SMALL MOLECULE STING ANTAGONISTS

Abstract

The present invention relates to compounds of formula (I). The compounds maybe used to antagonise the Stimulator of Interferon Genes (STING) protein and may thereby treat liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres syndrome (AGS), familial chilblain lupus (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and age-related macular degeneration (AMD).

Claims

1. A compound of formula (I): ##STR00369## wherein X.sup.2 is CR.sup.2 or N; X.sup.3 is CR.sup.3 or N; X.sup.6 is C═O, or CR.sup.7R.sup.8; the or each Z is independently CR.sup.9R.sup.10 or NR.sup.9; X.sup.7 is S, SO, SO.sub.2, O, NR.sup.11 or CR.sup.11R.sup.12; n is 0, 1 or 2; wherein, when n is 1 and Z is CR.sup.9R.sup.10; then X.sup.7 is S, SO, SO.sub.2, O or NR.sup.11; and when n is 1 and Z is NR.sup.9 then X.sup.7 is CR.sup.11R.sup.12; R.sup.1, R.sup.4, and R.sup.8 are each independently selected from the group consisting of H, halogen, OH, CN, COOR.sup.13, CONR.sup.13R.sup.14, NR.sup.13R.sup.14, NR.sup.13COR.sup.14, optionally substituted C.sub.1-C.sub.6 alkyl, 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.6-C.sub.12 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.9, R.sup.10, R.sup.11 and R.sup.12 are each independently selected from the group consisting of H, halogen, OH, CN, COOR.sup.13, CONR.sup.13R.sup.14, NR.sup.13R.sup.14, NR.sup.13COR.sup.14, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl and optionally substituted C.sub.2-C.sub.6 alkynyl; one of R.sup.2 and R.sup.3 is -L.sup.1-L.sup.2-L.sup.3-L.sup.4-R.sup.15 and, when X.sup.2 is CR.sup.2 and X.sup.3 is CR.sup.3, the other of R.sup.2 and R.sup.3 is selected from the group consisting of H, halogen, OH, CN, COOR.sup.13, CONR.sup.13R.sup.14, NR.sup.13R.sup.14, NR.sup.13COR.sup.14, optionally substituted C.sub.1-C.sub.6 alkyl, 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.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted aryloxy and optionally substituted heteroaryloxy, optionally substituted heterocyclyloxy; R.sup.5 and R.sup.7 are selected from the group consisting of H, halogen, OH, CN, COOR.sup.13, CONR.sup.13R.sup.14, NR.sup.13R.sup.14, NR.sup.13COR.sup.14, optionally substituted C.sub.1-C.sub.6 alkyl, 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.6-C.sub.12 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, optionally substituted heterocyclyloxy and L.sup.5-L.sup.6-R.sup.16; wherein a maximum of one of R.sup.5 and R.sup.7 is -L.sup.5-L.sup.6-R.sup.16; R.sup.13 and R.sup.14 are each independently selected from the group consisting of H, halogen, OH, CN, COOH, CONH.sub.2, NH.sub.2, NHCOH, optionally substituted C.sub.1-C.sub.6 alkyl, 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.6-C.sub.12 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; a) L.sup.1 is NR.sup.7 or O, L.sup.2 is C═O, C═S, C═NR.sup.19 or SO.sub.2, and L.sup.3 is absent, NR.sup.18 or O; b) L.sup.1 is absent, L.sup.2 is C═O, C═S, C═NR.sup.19 or SO.sub.2, and L.sup.3 is NR.sup.18 or O and when L.sup.2 is C═O, L.sup.3 is not NR.sup.18; c) L.sup.1 is absent or is a C.sub.1-C.sub.3 alkylene; L.sup.2 is absent; and L.sup.3 is O; or d) L.sup.1 is a C.sub.5-C.sub.6 cycloalkylene, a C.sub.6 arylene, a 5 membered heteroarylene or a 5 to 6 membered heterocyclylene; L.sup.2 is absent and L.sup.3 is absent; L.sup.4 is absent or is an optionally substituted C.sub.1-C.sub.6 alkylene, an optionally substituted C.sub.2-C.sub.6 alkenylene, an optionally substituted C.sub.2-C.sub.6 alkynylene, an optionally substituted C.sub.3-C.sub.6 cycloalkylene, an optionally substituted C.sub.6-C.sub.12 arylene, an optionally substituted 5 to 10 membered heteroarylene or an optionally substituted 3 to 8 membered heterocyclylene; L.sup.5 is absent or an optionally substituted C.sub.1-C.sub.6 alkylene, an optionally substituted C.sub.2-C.sub.6 alkenylene, an optionally substituted C.sub.2-C.sub.6 alkynylene, O, S, S═O, SO.sub.2 or NR.sup.19; L.sup.6 is absent or an optionally substituted C.sub.1-C.sub.6 alkylene, an optionally substituted C.sub.2-C.sub.6 alkenylene, an optionally substituted C.sub.2-C.sub.6 alkynylene, O, S, S═O, SO.sub.2 or NR.sup.19; R.sup.15 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or optionally substituted mono or bicyclic 3 to 8 membered heterocycle, wherein when R.sup.15 is an optionally substituted aryl the aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, halogen, OH, oxo, OP(O)(OR.sup.20)(OR.sup.21), optionally substituted C.sub.1-C.sub.6 alkoxy, NR.sup.20R.sup.21, CONR.sup.20R.sup.21, CN, C(O)R.sup.20, COOR.sup.20, NO.sub.2, azido, SO.sub.2R.sup.20, C(O)R.sup.20 and NR.sup.20COR.sup.21 and when R.sup.15 is an optionally substituted heteroaryl, an optionally cycloalkyl or an optionally substituted heterocycle the heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, halogen, OH, oxo, OP(O)(OR.sup.20)(OR.sup.21), optionally substituted C.sub.1-C.sub.6 alkoxy, NR.sup.20R.sup.21, CONR.sup.20R.sup.21, CN, C(O)R.sup.20, COOR.sup.20, NO.sub.2, azido, SO.sub.2R.sup.20, C(O)R.sup.20 and NR.sup.20COR.sup.21; R.sup.16 is H, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or optionally substituted mono or bicyclic 3 to 8 membered heterocycle; and R.sup.17 to R.sup.19 are independently H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.2-C.sub.6 alkenyl, an optionally substituted C.sub.2-C.sub.6 alkynyl or CN; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

2. (canceled)

3. The compound of claim 1, wherein R.sup.1 and R.sup.4 are independently H, halogen, OH, CN, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl.

4. The compound of claim 1, wherein X.sup.2 is CR.sup.2 and X.sup.3 is CR.sup.3, and one of R.sup.2 and R.sup.3 is -L.sup.1-L.sup.2-L.sup.3-L.sup.4-R.sup.15 and the other of R.sup.2 and R.sup.3 is H, halogen, OH, CN, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl.

5. The compound of claim 1, wherein; L.sup.1 is NR.sup.17, L.sup.2 is C═O, C═S, C═NR.sup.19 or SO.sub.2 and L.sup.3 is absent or is NR.sup.18; or L.sup.1 is absent, L.sup.2 is C═S, C═NR.sup.19 or SO.sub.2 and L.sup.3 is NR.sup.18; or L.sup.1 is absent or a C.sub.1-C.sub.3 alkylene, L.sup.2 is absent and L.sup.3 is O; or L.sup.1 is an optionally substituted C.sub.5-C.sub.6 cycloalkylene, an optionally substituted C.sub.6 arylene, an optionally substituted 5 membered heteroarylene or an optionally substituted 5 or 6 membered heterocyclylene, L.sup.2 is absent and L.sup.3 is absent.

6. (canceled)

7. (canceled)

8. The compound of claim 1, wherein -L.sup.1-L.sup.2-L.sup.3- are ##STR00370## —O—*, —CH.sub.2O—*, ##STR00371## where an asterisk indicates the point of bonding to L.sup.4 or, when L.sup.4 is absent, R.sup.15.

9. The compound of claim 1, wherein L.sup.4 is: absent, an optionally substituted C.sub.1-C.sub.6 alkylene, an optionally substituted C.sub.2-C.sub.6 alkenylene or an optionally substituted C.sub.2-C.sub.6 alkynylene; or an optionally substituted C.sub.3-C.sub.6 cycloalkylene, an optionally substituted C.sub.6-C.sub.12 arylene, an optionally substituted 5 to 10 membered heteroarylene or an optionally substituted 3 to 8 membered heterocyclylene.

10. (canceled)

11. The compound of claim 1, wherein -L.sup.1-L.sup.2-L.sup.3-L.sup.4- is —OCH.sub.2CH.sub.2—*, —CH.sub.2OCH.sub.2—* , ##STR00372## where an asterisk indicates the point of bonding to R.sup.15.

12. The compound of claim 1, wherein R.sup.17 and R.sup.18 are independently H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl and R.sup.19 is H, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl or C.sub.2-C.sub.3 alkynyl.

13. The compound of claim 1, wherein R.sup.15 is: a mono or bicyclic C.sub.6-C.sub.12 aryl and the aryl is unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, halogen, OH, oxo, OP(O)(OR.sup.20)(OR.sup.21), optionally substituted C.sub.1-C.sub.6 alkoxy, NR.sup.20R.sup.21, CONR.sup.20R.sup.21, CN, C(O)R.sup.20, COOR.sup.20, NO.sub.2, azido, SO.sub.2R.sup.20, C(O)R.sup.20 and NR.sup.20COR.sup.21; 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 3 to 8 membered heterocycle, and the heteroaryl, cycloalkyl or heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, halogen, OH, oxo, OP(O)(OR.sup.20)(OR.sup.21), optionally substituted C.sub.1-C.sub.6 alkoxy, NR.sup.20R.sup.21, CONR.sup.20R.sup.21, CN, C(O)R.sup.20, COOR.sup.20, NO.sub.2, azido, SO.sub.2R.sup.20, C(O)R.sup.20 and NR.sup.20COR.sup.21; or phenyl, ##STR00373## ##STR00374##

14. (canceled)

15. (canceled)

16. The compound of claim 1, wherein R.sup.5 is -L.sup.5-L.sup.6-R.sup.16.

17. The compound of claim 16, wherein L.sup.5 is absent, an optionally substituted C.sub.1-C.sub.3 alkylene, an optionally substituted C.sub.2-C.sub.3 alkenylene or an optionally substituted C.sub.2-C.sub.3 alkynylene, optionally wherein L.sup.5 is CH.sub.2, CH.sub.2CH.sub.2, CO, ##STR00375## or absent.

18. (canceled)

19. The compound of claim 16, wherein L.sup.6 is absent, O, S, S═O, SO.sub.2 or NR.sup.19.

20. The compound of claim 16, wherein R.sup.16 is: optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, mono or bicyclic optionally substituted C.sub.6-C.sub.12 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl or optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally wherein the cycloalkyl, aryl, heteroaryl or heterocycle is unsubstituted or substituted with one or more substituents selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, 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, halogen, OH, CN, oxo, C(O)R.sup.20, COOR.sup.20, OC(O)R.sup.20, CONR.sup.20R.sup.21, NR.sup.20R.sup.21, NR.sup.20C(O)R.sup.21, ═NOR.sup.20, SR.sup.20, SO.sub.2R.sup.20, OSO.sub.2R.sup.20, SO.sub.2NR.sup.20R.sup.21, OP(O)(OR.sup.20)(OR.sup.21), optionally substituted C.sub.6-C.sub.12 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C.sub.3-C.sub.6 cycloalkyl and optionally substituted 3 to 8 membered heterocycle; or cyclopropyl, cyclopentyl, phenyl, ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380##

21. (canceled)

22. (canceled)

23. The compound of claim 1, wherein R.sup.5 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl and/or R.sup.7 and R.sup.1 are independently H, halogen, OH, CN, COOR.sup.13, CONR.sup.13R.sup.14, NR.sup.13R.sup.14, NR.sup.13COR.sup.4, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl.

24.-25. (canceled)

26. The compound of claim 1, wherein n is 1.

27. The compound of claim 25, wherein Z is CR.sup.9R.sup.10 and X.sup.7 is S, SO, SO.sub.2, O or NR.sup.11, optionally wherein R.sup.9 and R.sup.10 are H, halogen, OH, CN, COOR.sup.13, CONR.sup.13R.sup.14, NR.sup.13R.sup.14, NR.sup.13COR.sup.4, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl and R.sup.13 and R.sup.4 are H, optionally substituted C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.2-C.sub.3 alkenyl or optionally substituted C.sub.2-C.sub.3 alkynyl and/or X.sup.7 is S or O.

28. (canceled)

29. (canceled)

30. The compound of claim 25, wherein Z is NR.sup.9 and X.sup.7 is CR.sup.11R.sup.12 optionally wherein R.sup.9 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl and R.sup.11 and R.sup.12 are independently H, halogen, OH, CN, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl.

31. (canceled)

32. The compound of claim 1, wherein n is 0.

33. The compound of claim 1, wherein the compound is a compound of formula (II) or (III): ##STR00381## optionally wherein the compound is a compound of formula (IIa), (IIb), (IIIa) or (IIb): ##STR00382##

34. (canceled)

35. The compound of claim 1, wherein the compound is: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-phenylurea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(4-fluorophenyl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(pyridin-3-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(pyridin-4-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-5-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(4-cyanobenzyl)urea; 1-(4-Fluorophenyl)-3-(3-oxo-4-(pyridin-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Fluorophenyl)-3-(3-oxo-4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-7-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)urea; 1-(4-(Benzo[d]isoxazol-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(3-Aminophenyl)-3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Fluorophenyl)-3-(4-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1-methyl-1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indazol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)urea; 1-(1H-Benzo[d]imidazol-6-yl)-3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)-1-methylurea; 1-(4-Benzyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-phenylurea; 4-(3-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)ureido)benzamide; (S)-1-(1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(4-fluorophenyl)urea; 1-(1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(4-fluorophenyl)urea; 1-(1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(1H-indol-6-yl)urea ex 40; 4-(2-Chloro-6-fluorobenzyl)-6-(4-fluorophenethoxy)-2H-benzo[b][1,4]thiazin-3(4H)-one; 4-(2-Chloro-6-fluorobenzyl)-6-(((4-fluorobenzyl)oxy)methyl)-2H-benzo[b][1,4]thiazin-3(4H)-one; 4-(2-Chloro-6-fluorobenzyl)-6-(5-phenyl-1H-imidazol-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one; 4-(2-Chloro-6-fluorobenzyl)-6-(5-phenyl-1H-1,2,4-triazol-3-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one; 6-(5-Benzyl-4H-1,2,4-triazol-3-yl)-4-(2-chloro-6-fluorobenzyl)-2H-benzo[b][1,4]thiazin-3(4H)-one; 4-(2-Chloro-6-fluorobenzyl)-6-(4-phenyloxazol-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one; N-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-(1H-indol-6-yl)acetamide; N-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-(furan-2-yl)acetamide; 4-Benzoyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(4-fluorophenyl)urea; 1-(4-(3-aminobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-1-(1H-indol-6-yl)-1-methylurea; 1-(1H-indol-6-yl)-3-(4-((2-methylpyridin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(5-methyl-1H-indol-6-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(2-methyl-1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,3-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,6-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 3-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzamide; 1-(4-(3-chloro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-(2-chlorophenoxy)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-([1,1′-biphenyl]-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-chloro-5-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-((6-chlorobenzo[d][1,3]dioxol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(3,5-difluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(4-((trifluoromethyl)thio)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(3-chloro-4-(trifluoromethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-fluoro-3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-(difluoromethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chlorophenethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-chloro-4-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(2-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(benzo[d][1,3]dioxol-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,5-dimethoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(benzo[d]thiazol-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 6-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)nicotinic acid; 1-(4-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-cyano-2-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(4-chloro-2-(methylsulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluoro-3-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluoro-3-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,6-difluoro-4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2,6-difluoro-4-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-(1H-1,2,4-triazol-1-yl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(furan-2-ylmethyl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(3-(4-chlorophenyl)-1H-pyrazol-4-yl)urea; 1-((1H-pyrrol-3-yl)methyl)-3-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)urea; 1-(4-((5-(tert-butyl)-1,2,4-oxadiazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(2,3-dihydro-1H-inden-2-yl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(4-phenylcyclohexyl)urea; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea; 1-(4-(4-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; methyl 2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoate; N-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; 1-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(indolin-6-yl)urea; 2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoic acid; 2-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzamide; 1-(4-((1,4-dioxan-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyridin-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(3-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-(hydroxymethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 3-((7-(3-(1H-indol-6-yl)ureido)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzamide; 1-(4-(3-(hydroxymethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-(2-hydroxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-(pyrimidin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-((1H-pyrazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-((1H-imidazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-((1,2,4-oxadiazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-(isoxazol-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 7-(3-(1H-indol-6-yl)ureido)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide; 1-(4-benzyl-6-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-fluorophenyl)-3-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 2-amino-N-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide; 1-(1H-indol-6-yl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; N-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-1H-indole-6-carboxamide; 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzoyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea; 1-(4-(cyclopropylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-(cyclopentylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-benzyl-1-oxido-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-(2-chloro-6-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-6-yl)urea; 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(4-fluorophenyl)urea; 1-(4-(2-fluoro-4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 4-benzyl-N-(1H-indol-6-ylsulfamoyl)-2,3-dihydro-1,4-benzoxazin-6-amine 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-pyrrolo[3,2-b]pyridin-6-yl)urea; 1-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)-1-methylurea; 6-(3-(1H-indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide; 1-(4-benzyl-7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(1H-Indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea; 1-(1H-Indol-6-yl)-3-(3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; N-1H-indol-6-yl-N′-(4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfuric diamide 1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-yl)urea; 1-(1H-indol-6-yl)-3-(3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)urea; 1-(1H-indol-6-yl)-3-(4-(oxazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea; 1-(4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(1H-indol-6-yl)urea; 1-(1-Benzylindolin-6-yl)-3-(1H-indol-6-yl)urea; 2-(6-(3-(1H-Indol-6-yl)ureido)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)acetamide; 1-(3-Allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-(2,3-dihydroxypropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-(2-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(4-Benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 1-(3-(Aminomethyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; 6-(3-(1H-Indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxamide; 1-(4-benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 1-(3-(aminomethyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea; 7-(3-(1H-indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxamide; 2-(6-(3-(1H-Indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide; 1-(4-(2-Hydroxy-1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea; Methyl 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate; 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-methyl-2-phenylacetamide; 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-cyclopropyl-2-phenylacetamide; 6-(4-(1H-Indol-6-yl)piperazin-1-yl)-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one; 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-cyano-3-(1H-indol-6-yl)guanidine; or 1-(4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea.

36. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

37.-41. (canceled)

42. A method of modulating the STING protein in a subject, the method comprising administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of formula (I), as defined by claim 1, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

43. A method of treating, ameliorating or preventing a disease selected from liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres syndrome (AGS), familial chilblain lupus (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and age-related macular degeneration (AMD); the method comprising administering, to a subject in need of such treatment, a therapeutically effective amount of a compound of formula (I), as defined by claim 1, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

44. The method of claim 42, wherein the disease is fibrosis or fatty liver disease, and the fibrosis is selected from the group consisting of liver fibrosis, pulmonary fibrosis or renal fibrosis, and the fatty liver disease is non-alcoholic (or simple) fatty liver or non-alcoholic steatohepatitis (NASH).

Description

EXAMPLES

[0344] Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (S) are given in parts-per-million downfield from tetramethylsilane (for .sup.1H-NMR) and upfield from trichloro-fluoro-methane (for .sup.19F NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl.sub.3, deuterochloroform; d.sub.6-DMSO, deuterodimethylsulphoxide; and CD.sub.3OD, deuteromethanol.

[0345] Mass spectra, MS (m/z), were recorded using electrospray ionisation (ESI). Where relevant and unless otherwise stated the m/z data provided are for isotopes .sup.19F, .sup.35Cl, .sup.79Br and .sup.127I.

[0346] 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.

[0347] Flash column chromatography was carried out using pre-packed silica gel cartridges in a Combi-Flash platform. Prep-HPLC purification was carried out according to the General purification and analytical methods described above. Thin layer chromatography (TLC) was carried out on Merck silica gel 60 plates (5729). All final compounds were >95% pure as judged by the LCMS or UPLC analysis methods described in the General Purification and Analytical methods above unless otherwise stated.

Example 1: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea

[0348] ##STR00073##

[0349] Example 1 was prepared according to the methods described in General Procedures 1-6, and the methods described below.

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

[0350] ##STR00074##

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

[0351] ##STR00075##

[0352] 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 the solution. The reaction mixture was cooled to 0-5° C. and ethyl thioglycolate (7.25 g, 62.7 mmol) was added dropwise. The reaction mixture was stirred for 30 min. at ice-cold temperature. It was then diluted with EtOAc and washed with a saturated solution of NH.sub.4Cl and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to dryness to give the title compound (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

[0353] ##STR00076##

[0354] 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), the reaction was cooled to room temperature and poured onto 1N HCl (250 mL) and then stirred for 1 h. The resulting 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 in vacuo to afford the title compound (3.5 g, 15.6 mmol, 91% yield) as a pale yellow solid. LCMS m/z: 222.05 [M−H].

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

[0355] ##STR00077##

[0356] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 1, Step 2) (5.0 g, 22.2 mmol) in DMF (50 mL) at 0-5° C. was added NaH (0.98 g, 24.4 mmol) portionwise and the whole stirred for another 5-10 min. at the same temperature. Then, benzyl bromide (2.8 mL, 23.3 mmol) was added and the reaction mixture was stirred for 1 h. Completion of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with a saturated solution of NH.sub.4Cl and diluted with ice-cold water. The aqueous reaction mixture was extracted with MTBE and washed with brine. The separated organic layer was then dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound (9.0 g) as a crude pale yellow solid which was used in the next step without any further purification. LCMS m/z: 314.16 [M+H].

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

[0357] ##STR00078##

[0358] To a stirred solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 2) (9.0 g, 28.8 mmol) in a mixture of solvents THF/MeOH/H.sub.2O (160 mL, 2:1:1) was added LiOH.H.sub.2O (4.8 g, 115.2 mmol) at RT and the combined mixture stirred for 2 h at the same temperature. Progress of the reaction was monitored by TLC and LC-MS, showing complete consumption of the starting material. The solvents were evaporated in vacuo and the resulting residue was diluted with water and washed with EtOAc. The aqueous layer was collected and acidified with 1N HCl to pH 5-6 to obtain a precipitate which was filtered, collected and dried by azeotropic distillation with MeCN to afford the title compound (5.0 g) as a crude white solid. LCMS m/z: 300.13 [M+H].

Preparation 4: tert-Butyl (4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate

[0359] ##STR00079##

[0360] To a stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 3) (4.5 g, 14.4 mmol) in DCM (50 mL) was added TEA (3 mL, 21.6 mmol) under an inert atmosphere at 0-5° C. followed by DPPA (6.3 mL, 28.8 mmol) and stirring then continued for 5 min. at the same temperature. The reaction mixture was brought slowly to room temperature and stirred for 4 h. Formation of the corresponding acyl azide was confirmed by TLC and UPLC-MS by quenching an aliquot of the reaction mixture into methanol. The solvents were evaporated, tert-butanol (50 mL) was added to the reaction mixture and the whole was refluxed overnight. Completion of the reaction was monitored by TLC and LC-MS, which showed formation of the desired product with complete consumption of the starting material. The solvents were evaporated in vacuo to obtain a crude oil which was adsorbed onto silica gel and purified by combi flash to afford the title compound (4.2 g, 80% yield) as an off white solid. LCMS m/z: 317.15 [M+H].

[0361] Preparation 5: 6-Amino-4-benzyl-2H-benzo[b][1,4]thiazin-(4H)-one

##STR00080##

[0362] To a stirred solution of tert-butyl (4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (Preparation 4) (1.0 g, 2.7 mmol) in 1,4-dioxane (15 mL) was added HCl (15 mL, 4M HCl solution in 1,4-dioxane) at 0-5° C. and the combined mixture stirred for 5 min. The reaction mixture was then stirred overnight at room temperature. UPLC showed consumption of the starting material. The solvent was evaporated in vacuo. The resulting crude residue was then washed with NaHCO.sub.3 solution and extracted with EtOAc. It was then evaporated in vacuo to give the title compound (750 mg, 90.5% yield) as a deep yellow solid. LCMS m/z: 271.23 [M+H].

Preparation 6: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea (Example 1)

[0363] ##STR00081##

[0364] To a stirred solution of 6-amino-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 5) (0.650 g, 2.39 mmol) in THF (15 mL) was added p-nitrophenyl-chloroformate (0.580 g, 2.87 mmol) at 0-5° C. and the combined mixture was stirred for 5 min. and then allowed to warm slowly to room temperature over 1 h at which point carbamate formation was confirmed by TLC. 6-aminoindole (0.349 g, 2.64 mmol) was added followed by TEA (1 mL, 7 mmol) at 0-5° C. and the reaction mixture was stirred at room temperature for a further 1 h. Urea formation was detected by UPLC-MS and TLC and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with 1 N NaOH solution followed by brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give the crude product which was purified by prep-HPLC to afford the title compound (270 mg, 27% yield) as a white solid. Purity by UPLC: 99.32%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.18 (s, 2H), 6.32 (s, 1H), 6.80 (d, J=8.32 Hz, 1H), 7.18-7.40 (m, 10H), 7.75 (s, 1H), 8.57 (s, 1H), 8.67 (s, 1H), 10.92 (s, 1H); LCMS m/z: 429.35 [M+H].

Example 69: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea

[0365] ##STR00082##

[0366] Example 69 was prepared according to General Procedure 1-6 and the methods described below.

Preparation 44: Methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[0367] ##STR00083##

Step 1: Methyl 3-(2-methoxy-2-oxoethoxy)-4-nitrobenzoate

[0368] ##STR00084##

[0369] To a stirred solution of NaH (1.5 g, 37.6 mmol, 60% suspension in mineral oil) in 1,4-dioxane (50 mL) was added commercially available methyl 2-hydroxyacetate (3.39 g, 37.6 mmol) at 5-10° C. and the combined mixture stirred for 30 min. Methyl 3-fluoro-4-nitrobenzoate (5.0 g, 25.11 mmol) in 1,4-dioxane (25 mL) was added and the whole stirred at RT for 16 h. Progress of the reaction was monitored by TLC and UPLC-MS and after completion the reaction mixture was diluted with ice-cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried in a vacuum oven at 60° C. for 2.5 h to afford the title compound (5.0 g) as a pale yellow crude solid. UPLC-MS m/z: 269.98 [M+H].

Step 2: Methyl 3-oxo-1,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[0370] ##STR00085##

[0371] To a stirred solution of methyl 3-(2-methoxy-2-oxoethoxy)-4-nitrobenzoate (Preparation 44, Step 1) (5.0 g, 18.57 mmol) in AcOH (25 mL) was added iron powder (4.15 g, 74.304 mmol) at RT. The resulting reaction mixture was stirred at 90° C. for 2 h. TLC and UPLC-MS showed formation of the desired compound and after completion of the reaction, the reaction mixture was quenched by pouring into ice-cold water (500 mL) and stirring for 30 min. The precipitated solid was filtered and washed several times with water. The washed solid material was then dried in a vacuum oven at 60° C. for 6 h to afford the title compound (3.8 g) as an ash colored solid. UPLC-MS m/z: 207.98 [M+H].

Preparation 45: 7-Amino-4-benzyl-2H-benzo[b][1,4]oxazin-(4H)-one

[0372] ##STR00086##

Step 1: Methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[0373] ##STR00087##

[0374] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 44, Step 2) (2.0 g, 9.65 mmol) in DMF (20 mL) was added NaH (425 mg, 10.62 mmol) followed by benzyl bromide (1.27 mL, 10.62 mmol) at 0-10° C. The whole was slowly allowed to warm to RT over 1 h. TLC and UPLC-MS showed formation of the desired product and after completion of the reaction the mixture was diluted with chilled water to give a solid precipitate which was filtered and dried in a vacuum oven to afford the title compound (2.6 g, 90% yield) as an ash coloured solid. UPLC-MS m/z: 298.88 [M+H].

Step 2: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid

[0375] ##STR00088##

[0376] To a stirred solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 45, Step 1) (2.6 g, 8.75 mmol) in a mixture of THF (30 mL) and MeOH (15 mL) was added a solution of LiOH.H.sub.2O (1.83 g, 43.73 mmol) in water (15 mL) at RT. The mixture was stirred at RT for 124 h. Progress of the reaction was monitored by UPLC-MS and after completion the solvents were evaporated in vacuo to give a residue which was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 6N HCl to give a precipitate which was filtered and dried in a rotary evaporator with acetonitrile as co-solvent to afford the title compound (2.2 g, 890% yield) as an off white crude solid. UPLC-MS m/z: 284.02 [M+H].

Step 3: tert-Butyl (4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)carbamate

[0377] ##STR00089##

[0378] To a stirred solution of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (Preparation 45, Step 2) (200 mg, 0.7 mmol) in DCM (5 mL) was added DMF (0.05 mL) and oxalyl chloride (0.092 mL, 1.06 mmol) at 0-5° C. The combined mixture was stirred at RT for 1 h. TLC showed formation of the corresponding acid chloride. The solvent was evaporated in vacuo to afford an orange crude mass which was treated with a saturated solution of NaN.sub.3 (91.78 mg, 1.41 mmol) in water (5 mL) and further stirred at RT for 1 h. TLC showed completion of the reaction. The reaction mixture was diluted with water and extracted with MTBE. The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated in vacuo to afford the corresponding crude acyl azide (250 g) intermediate which was dissolved in t-BuOH (10 mL) and stirred at 90° C. for 1 h. After complete consumption of the azide intermediate (monitored by UPLC-MS), the solvent was evaporated in vacuo to afford the crude product which was purified by Combi-flash (20 g column) using 20% EtOAc in hexane as eluent to give the title compound (120 g, 42% yield) as a white solid. UPLC-MS m/z: 355.13 [M+H].

Step 4: 7-Amino-4-benzyl-2H-benzo[b][1,4]oxazin-(4H)-one

[0379] ##STR00090##

[0380] A solution of tert-butyl (4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)carbamate (Preparation 45, Step 3) (120 mg, 0.34 mmol) in a 4M solution of HCl in dioxane (3.5 mL) was stirred at RT for 2 h under an inert atmosphere. UPLC-MS showed formation of the desired product. The solvent was evaporated to give the title compound (120 mg) as a crude yellow sticky mass which was used in the next step without any further purification. UPLC-MS m/z: 254.98 [M+H].

Preparation 46: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea (Example 69)

[0381] ##STR00091##

[0382] To a stirred solution of 6-amino indole (68 mg, 0.519 mmol) in THF (5 mL) was added triphosgene (70 mg, 0.235 mmol) at 0-5° C. The combined mixture was stirred at RT for 1 h. Completion of the first stage of the reaction was confirmed by TLC, after which 7-amino-4-benzyl-2H-benzo[b][1,4]oxazin-3(4H)-one (Preparation 45, Step 4) (120 mg, 0.472 mmol) and TEA (0.225 mL, 1.557 mmol) were added into the reaction mixture and stirring continued at RT for 1 h. Progress of the reaction was monitored by TLC and after completion the solvent was evaporated in vacuo to afford the crude material which was purified by prep-HPLC to give the title compound (23 mg, 12% yield) as a pale brownish solid. Purity by UPLC: 96.28%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 4.76 (s, 2H), 5.13 (s, 2H), 6.30 (t, J=1.04 Hz, 1H), 6.90-6.94 (m, 2H), 6.97-6.99 (m, 1H), 7.17-7.19 (m, 1H), 7.25-7.40 (m, 7H), 7.79-7.83 (m, 1H), 9.78 (s, 1H), 9.95 (s, 1H), 10.88 (s, 1H); UPLC-MS m/z: 413.11 [M+H].

Examples 2-4, 6, 9, 12, 16-19, 22-33, 51-53, 59-60, 87-96, 99, 116, 124-142, 144-162, 164-166 and 193-195

[0383] The examples in the table below were prepared according to the above methods used to make Example 1 and 69 as described in General Procedures 1-6 using the appropriate amines. Purification was as stated in the aforementioned methods

TABLE-US-00001 IUPAC LCMS Purity Ex Structure Name 1H-NMR [M + H] (%) 2 [00092] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3- phenylurea (500 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.17 (s, 2H), 6.96 (t, J = 7.25 Hz, 1H), 7.20-7.30 (m, 7H), 7.33- 7.35 (m, 3H), 7.39-7.41 (m, 2H), 8.65 (s, 1H),8.70 (s, 1H) 390.2 98.94 3 [00093] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][i, 4]thiazin-6- yl)-3-(4- fluorophenyl) urea (500 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.17 (s, 2H), 7.11-7.19 (m, 2H), 7.24- 7.32 (m, 8H), 7.40-7.41 (m, 2H), 8.75 (d, J = 8.45 Hz, 2H) 408.15 99.33 4 [00094] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3- (pyridin-3- yl)urea (500 MHz; DMSO-d.sub.6): δ 3.65 (s, 2H), 5.17 (s, 2H), 7.20-7.30 (m, 5H), 7.31- 7.41 (m, 4H), 7.89 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 3.65 Hz, 1H), 8.55 (d, J = 1.84 Hz, 1H), 8.83 (d, J = 7.85 Hz, 2H) 391.18 91.21 6 [00095] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3- (pyridin-4- yl)urea (500 MHz; DMSO-d.sub.6): δ 3.65 (s, 2H), 5.17 (s, 2H), 7.20-7.25 (m, 5H), 7.32- 7.37 (m, 3H), 7.38-7.39 (m, 2H), 8.34 (d, J = 6.25 Hz, 2H), 8.90 (s, 1H), 9.09 (s, 1H) 391.-17 98.66 9 [00096] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-5- yl)urea (500 MHz; DMSO-d.sub.6): δ 3.63 (s, 2H), 5.18 (s, 2H), 6.32 (s, 1H), 7.03 (d, J = = 8.45 Hz, 1H), 7.19-7.35 (m, 10H), 7.62 (s, 1H), 8.38 (s, 1H), 8.60 (s, 1H), 10.93 (s, 1H) 429.29 98.95 12 [00097] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(4- cyanobenzyl) urea (400 MHz; DMSO-d.sub.6): δ 3.60 (s, 2H), 4.33 (d, J = 6.04 Hz, 2H), 5.13 (s, 2H), 6.79 (t, J = 5.8 Hz, 1H), 7.12-7.29 (m, 8H), 7.44 (d, J = 8.32 Hz, 2H), 7.79 (d, J = 8.36 Hz, 2H), 8.78 (s, 1H) 429-33 98.26 16 [00098] l-(4- fluorophenyl)- 3-(3-oxo- 4-(pyridin- 3-ylmethyl)- 3,4-dihydro- 2H-benzo[b] [1,4]thiazin-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.65 (s, 2H), 5.19 (s, 2H), 7.11-7.64 (m, 9H), 8.46- 8.50 (m, 2H), 8.82-8.84 (m, 2H) 409.32 97.57 17 [00099] l-(4- fluorophenyl)- 3-(3-oxo-4- (pyridin-4- ylmethyl)- 3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.68 (s, 2H), 5.19 (s, 2H), 7.09-7.18 (m, 4H), 7.32-7.38 (m, 5H), 8.46- 8.56 (bs, 2H), 8.88-8.88 (m, 2H) 409.38 97.83 18 [00100] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-3- yl)urea (500 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.18 (s, 2H), 6.99 (t, J = 7.45 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.24-7.45 (m, 9H), 7.46-7.48 (m, 2H), 8.46 (s, 1H), 8.64 (s, 1H), 10.72 (s, 1H) 429.4 96.73 19 [00101] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-7- yl)urea (500 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.18 (s, 2H), 6.42 (bs, 1H), 6.92- 6.93 (m, 1H), 7.10-7.12 (m, 1H), 7.23-7.28 (m, 5H), 7-31-7-36 (m, 5H), 8.65 (bs, 1H), 9.05 (s, 1H), 10.76 (s, 1H) 429.27 99.0 22 [00102] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.66 (s, 2H), 5.21 (s, 2H), 6.32-6.33 (m, 1H), 6.82- 6.85 (dd, J1 = 1.84 Hz, J2 = 8.44 Hz 1H), 7.08 (d, J = 8.96 Hz, 1H), 7.13 7.24 (m, 1H), 7-30-7-33 (m, 4H), 7-39-7-40 (m, 2H), 7.41 (m, 1H), 7.64- 429.31 97.98 7.65 (m, 1H), 7.76 (s, 1H), 8.60 (s, 1H), 8.66 (s, 1H), 10.92 (s, 1H) 23 [00103] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H-benzo[b] [1,4]thiazin- 6-yl)-3-(2,3- dihydrobenzo [b][1,4] dioxin-6- yl)urea (500 MHz; DMS0-d.sub.6): δ 3.63 (s, 2H), 4.18-4.21 (m, 4H), 5.16 (s, 2H), 6.74 (s, 2H), 7.03 (s, 1H), 7.17-7.34 (m, 8H), 8.50 (s, 1H), 8.66 (s, 1H) 448.34 98.96 24 [00104] 1-(4- (benzo[d] isoxazol-3- ylmethyl)- 3-oxo-3,4- dihydro- 2H-benzo [b][1,4] thiazin-6- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.60 (s, 2H), 6.32 (s, 1H), 6.972- 6.81 (m, 1H), 7.21-7.22 (m, 1H), 7.229-7.32 (m, 2H), 7.38-7.46 (m, 3H), 7.65-7.69 (m, 1H), 7.74- 7.46 (m, 2H), 7.86-7.88 (m, 1H), 8.58 (s, 1H), 8.69 (s, 1H), 10.91 (s, 1H) 470.37 99.01 25 [00105] 1-(3- aminophenyl)- 3-(4-benzyl- 3-oxo-3,4- dihydro- 2H-benzo [b][1,4] thiazin-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.33 (s, 2H), 5.02 (bs, 2H), 5.17 (s, 2H), 6.16- 6.18 (m, 1H), 6.48-6.50 (m, 1H), 6.70-6.71 (m, 1H), 6.87 (t, J = 7.64 Hz 1H), 7.16-7.33 (m, 8H), 8.35 (s, 1H), 8.59 (s, 1H) 405.38 99.26 26 [00106] 1-(4- fluorophenyl)- 3-(4- (imidazo [1,2-a]pyridin- 2-ylmethyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)urea (500 MHz; DMSO-d.sub.6): δ 3.58 (s, 2H), 5.20 (s, 2H), 6.86 (t, J = 6.3 Hz, 1H), 7.07-7.11 (m, 2H), 7.20-7.24 (m, 1H), 7.30- 7.35 (m, 2H), 7.40-7.42 (m, 3H), 7.50-7.52 (m, 1H), 7.75 (s, 1H), 8.47 (d, J = 6.5 Hz, 1H), 8.83 (s, 1H), 8.91 (s, 1H) 448.30 95.04 27 [00107] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H-benzo[b] [1,4]thiazin- 6-yl)-3-(1- methyl-1H- indol-6- yl)urea (500 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 3.72 (s, 3H), 5.19 (s, 2H), 6.33 (s, 1H), 6.87 (d, J = 8.05 Hz, 1H), 7.21-7.42 (m, 10H), 7.68 (s, 1H), 8.58 (s, 1H), 8.66 (s, 1H) 443.37 97.20 28 [00108] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indazol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.19 (s, 2H), 6.88 (s, 1H), 7.25-7-33 (m, 8H), 7.65 (s, 1H), 7.92 (s, 2H), 8.86-8.94 (m, 2H), 12.80 (s, 1H) 430.34 99.51 29 [00109] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)-3-(2- oxo-1,2,3,4- tetrahydro- quinolin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 2.39-2.43 (m 2H), 2.76- 2.80 (m, 2H), 3.63 (s, 2H), 5.17 (s, 2H), 6.93- 6.94 (m, 1H), 7.0-7.04 (m, 2H), 7-17-7-35 (m, 8H), 8.65 (d, J = 4.4 Hz, 2H), 10.05 (s, 1H) 459.36 96.71 30 [00110] 1-(1H-benzo[d] imidazol-6-yl)- 3-(4-benzyl-3- oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.18 (s, 2H), 6.95-7.52 (s, 10H), 7.87 (s, 1H), 8.09 (s, 1H), 8.75 (s, 2H), 12.25 (s, 1H) 430.38 98.85 31 [00111] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-6-yl)- 1-methylurea (400 MHz; DMSO-d.sub.6): δ 3.14 (s, 3H), 3.68 (s, 2H), 5.21 (s, 2H), 6.32 (s, 1H), 6.88 (d, J = 8 Hz, 1H), 7.01 (d, J = 7.72 Hz, 1H), 7.14-7.22 (m, 7H), 7.34-7-42 (m, 2H), 7.44- 7.56 (m, 1H), 7.98 (s, 1H), 10.92 (s, 1H) 443.41 99.02 32 [00112] 1-(4-benzyl- 2-methyl-3- oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)-3- phenylurea (500 MHz; DMSO-d.sub.6): δ 1.39 (d, J = 6.8 Hz, 3H), 3.79-3.83 (q, J = 6.6 Hz, 1H), 5.17 (s, 2H), 6.96 (t, J = 7.2 Hz, 1H), 7.20- 7.41 (m, 12H), 8.73 (s, 1H), 8.79 (s, 1H) 404.14 99.12 33 [00113] 4-(3-(4- benzyl-3- oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)ureido) benzamide (500 MHz; DMSO-d.sub.6): δ 3.64 (s, 2H), 5.18 (s, 2H), 7.20-7.35 (m, 9H), 7.46 (d, J = 8.4 Hz, 2H), 7.79-7-83 (m, 3H), 8.99 (s, 1H), 9.10 (s, 1H) 433.18 98.49 51 [00114] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)-3-(3,4- dihydro-2H- benzo[b][1, 4]oxazin-6- yl)urea (500 MHz; DMSO-d.sub.6): δ 3.24 (s, 2H), 3.63 (s, 2H), 4.05 (s, 2H), 5.16 (s, 2H), 5.80 (s, 1H), 6.38-6.40 (m, 1H), 6.50- 6.52 (m, 1H), 6.75 (s, 1H), 7.15 (d, J = 6.64 Hz, 1H), 7.22-7.34 (m, 7H), 8.32 (s, 1H), 8.60 (s, 1H) 447.37 98.75 52 [00115] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-7- yl)-3-(4- fluorophenyl) urea (400 MHz; DMSO-d.sub.6): δ 3.66 (s, 2H), 5.20 (s, 2H), 7.08-7.13 (m, 4H), 7.19-7.23 (m, 3H), 7.29- 7.31 (m, 2H), 7.42-7.46 (m, 2H), 7.62 (s, 1H), 8.78-8.81 (m, 2H) 408.30 98.2 53 [00116] l-(4-(3- aminobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.59 (s, 2H), 5.03 (bs, 4H), 6.32-6.42 (m, 4H), 6.79-6.82 (m, 1H), 6.95 (t, J = 8.64 Hz, 1H), 7.20-7.28 (m, 4H), 7.31- 7.40 (m, 1H), 7.77 (s, 1H), 8.67 (s, 1H), 8.79 (s, 1H), 10.91 (s, 1H) 444.08 98.81 59 [00117] 3-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)-l-(1H- indol-6-yl)- 1-methylurea (500 MHz; DMSO-d.sub.6): δ 3.23 (s, 3H), 3-58 (s, 2H), 5.10 (s, 2H), 6.47 (s, 1H), 6.90 (d, J = 7.65 Hz, 1H), 7.18-7.19 (m, 1H), 7.21-7.23 (m, 4H), 7.25- 7.31 (m, 3H), 7.41-7.45 (m, 2H), 7.56 (d, J = 7.95 443.07 99.51 Hz, 1H), 7.86 (s, 1H), 11.19 (s, 1H) 60 [00118] 1-(1H-indol- 6-yl)-3-(4-(2- methylpyridin- 4-yl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 2.44 (s, 3H), 3.68 (s, 2H), 5.13 (s, 2H), 6.32 (s, 1H), 6.79-6.82 (dd, J1 = 1.88 Hz, J2 = 5.82 Hz, 1H), 7.03-7.05 (m, 1H), 7.13 (s, 1H), 7.180-7.185 (m, 1H), 7.20-7.22 (m, 2H), 7.23 (m, 1H), 7.33 444.09 97.15 (d, J = 8.44 Hz, 1H), 7.72-7.73 (m, 1H), 8.38- 8.39 (m, 1H), 8.58 (s, 1H), 8.70 (s, 1H), 10.91 (s, 1H) 87 [00119] 1-(1H-indol- 6-yl)-3-(4- methyl-3- oxo-3,4- dihydro-2H- benzo[b][1, (500 MHz; DMSO-d.sub.6): δ 3.49 (s, 5H), 6.34 (s, 1H), 6.89 (d, 1H, J = 6.75 Hz), 7.10 (s, 1H), 7.22 (s, 1H), 7.28 (d, 1H, J = 6.85 Hz), 7.40 (s, 1H), 7.58 (s, 1H), 353.26 96.08 4]thiazin-6- 7.82 (s, 1H), 8.89 (s, 1H), yl)urea 9.07 (s, 1H), 10.89 (s, 1H) 88 [00120] 1-(1H-indol- 6-yl)-3-(3- oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- (400 MHz; DMSO-d.sub.6): δ 4.54 (s, 2H), 6.32 (s, 1H), 6.85-6.78 (m, 2H), 6.95- 6.92 (m, 1 H), 6.24 (d, 2H, J = 11 Hz), 7.40 (d, 1H, J = 8.5 Hz), 7.78 (s, 323.04 97.67 yl)urea 1H), 8.6 (s, 1H), 8.65 (s, 1H), 10.56 (s, 1H), 10.91 (s, 1H). 89 [00121] 1-(4-(2- chloro-6- fluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.55 (s, 2H), 5-34 (s, 2H), 6.32 (s, 1H), 6.84 (dd, 1H, J = 8.44 Hz, 1.8 Hz), 7.22-7.13 (m, 4H), 7.34-7.25 (m, 2H), 7.40 (d, 1H, J = 8.3 Hz), 7.57 (d, 1H, J = 2.28 Hz), 7.75 (s, 1H), 8.67 (s, 1H), 8.73 (s, 1H), 10.92 (s, 1H). 481.02 98.52 90 [00122] 1-(4-benzyl- 2,2-dimethyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 1.51 (s, 6H), 5.12 (s, 2H), 6.33 (s, 1H), 6.84 (d, 1H, J = 8.52 Hz), 6.91 (s, 2H), 7.23-7.41 (m, 8H), 7.76 (s, 1H), 8.56 (s, 1H), 8.61 (s, 1H), 10.94 (s, 1H). 441.16 95.07 91 [00123] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(5- methyl-1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 2.27 (s, 3H), 4.79 (s, 2H), 5.13 (s, 2H), 6.27 (s, 1H), 6.89 (m, 2H), 7.20- 7.37 (m, 8H), 7.80 (s, 1 H), 7.85 (s, 1H), 8.99 (s, 1H), 10.94 (s, 1H). 427.13 99.1 92 [00124] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(2- methyl-1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 2.34 (s, 3H), 4.78 (s, 2H), 5.13 (s, 2H), 6.01 (s, 1H), 6.76 (m, 1H), 6.87- 6.93 (m, 2H), 7.23-7.36 (m, 7H), 7.66 (s, 1H), 8.59 (s, 1H), 8.60 (s, 1H), 10.74 (s, 1H). 427.15 96.55 93 [00125] l-(4-(2- chloro-6- fluorobenzy 1)-3-oxo- 3,4- dihydro- 2H- benzo[b][i, 4]oxazin-7- yl)-3-(1H- indol-6- (400 MHz; DMSO-d.sub.6): δ 4.67 (s, 2H), 5.28 (s, 2H), 6.32 (s, 1H), 6.84 (d, 1H, J = 8.4 Hz), 6.94 (s, 2H), 7.21-7.40 (m, 6H), 7.77 (s, 1H), 8.63 (s, 1H), 8.66 (s, 1 H), 10.92 (s, 1H). 465.05 99.16 yl)urea 94 [00126] 1-(4-(2- chloro-4- fluorobenzy 1)-3-oxo-3,4- dihydro-2H- benzo[b][1,4] oxazin-7-yl)- 3-(1H-indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.81 (s, 2H), 5.08 (s, 2H), 6.31 (d, 1H, J = 1.96 Hz), 6.72 (d, 1H, J = 8.8 Hz), 6.81-6.84 (dd, 1H, Jl = 1.72 Hz, J2 = 8.4 Hz), 6.90-6.93 (dd, 1H, J = 2.2 Hz, J2 =8.68 Hz), 6.14-6.17 (m, 2H), 7.20 465.04 99.37 (t, 1H, J = 2.64 Hz), 7.36 (d, 1H, J = 2.32 Hz), 7.39 (d, 1H, J = 8.48 Hz), 7.52-7.55 (dd, 1H, J1 = 2.32 Hz, J2 = 8.72 Hz), 7.77 (s, 1H), 8.58 (bs, 1H), 8.69 (bs, 1H), 10.90 (s, 1H). 95 [00127] 1-(4-(2,3- difluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.77 (s, 2H), 5.19 (s, 2H), 6.32 (s, 1H), 6.81-6.83 (dd, J1 = 1.72 Hz, J2 = 8.44 Hz, 1H), 6.89-6.95 (m, 2H), 6.98 (t, J = 7.2 Hz, 1H), 7.12-7.17 (m, 1H), 7.20 (t, J = 5 Hz, 1H), 7.31-7.40 (m, 3H), 7.76 (s, 1H), 8.540 (s, 1H), 8.63 (s, 1H), 10.90 (s, 1H). 449.1 98.57 96 [00128] 1-(4-(2,6- difluorobenzyl)- 3-oxo-3,4- dihydro-2H- benzo [b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.66 (s, 2H), 5.23 (s, 2H), 6.32 (s, 1H), 6.80- 6.82 (dd, J1 = 1.6 Hz, J2 = 8.36 Hz, 1H), 6.94- 6.97 (m, 2H), 7.01-7.09 (m, 2H), 7.20 (t, J = 3.88 Hz, 1H), 7.27 (d, J = 2.12 Hz, 1H), 7.35-7.40 (m, 2H), 7.75 (s, 1H), 8.50 (s, 1H), 8.54 (s, 1H), 10.90 (s, 1H). 449.1 99.65 99 [00129] l-(4-(3- chloro-5- (trifluoromethyl) benzyl)-3-oxo- 3,4-dihydro- 2H-benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.82 (s, 2H), 5.22 (s, 2H), 6.32 (s, 1H), 6.81 (d, 1H, J = 8.4 Hz), 6.92 (s, 2H), 7.20 (s, 1H), 7.32 (s, 1H), 7.39 (d, 1H, J = 8.52Hz), 6.66 (d, 2H, J = 3.96 Hz), 7.77 (d, 2H, J = 9.2 Hz), 8.51 (s, 1H), 8.58 (s, 1H), 10.90 (s, 1H). 515.12 99.69 116 [00130] l-(4-(3- cyanobenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.81 (s, 2H), 5.17 (s, 2H), 6.31 (s, 1H), 6.80-6.92 (m, 3H), 7.20 (d, J = 2.44 Hz, 1H), 7.32 (d, J = 1.88 Hz, 1H), 7.39 (d, J = 8.48 Hz, 1H), 7.50-7.58 (m, 1H), 7.61-7.63 (m, 1H), 7.63-7.77 (m, 3H), 438.23 100 8.52 (s, 1H), 8.60 (s, 1H), 10.90 (s, 1H). 124 [00131] l-(4-(2-chloro-6- fluoro-3- methoxybenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.53 (s, 2H), 3.79 (s, 3H), 5.33 (s, 2H), 6.31 (s, 1H), 6.86 (d, 1H, J = 8.44Hz), 7.01-7.05 (m, 1H), 7.08-7.14 (m, 2H), 7.16-4.20 (m, 2H), 7.38 (d, 1H, J = 8.4 Hz), 7.57 (d, 1H, J = 1.96 Hz), 7.74 (s, 1H), 8.90-8.95 (d, 511.17 98.13 2H, 19.72 Hz), 10.89 (s, 1H). 125 [00132] l-(4-(2-chloro-6- fluoro-3- hydroxybenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.32 (s, 1H), 3.53 (s, 2H), 5.30 (s, 2H), 6.32 (s, 1H), 6.82-6.85 (m, 2H), 6.94 (t, 1H, J = 9.36 Hz), 7.08 (d, 1H, J = 8.92 Hz), 7.15-7.21 (m, 2H), 7.39 (d, 1H, J = 8.44 Hz), 7.56 (d, 1H, J = 2.24 Hz), 7.75 (s, 1H), 8.72-8.75 (d, 2H, J = 12.64 Hz), 10.90 (s, 1H). 497.15 99.07 126 [00133] 1-(4-(2,6- difluoro-4- methoxybenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.51 (s, 2H), 3.71 (s, 3H), 5.22 (s, 2H), 6.30 (s, 1H), 6.63-6.67 (m, 2H), 6.90-6.92 (dd, 1H, J1 = 1.4 Hz, J2 = 8.48 Hz), 7.15-7.19 (m, 2H), 7.23- 7.26 (dd, 1H, J1 = 2.16 Hz, J2 = 8.36 Hz), 7.37 (d, 1H, J = 8.44 Hz), 495.14 96.12 7.59 (d, 1H, J = 2.24 Hz), 7.77 (s, 1H), 9.34 (bs, 1H), 9.54 (s, 1H), 10.87 (s, 1H). 127 [00134] 1-(4-(2,6- difluoro-4- hydroxybenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.51 (s, 2H), 5.18 (s, 2H), 6.32-6.3 (m, 3H), 6.81- 6.84 (dd, 1H, J1 = 1.72 Hz, J2 = 8.44 Hz), 7.14- 7.21 (m, 3H), 7.39 (d, 1H, J = 8.4 Hz), 7.55 (d, 1H, J = 2.24 Hz), 7.75 (s, 1H), 8.56 (d, 2H, J = 8.56 Hz), 10.31 (bs, 1H), 10.90 (s, 1H). 481.15 97.18 128 [00135] 1-(4-(4-(1H- 1,2,4- triazol-1- yl)benzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.80 (s, 2H), 5.19 (s, 2H), 6.31 (s, 1H), 6.81 (d, 1H, J = 4.28 Hz), 6.92 (m, 2H), 7.20 (s, 1H), 7.31 (s, 1H) 7.38 (d, 1H, J = 6.28 Hz), 7.47 (d, 2H, J = 8.12 Hz), 7.75 (s, 1H), 7.81 (d, 2H, J =8.28 Hz), 8.21 (s, 1H), 8.53 (s, 1H), 8.61 (s, 1H), 9.24 (s, 1H), 10.89 (s, 1H). 480.22 100 129 [00136] l-(4-(benzo[c][1, 2,5]oxadiazol-5- ylmethyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] oxazin-7-yl)-3- (1H-indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.810 (s, 2H), 5.22 (s, 2H), 6.31 (s, 1H), 6.81 (d, 1H, J = 8.4 Hz), 6.92 (s, 2H), 7.19 (d, 1H, J = 3 Hz), 7.29 (s, 1H), 7.38 (d, 1H, J = 8.4 Hz), 7.54 (d, 1H, J = 9.36 Hz), 7.69 (s, 1H), 7.81 (s, 1H), 8.04 455.14 99.44 (d, 1H, J = 9.36 Hz), 8.53 (s, 1H), 8.64 (s, 1H), 10.89 (s, 1H). 130 [00137] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(furan-2- ylmethyl)urea (400 MHz; DMSO-d.sub.6): δ 4.24 (d, J = 5.44 Hz, 2H), 4.74 (s, 2H), 5.10 (s, 2H), 6.22 (d, 1H, J = 2.84 Hz), 6.37-6.38 (m. 1H), 6.58 (t, 1H, J = 5.68 Hz), 6.81-6.83 (dd, 1H, J1 = 2.12 Hz, J2 = 8.76 Hz), 6.87 (d, 1H, J = 8.76 Hz), 7.22-7.26 (m, 4H), 378.15 99.29 7.30-7.34 (m, 2H), 7.56 (d, 1H, J = 1.0 Hz), 8.58 (s, 1H). 131 [00138] 1-(4-benzyl- 3-oxo-3,4- dihydro- 2H- benzo[b][1, 4]oxazin-7- yl)-3-(3-(4- chlorophen yl)-1H- pyrazol-4- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.75 (s, 2H), 5.11 (s, 2H), 6.85-6.91 (m, 2H), 7.22- 7.27 (m, 4H), 7.31-7.34 (m, 2H), 7.50 (bs, 2H), 7.68-7.70 (m, 2H), 7.89- 7.95 (m, 2H), 8.85 (s, 1H), 12.83 (s, 1H). 474.16 95.39 132 [00139] 1-((1H- pyrrol-3- yl)methyl)- 3-(4-benzyl-3- oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.06 (d, J = 5.04 Hz, 2H), 4.73 (s, 2H), 5.10 (s, 2H), 5.97 (d, 1H, J = 1.88 Hz), 619 (t, 1H, J = 5.16 Hz), 6.65 (bs, 2H), 6.77- 6.80 (dd, 1H, J1 = 2.12 Hz, J2 = 8.72 Hz), 6.86 (d, 1H, J= 8.8 Hz), 7.22- 7.26 (m, 4H), 7.30-7.34 (m, 2H), 8.45 (s, 1H), 10.57 (bs, 1H). 377.17 98.66 133 [00140] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(5,6,7,8- tetrahydro- naphthalen- 2-yl)urea (400 MHz; DMSO-d.sub.6): δ 1.70-1.706 (m, 4H), 2.62.65 (m, 4H), 4.76 (s, 2H), 5.12 (s, 2H), 6.86- 6-93 (m, 3H), 7.07-7.09 (dd, 1H, J1 = 2.04 Hz, J2 = 8.16 Hz), 7.13 (bs, 1H), 7.24-7.28 (m, 4H), 7.31-7.35 (m, 2H), 8.48 (s, 1H), 8.63 (s, 1H). 428.23 95.78 134 [00141] l-(4-((5- (tert-butyl)- 1,2,4-oxadiazol- 3-yl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][, 4]oxazin-7- yl)-3-(1H- (400 MHz; DMSO-d.sub.6): δ 1.35 (s, 9H), 4.70 (s, 2H), 5.22 (s, 2H), 6.33 (s, 1H), 6.84 (dd, 1H, J = 1.56 Hz, 8.4 Hz), 7.07-06.98 (m, 2H), 7.20 (t, 1H, J = 2.65 Hz), 7.30 (d, 1H, J = 2.12 Hz), 7.40 (d, 1H, J= 8.4 Hz), 7.75 (s, 1H), 461.5 98.99 indol-6- 8.51 (s, 1H), 8.61 (s, 1H), yl)urea 10.89 (s, 1H). 135 [00142] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1,2,3,4- tetrahydro- naphthalen- 2-yl)urea (400 MHz; DMSO-d.sub.6): δ 1.65-1.71 (m, 1H), 1.91- 1.95 (m, 1H), 2.57-2.63 (m, 1H), 2.80 (t, 2H, J = 6.4 Hz), 2.97-3.02 (dd, 1H, J1 = 4.96 Hz, J2 = 16.32 Hz), 3-89-3-93 (m, 1H), 4.73 (s, 2H), 5.10 (s, 2H), 6.22 (d, 1H, J = 7.6 428.24 98.75 Hz), 6.77-6.79 (dd, 1H, J1 = 2.2 Hz, J2 = 8.72 Hz), 6.86 (d, 1H, J = 8.8 Hz), 7.05-7.09 (m, 4H), 7.22-7.26 (m, 4H), 7.30- 7.34 (m, 2H), 8.37 (s, 1H). 136 [00143] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(2,3- dihydro-1H- inden-2- yl)urea (400 MHz; DMSO-d.sub.6): δ 2.71-2.76 (dd 2H, J1 = 5.24 Hz, J2 = 15.88 Hz), 3.13-3.18 (dd, 2H, J1 = 7.08 Hz, J2 = 15.84 Hz), 4.35-4.40 (m, 1H), 4.73 (s, 2H), 5.10 (s, 2H), 6.47 (d, 1H, J = 7.2 Hz), 6.77- 6.80 (dd, 1H, J1 = 2.12 414.19 97.29 Hz, J2 = 8.72 Hz), 6.86 (d, 1H, J = 8.8 Hz), 7.11- 7.16 (m, 2H), 7.22-7.28 (m, 6H), 7.30-7.34 (m, 2H), 8.35 (s, 1H). 137 [00144] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(4- phenyl- cyclohexyl)urea (400 MHz; DMSO-d.sub.6): δ 1.25-1.29 (m, 1H), 1.51- 1.55 (m, 1H), 1.62-1.72 (m, 4H), 1.78-1.81 (m, 1H), 1.93-1.96 (m, 1H), 3.46-3.48 (m, 1H), 3.49 (bs, 1H), 4.74(s, 2H), 5.10 (s, 2H), 6.20 (d, 1H, J = 7.88 Hz), 6.59 (d, 1H, 456.24 55.3 + 43-86 (Diastereo- meric mixture) J = 7.68 Hz), 6.79-6.82 (m, 1H), 6.85-6.88 (m, 1H), 7.14-7.19 (m, 1H), 7.22-7.34 (m, 9H), 8.47 (d, 1H, J = 6.84 Hz). 138 [00145] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1- phenyl-1H- pyrazol-3- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.78 (s, 2H), 5.13 (s, 2H), 6.57 (s, 1H, J = 2.48 Hz), 6.89-6.95 (m, 2H), 7.22- 7-35 (m, 7H), 7.46 (t, 2H, J = 7.76Hz), 7.74 (d, 2H, J = 7.88 Hz), 8.38 (d, 1H, J = 2.52 Hz), 8.91 (s, 1H), 9.24 (s, 1H). 440.22 97.07 139 [00146] 1-(4-(4- hydroxybenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.73 (s, 2H), 4.99 (s, 2H), 6.31 (s, 1H), 6.70 (d, 2H, J = 8.4 Hz), 6.82-6.84 (dd, 1H, J1 = 1.32 Hz, J2 = 8.4 Hz), 6.90-6.97 (m, 2H), 7.09 (d, 2H, J = 8.44 Hz), 7.20 (t, 1H, J = 2.48 Hz), 429.19 96.19 7.29 (d, 1H, J = 1.96 Hz), 7.40 (d, 1 H, J = 8.44 Hz), 7.76 (s, 1H), 8.67 (s, 1H), 8.75 (s, 1H), 9.25 (bs, 1H), 10.89 (s, 1H). 140 [00147] methyl 2- ((7-(3-(1H- indol-6- yl)ureido)- 3-oxo-2,3- dihydro-4H- benzo[b][1, 4]oxazin-4- yl)methyl) benzoate (400 MHz; DMSO-d.sub.6): δ 3.90 (s, 3H), 4.82 (s, 2H), 5.41 (s, 2H), 6.31 (s, 1H), 6.68 (d, 1H, J = 8.76 Hz), 6.81-6.87 (m, 2H), 7.12 (d, 1H, J = 7.84 Hz), 7.35-7.43 (m, 3H), 7.51 (t, 1H, J = 7.56H), 7.76 (s, 1H), 7.99 (d, 1H, J = 7.56 Hz), 8.57 (s, 1H), 8.57 (s, 1H), 8.67 (s, 1H), 10.89 (s, 1H). 469.23 [M − H] 99.12 141 [00148] N-(4-benzyl-3- oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3,4- dihydro- isoquinoline- 2(1H)- carboxamide (400 MHz; DMSO-d.sub.6): δ 2.82 (t, 2H, J = 8.36 Hz), 3.65 (t, 2H, J = 8.08 Hz), 4-59 (s, 2H), 4.74 (s, 2H), 5.11 (s, 2H), 6.89 (d, 1H, J = 8.8 Hz), 7.02- 7.04 (dd 1H, J1 = 2.16 Hz, J2 = 8.8 Hz) , 7.14- 7.17 (bs, 4H), 7.22-7.27 (m, 4H), 7.30-7.34 (m, 2H), 8.52 (s, 1H). 414.22 98.81 142 [00149] 1-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3- (indolin-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 2.80 (t, 2H, J = 8.36 Hz), 3.37 (t, 2H, J = 8.08 Hz), 4.76 (s, 2H), 5.11 (s, 2H), 5.45 (s, 1H), 6.46 (d, 1H, J = 7.64 Hz), 6.76 (s, 1H), 6.85-6.91 (m, 3H), 7.24-7.27 (m, 4H), 7.31-7.34 (m, 2H), 8.46 (s, 1H), 8.65 (s, 1H). 415.21 97.17 144 [00150] 2-((7-(3- (1H-indol-6- yl)ureido)- 3-oxo-2,3- dihydro-4H- benzo[b][1, 4]oxazin-4- yl)methyl) benzamide (400 MHz; DMSO-d.sub.6): δ 4.81 (s, 2H), 5.27 (s, 2H), 6.31 (s, 1H), 6.74 (d, 1H, J = 8.76 Hz), 6.80-6.87 (m, 2H), 7.04 (d, 1H, J = 7.24 Hz), 7.20 (t, 1H, J = 2.64 Hz), 7.32-7.40 (m, 4H), 7.53-7.5 (m, 1H), 7.58 (s, 1 H), 7.76 (s, 1H), 8.02 (s, 1H), 8.57 (s, 1H), 8.64 (s, 1H), 10.89 (s, 1H). 456.2 98.74 145 [00151] l-(4-((1,4- dioxan-2- yl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 3.28-3.33 (m, 1H), 3.46- 3.50 (m, 2H), 3.60-3.62 (m, 1H), 3-72-3.75 (m, 2H), 3.87-3.88 (m, 1H), 3-93-3-94 (m, 1H), 4.62 (s, 2H), 6.32 (s, 2H), 6.83-6.86 (dd, 1H, J1 = 1.28 Hz, J2 = 8.36 Hz), 7.02-7.04 (dd, 1H, J1 = 12.08 Hz, J2 = 8.72 Hz), 423.18 99.31 7.18-721 (m, 2H), 7.29 (d, 1H, J = 2.16 Hz), 7.39 (d, 1H, J = 8.4 Hz ), 7.78 (s, 1H), 8.66 (s, 1H), 8.76 (s, 1H), 10.90 (s, 1H). 146 [00152] 1-(1H-indol- 6-yl)-3-(3- oxo-4- ((tetrahydro- furan-2- yl)methyl)- 3,4-dihydro- 2H-benzo[b][1, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 1.57-1.61 (m, 1H), 1.78- 1.88 (m, 1H), 1.89-1.94 (m, 2H), 3.59-3.63 (m, 1H), 3.72-3.77 (m, 1H), 3.93 (d, 2H, J = 5.92 Hz), 4.05-4.08 (m, 1H), 4.61 (s, 2H), 6.32 (s, 1H), 6.83-6.85 (dd, 1H, J1 = 1.32 Hz, J2 = 8.44 Hz), 407.23 97.98 7.00-7.03 (dd, 1H, J1 = 2.16 Hz, J2 = 8.76 Hz ), 7.20 (s, 1H), 7.22 (d, 1H, J = 8.96 Hz), 7.28 (d, 1H, J = 2.16 Hz), 7.40 (d, 1H, J = 8.4 Hz), 7.78 (s, 1H), 8.62 (s, 1H), 8.70 (s, 1H), 10.90 (s, 1H) 147 [00153] 1-(iH-indol- 6-yl)-3-(3- oxo-4- (pyridin-4- ylmethyl)- 3,4-dihydro- 2H-benzo[b][1, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.81 (s, 2H), 5.15 (s, 2H), 6.31 (s, 1H), 6.80- 6.90 (m, 3H), 7.20-7.40 (m, 5H), 8.49-8.52 (t, 3H, J = 5 Hz), 8.58 (s, 1H), 10.90 (s, 1H). 414.35 99.2 148 [00154] 1-(1H-indol- 6-yl)-3-(3- oxo-4- (pyridin-3- ylmethyl)-3,4- dihydro-2H- benzo [b][1, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.78 (s, 2H), 5.17 (s, 2H), 6.32 (s, 1H), 6.80- 6.83 (m, 1H), 6.90-6.98 (m, 2H), 7.20 (t, 1H, J = 2.72 Hz), 7.30-7.40 (m, 3H), 7.67 (d, 1H, J = 7.92 Hz), 7.76 (s, 1H), 8.46- 8.50 (m, 2H), 8.56-8.58 (m, 2H), 10.90 (s, 1H). 414.35 98.54 149 [00155] 1-(iH-indol- 6-yl)-3-(3- oxo-4- (pyridin-2- ylmethyl)-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.76 (s, 2H), 5.17 (s, 2H), 6.32 (s, 1H), 6.80 (d, 1H, J = 7.08 Hz)), 6.88 (s, 2H), 7.20 (s, 1H), 7.27-7.40 (m, 4H), 7.76 (t, 2H, J = 7.12 Hz), 8.48-8.55 (m, 3H), 10.90 (s, 1H). 414.38 99.86 150 [00156] 1-(1H-indol- 6-yl)-3-(3- oxo-4- ((tetrahydro furan-3- yl)methyl)-3,4- dihydro-2H- benzo [b][1, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 1.55-1-65 (m, 1H), 1.82- 1.95 (m, 2H), 2.55-2.65 (m, 1H), 3.44-3.47 (m, 1H), 3.60-3.63 (m, 2H), 3.77-3.79 (m, 1H), 3.89- 3.94 (m, 2H), 4.62 (s, 2H), 6.32 (s, 1H), 6.82- 6.85 (dd, 1H, J1 = 1.52 Hz, J2 = 8.4 Hz), 7.03- 407.2 98.58 7.06 (dd, 1H, J1 = 2.2 Hz, J2 = 8.72 Hz), 7.17 (s, 1H), 7.19-7.22 (m, 2H), 7.28 (d, 1H, J = 2.24 Hz), 7.40 (d, 1 H, J = 8.4 Hz), 7.77 (s, 1H), 8.51 (s, 1H), 8.62 (s, 1H), 10.90 (s, 1H). 151 [00157] 1-(4-((1,3,4′- oxadiazol-2- yl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- (400 MHz; DMSO-d.sub.6): δ 4.72 (s, 2H), 5.42 (s, 2H), 6.31 (s, 1H), 6.87 (d, 1H, J = 8.44 Hz), 7.05 (d, 1H, J = 2Hz), 7.13 (d, 1H, J = 8.8 Hz), 7.20 (t, 1H, J = 2.48 Hz), 7.34 (d, 1H, J = 2.16 Hz), 7.38 (d, 1H, J = 8.44 405.18 99.04 yl)urea Hz), 7.78 (s, 1H), 8.80 (s, 1H), 9.1 (s, 1H), 9.22 (s, 1H), 10.89 (s, 1H). 152 [00158] 1-(4-(3- hydroxybenzyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.75 (s, 2H), 5.04 (s, 2H), 6.32 (s, 1H), 6.62 (s, 1H), 6.64 (s, 1H), 6.69 (d, 1H, J = 7.64 Hz), 6.82 (d, 1H, J = 7.12 Hz), 6.90 (s, 2H), 7.11 (t, 1H, J = 7.64 Hz), 7.20 (s, 1H), 7.31 (s, 1H), 7.38 (d, 427.0 98.75 1H, J = 8.4 Hz), 7.76 (s, 1H), 8.50 (s, 1H), 8.57 (s, 1H), 9.38 (s, 1H), 10.89 (s, 1H) 153 [00159] 1-(4-(4- (hydroxymethyl) benzyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMS0-d.sub.6): δ 4.44 (s, 2H), 4.76 (s, 2H), 5.12 (d, 3H, J = 7.6 Hz), 6.32 (s, 1H), 6.82 (d, 1H, J = 8.4 Hz), 6.87- 6.93 (m, 2H), 7.20-7.40 (m, 7H), 7.75 (s, 1H), 8.50 (s, 1H), 8.56 (s, 1H), 10.90 (s, 1H) 443.1 98.72 154 [00160] 1-(1H-indol- 6-yl)-3-(3- oxo-4- (pyrazin-2- ylmethyl)-3,4- dihydro-2H- benzo[b][i, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.76 (s, 2H), 5.27 (s, 2H, J = 7.6 Hz), 6.32 (s, 1H), 6.82 (d, 1H, J = 8.4 Hz), 6.91-6.98 (m, 2H), 7.20 (s, 1H), 7.31 (s, 1H), 7.39 (d, 1H, J = 8.4 Hz), 8.56- 8.68 (m, 5H), 10.90 (s, 1H) 415.0 94.46 155 [00161] 3-((7-(3- (1H-indol-6- yl)ureido)- 3-oxo-2,3- dihydro-4H- benzo[b][1, 4]oxazin-4- yl)methyl) benzamide (400 MHz; DMSO-d.sub.6): δ 4.79 (s, 2H), 5.16 (s, 2H, J = 7.6 Hz), 6.32 (s, 1H), 6.82 (d, 1H, J = 8.4 Hz), 6.89 (s, 2H), 7.20-7.41 (m, 6H), 7.76-7.97 (m, 4H), 8.51 (s, 1H), 8.58 (s, 1H), 10.90 (s, 1H) 415.0 99.39 156 [00162] 1-(4-(3- (hydroxymethyl) benzyl)-3-oxo- 3,4-dihydro- 2H-benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.46 (d, 2H, J = 5.7 Hz), 4-77 (s, 2H), 5.11-5.17 (m, 3H), 6.32 (s, 1H), 6.82 (d, 1H, J = 8.4 Hz), 6.90 (s, 2H), 7.15-7.40 (m, 6H), 7.75 (s, 1H), 8.50 (s, 1H), 8.56 (s, 1H), 10.90 (s, 1H) 443.4 99.27 157 [00163] 1-(4- (cyanomethyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMS0-d.sub.6): δ 4.74 (s, 2H), 5.07 (s, 2H), 6.30 (s, 1H), 6.87 (d, 1H, J = 8.36 Hz), 7.13 (d, 1H, J = 8.68 Hz), 7.19 (d, 2H, J = 8.28 Hz), 7.35 (s, 1H), 7.40 (d, 1H, J = 8.32 Hz), 7.78 (s, 1H), 8.74 (s, 1H), 8.89 (s, 362.14 96.91 1H), 10.88 (s, 1H). 158 [00164] 1-(1H-indol- 6-yl)-3-(3- oxo-4-((2- oxo-1,2- dihydropyridin- 3-yl)methyl)- 3,4-dihydro- 2H-benzo[b][1, 4]oxazin-7- yl)urea (400 MHz; DMS0-d.sub.6): δ 4.76 (s, 2H), 4.80 (s, 2H), 6.13 (t, 1H, J = 6.64 Hz), 6.32 (s, 1H), 6.78- 6.92 (m, 3H), 7.09-7.40 (m, 5H), 7.77 (s, 1H), 8.51 (s, 1H), 8.60 (s, 1H), 10.89 (s, 1H), 11.78 (s, 1H) 430.39 99.76 159 [00165] 1-(4-(2- hydroxybenzyl)- 3-oxo-3,4- dihydro-2H- benzo [b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.77 (s, 2H), 4.99 (s, 2H), 6.32 (s, 1H), 6.69- 6.87 (m, 6H), 7.05-7.40 (m, 4H), 7.76 (s, 1H), 8.51 (s, 1H), 8.58 (s, 1H), 9.82 (s, 1H), 10.90 (s, 1H) 429.3 98.17 160 [00166] 1-(1H-indol- 6-yl)-3-(3- oxo-4- (pyrimidin-4- ylmethyl)-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.78 (s, 2H), 5.19 (s, 2H), 6.32 (s, 1H), 6.80-6.91 (m, 3H), 7.20-7.46 (m, 4H), 7.76 (s, 1H), 8.50 (s, 1H), 8.58 (s, 1H), 8.75 (d, 1H, J = 5.16 Hz), 9.13 (s, 1H) 415.2 98.71 161 [00167] 1-(4-((1H- pyrazol-5- yl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.68 (s, 2H), 5.03 (s, 2H), 6.10 (s, 1H), 6.32 (s, 1H) 6.80-6.94 (m, 2H), 7.13-7.40 (m, 4H), 7.64 (s, 1H), 7.77 (s, 1H), 8.51 (s, 1H), 8.57 (s, 1H), 10.90 (s, 1H), 12.67 (s, 1H) 403.2 99.42 162 [00168] 1-(4-((1H- imidazol-5- yl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.65 (s, 2H), 4.93 (s, 2H), 6.32 (s, 1H) 6.80- 6.97 (m, 3H), 7.20-7.40 (m, 4H), 7.55 (s, 1H), 7.77 (s, 1H), 8.49 (s, 1H), 8.55 (s, 1H), 10.90 (s, 1H), 11.94 (s, 1H) 403.39 99.62 164 [00169] 1-(1H-indol- 6-yl)-3-(4- (isoxazol-3- ylmethyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.73 (s, 2H), 5.19 (s, 2H), 6.32 (s, 1H), 6.48 (d, 1H, J = 1.48 Hz), 6.82 (dd, 1H, J1 = 1.68 Hz, J2 = 8.4 Hz), 6.94-7.02 (m, 2H), 7.21 (t, 1H, J = 2.68 Hz), 7.32 (d, 1H, 2.16 Hz), 7.38 (d, 1H, J = 8.44 Hz), 7.77 (s, 1H), 404.2 99.92 8.50 (s, 1H), 8.59 (s, 1H), 8.88 (s, 1H), 10.90 (s, 1H) 165 [00170] 7-(3-(H- indol-6- yl)ureido)- 4-benzyl-3- oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazine-6- carboxamide (400 MHz; DMSO-d.sub.6): δ 4.84 (s, 2H), 5.24 (s, 2 H), 6.31 (s, 1H), 6.96 (d, 1H, J = 9.6 Hz), 7.20- 7.49 (m, 9H), 7.75 (s, 1H), 8.00 (s, 1H), 8.09 (s, 1H), 9.50 (s, 1H), 10.70 (s, 1H), 10.90 (s, 1H) 456.31 99.45 166 [00171] 1-(4-benzyl- 6-bromo-3- oxo-3,4- dihydro-2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO-d.sub.6): δ 4.82 (s, 2H), 5.16 (s, 2 H), 6.33 (s, 1H), 6.82- 6.85 (m, 1H), 7.21-7.42 (m, 8H), 7.78 (s, 1H), 7.82 (s, 1H), 7.97 (s, 1H), 9.31 (s, 1H), 10.94 (s, 1H) 491.18 99.23 193 [00172] l-(4- fluorophenyl)- 3-(4- methyl-3- oxo-3,4- dihydro-2H- (500 MHz; DMSO-d.sub.6): δ 3.48 (s, 3 H), 7.08-7.14 (m, 4 H), 7.29 (d, J = 8.4 Hz, 1H), 7.46-7.48 (m, 4H), 8.74 (s, 1 H), 8.82 (s, 1 H) 332.24 90.49 benzo[b][1, 4]thiazin-6- yl)urea 194 [00173] 2-amino-N- (4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1, 4]thiazin-6- yl)-7,8- dihydropyrido [4,3-d] (400 MHz; DMSO-d.sub.6): δ 2.64 (t, J = 5.96 Hz , 2H), 3.60 (s, 2H), 3.67 (s, 2H), 4.40 (s, 2H), 5.13 (s, 2H), 6.44 (s, 2H), 7.20-7.30 (m, 6H), 7.45 (d, J = 2 Hz, 1H), 8.04 (s, 1H), 8.10 (s, 1H), 8.72 (s, 1H). 447.33 91.22 pyrimidine-6(5H)- carboxamide 195 [00174] 1-(1H-indol- 6-yl)-3-(3- oxo-3,4- dihydro-2H- benzo[b][1, (500 MHz; DMSO-d4): δ 3.42 (s, 2H), 6.33 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 808 Hz, 1H), 7.18-7.24 (m, 2H), 339.3 95.25 4]thiazin-6- 7.40 (d, J = 8.16 Hz, yl)urea 2H), 7.79 (s, 1H), 8.64 (s, 1H), 8.82 (s, 1H), 10.53 (s, 1H), 10.93 (s, 1H)

Examples 97-98, 100-115, 117-123, 143 and 163

[0384] Examples 97-98, 100-115, 117-123, 143 and 163 were prepared using Library General Procedure 28 and 29 using the appropriate aryl halide. Purification was as stated in the aforementioned methods.

TABLE-US-00002 LCMS Purity Ex Structure IUPAC Name [M + H] (%)  97 [00175] 1-(4-((2,3- dihydrobenzo[b][1,4] dioxin-2-yl)methyl)-3- oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 471.13 99.9  98 [00176] 3-((7-(3-(1H-indol-6- yl)ureido)-3-oxo-2,3- dihydro-4H- benzo[b][1,4]oxazin-4- yl)methyl)benzamide 456.12 97.07 100 [00177] 1-(4-(2-(2- chlorophenoxy)ethyl)- 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 477.26 99.2 101 [00178] 1-(4-([1,1′-biphenyl]-2- ylmethyl)-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 489.39 98.73 102 [00179] 1-(4-(3-chloro-5- fluorobenzyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 465.16 99.12 103 [00180] 1-(4-((6- chlorobenzo[d][1,3] dioxol-5-yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 491.15 96.12 104 [00181] 1-(1H-indol-6-yl)-3-(3- oxo-4-((6- (trifluoromethyl)pyridin- 3-yl)methyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-7- yl)urea 482.2  98.05 105 [00182] 1-(4-(3,5- difluorobenzyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 449.34 100 106 [00183] 1-(1H-indol-6-yl)-3-(3- oxo-4-(4- ((trifluoromethyl)thio) benzyl)-3,4-dihydro- 2H- benzo[b][1,4]oxazin-7- yl)urea 511.39 [M − H] 98.66 107 [00184] 1-(4-(3-chloro-4- (trifluoromethoxy)benzyl)- 3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 531.39 99.48 108 [00185] 1-(4-(4-fluoro-3- methylbenzyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 445.32 98.58 109 [00186] 1-(4-(4- (difluoromethoxy)benzyl)- 3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 479.34 100 110 [00187] 1-(4-(2- chlorophenethyl)-3- oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 461.3  100 111 [00188] 1-(4-(3-chloro-4- fluorobenzyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 465.3  98.1 112 [00189] 1-(4-(3-fluoro-5- (trifluoromethyl)benzyl)- 3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 499.3  98.19 113 [00190] 1-(1H-indol-6-yl)-3-(3- oxo-4-(2- (trifluoromethyl)benzyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)urea 481.36 96.78 114 [00191] 1-(4- (benzo[d][1,3]dioxol-5- ylmethyl)-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 457.13 99.08 115 [00192] 1-(4-(2,5- dimethoxybenzyl)-3- oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 473.4  91.72 117 [00193] 1-(4-(benzo[d]thiazol- 2-ylmethyl)-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 470.33 100 118 [00194] 6-((7-(3-(1H-indol-6- yl)ureido)-3-oxo-2,3- dihydro-4H- benzo[b][1,4]oxazin-4- yl)methyl)nicotinic acid 458.36 94.68 119 [00195] 1-(4- (benzo[c][1,2,5]thiadiazol- 5-ylmethyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 469.40 [M − H] 100 120 [00196] 1-(4-(4-cyano-2- fluorobenzyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 456.39 100 121 [00197] 1-(1H-indol-6-yl)-3-(3- oxo-4-((3-phenyl-1,2,4- oxadiazol-5-yl)methyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)urea 481.46 100 122 [00198] 1-(4-(4-chloro-2- (methylsulfonyl)benzyl)- 3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 525.42 100 123 [00199] 1-(4-(4-cyanobenzyl)- 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 436.41 [M − H] 100 143 [00200] 2-((7-(3-(1H-indol-6- yl)ureido)-3-oxo-2,3- dihydro-4H- benzo[b][1,4]oxazin-4- yl)methyl)benzoic acid 457.20 98.52 163 [00201] 1-(4-((1,2,4-oxadiazol- 5-yl)methyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)-3-(1H-indol-6- yl)urea 405.18 98.69

Example 38: (S)-1-(1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-3-(4-fluorophenyl)urea

[0385] ##STR00202##

[0386] Example 38 was prepared according to the methods described in General Procedures 1-4, 10-14 and the methods described below

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

[0387] ##STR00203##

[0388] (S)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate was prepared in five steps according to the methods described in patent WO2018/234808.

Preparation 8: (S)-Methyl 1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

[0389] ##STR00204##

[0390] To a stirred solution of (S)-methyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 7) (1.0 g, 4.26 mmol) in DMF (12 mL) was added NaH (187 mg, 4.69 mmol) followed by benzyl bromide (0.53 mL, 4.48 mmol) at 0-5° C. The combined mixture was stirred at RT for 30 min. TLC showed complete consumption of the starting cyclic urea. Then the reaction mixture was quenched with ice-water to give a precipitate which was filtered, washed with hexane and dried under high vacuum to afford the title compound (1.1 g, 80% yield) as a white solid. LCMS m/z: 325 [M+H].

Preparation 9: (S)-1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

[0391] ##STR00205##

[0392] To a stirred solution of (S)-methyl 1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 8) (0.5 g, 1.54 mmol) in THF (5 mL) and MeOH (2.5 mL) was added a solution of LiOH.H.sub.2O (258 mg, 6.16 mmol) in water (2.5 mL) and the combined mixture stirred at room temperature for 2 h. TLC showed completion of the reaction. The solvents were evaporated and the residue was diluted with water, washed with MTBE and the aqueous layer acidified with 1N HCl to pH 4-5. The aqueous part was extracted with EtOAc, washed with brine, dried over anhydrous MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (450 mg, crude) as a white solid. LCMS m/z: 311 [M+H].

Preparation 10: (S)-1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonyl azide

[0393] ##STR00206##

[0394] To a stirred solution of (S)-1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 9) (200 mg, 0.65 mmol) in dry solvents DMF (50 uL) and DCM (10 mL) was added oxalyl chloride (164 mg, 1.29 mmol) at 0-5° C. The whole was stirred at RT for 1 h. Progress of the reaction was monitored by TLC and LCMS and after completion, the reaction mass was poured into an aqueous solution of NaN.sub.3 (209 mg, 3.22 mmol in 10 mL water) under stirring. After the formation of the acid azide was complete (confirmed by LCMS), the product was extracted with DCM, washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the title compound (210 mg, crude) as a white solid. LCMS m/z: 336.35 [M+H].

Preparation 11: (S)-1-(1-Benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(4-fluorophenylurea (Example 38)

[0395] ##STR00207##

[0396] To a stirred solution of (S)-1-benzyl-3,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbonyl azide (Preparation 10) (192 mg, 0.57 mmol) in DMF (6 mL) was added 4-fluoro aniline (254 mg, 2.29 mmol) at RT. The whole was stirred at 83° C. overnight. Progress of the reaction was monitored by TLS/LCMS and after completion, the reaction mixture was diluted with EtOAc and washed with cold water. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the title compound (196 mg, 82% yield) as an off white solid. Purity by UPLC: 99.05%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 1.27 (d, J=6.35 Hz, 3H), 2.98 (s, 3H), 4.52 (q, J=6.4 Hz, 1H), 4.96-5.10 (m, 2H), 6.87 (s, 1H), 7.04-7.12 (m, 4H), 7.21-7.23 (m, 3H), 7.31-7.34 (m, 2H), 7.39-7.42 (m, 2H), 8.55 (s, 1H), 8.61 (s, 1H); LCMS m/z: 419.12 [M+H].

Example 39: 1-(1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(4-fluorophenyl)urea

[0397] ##STR00208##

[0398] Example 39 was prepared according to the methods described in General Procedures 1b-4, 15, 16 and the methods described below.

Preparation 12: Methyl -methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

[0399] ##STR00209##

Step 1: Methyl -amino-4-formylbenzoate

[0400] ##STR00210##

[0401] To a stirred solution of commercially available methyl 4-formyl-3-nitrobenzoate (2.0 g, 9.56 mmol) in EtOH (20 mL) was added iron powder (2.14 g, 38.24 mmol) followed by 0.12 N HCl. The reaction mixture was refluxed for 30 min. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was quenched with a saturated NaHCO.sub.3 solution and extracted with DCM followed by a brine wash. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the title compound (2.0 g, crude) as a yellow solid which was used in the next step without any further purification. LCMS m/z: 180.01 [M+H].

Step 2: Methyl 3-((ethoxycarbonyl)amino)-4-formylbenzoate

[0402] ##STR00211##

[0403] To a stirred solution of methyl 3-amino-4-formylbenzoate (Preparation 12, step 1) (2.0 g, 11.16 mmol) in DCE (20 mL) was added pyridine (1.98 mL, 24.56) and ethyl chloroformate (1.27 mL, 13.39 mmol) at 0-5° C. The whole was stirred at 0-5° C. for 1 h. Completion of the reaction was confirmed by TLC and LC-MS. The reaction mixture was quenched by a 1N HCl solution and extracted with DCM followed by a brine wash. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the title compound (2.0 g, crude) as a yellow solid which was used in the next step without any further purification. LCMS m/z: 252.03 [M+H].

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

[0404] ##STR00212##

[0405] To a stirred solution of methylamine hydrochloride (0.27 g, 3.98 mmol) in MeOH (20 mL) was added TEA (0.67 mL, 4.78 mmol) under an inert atmosphere at RT and the resulting clear solution then stirred for 30 min. Methyl 3-((ethoxycarbonyl)amino)-4-formylbenzoate (Preparation 12, step 2) (1.0 g, 3.987 mmol) was added portionwise and the combined mixture stirred at room temperature for 24 h. During this period, the reaction mixture became a suspension. NaBH.sub.4 (227 mg, 5.97 mmol) was added and the mixture was further stirred for another 24 h. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was diluted with water and extracted with EtOAc followed by a brine wash. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the title compound (750 mg, crude) as a yellow solid which was used in the next step without any further purification. LCMS m/z: 221.04 [M+H].

Preparation 13: Methyl 1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

[0406] ##STR00213##

[0407] To a stirred solution of methyl 3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 12, step 3) (300 mg, 1.36 mmol) in DMF (3 mL) was added NaH (65 mg, 1.63 mmol) and benzyl bromide (183 μL, 1.50 mmol) at 10° C. under a nitrogen atmosphere. The whole was stirred at room temperature for 1 h. TLC showed complete consumption of the cyclic urea intermediate and the reaction mixture was then quenched over ice-water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the title compound (390 mg, crude) as a faint brown solid which was used in the next step without any further purification. LCMS m/z: 311.28 [M+H].

Preparation 14: 1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid

[0408] ##STR00214##

[0409] To a stirred solution of methyl 1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (Preparation 13) (390 mg, 1.26 mmol) in THF (10 mL) and MeOH (5 mL) was added a solution of LiOH (264 mg, 6.28 mmol) in water (1.5 mL) and the combined mixture stirred at room temperature for 3 h. TLC showed completion of the reaction. The solvents were evaporated in vacuo to give a residue which was diluted with water, washed with MTBE and the aqueous layer was acidified with 6N HCl resulting in a precipitate. The precipitate was filtered off and dried in vacuo to afford the title compound (330 mg, crude) as an off white solid which was used in the next step without any further purification. LCMS m/z: 297.46 [M+H].

Preparation 15: tert-Butyl (1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)carbamate

[0410] ##STR00215##

[0411] To a stirred solution of 1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (Preparation 14) (0.33 g, 1.11 mmol) in DCM (10 mL) was added TEA (0.241 mL, 1.67 mmol) followed by DPPA (0.483 mL, 2.23 mmol) at 0-5° C. The whole was stirred at room temperature for 3 h. Progress of the reaction was monitored by UPLC-MS and after completion the solvent was evaporated to afford the desired carbamate as a faint brownish solid (350 mg) which was then dissolved in tert-butanol (10 mL) and refluxed for 24 h. UPLC-MS showed completion of the reaction. The solvent was evaporated under reduced pressure and the residue was purified by Combi-flash to afford the title compound (225 mg, yield 55%) as an off white solid. LCMS m/z: 368.6 [M+H].

Preparation 16: 7-Amino-1-benzyl-3-methyl-3,4-dihydroquinazolin-2(1H)-one

[0412] ##STR00216##

[0413] To a stirred solution of tert-butyl (1-benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)carbamate (Preparation 15) (225 mg, 0.61 mmol) in THF (5 mL) was added 4M HCl in dioxane (5 mL) dropwise at 0-5° C. under an inert atmosphere. The whole was stirred at room temperature for 24 h. TLC showed formation of the desired compound. The solvent was evaporated in vacuo and the resulting residue was dissolved in water and neutralized with NaHCO.sub.3 solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and then evaporated in vacuo to afford the title compound (190 mg, crude) as a brownish oil which was used in the next step without any further purification. LCMS m/z: 268.4 [M+H].

Preparation 17: 1-(1-Benzyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(4-fluorophenyl)urea (Example 39)

[0414] ##STR00217##

[0415] To a stirred solution of 7-amino-1-benzyl-3-methyl-3,4-dihydroquinazolin-2(1H)-one (Preparation 16) (85 mg, 0.317 mmol) in DCM (10 mL) was added 4-fluorophenyl isocyanate (44 μL, 0.308 mmol) and TEA (55 μL, 0.308 mmol) at 0-5° C. The whole was stirred at RT for 1 h. TLC showed complete consumption of the starting material. The solvent was evaporated in vacuo to afford the crude product which was purified by prep-HPLC to give the title compound (14 mg, yield 11%) as a faint yellow solid. Purity by UPLC: 96.6%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 2.96 (s, 3H), 4.41 (s, 2H), 5.03 (bs, 2H), 6.86 (d, J=1.2 H, 1H), 7.05 (d, J=8.2 Hz, 1H), 7.11 (t, J=8.8 Hz, 3H), 7.21-7.25 (m, 3H), 7.31-7.34 (m, 2H), 7.39-7.42 (m, 2H), 8.68 (s, 1H), 8.73 (s, 1H); LCMS m/z: 405.36 [M+H].

Example 40

[0416] Example 40 was prepared according to the above methods used to make Example 39 as described in General Procedures 1b-4, 15, 16 using the appropriate amines or isocyanate. Purification was as stated in the aforementioned methods.

TABLE-US-00003 IUPAC LCMS Purity Ex Structure Name 1H-NMR [M + H] (%) 40 [00218] 1-(1- benzyl-3- methyl-2- oxo- 1,2,3.4- tetrahydro quinazolin- 7-yl)-3- (1H-indol- 6-yl)urea (500 MHz; DMSO-d.sub.6): δ 2.99 (s, 3H), 4-42 (s, 2H), 5.04 (s, 2H), 6.32 (s, 1H), 6.79 (d, J = 1.55 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H), 6.92 (m, 1H), 7.05 (m, 1H), 7.10-7.12 (m 4H), 7.21-7.26 (m, 2H), 7.33 (d, J = 7.5 Hz, 1H), 7.60 (s, 1H), 8.61- 8.65 (m, 2H), 10.92 (s, 1H) 426.42 95.4

Example 41: 4-(2-Chloro-6-fluorobenzyl)-6-(4-fluorophenethoxy)-2H-benzo[b][1,4]thiazin-3(4H)-one

[0417] ##STR00219##

[0418] Example 41 was prepared according to the methods described in General Procedures 4-6 and the methods described below.

Preparation 18: 6-Methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one

[0419] ##STR00220##

[0420] The title compound 6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one was prepared in two steps following an identical procedure to that described in Preparation 1, Steps 1-2.

Preparation 19: 4-(2-Chloro-6-fluorobenzyl)-6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one

[0421] ##STR00221##

[0422] To a stirred solution of 6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 18) (1.0 g, 5.102 mmol) in dry DMF (10 mL) was added K.sub.2CO.sub.3 (1.408 g, 10.204 mmol) followed by 2-chloro-6-fluorobenzyl bromide (1.053 mL, 7.653 mmol) at room temperature. The whole was then stirred at 90-120° C. for 12 h. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (0.6 g, yield 34.81%) as an off white solid. LCMS m/z: 338 [M+H].

Preparation 20: 4-(2-Chloro-6-fluorobenzyl)-6-hydroxy-2H-benzo[b][1,4]thiazin-3(4H)-one

[0423] ##STR00222##

[0424] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-6-methoxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 19) (400 mg, 1.187 mmol) in dry DCM (5 mL) was added BBr.sub.3 (0.5 mL, 1M solution in DCM) dropwise at 0-5° C. The whole was then stirred at room temperature for 4 h. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was evaporated to dryness, then diluted with EtOAc, washed with NaHCO.sub.3 solution followed by water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (200 mg, yield 52%) as an off white solid. LCMS m/z: 324 [M+H].

Preparation 21: 4-(2-Chloro-6-fluorobenzyl)-6-(4-fluorophenethoxy)-2H-benzo[b][1,4]thiazin-2(4H)-one (Example 41)

[0425] ##STR00223##

[0426] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-6-hydroxy-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 20) (110 mg, 0.341 mmol) in dry acetone (3 mL) was added K.sub.2CO.sub.3 (94 mg, 0.681 mmol) followed by KI (2.002 mg, 0.014 mmol) at room temperature. After 5 min. 1-(2-bromoethyl)-4-fluorobenzene (103.7 mg, 0.511 mmol) was added and the combined mixture was stirred at reflux for 16 h. Progress of the reaction was monitored by TLC and LC-MS which confirmed the desired product formation. The reaction mixture was evaporated to dryness, then diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by prep-TLC to afford the title compound (25 mg, yield 16.46%) as an off white solid. Purity by HPLC: 96.99%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.97 (s, 2H), 3.48 (s, 2H), 4.11 (d, J=6.36 Hz, 2H), 5.35 (s, 2H), 6.57 (d, J=8.76 Hz, 1H), 6.79 (s, 1H), 7.10-7.15 (m, 3H), 7.22-7.25 (m, 2H), 7.28-7.32 (m, 3H); LCMS m/z: 446.2 [M+H].

Example 42: 4-(2-Chloro-6-fluorobenzyl)-6-(((4-fluorobenzyl)oxy)methyl)-2H-benzo[b][1,4]thiazin-1(4H)-one

[0427] ##STR00224##

[0428] Example 42 was prepared according to the methods described in General Procedures 3-6 and the methods described below.

Preparation 22: 4-(2-Chloro-6-fluorobenzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid

[0429] ##STR00225##

[0430] The title compound 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid was prepared in four steps using an identical procedure to that described in Preparations 1-3.

Preparation 22: 4-(2-Chloro-6-fluorobenzyl)-6-(hydroxymethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one

[0431] ##STR00226##

[0432] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 22) (250 mg, 0.712 mmol) in dry THF (10 mL) was added TEA (0.985 mL, 0.712 mmol) at 0-5° C. and the resulting reaction mixture was treated with isobutylchloroformate (96.866 mg, 0.712 mmol). The whole was then stirred at 0-5° C. for a further 2 h. The reaction mixture was filtered and washed with THF. The filtrate was then stirred at 0-5° C. as firstly NaBH.sub.4 (53.889 mg, 1.425 mmol) and then water (3 mL) were added portionwise. The resulting suspension was warmed to room temperature and stirred for 2 h. Progress of the reaction was monitored by TLC and LC-MS which confirmed the desired product formation. The reaction mixture was neutralized with 1N HCl and diluted with water. The aqueous mixture was extracted with EtOAc, washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude compound which was purified by column chromatography to afford the title compound (200 mg, yield 83.13%) as an off white solid. LCMS m/z: 338 [M+H].

Preparation 24: 4-(2-Chloro-6-fluorobenzyl)-6-(((4-fluorobenzyloxy)methyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Example 42)

[0433] ##STR00227##

[0434] To a stirred suspension of 60% NaH (28.48 mg, 0.712 mmol) in THF (5 mL) was added a solution of 4-(2-chloro-6-fluorobenzyl)-6-(hydroxymethyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 23) (200 mg, 0.593 mmol) in THF (1.5 mL) at 0-5° C. The mixture was stirred at room temperature for 10 min. before a solution of 4-fluorobenzyl bromide (224.3 mg, 1.18 mmol) in THF (1 mL) was added to the reaction mixture and stirring continued at room temperature for 2 h. TLC and LCMS showed formation of the desired product, then the reaction mixture was quenched with water, extracted with EtOAc, washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (50 mg, yield 19%) as a white solid. Purity by HPLC: 98.89%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.55 (s, 2H), 4.40 (s, 4H), 5.37 (s, 2H), 6.95 (d, J=7.92 Hz, 1H), 7.05-7.10 (m, 1H), 7.16-7.27 (m, 5H), 7.33-7.35 (m, 3H); LCMS m/z: 446.0 [M+H].

Example 43: 4-(2-Chloro-6-fluorobenzyl)-6-(t-phenyl-1H-imidazol-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one

[0435] ##STR00228##

[0436] Example 43 was prepared according to the methods described in General Procedures 3-6 and the methods described below.

Preparation 25: 2-Oxo-2-phenylethyl 4-(2-chloro-6-fluorobenzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate

[0437] ##STR00229##

[0438] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 22) (300 mg, 0.822 mmol) in DMF (5 mL) was added DIPEA (429.93 mg, 2.466 mmol) followed by 2-bromo-1-phenylethanone (327.189 mg, 1.644 mmol) and the whole stirred overnight at room temperature. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was diluted with cold water and extracted with MTBE. The combined organics were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by trituration with pentane and diethyl ether to afford the title compound (250 mg, yield 64.73%) as an off white solid. LCMS m/z: 470 [M+H].

Preparation 26: 4-(2-Chloro-6-fluorobenzyl)-6-(5-phenyl-1H-imidazol-2-yl-2H-benzo[b][1,4]thiazin-(4H)-one (Example 43)

[0439] ##STR00230##

[0440] To a stirred solution of 2-oxo-2-phenylethyl 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 25) (70 mg, 0.149 mmol) in AcOH (3 mL) was added NH.sub.4OAc (287.3 mg, 3.73 mmol) at room temperature. After the addition was complete, the reaction mixture was heated at 120° C. for 48 h. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was concentrated in vacuo to dryness. The residue was diluted with water, neutralized with NaHCO.sub.3 solution then extracted with EtOAc, washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (10 mg, yield 14.89%) as a pale yellow solid. Purity by HPLC: 95.41%; .sup.1H NMR (400 MHz; DMSO-d.sub.6, at 100° C.): δ 3.55 (s, 2H), 5.45 (s, 2H), 7.07 (t, J=8.96 Hz, 1H), 7.19-7.30 (m, 3H), 7.36-7.39 (m, 2H), 7.45 (d, J=8.0 Hz, 1H), 7.53-7.71 (m, 2H), 7.86 (d, J=7.56 Hz, 2H), 7.95 (s, 1H), 12.33 (s, 1H); LCMS m/z: 450.2 [M+H].

Example 44: 4-(2-Chloro-6-fluorobenzyl)-6-(S-phenyl-1H-1,2,4-triazol-3-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one

[0441] ##STR00231##

[0442] Example 44 was prepared according to the methods described in General Procedures 3-6 and the methods described below.

Preparation 27: tert-Butyl 2-(4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl)hydrazinecarboxylate

[0443] ##STR00232##

[0444] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 22) (400 mg, 1.14 mmol) was added SOCl.sub.2 (10 mL) slowly at 0-5° C., then the combined reaction mixture was refluxed for 2 h. The mixture was evaporated under reduced pressure to give a crude residue which was diluted with THF. TEA was added dropwise, followed by tert-butyl hydrazinecarboxylate (300.85 mg, 2.279 mmol) at 0-5° C. The combined mixture was stirred at room temperature overnight. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was diluted with EtOAc, washed with water, NaHCO.sub.3 solution and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (400 mg, yield 75.33%, crude) as an off white solid. LCMS m/z: 466 [M+H].

Preparation 28: 4-(2-Chloro-6-fluorobenzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbohydrazide hydrochloride

[0445] ##STR00233##

[0446] To tert-butyl 2-(4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl)hydrazinecarboxylate (Preparation 27) (400 mg, 0.86 mmol) was added 4M HCl (10 mL, 4M solution in dioxane) slowly at 0-5° C. with stirring, and the mixture then allowed to warm slowly to room temperature over 4 h. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was concentrated in vacuo to dryness, then diethyl ether added to give a precipitate which was filtered off and dried under an inert atmosphere to afford the title compound (280 mg, yield 89.22%) as an off white solid. LCMS m/z: 366 [M+H].

Preparation 29: 4-(2-Chloro-6-fluorobenzyl)-6-(5-phenyl-1H-1,2,4-triazol-3-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Example 44)

[0447] ##STR00234##

[0448] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbohydrazide hydrochloride (Preparation 28) (100 mg, 0.215 mmol) and ethyl benzimidate hydrochloride (44.237 mg, 0.237 mmol) in MeCN (6 mL) was added TEA (15.639 mg, 0.155 mmol) dropwise at RT. The whole was stirred at 100° C. for 6 h. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was quenched with cold water, extracted with EtOAc, washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (15 mg, yield 15.47%) as a white solid. Purity by HPLC: 99.77%; .sup.1H NMR (400 MHz; DMSO-d.sub.6, at 100° C.): S 3.58 (s, 2H), 5.47 (s, 2H), 7.06 (t, J=8.24 Hz, 1H), 7.21-7.29 (m, 2H), 7.48-7.55 (m, 4H), 7.68 (d, J=8.12 Hz, 1H), 7.96 (s, 1H), 8.07 (d, J=7.32 Hz, 2H), 14.21 (s, 1H); LCMS m/z: 451 [M+H].

Example 41: 6-(5-Benzyl-4H-1,2,4-triazol-3-yl)-4-(2-chloro-6-fluorobenzyl)-2H-benzo[b][1,4]thiazin-1(4H)-one

[0449] ##STR00235##

[0450] Example 45 was prepared according to the methods described in General Procedures 4-6 and the methods described below.

Preparation 30: 4-(2-Chloro-6-fluorobenzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonitrile

[0451] ##STR00236##

[0452] The title compound 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonitrile was prepared in three steps following an identical procedure to that described in Preparations 18 and 19.

Preparation 31: 6-(5-Benzyl-4H-1,2,4-triazol-3-yl)-4-(2-chloro-6-fluorobenzyl-2H-benzo[b][1,4]thiazin-(4H)-one (Example 45)

[0453] ##STR00237##

[0454] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonitrile (Preparation 30) (50 mg, 0.151 mmol) in n-BuOH (2 mL) was added K.sub.2CO.sub.3 (41.566 mg, 0.301 mmol) followed by 2-phenylacetohydrazide (22.617 mg, 0.151 mmol). The whole was heated at 150° C. for 15 h. Progress of the reaction was monitored by TLC and LC-MS and after completion the reaction mixture was quenched with cold water, extracted with EtOAc, washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (20 mg, yield 29%) as an off white solid. Purity by HPLC: 90.01%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.58 (s, 2H), 4.08 (s, 2H), 5.40 (s, 2H), 7.05-7.07 (m, 1H), 7.21-7.28 (m, 4H), 7.32-7.37 (m, 3H), 7.41-7.45 (m, 1H), 7.55-7.57 (m, 1H), 7.86 (s, 1H), 13.95 (s, 1H); LCMS m/z: 465.2 [M+H].

Example 46: 4-(2-Chloro-6-fluorobenzyl)-6-(4-phenyloxazol-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one

[0455] ##STR00238##

[0456] Example 46 was prepared according to the methods described in General Procedures 3-6 and the methods described below.

Preparation 32: 2-Oxo-2-phenylethyl 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate

[0457] ##STR00239##

[0458] To a stirred solution of 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 22) (100 mg, 0.285 mmol) in EtOH (2 mL) was added TEA (0.079 mL, 0.57 mmol) followed by 2-bromo-1-phenylethanone (68 mg, 0.342 mmol) at RT under an inert atmosphere. The resulting reaction mixture was stirred at 60° C. for 2 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography to afford the title compound (85 mg, 63% yield) as a light yellow white solid. LCMS m/z: 470 [M+H].

Preparation 3: 4-(2-Chloro-6-fluorobenzyl)-6-(4-phenyloxazol-2-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (Example 46)

[0459] ##STR00240##

[0460] To a stirred solution of 2-oxo-2-phenylethyl 4-(2-chloro-6-fluorobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 32) (100 mg, 0.213 mmol) in xylene (2 mL) was added BF.sub.3.Et.sub.2O (0.02 mL) followed by AcNH.sub.2 (62.9 mg, 1.066 mmol) at RT. The resulting reaction mixture was heated at 150° C. for 15 h. Progress of the reaction was monitored by LCMS and after completion; the reaction mixture was cooled to RT and quenched with water. The resulting reaction mass was extracted with EtOAc, washed with water followed by brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography to afford the title compound (70 mg, 73% yield) as an off white solid. Purity by HPLC: 97.23%; .sup.1H NMR (400 MHz; CDCl.sub.3): δ. 3.50 (s, 2H), 5.56 (s, 2H), 6.85-6.91 (m, 1H), 7.08-7.10 (m, 2H), 7.32-7.36 (m, 1H), 7.39-7.45 (m, 3H), 7.67 (dd, J′=1.24 Hz, J″=7.96 Hz, 1H), 7.80 (d, J=7.44 Hz, 2H), 7.90 (d, J=1.12 Hz, 1H), 7.94 (s, 1H); LCMS m/z: 451.2 [M+H].

Example 47: N-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-(1H-indol-6-yl)acetamide

[0461] ##STR00241##

[0462] Example 47 was prepared according to the methods described in General Procedures 2-4, 6 and the methods described below.

Preparation 34: N-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-(1H-indol-6-yl)acetamide (Example 47)

[0463] ##STR00242##

[0464] To a stirred solution of 2-(1H-indol-6-yl)acetic acid (30 mg, 0.174 mmol) in THF (1.5 mL) was added HOBT.H.sub.2O (23 mg, 0.174 mmol), DIPEA (146 μl, 0.86 mmol) and EDCI.HCl (49 mg, 0.26 mmol) at 0-5° C. and the combined mixture allowed to stir for 15 min. Then, 6-amino-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one (Preparation 5) (55 mg, 0.204 mmol) was added to the reaction mixture and the whole stirred at RT overnight. Product formation was confirmed by TLC and UPLC. The reaction mixture was evaporated in vacuo to a low volume and then extracted with EtOAc, washed with 1N HCl solution to remove excess amine and further washed with a saturated solution of K.sub.2CO.sub.3 followed by brine. The organic layer was dried with anhydrous Na.sub.2SO.sub.4, filtered and evaporated in vacuo to give the crude product which was purified by prep-HPLC to produce a gummy material. This material was triturated with hexane and diethyl ether to afford the title compound (13 mg, 18% yield) as a white solid. Purity by HPLC: 99.1%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): S. 3.64 (s, 4H), 5.14 (s, 2H), 6.39 (s, 1H), 6.93 (d, J=6.85 Hz, 1H), 7.22-7.32 (m, 9H), 7.46 (d, J=7.05 Hz, 1H), 7.56 (s, 1H), 10.22 (s, 1H), 11.04 (s, 1H); LCMS m/z: 428.4 [M+H].

Examples 48 and 55

[0465] Examples 48 and 55 were prepared according to the above methods used to make Example 47 as described in General Procedures 2-4, 6 using the appropriate acid. Purification was as stated in the aforementioned methods.

TABLE-US-00004 IUPAC LCMS Purity Ex Structure Name 1H-NMR [M + H] (%) 48 [00243] N-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazin-6-yl)-2- (furan-2- yl)acetamide (500 MHz; DMSO-d.sub.6): δ 3-33-3.37 (m, 4H), 5.14 (s, 2H), 6.23 (s, 1H), 6.39 (s, 1H), 7.21- 7.36 (m, 7H), 7.49-7:57 (m, 2H), 10.23 (s, 1H) 379.2  97.64 55 [00244] N-(4-benzyl- 3-oxo-3,4- dihydro-2H- benzo[b][1,4] thiazin-6-yl)- 1H-indole-6- carboxamide (500 MHz; DMSO-d.sub.6): δ 3.67 (s, 2H), 5.20 (s, 2H), 6.53 (s, 1H), 7.26- 7.40 (m, 6H), 7-57-7.65 (m, 4H), 7.80 (s, 1H), 8.00 (s, 1H), 10.24 (s, 1H), 11.48 (s, 1H) 414.29 96.33

Example 49: 4-Benzol-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide

[0466] ##STR00245##

[0467] Example 49 was prepared according to General Procedure 17 and the methods described below.

Preparation 35: 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonyl chloride

[0468] ##STR00246##

[0469] Commercially available 2H-benzo[b][1,4]thiazin-3(4H)-one (1.0 g) was added portionwise to stirring chlorosulfonic acid (3 mL) at 0-5° C. The cooling bath was removed and the combined mixture was stirred at RT for 2 h. During this time the reaction mixture turned a deep blue. Progress of the reaction was monitored by UPLC and TLC. After completion of the reaction, it was poured into cold water and further stirred for 30 min. to give a precipitate which was filtered off and washed with water followed by hexane to afford the title compound (600 mg, 38% yield) as a white solid. LCMS m/z: 262 [M−H].

Preparation 36: N-(Furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide

[0470] ##STR00247##

[0471] To a stirred solution of furan-2-ylmethanamine (80 mg, 0.823 mmol) in DCM (6 mL) was added TEA (0.287 mL) at 0-5° C. Thereafter 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonyl chloride (Preparation 35) (216.64 mg, 0.823 mmol) was added into the reaction mixture and the whole stirred for 30 min. at RT. Progress of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was poured into ice-cold water and extracted with DCM. The organic extracts were then washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under high vacuum to afford the title compound (220 mg, 84% yield) as a white solid. LCMS m/z: 325 [M+H].

Preparation 37: N-(Furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide

[0472] ##STR00248##

[0473] To a stirred solution of N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide (Preparation 36) (300 mg, 0.925 mmol) in THF (4 mL) was added borane-THF solution (318 mg, 3.7 mL, 3.703 mmol, 1M solution in THF) dropwise at 0-5° C. under an inert atmosphere. The resulting reaction mixture was stirred at RT for 12 h. After completion of the reaction (monitored by TLC or LCMS), the reaction mixture was quenched by dropwise addition of MeOH (5 mL) at 0-5° C. The solvent was evaporated under reduced pressure to give a residue which was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness in vacuo to afford the title compound (120 mg, 42% yield) as a yellow sticky solid which was used in the next step without any further purification.

Preparation 38: 4-benzoyl-N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide (Example 49)

[0474] ##STR00249##

[0475] To a stirred solution of N-(furan-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-sulfonamide (Preparation 37) (60 mg, 0.193 mmol) in dry DCM (3 mL) was added TEA (58 mg, 0.581 mmol) at 0-5° C. The resulting reaction mixture was stirred for 5 min. then benzoyl chloride (41 mg, 0.290 mmol) was added and stirring was continued for a further 5 h. Progress of the reaction was monitored by TLC and LCMS and after completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude product which was purified by prep-HPLC to afford the title compound (20 mg, 25% yield) as a white solid. Purity by HPLC: 98.32%; .sup.1H NMR (500 MHz; DMSO-d.sub.6): δ 3.04 (dd, J′=3.0 Hz, J″=4.85 Hz, 2H), 3.50 (dd, J′=3.8 Hz, J″=6.5 Hz, 2H), 4.93 (s, 2H), 6.18 (d, J=3.1 Hz, 1H), 6.36-6.37 (m, 1H), 6.63 (s, 1H), 6.73-6.76 (m, 1H), 6.99 (s, 1H), 7.03 (d, J=8.2 Hz, 1H), 7.44-7.49 (m, 4H), 7.54-7.59 (m, 2H); LCMS m/z: 415.07 [M+H].

Example 50: 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea

[0476] ##STR00250##

[0477] Example 50 was prepared according to General Procedure 1-6, 17 and the methods described below.

Preparation 39: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine

[0478] ##STR00251##

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

[0479] ##STR00252##

[0480] A solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 2) (1.0 g, 3.19 mmol) in borane-THF complex (10.6 mL, 9.5 mmol; 0.9M solution in THF) was stirred at 0-5° C. for 2 h. UPLC-MS showed formation of the desired product. After completion of the reaction, the excess borane was quenched with methanol at the same temperature. The solvent was evaporated in vacuo and the residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude material which was purified by column chromatography using 10% EtOAc in hexane as eluent to afford the title compound (900 mg, yield 94%) as a white solid. LCMS m/z: 300.23 [M+H].

Step 2: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid

[0481] ##STR00253##

[0482] To a stirred solution of methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 39, Step 1) (120 mg, 0.4 mmol) in THF (5 mL) and MeOH (2.5 mL) was added a solution of LiOH (84 mg, 2.0 mmol) in water (2.5 mL) and the mixture was maintained at RT for 16 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated in vacuo to give a crude material which was diluted with water and acidified with 6N HCl. The product was extracted with EtOAc and the combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford the title compound (100 mg, crude) as a faint brownish solid which was used in the next step without any further purification. LCMS m/z: 286.22 [M+H].

Step 3: tert-Butyl (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate

[0483] ##STR00254##

[0484] A stirred solution of 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 39, Step 2) (100 mg, 0.35 mmol) in DCM (10 mL) was cooled to 0-5° C. and TEA (0.075 mL, 0.53 mmol) added followed by DPPA (0.152 mL, 0.7 mmol) at RT. The combined mixture was stirred at RT for 3 h. UPLC-MS showed consumption of the starting material. The solvent was evaporated in vacuo to give an intermediate product (130 mg) as a faint brownish solid. The solid was dissolved in tert-butanol (10 mL) and refluxed for 24 h. Progress of the reaction was monitored by UPLC-MS and after completion of the reaction, the solvent was evaporated in vacuo to give a residue which was purified by Combi-flash (12 g column) using 55% EtOAc in hexane as eluent to afford the title compound (100 mg, yield 80%) as an off white sticky oil. LCMS m/z: 357.3 [M+H].

Step 4: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine

[0485] ##STR00255##

[0486] A stirred solution of tert-butyl (4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (Preparation 39, Step 3) (100 mg, 0.28 mmol) in THF (2.5 mL) was cooled to 0-5° C. and 4M HCl in dioxane (2.5 mL) added dropwise under an inert atmosphere. The whole was allowed to warm slowly to RT over 24 h. Progress of the reaction was monitored by UPLC-MS. After completion of the reaction, the solvent was evaporated and the obtained crude material was dissolved in water and washed with ether. The aqueous layer was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to afford the title compound (80 mg, crude) as brownish oil which was used as such in the next step. LCMS m/z: 257.22 [M+H].

Preparation 40: 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl-3-(1H-indol-6-yl)urea (Example 50)

[0487] ##STR00256##

[0488] To a stirred solution of 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine (Preparation 39, Step 4) (80 mg, 0.312 mmol) in THF (10 mL) was added p-nitrophenyl chloroformate (63 mg, 0.374 mmol) at 0-5° C. and the mixture was allowed to warm slowly to RT over 1 h. TLC showed completion of the first part of the reaction. 6-amino-indole (45 mg, 0.34 mmol) and TEA (0.067 mL, 0.468 mmol) were added and the combined mixture maintained at RT for a further 1 h. TLC and UPLC-MS showed complete consumption of the intermediate. The solvent was evaporated in vacuo to afford the crude material which was purified by prep-HPLC to afford the title compound (8 mg, yield 6%) as a faint brownish solid. Purity by UPLC: 97.3%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ. 3.04-3.07 (m, 2H), 3.65-3.67 (m, 2H), 4.55 (s, 2H), 6.30-6.31 (m, 1H), 6.75 (t, J=2.16 Hz, 1H), 6.77-6.78 (m, 2H), 6.86 (d, J=8.64 Hz, 1H), 7.19-7.20 (m, 1H), 7.26-7.30 (m, 3H), 7.35-7.38 (m, 3H), 7.74 (t, J=0.86 Hz, 1H), 8.33 (s, 1H), 8.42 (s, 1H), 10.87 (s, 1H); LCMS m/z: 415.28 [M+H].

Example 62: 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3-(1H-indol-6-yl)urea

[0489] ##STR00257##

[0490] Example 62 was prepared according to General Procedure 1-6, 18 and the methods described below.

Preparation 42: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine

[0491] ##STR00258##

Step 1: Methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[0492] ##STR00259##

[0493] To a stirred solution of commercially available methyl 4-amino-3-hydroxybenzoate (0.5 g, 2.99 mmol) in DMF (5 mL) was added K.sub.2CO.sub.3 (2.75 g, 11.96 mmol) and 1,2-dibromoethane (1.035 mL, 11.96 mmol) at RT. The whole was stirred at 80° C. for 16 h. TLC and UPLC-MS showed formation of the desired product and after completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated in vacuo to give a crude material which was purified by Combi-flash (20 g column) using 20% EtOAc in hexane as eluent to afford the title compound (0.3 g, 52% yield) as a pale yellow solid. UPLC-MS m/z: 193.98 [M+H].

Step 2: Methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[0494] ##STR00260##

[0495] To a stirred solution of methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 42, Step 1) (300 mg, 1.55 mmol) in DMF (3 mL) was added NaH (68 mg, 1.71 mmol) portionwise at 0-5° C. After the addition was complete, benzyl bromide (0.204 mL, 1.71 mmol) was added and the whole was allowed to warm slowly to RT over 1.5 h. TLC and UPLC-MS showed formation of the desired product and after complete consumption of the starting material, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated in vacuo to afford the title compound (420 g, 95% yield) as a pale yellow solid. UPLC-MS m/z: 284.3 [M+H].

Step 3: 4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine

[0496] ##STR00261##

[0497] The title compound was prepared according to the methods described for the preparation of Example 50 (Preparation 40, Steps 2-4), starting from methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 42, Step 2), instead of methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 40, Step 1). UPLC-MS m/z: 241.4 [M+H].

Preparation 43: 1-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl-3-(1H-indol-6-yl)urea (Example 62)

[0498] ##STR00262##

[0499] To a stirred solution of 6-amino indole (60 mg, 0.416 mmol) in THF (5 mL) was added triphosgene (61 mg, 0.208 mmol) at 0-5° C. The resulting reaction mixture was allowed to warm to RT over 1 h. 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine (Preparation 42, Step 3) (100 mg, 0.416 mmol) and TEA (0.198 mL, 1.217 mmol) were then added into the reaction mixture which was further stirred at RT for 1 h. TLC showed complete consumption of the amine and a new polar material was observed. The solvent was evaporated in vacuo to afford the crude which was purified by prep-HPLC to give the title compound (35 mg, 21% yield) as a pale brownish solid. Purity by UPLC: 98.94%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.27-3.34 (m, 2H), 4.20-4.22 (m, 2H), 4.40 (s, 2H), 6.31-6.32 (m, 1H), 6.62 (d, J=8.76 Hz, 1H), 6.71 (dd, J′=8.68 Hz, J″=2.44 Hz, 1H), 6.80 (dd, J′=8.44 Hz, J″=1.84 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 7.19-7.20 (m, 1H), 7.22-7.27 (m, 1H), 7.31-7.33 (m, 3H), 7.34-7.35 (m, 1H), 7.37-7.39 (m, 1H), 7.77-7.78 (m, 1H), 8.24 (s, 1H), 8.42 (s, 1H), 10.89 (s, 1H); UPLC-MS m/z: 399.1 [M+H].

Example 176: 4-Benzyl-N-(1H-indol-6-ylsulfamoyl)-2,3-dihydro-1,4-benzoxazin-6-amine

[0500] ##STR00263##

[0501] Example 176 was prepared according to General Procedures 1-6, 17 and the methods described below.

Preparation 77: N-(4-Benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl-2-oxooxazolidine-3-sulfonamide

[0502] ##STR00264##

[0503] Chlorosulfonyl isocyanate (82 mg, 0.58 mmol) was taken in DCM (2 mL) and it was cooled to 0-5° C. Then bromoethanol (46.52 mg, 0.58 mmol) was added to it drop wise and the mixture was stirred at 0-5° C. for 30 min. To this reaction vessel was added a mixture of 4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-6-amine (Preparation 39, Step 4) (140 mg, 0.58 mmol) and Et3N (0.13 ml, 0.96 mmol) in DCM (1 mL) at 0-5° C. The whole reaction mixture was stirred at 0-5° C. for 30 min then warm to RT and stirred for 10 min at RT. Progress of the reaction was checked by LCMS and after completion of the reaction; solvent was evaporated in vacuo to get the title compound (150 mg, crude) as crude solid which was used in the next step without any further purification.

Preparation 78: 4-Benzyl-N-(1H-indol-6-ylsulfamoyl)-2,3-dihydro-1,4-benzoxazin-6-amine (Example 176)

[0504] ##STR00265##

[0505] To a solution of N-(4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-oxooxazolidine-3-sulfonamide (Preparation 77) (150.0 mg, 0.38 mmol) in acetonitrile (5 mL) were added 6-amino-indole (61.0 mg, 0.46 mmol) and Et3N (0.16 ml, 0.96 mmol) at RT and the reaction mixture was stirred at RT for 16 h. Progress of the reaction was checked by LCMS and after completion of the reaction; solvents were evaporated under reduced pressure to give crude product which was purified by reverse phase Prep-HPLC to afford the title compound (15 mg, 8.96% yield) as black sticky solid. Purity by UPLC: 98.94%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.27 (m, 2H), 4.12 (s, 2H), 4.30 (s, 2H), 6.34 (s, 1H), 6.36 (s, 1H), 6.45 (s, 1H), 6.56 (d, 1H, J=8.2 Hz), 6.77 (d, 1H, J=8.3 Hz), 7.16-7.36 (m, 8H), 9.37 (s, 1H), 9.61 (s, 1H), 10.96 (s, 1H); UPLC-MS m/z: 435.07 [M+H].

Examples 56-57, 63-68, 167-174 and 177-180

[0506] The examples in the table below were prepared according to the above methods used to make Examples 50, 62 and 176 as described in General Procedures 1-6, 17 and 18 using the appropriate amine. Purification was as stated in the aforementioned methods.

TABLE-US-00005 IUPAC LCMS Purity Ex Structure Name 1H-NMR [M + H] (%)  56 [00266] 1-(4-benzyl- 3,4- dihydro- 2H- benzo[b][1, 4]oxazin-6- yl)-3-(1H- indol-6- yl)urea (500 MHz; DMSO- d.sub.6): δ 3.34 (s, 2H), 4.18 (s, 2H), 4.48 (s, 2H), 6.31 (s, 1H), 6.62-6.63 (m, 2H), 6.77-6.79 (m, 1H), 6.84 (s, 1H), 7.20 (s, 1H), 7-33-7-38 (m, 6H), 7.77 (s, 1H), 8.27 (s, 1H), 8.43 (s, 1H), 10.87 (s, 1H) 399.14 96.73  57 [00267] 1-(4- benzoyl- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-6- yl)urea (500 MHz; DMSO- d.sub.6): δ 3.2-3.3 (m, 2H), 4.02 (bs, 2H), 6.32 (s, 1H), 6.76- 6.78 (m, 1H), 6.92 (s, 1H), 7.17-7.24 (m, 3H), 7.30-7.42 (m, 6H), 7.70 (s, 1H), 8.46-8.47 (m, 2H), 10.91 (s, 1H) 429.10 96.1   63 [00268] 1-(4-benzyl- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-7- yl)-3-(1H- indol-6- yl)urea (500 MHz; DMSO- d.sub.6): δ 3.11 (t, J = 4.7 Hz, 2H), 3.60 (t, J = 4.65 Hz, 2H), 4.50 (s, 2H), 6.32 (s, 1H), 6.57 (d, J = 8.9 HZ, 1H), 6.82-6.86 (m, 2H), 7.20-7.39 (m, 8H), 7.77 (s, 1H), 8.36 (s, 1H), 8.56 (s, 1H), 10.90 (s, 1H) 415.07 99.1   64 [00269] 1-(4-benzyl- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-3- yl)urea (500 MHz; DMSO- d.sub.6): δ 3.06 (t, J = 5 Hz, 2H), 3-67 (t, J = 4.7 Hz, 2H), 4.56 (s, 2H), 6.72 (s, 1H), 6.83-6.88 (m, 2H), 6.99 (t, J = 7-5 Hz, 1H), 7.08 (t, J = 7-35 Hz, 1H), 7.25-7.30 (m, 4H), 7-33-7:39 (m, 2H), 7.44-7.46 415.09 98.48 (m, 2H), 8.32 (s, 2H), 10.69 (s, 1H)  65 [00270] 1-(4- (cyclopropyl- methyl)- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-6- (400 MHz; DMSO- d.sub.6): δ 0.28-0.30 (111, 2H), 0.49-0.51 (m 2H), 1.07-1.11 (m, 1H), 2.9-3.02 (m, 2H), 3.17 (d, J = 6.36 Hz, 2H), 3.61-3.64 (m, 2H), 6.31-6.33 (m, 1H), 6.60-6.63 (m, 1H), 6.80-6.83 379.1  97.73 yl)urea (m, 2H), 7.10 (d, J = 2.04 Hz, 1H), 7.21 (d, J = 2.44 Hz, 1H), 7.38-7.41 (m, 1H), 7.80 (d, J = 1.84 Hz, 1H), 8.47 (d, J = 9.24 Hz, 2H),10.89 (s, 1H)  66 [00271] 1-(1H-indol- 6-yl)-3-(4- (pyridin-4- ylmethyl)- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)urea (400 MHz; DMSO- d.sub.6): δ 3.08-3.11 (m, 2H), 3.68-3.72 (m, 2H), 4.58 (s, 2H), 6.30 (s, 1H), 6.65 (d, J = 1.68 Hz, 1H), 6.74-6.79 (m, 2H), 6.88 (t, J = 8.32 Hz, 1H), 7.19 (t, J = 2.72 Hz, 1H), 7.28-7.30 (m, 2H), 7-35-7-37 416.1  97.07 (m, 1H), 7.72 (s, 1H), 8.34-8.43 (m, 2H), 8.52-8.54 (m, 2H), 10.87 (s, 1H)  67 [00272] 1-(4- (cyclopentyl methyl)- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-6- (400 MHz; DMSO- d.sub.6): δ 1.2-1.27 (m, 2H), 1.51-1.53 (m, 2H), 1.54-1.64 (m, 2H), 1.72-1.75 (m, 2H), 2.25-2.33 (m, 1H), 2.97-2.99 (m, 2H), 3.20 (d, J = 7.2 Hz, 2H), 3-59-3.62 (m, 2H), 6.32 (s, 1H), 407.14 99.18 yl)urea 6.63-6.66 (m, 1H), 6.78-6.84 (m, 2H), 7.95 (s, 1H), 7.20 (s, 1H), 7-39 (d, J = 8.44 Hz, 1H), 7.78 (s, 1H), 8.50 (s, 1H), 8.55 (s, 1H), 10.90 (s, 1H)  68 [00273] 1-(1H-indol- 6-yl)-3-(4- (2- (pyrrolidin- 1-yl)ethyl)- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)urea (400 MHz; DMSO- d.sub.6): δ 1.62-1.8 (m, 4H), 2.60-2.65 (m 3H), 2.97-3.08 (m, 2H), 3-33-3-40 (m, 3H), 3.52 (s, 1H), 3.6- 3.62 (m, 3H), 6.32 (s, 1H), 6.66-6.72 (m, 1H), 6.79-6.83 (m, 2H), 6.92 (s, 1H), 7.21 (s, 1H), 7.26-7.27 (m, 1H), 7-39-7-40 (m, 1H), 7.78 (s, 1H), 8.39 422.16 95.57 (s, 1H), 8.45 (s, 1H), 10.89 (s, 1H) 167 [00274] 1-(4-benzyl- 1-oxido-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO- d6): δ 2.85 (t, 1H, J = 13.6 Hz ), 3.07 (d, 1H, J = 13.9 Hz), 3.63 (d, 1H, J = 13.6 Hz), 3.98 (t, 1H, J = 13.2 Hz ), 4.78-4.64 (m, 2H), 6.32 (s, 1 H), 6.85 (d, 2H, 8.16), 7-39-7.13 (m, 9H), 7.77 (s, 1H), 9.16 (s, 1H), 9.32 (s, 1H), 10.89 (s, 1H) 431.1  97.75 168 [00275] 1-(1H-indol- 6-yl)-3-(4- methyl-3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- (500 MHz; DMSO- d.sub.6): δ 2.89 (s, 3H), 3.05 (t, 2H, J = 3.65 Hz), 3.51 (t, 2H, J = 5.2 Hz), 6.33 (s, 1H), 6.68-6.66 (m, 1H), 6.85-6.82 (m, 2H), 339.06 99.14 yl)urea 6.97 (d, 1H, J = 1.52 H), 7.22 (t, 1H, J = 2.65 Hz), 7.40 (d, 1H, J = 8.4 Hz), 7.81 (s, 1H), 8.46 (s, 1H), 8.50 (s, 1H), 10.89 (s, 1H). 169 [00276] 1-(4-(2- chloro-6- fluorobenzyl)- 3,4- dihydro- 2H- benzo[b][1, 4]oxazin-6- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO- d.sub.6): δ 3.08 (t, 2H, J = 4.08 Hz), 4.065 (m, 2H), 4.47 (s, 2H), 6.32 (s, 1H), 6.62 (d, 1H, J = 8.48 Hz), 6.70 (m, 1H), 6.82 (m, 1H), 7.15 (d, 1H, J = 1.68 Hz), 7.18 (m, 1H), 7.29-7.47 (m, 4H), 7.79 (s, 1H), 451.06 98.57 8.24 (s, 1H), 8.43 (s, 1H), 10.86 (s, 1H). 170 [00277] 1-(4-(2- chloro-6- fluorobenzyl)- 3,4- dihydro- 2H- benzo[b][1, 4]oxazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO- d.sub.6): δ 3.03 (s, 2H), 4.11 (s, 2H), 4.40 (s, 2H), 6.30 (s, 1H), 6.83 (s, 2H), 6.90 (d, 1H, J = 7.72 Hz), 6.98 (s, 1H), 7.18 (s, 1H), 7.28 (s, 1H), 7.40 (m, 3H), 7.77 (s, 1H), 8.49 (s, 1H), 8.62 (s, 1H), 10.87 (s, 1H). 451.1  98.74 171 [00278] 1-(4-(2- chloro-6- fluorobenzyl)- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-7- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO- d.sub.6): δ 3.00 (t, 2H, J = 4.96 Hz), 3.27 (s, 2H), 4.46 (s, 2H), 6.31 (s, 1H), 6.84 (d, 1H, J = 8.48 Hz), 6.91-6.97 (m, 2H), 7.19 (s, 1H), 7.26-7.44 (m, 5H), 7.76 (s, 1H), 8.38 (s, 1H), 8.54 (s, 1H), 10.88 (s, 1H). 467.08 95.27 172 [00279] 1-(4-benzyl- 3,4- dihydro- 2H- benzo[b][1, 4]oxazin-6- yl)-3-(1H- pyrrolo[2,3- b]pyridin- 6-yl)urea (400 MHz; DMSO- d.sub.6): δ 3.35 (t, 2H, J = 4.12 Hz), 4.17 (t, 2H, J = 4.12 Hz), 4.96 (s, 2H), 6.31 (s, 1H), 6.65 (d, 1H, J = 8.68 Hz), 6.73-6.67 (m, 1H), 6.98 (s, 1H), 7.18 (s, 1H), 7.23-7.36 (m, 6H), 7.86 (d, 1H, J = 8.44 Hz), 9.28 (s, 400.11 97.12 1H), 10.80 (s, 1H), 11.5 (s, 1H). 173 [00280] 1-(4-benzyl- 3,4- dihydro- 2H- benzo[b][1, 4]thiazin-6- yl)-3-(4- fluorophenyl) urea (400 MHz; DMSO- d.sub.6): δ 3.04 (t, 2H, J = 5.12 Hz), 3.65 (t, 2H, J = 4.84 Hz), 4.53 (s, 2H), 6.72-6.76 (m, 2H), 6.85 (d, 1H, J = 8.28 Hz), 7.05-7.10 (m, 2 H), 7-25-7-39 (m, 7H), 8.41 (s, 1H), 8.58 (s, 1H) 394.06 95.2  174 [00281] 1-(4-(2- fluoro-4- (trifluoro- methoxy) benzyl)-3,4- dihydro- 2H- benzo[b][1, 4]oxazin-6- yl)-3-(1H- indol-6- (400 MHz; DMSO- d.sub.6): δ 3.40 (t, 2H, J = 4.04 Hz), 4.17 (t, 2H, J = 3.92 Hz), 4.52 (s, 2H), 6.30 (s, 1H), 6.62 (d, 1H, J = 8.48 Hz), 6.66-6.67 (d, 1H, J = 2.0 Hz), 6.75-6.78 (m, 2H), 7.18 (t, 1H, J = 2.50 Hz), 7-2-7-25 (m, 1H), 7.36 (d, 1H, 501.09 99.0  yl)urea J = 8.44 Hz), 7.42- 7.45 (m, 2H), 7.74 (s, 1H), 8.23 (s, 1H), 8.36 (s, 1H), 10.85 (s, 1H). 177 [00282] 1-(4-benzyl- 3,4- dihydro- 2H- benzo[b][1, 4]oxazin-6- yl)-3-(1H- pyrrolo[3,2- b]pyridin- 6-yl)urea (400 MHz; DMSO- d.sub.6): δ 3.39 (s, 2H), 4.15-4.17 (t, J = 4.24 Hz, 2H), 4.46 (s, 2H), 6.43 (s, 1H), 6.59-6.65 (m, 2H), 6.81 (s, 1H), 7.23-7.27 (s, 1H), 7-31-7-37 (m, 4H), 7.46 (t, 1H, J = 2.68 Hz), 8.10 (d, 2H, J = 6.6 Hz), 8.39 (s, 400.15 98.23 1H), 8.63 (s, 1H), 11.05 (s, 1H). 178 [00283] 1-(4-benzyl- 3,4- dihydro- 2H- benzo[b][1, 4]oxazin-6- yl)-3-(1H- indol-6-yl)- 1- methylurea (400 MHz; DMSO- d.sub.6): δ 3.9 (s, 3H), 3.39 (s, 2H), 4.23 (s, 2H), 4.50 (s 2H), 6.29 (bs, 1H), 6.48- 6.51 (dd, 1H, J1 = 2.04 Hz, J2 = 8.32 Hz), 6.7.-6.76 (m, 3H), 7.18-7.21 (m, 2H), 7.20-7.321 (m, 6H), 7.57 (s, 1H), 413.21 99.69 10.86 (s, 1H). 179 [00284] 6-(3-(1H- indol-6- yl)ureido)- 4-benzyl- 3,4- dihydro- 2H- benzo[b][1, 4]oxazine- 7- carboxamide (400 MHz; DMSO- d.sub.6): δ 3.44 (s, 2H), 4.17 (s, 2 H), 4.53 (s, 2H), 6.29 (s, 1H), 6.95 (d, 1H, J = 8.52 Hz), 7.09-7-35 (m, 9H), 7-73 (s, 2H), 7.87 (s, 1H), 9.26 (s, 1H), 10.82 (s, 1H), 10.99 (s, 1H) 442.31 99.82 180 [00285] 1-(4-benzyl- 7-bromo- 3,4- dihydro- 2H- benzo[b][1, 4]oxazin-6- yl)-3-(1H- indol-6- yl)urea (400 MHz; DMSO- d.sub.6): δ 3.37 (t, 2H, J = 4.16 Hz), 4.18 (t, 2 H, J = 42 Hz), 4.46 (s, 2H), 6.31 (s, 1H), 6.78-6.81 (dd, 1H, J = 1.56 Hz, 8.63 Hz), 6.90 (s, 1H), 7.19- 7.49 (m, 8H), 7.71 (s, 1H), 7.77 (s, 1H), 9.07 (d, 1H, J = 4.12 Hz), 477.18 99.22 10.87 (s, 1H)

Example 72: 1-(1H-Indol-6-yl)-R-(4-phenyl-1,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea

[0507] ##STR00286##

[0508] Example 72 was prepared according to General Procedures 1-6, 17, 25 and the methods described below.

Preparation 47: 4-Phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine

[0509] ##STR00287##

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

[0510] ##STR00288##

[0511] BH.sub.3-THF (30 mL, 27 mmol) was added to methyl 3-oxo-3,4-dihydro-2H-benzo[b-1,4]thiazine-6-carboxylate (Preparation 1, Step 2) (2.0 g, 9.0 mmol) at 0-5° C. with stirring in an inert atmosphere. After the addition was complete, the mixture was brought to RT and stirred for 3 h. Completion of the reaction was confirmed by TLC and UPLC-MS. The reaction mixture was quenched by adding in portions to methanol in a conical flask and stirring until all effervescence had ceased. Then, the reaction mixture was concentrated in vacuo to give a crude material which was mixed with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (1.8 g) as a pale yellow crude solid. UPLC-MS m/z: 209.9 [M+H].

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

[0512] ##STR00289##

[0513] To a stirred solution of methyl 3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 47, Step 1) (500 mg, 2.39 mmol) in toluene (15 mL) was added phenyl iodide (0.4 mL, 3.6 mmol), cesium carbonate (1.56 g, 4.78 mmol) and BINAP (298 mg, 0.48 mmol) at RT. The whole was degassed with nitrogen for 20 min., then palladium acetate (54 mg, 0.24 mmol) was added into the reaction mixture and stirring continued at 110° C. for 24 h. Progress of the reaction was monitored by UPLC-MS which showed ˜40% formation of the desired product. The reaction mixture was concentrated in vacuo to give a crude material which was purified by column chromatography to afford the title compound (240 mg, 35% yield) as a pale yellow solid along with recovered unreacted starting material. UPLC-MS m/z: 285.98 [M+H].

[0514] Step: 4-Phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine hydrochloride

##STR00290##

[0515] The title compound was prepared according to the methods described for the preparation of Example 50 (Preparation 40, Steps 2-4), starting from methyl 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 50, Step 2), instead of methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 40, Step 1). UPLC-MS m/z: 242.96 [M+H].

Preparation 48: 3-(1H-Indol-6-yl)-3-(4-phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea (Example 72)

[0516] ##STR00291##

[0517] To a stirred solution of 6-amino-indole (147 mg, 1.11 mmol) in THF (6 mL) was added triphosgene (157 mg, 0.53 mmol) at 0-5° C. The reaction mixture was stirred at RT for 1.5 h. 4-Phenyl-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-amine (Preparation 47, Step 3) (50 mg, 0.18 mmol) was then added followed by TEA (0.77 mL, 5.5 mmol) at 0-5° C. The whole was again stirred at RT for 2 h. Progress of the reaction was monitored by UPLC-MS and after completion the reaction mixture was concentrated in vacuo to give a residue which was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated in vacuo to give the crude product which was purified by prep-HPLC to afford the title compound (12 mg, 17% yield) as a yellow solid. Purity by UPLC: 96.74%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.10 (t, J=3.16 Hz, 2H), 3.85-3.88 (m, 2H), 6.30 (s, 1H), 6.74-6.77 (m, 1H), 6.87 (s, 1H), 6.96-7.00 (m, 2H), 7.09 (t, J=7.36 Hz, 1H), 7.19-7.20 (m, 3H), 7.35-7.39 (m, 3H), 7.71 (s, 1H), 8.43 (s, 1H), 8.50 (s, 1H), 10.86 (s, 1H); UPLC-MS m/z: 401.12 [M+H].

Example 75: 1-(1H-Indol-6-yl)-3-(3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea

[0518] ##STR00292##

[0519] Example 75 was prepared according to General Procedures 1-6, 24 and the methods described below.

Preparation 53: 7-Amino-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one

[0520] ##STR00293##

Step 1: Methyl 3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

[0521] ##STR00294##

[0522] To a stirred solution of methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 44, Step 2) (800 mg, 3.86 mmol) in EDC (4 mL) was added phenylboronic acid (706 mg, 5.79 mmol) in EDC (4 mL), DBU (1.176 mL 7.72 mmol) and solution of Cu(OAc) (1.40 g, 7.72 mmol) at RT. The resulting reaction mixture was stirred at RT for 24 h. UPLC-MS showed ˜50% conversion. The reaction mixture was diluted with water and extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to afford the crude material which was purified by Combi-flash (20 g column) using 35% EtOAc in hexane as eluent to afford the title compound (420 mg, 38% yield) as an off white solid.

Step 2: 3-Oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonyl azide

[0523] ##STR00295##

[0524] To a stirred solution of methyl 3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (Preparation 53, Step 1) (420 mg, 1.48 mmol) in THF (8 mL) and MeOH (4 mL) was added a solution of LiOH.H.sub.2O (249 mg, 5.93 mmol) in water (4 mL) and the reaction maintained at RT for 2 h. TLC showed completion of the reaction. The solvents were evaporated in vacuo to give a crude material which was dissolved in water, washed with MTBE and the aqueous layer was acidified with 6N HCl. The neutralized aqueous mass was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to afford the corresponding intermediate acid (400 mg) which was then dissolved in DCM (45 mL) and HATU (845 mg, 2.22 mmol) and TEA (0.641 mL, 4.45 mmol) added at RT. The whole was stirred at RT for 24 h. UPLC-MS confirmed formation of the intermediate HATU-adduct. Sodium bicarbonate solution (10%) was added and the layers were separated. The organic layer was evaporated to afford a crude mass to which a saturated solution of sodium azide was added and the whole was stirred at RT for 30 min. UPLC-MS showed completion of the reaction, which was then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to afford the title compound (250 mg, crude) as pale yellow solid. UPLC-MS m/z: 194.98 [M+H].

[0525] Step 3: 7-Amino-4-phenyl-2H-benzo[b][1,4]oxazin-2(4H)-one

##STR00296##

[0526] To a stirred solution of 3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonyl azide (Preparation 53, Step 2) (0.25 g, 0.85 mmol) in tert-butanol (5 mL) was heated to 90° C. for 1 h. UPLC-MS showed formation of the desired intermediate. The solvent was evaporated to give a crude material which was purified by Combi-flash to afford the corresponding Boc-NH.sub.2 intermediate (130 mg). The Boc-NH.sub.2 intermediate (130 mg, 0.38 mmol) was dissolved in 20% TFA in DCM (10 mL) in an inert atmosphere at RT, and then further stirred at RT for 1 h. UPLC showed formation of the desired compound. The reaction mixture was quenched with a saturated sodium bicarbonate solution (pH ˜8) and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to afford the title compound (90 mg, crude) as an off white solid. UPLC-MS m/z: 241.3 [M+H].

Preparation 54: 1-(1H-Indol-6-yl-3-(3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)urea (Example 75)

[0527] ##STR00297##

[0528] To a stirred solution of 6-amino-indole (54 mg, 0.411 mmol) in THF (5 mL) was cooled to 0-5° C. followed by addition of triphosgene (55 mg, 0.187 mmol) and maintained at RT for 1 h, then added 7-amino-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one 1 (Preparation 53, Step 3) (90 mg, 0.374 mmol) and TEA (0.178 mL, 1.23 mmol) at RT. The resulting reaction mixture was stirred at RT for 1 h. TLC showed completion of reaction, then the reaction mixture was diluted with EtOAc and washed with water followed by 1N HCl and finally with brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated in vacuo to afford the crude material which was purified by prep-HPLC to give the title compound (38 mg, 25.5% yield) as an off white solid. Purity by UPLC: 99.18%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 4.80 (s, 2H), 6.22 (d, 1H, J=8.64), 6.33 (s, 1H), 6.85 (t, 2H, J=9.04 Hz) 7.21 (s, 1H), 7.60-7.33 (m, 7H), 7.79 (s, 1H), 8.62 (s, 1H), 8.76 (s, 1H), 10.91 (s, 1H); UPLC-MS m/z: 398.99 [M+H].

Examples 175, 181-185

[0529] The examples in the table below were prepared according to the above methods used to make Examples 72 and 75 as described in General Procedures 1-6, 17, 18 and 24-25 using the appropriate amine. Purification was as stated in the aforementioned methods.

TABLE-US-00006 IUPAC LCMS Purity Ex Structure Name 1H-NMR [M + H] (%) 175 [00298] N-1H-indol- 6-yl-N′-(4- phenyl-3,4- dihydro-2H- 1,4- benzoxazin- 7-yl)sulfuric diamide (400 MHz; DMSO- d.sub.6): δ 3.64 (t, 2H, J = 3.96 Hz), 4.17 (t, 2H, J = 4 Hz ), 6.34 (s, 1H), 6.50-6.53 (dd, 1H, 2.4, 8.68 Hz), 6.72 (d, 1H, 2.44 Hz), 6.74 (s, 1H), 6.83 (dd, 1H, J = 1.76 Hz, 8.48 Hz), 7.017 (s, 1H, 7.4 Hz), 7.14-7.40 (m, 7 H), 9.16 (s, 1H), 9.70 (s, 421.2  98.98 1H), 10.97 (s, 1H). 181 [00299] 1-(1H-indol- 6-yl)-3-(4- phenyl-3,4- dihydro-2H- benzo[b][1,4] oxazin-7- yl)urea (400 MHz; DMSO- d.sub.6): δ 3.67 (t, 2H, J = 4.16 Hz), 4.20 (t, 2H, J = 4.2 Hz), 6.33 (s, 1H), 6.84 - 6.74 (m, 3H) 7.03 (t, 1H, J = 14.48 Hz), 7.21-7.14 (m, 4H), 7.41-7.32 (m, 3H) 7.79 (s, 1H), 8.40 (s, 1H), 8.45 (s, 1H), 10.90 (s, 1H). 385.1  99.07 182 [00300] 1-(1H-indol- 6-yl)-3-(4- phenyl-3,4- dihydro-2H- benzo[b][1,4] thiazin-7- yl)urea (400 MHz; DMSO- d.sub.6): δ 3.67 (t, 2H, J = 4.92 Hz), 3.87- 3.85 (m, 2H), 6.78 (d, 1H, J = 8.8 Hz), 6.86-6.83 (m, 1H) 7.31-6.91 (m, 10H), 7.78 (s, 1H), 8.51 (s, 1H), 8.55 (s, 1H), 10.90 (s, 1H). 401.11 99.08 183 [00301] 1-(1H-indol- 6-yl)-3-(3- oxo-4- phenyl-3,4- dihydro-2H- benzo[b][1,4] oxazin-6- yl)urea (500 MHz; DMSO- d.sub.6): δ 4.77 (s, 2H), 6.31 (s, 1H), 6.55 (s, 1 H), 6.86 -6.79 (m, 3 H) 7.48-7.12 (m, 9 H), 7.79 (s, 1H), 8.51 (s, 1H), 10.92 (s, 1H). 399.1  95.78 184 [00302] 1-(1H-indol- 6-yl)-3-(4- phenyl-3,4- dihydro-2H- benzo[b][1,4] oxazin-6- yl)urea (500 MHz; DMSO- d.sub.6): δ 3.75 (s, 2 H), 4.27 (s, 2H), 6.37 (s, 1H), 6.86-6.79 (m, 3H) 7.48-7.12 (m, 9H), 7.79 (s, 1H), 8.51 (s, 1H), 10.92 (s, 1H). 385.13 98.3  185 [00303] 1-(1H-indol- 6-yl)-3-(4- (oxazol-2-yl)- 3,4-dihydro- 2H- benzo[b][1,4] oxazin-7- yl)urea 376.10 91.1 

Example 73: 1-(4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-3-(1H-indol-6-yl)urea

[0530] ##STR00304##

[0531] Example 73 was prepared according to General Procedures 4-5, 6d, 8, 17 and the methods described below.

Preparation 49: 4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-amine

[0532] ##STR00305##

Step 1: 2-Chloro-N-(2-fluoro-5-nitrophenyl)acetamide

[0533] ##STR00306##

[0534] To a stirred solution of commercially available 2-fluoro-5-nitroaniline (1.5 g, 9.61 mmol) in acetone (30 mL) was added chloroacetyl chloride (0.994 mL, 12.49 mmol) at RT and then the reaction mixture was stirred at RT for 1 h. TLC and UPLC-MS showed completion of the reaction. Thereafter ice-cold water was added to the reaction mixture to give a solid precipitate which was filtered, washed with water and then dried in an oven to afford the title compound (2.0 g, crude) as a brownish solid. UPLC-MS m/z: 231.3 [M−H].

Step 2: 4-Methyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one

[0535] ##STR00307##

[0536] To a stirred solution of 2-chloro-N-(2-fluoro-5-nitrophenyl)acetamide (Preparation 49, Step 1) (2.0 g, 1.07 mmol) in ethanol (5 mL) was added a solution of methyl amine in THF (25.79 mL, 2M solution) at RT and the whole stirred at 90° C. for 16 h. TLC and UPLC-MS showed completion of reaction. Thereafter the solvent was evaporated in vacuo to give a crude product which was purified by Combi-flash (20 g column) using EtOAC as eluent to afford the title compound (1.3 g, 73% yield) as a yellow solid. UPLC-MS m/z: 206 [M−H].

Step 3: 1-Benzyl-4-methyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one

[0537] ##STR00308##

[0538] To a stirred solution of 4-methyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one (Preparation 49, Step 2) (1.0 g, 4.83 mmol) in DMF (15 mL) was added NaH (212 mg, 5.31 mmol) at 0-10° C. followed by benzyl bromide (0.64 mL, 5.31 mmol) and the reaction mixture was allowed to warm slowly to RT over 8 h. TLC and UPLC-MS showed formation of the desired product along with a di-benzylated compound. The reaction mixture was diluted with chilled water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated in vacuo to afford a crude product which was purified by Combi-flash (20 g column). The title compound (400 mg, 28% yield) was eluted with 50% EtOAc in hexane as a pale brown solid and the undesired di-benzylated compound (C and N-benzylated product) was eluted with 35% EtOAc in hexane as a brownish solid. UPLC-MS m/z: 298.88 [M+H].

Step 4: 4-Benzyl-1-methyl-6-nitro-1,2,3,4-tetrahydroquinoxaline

[0539] ##STR00309##

[0540] Borane-THF complex (2.02 mL, 2.024 mmol, 1M solution in THF) was added portionwise to 1-benzyl-4-methyl-7-nitro-3,4-dihydroquinoxalin-2(1H)-one (Preparation 49, Step 3) (200 mg, 0.67 mmol) with stirring at 5-10° C. After the addition was completed, the combined mixture was stirred at RT for 1 h. UPLC-MS showed formation of the desired compound. The reaction mixture was diluted with MeOH (5 mL) and further stirred at RT for 10 min. to quench any excess borane. The solvents were evaporated in vacuo to give a residue which was diluted with water and extracted with EtOAc. The combined organic layers was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to afford the crude product which was purified by Combi-flash (12 g column) using 30% EtOAc in hexane as eluent to afford the title compound (150 mg, 79% yield) as an orange solid. UPLC-MS m/z: 284.3 [M+H].

Step 5: 4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-amine

[0541] ##STR00310##

[0542] To a stirred solution of 4-benzyl-1-methyl-6-nitro-1,2,3,4-tetrahydroquinoxaline (Preparation 49, Step 4) (150 mg, 0.53 mmol) in MeOH (5 mL) was added Boc.sub.2O (0.173 mL, 0.79 mmol) followed by NiCl.sub.2.6H.sub.2O (63 mg, 0.26 mmol) and NaBH.sub.4 (50 mg, 1.32 mmol) at 5-10° C. The combined mixture was then allowed to warm to RT over 5 h. Progress of the reaction was monitored by TLC and UPLC-MS which showed formation of the intermediate product. After completion, the reaction mixture was diluted with chilled water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to afford the crude product which was purified by Combi-flash (12 g column) using 35% EtOAc in hexane as eluent to provide the Boc-protected amine compound (180 mg, 96% yield). This material was dissolved in DCM (5 mL) and TFA (2 mL) and the whole was stirred at RT for 4 h. UPLC-MS showed formation of the desired product. The solvent was evaporated in vacuo to give the crude product which was neutralized with aqueous sodium carbonate solution and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to afford the title compound (110 mg, crude) as a brown semi-solid which was used in the next step without any further purification. UPLC-MS m/z: 254.23 [M+H].

Preparation so: 1-(4-Benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl-3-(1H-indol-6-yl)urea (Example 73)

[0543] ##STR00311##

[0544] To a stirred solution of 6-amino-indole (63 mg, 0.477 mmol) in THF (5 mL) at RT was added triphosgene (64 mg, 0.217 mmol). The mixture was stirred for 1 h, then 4-benzyl-1-methyl-1,2,3,4-tetrahydroquinoxalin-6-amine (Preparation 49, Step 5) (110 mg, 0.434 mmol) and TEA (0.206 mL, 1.432 mmol) were added to the reaction mixture and the whole stirred at RT for 1 h. TLC showed complete consumption of the amine and a new polar spot was observed. The solvent was evaporated in vacuo to give a residue which was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give the crude product which was purified by prep-HPLC to afford the title compound (40 mg, 22% yield) as a greenish solid. Purity by UPLC: 97.7%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.75 (s, 3H), 3.16 (t, J=4.96 Hz, 2H), 3.49 (t, J=4.52 Hz, 2H), 4.45 (s, 2H), 6.30 (s, 1H), 6.42 (d, J=8.48 Hz, 1H), 6.53 (d, J=2.24 Hz, 1H), 6.65-6.67 (m, 1H), 6.73-6.76 (m, 1H), 7.17 (d, J=2.48 Hz, 1H), 7.19-7.37 (m, 6H), 7.75 (s, 1H), 8.05 (s, 1H), 8.30 (s, 1H), 10.84 (s, 1H); UPLC-MS m/z: 410.21 [M−H].

Example 74: 1-(1-Benzylindolin-6-yl)-3-(1H-indol-6-yl)urea

[0545] ##STR00312##

[0546] Example 74 was prepared according to General Procedures 1-6 and the methods described below.

Preparation 51: 1-Benzylindolin-6-amine hydrochloride

[0547] ##STR00313##

Step 1: Methyl 1-benzylindoline-6-carboxylate

[0548] ##STR00314##

[0549] To a stirred solution of commercially available methyl indoline-6-carboxylate (50 mg, 0.28 mmol) in DMF (1 mL) was added NaH (12.4 mg, 0.31 mmol) at 0-5° C. under an inert atmosphere. After 15 min., benzyl bromide (0.035 ml, 0.3 mmol) was added to the reaction mixture and stirring was continued at RT for 2 h. Completion of the reaction was confirmed by UPLC-MS. The reaction mixture was diluted with water (20 mL) and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound (72 mg) as a crude yellow solid which was used in the next step without any further purification. UPLC-MS m/z: 268 [M+H].

Step 2: 1-Benzylindolin-6-amine hydrochloride

[0550] ##STR00315##

[0551] The title compound was prepared according to the methods described for the preparation of Example 50 (Preparation 39, Steps 2-4), starting from methyl 1-benzylindoline-6-carboxylate (Preparation 54, Step 1), instead of methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 40, Step 1). UPLC-MS m/z: 225 [M+H].

Preparation 52: 1-(1-Benzylindolin-6-yl)-3-(1H-indol-6-yl)urea (Example 74)

[0552] ##STR00316##

[0553] To a stirred solution of 1-benzylindolin-6-amine hydrochloride (Preparation 51, Step 2) (30 mg, 0.12 mmol) in THF (3 mL) was added TEA (0.016 ml, 0.12 mmol) at RT. After the addition was completed, the mixture was stirred at RT for 30 min. Triphosgene (13.66 mg, 0.05 mmol) was added and stirring was continued at RT for 1 h. 6-NH.sub.2-indole (22.8 mg, 0.17 mmol) and TEA (0.032 ml, 0.24 mmol) were then added and the whole stirred at RT overnight. Progress of the reaction was monitored by UPLC-MS and after completion the mixture was evaporated in vacuo to give the crude product which was purified by prep-HPLC to afford the title compound (3 mg, 7% yield) as a white solid. Purity by UPLC: 96.11%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.84 (t, J=8.16 Hz, 2H), 3.26-3.28 (m, 2H), 4.25 (s, 2H), 6.31 (s, 1H), 6.62-6.65 (m, 1H), 6.80-6.82 (m, 2H), 6.91-6.93 (m, 1H), 7.20 (t, J=2.64 Hz, 1H), 7.26-7.39 (m, 6H), 7.78 (s, 1H), 8.48 (s, 1H) 8.57 (s, 1H), 10.88 (s, 1H); UPLC-MS m/z: 383.11 [M+H].

Example 76: 2-(6-(3-(1H-Indol-6-yl)ureido)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)acetamide

[0554] ##STR00317##

[0555] Example 76 was prepared according to General Procedures 1-6, 26 and the methods described below.

Preparation 55: 4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid

[0556] ##STR00318##

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

[0557] ##STR00319##

[0558] To a stirred solution of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 2) (1.0 g, 3.2 mmol) in dry THF (20 mL) was added LiHMDS (3.6 mL, 4.8 mmol) at −78° C. under inert atmosphere and stirred for 5 min. then, bromoacetonitrile (270 μL, 3.85 mmol) was added to the reaction mixture and stirring continued for 30 min. at the same temperature. After this time the reaction mixture was brought to room temperature and stirred for 1 h. Completion of the reaction was monitored by TLC and UPLC-MS, after which the reaction mass was quenched with a saturated solution of ammonium chloride and extracted with EtOAc followed by a brine wash. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford a crude viscous oil which was purified by Combi-flash on a 20 g column by eluting with 30% EtOAc/hexane as an eluent to afford the title compound (550 mg, 48% yield) as a pale yellow solid. UPLC-MS m/z: 353 [M+H].

Step 2: 4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid

[0559] ##STR00320##

[0560] To a stirred solution of methyl 4-benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (Preparation 55, Step 1) (0.6 g, 1.7 mmol) in a mixture of THF:MeOH:H.sub.2O (12 mL, 2:1:1) was added LiOH.H.sub.2O (0.29 g, 6.8 mmol) at RT and stirred for 2 h at the same temperature. When TLC and UPLC-MS showed complete consumption of the starting material with formation of the desired hydrolysed product, the solvents were evaporated under reduced pressure. The resulting residue was diluted with water and washed with MTBE. The aqueous layer was collected and acidified with 1N HCl to pH 5-6, then extracted with EtOAc and the organic layer was separated, washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (550 mg, crude) as a pale yellow solid which was used in the next step without any further purification.

[0561] UPLC-MS m/z: 337 [M−H].

Preparation 56: 1-(4-Benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl-3-(1H-indol-6-yl)urea (Example 77)

[0562] ##STR00321##

[0563] To a stirred solution of 4-benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (Preparation 55, Step 2) (0.10 g, 0.30 mmol) in DCM (5 mL) was added TEA (0.065 mL, 0.45 mmol) at 0-5° C. under an inert atmosphere followed by DPPA (0.095 mL, 0.45 mmol) and stirring continued for 5 min. at the same temperature. Then, the reaction mixture was brought slowly to RT and stirred overnight. Formation of the intermediate acyl azide was confirmed by TLC and UPLC-MS. Then, the reaction mixture was concentrated and toluene (5 mL) added followed by 6-amino-indole (60 mg, 0.45 mmol) and the whole was refluxed for 3 h. Completion of the reaction was confirmed by TLC and UPLC-MS, after which the solvents were removed on a rotary evaporator to give a crude material which was purified by prep-HPLC to afford the title compound (40 mg, 28% yield) as a black solid. Purity by UPLC: 97.92%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 1.66-1.75 (m, 2H), 3.47-3.57 (m, 3H), 3.95-3.98 (dd, 1H, J1=1.88 Hz, J2=10.68 Hz), 4.17-4.20 (dd, 1H, J1=1.28 Hz, J2=10.68 Hz), 4.42-4.51 (m, 3H), 6.29 (s, 1H), 6.60-6.65 (m, 3H), 6.74-6.77 (dd, 1H, J1=1.68 Hz, J2=8.48 Hz), 7.18 (t, 1H, J=2.52 Hz), 7.24-7.26 (m, 1H), 7.30-7.36 (m, 5H), 7.73 (s, 1H), 8.19 (s, 1H), 8.38 (s, 1H), 10.84 (s, 1H); UPLC-MS m/z: 468.15 [M+H].

Preparation 57: 2-(6-(3-(1H-Indol-6-yl)ureido)-4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-yl)acetamide (Example 76)

[0564] ##STR00322##

[0565] To a stirred solution of 1-(4-benzyl-2-(cyanomethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-6-yl)urea (Example 77) (100 mg, 0.21 mmol) in DMSO (1 mL) was added potassium carbonate (150 mg, 1.05 mmol) followed by hydrogen peroxide solution (1.5 mL) at RT and the combined mixture stirred for 1 h. Completion of the reaction was monitored by TLC and UPLC-MS. After completion of the reaction, the mixture was quenched with a saturated solution of sodium bisulphite and extracted with EtOAc followed by a brine wash. The separated organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude product which was purified by prep-HPLC to afford the title compound (8 mg, 8% yield) as a pale yellow solid. Purity by UPLC: 95.05%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.36-2.42 (m, 1H), 2.73-2.78 (m, 1H), 3.91-3.95 (s, 1H), 4.51-4.23 (m, 1H), 6.31 (s, 1H), 6.62-6.84 (m, 1H), 6.98 (s, 2H), 7.18-7.24 (m, 5H), 7.27-7.37 (m, 3H), 7.39-7.43 (m, 1H), 7.44-7.45 (m, 2H), 7.76 (s, 1H), 8.88 (s, 1H), 9.03 (s, 1H), 10.89 (s, 1H); UPLC-MS m/z: 484.15 [M−H]

Example 78: 1-(3-Allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea

[0566] ##STR00323##

[0567] Example 78 was prepared according to General Procedures 1, 4, 6, 20-21 and the methods described below.

Preparation 58: 3-Allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

[0568] ##STR00324##

Step 1: 4-Benzyl-6-nitro-3-((trimethylsilyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0569] ##STR00325##

[0570] To a stirred solution of 4-benzyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (synthesized according to the method described in Preparation 2 from commercially available 6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one) (200 mg, 0.7 mmol) in DCM (7 mL) was added DIBAL-H (1 mL, 1.06 mmol) at −78° C. under a nitrogen atmosphere. The combined mixture was stirred for 2 h at the same temperature and then pyridine (0.33 mL, 2.46 mmol) and TMSOTf (0.38 mL, 2.11 mmol) were added to the reaction mixture. The temperature of the reaction was then slowly allowed to rise to 0-5° C. Progress of the reaction was monitored by TLC and after completion of the reaction, Et.sub.2O (200 mL) was added and the mixture was filtered. The separated organic layer was then concentrated in vacuo to afford the title compound (240 mg, crude) as a yellow solid which was used in the next step without any further purification.

Step 2: 3-Allyl-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

[0571] ##STR00326##

[0572] To a stirred solution of 4-benzyl-6-nitro-3-((trimethylsilyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 1) (240 mg, 0.67 mmol) in DCM (7 mL) was added allyl-TMS (0.42 mL, 2.68 mmol) and BF3.Et.sub.2O (0.55 mL, 2.68 mmol) at −78° C. under nitrogen. The temperature was then slowly raised to 0-5° C. Progress of the reaction was checked by UPLC-MS and after completion the reaction was quenched with water (50 mL) and extracted with EtOAc. The separated organic layer was collected, dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude product was purified by column chromatography to afford the title compound (160 mg, 73% yield) as a yellow solid. UPLC-MS m/z: 311 [M+H].

Step 3: 3-Allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

[0573] ##STR00327##

[0574] To a stirred solution of 3-allyl-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 2) (110 mg, 0.35 mmol) in EtOH (4 mL) was added Fe-powder (197.9 mg, 3-54 mmol) and NH.sub.4Cl (4 mL) at RT. It was then heated to 90° C. for 1 h. Progress of the reaction was monitored by UPLC-MS. After completion of the reaction it was diluted with water and extracted with EtOAc. The separated organic layer was collected and filtered over a silica gel bed. The filtrate was collected, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound (150 mg, crude). The crude obtained was taken on to the next step. UPLC-MS m/z: 281 [M+H].

Preparation 59: 1-(3-Allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea (Example 78)

[0575] ##STR00328##

[0576] To a stirred solution of 6-amino-indole (84.88 mg, 0.64 mmol) in THF (4 mL) was added triphosgene (55-58 mg, 0.19 mmol) at 0-5° C. under nitrogen. The stirring was continued at RT for 1 h, then 3-allyl-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (Preparation 58, Step 3) (150 mg, 0.54 mmol) and TEA (0.18 mL, 1.34 mmol) were added and the combined mixture was further stirred at RT for 2 h. Completion of the reaction was confirmed by UPLC-MS and after completion the solvent was evaporated and the resulting residue was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to give a crude material which was purified by Combi-flash followed by prep-HPLC to afford the title compound (27.2 mg, 76% yield) as a yellow solid. Purity by UPLC: 98.59%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.31-2.38 (m, 1H), 2.36-2.39 (m, 1H), 3.50 (s, 1H), 3.96 (d, 1H, J=9.6 Hz), 4.15 (d, 1H, J=10.5 Hz), 4.52 (s, 2H), 5.09 (m, 2H), 5.86 (m, 1H), 6.31 (s, 1H), 6.65 (d, 3H), 6.76 (d, 1H, J=8.36 Hz), 7.19-7.37 (m, 7H), 7.75 (s, 1H), 8.23 (s, 1H), 8.41 (s, 1H), 10.87 (s, 1H); UPLC-MS m/z: 439 [M+H].

Example 79: 1-(4-Benzyl-3-(2,3-dihydroxypropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea

[0577] ##STR00329##

[0578] Example 79 was prepared according to General Procedures 1, 4, 6, 20-22 and the methods described below.

Preparation 60: 3-(4-Benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)propane-1,2-diol

[0579] ##STR00330##

[0580] To a stirred solution of 3-allyl-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 2) (250 mg, 0.81 mmol) in tert-BuOH/H.sub.2O solution (10 mL, 1:1) was added OsO.sub.4 (20.48 mg 0.08 mmol) and NMO (188.7 mg, 1.61 mmol). The resulting reaction mixture was stirred at RT for 12 h. Progress of the reaction was checked by LCMS and after completion of the reaction it was further diluted with EtOAc. The organic layer was washed with 10% HCl, water and finally with brine. The organics were then dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound (240 mg, crude) as a brown solid. UPLC-MS m/z: 445 [M+H].

Example 79: 1-(4-Benzyl-3-(2,3-dihydroxypropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea

[0581] ##STR00331##

[0582] To a stirred solution of 6-amino-indole (133.7 mg, 1.01 mmol) in THF (4 mL) was added triphosgene (120 mg, 0.4 mmol) at 0-5° C. under nitrogen. Stirring was continued at RT for 1 h, then 3-(6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)propane-1,2-diol (prepared according to method described in Preparation 58, Step 3 from 3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)propane-1,2-diol (Preparation 60)) (212 mg, 0.67 mmol) and TEA (340.6 mg, 3.37 mmol) were added and the combined mixture was further stirred at RT for 2 h. Completion of the reaction was confirmed by UPLC-MS after which the solvent was evaporated and the resulting residue was purified by prep-HPLC to afford the title compound (60 mg, 19% yield) as a grey solid. Purity by UPLC: 96.96%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 1.35-1.46 (m, 1H), 1.73-1.80 (m, 1H), 3.20-3.30 (m, 1H), 3.57-3.59 (m, 2H), 4.0-4.01 (m, 1H), 4.17-4.24 (m, 1H), 4.42-4.50 (m 1H), 4.54-4.67 (m, 2H), 6.30 (bs, 1H), 6.59-6.65 (m, 3H), 6.73-6.77 (m, 1H), 7.18 (bs, 1H), 6.23-6.26 (m, 1H), 7.29-7.36 (m, 5H), 7.73 (s, 1H), 8.19 (s, 1H), 8.37-8.39 (m, 2H), (s, 1H), 10.85 (s, 1H); UPLC-MS m/z: 473 [M+H].

Example 80: 1-(4-Benzyl-3-(2-hydroxyethyl)-3-,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea

[0583] ##STR00332##

[0584] Example 80 was prepared according to General Procedures 1, 4, 6, 20-23 and the methods described below.

Preparation 61: 2-(4-Benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)ethan-1-ol

[0585] ##STR00333##

[0586] To a stirred solution of 3-allyl-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 2) (250 mg, 0.81 mmol) in tert-BuOH/H.sub.2O solution (10 mL, 1:1) was added OsO.sub.4 (20.48 mg, 0.08 mmol) and NMO (188.7 mg, 1.61 mmol). The resulting reaction mixture was stirred at RT for 12 h. Progress of the reaction was checked by LCMS and after completion the reaction was diluted with EtOAc and washed with 10% HCl, water and finally with brine. The organics were dried and concentrated in vacuo to afford the crude corresponding diol intermediate. The crude product was dissolved in tert-BuOH/H.sub.2O solution (10 mL, 1:1) and NaIO4 (689.19 mg, 3.22 mmol) added at RT. The resulting reaction mixture was stirred at RT for 12 h. Progress of the reaction was checked by LCMS and after completion of the reaction it was diluted with water and extracted with EtOAc. The separated organic layer was dried and concentrated in vacuo to afford the crude corresponding aldehyde (200 mg, 0.64 mmol) which was dissolved in methanol (8 mL) and NaBH.sub.4 (48.67 mg, 1.28 mmol) added at 0-5° C. Then the reaction mixture was further stirred at RT for 2 h. After completion of the reaction it was quenched with NH.sub.4Cl solution (20 mL). The aqueous reaction mixture was extracted with EtOAc. The separated organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound (200 mg, crude) which was taken on to the next step without any further purification. UPLC-MS m/z: 315 [M+H].

Example 80: 1-(4-Benzyl-3-(2-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl-3-(1H-indol-6-yl)urea

[0587] ##STR00334##

[0588] To a stirred solution of 6-aminoindole (81.72 mg, 0.62 mmol) in THF (4 mL) was added triphosgene (66.81 mg, 0.23 mmol) at 0-5° C. under nitrogen. Stirring was continued at RT for 1 h, then 2-(6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)ethan-1-ol (prepared according to method described in Preparation 58, Step 3 from 2-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)ethan-1-ol (Preparation 61)) (160 mg, 0.56 mmol) and TEA (0.17 ml, 1.24 mmol) were added and the whole further stirred at RT for 12 h. Completion of the reaction was confirmed by UPLC-MS and after completion the solvent was evaporated and the resulting residue was purified by prep-HPLC to afford the title compound (40 mg, 16% yield) as a grey solid. Purity by UPLC: 99.5%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 1.66-1.75 (m, 2H), 3.47-3.57 (m, 3H), 3.95-3.98 (dd, 1H, J1=1.88 Hz, J2=10.68 Hz), 4.17-4.20 (dd, 1H, J1=1.28 Hz, J2=10.68 Hz), 4.42-4.51 (m, 3H), 6.29 (s, 1H), 6.60-6.65 (m, 3H), 6.74-6.77 (dd, 1H, J1=1.68 Hz, J2=8.48 Hz), 7.18 (t, 1H, J=2.52 Hz), 7.24-7.26 (m, 1H), 7.30-7.36 (m, 5H), 7.73 (s, 1H), 8.19 (s, 1H), 8.38 (s, 1H), 10.84 (s, 1H); UPLC-MS m/z: 443 [M+H].

Example 81: 1-(4-Benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea

[0589] ##STR00335##

[0590] Example 81 was prepared according to General Procedures 1, 4, 6, 20 and the methods described below.

Preparation 62: 6-Amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile

[0591] ##STR00336##

Step 1: 4-Benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile

[0592] ##STR00337##

[0593] To a stirred solution of 4-benzyl-6-nitro-3-((trimethylsilyl)oxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (Preparation 58, Step 1) (355 mg, 0.99 mmol) in DCM (10 mL) was added TMSCN (0.49 mL, 3.96 mmol) and BF.sub.3.Et.sub.2O (0.81 mL, 3.96 mmol) at −78° C. under nitrogen. The temperature was then slowly raised to 0-5° C. Progress of the reaction was checked by UPLC and after 2 h formation of the desired product was confirmed. The reaction was quenched with water and then extracted with EtOAc. The combined organic layers were collected, dried over Na.sub.2SO.sub.4 and evaporated in vacuo to give the crude product which was purified by Combi-flash chromatography to afford the title compound (190 mg, 65% yield) as a yellow solid. UPLC-MS m/z: 296 [M+H].

Step 2: 6-Amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile

[0594] ##STR00338##

[0595] To a stirred solution of 4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile (Preparation 62, Step 1) (0.180 g, 0.61 mmol) in ethanol (4 mL) was added Fe powder (0.33 mg, 6.1 mmol) and a saturated solution of NH.sub.4Cl (4 mL) in ice-cold water. The mixture was kept at ice cold temperature for 5 min. after which time the mixture was refluxed for 1 h. Completion of the reaction was confirmed by TLC and LCMS. The reaction mixture was filtered through a celite pad and washed with ethanol. The ethanol mixture was evaporated under reduced pressure, diluted with water, extracted with EtOAc, dried with Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title compound (160 mg, crude) as a brown oily crude which was used in the next step without any further purification. UPLC-MS m/z: 264.15 [M+H].

Example 81: 1-(4-Benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea

[0596] ##STR00339##

[0597] To a stirring solution of 6-aminoindole (0.120 g, 0.9 mmol) in THF (3 mL) was added triphosgene (0.108 g, 0.39 mmol) at 0-5° C. and the mixture was stirred for five min. followed by 1 h at RT. Completion of the first stage of the reaction was confirmed by TLC and then 6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carbonitrile (Preparation 62, Step 2) (0.160 g, 0.60 mmol) and TEA (0.500 mL, 0.6 mmol) were added into the reaction mixture at 0-5° C. The resulting reaction mixture was stirred at RT for 1 h. UPLC and TLC showed mass of the desired product. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with 1 N NaOH solution followed by brine and dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to obtain a crude product which was purified by column chromatography using 2.5% MeOH in DCM as eluent to afford the title compound (180 mg, 72% yield) as a black solid. Purity by UPLC: 93.27%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.34 (d, 2H, J=11.2 Hz), 4.56 (m, 2H), 4.89 (s, 1H), 6.31 (s, 1H), 6.76-6.86 (m, 3H), 7.21-7.75 (m, 8H), 7.75 (s, 1H), 8.27 (s, 1H), 8.38 (s, 1H), 10.89 (s, 1H); UPLC-MS m/z: 424.19 [M+H].

Preparation 63: 1-(3-(Aminomethyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl-3-(1H-indol-6-yl)urea (Example 82)

[0598] ##STR00340##

[0599] To a stirring solution of 1-(4-benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea (Example 81) (80 mg, 0.189 mmol) in methanol (2 mL) was added NiCl.sub.2.6H.sub.2O (45 mg, 0.014 mmol) and NaBH.sub.4 (4.2 mg, 0.11 mmol) at 0-5° C. The reaction mixture was stirred at RT for 30 min. and after completion of the reaction (monitored by LCMS & TLC) the reaction mixture was quenched with NH.sub.4Cl solution. The methanol was evaporated under reduced pressure and the resulting residue was diluted with water, extracted with EtOAc, dried over anhydrous Na.sub.2SO.sub.4, and evaporated under reduced pressure to obtain the crude product which was purified by prep-HPLC to afford the title compound (10 mg, 12% yield) as a yellow solid. Purity by UPLC: 96.85%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.56-2.61 (m, 1H), 2.68-2.72 (m, 1H), 3.10-3.25 (m, 2H), 3.86 (d, 1H, J=9.8 Hz), 4.41 (d, 1H, J=10.56 Hz) 4.54 (s, 2H), 6.29 (s, 1H), 6.58-6.64 (m, 3H), 6.77 (d, 1H, J=8.28 Hz), 7.17 (s, 1H), 7.24 (d, 1H, J=6.56 Hz), 7.30-7.34 (m, 5H), 7.74 (s, 1H), 8.48 (s, 1H), 8.65 (s, 1H), 10.83 (s, 1H); UPLC-MS m/z: 428.32 [M+H].

Preparation 64: 6-3-(1H-Indol-6-yl)ureido)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxamide (Example 83)

[0600] ##STR00341##

[0601] To a stirred solution of 1-(4-benzyl-3-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea (Example 81) (100.0 mg, 0.24 mmol) in MeOH (8 mL) was added K.sub.2CO.sub.3 (163.18 mg, 1.18 mmol) at 0-5° C. and the whole was stirred for 5 min. Then H.sub.2O.sub.2 (0.6 mL, 30% aq.) was added at 0-5° C. and stirring continued for 2 h. The reaction was monitored by LCMS which showed formation of the desired product. The solvent was evaporated in vacuo to give the crude product which was purified by prep-HPLC to afford the title compound (12 mg, 12% yield) as a yellow solid. Purity by UPLC: 96.11%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 4.00 (s, 2H), 4.32 (d, 1H, J=16.5 Hz), 4.50 (d, 1H, J=9 Hz), 4.72 (d, 1H, J=16.44 Hz), 6.30 (s, 1H), 6.59-6.80 (m, 4H), 7.18-7.34 (m, 9H), 7.97 (s, 1H), 8.31 (s, 1H), 8.44 (s, 1H), 10.85 (s, 1H); UPLC-MS m/z: 442.31 [M+H].

Examples 186-188

[0602] The examples in the table below were prepared according to the above methods used to make Examples 78-83 as described in General Procedures 1-6 using the appropriate amine. Purification was as stated in the aforementioned methods.

TABLE-US-00007 IUPAC LCMS Purity Ex Structure Name 1H-NMR [M + H] (%) 186 [00342] 1-(4-benzyl- 3-cyano-3,4- dihydro-2H- benzo[b][1,4] oxazin-7-yl)- 3-(1H-indol- 6-yl)urea (400 MHz; DMSO- d.sub.6): δ 4.35 (m, 2H), 4.56 (m, 2H), 4.77 (s, 1H), 6.31 (s, 1H), 6.67 (d, 1H, J = 8.76 Hz), 6.80 (m, 2 H), 7.13 (s, 1H), 7.19 (s, 1H), 7-39-7-30 (m, 6H), 7.77 (s, 1H), 8.37 (s, 1H), 8.46 (s, 1 H), 10.89 (s, 1H). 424.13 99.04 187 [00343] 1-(3- (aminomethyl)- 4-benzyl- 3,4-dihydro- 2H- benzo[b][1,4] oxazin-7-yl)- 3-(1H-indol- 6-yl)urea (400 MHz; DMSO- d.sub.6): δ 2.59 (m, 2H), 2.99 (m, 2H), 3.94 (d, 1H, J = 10.2 Hz), 4.53-441 (m, 3H) 6.30 (s, 1H), 6.42 (d, 1H, J = 8.28 Hz), 6.69 (d, 1H, J = 7.28 Hz), 6.82 (m, 1H), 6.99 (s, 1H), 7.18- 7.37 (m, 7H), 7.77 (s, 1H), 8.44 (s, 1H), 428.16 96.08 8.64 (s, 1H), 10.86 (s, 1H). 188 [00344] 7-(3-(1H- indol-6- yl)ureido)-4- benzyl-3,4- dihydro-2H- benzo[b][1,4] oxazine-3- carboxamide (400 MHz; DMSO- d.sub.6): δ 3.94 (s, 1H)), 3-99 (s, 1H), 4.32 (d, 1H, J = 14.2 Hz), 4.50 (s, 1H), 4.66 (d, 1H, J = 15 Hz), 6.30 (s, 1H), 6.62 (s, 1H), 6.75-7-34 (m, 9H), 7.78 s, 1H), 8.47 (s, 1H), 8.63 (s, 1H), 10.85 (s, 1H). 442.09 97.28

Example 84: 2-(6-(3-(1H-Indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide

[0603] ##STR00345##

[0604] Example 84 was prepared according to General Procedures 1, 3-4, 6, 27 and the methods described below.

Preparation 65: 2-(6-Amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl-2-phenylacetamide

[0605] ##STR00346##

Step 1: Methyl 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate

[0606] ##STR00347##

[0607] To a stirred solution of commercially available 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (2 g, 11.1 mmol) in ACN (40.0 mL) was added methyl 2-bromo-2-phenylacetate (5.23 mL, 33.3 mmol) and the reaction mixture was stirred at 100° C. in a sealed tube for 16 h. The excess solvent was concentrated under reduced pressure and the reaction mixture was quenched with Na.sub.2CO.sub.3 solution and the organics extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (1×30 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude was purified by silica gel column chromatography (5-10% EtOAc-hexane) to afford the title compound (1.8 g, 49% yield) as a yellow sticky solid. LCMS m/z: 329.1 [M+H].

Step 2: 2-(6-Nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetic acid

[0608] ##STR00348##

[0609] To a stirred solution of methyl 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate (Preparation 65, Step 1) (0.200 g, 0.609 mmol) in THF:MeOH:water (10 mL, 2:1:1, v/v/v) was added LiOH.H.sub.2O (0.102 g, 2.437 mmol) at 0-5° C. and the reaction mixture was stirred at room temperature for 3 h. After complete consumption of the starting material (confirmed by LCMS), water was added and the reaction mixture was acidified with 1N HCl and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the title compound (172 mg, 90% yield) as a yellow solid. LCMS m/z: 315.2 [M+H].

Step 3: 2-(6-Nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl-2-phenylacetamide

[0610] ##STR00349##

[0611] To a stirred solution of 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetic acid (Preparation 65, Step 2) (0.172 g, 0.55 mmol) in DMF (3 mL) was added EDC-HCl (0.157 g, 0.82 mmol) and DIPEA (0.21 mL, 1.64 mmol) at 0-5° C. and the reaction mixture was stirred for 10 min. keeping the temperature at 0-5° C., then NH.sub.4Cl (0.150 g, 2.74 mmol) was added and the reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure, extracted with EtOAc, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by column chromatography using 40% EtOAc in hexane as eluent to afford the title compound (120 mg, 70% yield) as an off-white solid. LCMS m/z: 314.1 [M+H].

Step 4: 2-(6-Amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide

[0612] ##STR00350##

[0613] To a stirred solution of 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide (Preparation 65, Step 3) (0.200 g, 0.638 mmol) in MeOH (6 mL), was added Pd—C(0.05 g, 10% w/w) and the reaction mixture was stirred under hydrogen balloon pressure for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with MeOH. The filtrate was evaporated under reduced pressure to afford the crude material which was purified by column chromatography using 40% EtOAc in hexane as eluent to afford the title compound (100 mg, crude) as a gummy solid. LCMS m/z: 284.2 [M+H].

Preparation 66: 2-(6-3-(1H-Indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide (Example 84)

[0614] ##STR00351##

[0615] To a stirred solution of 1H-indol-6-amine (51.3 mg, 0.39 mmol) in THF (3 mL) was added p-nitrophenyl chloroformate (107 mg, 0.53 mmol) at 0-5° C. and the whole stirred at room temperature for 3 h. Then to the reaction mixture was added TEA (0.2 mL, 1.41 mmol) and 2-(6-amino-2, 3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetamide (Preparation 65, Step 4) (100 mg, 0.35 mmol) at the same temperature and the combined mixture was stirred for another 2 h. The reaction was monitored by LCMS. After completion the solvent was evaporated to obtain the crude product. The crude was purified by reverse phase prep-HPLC to afford the title compound (14 mg, 9% yield) as an off white solid. Purity by UPLC: 99.36%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.81-2.85 (m, 1H), 3.33-3.38 (m, 1H), 3.88 (t, 1H, J=7.56 Hz), 4.12 (m, 1H), 5.35 (s, 1H), 6.30 (s, 1H), 6.60 (d, 1H, J=8.44 Hz), 6.80-6.71 (m, 2H), 6.83 (s, 1H), 7.17 (s, 1H), 7.32-7.41 (m, 7H), 7.76 (s, 2H), 8.16 (s, 1H), 8.42 (s, 1H), 10.85 (s, 1H); LCMS m/z: 442.2 [M+H].

Example 81: 1-(4-(2-Hydroxy-1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-3-(1H-indol-6-yl)urea

[0616] ##STR00352##

[0617] Example 85 was prepared according to General Procedures 1, 3-4, 6 and the methods described below.

Preparation 67: Methyl 2-(6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl-2-phenylacetate

[0618] ##STR00353##

[0619] To a stirred and degassed solution of methyl 2-(6-nitro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate (Preparation 65, Step 1) (0.530 g, 1.614 mmol) in MeOH (20 mL) was added Pd—C(0.055 g, 10% w/w). The reaction mixture was then stirred at RT in the presence of hydrogen gas for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed thrice with MeOH. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography using 30% EtOAc in hexane as eluent to afford the title compound (0.4 g, 90% yield) as a yellow gummy solid. LCMS m/z: 299.25 [M+H].

Preparation 68: Methyl 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl-2-phenylacetate (Example 86)

[0620] ##STR00354##

[0621] To a stirred solution of 1H-indol-6-amine (0.05 g, 0.37 mmol) in THF (2.5 mL) was added Et.sub.3N (0.14 mL, 1.01 mmol) and p-nitrophenyl chloroformate (0.10 g, 0.50 mmol) at 0-5° C. and the resulting reaction mixture was stirred at 0-5° C. for 1 h. To the reaction mixture was added methyl 2-(6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate (Preparation 67) (0.10 g, 0.34 mmol) in THF (1.5 mL) at 0-5° C. and the reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC, 5% acetone in DCM), the solvent was evaporated under reduced pressure and extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by column chromatography using 2% acetone in DCM as eluent followed by trituration with pentane to give the title compound (0.05 g, 35% yield) as an off white solid. Purity by UPLC: 97.85%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.83 (d, 1H, J=12.44 Hz), 3.41-3.48 (m, 1H), 3.75 (s, 3H), 3.92 (t, 1H, J=9.24 Hz), 4.13 (t, 1H, J=94 Hz), 5.71 (s, 1H), 6.31 (s, 1H), 6.63 (d, 1H, J=8.68 Hz), 6.73-6.81 (m, 2H), 6.97 (s, 1H), 7.19 (s, 1H), 7.33-7.45 (m, 6H), 7.79 (s, 1H), 8.25 (s, 1H), 8.42 (s, 1H), 10.87 (s, 1H); LCMS m/z: 457.36 [M+H].

Preparation 69: 1-(4-(2-Hydroxy-1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl-3-(1H-indol-6-yl)urea (Example 85)

[0622] ##STR00355##

[0623] To a stirred solution of methyl 2-(6-(3-(1H-indol-6-yl)ureido)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2-phenylacetate (Example 86) (100 mg, 0.22 mmol) in THF (3 mL) was added DIBAL-H (0.66 mL, 0.66 mmol, 1M in toluene) dropwise at 0-5° C. The mixture was then stirred at the same temperature for 2 h. The reaction mixture was quenched by dropwise addition of a saturated solution of Rochelle salt at RT and the resulting solution was stirred at RT for 1 h. The reaction mass was filtered through a celite bed. The celite bed was washed with EtOAc, the organics were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain the crude product. This crude was purified by reverse phase prep-HPLC to afford the title compound (16 mg, 17% yield) as a yellow solid. Purity by UPLC: 98.85%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.31 (s, 1H), 3.51 (s, 1H), 3.91 (t, 2H, J=5.35 Hz), 4.05 (d, 1H, J=6.24 Hz), 4.12 (d, 1H, J=5.12 Hz), 4.84 (t, 1H, J=6.74 Hz), 4.99 (t, 1H, J=6.74 Hz) 6.31 (s, 1H), 6.55 (m, 2H), 6.78 (s, 2H), 6.90 (s, 1H), 7.19-7.38 (m, 6H), 7.77 (s, 1H), 8.14 (s, 1H), 8.32 (s, 1H), 10.85 (s, 1H); LCMS m/z: 429.2 [M+H].

Examples 189-190

[0624] The examples in the table below were prepared according to the above methods used to make Example 84-86 as described in General Procedures 1, 3-4, 6, 27 using the appropriate amine. Purification was as stated in the aforementioned methods.

TABLE-US-00008 IUPAC LCMS Purity Ex Structure Name 1H-NMR [M+H] (%) 189 [00356] 2-(6-(3- (1H-indol- 6- yl)ureido)- 2,3- dihydro- 4H- benzo[b][1, 4]oxazin-4- yl)-N- methyl-2- (400 MHz; DMSO- d.sub.6): δ 2.67 (s, 3H), 2.83-2.86 (m, 1H), 3.32 (d, 1H, J = 4.12 Hz), 3.91 (t, 1H, J = 7.28 Hz)), 4.11-4.15 (m, 1H), 5.37 (s, 1H), 6.31 (s, 1H), 6.63 (d, 1H, J = 8.4 Hz), 6.84- 6.71 (m, 3H), 7.19 (t, 1H, J = 2.48 Hz), 7.29- 456.44 98.67 phenylacetamide 7.42 (m, 5H), 7.78 (s, 1H), 8.18 (s, 1H), 8.27 (d, 1H, J = 4.64 Hz), 8.42 (s, 1H), 10.88 (s, 1H). 190 [00357] 2-(6-(3- (1H-indol- 6- yl)ureido)- 2,3- dihydro- 4H- benzo[b][1, 4]oxazin-4- yl)-N- cyclopropyl-2- (400 MHz; DMSO- d.sub.6): δ 0.47 (s, 2H), 0.64 (s, 2H), 2.70 (d, 1H, J = 11 Hz), 2.88 (d, 1H, J = 12.2 Hz)), 3.90 (s, 1H), 4.09 (S, 1H), 5-34 (s, 1H), 6.31 (s, 1H), 6.60-6.87 (m, 4H), 7.19-7.40 (m, 7H), 7.76 (s, 1H), 8.17 (s, 1H), 8.27 (d, 1H, J = 482.4  99.16 phenylacetamide 4.64 Hz), 8.45 (s, 2H), 10.87 (s, 1H).

Example 191: 6-(4-(1H-Indol-6-yl)piperazin-1-yl)-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one

[0625] ##STR00358##

[0626] Example 191 was prepared according to General Procedures 4, 25 and the methods described below.

Preparation 70: 4-Benzyl-6-bromo-2H-benzo[b][1,4]thiazin-3(4H)-one

[0627] ##STR00359##

[0628] K.sub.2CO.sub.3 (627 mg, 4.54 mmol) was added to a solution of commercially available 6-bromo-2H-benzo[b][1,4]thiazin-3(4H)-one (500 mg, 3.026 mmol) in DMF (3 mL) at RT. After stirring the mixture for 2-3 min., benzyl bromide (0.395 mL, 3.33 mmol) was added to the mixture and the whole was heated at 80° C. for 12 h. Progress of the reaction was monitored by LCMS and after completion the reaction mass was quenched with ice-water. The product was extracted with EtOAc. The combined organic layers were washed with water, brine solution, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (450 mg, 44.5% yield) as a white solid.

Preparation 71: 6-(Piperazin-1-yl)-1H-indole

[0629] ##STR00360##

Step 1: tert-Butyl 4-(1H-indol-6-yl)piperazine-1-carboxylate

[0630] ##STR00361##

[0631] LiHMDS (1.12 mL, 1.12 mmol) was added to a degassed mixture of commercially available 6-bromo-1H-indole (100 mg, 0.51 mmol), tert-butyl piperazine-1-carboxylate (114 mg, 0.61 mmol), Pd.sub.2(dba).sub.3 (4.6 mg, 0.005 mmol) and X-Phos (7.3 mg, 0.015 mmol) in THF (2 mL) in a sealed tube at RT. The tube was again purged with argon and then sealed. The mixture was stirred for 1-2 min. at RT and then heated at 65° C. for 24 h. Progress of the reaction was monitored by LCMS and after completion the reaction mixture was quenched with a saturated 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 concentrated under vacuum to obtain the crude product which was purified by silica gel column chromatography to afford the title compound (100 mg, 65% yield) as a white solid.

Step 2: 6-(Piperazin-1-yl)-1H-indole

[0632] ##STR00362##

[0633] 4M HCl in 1,4-Dioxane (3 mL) was added to a solution of tert-butyl 4-(1H-indol-6-yl) piperazine-1-carboxylate (Preparation 71, Step 1) (600 mg, 1.99 mmol) in dioxane at 0-5° C. Thereafter, the reaction was stirred at RT for 3 h. The reaction mass was quenched with saturated aqueous NaHCO.sub.3 solution and the product was extracted with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (210 mg, 52.4% yield) as a brown solid. LCMS m/z: 202 [M+H].

Preparation 72: 6-(4-(1H-indol-6-yl)piperazin-1-yl)-4-benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one (Example 191)

[0634] ##STR00363##

[0635] A mixture of 6-(piperazin-1-yl)-1H-indole (Preparation 71, Step 2) (60 mg, 0.29 mmol), 4-benzyl-6-bromo-3,4-dihydro-2H-1,4-benzothiazin-3-one (Preparation 70) (149 mg, 0.45 mmol), BrettPhos-Pd-G3 (27 mg, 0.03 mmol) and Cs.sub.2CO.sub.3 (291 mg, 0.894 mmol) in dioxane (4 mL) was heated at 100° C. for 24 h. Progress of the reaction was monitored by LCMS and after completion the solvents were evaporated under reduced pressure to give a crude compound which was purified by Prep-HPLC to afford the title compound (15 mg, 11% yield) as an off white sticky solid. Purity by HPLC 93.36%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 2.85 (s, 4H), 2.88 (s, 4H), 3.77 (s, 2H), 5.30 (s, 2H), 6.51 (d, 1H, J=2.96 Hz), 6.77 (s, 1H), 6.85 (d, 1H, J=8.8 Hz), 7.21-7.43 (m, 9H), 7.61 (d, 1H, J=8.32 Hz); LCMS m/z: 455.33 [M+H].

Example 192: 1-(4-Benzyl-R-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-2-cyano-3-(1H-indol-6-yl)guanidine

[0636] ##STR00364##

[0637] Example 192 was prepared according to General Procedures 2-4 and the methods described below.

Preparation 73: 6-Isothiocyanato-1H-indole

[0638] ##STR00365##

[0639] To a stirred solution of 6-amino indole (200 mg, 1.52 mmol) in DMF (10 mL) was added thio-CDI (297 mg, 1.67 mmol) in DMF (2 mL) dropwise at 0-5° C. The reaction was stirred at RT for 2 h. After completion of the reaction (checked by LCMS), it was quenched with ice-cold water (20 mL) and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain the title compound (40 mg, 20% yield) as a dark brown solid. The crude was used in the next step without any further purification.

Preparation 74: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl-3-(1H-indol-6-yl)thiourea

[0640] ##STR00366##

[0641] To a stirred solution of 6-isothiocyanato-1H-indole (Preparation 73) (40 mg, 0.23 mmol) in DCM (2.0 mL) was added 6-amino-4-benzyl-1,4-benzothiazin-3-one (Preparation 5) (62.1 mg, 0.23 mmol) at RT and the reaction mixture was stirred at the same temperature for 16 h. After completion of the reaction (monitored by LCMS) the reaction mass was evaporated to dryness to afford the title compound (80 mg, 78% yield) as a brown solid. The crude was used in the next step without any further purification. LCMS m/z: 445.41 [M+H].

Preparation 7.: Methyl-N′-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-N-(1H-indol-6-yl)carbamimidothioate

[0642] ##STR00367##

[0643] To a solution of 1-(4-benzyl-3-oxo-1,4-benzothiazin-6-yl)-3-(1H-indol-6-yl)thiourea (Preparation 74) (80 mg, 0.18 mmol) in acetone (2 mL) was added K.sub.2CO.sub.3 (62.3 mg, 0.45 mmol) and Mel (0.03 mL, 0.45 mmol) at RT. The reaction mixture was stirred at RT for 4 h. Progress of the reaction was monitored by LCMS and after completion the solvent was evaporated under vacuum. The residue was taken up in EtOAc and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (50 mg, 61% yield) as a brown solid.

[0644] The crude was used in the next step without any further purification. LCMS m/z: 459.17 [M+H].

Preparation 76: 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl-2-cyano-3-(1H-indol-6-yl)guanidine (Example 192)

[0645] ##STR00368##

[0646] A stirred solution of 3-(4-benzyl-3-oxo-1,4-benzothiazin-6-yl)-1-(1H-indol-6-yl)-2-methyl-isothiourea (Preparation 75) (50 mg, 0.11 mmol) in 2-propanol (1 mL) was treated with sodium hydrogencyanamide (8.74 mg, 0.14 mmol) and heated in a microwave at 80° C. for 1 h. After completion of the reaction (monitored by LCMS) the solvent was evaporated to obtain the crude product which was purified by prep-HPLC to afford the title compound (6 mg, 12.2% yield) as an off white sticky solid. Purity by HPLC 99.26%; .sup.1H NMR (400 MHz; DMSO-d.sub.6): δ 3.63 (s, 2H), 5.12 (s, 2H), 6.39 (s, 1H), 6.85 (d, 1H, J=7.92 Hz), 7.00 (d, 1H, J=7.96 Hz), 7.19-7.47 (m, 10H), 9.15 (s, 1H), 9.38 (s, 1H), 11.08 (s, 1H); LCMS m/z: 453.29 [M+H].

[0647] Biological Assay

[0648] Reporter Gene Expression Assay in THP-1 Cells

[0649] 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 IRF pathway, by assessing the activity of a secreted luciferase (Lucia) and the NF-κB pathway, by monitoring the activity of secreted SEAP. 5×10.sup.4 THP1-Dual™ cells were seeded in 384-well plates in growth medium and preincubated with novel compounds for 10 minutes followed by stimulation with 5 μM 2′,3′-cGAMP. After 20 hr of stimulation the supernatant was removed and the IRF pathway reporter protein was readily measured in the cell culture supernatant using QUANTI-Luc™ (Invivogen), a luciferase detection reagent on a Spectramax i3X luminometer.

[0650] In the tables below, IC.sub.50 value ranges for exemplary compounds are given. The IC.sub.50 ranges are indicated as “A” for values less than or equal to 1 μM, “B” for values greater than 1 μM and less than or equal to 10 μM, and “C” for values greater than 10 μM.

TABLE-US-00009 Activity data THP-1 (HAQ) Ex. No. Activity 1 B 2 B 3 B 4 B 6 B 9 B 12 C 16 C 17 C 18 A 19 B 22 A 23 B 24 B 25 B 26 B 27 C 28 B 29 B 30 B 31 B 32 B 33 B 38 C 39 B 40 B 41 B 42 B 43 B 44 B 45 B 46 C 47 B 48 C 49 C 50 A 51 B 52 B 53 C 55 B 56 B 57 C 59 B 60 B 62 C 63 C 64 B 65 A 66 A 67 A 68 B 69 A 72 A 73 B 74 B 75 B 76 B 77 B 78 A 79 B 80 B 81 B 82 C 83 B 84 B 85 B 86 B 87 B 88 C 89 A 90 B 91 C 92 B 93 B 94 A 95 A 96 C 97 A 98 B 99 A 100 B 101 A 102 A 103 A 104 A 105 A 106 A 107 A 108 A 109 A 110 B 111 B 112 A 113 B 114 A 115 B 116 B 117 A 118 C 119 B 120 B 121 B 122 B 123 B 124 A 125 A 126 A 127 B 128 C 129 A 130 C 131 C 132 B 133 B 134 B 135 B 136 B 137 B 138 C 139 B 140 B 141 B 142 B 143 C 144 B 145 B 146 B 147 B 148 B 149 B 150 B 151 C 152 B 153 C 154 C 155 C 156 B 157 B 158 C 159 B 160 B 161 C 162 C 163 C 164 B 165 B 166 B 167 C 168 C 169 A 170 B 171 A 172 B 173 B 174 A 175 B 176 B 177 B 178 B 179 B 180 B 181 A 182 A 183 C 184 B 185 A 186 B 187 B 188 B 189 B 190 B 191 B 192 C 193 C 194 C 195 C