SMALL MOLECULE MODULATORS OF HUMAN STING

Abstract

The present invention relates to compounds of formula (I). The compounds may be 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): ##STR00429## or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR.sup.9R.sup.10, O, S, SO or SO.sub.2; 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; the or each Z is CR.sup.11R.sup.12; n is 1 or 2; Q is CO, SO, SO.sub.2, CS or CR.sup.4R.sup.5; L is optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, 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, CO, SO, SO.sub.2, CH.sub.2C(O), CH.sub.2CONH, or CONH; Y is an optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, an optionally substituted C.sub.2-C.sub.6 alkenyl, an optionally substituted C.sub.2-C.sub.6 alkynyl, an optionally substituted C.sub.3-C.sub.6 cycloalkyl, an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CONR.sup.1R.sup.2, NR.sup.1R.sup.2, NHCOR, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, optionally substituted mono or bicyclic 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, optionally substituted C.sub.1-C.sub.6 alkoxycarbonyl group, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted heterocyclyloxy; R.sup.4 and R.sup.5 are each independently selected from the group consisting of H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted (C.sub.3-C.sub.6) cycloalkyl or R.sup.4 and R.sup.5 together with the atom to which they are attached form a spirocyclic ring; R.sup.6 is mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C.sub.3-C.sub.6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R.sup.7 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted sulfonyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.2-C.sub.6 alkenyl and optionally substituted C.sub.2-C.sub.6 alkynyl; R.sup.8 is mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; 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, CN, hydroxyl, CO.sub.2H, CONR.sup.1R.sup.2, azido, sulfonyl, NR.sup.1R.sup.2, NHCOR.sup.1, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.1-C.sub.6 thioalkyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, 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, optionally substituted C.sub.1-C.sub.6 alkoxycarbonyl, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; 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; and R.sup.11 and R.sup.12 are each independently selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, halogen, CN, hydroxyl, CO.sub.2H, CONR.sup.1R.sup.2, azido, sulfonyl, NR.sup.1R.sup.2, NHCOR.sup.1, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.1-C.sub.6 thioalkyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, 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, optionally substituted C.sub.1-C.sub.6 alkoxycarbonyl, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R.sup.11 and R.sup.12 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; with the proviso that when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO, L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is unsubstituted phenyl, ##STR00430## then R.sup.8 is not unsubstituted furanyl; and when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO, L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is ##STR00431## then R.sup.8 is not unsubstituted phenyl; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, for use in therapy.

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 any preceding claim, wherein X is O, S or CR.sup.9R.sup.10.

6. A compound according to claim 5, wherein X is S or CR.sup.9R.sup.10.

7. A compound according to any preceding claim, wherein at least one of R.sup.9 and R.sup.10 is an optionally substituted C.sub.1-C.sub.6 alkyl, halogen, H, a C.sub.3-C.sub.6 cycloalkyl or C.sub.1-C.sub.3 polyfluoroalkyl.

8. A compound according to claim 7, wherein both R.sup.9 and R.sup.10 are H.

9. A compound according to any preceding claim, wherein n is 1.

10. A compound according to any preceding claim, wherein at least one of R.sup.11 and R.sup.12 is H.

11. A compound according to claim 10, wherein both R.sup.11 and R.sup.12 is H.

12. A compound according to claim 10, wherein one of R.sup.11 and R.sup.12 is H and the other is an optionally substituted C.sub.1-C.sub.6 alkyl or an optionally substituted C.sub.2-C.sub.6 alkenyl.

13. A compound according to any preceding claim, wherein Q is CO, SO.sub.2 or CR.sup.4R.sup.5.

14. A compound according to claim 13, wherein Q is CO.

15. A compound according to any preceding claim, wherein L is CO or SO.sub.2, an optionally substituted C.sub.1-C.sub.6 alkyl, CH.sub.2C(O) or CH.sub.2CONH.

16. A compound according to claim 15, wherein L is CH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, C(Me)H, CF.sub.2 or C(H)F.

17. A compound according to any preceding claim, wherein R.sup.6 is a mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C.sub.3-C.sub.6 cycloalkyl or an optionally substituted C.sub.3-C.sub.6 heterocyclyl.

18. A compound according to claim 17, wherein R.sup.6 is an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted pyrazole, an optionally substituted thiazole or an optionally substituted isoxazole.

19. A compound according to either claim 17 or claim 20, wherein R.sup.6 is a mono or bicyclic C.sub.5-C.sub.10 aryl or a mono or bicyclic 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is substituted with between 1 and 5 substituents, and the or each substituent 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, CONR.sup.1R.sup.2 and OH.

20. A compound according to any one of claims 17 to 19, wherein the aryl is phenyl or naphthyl.

21. A compound according to claim 20, wherein phenyl or the naphthyl is substituted by 1 or 2 halogens.

22. A compound according to any preceding claim, wherein when X.sup.1 is CH, X.sup.2 is CH and X.sup.3 is CH then R.sup.6 does not comprise an unsubstituted phenyl.

23. A compound according to any preceding claim, wherein R.sup.7 is preferably H or an optionally substituted C.sub.1-C.sub.6 alkyl.

24. A compound according to any one of claims 1 to 22, wherein Y is an optionally substituted C.sub.1-C.sub.6 alkyl.

25. A compound according to claim 24, wherein Y is CH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH(CH.sub.3), CH(F) and CF.sub.2.

26. A compound according to any preceding claim, wherein R.sup.8 is a mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, an optionally substituted C.sub.3-C.sub.6 cycloalkyl or an optionally substituted C.sub.3-C.sub.6 heterocyclyl.

27. A compound according to claim 26, wherein R.sup.8 is an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted furanyl, an optionally substituted benzofuranyl, an optionally substituted thiophene, an optionally substituted pyridofuran, an optionally substituted benzoxazole or an optionally substituted benzothiazole.

28. A compound according to either claim 26 or claim 27, wherein R.sup.8 is a mono or bicyclic C.sub.5-C.sub.10 aryl or a mono or bicyclic 5 to 10 membered heteroaryl substituted with between 1 and 5 substituents, and the or 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, C.sub.1-C.sub.3 polyfluoroalkyl, CONR.sup.1R.sup.2, CN and azido.

29. A compound according to claim 1, wherein: X is S, O or CR.sup.9R.sup.10; X.sup.2 is CR.sup.2; n is 1; Q is CO or CR.sup.4R.sup.5; L is optionally substituted C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 polyfluoroalkyl; 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, C.sub.1-C.sub.3 polyfluoroalkyl, and optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl; R.sup.4 and R.sup.5 are each independently selected from the group consisting of H and C.sub.1-C.sub.6 alkyl; R.sup.6 is a mono or bicyclic substituted C.sub.5-C.sub.10 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or an optionally substituted C.sub.3-C.sub.6 cycloalkyl; R.sup.7 is H; R.sup.8 is a mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or an optionally substituted C.sub.3-C.sub.6 cycloalkyl; 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, CN, hydroxyl, azido, NR.sup.1R.sup.2, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy or optionally substituted C.sub.2-C.sub.6 alkenyl; and R.sup.11 and R.sup.12 are each independently selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, halogen, CN, hydroxyl, azido, NR.sup.1R.sup.2, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.1-C.sub.6 alkoxy or optionally substituted C.sub.2-C.sub.6 alkenyl.

30. A compound according to claim 29, wherein: L is a C.sub.1-C.sub.2 alkyl; and Y is a C.sub.1-C.sub.2 alkyl.

31. A compound according to claim 1, wherein: X is S or CR.sup.9R.sup.10; X.sup.1 is CH or N; X.sup.2 is CH; X.sup.3 is CH or N; n is 1; Q is CO; 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 mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl; R.sup.7 is H; R.sup.8 is a mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl or a mono or bicyclic optionally substituted 5 to 10 membered heteroaryl; R.sup.9 and R.sup.10 are each independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, H, halogen, CN and azido; and R.sup.11 and R.sup.12 are each independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, H, halogen, CN and azido.

32. A compound according to claim 31, wherein: L is CH.sub.2; Y is CH.sub.2; R.sup.6 is a phenyl ring substituted with at least one chlorine and/or fluorine; R.sup.8 is a phenyl ring substituted with at least one fluorine; 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 and R.sup.12 are each independently selected from the group consisting of C.sub.1-C.sub.3 alkyl and H.

33. A compound according to claim 1, wherein the compound is: 4-(2-chlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-oxo-2-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(2-(indolin-1-yl)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-oxo-2-(pyridin-4-ylamino)ethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-oxo-2-(phenylamino)ethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(benzo[d]thiazol-2-ylmethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(benzo[d]oxazol-2-ylmethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-phenethyl-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-((2-aminopyrimidin-5-yl)amino)-2-oxoethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((1-methyl-1H-pyrrol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2,3-dichlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2,3-dimethylbenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2,6-dimethylbenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(naphthalen-1-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(cyclohexylmethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(cyclohexylmethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(2-hydroxy-2-phenylethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; (S)N-(1-cyclohexylethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; (R)N-(1-cyclohexylethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(cyclopropylmethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N,4-bis(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-((6,6-dimethylbicyclo[3.1.1]heptan-3-yl)methyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(1-((3r,5r,7r)-adamantan-1-yl)ethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-((3r,5r,7r)-adamantan-1-ylmethyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(cyclohexylmethyl)-4-(2,3-dimethylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-N-(naphthalen-1-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(pyridin-3-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(1-phenylethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2,6-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(naphthalen-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-N-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2,4-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(cyclopentylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-((6-methylpyridin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(3-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 3-oxo-4-(pyridin-4-ylmethyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(3-cyano-2-phenylpropyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-benzhydryl-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2-cyclohexyl-2-phenylethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-((1-benzylpiperidin-3-yl)methyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-3-oxo-N-((1-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-([1,1-biphenyl]-2-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-([1,1-biphenyl]-3-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-((1-benzylpiperidin-4-yl)methyl)-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-3-oxo-N-((1-phenylpiperidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-benzyl-N-(furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-((6-aminopyridin-3-yl)methyl)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(2-(dimethylamino)-1-phenylethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-(pyrimidin-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(2,3-dichlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N,4-dibenzyl-N-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(1-(4-(methylsulfonyl)phenyl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(oxazol-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-(thiazol-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((5-methyloxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((5-methylthiazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((4-methylthiazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(1-(furan-2-yl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(benzofuran-3-ylmethyl)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(4-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(naphthalen-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-3-oxo-N-(1-phenylcyclopentyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((2-methylthiazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(2-(2-fluorophenyl)propan-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(1,2-diphenylethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(4-isopropylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(2-cyclohexylethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2,3-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(3-methyl-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-((5-methylisoxazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(3-carbamoylbenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(3-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chlorophenethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(3-chlorophenethyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(3-(trifluoromethyl)phenethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2,6-dichlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-cyanobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-((5-chlorothiophen-2-yl)methyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-((2-methylthiazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-((1-methylpiperidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-5-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2,5-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2,6-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(3-chloro-5-(trifluoromethyl)benzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-3-oxo-4-(2-(phenylsulfonyl)ethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(pyridin-3-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(cyclohexyl(phenyl)methyl)-4-(2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 2-(3-oxo-6-((2,4,6-trifluorobenzyl)carbamoyl)-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-phenylacetic acid; 4-(2,6-difluoro-4-methoxybenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2,6-difluoro-4-hydroxybenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-benzyl-N-(2-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N,4-dibenzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(4-chlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(4-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chlorobenzyl)-N-(4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N,4-bis(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(2-chlorobenzyl)-4-(3-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(4-chlorobenzyl)-3-oxo-N-(1-phenylethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-benzyl-4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-((1-(4-methylbenzyl)piperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-phenethyl-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-N-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-Benzyl-N-(furan-2-ylmethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 2-methyl-N-2,4,6-trifluorobenzyl-4-[(1-methyl-1H-pyrazol-4-yl)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 2-(dimethylamino)-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(cyclohexylmethyl)-4-(2-fluorobenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 2-ethoxy-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 2-(4-(2-fluorobenzyl)-6-((furan-2-ylmethyl)carbamoyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazin-2-yl)acetic acid; 4-(2-fluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-2-methyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chlorobenzyl)-2-methyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 2-allyl-4-(2-chloro-6-fluorobenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-3-oxo-2-propyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-(chloromethyl)-N-(2,4-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluoro-3-hydroxybenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-N-(furan-2-ylmethyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 2-methyl-3-oxo-4-(pyridin-4-ylmethyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 2-methyl-4-((3-methylisoxazol-5-yl)methyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 2-methyl-4-((5-methylisoxazol-3-yl)methyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3-carbamoylbenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-4-(2-fluorobenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 2-(cyanomethyl)-N-(2,4-difluorobenzyl)-4-(3,5-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-((5-methyloxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-hydroxy-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-fluoro-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 2-(2-aminoethyl)-N-(2,4-difluorobenzyl)-4-(3,5-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-(2-(methylsulfonamido)ethyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-benzyl-N-(3,4-dimethoxyphenethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 2-methyl-4-((1-methyl-1H-pyrazol-4-yl)methyl)-N-((5-methyloxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorophenethyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide; 2-(4-(2-fluorobenzyl)-6-((furan-2-ylmethyl)carbamoyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)acetic acid; 2-(2-amino-2-oxoethyl)-N-(2,4-difluorobenzyl)-4-(3,5-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 1-(2-Chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b-1,4]thiazine-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b-1,4]thiazine-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b-1,4]thiazine-7-carboxamide; 1-benzyl-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b-1,4]thiazine-7-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-pyrido[3,4-b-1,4]thiazine-7-carboxamide; N-(benzofuran-2-ylmethyl)-4-(3,5-difluorobenzyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-methyl-N-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(2,4-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-4-(2-chloro-6-fluorobenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-N-(furan-2-ylmethyl)-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; N-benzyl-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b-1,4]thiazine-6-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; N-(benzofuran-2-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-2-oxo-2,3-dihydro-H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide; N-(benzofuran-2-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; N-benzyl-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 4-(2-chloro-6-fluorobenzyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide; 4-(3,5-difluorobenzyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide; 4-(1-(3,5-difluorophenyl)ethyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide; 4-(3-carbamoylbenzyl)-2-methyl-N-((5-methylfuran-2-yl)methyl)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxamide; 1-((2-methoxypyridin-4-yl)methyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((5-methylfuran-2-yl)methyl)-2-oxo-2,3-dihydro-H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-(hydroxymethyl)-3-methyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-(hydroxymethyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-N-((5-methyloxazol-2-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(pyridazin-3-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(pyrazin-2-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxamide; 4-(2-fluorobenzyl)-2,2-dimethyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-Benzyl-8-cyano-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 8-cyano-4-(3,5-difluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 8-bromo-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(4-fluorobenzyl)-8-(2-hydroxyethyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(4-fluorobenzyl)-8-(1-hydroxyethyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 8-(aminomethyl)-4-(4-fluorobenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide hydrochloride; 4-(4-fluorobenzyl)-3-oxo-N6-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6,8-dicarboxamide; 4-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-8-methyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 8-cyclopropyl-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 7-bromo-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 7-cyclopropyl-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-7-methyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]oxazine-6-carboxamide; 2-Methyl-4-(3,5-difluorobenzyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide; (R)-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]oxazine-6-carboxamide; (S)-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]oxazine-6-carboxamide; (S)N-(benzofuran-2-ylmethyl)-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]oxazine-6-carboxamide; 1-(3,5-difluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b-1,4]oxazine-7-carboxamide; (S)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b-1,4]oxazine-7-carboxamide; (R)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b-1,4]oxazine-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b-1,4]oxazine-7-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b-1,4]oxazine-7-carboxamide; (S)N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide; (R)-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide; (S)-4-(3,5-difluorobenzyl)-2-methyl-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide; 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide 1-oxide; 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(2-hydroxy-2-phenylethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; N-(furan-2-ylmethyl)-4-(2-oxo-2-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(4-chlorobenzyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide 1-oxide; 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide 1,1-dioxide; 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide 1,1-dioxide; 4-benzoyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(cyclohexylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 2-methyl-4-(2-phenylacetyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-isonicotinoyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide; 4-(phenylsulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-((3,5-difluorophenyl)sulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]oxazine-6-carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]oxazine-6-carboxamide; 4-(2-chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]oxazine-6-carboxamide; 4-benzyl-N-(furan-2-ylmethyl)-3-thioxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(4-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide; 1-(2-chloro-6-fluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide; 1-(3,5-difluorobenzyl)-4,4-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide; 1-(3,5-difluorobenzyl)-N-(furo[2,3-c]pyridin-2-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide; 1-(3,5-difluorobenzyl)-N-(furo[3,2-c]pyridin-2-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide; 1-(3,5-difluorobenzyl)-N-(furo[2,3-b]pyridin-2-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide; 1-(3,5-difluorobenzyl)-N-(furo[3,2-b]pyridin-2-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxamide; 5-(3,5-difluorobenzyl)-6-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxamide; N-(2,4-difluorobenzyl)-5-(3,5-difluorobenzyl)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxamide; N-(benzofuran-2-ylmethyl)-5-(3,5-difluorobenzyl)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxamide; N-(2,4-difluorobenzyl)-8-(3,5-difluorobenzyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-2-carboxamide; N-(2,4-difluorobenzyl)-5-(4-fluorobenzyl)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxamide; N-(benzofuran-2-ylmethyl)-8-(3,5-difluorobenzyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-2-carboxamide; N-(2,4-difluorobenzyl)-8-(4-fluorobenzyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-2-carboxamide; (3,5-difluorobenzyl)-7-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-2-carboxamide; 1-(3,5-Difluorobenzyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxamide-2,2-dioxide; or 1-(3,5-difluorobenzyl)-3-methyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxamide 2,2-dioxide.

34. A pharmaceutical composition comprising a compound of Formula (I), as defined by any one of claims 1 to 33, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

35. A process for making the composition of claim 34, the process comprising contacting a therapeutically effective amount of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

36. A compound according to any one of claims 1 to 33 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 34, for use in modulating the Stimulator of Interferon Genes (STING) protein.

37. A compound or pharmaceutical composition for use according to claim 38, wherein the compound or composition is for use in activating, or agonising, the STING protein.

38. A compound according to any one of claims 1 to 33 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 34, for use in treating, ameliorating or preventing a disease selected from cancer, bacterial infection, viral infection, fungal infection, parasitic infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease.

39. A compound or pharmaceutical composition for use according to claim 38, wherein the disease is cancer.

40. A compound or pharmaceutical composition for use according to claim 39, wherein the cancer is 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.

41. A compound or pharmaceutical composition for use according to any one of claims 38 to 40, wherein the compound is for use with a second therapeutic agent, optionally wherein the second therapeutic agent comprises an antiviral agent, an anti-inflammation agent, conventional chemotherapy, an anti-cancer vaccine and/or hormonal therapy.

42. A compound or pharmaceutical composition for use according to claim 41, wherein the second therapeutic agent comprises a B7 costimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist (such as Ipilimumab and tremilimumab), an IDO inhibitor or IDO/TDO inhibitor (such as Epacadostat and GDC-o919), a PD-1 inhibitor (such as Nivolumab, Pembrolizumab, Pidilizumab, AMP-224, and MDX-1106), a PD-L1 inhibitor (such as Durvalumab, Avelumab and Atezolizumab), an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a 41BB/CD137 ligand, a CD27 ligand, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, a TLR agonist (such as Poly I:C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribine and a CpG dinucleotide) and/or detoxified endotoxins.

43. A compound of formula (I): ##STR00432## or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is CR.sup.9R.sup.10, O, S, SO or SO.sub.2; 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; the or each Z is CR.sup.11R.sup.12; n is 1 or 2; Q is CO, SO, SO.sub.2, CS or CR.sup.4R.sup.5; L is optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, 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, CO, SO, SO.sub.2, CH.sub.2C(O), CH.sub.2CONH, or CONH; Y is an optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, an optionally substituted C.sub.2-C.sub.6 alkenyl, an optionally substituted C.sub.2-C.sub.6 alkynyl, an optionally substituted C.sub.3-C.sub.6 cycloalkyl; R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CONR.sup.1R.sup.2, NR.sup.1R.sup.2, NHCOR.sup.1, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, optionally substituted mono or bicyclic 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, optionally substituted C.sub.1-C.sub.6 alkoxycarbonyl group, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted heterocyclyloxy; R.sup.4 and R.sup.5 are each independently selected from the group consisting of H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl and optionally substituted (C.sub.3-C.sub.6) cycloalkyl; or R.sup.4 and R.sup.5 together with the atom to which they are attached form a spirocyclic ring; R.sup.6 is mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C.sub.3-C.sub.6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R.sup.7 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted sulfonyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.2-C.sub.6 alkenyl and optionally substituted C.sub.2-C.sub.6 alkynyl; R.sup.8 is mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; 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, CN, hydroxyl, CO.sub.2H, CONR.sup.1R.sup.2, azido, sulfonyl, NR.sup.1R.sup.2, NHCOR.sup.1, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.1-C.sub.6 thioalkyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, 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, optionally substituted C.sub.1-C.sub.6 alkoxycarbonyl, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; 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; and R.sup.11 and R.sup.12 are each independently selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, halogen, CN, hydroxyl, CO.sub.2H, CONR.sup.1R.sup.2, azido, sulfonyl, NR.sup.1R.sup.2, NHCOR.sup.1, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.1-C.sub.6 thioalkyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, 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, optionally substituted C.sub.1-C.sub.6 alkoxycarbonyl, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R.sup.1 and R.sup.12 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; with the proviso that when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is ##STR00433## then R.sup.8 is not unsubstituted furanyl; when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is ##STR00434## then R.sup.8 is not unsubstituted phenyl, unsubstituted thiophenyl, unsubstituted pyridinyl, unsubstituted furanyl, unsubstituted tetrahydrofuranyl, ##STR00435## when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is CH.sub.2CH.sub.2; R.sup.7 is H; and R.sup.6 is ##STR00436## then R.sup.8 is not unsubstituted phenyl; when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is ##STR00437## R.sup.7 is H; and R.sup.6 is ##STR00438## then R.sup.8 is not unsubstituted phenyl; when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is unsubstituted phenyl then R.sup.8 is not unsubstituted furanyl, unsubstituted phenyl, ##STR00439## when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO or CH.sub.2; L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is ##STR00440## then R.sup.8 is not unsubstituted furanyl; when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is ##STR00441## then R.sup.8 is not unsubstituted furanyl; when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is ##STR00442## then R.sup.8 is not unsubstituted furanyl, ##STR00443## when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is CH.sub.2; R.sup.7 is H; and R.sup.6 is ##STR00444## then R.sup.8 is not unsubstituted furanyl or ##STR00445## and when X is S; X.sup.1, X.sup.2 and X.sup.3 are CH; n is 1; Z is CH.sub.2; Q is CO; L is CH.sub.2; Y is ##STR00446## R.sup.7 is H; and R.sup.6 is ##STR00447## then R.sup.8 is not unsubstituted phenyl; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

44. A compound of the formula (II) or (III): ##STR00448## wherein, X, X.sup.1, X.sup.2, X.sup.3, n, Z, Q, L, Y, R.sup.6, R.sup.7 and R.sup.8 are as defined in any one of claims 1 to 35; and R is H or a C.sub.1-C.sub.6 alkyl, to or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

45. A compound according to claim 44, wherein the compound is selected from: ##STR00449## ##STR00450## ##STR00451## ##STR00452## ##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461##

46. A conjugate of formula (IV): ##STR00462## wherein C is a compound as defined by any one of claims 1 to 33; L.sup.1 is a linker; T is a targeting moiety; and a is an integer between 1 and 10.

Description

[0389] 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:

[0390] FIG. 1 shows allele frequency of the major polymorphisms of human STING derived from the 1000 Genome Project database;

[0391] 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;

[0392] 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

[0393] FIG. 4 shows tumour growth against time (in days) in mice dosed intra-tumorally with compounds of the invention or a VC.

GENERAL SCHEMES

General Scheme 1

[0394] Compounds of formula (I) may be prepared from compounds of formula (II) and (III) using an amide bond forming reaction, as shown below.

##STR00071##

[0395] 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.

[0396] 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).

General Scheme 2

[0397] 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.

##STR00072##

[0398] 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.

General Scheme 3

[0399] Alternatively, compounds of formula (II) can be obtained from a halide of formula (V) as shown in the general scheme below.

##STR00073##

[0400] 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).

[0401] 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.

General Scheme 4

[0402] 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.

##STR00074##

[0403] The reaction could be conducted using CO gas in the presence of a suitable catalyst in an appropriate polar solvent. The catalyst may be a Pd, 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).

General Scheme 5

[0404] 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, alkyleyloalkyl halide, triflate or tosylate.

##STR00075##

General Scheme 6

[0405] Alternatively, a compound of formula (IX) may be prepared in a five-step process, as shown below, from a compound of formula (XIV), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00076##

[0406] First, the compound of formula (XIV) undergoes a nucleophilic substitution reaction with a compound of formula (XI), where R is methyl, ethyl, benzyl or tert-butyl, to produce a compound of formula (XIII). The nucleation substitution reaction may be conducted in the presence of a mild base, such as DBU, NaH, TEA, DIPEA, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or KHCO.sub.3. The solvent used may be 1,4-dioxane, acetone, MeCN, THF or DMF.

[0407] The nitro group on the compound of formula (XIII) may then be reduced to an amino group by using a reducing agent, such as Fe/AcOH, Zn/HCl, Zn/NH.sub.4Cl, Zn/HCOONH.sub.4, SnCl.sub.2/HCl or Pd/C/H.sub.2, in a suitable solvent, such as EtOH, MeOH or THF. The ensuing amino compounds undergo in-situ cyclization resulting in the formation of a compound of formula (XII).

[0408] 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).

[0409] It will be appreciated that the compound of formula (IX) is a compound of formula (I) where Q is CO.

General Scheme 7

[0410] Alternatively, a compound of formula (XV) may be prepared in a five-step process, as shown below, from a compound of formula (XII), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00077##

[0411] Firstly, the carbonyl group of the compound of formula (XII) may be reduced to the corresponding methylene group to give a compound of formula (XVIII). This can be achieved by using a suitable reducing agent, such as borane-THF or borane-DMSO, in a solvent such as THF or DMSO.

[0412] The compound of formula (XVIII) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XVII). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (XVI). Finally, this compound may be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XV).

[0413] It will be appreciated that the compound of formula (IX) is a compound of formula (I) where Q is CH.sub.2

General Scheme 8

[0414] A compound of formula (XIX) may be prepared in a six-step process, as shown below, from a compound of formula (XXV), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00078##

[0415] First the compound of formula (XXV) may react with an active olefin-containing compound via a Heck alkenylation reaction to give a compound of formula (XXIV). This reaction will be conducted in a sealed tube at an elevated temperature using a suitable transition metal catalyst and a suitable base in a suitable solvent. The transition metal catalyst might be a palladium catalyst, such as tetrakistriphenylphosphine palladium (0) or Ataphose, the base may be TEA or DIPEA and the solvent may be NMP, DMF, DMA or MeCN.

[0416] The compound of formula (XXIV) may then be reduced using a hydrogenation reaction with hydrogen gas and a suitable catalyst in a suitable solvent to provide a compound of formula (XXIII). The catalyst may be palladised charcoal and the solvent may EtOH or MeOH.

[0417] The compound of formula (XXIII) may then undergo a cyclization reaction to provide a compound of formula (XXII). The reaction may be conducted in an acidic medium at an elevated temperature in a suitable solvent, such as toluene, DMF, DMA or MeCN.

[0418] The compound of formula (XXII) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XXI). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (XX). Finally, this compound may be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XIX).

[0419] It will be appreciated that when m is 0 the compound of formula (XIX) is a compound of formula (I) where X is CH.sub.2 and Z is CH.sub.2, and when m is 1 the compound of formula (XIX) is a compound of formula (I) where X is CH.sub.2, one Z is CH.sub.2 and the other may be any one of the groups defined in claim 1.

General Scheme 9

[0420] A compound of formula (XXVI) may be prepared in a five-step process, as shown below, from a compound of formula (XXVI), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00079##

[0421] First, the compound of formula (XXXI) may undergo an amide formation to provide a compound of formula (XXX). The conditions used may be similar to those described under General Scheme 5.

[0422] The compound of formula (XXX) may then be cyclized to give a compound of formula (XXIX). For instance, a Friedel-Crafts cyclisation reaction could be used. This reaction would use a suitable Lewis acid reagent at elevated temperatures and in a suitable solvent. The Lewis acid reagent could be AlCl.sub.3 or FeCl.sub.3, and the solvent could be MeCN, toluene, EDC or MeOAc. Alternatively, Bronsted acids, such as TfOH, may be used to cause the compound of formula (XXX) to cyclise.

[0423] The compound of formula (XXIX) may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, to give a compound of formula (XXVIII). This compound may undergo a hydrolysis reaction, as described in General Scheme 2, to give a compound of formula (XXVII). Finally, this compound may be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XXVI).

[0424] It will be appreciated that the compound of formula (XXVI) is a compound of formula (I) where X is R.sup.9R.sup.10, Q is CO, n is 1 and Z is CH.sub.2.

General Scheme 10

[0425] A compound of formula (XXXII) may be prepared in a four- or five-step process, as shown below, from a compound of formula (XXXV), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00080##

[0426] The compound of formula (XXXV) is reacted with a suitable base and a suitable electrophile to cause an alkylation reaction and provide the compound of formula (XXXIII). The base may be a mild base, such as TEA, DIPEA, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 or KHCO.sub.3, or a stronger base, such as NaH or LiHMDS. The electrophile may be R.sup.9-G and/or R.sup.10-G where G is a suitable leaving group. The process may comprise sequential alkylation reactions, analogous to steps (xi) and (xii) shown above, or a double alkylation, analogous to step (xii).

[0427] The compound of formula (XXXIII may then undergo an alkylation/acylation/sulfonylation reaction, as described in General Scheme 5, a hydrolysis reaction, as described in General Scheme 2, and then the resulting compound may be reacted with a compound of formula (III), as described in General Scheme 1, to give a compound of formula (XXXII).

[0428] It will be appreciated that the compound of formula (XXXII) is a compound of formula (I) where Q is CO and n is 1.

General Scheme 11

[0429] Compounds of formula (XXXVII) and (XXXVI) can be synthesized by S-oxidation of compounds of formula (XXXVIII) with a suitable oxidizing agent, such as mCPBA, hydrogen peroxide or oxygen, in a solvent such as DCM, CHCl.sub.3, CCl.sub.4 or EDC.

##STR00081##

[0430] It will be appreciated that the compound of formula (XXXVII) is a compound of formula (I) where X is SO and the compound of formula (XXXVI) is a compound of formula (I) where X is SO.sub.2.

General Synthetic Procedures

General Procedure 1

[0431] ##STR00082##

[0432] To a stirred solution of a carboxylic acid (II) (1.277 mmol) in a suitable solvent, such as DCM, DMF, DMA or MeCN, (10 mL) was added amine (III) (1.2 eq.) and a coupling reagent, such as T.sub.3P, HATU, EDCl, 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).

[0433] Compounds of formula (I) were also prepared in parallel using library or array techniques according to one of the following methods.

Library General Procedure 1

Method 1

[0434] To a stirred solution of carboxylic acid (0.084 mmol, 1 eq.) in DMF (1.0 mL) was added DIPEA (0.209 mmol, 2.5 eq.) and T.sub.3P (0.251 mmol, 3.0 eq.) at RT and stirred for 5 min. The corresponding amine (1.5 eq.) was added and the whole stirred for 16 h at RT. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was purified by prep-HPLC.

Method 2

[0435] To a stirred solution of carboxylic acid (0.084 mmol, 1.0 eq.) in DMF (1.0 mL) was added DIPEA (0.209 mmol, 2.5 eq.) and the corresponding amine (1.5 eq.) followed by HATU (0.125 mmol, 1.5 eq.) and stirred for 16 h at RT. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was purified by prep-HPLC.

Method 3

[0436] To a stirred solution of carboxylic acid (0.084 mmol, 1.0 eq.) in DMF (1.0 mL) was added DIPEA (0.209 mmol, 2.5 eq.), HOBT (0.1 mmol, 1.2 eq.) and EDC.HCl (0.167 mmol, 2.0 eq.) followed by corresponding amine (1.5 eq.) and stirred for 16 h at room temperature. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was purified by prep-HPLC.

General Purification and Analytical Methods

[0437] 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.

Prep-HPLC

[0438] Preparative HPLC was carried out on a Waters auto purification instrument using either a YMC Triart C18 column (25020 mm, 5 m) or a Phenyl Hexyl column (25021.2 mm, 5 m) operating at between ambient temperature and 50 C. with a flow rate of 16.0-50.0 mL/min.

[0439] 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 600% 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.

[0440] 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.

[0441] LCMS method General 5 min method: Zorbax Extend C.sub.18 column (5004.6 mm, 5 m) 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 B in 1.5 min, and then to 10% 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.

UPLC Method

[0442] UPLC was carried out on a Waters auto purification instrument using a Zorbax Extend C.sub.18 column (504.6 mm, 5 m) 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 % 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.

[0443] 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.

General Procedure 2

[0444] ##STR00083##

[0445] 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.

General Procedure 3

[0446] ##STR00084##

Option 1

[0447] To a stirred solution of a compound of formula (VIII) (2.77 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 oils.

Option 2

[0448] Alternatively, to a stirred solution of a compound of formula (VIII) (2.77 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.

[0449] Compounds of formula (I) were prepared using a modification of General Procedure 3 in parallel using library or array techniques starting from the corresponding amide version of the compound of formula (VIII) according to one of the following methods.

Library General Procedure 2

Method 1

[0450] To a stirred suspension of lactam (0.104 mmol, 1.0 eq.) in EDC (1.5 mL/mmol) was added NaOH (2.0 eq., dissolved in 1.5 mL water) and TBAB (5 mg). The resulting reaction mixture was stirred for 1 h at RT, then corresponding aryl halide (1.5 eq.) was added to it. The reaction mixture was further stirred for 3-4 h at RT. The progress of the reactions was monitored by LCMS and after completion of reaction; the reaction mixture was diluted with DCM and washed with water. The organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness to obtain the crude product, which was purified by prep-HPLC.

Method 2

[0451] To a stirred solution of the lactam (0.104 mmol, 1.0 eq.) in DMF (3 mL/mmol) was added Cs.sub.2CO.sub.3 (1.5 eq.) at RT. After 10-15 min stirring, the corresponding aryl halides (1.5 eq.) were added and the whole stirred at 60 C. for 12 h. Progress of the reactions was monitored by LCMS. After completion, the reaction mixture was purified by prep-HPLC.

General Procedure 4

[0452] ##STR00085##

[0453] To a stirred solution of a compound of formula (XIV) (50.2 mmol, 1.0 eq.) and an appropriate nucleophile (XI) (1.25 eq.) in a suitable solvent, such as 1,4-dioxane, MeCN, DMF or THF, (3 mL/mmol) was added drop wise or portion wise a suitable base, such as TEA, DBU, NaH, K.sub.2CO.sub.3 (1.5 eq.) with ice bath cooling and allowed to stir at 0-25 C. for 1-16 h. The progress of the reaction was monitored by TLC or LCMS and on completion of the reaction; the reaction mixture was quenched with NH.sub.4Cl solution and 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 dryness. The crude compound of formula (XIII) (60-95% yield) obtained as a yellow solid which were pure enough to be used directly in the next step without further purification.

General Procedure 5

[0454] ##STR00086##

[0455] To a stirred solution of a compound of formula (XIII) (46.7 mmol, 1.0 eq.) in a suitable acid, such as AcOH or aq. HCl, (3 mL/mmol) was added iron powder or zinc powder (4.0 eq.) at RT. The reaction mixture was stirred at 75-85 C. for 2-5 h. The reaction was monitored by TLC or LCMS and on completion of the reaction, cooled to room temperature and poured into 1N HCl and then stirred for 1-2 h. The white precipitate was filtered off and washed with excess water. The residue obtained was re-dissolved in 5% MeOH in DCM and filtered through a bed of celite. The filtrate was evaporated under reduced pressure to obtain a compound of formula (XII) (80-95% yield) as a white solid which were pure enough to proceed in to the next step.

General procedure 6

##STR00087##

[0456] To a stirred solution of ester (XII) (2.24 mmol, 1.0 eq.) in a suitable solvent, such as THF or DMSO, was added borane-THF or borane-DMSO (5.0 eq.; 1M solution) at 0-5 C. The reaction mixture was allowed to stir at room temperature for 12-16 h. The progress of the reaction was monitored by TLC or LCMS and upon completion the reaction was quenched by drop wise addition of an appropriate amount of MeOH with ice cooling. The solvent was evaporated under reduced pressure. The residue obtained was partitioned between EtOAc and water; the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness to provide the crude products (XVIII) (85-96% yield) which were used without further purification.

General Procedure 7

[0457] ##STR00088##

[0458] To a stirred solution of a compound of formula (XXV) (8.65 mmol, 1.0 eq.) in a suitable dry solvent, such as DMF, NMP or DMA, (1.5 mL/mmol) was added an olefin derivative (3.8 eq.) and a base, such as TEA or DIPEA, in a sealed tube reaction container at RT and the resulting reaction mixture degassed by bubbling N.sub.2 gas through the solution for 5-10 min. A metal catalyst, such as bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium (II), (0.03 eq.) was added and the solution was further degassed for 5-10 min. The tube was then sealed and heated at 130-140 C. for 10-16 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was filtered through a small pad of celite and then thoroughly washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography by using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (XXIV) (20-50% yield).

General Procedure 8

[0459] ##STR00089##

[0460] To a stirred solution of a compound of formula (XXIV) (2.32 mmol, 1.0 eq.) in a suitable solvent, for example MeOH or EtOAc, (5 mL/mmol) was added an appropriate amount of PdC (10% w/w) under a N.sub.2 gas atmosphere at 0-25 C. The resulting reaction mixture was stirred at RT under H.sub.2 gas balloon pressure for 2-4 h. On completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed under a N.sub.2 gas atmosphere. The filtrate was concentrated under reduced pressure to obtain the crude product which was purified by column chromatography on silica gel using mixtures of EtOAc in hexanes as eluent to afford the reduced alkane derivative (XXIII) (80-85% yield).

General Procedure 9

[0461] ##STR00090##

[0462] To a stirred solution of a compound of formula (XXIII) (1.9 mmol, 1.0 eq.) in a suitable solvent, such as toluene, DMF, DMA or MeCN, (5 mL/mmol) was added formic acid (1.5 mL/mmol) and the resulting reaction mixture was heated to reflux (100-115 C.) for 1-12 h. After completion of the reaction the mixture was concentrated under reduced pressure to obtain a residue which was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine solution, 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 yield the cyclized compound of formula (XXII) in 60-70% yield.

General Procedure 10

[0463] ##STR00091##

[0464] To a stirred solution of a compound of formula (XXX) (0.86 mmol, 1.0 eq.) in a suitable solvent such as EDC or MeCN under an inert atmosphere was added anhydrous AiCl.sub.3 or FeCl.sub.3 (4.0 eq.) portionwise and the whole heated at reflux temperature for 1-2 h. After completion of the reaction (TLC/LCMS), the reaction mixture was diluted with EDC and washed with dilute HCl followed by brine solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness to obtain the crude product which was purified by column chromatography on silica gel using mixtures of EtOAc in hexanes as eluent to afford the desired compound of formula (XXIX) (50-55% yield) as a brown solid.

General Procedure 11

[0465] ##STR00092##

[0466] To a stirred solution of a compound of formula (XXXV) (26.16 mmol, 1.0 eq.) in DMF or THF (150 mL) at 65 to 78 C. was added dropwise a suitable base such as LiHMDS, LDA or NaH (1.0 eq.) and the mixture allowed to stir for 15-30 min. A suitable alkyl/aryl(het) halide (R.sup.9-L-G) (1.0 eq.) was added at the same temperature. The whole was allowed to stir at 0 to 10 C. for 0.5 to 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with an aqueous solution of NH.sub.4Cl, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The dried organics were evaporated under reduced pressure to obtain a crude residue which was purified by Combi-flash using EtOAc in hexanes as eluent to afford a compound of formula (XXXIV) (25-30% yield) as a light orange to faint pink solid.

General Procedure 12

[0467] ##STR00093##

[0468] To a stirred solution of (XXXIV) (26.16 mmol, 1.0 eq.) in DMF or THF (150 mL) at 65 to 78 C. was added dropwise a suitable base, such as LiHMDS, LDA or NaH, (1.0 eq.) and the whole allowed to stir for 15-30 min., then a suitable alkyl/aryl(het) halide (R.sup.10-L-G) (1.0 eq.) was added at the same temperature. The whole was allowed to stir at 0 to 10 C. for 0.5 to 1 h. After completion of the reaction, the mixture was quenched with an aqueous solution of NH.sub.4Cl, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The dried organics were evaporated under reduced pressure to obtain a crude residue which was purified by Combi-flash using 35-50% EtOAc in hexanes as eluent to afford a compound of formula (XXXIII) (65-70% yield) as a light orange to faint pink solid.

General Procedure 13

[0469] ##STR00094##

[0470] To a stirred solution of a compound of formula (XXXVIII) (1.0 eq.) in suitable solvents, such as DCM, CHCl.sub.3, CCl.sub.4 or EDC, (2 mL) was added mCPBA (1.0-3.0 eq.) at RT. The reaction mixture was further stirred at the same temperature for 2-16 h. The progress of the reaction was monitored by TLC and after completion of the reaction the mixture was diluted with more solvent and washed with a saturated solution of aqueous NaHCO.sub.3 followed by brine. The organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product was purified by prep-HPLC to afford sulfoxide (XXXVII) and sulfone (XXXVI) as off white solids.

EXAMPLES

[0471] Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (6) are given in parts-per-million (ppm) 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.

[0472] 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, 35Cl, .sup.79Br and .sup.127I.

[0473] 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.

[0474] 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: 4-(2-chlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0475] ##STR00095##

[0476] Example 1 was prepared according to the methods described in General Procedures 1-3, and the methods described below.

Preparation 1: Methyl 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate

[0477] ##STR00096##

Step 1: Methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate

[0478] ##STR00097##

[0479] Methyl 4-fluoro-3-nitrobenzoate (10.0 g, 50.2 mmol) was taken up in MeCN (2.0 L) and TEA (7.61 g, 75.38 mmol) was added to it. The reaction mixture was cooled to 0 C. and ethyl thioglycolate (7.25 g, 62.7 mmol) was added drop wise. The reaction mixture was stirred for 30 min. at ice cold temperature. It was then diluted with EtOAc and washed with saturated solution of NH.sub.4Cl and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness to give methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate (14.0 g, 46.82 mmol, 93% yield) as a yellow solid, which was pure enough to be used in the next step without any further purification. LCMS m/z: 300.06 [M+H].

Step 2: Methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate

[0480] ##STR00098##

[0481] To a stirred solution of methyl 4-((2-ethoxy-2-oxoethyl)thio)-3-nitrobenzoate (Step 1) (5.0 g, 16.7 mmol) in acetic acid (50 mL) was added iron powder (3.73 g, 66.8 mmol). The resulting reaction mixture was stirred at 80 C. for 3 h. On completion (monitored by TLC), it was cooled to room temperature and poured onto 1N HCl (250 mL) and then stirred for 1 h. The white precipitate was filtered off and washed with water. The residue obtained was re-dissolved in 5% MeOH in DCM (50 mL) and filtered through a bed of celite. The filtrate was evaporated to dryness to afford the methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (3.5 g, 15.6 mmol, 91% yield) as a golden white solid. LCMS m/z: 222.05 [MH].

Preparation 4: Methyl 4-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6 carboxylate

[0482] ##STR00099##

[0483] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 1) (0.3 g, 1.34 mmol) in EDC (5 mL) was added NaOH solution (0.107 g, 2.69 mmol in 5 mL H.sub.2O) portion wise followed by TBAB (0.05 g, 0.15 mmol) at RT. The whole was stirred for 30 min at RT and then 2-chloro-benzyl bromide (0.209 mL, 1.61 mmol) was added drop wise. The reaction mixture was then stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and after completion; the reaction mixture was diluted with DCM, washed with water and brine solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness to give 4-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (0.32 g, 0.92 mmol, 69% yield) which was used directly in Preparation 5. LCMS m/z: 348.19 [M+H].

Preparation 5: 4-(2-Chlorobenzoyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylic acid

[0484] ##STR00100##

[0485] To a stirred solution of methyl 4-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 4) (0.32 g, 0.92 mmol) in a mixture of MeOH, water and THF (1:1:2; 12 mL) was added LiOH.H.sub.2O (0.077 g, 1.84 mmol) at RT. The reaction was allowed to stir at RT for 2 h. Upon completion of the reaction, the solvents were evaporated under reduced pressure and the residue was dissolved in water, washed with EtOAc and then acidified to pH 5. The acidified aqueous solution was then extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness to give 4-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylic acid (0.22 g. 0.66 mmol, 72% yield) as white solid which was used in the next step without any further purification. LCMS m/z: 332.12 [MH].

Preparation 6: 4-(2-chlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-, 4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0486] ##STR00101##

[0487] To a stirred solution of 4-(2-chlorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylic acid (Preparation 5) (0.1 g, 0.3 mmol) in DMF (5 mL) was added HATU (0.136 g, 0.36 mmol) followed by TEA (0.104 mL, 1.03 mmol) at RT. The resulting reaction mixture was stirred at RT for 30 min. then 1-(furan-2-yl)-methanamine (0.026 mL, 0.27 mmol) was added and stirring continued at RT for 2 h. After this time, the reaction mixture was diluted with EtOAc and washed with chilled water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness. The crude material obtained was purified by prep-HPLC to afford 4-(2-chlorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 1) (0.04 g, 0.097 mmol, 32% yield) as a white solid. LCMS m/z: 413.18 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.76 (s, 2H), 4.41 (d, J=5.6 Hz, 2H), 5.24 (s, 2H), 6.20 (d, J=2.7 Hz, 1H), 6.37-6.38 (dd, J.sub.1=1.85 Hz, J.sub.2=2.9 Hz, 1H), 7.07 (d, J=7.55 Hz, 1H), 7.26-7.31 (m, 2H), 7.49-7.52 (m, 2H), 7.55-7.57 (m, 3H), 9.00 (t, J=5.65 Hz, 1H).

Examples 2-49

[0488] Examples 2-49 were prepared according to the above methods used to make Example 1 as described in General Procedures 1-3 using the appropriate amines and acids.

[0489] Purification was as stated in the aforementioned methods.

TABLE-US-00001 IUPAC LCMS Example Structure Name .sup.1H-NMR [M + H] 2 [00102] N-(furan-2- ylmethyl)-3- oxo-4-(2-oxo- 2- phenylethyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.36 (s, 2H), 4.42 (d, J = 5.55 Hz, 2H), 5.57 (s, 2H), 6.21 (d, J = 2.55 Hz, 1H), 6.36 (s, 1H), 7.40 (s, 1H), 7.54 (s, 1H), 7.57 (s, 2H), 7.63 (t, J = 7.65 Hz, 2H), 7.75 (t, J = 7.45 Hz, 1H), 8.13 (d, J = 7.75 Hz, 2H), 9.01 (t, J = 5.5 Hz, 1H). 407.26 3 [00103] N-(furan-2- ylmethyl)-4- (2-(indolin-1- yl)-2- oxoethyl)-3- oxo-3,4- dihyrdo-2H- benzo[b- 1,4]thiazine- 6- carboxamide (500 MHz; DMSO-d.sub.6): 3.25 (m, 2H), 3.63 (s, 2H), 4.28 (t, J = 8.4 Hz, 2H), 4.44 (d, J = 5.55 Hz, 2H), 4.93 (s, 2H), 6.22 (d, J = 2.8 Hz, 1H), 6.34 (bs, 1H), 7.04 (t, J = 7.35 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.25 Hz, 1H), 7.52- 7.54 (m, 2H), 7.55-7.57 (m 2H), 8.01 (d, J = 8.05 Hz, 1H) 9.01-9.03 (m, 1H). 448.20 4 [00104] N-(furan-2- ylmethyl)-3- oxo-4-(2-oxo- 2-(pyridin-4- ylamino)ethyl)- 3,4-dihydro- 2H-benzo[b- 1,4]-thiazine- 6- carboxamide (500 MHz; DMSO-d.sub.6): 3.65 (s, 2H), 4.50 (d, J = 5.5 Hz, 2H), 4.95 (s, 2H), 6.24 (d, J = 2.7 Hz, 1H), 6.37 (s, 1H), 7.55- 7.63 (m, 4H), 8.00 (d, J = 5.8 Hz, 2H), 8.68 (d, J = 5.85 Hz, 2H), 9.10 (t, J = 5.45 Hz, 1H), 11.84 (bs, 1H). 423.19 5 [00105] N-(furan-2- ylmethyl)-3- oxo-4-(2-oxo- 2- (phenylamino) ethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.63 (s, 2H), 4.45 (d, J = 5.55 Hz, 2H), 4.79 (s, 2H), 6.24 (d, J = 2.5 Hz, 1H), 6.37 (s, 1H), 7.08 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 7.75 Hz, 2H), 7.53-7.61 (m, 6H), 9.07 (t, J = 5.45 Hz, 1H), 10.34 (s, 1H). 422.22 6 [00106] 4- (benzo[d] thiazol-2- ylmethyl)-N- (furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.73 (s, 2H), 4.43 (d, J = 5.55 Hz, 2H), 5.68 (s, 2H), 6.23 (d, J = 2.55 Hz, 1H), 6.37 (s, 1H), 7.43 (t, J = 7.55 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.56-7.58 (m, 3H), 7.88 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 9.03 (t, J = 5.4 Hz, 1H). 436.19 7 [00107] 4-(benzo[d] oxazol-2- ylmethyl)-N- (furan-2- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.70 (s, 2H), 4.43 (d, J = 5.55 Hz, 2H), 5.52 (s, 2H), 6.21 (d, J = 2.45 Hz, 1H), 6.35 (s, 1H), 7.36-7.42 (m, 2H), 7.54 (s, 1H), 7.57-7.61 (m, 2H), 7.70-7.74 (m, 2H), 7.79 (s, 1H), 9.01 (t, J = 5.35 Hz, 1H). 420.20 8 [00108] N-(furan-2- ylmethyl)-3- oxo-4- phenethyl- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 2.83-2.86 (m, 2H), 3.54 (s, 2H), 4.23-4.26 (m, 2H), 4.51 (d, J = 5.4 Hz, 2H), 6.32 (s, 1H), 6.43 (s, 1H), 7.19-7.20 (m, 3H), 7.26-7.29 (m, 2H), 7.51-7.62 (m, 3H), 7.79 (s, 1H), 9.09 (t, J = 5.2 Hz, 1H). 393.24 9 [00109] 4-(2-((2- amino- pyrimidin-5- yl)amino)-2- oxoethyl)-N- (furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- (500 MHz; DMSO-d.sub.6): 3.62 (s, 2H), 4.46 (d, J = 5.55 Hz, 2H), 4.75 (s, 2H), 6.26 (d, J = 2.6 Hz, 1H), 6.38 (s, 1H), 6.57 (bs, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.57-7.60 (m, 3H), 8.38 (s, 2H), 9.07 (t, J = 5.5 Hz, 1H), 10.13 (s, 1H). 439.21 6-carboxamide 10 [00110] 4-benzyl-N- ((1-methyl- 1H-pyrrol-2- yl)methyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.50 (s, 3H), 3.72 (s, 2H), 4.39 (d, J = 5.25 Hz, 2H), 5.28 (s, 2H), 5.88-5.91 (m, 2H), 6.66 (s, 1H), 7.19-7.24 (m, 3H), 7.31 (t, J = 7.45 Hz, 2H), 7.49-7.53 (m, 2H), 7.63 (s, 1H), 8.77 (t, J = 5.1 Hz, 1H). 392.24 11 [00111] 4-(2,3- dichloro- benzyl)-N- (furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.77 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 5.25 (s, 2H), 6.20 (d, J = 2.85 Hz, 1H), 6.37 (s, 1H), 7.07 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.53-7.60 (m, 4H), 9.02 (t, J = 5.55 Hz, 1H). 447.14 12 [00112] 4-(2,3- dimethyl- benzyl)-N- (furan-2- ylmethyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-caroxamide (400 MHz; DMSO-d.sub.6): 2.20 (s, 3H), 2.24 (s, 3H), 3.70 (s, 2H), 4.37 (d, J = 5.56 Hz, 2H), 5.16 (s, 2H), 6.16 (d, J = 2.96 Hz, 1H), 6.34-6.35 (m, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.92 (t, J = 7.64 Hz, 1H), 7.01 (d, J = 7.36 Hz, 1H), 7.47 (s, 1H), 7.51-7.52 (m, 3H), 8.94 (t, J = 5.44 Hz, 1H). 407.25 13 [00113] 4-(2,6- dimethyl- benzyl)-N- (furan-2- ylmethyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (400 MHz; DMSO-d.sub.6): 2.27 (s, 6H), 3.56 (s, 2H), 4.41 (d, Hz, 2H), 5.25 (s, 2H), 6.21 (d, J = 2.84 Hz, 1H), 6.38-6.39 (m, 1H), 6.84 (d, J = 7.4 Hz, 2H), 6.89-6.93 (m, 1H), 7.41- 7.46 (m, 2H), 7.58 (d, J = 12.52 Hz, 2H), 8.87 (t, J = 5.40 Hz, 1H). 407.27 14 [00114] N-(furan-2- ylmethyl)-4- (naphthalen- 1-ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (400 MHz; DMSO-d.sub.6): 3.78 (s, 2H), 4.31 (d, J = 5.6 Hz, 2H), 5.67 (s, 2H), 6.09 (d, J = 3.04 Hz, 1H), 6.29-6.31 (m, 1H), 7.14 (d, J = 7.08 Hz, 1H), 7.36 (d, J = 7.48 Hz, 1H), 7.48 (bs, 1H), 7.50-7.55 (m, 3H), 7.57-7.61 (m, 2H), 7.81 (d, J = 8.16 Hz, 1H), 8.95-8.97 (m, 1H), 8.16 (d, J = 7.96 Hz, 1H), 8.91 (t, J = 5.64 Hz, 1H). 429.26 15 [00115] 4- (cyclohexyl- methyl)-N- (furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (400 MHz; DMSO-d.sub.6): 0.88-0.90 (m, 2H), 1.04 (bs, 3H), 1.50-1.59 (m, 6H), 3.50 (s, 2H), 3.94 (s, 2H), 4.46 (s, 2H), 6.25 (s, 1H), 6.38 (s, 1H), 7.48-7.56 (m, 3H), 7.78 (s, 1H), 9.02 (bs, 1H). 385.26 16 [00116] N- (cyclo- hexylmethyl)-4- (2-fluoro- benzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 0.82-0.88 (m, 2H), 1.09-1.18 (m, 3H), 1.47 (bs, 1H), 1.61-1.64 (m, 5H), 3.04 (t, J = 6.15 Hz, 2H), 3.73 (s, 2H), 5.29 (s, 2H), 7.10 (d, J = 5.75 Hz, 2H), 7.22 (t, J = 9.9 Hz, 1H), 7.30-7.31 (m, 1H), 7.51-7.54 (m, 3H), 8.47 (t, J = 5.4 Hz, 1H). 413.33 17 [00117] N-(furan-2- ylmethyl)-4- (2-hydroxy-2- phenylethyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide 500 MHz; DMSO-d.sub.6): 3.48-3.56 (q, J = 14.4 Hz, 2H), 4.06-4.10 (m, 1H), 4.18-4.21 (m, 1H), 4.45-4.54 (m, 2H), 4.83- 4.86 (m, 1H), 5.61 (d, J = 4.2 Hz, 1H), 6.32 (d, J = 2.75 Hz, 1H), 6.43 (s, 1H), 7.21-7.24 (m, 1H), 7.28-7.35 (m, 4H), 7.46 (d, J = 8.05 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 8.04 (s, 1H), 9.03 (t, J = 5.5 Hz, 1H). 409.25 18 [00118] (S)-N-(1- cyclohexyl- ethyl)-4-(2- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 0.81-0.92 (m, 2H), 1.05- 1.14 (m, 6H), 1.33-1.35 (m, 1H), 1.58-1.69 (m, 5H), 3.69-3.77 (m, 3H), 5.24 (d, J = 16.75 Hz, 1H), 5.35 (d, J = 16.85 Hz, 1H), 7.10 (d, J = 4.7 Hz, 2H), 7.21 (t, J = 10.0 Hz, 1H), 7.30-7.32 (m, 1H), 7.52 (s, 3H), 8.12 427.32 (d, J = 8.7 Hz, 1H). 19 [00119] (R)-N-(1- cyclohexyl- ethyl)-4-(2- flurobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 0.83-0.92 (m, 2H), 1.05-1.16 (m, 6H), 1.33- 1.35 (m, 1H), 1.58-1.69 (m, 5H), 3.69-3.77 (m, 3H), 5.24 (d, J = 16.9 Hz, 1H), 5.35 (d, J = 16.75 Hz, 1H), 7.10 (d, J = 4.65 Hz, 2H), 7.22 (t, J = 9.7 Hz, 1H), 7.30- 7.31 (m, 1H), 7.52 (s, 427.33 3H), 8.12 (d, J = 8.6 Hz, 1H). 20 [00120] N- (cyclopropyl- methyl)-4-(2- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 0.18 (d, J = 4.55 Hz, 2H), 0.40 (d, J = 7.8 Hz, 2H), 0.95-1.10 (m, 1H), 3.08-3.10 (m, 2H), 3.73 (s, 2H), 5.28 (s, 2H), 7.08-7.13 (m, 2H), 7.23 (t, J = 9.85 Hz, 1H), 7.29-7.32 (m, 1H), 7.54 (s, 2H), 7.58 (s, 1H), 8.60 (t, J = 5.15 Hz, 1H). 371.22 21 [00121] N,4-bis(2- chloro-6- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- carboxamide (500 MHz; DMSO-d.sub.6): 3.58 (s, 2H), 4.47 (d, J = 4.5 Hz, 2H), 5.37 (s, 2H), 7.11 (t, J = 9.4 Hz, 1H), 7.22-7.31 (m, 3H), 7.35 (d, J = 7.9 Hz, 1H), 7.38-7.41 (m, 1H), 7.45 (s, 2H), 7.74 (s, 1H), 8.72 (t, J = 4.75 Hz, 1H). 493.20 22 [00122] N-((6,6- dimethyl- bicyclo[3.1.1] heptan-3- yl)methyl)-4- (2- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine 6-carboxamide (500 MHz; DMSO-d.sub.6): 0.81-0.83 (m, 1H), 1.03 (s, 3H), 1.14 (s, 3H), 1.42-1.48 (m, 1H), 1.74- 1.90 (m, 5H), 2.21-2.24 (m, 1H), 2.28-2.31 (m, 1H), 3.20 (t, J = 6.95 Hz, 2H), 3.73 (s, 2H), 5.25-5.32 (m, 2H), 7.08- 7.12 (m, 2H), 7.22 (t, J = 10.15 Hz, 1H), 7.29-7.32 (m, 1H), 7.48-7.54 (m, 453.31 3H), 8.47 (t, J = 5.4 Hz, 1H). 23 [00123] N-(1- ((3r,5r,7r)- adamantan-1- yl)ethyl)-4-(2- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 1.00 (d, J = 6.9 Hz, 3H), 1.38-1.52 (m, 9H), 1.61- 1.63 (s, 3H), 1.88 (bs, 3H), 3.68-3.75 (m, 2H), 3.77-3.80 (m, 1H), 5.23 (d, J = 17.0 Hz, 1H), 5.40 (d, J = 16.9 Hz, 1H), 7.10-7.11 (m, 2H), 7.20 (t, J = 9.8 Hz, 1H), 7.29-7.30 (m, 1H), 7.48- 479.35 7.53 (m, 3H), 7.93 (d, J = 9.25 Hz, 1H), 8.47 (t, J = 5.4 Hz, 1H). 24 [00124] N-((3r,5r,7r)- adamantan-1- ylmethyl)-4- (2- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 1.39 (s, 6H), 1.53 (d, J = 11.7 Hz, 3H), 1.63 (d, J = 11.85 Hz, 3H), 1.88 (bs, 3H), 2.92 (d, J = 6.25 Hz, 2H), 3.74 (s, 2H), 5.30 (s, 2H), 7.10-7.11 (m, 2H), 7.21 (t, J = 9.8 Hz, 1H), 7.29-7.30 (m, 1H), 7.49-7.54 (m, 3H), 8.31 (bs, 1H). 465.34 25 [00125] N- (cyclohexyl- methyl)-4-(2,3- dimethyl- benzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide 500 MHz; DMSO-d.sub.6): 0.81-0.88 (m, 2H), 1.08-1.15 (m, 3H), 1.45 (s, 1H), 1.60-1.63 (m, 5H), 2.25 (d, J = 13.15 Hz, 6H), 3.02 (t, J = 6.2 Hz, 2H), 3.74 (s, 2H), 5.18 (s, 2H), 6.76 (d, J = 7.7 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 7.35 Hz, 1H), 7.43 (s, 1H), 7.47-7.53 (m, 2H), 8.43 (t, J = 5.7 Hz, 1H). 423.31 26 [00126] 4-(2- fluorobenzyl)- N- (naphthalen- 1-ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide 500 MHz; DMSO-d.sub.6): 3.74 (s, 2H), 4.91 (d, J = 5.45 Hz, 2H), 5.29 (s, 2H), 7.09-7.10 (m, 2H), 7.22 (t, J = 10.0 Hz, 1H), 7.30-7.31 (m, 1H), 7.40 (d, J = 6.95 Hz, 1H), 7.46 (t, J = 7.30 Hz, 1H), 7.53-7.60 (m, 4H), 7.66 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.95-7.97 (m, 456.98 1H), 8.11-8.12 (m, 1H), 9.12 (t, J = 5.25 Hz, 1H). 27 [00127] N-(furan-2- ylmethyl)-3- oxo-4- (pyridin-3- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.74 (s, 2H), 4.43 (d, J = 5.55 Hz, 2H), 5.32 (s, 2H), 6.22 (d, J = 2.8 Hz, 1H), 6.39 (m, 1H), 7.34- 7.36 (m, 1H), 7.53-7.59 (m, 4H), 7.64 (s 1H), 8.45-8.47 (m, 2H), 9.02 (t, J = 5.5 Hz, 1H). 379.93 28 [00128] N-(furan-2- ylmethyl)-3- oxo-4- (pyridin-4- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.76 (s, 2H), 4.41 (d, J = 5.40 Hz, 2H), 5.29 (s, 2H), 6.21 (d, J = 1.95 Hz, 1H), 6.38 (s, 1H), 7.22 (d, J = 4.75 Hz, 2H), 7.51-7.57 (m, 4H), 8.50 (d, J = 4.8 Hz, 2H), 9.01 (t, J = 5.2 Hz, 1H). 379.92 29 [00129] N-(furan-2- ylmethyl)-3- oxo-4-(1- phenylethyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 1.73 (d, J = 7.0 Hz, 3H), 3.55 (d, J = 14.5 Hz, 1H), 3.66 (d, J = 14.45 Hz, 1H), 4.39-4.40 (m, 2H), 5.98-6.02 (m, 1H), 6.21 (d, J = 2.9 Hz, 1H), 6.39 (s, 1H), 7.23-7.35 (m, 5H), 7.48 (s, 1H), 7.52-7.57 (m, 3H), 8.98 (t, J = 5.5 Hz, 1H). 393.26 30 [00130] N-(furan-2- ylmethyl)-3- oxo-4-(2- (trifluoro- methyl)benzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.80 (s, 2H), 4.39 (d, J = 5.6 Hz, 2H), 5.34 (s, 2H), 6.20 (d, J = 2.95 Hz, 1H), 6.36-6.37 (m, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.45-7.61 (m, 6H), 7.81 (d, J = 7.7 Hz, 1H), 8.01 (t, J = 5.65 Hz, 1H). 446.97 31 [00131] 4-(2-chloro-6- fluorobenzyl)- N-(2,6- difluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.58 (s, 2H), 4.50 (d, J = 5.05 Hz, 2H), 5.36 (s, 2H), 7.08-7.13 (m, 3H), 7.22-7.23 (m, 1H), 7.26- 7.31 (m, 1H), 7.38-7.47 (m, 3H), 7.74 (s, 1H), 8.84 (t, J = 5.5 Hz, 1H). 477.25 32 [00132] 4-(2-chloro-6- fluorobenzyl)- N- (naphthalen- 2-ylmethyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.60 (s, 2H), 4.64 (d, J = 5.8 Hz, 2H), 5.40 (s, 2H), 7.11 (t, J = 9.45 Hz, 1H), 7.24 (d, J = 7.85 Hz, 1H), 7.27-7.31 (m, 1H), 7.46-7.51 (m, 5H), 7.79 (s, 1H), 7.83 (s, 1H), 7.87-7.92 (m, 3H), 9.14 (t, J = 5.8 Hz, 1H). 491.27 33 [00133] 4-benzyl-N- (furan-2- ylmethyl)-N- methyl-3-oxo- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (400 MHz; DMSO-d.sub.6): 2.59-2.80 (m, 3H), 3.72 (s, 2H), 4.20 (bs, 1H), 4.56 (bs, 1H), 5.25 (s, 2H), 6.21-6.30 (m, 1H), 6.41 (bs, 1H), 7.03- 7.21 (m, 5H), 7.26-7.29 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.55-7.59 (m, 1H). 393.2 34 [00134] 4-(2-chloro-6- fluorobenzyl)- N-(2,4- difluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.60 (s, 2H), 4.46 (d, J = 5.5 Hz, 2H), 5.39 (s, 2H), 7.08-7.14 (m, 2H), 7.24-7.32 (m, 3H), 7.35- 7.40 (m, 1H), 7.49 (s, 2H), 7.78 (s, 1H), 9.00 (t, J = 5.65 Hz, 1H). 477.35 35 [00135] 4-(2-chloro-6- fluorobenzyl)- N- (cyclopentyl- methyl)-3-oxo- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.20-126 (m, 2H), 1.49- 1.53 (m, 2H), 1.57-1.58 (m, 2H), 1.61-1.68 (m, 2H), 2.09-2.14 (m, 1H), 3.16 (t, J = 6.2 Hz, 2H), 3.59 (s, 2H), 5.39 (s, 2H), 7.11 (t, J = 9.75 Hz, 1H), 7.23-7.31 (m, 2H), 7.43-7.48 (m, 2H), 7.31 (s, 1H), 8.44 (t, J = 5.45 Hz, 1H). 433.28 36 [00136] 4-(2-chloro-6- fluorobenzyl)- N-((6- methyl- pyridin- 3-yl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 2.45 (s, 3H), 3.59 (s, 2H), 4.43 (d, J = 5.7 Hz, 2H), 5.38 (s, 2H), 7.12 (t, J = 9.45 Hz, 1H), 7.22-7.25 (m, 2H), 7.27- 7.31 (m, 1H), 7.46-7.50 (m, 2H), 7.57 (d, J = 7.95 Hz, 1H), 7.77 (s, 1H), 8.39 (bs, 1H), 9.03 (t, J = 5.65 Hz, 1H). 456.30 37 [00137] 4-(2-chloro-6- fluorobenzyl)- N-(3- methylbenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 2.30 (s, 3H), 3.60 (s, 2H), 4.43 (d, J = 5.85 Hz, 2H), 5.39 (s, 2H), 7.06-7.13 (m, 4H), 7.21- 7.32 (m, 3H), 7.48-7.52 (m, 2H), 7.81 (s, 1H), 9.00 (t, J = 5.85 Hz, 1H). 455.28 38 [00138] 4-(2-chloro-6- fluorobenzyl)- N-(3- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.60 (s, 2H), 4.48 (d, J = 5.75 Hz, 2H), 5.40 (s, 2H), 7.08-7.14 (m, 4H), 7.24 (d, J = 8.0 Hz, 1H), 7.27-7.32 (m, 1H), 7.37- 7.42 (m, 1H), 7.501 (s, 2H), 7.80 (s, 1H), 9.08 (t, J = 5.80 Hz, 1H). 459.22 39 [00139] 3-oxo-4- (pyridin-4- ylmethyl)-N- (2,4,6- trifluoro- benzyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.75 (s, 2H), 4.40 (d, J = 3.85 Hz, 2H), 5.28 (s, 2H), 7.16-7.20 (m, 4H), 7.47-7.55 (m, 3H), 8.50 (bs, 2H), 8.93 (bs, 1H). 444.28 40 [00140] N- (benzofuran- 2-ylmethyl)- 4-(2-chloro-6- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (500 MHz; DMSO-d.sub.6): 3.59 (s, 2H), 4.63 (d, J = 5.5 Hz, 2H), 5.39 (s, 2H), 6.74 (s, 1H), 7.10 (t, J = 9.55 Hz, 1H), 6.21-7.31 (m, 4H), 7.49- 7.55 (m, 3H), 7.60 (d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 9.13 (t, J = 5.5 Hz, 1H). 481.25 41 [00141] 4-(2-chloro-6- fluorobenzyl)- N-(3-cyano-2- phenylpropyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6-carboxamide (400 MHz; DMSO-d.sub.6): 2.89-2.92 (m, 2H), 3.26-3.28 (m, 1H), 3.49- 3.52 (m, 2H), 3.57 (s, 2H), 5.36 (d, J = 4.12 Hz, 2H), 7.08-7.13 (m, 1H), 7.22-7.38 (m, 8H), 7.45 (d, J = 8.08 Hz, 1H), 7.68 (s, 1H), 8.52- 8.53 (m, 1H). 494.1 42 [00142] N- benzhydryl-4- (2- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.45-1.53 (m, 3H), 1.64- 1.66 (m, 2H), 1.81-1.85 (m, 2H), 3.73-3.75 (m, 2H), 4.13-4.17 (m, 1H), 5.28-5.32 (m, 2H), 7.07- 7.13 (m, 2H), 7.21-7.35 (m, 5H), 7.5.-7.62 (m, 3H), 8.28-8.30 (m, 1H). 483.26 43 [00143] 4-(2-chloro-6- fluorobenzyl)- N-(2- cyclohexyl-2- phenylethyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (400 MHz; DMSO-d.sub.6): 0.73 (m, 1H), 0.94-1.08 (m, 3H), 1.08-1.18 (m, 2H), 1.46 (m, 1H), 1.50- 1.55 (m, 3H), 1.56-1.59 (m, 1H), 1.67-1.81 (m, 1H), 3.40-3.45 (m, 1H), 3.54 (s, 2H), 3.68 (m, 1H), 5.33 (d, J = 6.08 Hz, 2H), 7.06-7.71 (m, 4H), 7.22-7.29 (m, 5H), 7.39 (d, J = 8.04 Hz, 1H), 7.59 (s, 1H), 8.17 (bs, 1H). 537 44 [00144] N-((1- benzylpiperidin- 3-yl)methyl)-4- (2- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 0.84-0.91 (m, 1H), 1.24 (s, 2H), 1.43-1.48 (m, 1H), 1.60-1.68 (m, 2H), 1.91 (s, 1H), 2.69 (s, 4H), 3.09 (bs, 2H), 3.73 (s, 2H), 5.28 (s, 2H), 7.07-7.13 (m, 2H), 7.20- 7.57 (m, 10H), 8.50- 8.65 (m, 1H). 504.42 45 [00145] 4-(2- fluorobenzyl)- 3-oxo-N-((1- phenyl- piperidin-4- yl)methyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.22-1.24 (m, 2H), 1.65- 1.70 (m, 3H), 2.56-2.60 (m, 2H), 3.14 (t, J = 5.95 Hz, 2H), 3.65-3.73 (m, 4H), 5.29 (s, 2H), 6.74 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 8.15 Hz, 2H), 7.11-7.12 (m, 2H), 7.17- 7.25 (m, 3H), 7.31-7.32 (m, 1H), 7.53-7.57 (m, 3H), 8.55 (t, J = 5.5 Hz, 1H). 490.40 46 [00146] N-([1,1- biphenyl]-2- ylmethyl)-4- (2-chloro-6- fluorobenzyl)- 3-oxo-3,4- dihyddro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.60 (s, 2H), 4.41 (d, J = 5.50 Hz, 2H), 5.39 (s, 2H), 7.13 (t, J = 9.35 Hz, 1H), 6.25 (d, J = 7.7 Hz, 2H), 7.28-7.31 (m, 1H), 7.32-7.42 (m, 6H), 7.46- 7.48 (m, 4H), 7.77 (bs, 1H), 8.91 (t, J = 5.5 Hz, 1H). 517.34 47 [00147] N-([1,1- biphenyl]-3- ylmethyl)-4- (2-chloro-6- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.59 (s, 2H), 4.55 (d, J = 5.80 Hz, 2H), 5.39 (s, 2H), 7.04 (t, J = 9.50 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.22-7.26 (m, 1H), 7.30 (d, J = 7.50 Hz, 1H), 7.38 (t, J = 7.20 Hz, 1H), 7.43-7.51 (m, 6H), 7.59 (s, 1H), 7.64 (d, J = 7.4 Hz, 2H), 7.81 (bs, 1H), 9.07 (t, J = 5.85 Hz, 1H). 517.31 48 [00148] N-((1- benzylpiperidin- 4-yl)methyl)-4- (2-chloro-6- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.24-1.30 (bs, 2H), 1.76 (bs, 5H), 2.08 (s, 1H), 2.89 (bs, 2H), 3.14 (bs, 2H), 3.59 (s, 2H), 4.28 (bs, 1H), 5.38 (s, 2H), 7.11 (t, J = 9.3 Hz, 1H), 7.22-7.49 (m, 9H), 7.72 (s, 1H), 8.50 (bs, 1H). 538.37 49 [00149] 4-(2- fluorobenzyl)- 3-oxo-N-((1- phenyl- piperidin-3- yl)methyl)- 3,4-dihydro- 2H benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.05-1.12 (m, 1H), 1.50- 1.55 (m, 1H), 1.71 (d, J = 10.25 Hz, 2H), 1.84 (bs, 1H), 2.41 (t, J = 10.65 Hz, 1H), 2.64 (t, J = 10.75 Hz, 1H), 3.13-3.24 (m, 2H), 3.52-3.56 (m, 2H), 3.73 (s, 2H), 5.29 (s, 2H), 6.74 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 490.42 8.20 Hz, 2H), 7.07-7.12 (m, 2H), 7.16-7.21 (m, 3H), 7.26-7.30 (m, 1H), 7.53-7.58 (m, 3H), 8.58 (t, J = 5.60 Hz, 1H).

Examples 50-105

[0490] Examples 50-105 were prepared using Library general procedure 1 or 2 as indicated in the table below.

TABLE-US-00002 Method Purity Exam- of LCMS (%) by ple Structure IUPAC Name synthesis [M + H] UPLC 50 [00150] 4-benzyl-N-(furan- 3-ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 379 95.39 51 [00151] 4-benzyl-3-oxo-N- ((4-oxo-3,4- dihydrophthalazin- 1-yl)methyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 457 99.17 52 [00152] N-((6- aminopyridin-3- yl)methyl)-4- benzyl-3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 405 98.95 53 [00153] 4-benzyl-N-(2- (dimethylamino)-1- phenylethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 3 446 98.96 54 [00154] 4-benzyl-3-oxo-N- (pyrimidin-2- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 391 98.95 55 [00155] 4-benzyl-N-(2,3- dichlorobenzyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 457 100 56 [00156] N,4-dibenzyl-N- (cyanomethyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 3 428 93.19 57 [00157] 4-benzyl-N-(1-(4- (methylsulfonyl) phenyl)ethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 2 481 99.79 58 [00158] 4-benzyl-3-oxo-N- (pyrazin-2- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 391 98.59 59 [00159] 4-benzyl-N-(oxazol- 2-ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 380 100 60 [00160] 4-benzyl-3-oxo-N- (thiazol-2- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 396 99.5 61 [00161] 4-benzyl-3-oxo-N- (thiophen-3- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 395 98.32 62 [00162] 4-benzyl-N-((5- methylfuran-2- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 393 99.05 63 [00163] 4-benzyl-N-((5- methyloxazol-2- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 394 100 64 [00164] 4-benzyl-N-((5- methylthiazol-2- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 410 100 65 [00165] 4-benzyl-N-((4- methylthiazol-2- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 410 99.21 66 [00166] 4-benzyl-N-((3- methyl-1,2,4- oxadiazol-5- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 395 95.74 67 [00167] 4-benzyl-N-((1- methyl-1H-pyrazol- 5-yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 393 100 68 [00168] 4-benzyl-N-(1- (furan-2-yl)ethyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 391 99.2 69 [00169] N-(benzofuran-2- ylmethyl)-4-benzyl- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 429 100 70 [00170] N-(benzofuran-3- ylmethyl)-4-benzyl- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 429 100 71 [00171] 4-benzyl-N-(4- cyanobenzyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 412 [M H] 100 72 [00172] 4-benzyl-3-oxo-N- (4- (trifluoromethyl) benzyl)-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 457 100 73 [00173] 4-benzyl-N-(4- chlorobenzyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 423 100 74 [00174] 4-benzyl-N- (naphthalen-2- ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 439 100 75 [00175] 4-benzyl-3-oxo-N- (1- phenylcyclopentyl)- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 443 91.82 76 [00176] 4-benzyl-N-(3- methylbenzyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 403 100 77 [00177] 4-benzyl-N-((2- methylthiazol-4- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 410 100 78 [00178] 4-benzyl-N-(2-(2- fluorophenyl) propan-2-yl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 435 100 79 [00179] 4-benzyl-N-(1,2- diphenylethyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 479 100 80 [00180] 4-benzyl-N-(4- isopropylbenzyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 431 100 81 [00181] 4-benzyl-N-(2- cyclohexylethyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 409 100 82 [00182] 4-(2,3- difluorobenzyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 415 100 83 [00183] N-(furan-2- ylmethyl)-4-(3- methyl-5- (trifluoromethyl) benzyl)-3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 459 [M H] 98.65 84 [00184] N-(furan-2- ylmethyl)-4-((3- methyl-1,2,4- oxadiazol-5- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 385 100 85 [00185] N-(furan-2- ylmethyl)-4-((5- methylisoxazol-3- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 384 100 86 [00186] 4-(3- carbamoylbenzyl)- N-(furan-2- ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 422 90.6 87 [00187] 4-(3,5- difluorobenzyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide Library general procedure 2, Method 1 415 98.88 88 [00188] N-(furan-2- ylmethyl)-3-oxo-4- (3- (trifluoromethoxy) benzyl)-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 463 98.28 89 [00189] 4-(2- chlorophenethyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 427 94.24 90 [00190] 4-(3- chlorophenethyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 427 100 91 [00191] N-(furan-2- ylmethyl)-3-oxo-4- (2- (trifluoromethoxy) benzyl)-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 463 100 92 [00192] N-(furan-2- ylmethyl)-3-oxo-4- (3- (trifluoromethyl) phenethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 461 100 93 [00193] 4-(2,6- dichlorobenzyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 447 100 94 [00194] 4-(2-cyanobenzyl)- N-(furan-2- ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 404 100 95 [00195] 4-((5- chlorothiophen-2- yl)methyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 419 100 96 [00196] N-(furan-2- ylmethyl)-4-((2- methylthiazol-4- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 400 100 97 [00197] N-(furan-2- ylmethyl)-3-oxo-4- (3- (trifluoromethyl) benzyl)-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 447 99.71 98 [00198] N-(furan-2- ylmethyl)-4-((1- methylpiperidin-3- yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 400 100 99 [00199] 4-(2-chloro-5- fluorobenzyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 431 100 100 [00200] 4-(2,5- difluorobenzyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 415 98.39 101 [00201] 4-(2,6- difluorobenzyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 415 100 102 [00202] 4-(3-chloro-5- (trifluoromethyl) benzyl)-N-(furan-2- ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 481 100 103 [00203] N-(furan-2- ylmethyl)-3-oxo-4- (2- (phenylsulfonyl) ethyl)-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 457 100 104 [00204] N-(furan-2- ylmethyl)-4- (imidazo[2,1- b]thiazol-6- ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 425 100 105 [00205] 4-((4,5-dimethyl- 4H-1,2,4-triazol-3- yl)methyl)-N- (furan-2-ylmethyl)- 3-oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 398 100

Examples 106-121

[0491] Examples 106-115 were prepared according to the above methods used to make Example 1 as described in General Procedures 1-3 using the appropriate amines and acids. Purification was as stated in the aforementioned methods.

[0492] Examples 116-121 were prepared using Library general procedure 1 or 2 as indicated in the table below.

TABLE-US-00003 Ex- LCMS ample Structure IUPAC Name .sup.1H-NMR [M + H] 106 [00206] 4-(2- fluorobenzyl)- N-(furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.73 (s, 2H), 443 (d, J = 5.45 Hz, 2H), 5.29 (s, 2H), 6.21 (bs, 1H), 6.38 (bs, 1H), 7.10-7.11 (m, 2H), 7.22 (m, 1H), 7.30- 7.32 (m, 1H), 7.55-7.56 (m, 3H), 7.61 (s, 1H), 9.00 (bs, 1H). 397.21 107 [00207] 4-(2-chloro-6- fluorobenzyl)- 3-oxo-N- (thiophen-2- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.59 (s, 2H), 4.62 (d, J = 5.8 Hz, 2H), 5.38 (s, 2H), 6.97-7.01 (m, 2H), 7.11 (t, J = 9.1 Hz, 1H), 7.23-7.29 (m, 2H), 7.40- 7.41 (dd, J.sub.1 = 1.15 Hz, J.sub.2 = 5.05 Hz, 1H), 7.48 (s, 2H), 7.78 (s 1H), 9.09-9.11 (m, 1H). 447.07 108 [00208] 4-(2-chloro-6- fluorobenzyl)- 3-oxo-N- (pyridin-2- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide 500 MHz; DMSO-d.sub.6): 3.60 (s, 2H), 4.56 (d, J = 5.8 Hz, 2H), 5.39 (s, 2H), 7.13 (t, J = 9.15 Hz, 1H), 7.24-7.31 (m, 4H), 7.50- 7.55 (m, 2H), 7.79-7.82 (m, 2H), 8.52-8.53 (m, 1H), 9.12 (bs, 1H). 442.14 109 [00209] 4-(2-chloro-6- fluorobenzyl)- 3-oxo-N- (pyridin-3- ylmethyl)-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.65 (s, 2H), 4.45 (d, J = 5.5 Hz, 2H), 4.95 (s, 2H), 6.24 (d, J = 2.7 Hz, 1H), 6.37 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.23-7.29 (m, 2H), 7.40-7.41 (dd, J.sub.1 = 1.15 Hz, J.sub.2 = 5.05 Hz, 1H), 7.48 (s, 2H), 7.78 (s 1H), 9.09-9.11 (m, 1H). 442.15 110 [00210] N- (cyclohexyl (phenyl) methyl)-4-(2- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 0.79-0.86 (m, 1H), 0.90- 0.97 (m, 1H), 1.04-1.20 (m, 4H), 1.57-1.59 (m, 2H), 1.67-1.75 (m, 2H), 1.84-1.86 (m, 1H), 3.73 (bs, 2H), 4.61 (t, J = 9.2 Hz, 1H), 5.30 (bs, 2H), 7.07 (d, J = 4.5 Hz, 2H), 7.19-7.23 (m, 2H), 7.28- 7.30 (m, 5H), 7.50 (s, 1H), 7.53 (s, 2H), 8.70 (d, J = 8.75 Hz, 1H). 489.04 111 [00211] 4-benzyl-N- (furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.72 (s, 2H), 4.42 (d, J = 5.5 Hz, 2H), 5.28 (s, 2H), 6.22 (d, J = 2.8 Hz, 1H), 6.39 (s, 1H), 7.20-7.24 (m, 3H), 7.29-7.32 (m, 2H), 7.51-7.54 (m, 2H), 7.57 (s, 1H), 7.65 (s, 1H), 8.99 (t, J = 5.45 Hz, 1H). 379.18 112 [00212] 4-(2-chloro-6- fluorobenzyl)- 3-oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.58 (s, 2H), 4.45 (d, J = 4.9 Hz, 2H), 5.36 (s, 2H), 7.10 (t, J = 9.2 Hz, 1H), 7.20-7.31 (m, 4H), 7.42- 7.47 (m, 2H), 7.73 (s, 1H), 8.85 (t, J = 5.1 Hz, 1H). 495.24 113 [00213] 2-(3-oxo-6- ((2,4,6- trifluorobenzyl) carbamoyl)-2H- benzo[b][1,4] thiazin-4(3H)-yl)- 2-phenylacetic acid (400 MHz; DMSO-d.sub.6): 3.61 (s, 2H), 4.37 (s, 2H), 6.17 (s, 1H), 7.33-7.14 (m, 9H), 7.57 (s, 1H), 8.78 (s, 1H), 13.0 (bs, 1H). 487.3 114 [00214] 4-(2,6-difluoro- 4- methoxybenzyl)- 3-oxo-N- (2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] (500 MHz; DMSO-d.sub.6): 3.57 (s, 2H), 3.71 (s, 3H), 4.46 (d, J = 4.05 Hz, 2H), 5.26 (s, 2H), 6.61 (d, J = 9.85 Hz, 2H), 7.21 (t, J = 8.4 Hz, 2H), 7.45 (s, 2H), 7.78 (s, 1H), 8.85 (bs, 1H) 509.16 thiazine-6- carboxamide 115 [00215] 4-(2,6-difluoro- 4- hydroxybenzyl)- 3-oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- (500 MHz; DMSO-d.sub.6): 3.56 (s, 2H), 4.46 (d, J = 4.3 Hz, 2H), 5.22 (s, 2H), 6.31 (d, J = 9.75 Hz, 2H), 7.20 (t, J = 8.4 Hz, 2H), 7.44 (s, 2H), 7.76 (s, 1H), 8.84 (bs, 1H), 10.32 (s, 1H) 495.16 carboxamide Method Purity Ex- of LCMS (%) by ample Structure IUPAC Name synthesis [M + H] UPLC 116 [00216] 4-benzyl-N-(2- methoxybenzyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 419 100 117 [00217] 4-benzyl-N-(2- chlorobenzyl)-3- oxo-3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 423 100 118 [00218] N,4-dibenzyl-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 1, Method 1 389 100 119 [00219] 4-(4-chlorobenzyl)- N-(furan-2- ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 1 413 99.31 120 [00220] 4-(4-fluorobenzyl)- N-(furan-2- ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide Library general procedure 2, Method 2 397 100 121 [00221] 4-benzyl-N-((1- methyl-1H-pyrazol- 4-yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide Library general procedure 1, Method 3 393 98.9

Examples 122-131

[0493] Certain analogous (Examples 122-131) derivative compounds of formula (I) may also be obtained from commercial suppliers, which are also incorporated herein.

TABLE-US-00004 Ex- LCMS ample Structure IUPAC Name [M + H] 122 [00222] 4-(2-chlorobenzyl)-N-(4- fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b-1,4]thiazine-6-carboxamide 441.17 123 [00223] N,4-bis(2-chlorobenzyl)-3-oxo-3,4- dihydro-2H-benzo[b-1,4]thiazine-6- carboxamide 457.13 124 [00224] N-(2-chlorobenzyl)-4-(3- chlorobenzyl)-3-oxo-3,4-dihydro- 2H-benzo[b-1,4]thiazine-6- carboxamide 457.18 125 [00225] 4-(4-chlorobenzyl)-3-oxo-N-(1- phenylethyl)-3,4-dihydro-2H- benzo[b-1,4]thiazine-6-carboxamide 437.2 126 [00226] N-benzyl-4-(2-chloro-6- fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b-1,4]thiazine-6-carboxamide 441.19 127 [00227] 4-(2-chloro-6-fluorobenzyl)-N-(4- fluorobenzyl)-3-oxo-3,4-dihydro-2H- benzo[b-1,4]thiazine-6-carboxamide 459.2 128 [00228] 4-(2-chloro-6-fluorobenzyl)-N-((1- (4-methylbenzyl)piperidin-4- yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]thiazine-6-carboxamide 552.2 129 [00229] 4-(2-chloro-6-fluorobenzyl)-3-oxo- N-phenethyl-3,4-dihydro-2H- benzo[b-1,4]thiazine-6-carboxamide 455.2 130 [00230] 4-(2-chloro-6-fluorobenzyl)-3-oxo- N-((tetrahydrofuran-2-yl)methyl)- 3,4-dihydro-2H-benzo[b- 1,4]thiazine-6-carboxamide 435.19 131 [00231] 4-(2-chloro-6-fluorobenzyl)-N- (furan-2-ylmethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]thiazine-6- carboxamide 431.05

Example 132: 4-Benzyl-N-(furan-2-ylmethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0494] ##STR00232##

Preparation 7: Methyl benzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate

[0495] ##STR00233##

[0496] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 1) (1.0 g, 4.48 mmol) in EDC (20 mL) was added NaOH solution (0.358 g, 5.38 mmol in 20 mL H.sub.2O) portionwise followed by TBAB (0.105 g, 0.33 mmol) at RT. The whole was stirred for 30 min at RT and then benzyl bromide (0.643 mL, 5.38 mmol) was added dropwise. The reaction mixture was further stirred at RT for 2.5 h. Progress of the reaction was monitored by TLC and after completion; the reaction mixture was diluted with DCM, washed with water and brine solution. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness to give crude material which was purified by column chromatography eluting with 20% EtOAc in hexanes to afford methyl benzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (0.75 g, 2.396 mmol, 54% yield) as a white solid. LCMS m/z: 314.09 [M+H].

Preparation 8: Methyl 4-benzyl-2.2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate

[0497] ##STR00234##

[0498] To a stirred solution of methyl benzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 7) (0.15 g, 0.48 mmol) in THF (2 mL) at 78 C. was added LiHMDS (0.52 mL, 1M solution in THF) drop wise. The mixture was stirred at 78 OC for 15 min. then Mel (0.032 mL, 0.527 mmol) added and the whole allowed to stir for another 30 min. at the same temperature then the reaction mixture was slowly brought to RT and further stirred for 3 h. The reaction mixture was quenched with aqueous NH.sub.4Cl solution and extracted with DCM. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give a crude product which was purified by column chromatography using 10% EtOAc in hexanes as eluent to afford methyl 4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (0.13 g, 0.381 mmol, 80% yield) as a viscous oil. LCMS m/z: 342.29 [M+H].

Preparation 9: 4-Benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylic acid

[0499] ##STR00235##

[0500] To a stirred solution of methyl 4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (Preparation 8) (0.13 g, 0.381 mmol) in a mixture of MeOH, water and THF (1:1:2; 1.7 mL) was added LiOH.H.sub.2O (0.032 g, 0.761 mmol) at RT. The reaction was allowed to stir at RT for 3 h. On completion of the reaction, the solvents were evaporated under reduced pressure and the residue was dissolved in water, washed with EtOAc and then acidified to pH 5 with dilute HCl and the resulting aqueous solution was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness to give 4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylic acid (0.075 g. 0.229 mmol, 60% yield) as a colourless solid which was used in the next step without any further purification. LCMS m/z: 326.13 [MH].

Preparation 10: 4-Benzyl-N-(furan-2-ylmethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0501] ##STR00236##

[0502] To a stirred solution of 4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylic acid (Preparation 9) (0.07 g, 0.21 mmol) in DMF (2 mL) was added HATU (0.098 g, 0.26 mmol) followed by TEA (0.066 mL, 0.47 mmol) at RT. The resulting reaction mixture was stirred at RT for 15 min. then 1-(furan-2-yl)-methanamine (0.021 mL, 0.24 mmol) was added and the whole further stirred at RT for 3 h. After complete consumption of the starting material, the reaction mixture was diluted with EtOAc and washed with chilled water and brine. The organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness. The crude material obtained was purified by prep-HPLC to afford 4-Benzyl-N-(furan-2-ylmethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 132) (0.015 g, 0.036 mmol, 18% yield) as a white solid. LCMS m/z: 407.25 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.43 (s, 6H), 4.42 (d, J=5.55 Hz, 2H), 5.28 (s, 2H), 6.23 (bs, 1H), 6.39 (s, 1H), 7.17 (d, J=7.75 Hz, 2H), 7.23-7.25 (m, 1H), 7.31-7.34 (m, 2H), 7.51 (d, J=8.05 Hz, 1H), 7.56 (d, J=8.35 Hz, 2H), 7.64 (s, 1H), 9.02 (t, J=5.5 Hz, 1H).

Examples 133-176

Preparation 2: Methyl 2-bromo-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate

[0503] ##STR00237##

[0504] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (Preparation 1) (1.0 g, 4.48 mmol) in CCl.sub.4 was added NBS (0.797 g, 4.48 mmol) and benzoyl peroxide (0.0035 g. 0.14 mmol) at ice cold temperature. The reaction was allowed to warm to RT and then refluxed at 70 C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature and the solid obtained was filtered off. It was washed with water and dried under reduced pressure to obtain pure methyl 2-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (0.8 g, 2.65 mmol, 60% yield) as a white solid. LCMS m/z: 238.05 [MH] in MeCN.

Preparation 3: Methyl 2-(dimethylamino)-3-oxo-3,4-dihydro-2H-1,4-benzo[b-1,4]thiazine-6-carboxylate

[0505] ##STR00238##

[0506] To a stirred solution of methyl 2-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 2) (0.25 g, 0.82 mmol) in THF (2.5 mL) was added dimethyl amine.HCl (0.202 g, 2.4 mmol) followed by TEA (0.7 mL, 4.92 mmol) at RT. The resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction, the reaction mixture was diluted with EtOAc and washed with water and brine. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the methyl 2-(dimethylamino)-3-oxo-3,4-dihydro-2H-1,4-benzo[b-1,4]thiazine-6-carboxylate (0.2 g, 0.75 mmol, 90% yield) as a crude sticky residue which was used as such without any further purification. LCMS m/z: 267.10 [M+H].

[0507] Examples 133-176 were prepared according to the above method used to make Example 132 and Preparation 3 as described in General Procedure 11 using the appropriate reagents. Purification was as stated in the aforementioned methods.

TABLE-US-00005 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 133 [00239] 2-methyl-N-2,4,6- trifluorobenzyl- 4-[(1-methyl- 1H-pyrazol-4- yl)methyl]-3- oxo-3,4- dihydro-2H- 1,4- benzothiazine- 6-carboxamide (500 MHz; DMSO- d.sub.6): 1.35 (d, J = 6.0 Hz, 3H), 3.76-3.78 (m, 4H), 4.47 (s, 2H), 5.05 (s, 2H), 7.19-7.22 (m, 2H), 7.28 (s, 1H), 7.47-7.53 (m, 3H), 7.77 (s, 1H), 8.98 (s, 1H) 461.56 134 [00240] 4-benzyl-N- (furan-2- ylmethyl)-2- methyl-3-oxo- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.39 (d, J = 6.95 Hz, 3H), 3.89-3.93 (q, J = 6.85 Hz, 1H), 4.42 (d, J = 5.65 Hz, 2H), 5.28 (s, 2H), 6.22 (d, J = 2.85 Hz, 1H), 6.39 (s, 1H), 7.19 (d, J = 7.55 Hz, 2H), 7.21- 7.24 (m, 1H), 7.30- 393.23 7.33 (m, 2H), 7.51-7.57 (m, 3H), 7.66 (s, 1H), 9.00 (t, J = 5.6 Hz, 1H). 135 [00241] 2- (dimethylamino)- 4-(2- fluorobenzyl)- N-(furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 2.26 (s, 6H), 4.43 (bs, 2H), 4.92 (s, 1H), 5.32 (bs, 2H), 6.22 (s, 1H), 6.39 (s, 1H), 7.06-7.13 (m, 2H), 7.23-7.30 (m, 2H), 7.56-7.66 (m, 4H), 9.02 (bs, lH). 440.24 136 [00242] N- (cyclohexylmethyl)- 4-(2- fluorobenzyl)- 2,2-dimethyl-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.13-1.16 (m, 2H), 1.24-1.30 (m, 4H), 1.43-1.47 (m, 6H), 1.59-1.65 (m, 5H), 3.04 (t, J = 6.25 Hz, 2H), 5.29 (s, 2H), 6.95 (t, J = 7.65 Hz, 0H), 7.13 (t, J = 7.5 Hz, 1H), 7.22-7.26 (m, 1H), 7.30-7.32 (m, 441.38 1H), 7.50-7.55 (m, 3H), 8.49-8.51 (m, 1H). 137 [00243] 2-ethoxy-4-(2- fluorobenzyl)- N-(furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.03 (t, J = 7.0 Hz, 3H), 3.51-3.57 (m, 1H), 3.59-3.61 (m, 1H), 3.66-3.72 (m, 1H), 4.43 (d, J = 5.55 Hz, 2H), 5.25 (d, J = 16.95 Hz, 1H), 5.44 (d, J = 16.95 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 6.39 (s, 1H), 6.96 441.26 (t, J = 7.55 Hz, 1H), 7.12 (t, J = 7.55 Hz, 1H), 7.24 (t, J = 9.85 Hz, 1H), 7.30-7.34 (m, 1H), 7.55-7.59 (m, 3H), 7.66 (s, 1H), 9.04 (t, J = 5.4 Hz, 1H). 138 [00244] 4-(2-chloro-6- fluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.31 (d, J = 6.95 Hz, 3H), 3.72-3.76 (q, J = 6.35 Hz, 1H), 4.45 (d, J = 4.7 Hz, 2H), 5.29 (d, J = 15.7 Hz, 1H), 5.45 (d, J = 15.75 Hz, 1H), 7.10 (t, J = 9.5 Hz, 1H), 7.20-7.30 (m, 4H), 7.46 (s, 2H), 7.72 (s, 1H), 8.86 (bs, 1H). 509.26 139 [00245] 2-(4-(2- fluorobenzyl)- 6-((furan-2- ylmethyl)carba moyl)-2- methyl-3-oxo- 3,4-dihydro- 2H-benzo[b- 1,4]thiazin-2- yl)acetic acid (500 MHz; DMSO- d.sub.6 + D.sub.2O): 1.51 (s, 3H), 2.64 (s, 2H), 4.40- (d, J = 5.45 Hz, 2H), 5.22-5.30 (m, 2H), 6.21 (d, J = 3.05 Hz, 1H), 6.36-6.37 (m, 1H), 6.99 (t, J = 7.4 Hz, 1H), 7.06-7.12 (m, 1H), 7.19 (t, J = 10.05 Hz, 1H), 7.27-7.32 (m, 469.31 1H), 7.49-7.54 (m, 3H), 7.60 (s, 1H), 9.06 (t, J = 5.5 Hz, 1H). 140 [00246] 4-(2- fluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.38 (bs, 3H), 3.91 (bs, 1H), 4.42 (bs, 2H), 5.28 (s, 2H), 7.03-7.30 (m, 6H), 7.53-7.59 (m, 3H), 8.93 (bs, 1H). 475.26 141 [00247] 4-(2- fluorobenzyl)- 2-methyl-N-(3- methylbenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.40 (d, J = 6.95 Hz, 3H), 2.26 (s, 3H), 3.91-3.95 (m, 1H), 4.41 (d, J = 5.85 Hz, 2H), 5.29-5.31 (m, 2H), 7.03-7.06 (m, 4H), 7.10-7.16 (m, 1H), 7.17-7.33 (m, 3H), 7.55-7.58 (m, 2H), 7.65 (s, 1H), 9.06 435.32 (t, J = 5.8 Hz, 1H). 142 [00248] 4-(2- fluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.38 (d, J = 6.95 Hz, 3H), 3.89-3.93 (m, 1H), 4.41 (d, J = 5.0 Hz, 2H), 5.24-5.32 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.16-7.24 (m, 3H), 7.29-7.33 (m, 1H), 7.52 (s, 2H), 7.59 (s, 1H), 8.93 (t, J = 475.34 5.05 Hz, 1H). 143 [00249] 4-(2- chlorobenzyl)- 2-methyl-N-(3- methylbenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide 500 MHz; DMSO-d.sub.6): 1.40 (d, J = 6.95 Hz, 3H), 2.26 (s, 3H), 3.95-3.99 (m, 1H), 4.39 (d, J = 5.8 Hz, 2H), 5.20 (d, J = 17.4 Hz, 1H), 5.31 (d, J = 17.35 Hz, 1H), 7.00- 7.05 (m, 4H), 7.18 (t, J = 7.45 Hz, 1H), 7.26- 7.33 (m, 2H), 7.52 (d, J = 8.25 Hz, 2H), 7.57- 451.30 7.62 (m, 2H), 9.07 (t, J = 5.8 Hz, 1H). 144 [00250] 4-(3,5- difluorobenzyl)- 2-methyl-N-(3- methylbenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide 500 MHz; DMSO-d.sub.6): 1.40 (d, J = 6.95 Hz, 3H), 2.27 (s, 3H), 3.96-4.01 (q, J = 6.8 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 5.22 (d, J = 17.1 Hz, 1H), 5.36 (d, J = 17.1 Hz, 1H), 6.92 (d, J = 6.7 Hz, 2H), 7.04-7.07 (m, 3H), 7.12-7.20 (m, 2H), 7.55-7.60 (m, 3H), 9.06 (t, J = 5.9 Hz, 1H). 453.27 145 [00251] 4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.39 (d, J = 6.95 Hz, 3H), 3.97 (d, J = 6.95 Hz, 1H), 4.42 (s, 2H), 5.20 (d, J = 17.05 Hz, 1H), 5.34 (d, J = 17.05 Hz, 1H), 6.89 (d, J = 6.7 Hz, 2H), 7.14- 7.18 (m, 3H), 7.53 (s, 3H), 8.94 (t, J = 5.1 Hz, 1H). 493.29 146 [00252] 2-allyl-4-(2- chloro-6- fluorobenzyl)- 3-oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 2.24-2.30 (m, 1H), 2.50-2.56 (m, 1H), 3.74-3.77 (m, 1H), 4.45 (d, J = 4.95 Hz, 2H), 5.05-5.08 (m, 2H), 5.34-5.42 (m 2H), 5.71-5.79 (m, 1H), 7.10 (t, J = 9.6 Hz, 1H), 7.19-7.24 (m, 3H), 7.27-7.31 (m, 1H), 7.46 (s, 2H), 7.74 535.31 (s, 1H), 8.85 (t, J = 5.05 Hz, 1H). 147 [00253] 4-(2-chloro-6- fluorobenzyl)- 3-oxo-2-propyl- N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 0.83 (t, J = 7.15 Hz, 3H), 1.29-1.44 (m, 3H), 1.65-1.69 (m, 1H), 3.66 (t, J = 6.95 Hz, 1H), 4.41-4.49 (m, 2H), 5.32 (d, J = 15.75 Hz, 1H), 5.42 (d, J = 15.75 Hz, 1H), 7.11 (t, J = 9.65 Hz, 1H), 7.19- 7.31 (m, 4H), 7.46 (bs, 2H), 7.72 (s, 1H), 8.85 537.34 (t, J = 5.0 Hz, 1H). 148 [00254] 4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.39 (d, J = 6.8 Hz, 3H), 3.98-3.94 (m, 1H), 4.42 (s, 2H), 5.35-5.19 (m, 2H), 6.89 (d, J = 6.8 Hz, 2H), 7.18-7.13 (m, 3H), 7.53 (s, 3H), 8.92 (s, 1H). 493.37 149 [00255] N-(benzofuran- 2-ylmethyl)-4- (3,5- difluorobenzyl)- 2-methyl-3- oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.41 (d, J = 6.9 Hz, 3H), 4.00-3.96 (m, 1H), 4.61 (d, J = 5.6 Hz, 2H), 5.38-5.21 (m, 2H), 6.70 (s, 1H), 6.92 (d, J = 6.7 Hz, 2H), 7.13 (t, J = 9.3 Hz, 1H), 7.28-7.20 (m, 2H), 7.62-7.51 (m, 5H), 9.17 (t, J = 5.6 Hz, 1H). 479.33 150 [00256] 4-(2-chloro-6- fluorobenzyl)-2- (chloromethyl)- N-(2,4- difluorobenzyl)- 2-methyl-3- oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.43 (s, 3H), 3.81-3.67 (m, 2H), 4.44 (d, J = 3.2 Hz, 2H), 5.50-5.31 (m, 2H), 7.11-7.07 (m, 2H), 7.31-7.19 (m, 3H), 7.40-7.34 (m, 1H), 7.55-7.48 (m, 2H), 7.81 (s, 1H), 9.00 (t, J = 5.6 Hz, 1H). 539.28 151 [00257] 4-(2-chloro-6- fluorobenzyl)- N-(2,4- difluorobenzyl)-2- (hydroxymethyl)- 2-methyl-3- oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.31 (s, 3H), 3.43 (d, J = 6 Hz, 2H), 4.43 (d, J = 5.6 Hz, 2H), 5.27-5.20 (m, 2H), 5.49 (d, J = 15.8 Hz, 1H), 7.11-7.04 (m, 2H), 7.50-7.18 (m, 6H), 7.72 (bs, 1H), 8.96 (t, J = 5.6 Hz, 1H). 521.30 152 [00258] 4-(3,5- difluorobenzyl)- 2-methyl-N-((5- methylfuran-2- yl)methyl)-3- oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.40 (d, J = 6.9 Hz, 3H), 2.21 (s, 3H), 4.00-3.95 (s, 1H), 4.37 (d, J = 5.5 Hz, 2H), 5.37-5.20 (m, 2H), 5.97 (d, J = 1.9 Hz, 1H), 6.08 (d, J = 2.8 Hz, 1H), 6.91 (d, J = 6.6 Hz, 2H), 7.14 (t, J = 9.3 Hz, 1H), 7.57- 7.54 (m, 3H), 8.97 (t, J = 5.6 Hz, 1H). 443.27 153 [00259] 4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.39 (d, J = 6.8 Hz, 3H), 3.98-3.94 (m, 1H), 4.42 (s, 2H), 5.35-5.19 (m, 2H), 6.89 (d, J = 6.9 Hz, 2H), 7.18-7.13 (m, 3H), 7.53 (s, 3H), 8.92 (s, 1H). 493.37 154 [00260] N-(benzofuran- 2-ylmethyl)-4- (2-chloro-6- fluorobenzyl)- 2,2-dimethyl-3- oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.32 (s, 6H), 4.60 (d, J = 5.5 Hz, 2H), 5.37 (S, 2H), 6.72 (s, 1H), 7.11-7.06 (m, lH), 7.28-7.18 (m, 4H), 7.58-7.46 (m, 4H), 7.78 (s, 1H), 9.11 (t, J = 5.6 Hz, 1H). 509.22 155 [00261] 4-(2-chloro-6- fluoro-3- hydroxybenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO- d.sub.6): 1.31 (d, J = 6.85 Hz, 3H), 3.72 (d, J = 6.9 Hz, 1H), 4.44 (d, J = 4.25 Hz, 2H), 5.26 (d, J = 15.65 Hz, 1H), 5.40 (d, J = 15.60 Hz, 1H), 6.81-6.92 (m, 2H), 7.18-7.21 (m, 2H), 7.46 (s, 2H), 7.69 (s, 1H), 8.38 (s, 1H), 10.09 (s, 1H). 525.13 LCMS Example Structure IUPAC Name [M + H].sup.+ 156 [00262] 4-(3,5- difluorobenzyl)- N-(furan-2- ylmethyl)-2-methyl- 3- oxo-3,4- dihydro-2H-benzo [b][1,4]thiazine-6- carboxamide 429.33 157 [00263] 2-methyl-3-oxo-4- (pyridin-4- ylmethyl)-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 458.35 158 [00264] 2-methyl-4-((3- methylisoxazol- 5-yl)methyl)-3-oxo- N-(2,4,6- trifluorobenzyl)- 3,4-dihydro-2H- benzo[b][1,4] thiazine- 6-carboxamide 461.56 159 [00265] 2-methyl-4-((5- methylisoxazol- 3-yl)methyl)-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 474.56 160 [00266] 4-(3- carbamoylbenzyl)- 2-methyl-3- oxo-N- (2,4,6- trifluorobenzyl)- 3,4-dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 500.17 161 [00267] N-(benzofuran-2- ylmethyl)-4-(2- fluorobenzyl)- 2,2-dimethyl-3-oxo- 3,4-dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 475.36 162 [00268] 2-(cyanomethyl)- N-(2,4- difluorobenzyl)- 4-(3,5- difluorobenzyl)-3- oxo-3,4-dihydro- 2H-benzo[b][1,4] thiazine-6- carboxamide 500.32 163 [00269] 4-(3,5- difluorobenzyl)- 2-methyl-N- ((5-methyloxazol- 2-yl)methyl)-3- oxo-3,4-dihydro- 2H-benzo[b][1,4] thiazine-6- carboxamide 444.34 164 [00270] 4-(2-chloro- 6-fluorobenzyl)- 2-hydroxy-2- methyl-3-oxo-N- (2,4,6- trifluorobenzyl)- 3,4-dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 525.31 165 [00271] 4-(2- chloro-6- fluorobenzyl)-2- fluoro-2-methyl- 3-oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 527.28 166 [00272] 2-(2- aminoethyl)- N-(2,4- difluorobenzyl)- 4-(3,5- difluorobenzyl)- 3-oxo-3,4- dihydro- 2H-benzo[b] [1,4]thiazine- 6- carboxamide 504.32 167 [00273] 4-(3,5- difluorobenzyl)- 2-methyl-N- ((3-methyl-1,2,4- oxadiazol-5- yl)methyl)-3- oxo-3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide 445.38 168 [00274] 4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(pyrazin- 2-ylmethyl)- 3,4- dihydro- 2H-benzo [b][1,4]thiazine- 6- carboxamide 441.54 169 [00275] 4-(3,5- difluorobenzyl)- 2-methyl-N- ((1-methyl-1H- pyrazol-4-yl) methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 443.55 170 [00276] 4-(3,5- difluorobenzyl)- 2-(2- (methyl- sulfonamido) ethyl)-3-oxo-N- (2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b] [1,4]thiazine- 6- carboxamide 600.59 171 [00277] 4-benzyl-N- (3,4- dimethoxy- phenethyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 463.2 172 [00278] 4-(2-chloro- 6-fluorobenzyl)- 2-methyl-N- ((1-methyl-1H- pyrazol-3- yl)methyl)-3- oxo-3,4-dihydro- 2H-benzo[b] [1,4]thiazine-6- carboxamide 459.16 173 [00279] 2-methyl-4- ((1-methyl-1H- pyrazol-4- yl)methyl)-N- ((5-methyloxazol- 2-yl)methyl)- 3-oxo-3,4-dihydro- 2H-benzo[b][1,4] thiazine-6- carboxamide 412.14 174 [00280] 4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluoro- phenethyl)- 3,4-dihydro-2H- pyrido[3,2- b][1,4]thiazine- 6-carboxamide 508.3 175 [00281] 2-(4-(2- fluorobenzyl)- 6-((furan-2- ylmethyl) carbamoyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazin-2- yl)acetic acid 455.3 176 [00282] 2-(2-amino-2- oxoethyl)-N- (2,4- difluorobenzyl)- 4-(3,5- difluorobenzyl)- 3-oxo-3,4- dihydro- 2H-benzo[b] [1,4]thiazine-6- carboxamide 518.31

Example 177: 1-(2-Chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b-1,4]thiazine-7-carboxamide

[0508] ##STR00283##

Preparation 11: Methyl 6-((2-ethoxy-2-oxoethyl)thio)-5-nitronicotinate

[0509] ##STR00284##

[0510] To a stirred solution of methyl-6-chloro-5-nitronicotinate (0.8 g, 3.70 mmol) in acetonitrile (10 mL) was added TEA (1.03 mL, 7.41 mmol) followed by ethyl thioglycolate (0.50 mL, 5.63 mmol) dropwise at RT. The reaction mixture was stirred for 15 min. and then diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness to give methyl 6-((2-ethoxy-2-oxoethyl)thio)-5-nitronicotinate (1.1 g, 3.66 mmol, 99% yield) as a yellowish solid, which was pure enough to be used in the next step without any further purification. LCMS m/z: 301.07 [M+H].

Preparation 12: Methyl 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylate

[0511] ##STR00285##

[0512] To a stirred solution of methyl 6-((2-ethoxy-2-oxoethyl)thio)-5-nitronicotinate (Preparation 11) (1.0 g, 3.66 mmol) in AcOH (10 mL) was added iron powder (0.819 g, 14.66 mmol) at RT. The resulting reaction mixture was stirred at 90 C. for 2.5 h, after which time the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to dryness to give methyl 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylate (1.0 g, 4.46 mmol, 99% yield) as a brown solid, which was pure enough to be used in the next step without any further purification. LCMS m/z: 225.03 [M+H].

Preparation 13: 1-(2-Chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b-1,4]thiazine-7-carboxamide

[0513] ##STR00286##

[0514] 1-(2-Chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b-1,4]thiazine-7-carboxamide (Example 177) was made from methyl 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-7-carboxylate (Preparation 12) using the methods described in Preparation 4, Preparation 5 and Preparation 6, using 2-chloro-6-fluoro-benzyl chloride and 1-(furan-2-yl)-methanamine. LCMS m/z: 432.05 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.77 (s, 2H), 4.48 (d, J=5.5 Hz, 2H), 5.34 (s, 2H), 6.29 (d, J=2.35 Hz, 1H), 6.42 (s, 1H), 7.14 (t, J=9.25 Hz, 1H), 7.25-7.33 (m, 2H), 7.61 (s, 1H), 8.03 (s, 1H), 8.54 (s, 1H), 9.14 (t, J=5.5 Hz, 1H).

Examples 178-218

[0515] Examples 178-218 were prepared according to the methods described for the synthesis of Example 177 as described in General Procedures 4 and 5 and 1-3 starting from an appropriate pyridine and using the appropriate benzyl halides and amines.

TABLE-US-00006 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 178 [00287] 1-(2-chloro-6- fluorobenzyl)- 2-oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3- b-1,4]thiazine- 7-carboxamide (500 MHz; DMSO- d.sub.6): 3.76 (s, 2H), 4.47 (d, J = 4.85 Hz, 2H), 5.32 (s, 2H), 7.11- 7.33 (m, 5H), 7.98 (s, 1H), 8.49 (s, 1H), 9.03 (t, J = 4.95 Hz, lH). 469.19 179 [00288] 1-(2-chloro-6- fluorobenzyl)- N- (cyclohexyl- methyl)- 2-oxo-2,3- dihydro-1H- pyrido[2,3-b- 1,4]thiazine-7- carboxamide (500 MHz; DMSO- d.sub.6): 0.87-0.94 (m, 2H), 1.13-1.23 (m, 3H), 1.51-1.70 (m, 6H), 3.08-3.11 (m, 2H), 3.77 (s, 2H), 5.35 (s, 2H), 7.13 (t, J = 9.05 Hz, 1H), 7.24- 7.31 (m, 2H), 7.96 (s, 1H), 8.49 (s, 1H), 8.59 (bs, 1H). 448.24 180 [00289] 1-benzyl-N- (furan-2- ylmethyl)-2- oxo-2,3- dihydro-1H- pyrido[2,3-b- 1,4]thiazine-7- carboxamide (500 MHz; DMSO- d.sub.6): 3.92 (s, 2H), 4.45 (d, J = 5.35 Hz, 2H), 5.24 (s, 2H), 6.26 (d, J = 2.15 Hz, 1H), 6.40 (s, 1H), 6.20-6.25 (m, 3H), 7.31-7.34 (m, 2H), 7.59 (s, 1H), 7.86 (s, 1H), 8.57 (s, 1H), 9.16 (t, J = 5.15 1H). 380.18 181 [00290] 4-(2-chloro-6- fluorobenzyl)- N-(furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- pyrido[3,2-b- 1,4]thiazine-6- carboxamide (400 MHz; DMSO- d.sub.6): 3.70 (s, 2H), 4.49 (d, J = 5.76 Hz, 2H), 5.61 (s, 2H), 6.25 (s, 1H), 6.40 (s, 1H), 7.06 (t, J = 8.52 Hz, 1H), 7.21-7.28 (m, 2H), 7.58 (s, 1H), 7.68 (d, J = 7.88 Hz, 1H), 8.04 (d, J = 7.96 Hz, 1H), 8.83 (bs, 1H). 432.0 182 [00291] 1-(2-chloro-6- fluorobenzyl)- N-(furan-2- ylmethyl)-2- oxo-2,3- dihydro-1H- pyrido[3,4-b- 1,4]thiazine-7- carboxamide (400 MHz; DMSO- d.sub.6): 3.70 (s, 2H), 4.43 (d, J = 6.08 Hz, 2H), 5.41 (s, 2H), 6.21 (d, J = 3.0 Hz, 1H), 6.37 (t, J = 2.88 Hz, 1H), 7.15-7.17 (m, 1H), 7.26-7.32 (m, 2H), 7.54 (s, 1H), 7.81 (s, 1H), 8.56 (s, 1H), 9.04-9.06 (m, 1H). 432.0 183 [00292] N-(benzofuran- 2-ylmethyl)-4- (3,5- difluorobenzyl)- 3-oxo-3,4- dihydro-2H- pyrido[3,2-b- 1,4]thiazine-6- carboxamide (400 MHz; DMSO- d.sub.6): 3.85 (s, 2H), 4.65 (d, J = 5.32 Hz, 2H), 5.57 (s, 2H), 6.58 (s, 1H), 6.95-7.01 (m, 3H), 7.19-7.27 (m, 2H), 7.49-7-55 (m, 2H), 7.69 (d, J = 7.88 Hz, 1H), 8.06 (d, J = 7.80 Hz, 1H), 9.09 (bs, 1H). 466.1 184 [00293] 4-(2-chloro-6- fluorobenzyl)- 2-methyl-N-(3- methylbenzyl)- 3-oxo-3,4- dihydro-2H- pyrido[3,2-b- 1,4]thiazine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.33 (d, J = 7.0 Hz, 3H), 2.26 (s, 3H), 3.88-3.91 (m, 1H), 4.46 (t, J = 5.56 Hz, 2H), 5.54 (d, J = 15.08 Hz, 1H), 5.75 (d, J = 15.16 Hz, 1H), 7.02- 7.09 (m, 4H), 7.18- 7.27 (m, 3H), 7.71 (d, J = 7.88 Hz, 1H), 8.06 (d, J = 7.88 Hz, 1H), 470.3 8.93-8.95 (m, 1H). 185 [00294] 4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-pyrido[3,2- b-1,4]thiazine- 6-carboxamide (400 MHz; DMSO-d.sub.6): 1.40 (d, J = 6.96 Hz, 3H), 4.07-4.09 (m, 1H), 4.49 (t, J = 3.84 Hz, 2H), 4.99 (d, J = 15.44 Hz, 1H), 5.75 (d, J = 15.4 Hz, 1H), 6.88 (d, J = 6.48 Hz, 2H), 7.02-7.03 (m, 1H), 7.11 (t, J = 8.72 Hz, 2H), 7.65 (d, J = 7.88 Hz, 1H), 8.04 (d, J = 7.88 Hz, 1H), 8.76 (m, 1H). 494.1 186 [00295] 4-(2-chloro-6- fluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-pyrido[3,2- b-1,4]thiazine- 6-carboxamide (400 MHz; DMSO-d.sub.6): 1.33 (d, J = 6.88 Hz, 3H), 3.88-3.93 (q, J = 7.16 Hz, 1H), 4.52 (t, J = 6.04 Hz, 2H), 5.51 (d, J = 15.32 Hz, 1H), 5.66 (d, J = 15.24 Hz, 1H), 7.03 (t, J = 9.56 Hz, 1H), 7.17-7.27 (m, 4H), 7.66 (d, J = 7.84 Hz, H), 8.04 (d, J = 7.80 Hz, 1H), 8.65 (bs, 1H). 510.2 187 [00296] 4-(2-chloro-6- fluorobenzyl)- N-(2,4- difluorobenzyl)- 2-methyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b- 1,4]thiazine-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.33 (d, J = 6.88 Hz, 3H), 3.90-3.91 (m, 1H), 4.51 (s, 2H), 5.55 (d, J = 15.40 Hz, 1H), 5.75 (d, J = 15.08 Hz, 1H), 7.04-7.06 (m, 2H), 7.21-7.28 (m, 3H), 7.32-7-36 (m, 1H), 7.70 (d, J = 7.76 Hz, 1H), 8.06 (d, J = 7.68 Hz, 1H), 8.98 (bs, 1H). 492.2 188 [00297] N-(benzofuran- 2-ylmethyl)-4- (2-chloro-6- fluorobenzyl)- 2-methyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b- 1,4]thiazine-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.32 (d, J = 6.68 Hz, 3H), 3.89-3.91 (m, 1H), 4.66 (s, 2H), 5.56 (d, J = 15.24 Hz, 1H), 5.76 (d, J = 14.88 Hz, 1H), 6.72 (bs, 1H), 7.05-7.08 (m, 1H), 7.19-7.26 (m, 4H), 7.52 (d, J = 6.76 Hz, 1H), 7.58 (d, J = 8.08 Hz, 1H), 7.72 (d, J = 496.2 8.0 Hz, 1H), 8.07 (d, J = 7.88 Hz, 1H), 9.05 (bs, 1H). 189 [00298] 4-(3,5- difluorobenzyl)- N-(furan-2- ylmethyl)-2- methyl-3-oxo- 3,4-dihydro- 2H-pyrido[3,2- b-1,4]thiazine- 6-carboxamide (400 MHz; DMSO- d.sub.6): 1.40 (d, J = 6.76 Hz, 3H), 4.08 (d, J = 7.0 Hz, 1H), 4.48 (d, J = 4.92 Hz, 2H), 5.49 (d, J = 15.48 Hz, 1H), 5.61 (d, J = 15.28 Hz, 1H), 6.16 (s, 1H), 6.37 (s, 1H), 6.92 (d, J = 6.24 Hz, 2H), 7.05- 7.07 (m, 1H), 7.53 (s, 1H), 7.69 (d, J = 7.84 Hz, 1H), 8.04 (d, J = 429.9 7.88 Hz, 1H), 8.95 (bs, 1H). 190 [00299] 4-(3,5- difluorobenzyl)- 2-methyl-N-((5- methylfuran-2- yl)methyl)-3- oxo-3,4- dihydro-2H- pyrido[3,2-b- 1,4]thiazine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.40 (d, J = 6.64 Hz, 3H), 2.20 (s, 3H), 4.08 (d, J = 6.56 Hz, 1H), 4.40 (s, 2H), 5.49 (d, J = 15.12 Hz, 1H), 5.61 (d, J = 15.16 Hz, 1H), 5.95 (s, 1H), 6.02 (s, 1H), 6.92 (d, J = 6.84 Hz, 2H), 7.05 (m, 1H), 7.69 (d, J = 7.56 Hz, 1H), 8.05 (d, J = 7.80 Hz, 1H), 8.88 (bs, 1H). 444.2 191 [00300] N-benzyl-4- (3,5- difluorobenzyl)- 2-methyl-3- oxo-3,4- dihydro-2H- pyrido[3,2-b- 1,4]thiazine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.41 (d, J = 6.80 Hz, 3H), 4.08-4.11 (m, 1H), 4.50 (s, 2H), 5.52 (d, J = 15.44 Hz, 1H), 5.63 (d, J = 15.32 Hz, 1H), 6.94 (d, J = 6.2 Hz, 2H), 7.03-7.05 (m, 1H), 6.23-7.28 (m, 5H), 7.69 (d, J = 7.80 Hz, 1H), 8.06 (d, J = 7.84 Hz, 1H), 9.09 (bs, 1H). 437.9 [M H] 192 [00301] 1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3- b][1,4]thiazine- 7-carboxamide (400 MHz; DMSO- d.sub.6): 1.42 (d, J = 7.0 Hz, 3H), 4.19-4.14 (m, 1H), 4.42 (d, J = 5.0 Hz, 2H), 5.31-5.11 (m, 2H), 6.89 (d, J = 6.4 Hz, 2H), 7.17-7.09 (m, 3H), 7.73 (d, J = 1.7 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 9.06 (t, J = 5.0 Hz, 1H). 494.31 193 [00302] N-(benzofuran- 2-ylmethyl)-1- (3,5- difluorobenzyl)- 3-methyl-2- oxo-2,3- dihydro-1H- pyrido[2,3- b][1,4]thiazine- 7-carboxamide (500 MHz; DMSO- d.sub.6): 1.46 (d, J = 7.0 Hz, 3H), 4.23-4.19 (m, 1H), 4.64 (d, J = 5.5 Hz, 2H), 5.36-5.19 (m, 2H), 6.75 (s, 1H), 6.94 (d, J = 6.6 Hz, 2H), 7.29-7.13 (m, 3H), 7.52 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 8.66 (d, J = 1.2 Hz, 1H), 9.33 (t, J = 5.5 Hz, 1H). 480.27 194 [00303] N-(benzofuran- 2-ylmethyl)-1- (3,5- difluorobenzyl)- 3-methyl-2- oxo-2,3- dihydro-1H- pyrido[2,3- b][1,4]thiazine- 7-carboxamide (400 MHz; DMSO- d.sub.6): 1.45 (d, J = 7.0 Hz, 3H), 4.22-4.17 (m, 1H), 4.63 (d, J = 5.5 Hz, 2H), 5.33-5.15 (m, 2H), 6.74 (s, 1H), 6.94 (d, J = 6.7 Hz, 2H), 7.28-7.11 (m, 3H), 7.58-7.50 (m, 2H), 7.82 (s, 1H), 8.66 (s, 1H), 9.30 (t, J = 5.5 Hz, 1H). 479.9 195 [00304] 1-(2-chloro-6- fluorobenzyl)- 3-methyl-N-((5- methylfuran-2- yl)methyl)-2- oxo-2,3- dihydro-1H- pyrido[2,3- b][1,4]thiazine- 7-carboxamide (500 MHz; DMSO-d.sub.6): 1.36 (d, J = 7.0 Hz, 3H), 2.24 (s, 3H), 3.96-3.92 (m, 1H), 4.42 (d, J = 5.3 Hz, 2H), 544-5.26 (m, 2H), 6.01 (s, 1H), 6.16 (d, J = 2.2 Hz, 1H), 7.14 (t, J = 9.7 Hz, 1H), 3.34-7.26 (m, 2H), 8.04 (s, 1H), 8.58 (s, 1H), 9.08 (t, J = 5.3 Hz, 1H). 460.33 196 [00305] 1-(2-chloro-6 fluorobenzyl) 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3- b][1,4]thiazine- 7-carboxamide (500 MHz; DMSO- d.sub.6): 1.37 (d, J = 6.9 Hz, 3H), 3.96-3.92 (m, 1H), 4.48 (d, J = 4.7 Hz, 2H), 5.44-5.23 (m, 2H), 7.13 (t, J = 9.2 Hz, 1H), 7.33-7.20 (m, 4H), 7.99 (s, 1H), 8.52 (s, 1H), 9.02 (bs, 1H). 510.26 197 [00306] N-(benzofuran- 2-ylmethyl)-1- (2-chloro-6- fluorobenzyl)- 2-oxo-2,3- dihydro-1H- pyrido[2,3- b][1,4]thiazine- 7-carboxamide (400 MHz; DMSO- d.sub.6): 3.31 (s, 2H), 4.63 (d, J = 5.5 Hz, 2H), 5.32 (s, 2H), 6.75 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.30-7.19 (m, 4H), 7.59-7.51 (dd, 2H), 8.02 (d, J = 1.3 Hz, 1H), 8.56 (d, J = 1.4 Hz, 1H), 9.25 (t, J = 5.6 Hz, 1H). 482.52 LCMS Example Structure IUPAC Name [M + H] 198 [00307] 4-(3,5- difluorobenzyl)- 2-methyl-N- ((5-methylfuran- 2-yl)methyl)-3- oxo-3,4-dihydro- 2H-pyrido[3,2- b][1,4]thiazine- 6-carboxamide 444.0 199 [00308] N-(benzofuran- 2-ylmethyl)-1- (2-chloro-6- fluorobenzyl)- 3-methyl-2- oxo-2,3-dihydro- 1H-pyrido[2,3- b][1,4]thiazine- 7-carboxamide 496.33 200 [00309] 1-(3,5- difluorobenzyl)- 2-oxo-N- (2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3-b] [1,4]thiazine-7- carboxamide 480.31 201 [00310] N-benzyl-1- (2-chloro-6- fluorobenzyl)- 3-methyl-2- oxo-2,3- dihydro-1H- pyrido[2,3- b][1,4]thiazine- 7-carboxamide 456.33 202 [00311] 4-(2-chloro-6- fluorobenzyl)-2- methyl-N-((5- methylfuran-2- yl)methyl)-3- oxo-3,4-dihydro- 2H- pyrido[3,2-b] [1,4]thiazine-6- carboxamide 460.1 203 [00312] 4-(3,5- difluorobenzyl)- 2-methyl-N- ((5-methylfuran- 2-yl)methyl)-3- oxo-3,4-dihydro- 2H-pyrido[3,2- b][1,4]thiazine- 6-carboxamide 444.2 204 [00313] 4-(1-(3,5- difluorophenyl) ethyl)-2- methyl-N-((5- methylfuran-2- yl)methyl)-3-oxo- 3,4-dihydro-2H- pyrido[3,2-b] [1,4] thiazine-6- carboxamide 458.0 205 [00314] 4-(3-carbamoyl- benzyl)- 2-methyl-N- ((5-methylfuran-2- yl)methyl)-3-oxo- 3,4-dihydro-2H- pyrido[3,2- b][1,4]thiazine- 6-carboxamide 451.0 206 [00315] 1-((2- methoxypyridin- 4-yl)methyl)- 3-methyl-2-oxo- N-(2,4,6- trifluorobenzyl)- 2,3-dihydro-1H- pyrido[2,3-b][1,4] thiazine-7- carboxamide 489.32 207 [00316] 1-(2-chloro-6- fluorobenzyl)- N-((5- methylfuran- 2-yl)methyl)-2 -oxo-2,3- dihydro-1H-pyrido [2,3-b][1,4] thiazine-7- carboxamide 446.28 208 [00317] N-(benzofuran- 2-ylmethyl)-1- (3,5- difluorobenzyl)- 3-methyl-2-oxo- 2,3- dihydro-1H- pyrido[2,3- b][1,4] thiazine-7- carboxamide 479.8 209 [00318] 1-(3,5- difluorobenzyl)- 3- (hydroxymethyl)- 3-methyl-N-((5- methylfuran-2-yl) methyl)-2-oxo- 2,3-dihydro- 1H-pyrido [2,3-b] [1,4]thiazine- 7-carboxamide 474.56 210 [00319] N-(benzofuran-2- ylmethyl)-1-(3,5- difluorobenzyl)- 3- (hydroxymethyl)- 3-methyl-2-oxo- 2,3- dihydro-1H- pyrido[2,3-b] [1,4] thiazine-7- carboxamide 510.57 211 [00320] 1-(3,5- difluorobenzyl)- 3- (hydroxymethyl)- 3-methyl-2-oxo- N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido [2,3-b] [1,4]thiazine-7- carboxamide 524.55 212 [00321] 1-(3,5- difluorobenzyl)- 3-methyl-N- ((3-methyl-1,2,4- oxadiazol-5- yl)methyl)-2- oxo-2,3- dihydro-1H- pyrido[2,3-b] [1,4] thiazine-7- carboxamide 446.36 213 [00322] 1-(3,5- difluorobenzyl)- 3-methyl-N- ((5- methyloxazol- 2-yl)methyl)-2- oxo-2,3-dihydro- 1H-pyrido[2,3- b][1,4]thiazine- 7- carboxamide 445.38 214 [00323] 1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N- (pyridazin- 3-ylmethyl)-2,3- dihydro-1H- pyrido [2,3-b][1,4] thiazine-7- carboxamide 442.40 215 [00324] 1-(3,5- difluorobenzyl)- 3-methyl-N- ((1-methyl-1H- pyrazol-3-yl) methyl)- 2-oxo-2,3- dihydro- 1H-pyrido[2,3- b][1,4]thiazine- 7-carboxamide 444.15 216 [00325] 1-(3,5- difluorobenzyl)- 3-methyl-N- ((1-methyl-1H- pyrazol-4-yl) methyl)- 2-oxo-2,3- dihydro-1H- pyrido[2,3- b][1,4] thiazine-7- carboxamide 444.56 217 [00326] 1-(3,5- difluorobenzyl)- 3-methyl oxo-N-(pyrazin- 2-ylmethyl)-2,3 dihydro-1H- pyrido[2,3- b][1,4]thiazine- 7-carboxamide 442.29 218 [00327] 4-(2- fluorobenzyl)- 2,2-dimethyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide 489.29

Example 219: 4-Benzyl-8-cyano-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0516] ##STR00328##

Preparation 14: Methyl 3-bromo-4-((2-ethoxy-2-oxoethyl)thio)-5-nitrobenzoate

[0517] ##STR00329##

[0518] To a stirred solution of commercially available methyl 3-bromo-4-fluoro-5-nitrobenzoate (0.25 g, 0.89 mmol) in MeCN (10 mL) was added ethyl thioglycolate (0.118 mL, 0.98 mmol) followed by TEA (0.188 mL, 1.85 mmol) at 0-5 C. and further stirred at the same temperature for 10 min. The reaction performance was monitored by TLC and after completion the reaction mixture was diluted with EtOAc and washed with water followed by brine. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to dryness to afford methyl 3-bromo-4-((2-ethoxy-2-oxoethyl)thio)-5-nitrobenzoate (0.30 g, 0.79 mmol, 89% yield) which was used in the next step as such. LCMS m/z: 378.09 [M+H].

Preparation 15: Methyl 8-bromo-1-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate

[0519] ##STR00330##

[0520] Methyl 8-bromo-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate was made from methyl 3-bromo-4-((2-ethoxy-2-oxoethyl)thio)-5-nitrobenzoate (Preparation 14) using the method described for Preparation 1. LCMS m/z: 300.01 [MH].

Preparation 16: 8-Bromo-4-benzyl-N-(furan-2-ylmethyl)-3-oxo-, 4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0521] ##STR00331##

[0522] 8-Bromo-4-benzyl-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide was made from methyl 8-bromo-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (Preparation 15) using the methods described in Preparation 4, Preparation 5 and Preparation 6, using benzyl chloride and 1-(furan-2-yl)-methanamine. .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.82 (s, 2H), 4.42 (d, J=5.55 Hz, 2H), 5.27 (s, 2H), 6.24 (d, J=3.05 Hz, 1H), 6.39-6.40 (m, 1H), 7.11-7.12 (m, 2H), 7.21-7.25 (m, 1H), 7.30-7.33 (m, 1H), 7.58-7.61 (m, 2H), 7.89 (d, J=1.20 Hz, 1H), 9.11 (t, J=5.5 Hz, 1H).

Preparation 17: 4-Benzyl-8-cyano-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0523] ##STR00332##

[0524] A stirred solution of 4-benzyl-8-bromo-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Preparation 16) (0.095 g, 0.20 mmol) in NMP (20 mL) was degassed thoroughly with Ar. To the mixture was added CuCN (0.093 g, 1.03 mmol) under an Ar atmosphere and the resulting reaction mixture was heated at 145-150 C. for 16 h. After completion of the reaction (monitored by TLC/LCMS), the reaction mass was cooled to RT, diluted with EtOAc and washed with an aqueous FeCl.sub.3 solution followed by water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product obtained was purified by column chromatography using 30% EtOAc in hexanes as eluent to afford 4-benzyl-8-cyano-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 219) (0.02 g, 0.049 mmol, 25% yield) as an off white solid. LCMS m/z: 402.28 [MH]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.91 (s, 2H), 4.43 (d, J=5.35 Hz, 2H), 5.30 (s, 2H), 6.26 (d, J=2.6 Hz, 1H), 6.40 (s, 1H), 7.20-7.26 (m, 3H), 7.31-7.34 (m, 2H), 7.59 (s, 1H), 7.85 (s, 1H), 8.04 (s, 1H), 9.16 (t, J=5.25 Hz, 1H).

Examples 220-225

[0525] Examples 220-225 were prepared in an entirely analogous manner to Example 219 using the methods described in Preparations 15 and 16, as described in General Procedures 4, 5 and 1-3 starting with an appropriate nitroarene and using the appropriate benzyl amine and either 1-(furan-2-yl)-methanamine or 2,4,6-trifluorobenzyl-amine.

TABLE-US-00007 LCMS Example Structure IUPAC Name .sup.1H-NMR [M+ H] 220 [00333] 8-cyano-4- (3,5- difluorobenzyl)- N-(furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.95 (s, 2H), 4.44 (d, J = 5.45 Hz, 2H), 5.29 (s, 2H), 6.26 (d, J = 2.75 Hz, 1H), 6.39 (s, 1H), 6.98 (d, J = 6.75 Hz, 2H), 7.16 (t, J = 9.2 Hz, 1H), 7.58 (s, 1H), 7.71 (s, 1H), 8.08 (s, 1H), 9.17 (t, J = 5.45 Hz, 1H). 440.26 221 [00334] 8-bromo-4-(2- fluorobenzyl)- N-(furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]thiazine-6- carboxamide 500 MHz; DMSO-d.sub.6): 3.82 (s, 2H), 4.42 (d, J = 5.55 Hz, 2H), 5.27 (s, 2H), 6.24 (d, J = 3.05 Hz, 1H), 6.39-6.40 (m, 1H), 7.11-7.12 (m, 2H), 7.21-7.25 (m, 1H), 7.30- 7.33 (m, 1H), 7.58-7.61 (m, 2H), 7.89 (d, J = 1.20 Hz, 1H), 9.11 (t, J = 5.5 Hz, 1H). 474.88 222 [00335] 4-(4- fluorobenzyl)- 8-(2- hydroxyethyl)- 3-oxo-N- (2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 2.87 (t, J = 6.90 Hz, 2H), 3.56-3.60 (q, J = 6.70 Hz, 2H), 3.64 (s, 2H), 4.41 (d, J = 4.8 Hz, 2H), 4.78 (t, J = 5.20 Hz, 1H), 5.22 (s, 2H), 7.13 (t, J = 8.75 Hz, 2H), 7.17-7.25 (m, 4H), 7.47 (d, J = 3.7 Hz, 2H), 8.86 (t, J = 4.75 Hz, 1H). 505.31 223 [00336] 4-(4- fluorobenzyl)- 8-(1- hydroxyethyl)- 3-oxo-N- (2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.33 (d, J = 6.3 Hz, 3H), 3.58-3.65 (m, 2H), 4.40-4.47 (m, 2H), 4.96-4.98 (m, 1H), 5.18- 5.30 (m, 2H), 5.48 (d, J = 3.9 Hz, 1H), 7.13 (t, J = 8.80 Hz, 2H), 7.17- 7.25 (m, 4H), 7.53 (bs, 1H), 7.72 (bs, 1H), 8.95- 8.96 (m, 1H). 505.30 224 [00337] 8- (aminomethyl)- 4-(4- fluorobenzyl)- 3-oxo-N- (2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide hydrochloride (500 MHz; DMSO-d.sub.6): 3.69 (s, 2H), 4.11 (s, 2H), 4.46 (d, J = 4.8 Hz, 2H), 5.32 (s, 2H), 7.11 (t, J = 8.8 Hz, 2H), 7.19- 7.25 (m, 4H), 7.75 (d, J = 5.95 Hz, 2H), 8.41 (bs, 3H), 8.01 (t, J = 4.8 Hz, 1H). 490.32 225 [00338] 4-(4- fluorobenzyl)- 3-oxo-N6- (2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6,8- dicarboxamide (400 MHz; DMSO-d.sub.6): 3.47 (s, 2H), 4.42 (d, J = 5.0 Hz, 2H), 5.23 (s, 2H), 7.12-7.08 (m, 2H), 7.21-7.18 (m, 4H), 7.64 (bs, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.74 (d, J = 1.3 Hz, 1H), 8.00 (s, 1H), 8.86 (t, J = 5.1 Hz, 1H). 504.30

Example 226: 4-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-8-meth yl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0526] ##STR00339##

Preparation 18

[0527] To a stirred solution of 8-bromo-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 221) (0.08 g, 0.20 mmol) in a mixture of 1,4-dioxane and water (10:1; 9 mL) was added trimethylboroxin (0.07 mL, 0.50 mmol) and K.sub.2CO.sub.3 (0.056 g, 0.40 mmol) at RT in a sealed tube. The resulting reaction mixture was degassed with Ar for 15 min. then Pd(PPh.sub.3).sub.4(0.047 g, 0.040 mmol, 20 mol %) was added at RT. Finally, the reaction mixture was heated at 110 C. for 16 h. The progress of reaction was monitored by TLC/LCMS and after completion; the reaction mixture was cooled down to RT, diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford crude material which was purified by prep-HPLC to give 4-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-8-methyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 226) (0.02 g, 0.048 mmol, 25% yield) as an off white solid. LCMS m/z: 411.01 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 2.36 (s, 3H), 3.70 (s, 2H), 4.42 (d, J=5.20 Hz, 2H), 5.28 (s, 2H), 6.21 (S, 1H), 6.39 (s, 1H), 7.09-7.12 (m, 2H), 7.22 (t, J=9.7 Hz, 1H), 7.30-7.33 (m, 1H), 7.49-7.61 (m, 3H), 8.97 (bs, 1H).

Example 227

[0528] Example 227 was prepared in an entirely analogous manner to Examples 226 and 219 (below) starting from Example 221.

TABLE-US-00008 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 227 [00340] 8-cyclopropyl-4- (2-fluorobenzyl)- N-(furan-2- ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]thi- azine-6- carboxamide (500 MHz; DMSO- d.sub.6): 0.74-0.86 (m, 2H), 0.99-1.02 (m, 2H), 2.05-2.11 (m, 1H), 3.72 (s,2H), 4.41 (d, J = 5.65 Hz, 2H), 5.24 (s,2H), 6.21 (d, J = 3.05 Hz, 1H), 6.38-6.39 (m, 1H), 7.08-7.13 (m, 2H), 7.21-7.25 (m, 2H), 7.29-7.33 (m, 1H), 7.44 (d, J = 1.15 Hz, 1H), 7.57 (d, J = 0.9 Hz, 1H), 8.99 (t, J = 5.65 Hz, 1H). 436.94

Example 228: 7-bromo-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide

[0529] ##STR00341##

Preparation 19: Methyl 2-bromo-4-fluoro-5-nitrobenzoate

[0530] ##STR00342##

[0531] Methyl 2-bromo-4-fluorobenzoate (1.0 g, 4.31 mmol) was dissolved in H.sub.2SO.sub.4 (10 mL) and cooled to 0-5 C., then potassium nitrite (0.43 g, 4.31 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mass was poured into crushed ice and stirred for 30 min. The solid obtained was filtered, washed with cold water and dried under reduced pressure to obtain methyl 2-bromo-4-fluorobenzoate (0.86 g, 3.09 mmol, 72% yield) as a yellow solid which was pure enough to be used in the next step. LCMS m/z: 276.07 [MH].

Preparation 20: Methyl 7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate

[0532] ##STR00343##

[0533] Methyl 7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate was made from methyl 2-bromo-4-fluoro-5-nitrobenzoate (Preparation 19) using the method described in Preparation 1. LCMS m/z: 300.03 [MH].

Preparation 21: 7-bromo-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide

[0534] ##STR00344##

[0535] 4-Benzyl-8-bromo-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-1,4-benzo[b-1,4]thiazine-6-carboxamide (Example 228) was made from methyl-7-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 20) using the methods described in Preparations 4 to 6, according to the General Procedures 1-3 using 2-fluorobenzyl chloride and 1-(furan-2-yl)-methanamine. LCMS m/z: 474.85 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.74 (s, 2H), 4.37 (d, J=5.7 Hz, 2H), 5.24 (s, 2H), 6.15 (d, J=2.65 Hz, 1H), 6.38 (s, 1H), 7.09-7.15 (m, 3H), 7.24 (t, J=9.8 Hz, 1H), 7.32-7.36 (m, 1H), 7.55 (s, 1H), 7.78 (s, 1H), 8.91 (bs, 1H).

Example 229

Preparation 22: 7-Cyclopropyl-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0536] ##STR00345##

[0537] To a stirred solution of 4-benzyl-8-bromo-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-1,4-benzo[b-1,4]thiazine-6-carboxamide (Example 228/Preparation 21) (0.14 g, 0.29 mmol) in a mixture of 1,4-dioxane and water (10:1; 11 mL) was added cyclopropylboronic acid (0.076 g, 0.88 mmol) and sodium tert-butoxide (0.056 g, 0.58 mmol) at RT in a sealed tube. The resulting reaction mixture was degassed with Ar for 15 min. then tricyclohexylphosphine (0.016 g, 0.058 mmol) and PdCl.sub.2(PPh.sub.3)2 (0.020 g, 0.029 mmol, 10 mol %) was added at RT. Finally, the reaction mixture was heated at 110 C. for 16 h. The progress of reaction was monitored by TLC/LCMS and after completion; the reaction mixture was cooled down to RT, diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford crude material which was purified by prep-HPLC to give 7-cyclopropyl-4-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 229) (0.01 g, 0.022 mmol, 8% yield) as an off white solid. LCMS m/z: 437.36 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 0.64 (d, J=4.1 Hz, 2H), 0.83 (d, J=7.85 Hz, 2H), 2.11 (bs, 1H), 3.68 (s, 2H), 4.38 (d, J=5.3 Hz, 2H), 5.22 (s, 2H), 6.07 (s, 1H), 6.37 (s, 1H), 6.98 (d, J=15.15 Hz, 2H), 7.08-7.15 (m, 2H), 7.25 (t, J=9.55 Hz, 1H), 7.33-7.34 (m, 1H), 7.53 (s, 1H), 8.80 (bs, 1H).

Example 230: 4-Benzyl-N-(furan-2-ylmethyl)-7-methyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0538] Example 230 was prepared in an entirely analogous manner to Example 229 from Example 228.

TABLE-US-00009 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 230 [00346] 4-benzyl-N- (furan-2- ylmethyl)-7- methyl-3-oxo- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 2.23 (s, 3H), 3.68 (s, 2H), 4.37 (d, J = 5.65 Hz, 2H), 5.22 (s, 2H), 6.10 (d, J = 2.5 Hz, 1H), 6.39 (s, 1H), 7.08 (s, 1H), 7.20-7.26 (m, 3H), 7.31-7.34 (m, 3H), 7.57 (s, 1H), 8.73 (t, J = 5.6 Hz, 1H). 393.26

Example 231: 4-(2-Chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]oxazine-6-carboxamide

[0539] Example 231 was prepared in an entirely analogous manner to Example 1, as described in General procedures 1-6, starting with an appropriate alcohol in place of the thiol.

TABLE-US-00010 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 231 [00347] 4-(2-chloro-6- fluorobenzyl)- N-(furan-2- ylmethyl)-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]oxazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 4.43 (d, J = 5.6 Hz, 2H), 4.75 (s, 2H), 5.33 (s, 2H), 6.24 (d, J = 2.9 Hz, 1H), 6.40-6.41 (m, 1H), 7.07 (d, J = 8.35 Hz, 1H), 7.17 (t, J = 9.8 Hz, 1H), 7.31-7.35 (m, 2H), 7.52-7.54 (dd, J.sub.1= 1.65 Hz, J.sub.2= 8.35 Hz, 1H), 7.58 (s, 1H), 7.68 (d, J = 1.5 Hz, 1H), 8.85 (t, J = 5.6 Hz, 1H). 414.99

Preparation 23: Methyl 4-((1-ethoxy-1-oxopropan-2-yl)oxy)-3-nitrobenzoate

[0540] ##STR00348##

[0541] Methyl-4-fluoro-3-nitrobenzoate (0.5 g, 2.5 mmol) and 2-hydroxy methyl propionate (0.356 g, 0.30 mmol) were dissolved in 1,4-dioxane (5 mL) at RT. In to the resulting reaction mixture, NaH (0.0726 g, 3.01 mmol; 60% suspension in oil) was added portionwise with ice bath cooling and allowed to stir at room temperature for 16 h. On completion of the reaction it was quenched with aqueous NH.sub.4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford methyl 4-((1-ethoxy-1-oxopropan-2-yl)oxy)-3-nitrobenzoate (0.6 g, 2.02 mmol, 81% yield) as a colourless oil which was used directly in the next step without further purification. LCMS m/z: 298.16 [M+H].

Preparation 24: Methyl 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

[0542] ##STR00349##

[0543] Methyl 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate was prepared from Preparation 23 using the method described in Preparation 1. LCMS m/z: 222.06 [M+H].

Example 232

Preparation 25: 2-Methyl-4-(3,5-difluorobenzvyl)-3-oxo-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

[0544] ##STR00350##

[0545] Example 232 was made from Preparation 24 using the methods described in Preparations 4 to 6, using 3,5-difluorobenzyl chloride and 1-(2,4,6-trifluorophenyl)-methanamine. LCMS m/z: 477.28 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.53 (d, J=6.65 Hz, 3H), 4.41 (s, 2H), 5.02-5.10 (m, 2H), 5.29 (d, J=16.8 Hz, 1H), 6.99 (d, J=6.5 Hz, 2H), 7.11-7.17 (m, 4H), 7.41 (s, 1H), 7.53 (d, J=8.25 Hz, 1H), 8.73 (bs, 1H).

Examples 233-235

[0546] Examples 233-235 were prepared in an analogous manner to Example 232, following the methods described in Preparations 23 to 25, starting with an appropriate nitroarene and alcohol.

TABLE-US-00011 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 233 [00351] (R)-4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4.,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]oxazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.52 (d, J = 6.75 Hz, 3H), 4.37-4.44 (m, 2H), 5.01- 5.05 (m, 1H), 5.08 (d, J = 16.9 Hz, 1H), 5.28 (d, J = 16.85 Hz, 1H), 6.99 (d, J = 6.35 Hz, 2H), 7.11 (d, J = 8.35 Hz, 1H), 7.14-7.18 (m, 3H), 7.40 (d, J = 1.7 Hz, 1H), 7.52-7.54 (dd, J.sub.1 = 8.35 Hz, J.sub.2 = 1.8 Hz, 1H), 8.83 (t, J = 5.05 Hz, 1H). 477.30 234 [00352] (S)-4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H-benzo[b- 1,4]oxazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.51-1.53 (m, 3H), 4.37- 4.44 (m, 2H), 4.98-5.05 (m, 1H), 5.08 (d, J = 16.8 Hz, 1H), 5.28 (d, J = 16.85 Hz, 1H), 6.99 (d, J = 6.8 Hz, 2H), 7.09-7.18 (m, 4H), 7.40 (s, 1H), 7.52-7.54 (m, 1H), 8.83 (t, J = 5.0 Hz, 1H). 476.9 235 [00353] (S)-N- (benzofuran-2- ylmethyl)-4- (3,5- difluorobenzyl)- 2-methyl-3- oxo-3,4- dihydro-2H- benzo[b- 1,4]oxazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.54 (d, J = 6.7 Hz, 3H), 4.59 (d, J = 5.5Hz, 2H), 5.01-5.07 (m, 1H), 5.11 (d, J = 16.85 Hz, 1H), 5.31 (d, J = 16.9 Hz, 1H), 6.68 (s, 1H), 7.02 (d, J = 6.7 Hz, 2H), 7.14-7.28 (m, 4H), 7.49-7.52 (m, 2H), 7.57 (d, J = 7.45 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 9.06 (t, J = 5.45 Hz, 1H). 463.32

Examples 236-243

[0547] Examples 236-243 were prepared in an entirely analogous manner to Examples 233-235 as described in General Procedures 1-5, starting with an appropriate alcohol in place of the thiol.

TABLE-US-00012 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 236 [00354] 1-(3,5- difluorobenzyl)- 2-oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3- b-1,4]oxazine-7- carboxamide (500 MHz; DMSO-d.sub.6): 4.42 (d, J = 4.7 Hz, 2H), 5.10 (s, 2H), 5.17 (s, 2H), 7.09-7.19 (m, 5H), 7.57 (s, 1H), 8.32 (s, 1H), 8.98 (bs, 1H). 464.24 237 [00355] (S)-1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3- b-1,4]oxazine-7- carboxamide (400 MHz; DMSO-d.sub.6): 1.55 (d, J = 6.8 Hz, 3H), 4.40 (d, J = 4.88 Hz, 2H), 5.03 (d, J = 16.96 Hz, 1H), 5.22- 5.26 (m 2H), 7.01 (d, J = 6.44 Hz, 2H), 7.11- 7.16 (m, 3H), 7.61 (d, J = 1.88 Hz, 1H), 8.32 (d, J = 1.92 Hz, 1H), 8.94 (t, J = 4.92 Hz, 1H). 478.32 238 [00356] (R)-1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3- b-1,4]oxazine-7- carboxamide (400 MHz; DMSO-d.sub.6): 1.55 (d, J = 6.76 Hz, 3H), 4.40 (d, J = 4.72 Hz, 2H), 5.03 (d, J = 16.84 Hz, 1H), 5.22- 5.26 (m 2H), 7.01 (d, J = 6.56 Hz, 2H), 7.12- 7.16 (m, 3H), 7.61 (d, J = 1.88 Hz, 1H), 8.31 (d, J = 1.88 Hz, 1H), 8.94 (t, J = 5.12 Hz, 1H). 478.34 239 [00357] 1-(2-chloro-6- fluorobenzyl)- 2-oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3- b-1,4]oxazine-7- carboxamide (500 MHz; DMSO-d.sub.6): 4.43 (d, J = 4.64 Hz, 2H), 4.92 (s, 2H), 5.25 (s 2H), 7.16-7.20 (m, 3H), 7.30-7.33 (m, 2H), 7.86 (d, J = 1.68 Hz, 1H), 8.26 (d, J = 1.76 Hz, 1H), 8.89 (t, J = 4.92 Hz, 1H). 480.26 240 [00358] 1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrido[2,3- b-1,4]oxazine-7- carboxamide (500 MHz; DMSO-d.sub.6): 1.58 (d, J = 6.75 Hz, 3H), 4.43 (bs, 2H), 5.25-5.29 (m, 2H), 7.05 (d, J = 6.65 Hz, 2H), 7.17 (t, J = 8.65 Hz, 3H), 7.64 (s, 1H), 8.35 (s, 1H), 8.89 (bs, 1H). 478.30 241 [00359] (S)-N- (benzofuran-2- ylmethyl)-1- (3,5- difluorobenzyl)- 3-methyl-2- oxo-2,3- dihydro-1H- pyrido[2,3- b][1,4]oxazine- 7-carboxamide (500 MHz; DMSO-d.sub.6): 1.59 (d, J = 6.75 Hz, 3H), 4.62 (d, J = 5.55Hz, 2H), 5.07 (d, J = 17 Hz, 1H), 5.27-5.32 (m, 2H), 6.73 (s, 1H), 7.07 (d, J = 6.6 Hz, 2H), 7.15-7.28 (m, 3H), 7.51-7.58 (m, 2H), 7.71 (d, J = 1.8 Hz, 1H), 8.43 (d, J = 1.85 Hz, 1H), 9.22 (t, J = 5.6 Hz, 1H). 464.33 242 [00360] (R)-4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] oxazine-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.52 (d, J = 6.7 Hz, 3H), 4.40 (d, J = 4.9 Hz, 2H), 5.29-5.00 (m, 3H), 6.98 (d, J = 6.5 Hz, 2H), 7.16-7.08 (m, 4H), 7.40 (d, J = 1.5 Hz, 1H), 7.53-7.51 (m, 1H), 8.79 (bs, 1H). 477.1 243 [00361] (S)-4-(3,5- difluorobenzyl)- 2-methyl-3- oxo-N-(2,4,6- trifluorobenzyl)- 3,4-dihydro- 2H- benzo[b][1,4] oxazine-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.52 (d, J = 6.7 Hz, 3H), 4.40 (d, J = 4.1 Hz, 2H), 5.29-5.00 (m, 3H), 6.98 (d, J = 6.3 Hz, 2H), 7.16-7.08 (m, 4H), 7.40 (s, 1H), 7.52 (d, J = 7Hz, 1H), 8.79 (bs, 1H). 477.1 244 [00362] 1-(2-chloro-6- fluorobenzyl)- 3-methyl-2- oxo-N-(3- (trifluoromethyl) benzyl)-2,3- dihydro-1H- pyrido[2,3- b][1,4]oxazine- 7-carboxamide (500 MHz; DMSO-d.sub.6): 1.51 (d, J = 5.3 Hz, 3H), 4.56 (bs, 2H), 5.08 (d, J = 5.8 Hz, 1H), 5.42-5.20 (m, 2H), 7.18 (t, J = 8.6 Hz, 1H), 7.35-7.32 (m, 2H), 7.66-7.59 (m, 4H), 7.95 (s, 1H), 8.40 (s, 1H), 9.20 (s, 1H). 508.13

Example 245

Preparation 26: 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide 1-oxide

[0548] ##STR00363##

[0549] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 131) (0.03 g 0.069 mmol) in dry DCM (2 mL) was added mCPBA (0.012 g, 0.069 mmol) at 0-5 C. The resulting reaction mixture was stirred at room temperature for 1 h. It was then quenched with saturated Na.sub.2S.sub.2O.sub.3 solution and extracted with EtOAc. The combined organics were washed with NaHCO.sub.3 solution followed by water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product obtained was purified by prep-HPLC to obtain 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo-[b-1,4 thiazine-6-carboxamide-1-oxide (Example 245) (0.008 g, 0.017 mmol, 26% yield) as an off white solid. LCMS m/z: 447.09 [M+H]. .sup.1H NMR (500 MHz; DMSO-d.sub.6): 4.28 (s, 2H), 4.48 (t, J=4.75 Hz, 2H), 5.36 (d, J=15.9 Hz, 1H), 5.45 (d, J=15.9 Hz, 1H), 6.29 (d, J=2.8 Hz, 1H), 6.41-6.42 (m, 1H), 7.15 (t, J=9.05 Hz, 1H), 7.30-7.35 (m, 2H), 7.60 (d, J=0.8 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H), 9.18 (t, J=5.5 Hz, 1H).

Example 246: 4-Benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0550] ##STR00364##

Preparation 27: Methyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylat

[0551] ##STR00365##

[0552] To a stirred suspension of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 7) (0.25 g, 0.80 mmol) in THF (2.5 mL) was added borane-THF solution (5.6 mL, 0.9 mol/L solution in THF) at 0-5 C. The resulting reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was quenched by dropwise addition of MeOH (15 mL) at 0-5 C. The solvent was evaporated under reduced pressure. The residue obtained was partitioned between EtOAc and water; the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness. The crude product obtained of methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (0.25 g, 0.84 mmol) was used in next step without any further purification. LCMS m/z: 300.19 [M+H].

Preparation 28: 4-Benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0553] ##STR00366##

[0554] 4-Benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 246) was prepared from methyl 4-benzyl-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (Preparation 27) using an identical procedure to that described for Preparations 5 and 6. LCMS m/z: 365.22 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.13 (t, J=5.0 Hz, 2H), 3.63-3.65 (m, 2H), 4.38 (d, J=5.65 Hz, 2H), 4.62 (s, 2H), 6.18 (d, J=2.85 Hz, 1H), 6.37 (s, 1H), 7.04-7.09 (m, 2H), 7.17 (s, 1H), 7.24-7.30 (m, 3H), 7.34-7.37 (m, 2H), 7.55 (s, 1H), 8.76 (t, J=5.6 Hz, 1H).

Examples 247-249

[0555] Examples 247-249 were prepared in an analogous manner to Example 246 as described in General Procedure 6 starting from the appropriate lactam.

TABLE-US-00013 IUPAC LCMS Example Structure Name .sup.1H-NMR [M + H] 247 [00367] 4-(2- fluorobenzyl)- N-(furan-2- ylmethyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine- 6- carboxamide (500 MHz; DMSO-d.sub.6): 3.12-3.14 (m, 2H), 3.65-3.67 (m, 2H), 4.37 (d, J = 5.65 Hz, 2H), 4.68 (s, 2H), 6.17 (d, J = 2.8 Hz, 1H), 6.37 (s, 1H), 7.05-7.27 (m, 6H), 7.31-7.35 (m, 1H), 7.55 (s, 1H), 8.78 (t, J = 5.45 Hz, 1H). 383.26 248 [00368] N-(furan-2- ylmethyl)-4- (2-hydroxy- 2- phenylethyl)- 3,4-dihydro- 2H-benzo[b- 1,4]thiazine- 6- carboxamide (500 MHz; DMSO-d.sub.6): 2.89-3.01 (m, 2H), 3.47- 3.54 (m, 3H), 3.68-3.72 (m, 1H), 4.41-4.51 (m, 2H), 4.89-4.91 (m, 1H), 5.55 (d, J = 4.05 Hz, 1H), 6.28 (d, J = 2.15 Hz, 1H), 6.42 (s, 1H), 7.00 (d, J = 7.95 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 7.29-7.30 (m, 2H), 7.34- 7.40 (m, 4H), 7.60 (s, 1H), 8.84 (t, J = 5.4 Hz, 1H). 395.24 249 [00369] N-(furan-2- ylmethyl)-4- (2-oxo-2- phenylethyl)- 3,4-dihydro- 2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.13-3.15 (m, 2H), 3.66- 3.68 (m, 2H), 4.34 (d, J = 5.6 Hz, 2H), 5.09 (s, 2H), 6.13 (d, J = 2.6 Hz, 1H), 6.33 (s, 1H), 6.88 (s, 1H), 7.03-7.09 (q, J = 8.1 Hz, 2H), 7.51 (s, 1H), 7.60 (t, J = 7.6 Hz, 2H), 7.71-7.74 (m, 1H), 8.06 (d, J = 7.7 Hz, 2H), 8.73 (t, J = 5.65 Hz, 1H). 393.25

Example 250: 4-(4-Chlorobenzyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0556] ##STR00370##

[0557] 4-(4-Chlorobenzyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 250) was purchased from a commercial supplier. LCMS m/z: 399.24 [M+H].

Example 251

Preparation 29: 4-Benzyl-N-(furan-2-ylmethyl)-, 4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide-1-oxide

[0558] ##STR00371##

[0559] 4-Benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide 1-oxide (Example 251) was prepared from 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 246) using an identical procedure to that described in Preparation 26 and described in General Procedure 16. LCMS m/z: 381.29 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 2.93-2.99 (m, 1H), 3.16-3.19 (m, 1H), 3.66-3.68 (m, 1H), 3.95 (t, J=13 Hz, 1H), 4.41 (d, J=5.60 Hz, 2H), 4.78-4.88 (q, J=17.2 Hz, 2H), 6.20 (d, J=2.7 Hz, 1H), 6.38 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.29 (t, J=6.95 Hz, 4H), 7.34-7.37 (m, 2H), 7.57-7.61 (m, 2H), 9.00 (t, J=5.6 Hz, 1H).

Example 252

Preparation 30: 4-Benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide 1,1-dioxide

[0560] ##STR00372##

[0561] To a stirred solution of 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 246) (0.1 g 0.27 mmol) in dry DCM (2 mL) was added mCPBA (0.142 g, 0.82 mmol) in 3 equal portions at an interval of 6 h between portions at 0-5 C. under an inert atmosphere. The resulting reaction mixture was then stirred at room temperature for 20 h. It was quenched with saturated Na.sub.2S.sub.2O.sub.3 solution and extracted with EtOAc. The combined organics were washed with NaHCO.sub.3 solution followed by water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product obtained was purified by prep-HPLC to obtain 4-benzyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide 1,1-dioxide (Example 252) (0.03 g, 0.075 mmol, 28% yield) as an off white solid. LCMS m/z: 397.21 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.65-3.67 (m, 2H), 3.97-3.99 (m, 2H), 4.41 (d, J=5.60 Hz, 2H), 4.78 (s, 2H), 6.21 (d, J=2.9 Hz, 1H), 6.38 (s, 1H), 7.21-7.24 (m, 2H), 7.27-7.30 (m, 3H), 7.35-7.38 (m, 2H), 7.57 (s, 1H), 7.71 (d, J=8.15 Hz, 1H), 9.04 (t, J=5.6 Hz, 1H).

Example 253: 4-(2-Fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0562] ##STR00373##

Preparation 31: Methyl-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate

[0563] ##STR00374##

[0564] Methyl-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate was prepared from methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]-thiazine-6-carboxylate (Preparation 1, Step 2) using an identical procedure to that described for Preparation 27. LCMS m/z: 210.08 [M+H].

Preparation 32: Methyl 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate

[0565] ##STR00375##

[0566] To a stirred solution of methyl 3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 31) (0.2 g, 0.96 mmol) in dry DCM (5 mL) was added TEA (0.33 mL, 2.39 mmol) at RT, then 2-fluorobenzoyl chloride (0.227, 1.44 mmol) was added dropwise with ice cooling and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction it was diluted with DCM and washed successively with 1N HCl, saturated NaHCO.sub.3 solution and then brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness. The crude product of methyl 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (0.25 g, 0.76 mmol, 79% yield) obtained was used in the next step with no further purification. LCMS m/z: 332.15 [M+H].

Preparation 33: 4-(2-Fluorobenzoyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid

[0567] ##STR00376##

[0568] To a stirred solution of methyl 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 32) (0.25 g, 0.76 mmol) in a mixture of MeOH, water and THF (1:1:2; 20 mL) was added LiOH.H.sub.2O (0.064 g, 1.51 mmol) at RT. The reaction was allowed to stir at room temperature for 16 h. Upon completion of the reaction, the solvents were evaporated under reduced pressure and the residue was dissolved in water, washed with EtOAc and then acidified to pH 5 with dilute HCl. The acidified aqueous solution was then extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness to give 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (0.2 g. 0.63 mmol, 84% yield) as an off white solid which was used in the next step without any further purification. LCMS m/z: 316.12 [M+H].

Preparation 34: 4-(2-Fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0569] ##STR00377##

[0570] 4-(2-Fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 253) was prepared from 4-(2-fluorobenzoyl)-3,4-dihydro-2H-benzo[b-1,4]-thiazine-6-carboxylic acid (Preparation 33) following the method described for Example 1. LCMS m/z: 397.23 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.32 (bs, 2H), 3.37 (s, 2H), 4.34 (bs, 2H), 6.12 (bs, 1H), 6.39 (s, 1H), 7.05-7.23 (m, 3H), 7.32 (d, J=8.25 Hz, 2H), 7.33-7.45 (m, 2H), 7.52-7.53 (m, 1H), 7.57 (s, 1H), 8.70 (bs, 1H).

Example 254

Preparation 35: 4-(2-Fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide 1,1-dioxide

[0571] ##STR00378##

[0572] 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide 1,1-dioxide (Example 254) was prepared from 4-(2-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 253) following the method described for Preparation 30/Example 249. LCMS m/z: 429.23 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 3.92 (s, 2H), 4.38 (bs, 4H), 6.18 (s, 1H), 6.41 (s, 1H), 7.22-7.29 (m, 2H), 7.54-7.59 (m, 3H), 7.69 (bs, 1H), 7.84 (d, J=8.05 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 9.11 (bs, 1H).

Examples 255-258

[0573] Examples 255-258 were prepared in an analogous manner to that described for Example 253 starting from Preparation 31 using the appropriate acyl halides and amines.

TABLE-US-00014 IUPAC LCMS Example Structure Name .sup.1H-NMR [M + H] 255 [00379] 4-benzoyl-N- (furan-2- ylmethyl)-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.33-3.36 (m, 2H), 4.04 (bs, 2H), 4.33 (d, J = 5.4 Hz, 2H), 6.10 (s, 1H), 6.38 (s, 1H), 7.33-7.36 (m, 6H), 7.40-7.41 (m, 1H), 7.53-7.55 (m, 2H), 8.71-8.73 (m, 1H). 379.23 256 [00380] 4-(2-chloro-6- fluorobenzoyl)- N-(furan-2- ylmethyl)-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.95 (bs, 1H), 4.33 (d, J = 5.3 Hz, 3H), 6.13 (d, J = 2.5 Hz, 1H), 6.40 (s, 1H), 7.19-7.70 (m, 9H), 8.77 (t, J =5.5 Hz, 1H). 431.17 257 [00381] 4-(2-chloro-6- fluorobenzoyl)- N- (cyclohexyl methyl)-3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 0.83 (bs, 1H), 1.16 (bs, 4H), 1.40 (bs, 1H), 1.59- 1.68 (m, 5H), 2.95 (bs, 2H), 3.11 (bs, 1H), 3.76 (bs, 1H), 3.97 (bs, 1H), 4.33 (bs, 1H), 7.16-7.46 (m, 6H), 8.19 (bs, 1H). 447.25 258 [00382] 4-(2-chloro-6- fluorobenzoyl)- N-(2,4,6- trifluorobenzyl)- 3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.73-3.76 (m, 1H), 3.92 (bs, 1H), 4.32-4.35 (m, 3H), 7.14 (s, 1H), 7.17- 7.22 (m, 4H), 7.29 (d, J = 8.25 Hz, 1H), 7.34- 7.41 (m, 1H), 7.45-7.48 (m, 1H), 7.53-7.67 (m, 1H), 8.66 (t, J = 4.5 Hz, 1H). 495.24 259 [00383] 2-methyl-4- (2- phenylacetyl)- N-(2,4,6- trifluorobenzyl)- 3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.24 (d, J = 6.6 Hz, 3H), 3.19 (bs, 1H), 3.52 (bs, 1H), 3.85 (s, 2H), 4.31 (bs, 1H), 4.44 (s, 2H), 7.24-7.14 (m, 8H), 7.58 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 8.81 (s, 1H). 471.26 260 [00384] 4- isonicotinoyl- N-(2,4,6- trifluorobenzyl)- 3,4- dihydro-2H- benzo[b][1,4] thiazine-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.30 (s, 2H), 4.00 (bs, 2H), 4.34 (s, 2H), 7.17 (t, J = 8.5 Hz, 2H), 7.29 (bs, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.54 (d, 8.1 Hz, 1H), 8.58 (s, 2H), 8.64 (s, 1H). 444.30

Example 261: 4-(Phenylsulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0574] ##STR00385##

Preparation 36: Methyl-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate

[0575] ##STR00386##

[0576] To a stirred solution of methyl 3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 31) (0.15 g, 0.72 mmol) in dry pyridine (6 mL) was added DMAP (0.01 g, 0.082 mmol) at RT, then benzenesulfonyl chloride (0.142 mL, 1.1 mmol) was added dropwise with ice cooling, then the reaction mixture was stirred at 60 C. for 4 h. After this time, the reaction mixture was acidified with 3N HCl and the resulting solution was extracted with EtOAc. The organic layer was washed with saturated NaHCO.sub.3 solution and then brine and then dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness. The crude product of methyl-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (0.2 g, 0.57 mmol, 80% yield) obtained was used in the next step with no further purification. LCMS m/z: 350.16 [M+H].

Preparation 37: 4-(Phenylsulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0577] ##STR00387##

[0578] 4-(Phenylsulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 261) was prepared using the method described in Preparation 36 and Example 1 using the General Procedures 1-3. LCMS m/z: 479.27 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 2.90 (t, J=5.4 Hz, 2H), 3.93 (t, J=5.35 Hz, 2H), 4.46 (d, J=4.85 Hz, 2H), 7.20-7.23 (m, 3H), 7.51-7.64 (m, 5H), 7.70 (t, J=6.9 Hz, 1H), 8.04 (d, J=1.25 Hz, 1H), 8.92-8.94 (m, 1H).

Example 262: 4-((1,5-Difluorophenyl)sulfonyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0579] Example 262 was prepared in an analogous manner to Example 261 using 3,5-difluorobenzene sulfonyl chloride and 2,4,6-trifluorobenzyl amine.

TABLE-US-00015 IUPAC LCMS Example Structure Name .sup.1H-NMR [M + H] 262 [00388] 4-((3,5- difluorophenyl) sulfonyl-N- (2,4,6- trifluorobenzyl)- 3,4- dihydro-2H- benzo[b- 1,4]thiazine- 6- carboxamide (400 MHz; DMSO-d.sub.6): 3.00 (t, J = 5.72 Hz, 2H), 3.95 (t, J = 5.52 Hz, 2H), 4.44 (d, J = 4.88 Hz, 2H), 7.17 (t, J = 8.56 Hz, 2H), 7.25 (d, J = 8.28 Hz, 1H), 7.31-7.33 (m, 2H), 7.62- 7.64 (m, 1H), 7.68-7.73 (m, 1H), 7.91 (d, J = 1.72 Hz, 1H), 8.90 (t, J = 5.12 Hz, 1H). 515.27

Examples 263-26t

[0580] Examples 263-265 were prepared in an entirely analogous manner to Example 253, starting with the appropriate lactam and using the appropriate acyl halide, alkyl halide and amine as described in General Procedures 1-3 and 6.

TABLE-US-00016 IUPAC LCMS Example Structure Name .sup.1H-NMR [M + H] 263 [00389] 4-(2- fluorobenzoyl)- N-(furan- 2-ylmethyl)- 3,4-dihydro- 2H-benzo[b- 1,4]oxazine- 6- carboxamide (500 MHz; DMSO-d.sub.6): 3.78-3.79 (m, 2H), 4.34- 4.39 (m, 5H), 6.20 (bs, 1H), 6.40 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.23- 7.33 (m, 1H), 7.57-7.60 (m, 5H), 8.66-8.85 (m, 1H). 381.19 264 [00390] 4-(2-chloro- 6- fluorobenzoyl)- N-(2,4,6- trifluorobenzyl)- 3,4- dihydro-2H- benzo[b- 1,4]oxazine- 6- carboxamide (500 MHz; DMSO-d.sub.6): 3.68 (bs, 1H), 3.94-3.98 (m, 0.5H), 4.32 (bs, 2H), 4.45 (s, 2H), 6.94-7.03 (m, 2H), 7.20-7.29 (m, 3H), 7.45-7.53 (m, 2H), 7.60-7.66 (m, 1H), 8.54- 8.58 (m, 0.5H), 8.75- 8.86 (m, 1H). 479.23 265 [00391] 4-(2-chloro- 6- fluorobenzoyl)- N-(furan- 2-ylmethyl)- 3,4-dihydro- 2H-benzo[b- 1,4]oxazine- 6- carboxamide (500 MHz; DMSO-d.sub.6): 3.60-3.69 (m, 1.5H), 3.98-4.00 (m, 0.5H), 4.32 (bs, 2H), 4.46-4.47 (m, 2H), 6.13-6.27 (m, 1H), 6.40 (s, 1H), 6.96- 7.10 (m, 1H), 7.27-7.31 (m, 1H), 7.44-7.70 (m, 4H), 8.69-8.96 (m, 2H). 415.24

Example 266: 4-Benzyl-N-(furan-2-ylmethyl)-3-thioxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0581] ##STR00392##

Preparation 38: Methyl-4-benzyl-3-thioxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate

[0582] ##STR00393##

[0583] To a stirred solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 7) (0.24 g, 0.80 mmol) in xylene (8 mL) was added Lawesson's reagent (0.258 g, 0.64 mmol) at RT. The resulting reaction mixture was heated at 115-120 C. for 24 h. TLC and LCMS showed product formation along with some starting material. The reaction mixture was diluted with water, 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 using 5-10% EtOAc in hexanes to afford methyl 4-benzyl-3-thioxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (0.12 g, 0.36 mmol, 46% yield) as a yellow solid. LCMS m/z: 330.2 [M+H].

Preparation 39: 4-Benzyl-N-(furan-2-ylmethyl)-3-thioxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide

[0584] ##STR00394##

[0585] 4-benzyl-N-(furan-2-ylmethyl)-3-thioxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxamide (Example 266) was prepared from methyl 4-benzyl-3-thioxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 38) using identical methods described in Preparations 5 and 6. LCMS m/z: 393.0 [MH]; .sup.1H NMR (400 MHz; CDCl.sub.3): 0.86-0.88 (m, 1H), 4.03 (s, 2H), 4.55 (d, J=4.84 Hz, 2H), 5.91 (s, 2H), 6.25 (s, 1H), 6.14 (s, 1H), 6.24 (s, 1H), 6.33 (s, 1H), 7.19-7.20 (m, 1H), 7.25-7.33 (m, 3H), 7.36-7.39 (m, 2H), 7.68 (bs, 1H).

Example 267: 1-(2-Chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide

[0586] ##STR00395##

Preparation 40: Methyl-1-(2-chloro-6-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydro quinoline-7-carboxylate

[0587] ##STR00396##

[0588] Methyl-1-(2-chloro-6-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate was prepared from commercially available methyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate and 2-chloro-6-fluoro-benzyl chloride using an identical method to that described in Preparation 4. LCMS m/z: 348.14 [M+H].

Preparation 41: Methyl-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate

[0589] ##STR00397##

[0590] To a stirred solution of methyl 1-(2-chloro-6-fluorobenzyl)-2-oxo-1,2,3,4 tetrahydroquinoline-7-carboxylate (Preparation 40) (0.6 g, 0.28 mmol) in dry THF (20 mL) was added LiHMDS (1.6 mL, 2.07 mmol) at 78 C. and allowed to stir for 15 min. at 78 C followed by addition of Mel (0.16 mL, 2.07 mmol) and maintained at 78 C. for 30 min. After completion of reaction (monitored by TLC or and LCMS), the reaction mixture was quenched with water, extracted with EtOAc, dried and evaporated to obtain the crude which was purified by Combi-flash (4.0 g column) and eluted with 32% EtOAc in hexanes to afford methyl 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (0.11 g, 0.35 mmol, 17% yield) as a colourless oil. LCMS m/z: 362.21 [M+H].

Preparation 42: 1-(2-Chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide

[0591] ##STR00398##

[0592] 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide (Example 267) was prepared from methyl-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (Preparation 41) using identical methods described in Preparations 5 and 6. LCMS m/z: 491.27 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.14 (d, J=6.4 Hz, 3H), 2.56-2.68 (m, 2H), 2.93-2.96 (m, 1H), 4.39-4.48 (m, 2H), 5.16 (d, J=15.85 Hz, 1H), 5.45 (d, J=15.9 Hz, 1H), 7.10-7.14 (m, 1H), 7.21 (t, J=8.7 Hz, 2H), 7.27-7.32 (m, 3H), 7.41-7.43 (dd, J.sub.1=7.7 Hz, J.sub.2=0.95 Hz, 1H), 7.50 (s, 1H), 8.78 (t, J=5.1 Hz, 1H).

Examples 268-275

[0593] Examples 268-275 were prepared in an identical manner to that described for Example 267 starting from an appropriate nitroarene and using the appropriate benzyl halides and amines as described for General procedures 7-10.

TABLE-US-00017 IUPAC LCMS Example Structure Name .sup.1H-NMR [M + H] 268 [00399] 1-(2-chloro- 6- fluorobenzyl)- N-(furan-2- ylmethyl)-2- oxo-1,2,3,4- tetrahydro quinoline-7- carboxamide (500 MHz; DMSO-d.sub.6): 2.60 (t, J = 7.6 Hz, 2H), 2.88 (t, J = 6.55 Hz, 2H), 4.43 (d, J = 5.65 Hz, 2H), 5.31 (s, 2H), 6.24 (d, J = 2.8 Hz, 1H), 6.40-6.41 (m, 1H), 7.12-7.16 (m, 1H), 7.27-7.33 (m, 3H), 7.46-7.48 (m, 1H), 7.57- 7.59 (m, 2H), 8.90 (t, J = 5.5 Hz, 1H). 412.94 269 [00400] 1-(2-chloro- 6- fluorobenzyl)- N-(4- fluorobenzyl)- 2-oxo- 1,2,3,4- tetrahydro quinoline-7- carboxamide (500 MHz; DMSO-d.sub.6): 2.59-2.64 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 4.43 (d, J = 5.85 Hz, 2H), 5.32 (s, 2H), 7.13-7.57 (m, 10H), 8.98 (t, J = 5.8 Hz, 1H). 441.25 270 [00401] 1-(2-chloro- 6- fluorobenzyl)- 2-oxo-N- (2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydro quinoline-7- carboxamide (500 MHz; DMSO-d.sub.6): 2.59 (t, J = 7.65 Hz, 2H), 2.86 (t, J = 6.75 Hz, 2H), 4.43 (d, J = 4.95 Hz, 2H), 5.30 (s, 2H), 7.13-7.15 (m, 1H), 7.21 (t, J = 8.55 Hz, 2H), 7.26-7.31 (m, 3H), 7.42 (d, J = 7.75 Hz, 1H), 7.51 (s, 1H), 8.78 (bs, 1H). 477.42 271 [00402] 1-(3,5- difluorobenzyl)- 4,4- dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 1,2,3,4- tetrahydro quinoline-7- carboxamide (400 MHz; DMSO-d.sub.6): 1.26 (s, 6H), 2.66 (s, 2H), 4.41 (d, J = 4.92 Hz, 2H), 5.20 (s, 2H), 6.93-6.94 (m, 2H), 7.10-7.16 (m, 3H), 7.32 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.84 Hz, 1H), 8.85 (t, J = 4.88 Hz, 1H). 489.1 272 [00403] 1-(3,5- difluorobenzyl)- N- (furo[2,3- c]pyridin-2- ylmethyl)-2- oxo-1,2,3,4- tetrahydro quinoline-7- carboxamide (400 MHz; DMSO-d.sub.6): 2.74 (t, J = 7.4 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H), 5.19 (s, 2H), 6.80 (s, 1H), 6.96 (d, J = 6.5 Hz, 2H), 7.1 (bs, 1H), 7.36 (bs, 2H), 7.60-7.53 (m, 2H), 8.41 (d, J = 5.6 Hz, 1H), 8.86 (s, 1H), 9.09 (bs, 1H). 448.2 273 [00404] 1-(3,5- difluorobenzyl)- N- (furo[3,2- c]pyridin-2- ylmethyl)-2- oxo-1,2,3,4- tetrahydro quinoline-7- carboxamide (400 MHz; DMSO-d.sub.6): 2.74 (t, J = 7.3 Hz, 2H), 3.02 (t, J = 7.3 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H), 5.19 (s, 2H), 6.81 (s, 1H), 6.96 (d, J = 6.9 Hz, 2H), 7.11 (bs, 1H), 7.36 (bs, 2H), 7.60-7.54 (m, 2H), 8.41 (d, J = 5.7 Hz, 1H), 8.86 (s, 1H), 9.09 (bs, 1H). 448.1 274 [00405] 1-(3,5- difluorobenzyl)- N- (furo[2,3- b]pyridin-2- ylmethyl)-2- oxo-1,2,3,4- tetrahydro quinoline-7- carboxamide (400 MHz; DMSO-d.sub.6): 2.71 (t, J = 7.3 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 4.58 (d, J = 5.5 Hz, 2H), 5.16 (s, 2H), 6.68 (s, 1H), 6.93 (d, J = 6.6 Hz, 2H), 7.07 (t, J = 9.3 Hz, 1H), 7.34-7.26 (m, 3H), 7.52 (d, J = 7.8 Hz, 1H), 8.00- 7.98 (dd, 1H), 8.21-8.19 (dd, 1H), 9.07 (t, J = 5.6 Hz, 1H). 447.9 275 [00406] 1-(3,5- difluorobenzyl)- N- (furo[3,2- b]pyridin-2- ylmethyl)-2- oxo-1,2,3,4- tetrahydro quinoline-7- carboxamide (400 MHz; DMSO-d.sub.6): 2.74 (t, J = 7.3 Hz, 2H), 3.02 (t, J = 7.3 Hz, 2H), 4.64 (d, J = 5.5 Hz, 2H), 5.19 (s, 2H), 6.85 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 7.09 (t, J = 9.1 Hz, 1H), 7.31-7.26 (m, 3H), 7.56 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 8.45 (d, J = 4.6 Hz, 1H), 9.1 (t, J = 5.6 Hz, 1H). 448.2

Example 276: 5-(3,5-Difluorobenzyl)-6-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxamide

[0594] ##STR00407##

Preparation 43: (E)-Methyl-5-amino-6-(3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate

[0595] ##STR00408##

[0596] A sealed tube was charged with commercially available 5-amino-6-bromo-nicotinic acid methyl ester (2.0 g, 8.66 mmol), DMF (1.0 mL), ethyl acrylate (2.16 mL, 20.30 mmol) and then TEA (2.19 mL, 15.7 mmol) and the whole degassed with N.sub.2 gas for 15 min. ATAPHOS (0.307 g, 0.44 mmol, 50 mol %) was then added at RT. The resulting reaction mixture was heated at 140 C. for 12 h. After completion of the reaction, the reaction mixture was poured into 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 obtain the crude product which was purified by column chromatography to afford (E)-methyl 5-amino-6-(3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate (0.95 g, 3.8 mmol, 44% yield). LCMS m/z: 251.2 [M+H].

Preparation 44: Methyl-5-amino-6-(3-ethoxy-3-oxopropyl)nicotinate

[0597] ##STR00409##

[0598] To a stirred solution of (E)-methyl-5-amino-6-(3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate (Preparation 43) (0.5 g, 2.0 mmol) in MeOH (15 mL) was added Pd/C (0.55 g, 10% w/w) under a N.sub.2 gas atmosphere at RT. The resulting reaction mixture was stirred under H.sub.2 gas balloon pressure at 0-5 C. for 2 h. The reaction was monitored by TLC and after completion the whole was filtered through a celite bed and washed with MeOH. The filtrate was concentrated under reduced pressure to give methyl 5-amino-6-(3-ethoxy-3-oxopropyl)nicotinate (0.45 g, 1.79 mmol, 89% yield) as a crude solid which was used as such in the next step without further purification.

[0599] LCMS m/z: 252.9 [M+H].

Preparation 45: Methyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate

[0600] ##STR00410##

[0601] To a stirred solution of methyl-5-amino-6-(3-ethoxy-3-oxopropyl)nicotinate (Preparation 44) (0.4 g, 1.59 mmol) in toluene (5 mL) was added formic acid (3.0 mL) at RT. The resulting mixture was heated to reflux for 1h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a yellow residue, which was diluted with water and extracted with EtOAc. The combined organics were 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 methyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (0.25 g, 1.21 mmol, 76% yield) as an off white solid. LCMS m/z: 207.1 [M+H].

Preparation 46: 5-(3,5-Difluorobenzyl)-6-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxamide

[0602] ##STR00411##

[0603] 5-(3,5-Difluorobenzyl)-6-oxo-N-(2,4,6-trifluorobenzyl)-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxamide (Example 276) was prepared from methyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate (Preparation 45) using identical methods described in Preparations 5 and 6. LCMS m/z: 462.1 [M+H]; .sup.1H NMR (400 MHz; DMSO-d.sub.6): 2.87 (t, J=7.76 Hz, 2H), 3.18 (t, J=7.12 Hz, 2H), 4.43 (d, J=4.24 Hz, 2H), 5.15 (s, 2H), 6.68 (d, J=6.24 Hz, 2H), 7.09-7.18 (m, 3H), 7.51 (s, 1H), 8.56 (s, 1H), 9.02 (bs, 1H).

Examples 277-283

[0604] Examples 274-280 were made in an analogous manner to Example 273 starting from the appropriate pyridine and using the appropriate benzyl halides and amines as described for General procedures 7-10.

TABLE-US-00018 IUPAC LCMS Example Structure Name .sup.1H-NMR [M + H] 277 [00412] N-(2,4- difluorobenzyl)- 5-(3,5- difluorobenzyl)- 6-oxo- 5,6,7,8- tetrahydro- 1,5- naphthyridine- 3- carboxamide (400 MHz; CDCl.sub.3): 2.91 (t, J = 7.92 Hz, 2H), 3.25 (t, J = 7.28 Hz, 2H), 4.60 (d, J = 5.8 Hz, 2H), 5.12 (s, 2H), 6.43 (bs, 1H), 6.66-6.71 (m, 3H), 6.80- 6.87 (m, 2H), 7.35-7.37 (m, 1H), 7.56 (s, 1H), 8.44 (s, 1H). 444.2 278 [00413] N- (benzofuran- 2-ylmethyl)-5- (3,5- difluorobenzyl)- 6-oxo- 5,6,7,8- tetrahydro- 1,5- naphthyridine- 3- carboxamide (400 MHz; CDCl.sub.3): 2.91 (t, J = 7.76 Hz, 2H), 3.25 (t, J = 7.72 Hz, 2H), 4.750 (s, 2H), 5.13 (s, 2H), 6.48 (bs, 1H), 6.67-6.70 (m, 4H), 7.21-7.25 (m, 1H), 7.43 (d, J = 8.12 Hz, 1H), 7.52 (d, J = 6.92 Hz, 1H), 7.60 (s, 1H), 8.4 (s, 1H). 448.4 279 [00414] N-(2,4- difluorobenzyl)- 8-(3,5- difluorobenzyl)- 7-oxo- 5,6,7,8- tetrahydro- 1,8- naphthyridine- 2- carboxamide (400 MHz; DMSO-d.sub.6): 2.77 (t, J = 7.60 Hz, 2H), 3.03 (t, J = 6.20 Hz, 2H), 4.49 (d, J = 6.08 Hz, 2H), 5.43 (s, 2H), 6.96-7.03 (m, 4H), 7.20-7.22 (m, 2H), 7.65 (d, J = 7.76 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H), 8.93 (bs, 1H). 444.2 280 [00415] N-(2,4- difluorobenzyl)- 5-(4- fluorobenzyl)- 6-oxo-5,6,7,8- tetrahydro- 1,5- naphthyridine- 3- carboxamide (400 MHz; DMSO-d.sub.6): 2.85 (t, J = 7.96 Hz, 2H), 3.17 (t, J = 7.28 Hz, 2H), 4.44 (d, J = 5.48 Hz, 2H), 5.14 (s, 2H), 7.04 (t, J = 9.28 Hz, 1H), 7.13 (t, J = 8.76 Hz, 2H), 7.22-7.28 (m, 3H), 7.30-7.36 (m, 1H), 7.64 (s, 1H), 8.60 (s, 1H), 9.13 (t, J = 5.64 Hz, 1H). 426.1 281 [00416] N- (benzofuran- 2-ylmethyl)- 8-(3,5- difluorobenzyl)- 7-oxo- 5,6,7,8- tetrahydro- 1,8- naphthyridine- 2- carboxamide (400 MHz; DMSO-d.sub.6): 2.77 (t, J = 7.80 Hz, 2H), 3.03 (t, J = 7.0 Hz, 2H), 4.65 (d, J = 5.84 Hz, 2H), 5.45 (s, 2H), 6.56 (s, 1H), 6.98-7.06 (m, 3H), 7.19- 7.27 (m, 2H), 7.49-7.55 (m, 2H), 7.68 (d, J = 7.44 Hz, 1H), 7.84 (d, J = 7.44 Hz, 1H), 9.04 (bs, 1H). 448.3 282 [00417] N-(2,4- difluorobenzyl)- 8-(4- fluorobenzyl)- 7-oxo-5,6,7,8- tetrahydro- 1,8- naphthyridine- 2- carboxamide (400 MHz; DMSO-d.sub.6): 2.74 (t, J = 7.28 Hz, 2H), 2.96 (t, J = 7.92 Hz, 2H), 4.51 (d, J = 5.52 Hz, 2H), 5.40 (s, 2H), 6.98-7.06 (m, 3H), 7.23-7.37 (m, 4H), 7.64 (d, J = 7.8 Hz, 1H), 7.80 (d, J =6.96 Hz, 1H), 8.93 (bs, 1H). 426.3 283 [00418] (3,5- difluorobenzyl)- 7-oxo-N- (2,4,6- trifluorobenzyl)- 5,6,7,8- tetrahydro- 1,8- naphthyridine- 2- carboxamide (400 MHz; DMSO-d.sub.6): 2.76 (t, J = 7.60 Hz, 2H), 3.01 (t, J = 7.08 Hz, 2H), 4.49 (d, J = 5.56 Hz, 2H), 5.37 (s, 2H), 6.96-7.00 (m, 3H), 7.11 (t, J = 8.32 Hz, 2H), 7.63 (d, J = 7.76 Hz, 1H), 7.81 (d, J = 7.28 Hz, 1H), 8.63 (bs, 1H). 462.2

Example 284: 1-(3,5-Difluorobenzyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxamide-2,2-dioxide

[0605] ##STR00419##

[0606] Example 284 was prepared according to the methods described in General Procedures 1-3, and the methods described below.

Preparation 47: Methyl-3-amino-4-formylbenzoate

[0607] ##STR00420##

[0608] To a stirred solution of commercially available methyl 4-formyl-3-nitrobenzoate (2.0 g, 9.57 mmol) in EtOH (30 mL) was added Fe powder (1.60 g, 28.70 mmol) followed by 0.15 M HCl (816 mL) and resulting reaction mixture was refluxed for 2 h. The progress of reaction was monitored by TLC and LCMS and after completion the mixture was filtered, washed with water, extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (1.7 g, 99% yield and purity >97%) as a brown oily liquid which was used in the next step without any further purification. LCMS m/z: 180.08 [M+H].

Preparation 48: Methyl 4-formyl-3-(methylsulfonamido)benzoate

[0609] ##STR00421##

[0610] To a stirred solution of methyl 3-amino-4-formylbenzoate (Preparation 47) (1.5 g, 8.38 mmol) in pyridine (31 mL) was added DMAP (1.54 g, 12.57 mmol) followed by methanesulfonyl chloride (0.713 mL, 9.21 mmol) dropwise and the whole was allowed to stir at RT for 48 h. After complete consumption of the starting material (monitored by TLC and LCMS) the mixture was diluted with EtOAc and successively washed with 1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated brine solutions. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a crude product which was purified by Combi-flash column chromatography using a 4 g silica column using 50% EtOAc in hexane as eluent to afford the title compound (0.6 g, 40% yield and purity 97%) as a yellow solid. LCMS m/z: 258.04 [M+H].

Preparation 49: Methyl 1-(3,5-difluorobenzyl)-1H-benzo[1,2]thiazine-7-carboxylate 2,2-dioxide

[0611] ##STR00422##

[0612] To a stirred solution of methyl 4-formyl-3-(methylsulfonamido)benzoate (Preparation 48) (0.15 g, 0.58 mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (0.38 g, 1.17 mmol) followed by 3,5-difluorobenzyl bromide (0.15 mL, 1.17 mmol) under an inert atmosphere and the whole was refluxed at 50 C. for 12 h. The course of reaction was monitored by TLC and LCMS and after completion the mixture was diluted with EtOAc and successively washed with ice cold water, brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give a crude residue which was purified by column chromatography in Combi-flash eluting with 25-30% EtOAc/hexane to give the title compound (0.1 g, 84% yield and purity >98%) as a yellow solid. LCMS m/z: 366.1 [M+H].

Preparation 50: Methyl 1-(3,5-difluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxylate 2,2-dioxide

[0613] ##STR00423##

[0614] To a stirred solution of methyl 1-(3,5-difluorobenzyl)-1H-benzo[c][1,2]thiazine-7-carboxylate 2,2-dioxide (Preparation 49) (0.1 g, 0.032 mmol) in MeOH (5 mL) was added 10% PdC (10 mg, 50% w/w in water) under a N.sub.2 gas atmosphere. The resulting reaction mixture was then stirred under H.sub.2 gas balloon pressure at RT for 1 h. After completion of the reaction the mixture was filtered carefully through a celite bed. The filtrate was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give the title compound (0.1 g, 95% yield and purity 99%) as a white solid. LCMS m/z: 368.07 [M+H].

Example 284: 1-(3,5-Difluorobenzyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxamide 2,2-dioxide

[0615] ##STR00424##

[0616] 1-(3,5-Difluorobenzyl)-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxamide 2,2-dioxide (Example 284) was prepared from methyl 1-(3,5-difluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxylate 2,2-dioxide (Preparation 50) using identical methods described in Preparation 5 and 6. White solid; Yield 56%; Purity 98%; LCMS m/z: 497.56 [M+H]; .sup.1H NMR (400 MHz; DMSO-d.sub.6): 3.41 (t, J=6.9 Hz, 2H), 3.67 (t, J=6.9 Hz, 2H), 4.38 (d, J=4.9 Hz, 2H), 5.00 (s, 2H), 7.19-7.05 (m, 6H), 7.32 (d, J=8 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 8.81 (t, J=5.1 Hz, 1H).

Example 285: 1-(3,5-difluorobenzyl)-3-methyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxamide 2,2-dioxide

[0617] ##STR00425##

Preparation 51: Methyl 3-methyl-1H-benzo[c][1,2]thiazine-7-carboxylate 2,2-dioxide

[0618] ##STR00426##

[0619] To a stirred solution of methyl 3-amino-4-formylbenzoate (Preparation 47) (0.5 g, 2.79 mmol) in DCM (10 mL) was added TEA (2.2 mL, 22.34 mmol) followed by ethanesulfonyl chloride (0.064 mL, 6.70 mmol) in portion wise and allowed to stir at RT for 48 h. The progress of reaction was monitored by TLC and LCMS and after completion the mixture was diluted with EtOAc and washed with water. The organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give a crude product which was purified by column chromatography using 50% EtOAc/hexane as eluent to give the title compound (0.2 g, 48% yield and purity >96%) as a white solid. LCMS m/z: 254.04 [M+H].

Preparation 52: Methyl 1-(3,5-difluorobenzyl)-3-methyl-1H-benzo[c][1,2]thiazine-7-carboxylate 2,2-dioxide

[0620] ##STR00427##

[0621] To a stirred solution of methyl 3-methyl-1H-benzo[c][1,2]thiazine-7-carboxylate 2,2-dioxide (Preparation 51) (0.1 g, 0.40 mmol) in DMF (5 mL) was added NaH (22 mg, 0.47 mmol) followed by 3,5-difluorobenzyl bromide (0.056 mL, 0.43 mmol) under an inert atmosphere at 0-5 C. The resulting reaction mixture was allowed to stir for 15 min. at RT. After completion of the reaction the mixture was diluted with EtOAc and washed with ice cold water and brine. The organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to give a crude product which was purified by Combi-flash using 10% EtOAc/hexane as eluent to afford the title compound (0.1 g, 67% yield and purity >97%) as a yellow solid. LCMS m/z: 380.07 [M+H].

Example 285: 1-(3,5-Difluorobenzyl)-3-methyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxamide 2,2-dioxide

[0622] ##STR00428##

[0623] 1-(3,5-Difluorobenzyl)-3-methyl-N-(2,4,6-trifluorobenzyl)-3,4-dihydro-1H-benzo[c][1,2]thiazine-7-carboxamide 2,2-dioxide (Example 285) was prepared from methyl 1-(3,5-difluorobenzyl)-3-methyl-1H-benzo[c][1,2]thiazine-7-carboxylate 2,2-dioxide (Preparation 52) using identical methods described in Preparation 50, 5 and 6. White solid; Yield 60%; Purity 99%; LCMS m/z: 511.1 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.36 (d, J=4.9 Hz, 3H), 3.20-3.15 (m, 1H), 3.54 (d, J=16.6 Hz, 1H), 3.83 (bs, 1H), 4.41 (s, 2H), 5.07 (s, 2H), 7.20-7.11 (m, 6H), 7.32 (d, J=7.2 Hz, 1H), 7.49 (d, J=6.8 Hz, 1H), 8.84 (s, 1H).

Biological Assays

Stable Cell Line Generation

[0624] a) Stable STING expressing cellsStable HEK293T STING-expressing cell lines were generated using plasmids purchased from Invivogen, Calif., USA, that contain STING cDNA cloned into the pUNO-1 vector under hEF1-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. [0625] b) Stable Luciferase reporter gene expressing cellsStable 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.

LuciferaseAssay

[0626] 510.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.

[0627] 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 M, B for values greater than 1 M and less than or equal to 10 M, and C for values greater than 10 M.

[0628] All compounds were first tested in a primary screen using WT/R232 STING protein 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. These active compounds were then further investigated to obtain an EC.sub.50 value.

TABLE-US-00019 R232 activity R232 Example Activity 1 C 2 C 3 C 4 C 5 C 6 C 7 C 8 C 9 C 10 C 11 B 12 B 13 B 14 B 15 C 16 B 17 C 18 C 19 C 20 C 21 B 22 C 23 C 24 C 25 C 26 C 27 C 28 C 29 C 30 C 31 A 32 B 33 C 34 A 35 C 36 C 37 A 38 B 39 B 40 A 41 C 42 C 43 C 44 C 45 C 46 C 47 C 48 C 49 C 50 C 51 C 52 C 53 C 54 C 55 C 56 C 57 C 58 C 59 C 6o C 61 B 62 B 63 C 64 C 65 C 66 B 67 C 68 C 69 B 70 C 71 B 72 C 73 B 74 B 75 C 76 C 77 C 78 C 79 C 8o C 81 C 82 B 83 B 84 C 85 C 86 C 87 A 88 C 89 C 90 C 91 C 92 C 93 B 94 C 95 C 96 C 97 C 98 C 99 B 100 B 101 B 102 B 103 C 104 C 105 C 106 C 107 B 108 C 109 C 110 C 111 C 112 A 113 C 114 A 115 A 116 C 117 C 118 B 119 B 120 B 121 C 122 B 123 C 124 C 125 C 126 B 127 B 128 C 129 C 130 C 131 B 132 C 133 B 134 B 135 C 136 B 137 C 138 A 139 C 140 A 141 A 142 A 143 B 144 A 145 A 146 A 147 A 148 A 149 A 150 A 151 A 152 A 153 A 154 A 155 A 156 A 157 A 158 A 159 A 160 A 161 B 162 B 163 B 164 B 165 C 166 C 167 B 168 C 169 C 170 C 171 C 172 C 173 C 174 C 175 C 176 C 177 C 178 A 179 C 180 C 181 B 182 C 183 B 184 C 185 B 186 B 187 B 188 A 189 A 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 B 198 A 199 A 200 A 201 B 202 B 203 B 204 B 205 B 206 B 207 B 208 C 209 C 210 C 211 C 212 C 213 C 214 C 215 C 216 C 217 C 218 A 219 C 220 C 221 C 222 C 223 C 224 C 225 C 226 C 227 C 228 C 229 C 230 C 231 C 232 A 233 A 234 A 235 A 236 C 237 B 238 B 239 C 240 B 241 B 242 A 243 A 244 C 245 C 246 C 247 C 248 C 249 C 250 C 251 C 252 C 253 C 254 C 255 C 256 C 257 B 258 B 259 C 260 C 261 B 262 C 263 C 264 C 265 C 266 C 267 A 268 C 269 A 270 A 271 A 272 C 273 C 274 C 275 C 276 B 277 B 278 C 279 B 280 C 281 B 282 B 283 B 284 A 285 B

STING Polymorphisms

[0629] 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.

[0630] The tables below show the potency of selected compounds of the invention against the most common polymorphisms.

TABLE-US-00020 H232 activity H232 H232 H232 Example activity Example activity Example activity 145 A 192 A 136 C 269 C 151 B 258 C 270 A 150 B 138 A 178 C 157 B 140 A 267 A 156 B 87 B 40 B 242 C 83 C 233 B 243 A 181 C 234 B 196 A 69 B 183 B 203 B 118 B 271 A 201 B 120 B 187 C 199 A 82 B 188 B 195 B 93 B 146 B 158 B 31 A 147 B 197 B 141 B 235 B 284 C 142 A 153 B 202 B 34 A 148 A 198 A 37 B 232 B 133 B 39 B 218 B 160 C 144 B 279 C 159 B 152 C 161 C 285 B 149 A 189 B 154 B 193 B 281 B 131 B 200 B 190 B 127 B 194 A 191 B 112 A

TABLE-US-00021 HAQ activity HAQ HAQ HAQ Example activity Example activity Example activity 145 A 192 A 136 C 269 B 151 B 258 C 270 B 150 B 138 A 178 C 157 B 140 A 267 A 156 B 87 C 40 B 242 B 83 C 233 B 243 A 181 C 234 B 196 A 69 B 183 B 203 B 118 C 271 A 201 B 120 C 187 C 199 A 82 B 188 B 195 B 93 C 146 B 158 B 31 B 147 B 197 B 141 A 235 B 284 C 142 A 153 B 202 B 34 B 148 A 198 A 37 C 232 B 133 B 39 B 218 B 160 C 144 B 279 C 159 B 152 C 161 B 285 B 149 A 189 B 154 A 193 B 281 B 131 C 200 B 190 B 127 B 194 A 191 B 112 A

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

[0631] 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-B pathway, by monitoring the activity of secreted SEAP, and the IRF pathway, by assessing the activity of a secreted luciferase (Lucia). 510.sup.5 THP1-Dual cells were seeded in 384-well plates in growth medium and stimulated with novel compounds. After 2 ohr of stimulation supernatant 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. 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 M, B for values greater than 1 M and less than or equal to 10 M, and C for values greater than 10 M.

TABLE-US-00022 IRF/NF.sub.KB activity THP- THP- THP- IRF NF.sub.KB THP-IRF NF.sub.KB Example activity activity Example activity activity 145 B B 158 B B 269 C C 197 C C 270 C B 284 C C 178 C C 202 C C 267 B B 198 B B 40 B B 133 C B 233 C C 160 C C 234 C C 159 B B 183 C B 285 C C 271 B B 154 B B 187 C C 131 C C 188 C B 127 C C 146 C C 112 C C 147 C C 136 C C 235 B B 258 C C 153 B B 138 B B 148 B A 140 B B 232 C C 87 C C 218 B B 83 C C 279 C C 181 C C 161 C C 69 C C 189 C C 118 C C 281 C C 120 C C 190 B B 82 C C 191 B B 93 C C 192 B B 31 C C 151 B B 141 B B 150 B B 142 B B 157 B B 34 C C 156 B B 37 C C 242 C C 39 C C 243 C C 144 B B 196 B B 152 C C 203 C C 149 B A 201 C C 193 C C 199 B B 200 C C 195 C B 194 B B

Western Blot Assay

[0632] 510.sup.5 clonally selected HEK293T-hSTING-Luciferase cells were seeded in 24-well plates in 500 l 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 cells pellet 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 g 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 help of the BioRad XRS plus imager. The Western blot assays are shown in FIG. 2.

Analysis of Cytokines by ELISA

[0633] Freshly isolated 210.sup.5 human PBMCs using Histopaque (Sigma) from different healthy donors were stimulated with novel compounds (10 M) in 200 l growth medium for 6 hr. Post treatment supernatant media was harvested and stored at 80 C. in different aliquots for secreted Cytokine analysis. Key cytokines like IFN, IFN, IL6, CXCL10, and TNF were measured using respective manufacturers recommendations. IFN, IFN were purchased from PBL Assay science, IL6, CXCL10 were procured from Abcam and TNF was purchased from R&D systems. The results are shown in FIG. 3.

In Vivo Tumor Experiments

[0634] 110.sup.6 CT26 tumor cells stably expressing R232.hSTING were injected subcutaneously in 100 l RPMI on the right side of the flank of Balb/C mice. Following tumor implantation, when the average tumors size was around 50 mm.sup.3 to 70 mm.sup.3, mice were randomized into different groups. Total number of animals per group is around 5 to 8. New chemical entity which was tested in this tumor model was formulated in 100% PEG400. For the treatment groups compounds were dosed intra-tumorally thrice in a week. Control animals were injected vehicle by same route as per same scheduled of compound dosing, and are identified as vehicle controls (VC). Growth of the tumors was measured regularly during the course of the study.

CONCLUSION

[0635] 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.