) TABLE-US-00011 H232/REF H232 H232 Ex. activity Ex. activity 20 B 38 B 76 A 39 C 153 A 193 A 154 A 196 A 203 A 54 B 206 A 204 B 208 A 162 A 212 B 167 C 213 B 169 A 171 A 175 B 174 A 177 A 180 A 179 A 227 B 232 A 148 A 235 B 237 A 77 A 78 A 239 B 238 B 182 A 242 A 241 A 243 B 80 A 246 A 257 A 252 A 261 A 88 A 262 A 87 A 141 A 137 A 81 A 264 A 268 B 138 A 290 A 281 A 188 A 283 A 296 A 285 A 147 A 85 A 185 A 293 A 298 A

(427) TABLE-US-00012 HAQ HAQ HAQ Ex. activity Ex. activity 20 B 196 A 76 A 54 B 153 A 203 A 154 A 204 B 38 B 162 A 39 C 206 A 193 A 208 A 212 B 167 C 213 B 169 A 175 B 171 A 177 A 174 A 179 A 227 B 180 A 148 A 232 A 137 A 235 B 268 B 77 A 87 A 237 A 246 A 78 A 252 A 238 B 88 A 239 B 80 A 182 A 257 A 241 A 261 A 242 A 262 A 243 B 285 A 264 B 85 A 141 A 290 A 81 A 188 A 138 A 293 A 281 A 296 A 283 A 147 A 185 A 298 A

(428) Reporter Gene Expression Assay for IRF & NFkB Axis in THP-1 Cells

(429) THP1-Dual™ cells (Invivogen) were derived from the human THP-1 monocyte cell line by stable integration of two inducible reporter constructs. As a result, THP1-Dual™ cells allow the simultaneous study of the NF-κB pathway, by monitoring the activity of secreted SEAP, and the IRF pathway, by assessing the activity of a secreted luciferase (Lucia). 5×10.sup.5 THP1-Dual™ cells were seeded in 384-well plates in growth medium and stimulated with novel compounds. After 20 hr of stimulation supernatants were removed and reporter proteins were readily measured in the cell culture supernatant using QUANTI-Blue™ (Invivogen), a SEAP detection reagent, and QUANTI-Luc™ (Invivogen), a luciferase detection reagent on a Spectramax i3X luminometer.

(430) EC.sub.50 value ranges for exemplary compounds tested in the above assay are given. The EC.sub.50 ranges are indicated as “A” for values less than or equal to 1 μM, “B” for values greater than 1 μM and less than or equal to 10 μM, and “C” for values greater than 10 μM.

(431) TABLE-US-00013 IRF/NF.sub.KB THP- THP- THP- THP- IRF NFκB IRF NFκB Ex. activity activity Ex. activity activity 20 B B 38 C B 76 A A 39 C C 153 A A 193 A A 154 A A 196 A A 167 C C 204 C C 169 A A 162 A A 171 A A 54 B B 174 B B 203 A A 175 C C 206 A A 177 A A 208 B B 179 A A 212 C C 180 A A 213 B B 227 B B 77 A A 148 B B 237 B B 232 A A 78 A A 235 C C 238 B B 252 B B 239 B B 88 A A 182 A A 80 B B 241 A A 257 A A 242 A A 87 A A 243 C C 137 A A 246 A A 261 A A 264 B B 262 A A 141 A A 81 A A 281 A A 268 B B 283 A A 138 A A 285 A A 188 A A 85 A A 290 A A 296 A A 147 A A 185 B B 298 A A 293 A A

(432) Western Blot Assay

(433) 5×10.sup.5 clonally selected HEK293T-hSTING-Luciferase cells were seeded in 24-well plates in 500 μl growth medium and stimulated with novel compounds or a vehicle control (VC), i.e. the solvent with no compound. After 2 hr of stimulation cells were harvested through centrifugation and cell pellets were lysed in RIPA buffer (20 mM tris-Cl, 150 mM NaCl, 0.5 mM EDTA, 1% NP40, 0.05% SDS) containing Ix phosphatase inhibitor cocktail 3 (Sigma) and Ix protease inhibitor (Roche) to extract the soluble fraction of protein. 10 μg of extracted protein was electrophoresed in 10% SDS-PAGE gels and transferred onto Immobilon-P membranes (Millipore). Blots were incubated with antibodies specific for phosphorylated STING (Ser366), phosphorylated IRF3 (Ser396), total STING, ACTIN (Cell Signaling) and IRF3 (Abcam). Anti-rabbit HRP label secondary antibody (Abcam) and Clarity Max™ western ECL substrate (Biorad) were used for visualization of bands with the help of the BioRad XRS plus imager. The assays are shown in FIG. 2.

(434) Analysis of Cytokines by ELISA

(435) Freshly isolated 2×10.sup.5 human PBMCs using Histopaque (Sigma) from different healthy donors were stimulated with novel compounds (10 μM) in 200 μl growth medium for 6 hr. Post treatment supernatant media was harvested and stored at −80° C. in different aliquots for secreted Cytokine analysis. The cytokines IFNβ, IFNα, IL6, CXCL10 and TNFα were measured using the respective manufacturers recommendations. IFNβ, IFNα were purchased from PBL Assay science, IL6, CXCL10 were procured from Abcam and TNFα was purchased from R&D systems. The results are shown in FIG. 3.

(436) In Vivo Tumor Experiments

(437) 1×10.sup.6 CT26 tumor cells stably expressing R232.hSTING were injected subcutaneously in 100 μl RPMI on the right side of the flank of Balb/C mice. Following tumor implantation, when the average tumor size was around 50 mm.sup.3 to 70 mm.sup.3, mice were randomized into different groups. Total number of animals per group was around 5 to 8. New chemical entities which were tested in this tumor model were formulated in 100% PEG400. For the treatment groups compounds were dosed intra-tumorally thrice in a week. Control animals were injected with vehicle by the same route and same schedule of compound dosing, and are identified as vehicle controls (VC). Growth of the tumors was measured regularly during the course of the study, and the results are shown in FIG. 4.

CONCLUSION

(438) The inventors have synthesised a large number of compounds which fall within the general formula (I). They have shown that these compounds activate the STING protein, and so could be used to treat a number of diseases, including cancer.