HETEROCYCLIC SMALL MOLECULE MODULATORS OF HUMAN STING

Abstract

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

##STR00001##

Claims

1. A compound of formula (I): ##STR00292## wherein: X is CR.sup.9R.sup.10, NR.sup.9, CO, O, S, SO or SO.sub.2; X.sup.1 is CR.sup.1 or N; X.sup.2 is CR.sup.2 or N; X.sup.3 is CR.sup.3 or N; Q is CO, SO, SO.sub.2, CS or CR.sup.4R.sup.5; L is optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, CO, SO, SO.sub.2, CH.sub.2C(O), CH.sub.2CONH, or CONH; Y is an optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, an optionally substituted C.sub.2-C.sub.6 alkenyl, an optionally substituted C.sub.2-C.sub.6 alkynyl or an optionally substituted C.sub.3-C.sub.6 cycloalkyl; R.sup.1, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, halogen, CN, hydroxyl, COOH, CONR.sup.1R.sup.2, NR.sup.1R.sup.2, NHCOR.sup.1, optionally substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted C.sub.1-C.sub.6 alkoxycarbonyl group, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic 3 to 8 membered heterocycle, optionally substituted aryloxy, optionally substituted heteroaryloxy, and optionally substituted heterocyclyloxy; R.sup.4 and R.sup.5 are each independently selected from the group consisting of H, halogen, optionally substituted C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.6 cycloalkyl; or R.sup.4 and R.sup.5 together with the atom to which they are attached form a spirocyclic ring; R.sup.6 is mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted C.sub.3-C.sub.6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; R.sup.7 is H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted sulfonyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.2-C.sub.6 alkenyl or optionally substituted C.sub.2-C.sub.6 alkynyl; R.sup.8 is mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted mono or bicyclic C.sub.3-C.sub.6 cycloalkyl or an optionally substituted mono or bicyclic 3 to 8 membered heterocycle; and R.sup.9 and R.sup.10 are each independently selected from the group consisting of optionally substituted C.sub.1-C.sub.6 alkyl, H, halogen, CN, hydroxyl, CO.sub.2H, CONR.sup.1R.sup.2, azido, sulfonyl, NR.sup.1R.sup.2, NHCOR.sup.1, C.sub.1-C.sub.3 polyfluoroalkyl, optionally substituted C.sub.1-C.sub.6 thioalkyl, optionally substituted C.sub.1-C.sub.6 alkylsulfonyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 alkoxy, optionally substituted C.sub.1-C.sub.6 alkoxycarbonyl, mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl, mono or bicyclic optionally substituted 5 to 10 membered heteroaryl, optionally substituted 3 to 8 membered heterocycle, optionally substituted aryloxy, and an optionally substituted heteroaryloxy; or R.sup.9 and R.sup.10 together with the C atom to which they are attached can combine to form an optionally substituted spirocyclic ring; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

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

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

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

5. A compound according to any preceding claim, wherein X is CR.sup.9R.sup.10.

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

7. A compound according to claim 6, wherein both R.sup.9 and R.sup.10 are a C.sub.1-C.sub.6 alkyl.

8. A compound according to any one of claims 1 to 6, wherein at least one of R.sup.9 and R.sup.10 is a halogen, CN, hydroxyl, azido, NH.sub.2, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl or a C.sub.1-C.sub.6 alkyl substituted with a CN group.

9. A compound according to any one of claims 1 to 5, wherein R.sup.9 and R.sup.10 together with the C atom to which they are attached combine to form a C.sub.3-C.sub.6 spirocyclic ring or a 3 to 8 membered heterospirocyclic ring.

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

11. A compound according to claim 10, wherein Q is CO.

12. A compound according to any preceding claim, wherein L is CO, SO.sub.2 or an optionally substituted C.sub.1-C.sub.6 alkyl.

13. A compound according to claim 12, wherein L is CH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH(CH.sub.3), CH(F) or CF.sub.2.

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

15. A compound according to claim 14, wherein R.sup.6 is an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted oxazole or an optionally substituted pyrazole.

16. A compound according to either claim 14 or claim 15, wherein R.sup.6 is a mono or bicyclic C.sub.5-C.sub.10 aryl or a mono or bicyclic 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is substituted with between 1 and 5 substituents, and the or each substituent is independently selected from the list consisting of halogen, C.sub.1-C.sub.6 alkyl, CN, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 polyfluoroalkyl, azido, CONR.sup.1R.sup.2 and OH.

17. A compound according to any one of claims 14 to 16, wherein the aryl is phenyl or naphthyl.

18. A compound according to claim 17, wherein phenyl or the naphthyl is substituted by 1 or 2 halogens.

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

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

21. A compound according to any preceding claim, wherein Y is an optionally substituted C.sub.1-C.sub.6 alkyl.

22. A compound according to claim 21, wherein Y is CH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH(CH.sub.3), CH(F) and CF.sub.2.

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

24. A compound according to claim 23, wherein R.sup.8 is an optionally substituted phenyl, an optionally substituted pyridine, an optionally substituted naphthyl, an optionally substituted furanyl, an optionally substituted benzofuranyl, an optionally substituted thiophene, an optionally substituted pyridofuran, an optionally substituted benzoxazole or an optionally substituted benzothiazole.

25. A compound according to either claim 23 or claim 24, wherein R.sup.8 is a mono or bicyclic C.sub.5-C.sub.10 aryl or a mono or bicyclic 5 to 10 membered heteroaryl substituted with between 1 and 5 substituents, and the or each substituent is independently selected from the list consisting of C.sub.1-C.sub.6 alkyl, halogen, OH, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 polyfluoroalkyl, CONR.sup.1R.sup.2, CN and azido.

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

27. A compound according to claim 26, wherein: L is a C.sub.1-C.sub.2 alkyl; Y is a C.sub.1-C.sub.2 alkyl; R.sup.6 is optionally substituted phenyl, optionally substituted pyridine, optionally substituted naphthyl, optionally substituted oxazole or optionally substituted pyrazole, wherein the phenyl, pyridine, naphthyl, oxazole or pyrazole is optionally substituted with C.sub.1-C.sub.6 alkyl, halogen and/or C.sub.1-C.sub.3 polyfluoroalkyl; and R.sup.8 is optionally substituted phenyl, optionally substituted pyridine, optionally substituted naphthyl, optionally substituted furanyl, optionally substituted benzofuranyl, optionally substituted thiophene, optionally substituted pyridofuran, optionally substituted benzoxazole or optionally substituted benzothiazole, wherein the phenyl, pyridine, naphthyl, furanyl, benzofuranyl, thiophene, pyridofuran, benzoxazole or benzothiazole is optionally substituted with C.sub.1-C.sub.6 alkyl, halogen, OH, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3 polyfluoroalkyl, CONR.sup.1R.sup.2, CN and/or azido.

28. A compound according to claim 26, wherein: X is CR.sup.9R.sup.10; X.sup.2 is CH; Q is CO; L is C.sub.1-C.sub.2 alkyl; Y is an a C.sub.1-C.sub.3 alkyl; R.sup.6 is a mono or bicyclic C.sub.5-C.sub.10 aryl substituted with at least one halogen; R.sup.7 is H; R.sup.8 is a mono or bicyclic optionally substituted C.sub.5-C.sub.10 aryl or mono or bicyclic optionally substituted 5 to 10 membered heteroaryl; and R.sup.9 and R.sup.10 are each independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, halogen, CN, azido, NR.sup.1R.sup.2, C.sub.3-C.sub.6 cycloalkyl, and C.sub.1-C.sub.6 alkoxy.

29. A compound according to claim 28, wherein: L is CH.sub.2; Y is CH.sub.2; R.sup.6 is a phenyl ring substituted with at least one chlorine and/or fluorine; R.sup.8 is a phenyl ring substituted with at least one fluorine; and R.sup.9 and R.sup.10 are each independently selected from the group consisting of C.sub.1-C.sub.3 alkyl, CN and halogen.

30. A compound according to claim 1, wherein the compound is: 1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 2-(1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxamido)acetic acid; 1-(3,5-difluorobenzyl)-3,3-dimethyl-N-(3-methylbenzyl)-2-oxoindoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(thiophen-2-ylmethyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-(3-methylbenzyl)-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(3-chlorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; N,1-dibenzyl-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-benzyl-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(3-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(3-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-1-(3-methyl-5-(trifluoromethyl)benzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-1-(3-(trifluoromethyl)benzyl)indoline-6-carboxamide; 3,3-dimethyl-1-(3-methylbenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3-chlorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide 1-(4-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-2-oxo-1-(pyridin-4-ylmethyl)-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-((5-methylthiophen-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(4-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(2,4-difluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(2,6-difluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-N-((6-methylpyridin-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-oxoindoline-6-carboxamide; N-(benzo[d]oxazol-2-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-((2-methyloxazol-5-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-((4-methylpyridin-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2,3-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-7-fluoro-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(3,5-difluorobenzyl)-7-fluoro-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(benzofuran-2-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(3-carbamoylbenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3-carbamoylbenzyl)-N-(2,4-difluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(3,5-difluorobenzyl)-N-((3,3-difluorocyclopentyl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; N-(benzo[d]thiazol-2-ylmethyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(4-fluorobenzyl)-N-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(3-fluorobenzyl)-N-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(3,5-difluorobenzyl)-N-((4,4-difluorocyclohexyl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; N-(3-cyanobenzyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(3-(trifluoromethyl)benzyl)indoline-6-carboxamide; 1-(3,4-difluorobenzyl)-N-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; N-(3-azidobenzyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; N-(4-azidobenzyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-((2-fluoropyridin-4-yl)methyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2,6-difluorobenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2-chlorobenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 3,3-dimethyl-1-((3-methylisoxazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-1-((2-methylpyridin-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-1-((2-methylpyridin-4-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(4-azidobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3-azidobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-1-((2-methylthiazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-1-phenethylindoline-6-carboxamide; 1-(4-fluorobenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2,3-difluorobenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-1-(2-oxo-2-phenylethyl)indoline-6-carboxamide; 1-(2-fluoro-6-methylbenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2,6-difluoro-4-methoxybenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2,6-difluoro-4-hydroxybenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluoro-3-methoxybenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluoro-3-hydroxybenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3,5-difluorobenzyl)-N-((5-fluorofuran-2-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 3,3-dimethyl-1-((5-methylisoxazol-3-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(benzofuran-5-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(2-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-fluoro-3-methylbenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((6-fluorobenzofuran-2-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((5-fluorobenzofuran-2-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-cyano-6-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-1-((1-methyl-1H-pyrazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-1-((5-methyl-2-(m-tolyl)oxazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3-carbamoyl-2-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-1-((2-methyloxazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-fluoro-6-(trifluoromethyl)benzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(4-aminobenzyl)-1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; N-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; N-(benzo[d][1,3]dioxol-4-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-((5-hydroxybenzofuran-2-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(3-fluoro-5-methoxybenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(benzofuran-6-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 3,3-dimethyl-1-((5-methyl-2-phenyloxazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(benzofuran-2-ylmethyl)-3-cyano-1-(3,5-difluorobenzyl)-3-methyl-2-oxoindoline-6-carboxamide; N-(benzofuran-4-ylmethyl)-1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-((5-nitrobenzofuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-2-oxo-N-((2-oxoindolin-5-yl)methyl)indoline-6-carboxamide; 3,3-dimethyl-1-((1-methyl-1H-indazol-7-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(isoxazolo[5,4-b]pyridin-3-ylmethyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(benzo[d]isoxazol-3-ylmethyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-2-oxo-1-(pyridin-2-ylmethyl)-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(benzofuran-3-ylmethyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(benzo[d]oxazol-2-ylmethyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-fluoro-6-methoxybenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-fluoro-6-methylbenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-fluoro-3-methoxybenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-((4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(benzofuran-2-ylmethyl)-1-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(2-bromo-6-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2,6-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2,6-dimethylbenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-(difluoromethoxy)-6-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(benzofuran-2-ylmethyl)-1-((4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 3,3-dimethyl-1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-((5,6-difluorobenzofuran-2-yl)methyl)-1-((4-fluoro-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-((4-fluoro-1,3-dimethyl-1H-pyrazol-5-yl)methyl)-N-((5-fluorobenzofuran-2-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)-N-((5-fluorobenzofuran-2-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-((4-fluoro-1-(2-methoxyethyl)-3-methyl-1H-pyrazol-5-yl)methyl)-N-((5-fluorobenzofuran-2-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-((4-fluoro-1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-5-yl)methyl)-N-((5-fluorobenzofuran-2-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide; 1-(4-carbamoylbenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(4-carbamoyl-2-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3,4-difluorobenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(1-(4-fluorophenyl)ethyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2-cyanobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(3,5-difluorobenzyl)-3,3-dimethyl-1-((5-methylfuran-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-((5-methyloxazol-2-yl)methyl)-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-((1-methyl-1H-pyrrol-2-yl)methyl)-2-oxoindoline-6-carboxamide; 3,3-dimethyl-1-((2-methyloxazol-5-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3,3-dimethyl-1-((5-methyl-2-(p-tolyl)oxazol-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-((2-(4-fluorophenyl)-5-methyloxazol-4-yl)methyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(benzofuran-2-ylmethyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,3-dimethylindoline-6-carboxamide; 3,3-difluoro-1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-(2,4,6-trifluorobenzyl)-1,3-dihydrobenzo[c]isothiazole-6-carboxamide 2,2-dioxide; 1-(2-chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)indoline-6-carboxamide; 3,3-dimethyl-1-(2-phenylacetyl)-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3,5-difluorobenzyl)-2-oxo-N-(2,4,6-trifluorobenzyl)spiro[cyclopentane-1,3-indoline]-6-carboxamide; 1-(3,5-difluorobenzyl)-7-fluoro-2-oxo-N-(2,4,6-trifluorobenzyl)spiro[cyclohexane-1,3-indoline]-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxospiro[cyclopropane-1,3-indoline]-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-1,3-dihydrobenzo[c]isothiazole-6-carboxamide 2,2-dioxide; 1-(3,5-difluorobenzyl)-2,3-dioxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-2,3-dioxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-chloro-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6 trifluorobenzyl) indoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3-methyl-3-(methylamino)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-chloro-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-chloro-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3-hydroxy-3-methyl-2-oxoindoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3-fluoro-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-methoxy-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-(dimethylamino)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-azido-1-(2-chloro-6-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-amino-1-(2-fluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-chloro-1-(2-chloro-6-fluorobenzyl)-3-ethyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-chloro-1-(2-chloro-6-fluorobenzyl)-2-oxo-3-phenyl-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-chloro-1-(2-chloro-6-fluorobenzyl)-3-isopropyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-ethyl-3-hydroxy-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-3-isopropyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-2-oxo-3-phenyl-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-ethyl-3-methoxy-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3-hydroxy-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-cyano-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-cyano-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-cyano-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-cyano-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 2-(1-(3,5-difluorobenzyl)-3-methyl-2-oxo-6-((2,4,6-trifluorobenzyl)carbamoyl)indolin-3-yl)acetic acid; 1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N6-(2,4,6-trifluorobenzyl)indoline-3,6-dicarboxamide; 1-(3,5-difluorobenzyl)-3-methyl-3-(2-morpholinoethyl)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-(aminomethyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-(2-aminoethyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(2,4-difluorobenzyl)-1-(3,5-difluorobenzyl)-3-(2-hydroxyethyl)-3-methyl-2-oxoindoline-6-carboxamide; 3-allyl-1-((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; N-(2,4-difluorobenzyl)-1-(3,5-difluorobenzyl)-3-(hydroxymethyl)-3-methyl-2-oxoindoline-6-carboxamide; 1-(2-chloro-6-fluorobenzyl)-3-(3-hydroxypropyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 3-(cyanomethyl)-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; 1-(4-fluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-(benzofuran-2-ylmethyl)-3,3-dimethyl-1-((2-methylpyridin-4-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; 3,3-dimethyl-2-oxo-1-(pyridin-4-ylmethyl)-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; 3,3-dimethyl-1-((2-methylpyridin-4-yl)methyl)-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboxamide; 1-(3,5-difluorobenzyl)-N-(furo[2,3-c]pyridin-2-ylmethyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; 1-(3,5-difluorobenzyl)-N-(4-fluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorophenethyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-benzyl-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-(4-cyanobenzyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; N-(benzofuran-2-ylmethyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrol o[3,2-b]pyridine-6-carboxamide; 1-(2-fluoro-6-methylbenzyl)-N-(4-fluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-H-pyrrolo[2,3-b]pyridine-6-carboxamide; 1-(2-fluoro-6-methylbenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; 1-(2-fluoro-6-methylbenzyl)-3,3-dimethyl-N-((5-methylfuran-2-yl)methyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide; 1-(2-fluoro-6-methylbenzyl)-N-(4-fluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrol o[3,2-b]pyridine-6-carboxamide; 1-(3,5-difluorobenzyl)-N-(4-fluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide; N-(2,4-difluorobenzyl)-1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide; 3-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide; 3-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydrobenzo[d]thiazole-5-carboxamide; or 3-(2-chlorobenzyl)-N-(furan-2-ylmethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

32. A compound according to any one of claims 1 to 30 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 31, for use in therapy.

33. A compound according to any one of claims 1 to 30 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 31, for use in modulating the Stimulator of Interferon Genes (STING) protein.

34. A compound for use according to claim 33, wherein the compound is for use in activating the STING protein.

35. A compound according to any one of claims 1 to 30 or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, or a pharmaceutical composition according to claim 31, for use in treating, ameliorating or preventing cancer, bacterial infection, viral infection, parasitic infection, fungal infection, immune-mediated disorder, central nervous system disease, peripheral nervous system disease, neurodegenerative disease, mood disorder, sleep disorder, cerebrovascular disease, peripheral artery disease or cardiovascular disease.

36. A compound for use according to claim 35, wherein the disease is cancer.

37. A compound for use according to claim 36, wherein the cancer is selected from the group consisting of colorectal cancer, aero-digestive squamous cancer, lung cancer, brain cancer, liver cancer, stomach cancer, sarcoma, leukaemia, lymphoma, multiple myeloma, ovarian cancer, uterine cancer, breast cancer, melanoma, prostate cancer, bladder cancer, pancreatic carcinoma or renal carcinoma.

38. A compound for use according to any one of claims 32 to 37, wherein the compound is for use with a second therapeutic agent, optionally wherein the second therapeutic agent comprises an antiviral agent, an anti-inflammation agent, conventional chemotherapy, an anti-cancer vaccine and/or hormonal therapy.

39. A compound for use according to claim 38, wherein the second therapeutic agent comprises a B7 costimulatory molecule, interleukin-2, interferon-g, GM-CSF, a CTLA-4 antagonist (such as Ipilimumab and tremilimumab), an IDO inhibitor or IDO/TDO inhibitor (such as Epacadostat and GDC-0919), a PD-1 inhibitor (such as Nivolumab, Pembrolizumab, Pidilizumab, AMP-224, and MDX-1106), a PD-L1 inhibitor (such as Durvalumab, Avelumab and Atezolizumab), an OX-40 ligand, a LAG3 inhibitor, a CD40 ligand, a 41BB/CD137 ligand, a CD27 ligand, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, a TLR agonist (such as Poly I:C, MPL, LPS, bacterial flagellin, imiquimod, resiquimod, loxoribine and a CpG dinucleotide) and/or detoxified endotoxins.

40. A process for making the composition of claim 31, the process comprising contacting a therapeutically effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

41. A compound of formula (II) or (III): ##STR00293## wherein, X, X.sup.1, X.sup.2, X.sup.3, Q, L, Y, R.sup.6, R.sup.7 and R.sup.8 are as defined in any one of claims 1 to 30; and R is H or a C.sub.1-C.sub.6 alkyl, or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.

42. A compound according to claim 41, wherein the compound is selected from: ##STR00294## ##STR00295## ##STR00296##

43. A conjugate of formula (IV): ##STR00297## wherein C is a compound according to any one of claims 1 to 30; L.sup.1 is a linker; T is a targeting moiety; and a is an integer between 1 and 10.

Description

[0245] For a better understanding of the invention, and to show embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which:

[0246] FIG. 1 shows allele frequency of the major polymorphisms of human STING derived from the 1000 Genome Project database;

[0247] FIG. 2 are Western blots of human STING proteins combined with compounds of the invention or a vehicle control (VC) and incubated with antibodies specific for phosphorylated STING (pSTING), phosphorylated IRF3 (pIRF3), ACTIN, total STING (STING), and IRF3;

[0248] FIG. 3 shows the results of cytokines measured by an ELISA assay of human PBMCs stimulated with compounds of the invention compared to an unstimulated control (Unstm); and

[0249] FIG. 4 shows tumour growth against time (in days) in mice dosed intra-tumorally with compounds of the invention or a VC.

GENERAL SCHEMES

General Scheme 1

[0250] A compound of Formula (I) may be prepared in a four-step process, as shown below, from a compound of Formula (VII), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00024##

[0251] First, the compound of formula (VII) is reacted with a suitable base and a suitable electrophile to cause an alkylation reaction and provide the compound of formula (VI). The base may be K.sub.2CO.sub.3, Li.sub.2CO.sub.3, NaH, LiHMDS or BuLi, and the electrophile may be R.sup.9-G and/or R.sup.10-G where G is a suitable leaving group.

[0252] The compound of formula (VI) may then be reacted with a suitable base and a compound of formula (V), where G is a suitable leaving group to cause it to undergo an alkylation/acylation reaction and provide a compound of formula (IV). The suitable base may be, such as K.sub.2CO.sub.3, Li.sub.2CO.sub.3, NaH, LiHMDS or BuLi and the suitable leaving group may be an optionally substituted alkylaryl(het), alkyl, aryl(het), cycloalkyl, alkylcycloalkyl halide, triflate or tosylate.

[0253] The compound of Formula (IV) may then be reacted with a suitable base to cause it to undergo hydrolysis and provide a compound of formula (II). The suitable base may be LiOH, KOH or NaOH, and the reaction may be conducted in a suitable organic solvent such as THF or DMA.

[0254] Finally, the compound of formula (II) may be reacted with a compound of formula (III) to provide a compound of formula (I). Typical conditions for this amide bond forming reaction may include the use of a suitable organic base and a suitable coupling agent. Preferred coupling agents are either EDCI with HOBt, HATU, HBTU, T.sub.3P or BOP. Preferred organic bases comprise either DIPEA or TEA in a suitable organic solvent such as DCM, DMF, DMA or MeCN. The reaction may be shaken or stirred at room temperature.

General Scheme 2

[0255] Alternatively, a compound of formula (VIII) may be prepared in a four-step process, as shown below, from a compound of formula (XIII), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00025##

[0256] A compound of formula (XIII) may be reacted with a malonate reagent, such as diethyl malonate, and a suitable base, such as NaH, to produce a compound of formula (XII). Hydrolysis followed by decarboxylation, using for example LiCl in a polar solvent such as DMSO, provides a compound of formula (XI).

[0257] The compound of formula (XI) may be reduced to give a compound of formula (X) and then alkylated to give a compound of formula (VIII). Alternatively, the compound of formula (XI) may be alkylated to give a compound of formula (IX) and then reduced to give a compound of formula (VIII). In either case, the reduction reaction may be conducted using hydrogen gas or a hydrogen source (such as ammonium formate) and a suitable catalyst (such as a Pt or Pd-based reagent) in a polar solvent (such as MeOH or EtOH). The alkylation reaction may be analogous to the reaction described above in relation to step (iii) of General Scheme 1.

[0258] It will be appreciated that the compound of formula (VIII) is a compound of formula (IV), as identified in General Scheme 1, where Q is CO. Accordingly, the compound of formula (VIII) can be further reacted, as described in General Scheme 1, to give a compound of formula (I), where Q is CO.

General Scheme 3

[0259] Alternatively, the compound of formula (X), obtained in General Scheme 2, may be further reacted like so:

##STR00026##

[0260] First the compound of formula (X) is oxidized at the benzylic position to provide the compound of formula (XX). The oxidation reaction uses a suitable oxidant, such as selenium dioxide or manganese dioxide.

[0261] The compound of formula (XX) may then undergo alkylation to give a compound of formula (XIX), subsequent hydrolysis to give a compound of formula (XVIII) and subsequent amide formation to provide a compound of formula (XVII). These reactions may be analogous to the reactions described above in relation to steps (iv), (ii) and (i), respectively, of General Scheme 1. It will be noted that this product is a compound of formula (I) where X is CO.

[0262] The compound of formula (XVII) can then be alkylated using a suitable Grignard or other organometallic reagent to provide a compound of formula (XVI). Again, it will be noted that this product is a compound of formula (I) where X is CR.sup.9R.sup.10 and R.sup.10 is OH.

[0263] The hydroxyl group on the compound of formula (XVI) can then is converted into a suitable leaving group, G to provide a compound of formula (XV). The suitable leaving group may be a halide, a triflate or a tosylate. Finally, the leaving group can be displaced by an R.sup.12ZH group, where Z is O, N or C and R.sup.12Z is R.sup.10.

General Scheme 4

[0264] Alternatively, the compound of formula (XIX), obtained in General Scheme 3, can then be alkylated using a suitable Grignard or other organometallic reagent to provide a compound of formula, as described in relation to step (ix) of General Scheme 3 to generate ta compound of formula (XXIII). The hydroxyl group on the compound of formula (XXIII) can then be converted into a suitable leaving group, G, as described in relation to step (x) of General Scheme 3, which can then be displacement with an alcohol to give a compound of formula (XXII). Alternatively, the compound of formula (XXIII) can be converted by direct alkylation of the alcohol to give the compound of formula (XXII) in a one-step process.

[0265] The compound of formula (XXII) may then undergo hydrolysis and reaction with a compound of formula (III), as described in relation to steps (ii) and (i), respectively, of General Scheme 1 to provide a compound of formula (XIV).

##STR00027##

General Scheme 5

[0266] The compound of formula (VIII), obtained in General Scheme 2, may be further reacted like so:

##STR00028##

[0267] First, the compound of formula (VIII) undergoes a reduction reaction using a suitable reducing agent, such as LiAlH.sub.4 or DIBAL-H, to provide a compound of formula (XXVII).

[0268] The compound of formula (XXVII) can then undergo an alkylation/acylation reaction, as described in relation to process step (iv) in General Scheme 1, to give a compound of formula (XXVI). This compound can the undergo hydrolysis, as described in relation to process step (ii) in General Scheme 1, to give a compound of formula (XXV). Finally, this compound may be reacted with a compound of formula (III), as described in relation to process step (i) in General Scheme 1, to provide a compound of formula (XXIV).

[0269] It will be appreciated that the compound of formula (XXIV) is a compound of formula (I) where Q is CH.sub.2.

General Scheme 6

[0270] Alternatively, a compound of Formula (XXVIII) may be prepared in an eight-step process, as shown below, from a compound of Formula (XXXVI), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00029## ##STR00030##

[0271] First, the compound of formula (XXXVI) is halogenated. In the scheme shown, the compound is brominated using Br.sub.2 or a Br source such as NBS, to yield a compound of formula (XXXV). While this is the preferred method, it is appreciated that other halogens could be used.

[0272] The compound of formula (XXXV) is then reacted with a suitable reagent, such as sodium sulphite, to displace the halide and give a compound of formula (XXXIV). This compound can then be reduced, as described in relation to step (vii) of General Scheme 2, to provide a compound of formula (XXXIII). The compound of formula (XXXIII) may then be reacted with a suitable reagent, such as POCl.sub.3, to provide a compound of formula (XXXII).

[0273] The compound of formula (XXXII) can then undergo an alkylation/acylation reaction, as described in relation to process step (iv) in General Scheme 1, to give a compound of formula (XXXI). The compound of formula (XXXI) may be alkylated, as described in relation to process step (iii) in General Scheme 2, to give a compound of formula (XXX). This compound can the undergo hydrolysis, as described in relation to process step (ii) in General Scheme 1, to give a compound of formula (XXIX). Finally, this compound may be reacted with a compound of formula (III), as described in relation to process step (i) in General Scheme 1, to provide a compound of formula (XXVIII).

[0274] It will be appreciated that the compound of formula (XXVIII) is a compound of formula (I) where Q is SO.sub.2.

General Scheme 7

[0275] A compound of Formula (XXXVII) may be prepared in a five-step process, as shown below, from a compound of Formula (XLII), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00031##

[0276] Firstly, the compound of formula (XLII) undergoes acylation using a suitable acylating agent, such as ethyl/methylchloroformate, in the presence of a suitable base, such as TEA, DIPEA, pyridine or NaH, to provide a compound of formula (XLI). This compound then undergoes Ullman or Buchwald amination with a suitable aminating agent (V) to give a cyclized compound of formula (XL).

[0277] The compound of formula (XL) may be alkylated, as described in relation to process step (iii) in General Scheme 2, to give a compound of formula (XXXIX). This compound can the undergo hydrolysis, as described in relation to process step (ii) in General Scheme 1, to give a compound of formula (XXXVIII). Finally, this compound may be reacted with a compound of formula (III), as described in relation to process step (i) in General Scheme 1, to provide the compound of formula (XXXVII).

[0278] It will be appreciated that the compound of formula (XXXVII) is a compound of formula (I) where Q is CO and X is CR.sup.9H or NR.sup.9.

General Scheme 8

[0279] Finally, compounds of Formula (I) may be prepared using a modification of the above processes, as shown below, from a compound of Formula (VI), where R is methyl, ethyl, benzyl or tert-butyl.

##STR00032##

[0280] Firstly, the compound of formula (VI) undergoes hydrolysis, as described in relation to process step (ii) in General Scheme 1, to give a compound of formula (XLIV). This compound may be reacted with a compound of formula (III), as described in relation to process step (i) in General Scheme 1, to provide the compound of formula (XLIII). Finally, this compound can be substituted as described for process step (iv) with a compound of formula (V) to provide compounds of formula (I).

[0281] It will be appreciated that this compound is a compound of formula (I) where Q is CO and X is CR.sup.9R.sup.10.

General Synthetic Procedures

General Procedure 1

[0282] ##STR00033##

[0283] To a stirred solution of carboxylic acid (II) (1.277 mmol) in a suitable solvent such as DCM, DMF, DMA or MeCN (10 mL) was added amine (III) (1.2 eq.) and a coupling reagent such as T.sub.3P, HATU, EDCl, HOBT, BOP or HBTU (1.5 eq.), followed by addition of an organic base such as DIPEA or TEA (2.0 eq.) dropwise to the solution and the mixture allowed to stir at RT for 2-3 h. When UPLC or TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO.sub.3 solution followed by dilute aqueous HCl and finally with brine, and then dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to obtain the crude material which was purified by Combi-flash or prep-HPLC purification using appropriate solvent mixtures as eluent to afford a pyrrolidinone compound of formula (I) (70-80% yield) as a pale yellow solid. A similar procedure can be followed to synthesize all amides of formula (I).

General Purification and Analytical Methods

[0284] All final compounds were purified by either Combi-flash or prep-HPLC purification, and analysed for purity and product identity by UPLC or LCMS according to one of the below conditions.

Prep-HPLC

[0285] Preparative HPLC was carried out on a Waters auto purification instrument using either a YMC Triart C18 column (25020 mm, 5 m) or a Phenyl Hexyl column (25021.2 mm, 5 m) operating at between ambient temperature and 50 C. with a flow rate of 16.0-50.0 mL/min.

[0286] Mobile phase 1: A=20 mM Ammonium Bicarbonate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 60% A and 40% B after 3 min., then to 30% A and 70% B after 20 min., then to 5% A and 95% B after 21 min., held at this composition for 1 min. for column washing, then returned to initial composition for 3 min.

[0287] Mobile phase 2: A=10 mM Ammonium Acetate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 90% A and 10% B, then to 70% A and 30% B after 2 min., then to 20% A and 80% B after 20 min., then to 5% A and 95% B after 21 min., held at this composition for 1 min. for column washing, then returned to initial composition for 3 min.

LCMS Method

[0288] General 5 min method: Zorbax Extend C18 column (504.6 mm, 5 um) operating at ambient temperature and a flow rate of 1.2 mL/min. Mobile phase: A=10 mM Ammonium Acetate in water, B=Acetonitrile; Gradient profile: from 90% A and 10% B to 70% A and 30 B in 1.5 min, and then to 10% A and 90% B in 3.0 min, held at this composition for 1.0 min, and finally back to initial composition for 2.0 min.

UPLC Method

[0289] UPLC was carried out on a Waters auto purification instrument using a Zorbax Extend C18 column (504.6 mm, 5 m) at ambient temperature and a flow rate of 1.5 ml/min.

[0290] Mobile phase 1: A=5 mM Ammonium Acetate in water, B=5 mM Ammonium Acetate in 90:10 Acetonitrile/water; Gradient profile from 95% A and 5% B to 65% A and 35% B in 2 min., then to 10% A and 90% B in 3.0 min., held at this composition for 4.0 min. and finally back to the initial composition for 5.0 min.

[0291] Mobile phase 2: A=0.05% formic acid in water, B=Acetonitrile; Gradient profile from 98% A and 2% B over 1 min., then 90% A and 10% B for 1 min., then 2% A and 98% B for 2 min. and then back to the initial composition for 3 min.

General Procedure 2

[0292] ##STR00034##

Basic Hydrolysis

[0293] To a stirred solution of an ester (IV) (1.49 mmol) in a mixture of MeOH or THF (10 mL) and water (5 mL) was added LiOH, NaOH or KOH (2.0 eq.) at RT and the resulting reaction mixture was stirred at RT for 2-16 h. TLC showed complete consumption of the ester (IV), upon which the solvent was evaporated under reduced pressure and the resulting residue was washed with ether. The residue was then acidified with 1N HCl to pH 2-4, which resulted in the formation of a precipitate, which was filtered and washed with water and then dried under reduced pressure at 50-60 C. to afford the desired carboxylic acid of formula (II) (70-85% yield) as an off white solid.

Acidic Hydrolysis

[0294] Alternatively, a stirred solution of ester (IV) (1.49 mmol) in a mixture of HCl (conc.)-AcOH (1:1; 10 mL) was heated at 70-80 C. for 8-10 h. The reaction was monitored by LCMS, and after completion, the residue was cooled to 0-5 C. The resulting precipitate was filtered, washed with cold water and hexane, and then dried under reduced pressure at 50-60 C. to afford a compound of formula (II) (70-97% yield) as a yellow solid.

General Procedure 3

[0295] ##STR00035##

[0296] To a stirred solution of a compound of formula (VII) (26.16 mmol, 1.0 eq.) in DMF or THF (150 mL) was added an alky/aryl(het) halide or dihalide, R.sup.9-G or G-R.sup.9-G, (2.0 eq.) and the mixture cooled to between 0 and 10 C. followed by portionwise addition of K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3, NaOH or NaH (2.0 eq, 60% suspension in mineral oil). The solution was allowed to stir at between 0 and 10 C. for 0.5 to 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The dried organics were evaporated under reduced pressure to obtain a crude residue which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (VI) (60-75% yield) as a light orange to faint pink solid.

General Procedure 4

[0297] ##STR00036##

Option 1

[0298] To a stirred solution of a compound of formula (VI) (2.77 mmol, 1.0 eq.) in DMF or THF (10 mL) was added K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3, NaOH or NaH (2.0-3.0 eq.) followed by addition of a compound of formula R.sup.6-L-G, i.e. a compound of formula (V), (1.1-1.5 eq.) and the mixture allowed to stir at RT for 0.5 to 16 h. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was diluted with water, extracted with EtOAc, and the organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organics were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (IV) (80-100% yield) as a colourless oil.

Option 2

[0299] To a stirred solution of a compound of formula (VI) (2.77 mmol, 1.0 eq.) in DCM, MeCN or THF (10 mL) was added TEA or DIPEA (2.0 eq.) followed by addition of a compound of formula R.sup.6-L-G, i.e. a compound of formula (V), (1.5 eq.) and the mixture allowed to stir at RT for 0.5 to 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organic layers were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (IV) (60-80% yield) as colourless oil.

General Procedure 5

[0300] ##STR00037##

[0301] To a stirred suspension of a suitable base such as Cs.sub.2CO.sub.3 or NaH (1.5 eq., 60%) in dry THF or DMF (15 mL) in a 2-neck round bottom flask fitted with a condenser was added an appropriate activated methylene compound such as diethylmalonate (1.2 eq.) at 0 C. and the whole stirred for 15 min. under an inert atmosphere. Thereafter, a compound of formula (XII) (6.925 mmol, 1.0 eq.) was added to the suspension at RT by dissolving in dry THF or DMF (5 mL) and injecting this solution into the reaction mixture. The mixture was allowed to stir at 0 C. for 1-2 h and then at 80 C. for 2-4 h. After completion of the reaction by LCMS and/or TLC, the reaction mixture was quenched by the addition of an aqueous saturated solution of NH.sub.4Cl, diluted with water and then extracted with EtOAc (315 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4 and then evaporated under reduced pressure to afford a crude solid which was purified by trituration with pentane to give a compound of formula (XII) (80-90% yield).

General Procedure 6

[0302] ##STR00038##

[0303] To a stirred solution of a compound of formula (XII) (2.94 mmol) in a polar solvent such as DMSO (5 mL) containing water (0.25 mL) was added anhydrous LiCl (2.0 eq.) and the whole was stirred at 90-100 C. for 12-16 h. The reaction mixture was cooled to RT and diluted with water, and was then extracted with EtOAc. The combined organic layer was washed successively with water and brine and was then dried over anhydrous Na.sub.2SO.sub.4. The filtered organics were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (XI) (50-55% yield) as reddish to brown oily liquid.

General Procedure 7

[0304] ##STR00039##

[0305] To a purged solution of a compound of formula (XI) (1.014 mmol) in a suitable solvent, such as EtOAc, MeOH or EtOH (4 mL), was added ammonium formate (44.0 eq.) and a suitable catalytic amount of wet Pd-C (10% w/w on charcoal). The reaction mixture was refluxed for 2-4 h under an Ar atmosphere. The progress of the reaction was monitored by TLC or LCMS and after consumption of starting material the reaction mixture was filtered through a bed of celite, the filtrate was evaporated under reduced pressure and the residue was taken up in EtOAc and water. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, and then filtered and evaporated to dryness to give a solid residue which upon trituration with n-pentane furnished a compound of formula (X) (50-60% yield) as a fluffy white to off white solid.

General Procedure 8

[0306] ##STR00040##

[0307] To a stirred solution of a compound of formula (VII) (52.33 mmol) in 1,4-dioxane (500 mL) was added oxidizing agents such as manganese dioxide or selenium dioxide (5.0 eq.) and the resulting reaction mixture was stirred vigorously at 100 C. for 1-2 h. The progress of the reaction was monitored by TLC or LCMS. After completion of the reaction, the reaction mixture was diluted with EtOAc and water and filtered through a bed of celite. The filtrate layers were separated and the organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4 and then evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (VI) (25-35% yield) as a light yellow to orange coloured solid.

General Procedure 9

[0308] ##STR00041##

[0309] To a stirred solution of a compound of formula (XVII) (8.6 mmol) in dry diethyl ether or dry THF (12 ml/mmol) at 0-5 C. was added a solution of R.sup.9MgBr (2.0 eq., 3M solution in diethyl ether) and the resulting reaction mixture was stirred at 0-25 C. for 10-16 h. The reaction was monitored by TLC or LCMS, and after completion of the reaction, the reaction mixture was quenched with aqueous HCl solution and extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (XVI) (50-70% yield) as a pale yellow to off white solid.

General Procedure 10

[0310] ##STR00042##

[0311] To a stirred solution of a compound of formula (XVI) (3.15 mmol) in DCM, THF or EDC at 0-5 C. was added a suitable base, such as TEA, DIPEA or pyridine, (2.0 eq.) followed by a halogenating reagent, such as SOCl.sub.2 or oxalyl chloride or POBr.sub.3, (4.0 eq.) and the whole maintained at 0-5 C. for 1-2 h. Alternatively, a corresponding leaving group such as tosylate or mesylate or triflate can also be prepared using p-toluenesulfonyl chloride or methanesulfonyl chloride or triflic anhydride (1.2 eq.) with a suitable organic base, such as TEA, DIPEA or pyridine, (3.0 eq.) in a suitable solvent such as DCM or THF or EDC. The progress of the reaction was monitored by LCMS and TLC. After complete consumption of the starting material, the reaction mixture was diluted with water and extracted with DCM or EtOAc. The organic layer was washed with dilute HCl (1-2 N) solution followed by dilute NaHCO.sub.3 solution and finally with brine. The organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (XV) (60-70% yield) as an off white to pale yellow solid.

General Procedure 11

[0312] ##STR00043##

[0313] To a stirred solution of a compound of formula (XV) (1.0 eq.) in a suitable solvent, such as MeCN, THF or DMF, (2 mL) was added a base, such as DIPEA, TEA, NaH or K.sub.2CO.sub.3, (3.0 eq.) followed by the addition of alkylating agents R.sup.10ZH (2.0 eq.), such as an alcohol, amine or activated carbon nucleophile, and the mixture was maintained at 80-90 C. for 10-16 h. The reaction was monitored by LCMS, and after completion of the reaction, solvents were evaporated and the crude product was purified by prep-HPLC to afford a compound of formula (XIV) (15-20% yield) as a white to off white solid.

General Procedure 12

[0314] ##STR00044##

[0315] To a stirred solution of an ester of formula (VIII) (2.24 mmol) in THF (5 mL/mmol) was added borane-THF or borane-DMSO (5 eq.; 1M solution) at 0-25 C. The reaction mixture was allowed to stir at room temperature for 12-16 h. On completion, the reaction was quenched by dropwise addition of MeOH (15 mL) under ice cooling. The solvent was evaporated under reduced pressure. The residue obtained was partitioned between EtOAc and water; the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness to obtain (XXVII).

General Procedure 13

[0316] ##STR00045##

[0317] To a stirred solution of a compound of formula (XXXVI) (1.0 eq.) in a suitable solvent, such as CCl.sub.4 or trifluoro-toluene, (100 mL) was added NBS (1.2 eq.) and benzoyl peroxide (0.1 eq.). The reaction mixture was heated at 70-100 C. for 12-16 h. The progress of the reaction was monitored by TLC and after completion of the reaction the mixture was quenched with a saturated solution of Na.sub.2S.sub.2O.sub.3 and extracted with EtOAc. The combined organic layers were washed with a brine solution and then dried over anhydrous Na.sub.2SO.sub.4. The crude product obtained after concentration of the organic layer under reduced pressure was purified by Combi-Flash using mixtures of EtOAc in hexanes to afford a compound of formula (XXXV) (30-35% yield).

General Procedure 14

[0318] ##STR00046##

[0319] To a stirred solution of TBAB (0.5 eq.) in water (1.0 mL) was added sodium sulfite (5.0 eq.) at RT. To this reaction mixture a compound of formula (XXXV) (0.145 mmol) in MeOH (1.5 mL) was added at RT. The resultant mixture was then refluxed at 90-100 C. for 3-4 h. After completion of the reaction, water and MeOH were removed under reduced pressure. The residual water was then azeotroped with toluene 3 times to obtain a crude solid product which was triturated twice with acetone, EtOAc and diethyl ether respectively to obtain a crude compound of formula (XXXIV). This crude product was used in the next step without further purification.

General Procedure 15

[0320] ##STR00047##

[0321] To a stirred solution of the crude compound of formula (XXXIV) (36.63 mmol) in an alcoholic solvent such as MeOH or EtOH was added a catalytic amount of Pd-C (10% on activated charcoal) under nitrogen gas, and the reaction mixture was then stirred at RT for 10-16 h under a hydrogen gas balloon pressure. The reaction mixture was filtered through a celite bed and washed with excess solvent. The filtrate was concentrated under reduced pressure to afford a crude compound of formula (XXXIII). Again, this crude product was used in the next step without further purification.

General Procedure 16

[0322] ##STR00048##

[0323] A stirred solution of a compound of formula (XXXIII) (0.0795 mmol) in POCl.sub.3 (2 mL) was heated to reflux at 140-150 C. for 3-5 h. After this time, the reaction mixture was allowed to cool to room temperature and excess POCl.sub.3 was then distilled off under reduced pressure. Traces of POCl.sub.3 were then removed by co-distilling with DCM several times under reduced pressure. The crude material was purified by Combi-Flash using mixtures of EtOAc in hexanes as eluent to afford the desired compound of formula (XXXII) (16-18% yield) as a white to off white solid.

General Procedure 17

[0324] ##STR00049##

[0325] To a stirred solution of a compound of formula (XLII) (4.81 mmol) in a base, such as TEA, DIPEA or pyridine, (10 mL) at 0-5 C. was added an acylating agent, such as ethyl chloroformate, (1.0 eq.) and the resulting reaction mixture was stirred at 0-5 C. for 1-2 h. After completion of the reaction, the reaction mixture was quenched with ice cold water and the precipitated solid was filtered, washed with water, and then dried under reduced pressure to afford a compound of formula (XLI) (45-55% yield) as an off white solid.

General Procedure 18

[0326] ##STR00050##

[0327] To a stirred solution of (XLI) (2.533 mmol) in a suitable solvent such as DMSO, DMF or THF (10 mL) was added CuI (0.25 eq.), 4-hydroxy trans-L-proline (0.5 eq.) and an inorganic base, such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NaF or K.sub.3PO.sub.4, (2.0 eq.). An R.sup.6-L-G reagent such as 2-chloro benzyl amine (1.0 eq.) was then added and the resulting reaction mixture was stirred at 70-80 C. for 20-24 h. The progress of the reaction was monitored by TLC or LCMS. After completion of the reaction, the mixture was quenched with ice cold 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 crude product which was purified by Combi-flash using mixtures of EtOAc in hexanes as eluent to afford a compound of formula (XL) (25-30% yield) as a yellow to pale yellow solid.

EXAMPLES

[0328] Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (6) are given in parts-per-million (ppm) downfield from tetramethylsilane (for .sup.1H-NMR) and upfield from trichloro-fluoro-methane (for .sup.19F NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl.sub.3, deuterochloroform; d.sub.6-DMSO, deuterodimethylsulphoxide; and CD.sub.3OD, deuteromethanol.

[0329] 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.

[0330] 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.

[0331] 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-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide

[0332] ##STR00051##

[0333] Example 1 was prepared according to the methods described in General Procedures 1-4, and the methods described below.

Preparation 1: Methyl 3,3-dimethyl-2-oxoindoline-6-carboxylate

[0334] ##STR00052##

[0335] To a stirred solution of methyl 2-oxoindoline-6-carboxylate (5.0 g, 26.16 mmol) in DMF (150 mL) was added MeI (7.42 g, 52.34 mmol) and the mixture cooled to between 0 and 10 C. followed by portionwise addition of NaH (2.19 g, 54.27 mmol, 60% suspension in mineral oil). The whole was allowed to stir at between 0 and 10 C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The dried organics were evaporated under reduced pressure to obtain a crude residue which was purified by Combi-flash using 35-50% EtOAc in hexanes as eluent to afford methyl 3,3-dimethyl-2-oxoindoline-6-carboxylate (4.4 g, 20.09 mmol, 77% yield) as a light orange solid. LCMS m/z: 220.03 [M+H].

Preparation 2: Methyl 1-(2-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate

[0336] ##STR00053##

[0337] To a stirred solution of methyl 3,3-dimethyl-2-oxoindoline-6-carboxylate (Preparation 1) (0.33 g, 2.77 mmol) in DMF (10 mL) was added NaH (0.136 g, 3.4 mmol) followed by addition of 1-(bromomethyl)-2-fluorobenzene (0.584 g, 3.09 mmol) and the mixture allowed to stir at RT for 1 h. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was diluted with water, extracted with EtOAc, and the organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organics were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using 22% EtOAc in hexanes as eluent to afford methyl 1-(2-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (0.490 g, 1.50 mmol, 99% yield) as a colorless oil. LCMS m/z: 328.70 [M+H].

Preparation 3: 1-(2-Fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid

[0338] ##STR00054##

[0339] To a stirred solution of methyl 1-(2-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (Preparation 2) (0.49 g, 1.50 mmol) in a mixture of THF (10 mL) and water (5 mL) was added LiOH (0.125 g, 2.99 mmol) at RT and the resulting reaction mixture was stirred for 16 h. TLC showed complete consumption of the ester, upon which the solvent was evaporated under reduced pressure and the resulting residue was washed with diethyl ether. The residue was then acidified with 1N HCl to pH 4, which resulted in the formation of a precipitate, which was filtered and washed with water and then dried under reduced pressure at 50-60 C. to afford 1-(2-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (0.4 g, 1.28 mmol, 85% yield) as an off white solid. LCMS m/z: 313.66 [M+H].

Preparation 4: 1-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide

[0340] ##STR00055##

[0341] To a stirred solution of 1-(2-fluorobenzyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (Preparation 3) (0.4 g, 1.28 mmol) in DCM (10 mL) was added furan-2-ylmethanamine (0.136 g, 1.40 mmol) and a coupling reagent HATU (0.728 g, 1.92 mmol) followed by addition of base TEA (0.368 mL, 2.55 mmol) dropwise to the solution and the mixture allowed to stir at RT for 2 h. When UPLC and TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO.sub.3 solution followed by dilute aqueous HCl and finally with brine, and then dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to obtain the crude material which was purified by Combi-flash using 55% EtOAc in hexanes as eluent to afford 1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide, i.e. Example 1, (0.403 g, 1.03 mmol, 80% yield) as a pale yellow solid. LCMS m/z: 393.28 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.36 (s, 6H) 4.45 (d, J=5.6 Hz, 2H), 4.96 (s, 2H), 6.24 (d, J=2.85 Hz, 1H), 6.39 (s, 1H), 7.06-7.12 (m, 3H), 7.37-7.74 (m, 3H), 7.74-7.61 (m, 2H), 8.92 (t, J=5.55 Hz, 1H).

Examples 2-131

[0342] Examples 2-131 were prepared according to the above method used to make Example 1 using the appropriate amines and acids as described in General procedures 1-4. Purification was as stated in the aforementioned method.

TABLE-US-00001 LCMS Exam- [M + ple Structure IUPAC Name .sup.1H-NMR H] 2 [00056] 1-(2-chloro-6- fluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.28 (s, 6H), 4.42 (d, J = 4.95 Hz, 2H), 5.03 (s, 2H), 7.19-7.26 (m, 3H), 7.31 (s, 1H), 7.35-7.44 (m, 3H), 7.50 (d, J = 7.8 Hz, 1H), 8.80 (t, J = 4.95 Hz, 1H). 491.32 3 [00057] 2-(1-(2- fluorobenzyl)- N-(furan-2- ylmethyl)-3,3- dimethyl-2- oxoindoline-6- carboxamido)ace- tic acid (400 MHz; DMSO-d.sub.6): 1.36 (d, J = 12.04 Hz, 6H), 3.76 (bs, 1H), 3.94 (s, 1H), 4.39 (s, 1H), 4.63 (s, 1H), 4.94 (d, J = 11.2 Hz, 2H), 6.31 (s, 1H), 6.41 (d, J = 12.52 Hz, 1H), 6.93-7.19 (m, 5H), 7.38-7.63 (m, 3H), 12.96 (bs, 1H). 451.29 4 [00058] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-N- (3- methylbenzyl)- 2-oxoindoline- 6-carboxamide (400 MHz; DMSO-d.sub.6): 1.36 (s, 6H), 2.26 (s, 3H), 4.42 (d, J = 5.36 Hz, 2H), 4.96 (s, 2H), 6.97 (d, J = 6.04 Hz, 2H), 7.03-7.07 (m, 3H), 7.17-7.19 (m, 2H), 7.42 (bs, 1H), 7.50 (d, J = 7.524 Hz, 1H), 7.63 (d, J = 8.08 Hz, 1H), 8.93 (bs, 1H). 435.2 5 [00059] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.31 (s, 6H), 4.41 (d, J = 4.24 Hz, 2H), 4.92 (s, 2H), 6.92 (d, J = 6.04 Hz, 2H), 7.13 (t, J = 8.23 Hz, 3H), 7.33 (bs, 1H), 7.44 (d, J = 7.64 Hz, 1H), 7.54 (d, J = 7.56 Hz, 1H), 8.78 (bs, 1H). 475.2 6 [00060] 1-(2- fluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.33 (s, 6H), 4.41 (d, J = 4.96 Hz, 2H), 4.96 (s, 2H), 7.13-7.25 (m, 5H), 7.31-7.31 (m, 2H), 7.46 (d, J = 7.72 Hz, 1H), 7.55 (d, J = 7.24 Hz, 1H), 8.79 (bs, 1H). 457.2 7 [00061] 1-(2-chloro-6- fluorobenzyl)- 3,3-dimethyl-2- oxo-N- (thiophen-2- ylmethyl)indoline- 6- carboxamide (400 MHz; DMSO-d.sub.6): 1.29 (s, 6H), 4.59 (d, J = 5.84 Hz, 2H), 5.05 (s, 2H), 6.94-6.98 (m, 2H), 7.20-7.25 (m, 1H), 7.35- 7.40 (m, 4H), 7.44 (d, J = 7.72 Hz, 1H), 7.51-7.54 (m, 1H), 9.02 (t, J = 5.76 Hz, 1H). 443.3 8 [00062] 1-(2-chloro-6- fluorobenzyl)- 3,3-dimethyl-N- (3- methylbenzyl)- 2-oxoindoline- 6-carboxamide (400 MHz; DMSO-d.sub.6): 1.29 (s, 6H), 2.27 (s, 3H), 4.40 (d, J = 5.76 Hz, 2H), 5.06 (s, 2H), 7.03-7.07 (m, 3H), 7.18- 7.22 (m, 2H), 7.36-7.40 (m, 3H), 7.45 (d, J = 7.72 Hz, 1H), 7.57 (d, J = 7.48 Hz, 1H), 8.90 (bs, 1H). 451.1 9 [00063] 1-(2-chloro-6- fluorobenzyl)- N-(3- chlorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.29 (s, 6H), 4.44 (d, J = 5.56 Hz, 2H), 5.06 (s, 2H), 7.21-7.25 (m, 2H), 7.31-7.40 (m, 5H), 7.46 (d, J = 7.48 Hz, 1H), 7.57 (d, J = 7.08 Hz, 1H), 8.89 (bs, 1H). 471.2 10 [00064] N,1-dibenzyl- 3,3-dimethyl-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.35 (s, 6H), 4.44 (d, J = 5.75 Hz, 2H), 4.93 (s, 2H), 7.22-7.34 (m, 7H), 7.39 (bs, 1H), 7.48 (d, J = 7.44 Hz, 1H), 7.61 (d, J = 7.88 Hz, 1H), 8.96 (bs, 1H). 385.2 11 [00065] 1-benzyl-3,3- dimethyl-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.33 (s, 6H), 4.42 (d, J = 4.36 Hz, 2H), 4.91 (s, 2H), 7.16 (t, J = 8.64 Hz, 2H), 7.23-7.25 (m, 3H), 7.31-7.33 (m, 3H), 7.45 (d, J = 7.64 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 8.81 (bs, 1H). 439.2 12 [00066] 1-(2-chloro-6- fluorobenzyl)- N-(3- fluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.29 (s, 6H), 4.45 (d, J = 5.8 Hz, 2H), 5.06 (s, 2H), 7.04-7.13 (m, 3H), 7.20-7.25 (m, 1H), 7.34- 7.40 (m, 4H), 7.46 (d, J = 7.68 Hz, 1H), 7.57 (d, J = 7.88 Hz, 1H), 8.89 (t, J = 5.6 Hz, 1H). 455.3 13 [00067] 1-(2-chloro-6- fluorobenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.28 (s, 6H), 2.21 (s, 3H), 4.36 (d, J = 5.64 Hz, 2H), 5.05 (s, 2H), 5.98 (bs, 1H), 6.09 (d, J = 2.75 Hz, 1H), 7.23 (t, J = 9.04 Hz, 1H), 7.34- 7.44 (m, 4H), 7.54 (d, J = 7.56 Hz, 1H), 8.80 (t, J = 5.88 Hz, 1H). 441.2 14 [00068] 1-(3- fluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.34 (s, 6H), 4.42 (d, J = 4.96 Hz, 2H), 4.94 (s, 2H), 7.04-7.18 (m, 5H), 7.35-7.39 (m, 2H), 7.46 (d, J = 7.68 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 8.82 (t, J = 5.04 Hz, 1H). 457.2 15 [00069] 3,3-dimethyl-1- (3-methyl-5- (trifluoromethyl) benzyl)-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.34 (s, 6H), 2.34 (s, 3H), 4.43 (d, J = 5.0 Hz, 2H), 4.98 (s, 2H), 7.15 (t, J = 8.64 Hz, 2H), 7.33 (bs 1H), 7.39 (d, J = 5.6 Hz, 2H), 7.47 (d, J = 7.88 Hz, 2H), 7..54 (m, 1H), 8.80 (m, 1H). 521.3 16 [00070] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.35 (s, 6H), 2.07 (s, 3H), 4.38 (d, J = 5.52 Hz, 2H), 4.96 (s, 2H), 5.97 (d, J = 2.68 Hz, 1H), 6.09 (d, J = 2.8 Hz, 1H), 6.96 (d, J = 6.6 Hz, 2H), 7.16 (t, J = 9.36 Hz, 1H), 7.40 (s, 1H), 7.49 (d, J = 7.64 Hz, 1H), 7.61 (d, J = 7.68 Hz, 1H), 8.83 (t, J = 5.76 Hz, 1H). 425.2 17 [00071] 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 1-(3- (trifluoromethyl) benzyl)indoline- 6- carboxamide (400 MHz; DMSO-d.sub.6): 1.34 (s, 6H), 4.43 (d, J = 4.08 Hz, 2H), 5.03 (s, 2H), 7.15 (t, J = 8.76 Hz, 2H), 7.39 (bs, 1H), 7.46- 7.51 (m, 2H), 7.54-7.59 (m, 2H), 7.63-7.65 (m, 2H), 8.79 (bs, 1H). 507.1 18 [00072] 3,3-dimethyl-1- (3- methylbenzyl)- 2-oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.33 (s, 6H), 2.25 (s, 3H), 4.42 (d, J = 4.76 Hz, 2H), 4.87 (s, 2H), 7.00 (d, J = 7.72 Hz, 1H), 7.05-7.07 (m, 2H), 7.13-7.22 (m, 3H), 7.32 (bs, 1H), 7.45 (d, J = 7.68 Hz, 1H), 7.54 (d, J = 7.64 Hz, 1H), 8.80 (t, J = 4.92 Hz, 1H). 453.1 19 [00073] 1-(3- chlorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.34 (s, 6H), 4.43 (d, J = 4.6 Hz, 2H), 4.93 (s, 2H), 7.14-7.18 (m, 3H), 7.34-7.36 (m, 4H), 7.46 (d, J = 7.68 Hz, 1H), 7.55 (d, J= 7.32 Hz, 1H), 8.81 (bs, 1H). 473.5 20 [00074] 1-(4- fluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.33 (s, 6H), 4.42 (d, J = 5.0 Hz, 2H), 4.91 (s, 2H), 7.16-7.20 (m, 4H), 7.29-7.32 (m, 2H), 7.36 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.54-7.56 (m, 1H), 8.85 (t, J = 5.15 Hz, 1H). 457.37 21 [00075] 1-(2-chloro-6- fluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.35 (d, J = 7.6 Hz, 3H), 3.57-3.62 (q, J.sub.1 = 7.55 Hz, J.sub.2 = 15.1 Hz, 1H), 4.42 (d, J = 4.8 Hz, 2H), 5.03 (d, J = 4.15 Hz, 2H), 7.19-7.24 (m, 3H), 7.35-7.41 (m, 4H), 7.49 (d, J = 7.6 Hz, 1H), 8.81 (t, J = 5.0 Hz, 1H). 477.33 22 [00076] 3,3-dimethyl-2- oxo-1-(pyridin- 4-ylmethyl)-N- (2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 4.42 (d, J = 4.55 Hz, 2H), 4.98 (s, 2H), 7.15-7.22 (m, 4H), 7.32 (s, 1H), 4.50 (d, J = 7.75 Hz, 1H), 7.58 (d, J = 7.75 Hz, 1H), 8.53 (d, J = 5.55 Hz, 1H), 8.83 (bs, 1H). 440.34 23 [00077] N-(benzofuran- 2-ylmethyl)-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 3.58 (s, 2H), 4.62 (d, J = 5.0 Hz, 2H), 4.98 (s, 2H), 6.72 (s, 1H), 6.98 (d, J = 7.05 Hz, 2H), 7.17-7.27 (m, 3H), 7.44 (s, 1H), 7.51- 7.58 (m, 3H), 7.66 (d, J = 7.65 Hz, 1H), 9.09- 9.10 (m, 1H). 461.30 24 [00078] 1-(2-chloro-6- fluorobenzyl)- 3,3-dimethyl-N- ((5- methylthiophen- 2-yl)methyl)- 2-oxoindoline- 6-carboxamide (400 MHz; DMSO-d.sub.6): 1.28 (s, 6H), 2.37 (s, 3H), 4.49 (d, J = 5.68 Hz, 2H), 5.05 (s, 2H), 6.60 (bs, 1H), 6.74 (d, J = 3.16 Hz, 1H), 7.23 (t, J = 8.92 Hz, 1H), 7.34- 7.44 (m, 4H), 7.51 (d, J= 7.72 Hz, 1H), 8.96 (t, J = 5.64 Hz, 1H). 457.3 25 [00079] 1-(2-chloro-6- fluorobenzyl)- N-(4- fluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.30 (s, 6H), 4.42 (d, J = 5.85 Hz, 2H), 5.07 (s, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.25 (t, J= 8.5 Hz, 1H), 7.31-7.47 (m, 6H), 7.58 (d, J = 7.7 Hz, 1H), 8.98 (t, J = 5.9 Hz, 1H). 455.30 26 [00080] 1-(2-chloro-6- fluorobenzyl)- N-(2,4- difluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.28 (s, 6H), 4.48 (d, J = 5.05 Hz, 2H), 5.05 (s, 2H), 7.09 (t, J = 7.85 Hz, 2H), 7.24 (t, J = 9.7 H, 2H), 7.32-7.43 (m, 5H), 7.50-7.52 (m, 1H), 8.79 (t, J = 5.15 Hz, 1H). 473.31 27 [00081] 1-(2-chloro-6- fluorobenzyl)- N-(2,6- difluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.30 (s, 6H), 4.44 (d, J = 5.50 Hz, 2H), 5.06 (s, 2H), 7.06 (t, J = 8.55 Hz, 1H), 7.24 (t, J = 9.75 Hz, 2H), 7.35-7.47 (m, 5H), 7.57 (d, J = 7.7 Hz, 1H), 8.95 (t, J = 5.7 Hz, 1H). 473.27 28 [00082] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-N- ((6- methylpyridin- 2-yl)methyl)-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 2.44 (s, 3H), 4.50 (d, J = 5.75 Hz, 2H), 4.98 (s, 2H), 6.98 (d, J = 6.4 Hz, 2H), 7.06 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 9.35 Hz, 1H), 7.45 (s, 1H), 7.54 (d, J = 6.12 Hz, 1H), 7.62 (t, J= 7.7 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 9.06 (t, J = 5.7 Hz, 1H). 436.33 29 [00083] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-N- ((5-methyl- 1,3,4-oxadiazol- 2-yl)methyl)-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 2.46 (s, 3H), 4.65 (d, J = 5.6 Hz, 2H), 4.97 (s, 2H), 6.98 (d, J = 6.6 Hz, 2H), 7.19 (t, J = 9.25 Hz, 1H), 7.42 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 764 (d, J = 7.7 Hz, 1H), 9.17 (t, J = 5.6 Hz, 1H). 427.32 30 [00084] N- (benzo[d]oxazol- 2-ylmethyl)-1- (2-chloro-6- fluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.33 (s, 6H), 4.75 (d, J = 5.55 Hz, 2H), 5.07 (s, 2H), 7.23-7.25 (m, 1H), 7.34-7.40 (m, 5H), 7.50 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.70-7.71 (m, 2H), 9.24 (t, J = 5.5 Hz, 1H). 478.32 31 [00085] 1-(2-chloro-6- fluorobenzyl)- 3,3-dimethyl-N- ((2- methyloxazol-5- yl)methyl)-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.26 (s, 6H), 2.33 (s, 3H), 4.42 (d, J = 5.36 Hz, 2H), 5.03 (s, 2H), 6.82 (s, 1H), 7.19-7.24 (m, 1H), 7.33-7.38 (m, 3H), 7.42 (d, J = 7.76 Hz, 1H), 7.52 (d, J = 7.52 Hz, 1H), 8.86 (t, J= 5.4 Hz, 1H). 442.31 32 [00086] 1-(2-chloro-6- fluorobenzyl)- 3,3-dimethyl-N- ((4- methylpyridin- 2-yl)methyl)-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.28 (s, 6H), 2.26 (s, 3H), 4.47 (d, J= 5.84 Hz, 2H), 5.04 (s, 2H), 7.06-7.07 (m, 2H), 7.19- 7.24 (m, 1H), 7.32-7.40 (m, 3H), 7.45 (d, J = 7.68 Hz, 1H), 7.60 (d, J = 6.76 Hz, 1H), 8.96 (t, J = 5.72 Hz, 1H). 452.33 33 [00087] 1-(2,3- difluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.31 (s, 6H), 4.41 (d, J = 4.96 Hz, 2H), 4.99 (s, 2H), 6.92 (t, J = 6.64 Hz, 1H), 7.14 (t, J = 9.52 Hz, 3H), 7.31-7.37 (m, 2H), 7.45 (d, J= 7.72 Hz, 1H), 7.53-7.55 (dd, J.sub.1 = 1.28 Hz, J.sub.2 = 7.76 Hz, 1H), 8.80 (t, J = 4.76 Hz, 1H). 475.33 34 [00088] N-(benzofuran- 2-ylmethyl)-1- (3,5- difluorobenzyl)- 7-fluoro-3,3- dimethyl-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.36 (s, 6H), 4.56 (d, J = 5.56 Hz, 2H), 5.00 (s, 2H), 6.70 (d, J = 0.48 Hz, 1H), 6.90 (d, J = 6.36 Hz, 2H), 7.13-7.29 (m, 4H), 7.34 (d, J = 7.64 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.08 Hz, 1H), 8.96 (t, J = 5.6 Hz, 1H). 479.30 35 [00089] 1-(3,5- difluorobenzyl)- 7-fluoro-3,3- dimethyl-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.34 (s, 6H), 4.38 (d, J = 5.2 Hz, 2H), 4.98 (s, 2H), 6.87 (d, J = 6.4 Hz, 2H), 7.13-71.8 (m, 4H), 7.30 (d, J = 7.64 Hz, 1H), 8.76 (t, J = 5.2 Hz, 1H). 493.33 36 [00090] N-(benzofuran- 2-ylmethyl)-1- (2-chloro-6- fluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.29 (s, 6H), 4.60 (d, J = 5.36 Hz, 2H), 5.06 (s, 2H), 6.71 (bs, 1H), 7.21- 7.26 (m, 3H), 7.33-7.40 (m, 3H), 7.46 (d, J = 7.72 Hz, 1H), 7.52 (d, J = 7.92 Hz, 1H), 7.58 (t, J = 6.92 Hz, 2H), 9.02 (bs, 1H). 477.3 37 [00091] 1-(3- carbamoylbenzyl)- 3,3-dimethyl- 2-oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.35 (s, 6H), 4.41 (d, J = 5.04 Hz, 2H), 4.96 (s, 2H), 7.15 (t, J = 8.6 Hz, 2H), 7.32-7.35 (m, 3H), 7.38-7.40 (m, 1H), 7.46 (d, J = 7.68 Hz, 1H), 7.54 (d, J = 6.92 Hz, 1H), 7.74-7.77 (m, 2H), 7.96 (bs, 1H), 8.79 (bs, 1H). 482.1 38 [00092] 1-(3- carbamoylbenzyl)- N-(2,4- difluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.36 (s, 6H), 4.43 (d, J = 4.84 Hz, 2H), 4.98 (s, 2H), 7.03 (m, 1H), 7.20 (m, 1H), 7.36-7.42 (m, 5H), 7.50 (d, J = 7.72 Hz, 1H), 7.60 (d, J = 7.72 Hz, 1H), 7.74-7.79 (m, 2H), 7.96 (bs, 1H), 8.94 (bs, 1H). 464.3 39 [00093] 1-(3,5- difluorobenzyl)- N-((3,3- difluorocyclo- pentyl)methyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.36 (s, 6H), 1.46-1.53 (m, 1H), 1.78-1.86 (m, 2H), 2.00-2.09 (m, 1H), 2.10-2.20 (m, 2H), 2.35- 2.41 (m, 1H), 3.22-3.29 (m, 2H), 4.98 (s, 2H), 6.98 (d, J = 6.5 Hz, 2H), 7.18 (t, J = 9.2 Hz, 1H), 7.35 (s, 1H), 7.51 (d, J = 7.65 Hz, 1H), 7.57 (d, J = 7.75 Hz, 1H), 8.50 (t, J = 5.7 Hz, 1H). 449.38 40 [00094] N- (benzo[d]thiazol- 2-ylmethyl)-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.38 (s, 6H), 4.86 (d, J = 5.8 Hz, 2H), 4.99 (s, 2H), 6.99 (d, J = 6.45 Hz, 2H), 7.19 (t, J = 9.3 Hz, 1H), 7.41-7.46 (m, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 9.48 (t, J = 5.75 Hz, 1H). 478.32 41 [00095] 1-(4- fluorobenzyl)- N-(furan-2- ylmethyl)-3,3- dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.35 (s, 6H), 4.44 (d, J = 5.6 Hz, 2H), 4.92 (s, 2H), 6.25 (d, J = 2.85 Hz, 1H), 6.39 (s, 1H), 7.18 (t, J = 8.8 Hz, 2H), 7.31-7.33 (m, 2H), 7.40 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.57-7.60 (m, 2H), 8.91 (t, J = 5.55 Hz, 1H). 393.31 42 [00096] 1-(3- fluorobenzyl)- N-(furan-2- ylmethyl)-3,3- dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.36 (s, 6H), 4.44 (d, J = 5.55 Hz, 2H), 4.96 (s, 2H), 6.24 (d, J = 2.65 Hz, 1H), 6.39 (s, 1H), 7.07-7.12 (m, 3H), 7.37- 7.42 (m, 2H), 7.50 (d, J = 7.65 Hz, 1H), 7.57 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 8.91 (t, J = 5.45 Hz, 1H). 393.32 43 [00097] 1-(3,5- difluorobenzyl)- N-((4,4- difluorocyclo- hexyl)methyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.15-1.22 (m, 2H), 1.36 (s, 6H), 1.67-1.82 (m, 5H), 1.99 (d, J = 7.85 Hz, 2H), 3.15 (t, J = 6.25 Hz, 2H), 4.97 (s, 2H), 6.98 (d, J = 6.45 Hz, 2H), 7.19 (t, J = 9.3 Hz, 1H), 7.36 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 8.48 (t, J = 5.7 Hz, 1H). 463.39 44 [00098] N-(3- cyanobenzyl)-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 4.51 (d, J = 5.8 Hz, 2H), 4.98 (s, 2H), 6.98 (d, J = 6.6 Hz, 2H), 7.18 (t, J = 9.35 Hz, 1H), 7.43 (s, 1H), 7.54 (t, J = 8.05 Hz, 2H), 7.63- 7.66 (m, 2H), 7.73 (d, J = 1.7 Hz, 2H), 9.08 (t, J = 5.85 Hz, 1H). 446.34 45 [00099] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-N-(3- (trifluoromethyl) benzyl)indoline- 6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 4.55 (d, J = 5.85 Hz, 2H), 4.98 (s, 2H), 6.98 (d, J = 6.3 Hz, 2H), 7.18 (t, J = 9.3 Hz, 1H), 7.42 (s, 1H), 7.53- 7.65 (m, 6H), 9.10 (t, J = 5.8 Hz, 1H). 489.35 46 [00100] 1-(3,4- difluorobenzyl)- N-(furan-2- ylmethyl)-3,3- dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.36 (s, 6H), 4.45 (d, J = 5.6 Hz, 2H), 4.93 (s, 2H), 6.25 (d, J = 2.85 Hz, 1H), 6.39 (s, 1H), 7.09 (bs, 1H), 7.36-7.44 (m, 3H), 7.50 (d, J = 7.75 Hz, 1H), 7.57 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 8.91 (t, J = 5.6 Hz, 1H). 411.30 47 [00101] N-(3- azidobenzyl)-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 4.46 (d, J = 5.9 Hz, 2H), 4.97 (s, 2H), 6.97-7.03 (m, 4H), 7.12 (d, J = 7.75 Hz, 1H), 7.16-7.20 (m, 1H), 7.36 (t, J = 7.75 Hz, 1H), 7.42 (s, 1H), 7.5 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.75 Hz, 1H), 9.03 (t, J = 5.85 Hz, 1H). 462.31 48 [00102] N-(4- azidobenzyl)-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 4.45 (d, J = 5.8 Hz, 2H), 4.97 (s, 2H), 6.98 (d, J = 6.75 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 7.19 (t, J = 9.15 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.42 (s, 1H), 7.52 (d, J = 7.65 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 9.01 (t, J = 5.8 Hz, 1H). 462.33 49 [00103] 1-((2- fluoropyridin- 4-yl)methyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 4.43 (d, J = 4.5 Hz, 2H), 5.04 (s, 2H), 7.05 (s, 1H), 7.14- 7.19 (m, 3H), 7.35 (s, 1H), 7.50 (d, J = 7.65 Hz, 1H), 7.59 (d, J = 7.65 Hz, 1H), 8.21 (d, J = 5 Hz, 1H), 8.84 (bs, 1H). 458.29 50 [00104] 1-(2,6- difluorobenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxoindoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.29 (s, 6H), 2.23 (s, 3H), 4.38 (d, J = 5.55 Hz, 2H), 5.00 (s, 2H), 5.99 (s, 1H), 6.11 (d, J = 2.70 Hz, 1H), 7.11 (t, J = 8.15 Hz, 2H), 7.38-7.45 (m, 3H), 7.57 (d, J = 7.6 Hz, 1H), 8.85 (t, J = 5.50 Hz, 1H). 425.36 51 [00105] 1-(2- chlorobenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxoindoline-6- carboxamide (50 MHz; DMSO-d.sub.6): 1.39 (s, 6H), 2.21 (s, 3H), 4.36 (d, J = 5.60 Hz, 2H), 4.99 (s, 2H), 5.97 (d, J = 1.9 Hz, 1H), 6.09 (d, J = 2.85 Hz, 1H), 6.98 (d, J = 7.05 Hz, 1H), 7.29 (t, J = 7.05 Hz, 1H), 7.33-7.35 (m, 2H), 7.53 (t, J = 7.1 Hz, 2H), 7.62 (d, J = 6.80 Hz, 1H), 8.85 (t, J = 5.6 Hz, 1H). 423.34 52 [00106] 3,3-dimethyl-1- ((3- methylisoxazol- 5-yl)methyl)-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.32 (s, 6H), 2.18 (s, 3H), 4.46 (d, J = 4.90 Hz, 2H), 5.06 (s, 2H), 6.23 (s, 1H), 7.19 (t, J = 8.55 Hz, 2H), 7.47-7.51 (m, 2H), 7.60 (d, J = 7.75 Hz, 1H), 8.85 (t, J = 4.70 Hz, 1H). 444.34 53 [00107] 1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.41 (d, J = 7.6 Hz, 3H), 3.73-3.78 (m, 1H), 4.44 (d, J = 5.0 Hz, 2H), 4.90 (d, J = 16.45 Hz, 1H), 4.99 (d, J= 16.4 Hz, 1H), 7.01 (d, J = 6.55 Hz, 2H), 7.17 (t, J = 8.70 Hz, 3H), 7.32 (s, 1H), 7.43 (d, J = 7.75 Hz, 1H), 7.56 (d, J = 7.65 Hz, 1H), 8.84 (t, J = 4.95 Hz, 1H). 461.33 54 [00108] 3,3-dimethyl-1- ((2- methylpyridin- 4-yl)methyl)-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.36 (s, 6H), 2.41 (s, 3H), 4.41 (d, J = 5.08 Hz, 2H), 4.91 (s, 2H), 6.96 (d, J = 5.2 Hz, 1H), 7.08 (s, 1H), 7.15 (t, J = 8.52 Hz, 2H), 7.29 (s, 1H), 7.48 (d, J = 7.72 Hz, 1H), 7.56 (d, J = 7.72 Hz, 1H), 8.36 (d, J = 5.08 Hz, 1H), 8.81 (t, 454.3 J = 4.92 Hz, 1H). 55 [00109] 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-1- ((2- methylpyridin- 4-yl)methyl)-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.37 (s, 6H), 2.20 (s, 3H), 2.42 (s, 3H), 4.36 (d, J = 5.0 Hz, 2H), 4.92 (s, 2H), 5.96 (s, 1H), 6.08 (s, 1H), 6.96 (bs, 1H), 7.09 (bs, 1H), 7.34 (bs, 1H), 7.50 (d, J = 7.52 Hz, 1H), 7.61 (d, J = 8.08 Hz, 1H), 8.37 (d, J = 4.96 Hz, 1H), 8.83 404.3 (bs, 1H). 56 [00110] 1-(4- azidobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.34 (s, 6H), 4.43 (d, J = 4.6 Hz, 2H), 4.91 (s, 2H), 7.00 (d, J = 8.3 Hz, 2H), 7.18 (t, J= 8.45 Hz, 2H), 7.31 (d, J = 8.20 Hz, 2H), 7.35 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.65 Hz, 1H), 8.85 (t, J = 4.65 Hz, 1H). 480.38 57 [00111] 1-(3- azidobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- triflurobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.35 (s, 6H), 4.43 (d, J = 4.9 Hz, 2H), 4.94 (s, 2H), 7.00 (bs, 1H), 7.02- 7.05 (m, 2H), 7.17 (t, J = 8.55 Hz, 2H), 7.35-7.40 (m, 2H), 7.48 (d, J = 7.70 Hz, 1H), 7.56 (d, J = 7.80 Hz, 1H), 8.83 (t, J = 5.05 Hz, 1H). 480.38 58 [00112] 3,3-dimethyl-1- ((2- methylthiazol- 5-yl)methyl)-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.29 (s, 6H), 2.56 (s, 3H), 4.47 (d, J = 4.8 Hz, 2H), 5.09 (s, 2H), 7.19 (t, J = 8.55 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.80 Hz, 2H), 7.68 (s, 1H), 8.85 (t, J = 4.8 Hz, 1H). 460.30 59 [00113] 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxo-1- phenethylindoline- 6- carboxamide (500 MHz; DMSO-d.sub.6): 1.18 (s, 6H), 2.25 (s, 3H), 2.95 (t, J = 7.0 Hz, 2H), 3.95 (t, J = 7.0 Hz, 2H), 4.45 (d, J = 5.40 Hz, 2H), 6.02 (s, 1H), 6.16 (d, J = 2.15 Hz, 1H), 7.15-7.17 (m, 3H), 7.21- 7.24 (m, 2H), 7.42 (d, J = 7.65 Hz, 1H), 7.53 (s, 1H), 7.59 (d, J = 7.65 Hz, 1H), 8.92 (t, J = 5.25 Hz, 1H). 403.38 60 [00114] 1-(4- fluorobenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.32 (s, 6H), 2.19 (s, 3H), 4.35 (d, J = 5.56 Hz, 2H), 4.90 (s, 2H), 5.95 (d, J = 1.92 Hz, 1H), 6.07 (d, J = 2.92 Hz, 1H), 7.15 (t, J = 8.84 Hz, 2H), 7.27-7.31 (m, 2H), 7.38 (s, 1H), 7.45 (d, J = 7.68 Hz, 1H), 7.56-7.58 (dd, J.sub.1 = 1.16 407.34 Hz, J.sub.2 = 7.72 Hz, 1H), 8.82 (t, J = 5.56 Hz, 1H). 61 [00115] 1-(2,3- difluorobenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.33 (s, 6H), 2.19 (s, 3H), 4.35 (d, J = 5.56 Hz, 2H), 5.01 (s, 2H), 5.95 (d, J = 1.96 Hz, 1H), 6.07 (d, J = 2.84 Hz, 1H), 6.92 (t, J = 6.68 Hz, 1H), 7.12-7.17 (m, 1H), 7.31-7.38 (m, 2H), 7.47 (d, J = 7.72 Hz, 1H), 7.58-7.60 (dd, J.sub.1 = 1.08 Hz, J.sub.2 = 7.72 Hz, 1H), 8.81 (t, J = 5.52 Hz, 1H). 425.34 62 [00116] 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxo-1-(2-oxo-2- phenylethyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.33 (s, 6H), 2.17 (s, 3H), 4.34 (d, J = 5.64 Hz, 2H), 5.35 (s, 2H), 5.93 (d, J = 1.92 Hz, 1H), 6.07 (d, J = 2.88 Hz, 1H), 7.41 (s, 1H), 7.46 (d, J = 7.72 Hz, 1H), 7.59 (d, J = 7.72 Hz, 3H), 7.72 (t, J = 7.40 Hz, 1H), 8.09 (d, J = 7.28 Hz, 2H), 8.75 (t, J = 5.52 Hz, 1H). 417.37 63 [00117] 1-(2-fluoro-6- methylbenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxoindoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.27 (s, 6H), 2.20 (s, 3H), 2.31 (s, 3H), 4.34 (d, J = 5.56 Hz, 2H), 4.93 (s, 2H), 5.95-5.96 (m, 1H), 6.07 (d, J = 2.92 Hz, 1H), 6.98-7.03 (m, 2H), 7.19-7.24 (m, 1H), 7.31 (s, 1H), 7.41 (d, J = 7.68 Hz, 1H), 7.51- 7.53 (dd, J.sub.1 = 1.2 Hz, J.sub.2 = 7.76 Hz, 1H), 8.78 (t, J = 5.6 Hz, 1H). 421.38 64 [00118] 1-(2,6-difluoro- 4- methoxybenzyl)- 3,3-dimethyl- 2-oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.27 (s, 6H), 3.75 (s, 3H), 4.42 (d, J = 4.35 Hz, 2H), 4.89 (s, 2H), 6.74 (d, J = 9.9 Hz, 2H), 7.20 (m, 2H), 7.34 (s, 1H), 7.42 (d, J = 7.55 Hz, 1H), 7.50 (d, J = 7.1 Hz, 1H), 8.81 (bs, 1H) 505.24 65 [00119] 1-(2,6-difluoro- 4- hydroxybenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.26 (s, 6H), 4.44 (d, J = 4.25 Hz, 2H), 4.84 (s, 2H), 6.44 (d, J = 9.75 Hz, 2H), 7.19 (m, 2H), 7.32 (s, 1H), 7.41 (d, J = 7.65 Hz, 1H), 7.49 (d, J = 7.55 Hz, 1H), 8.81 (s, 1H), 10.54 (bs, 1H) 491.22 66 [00120] 1-(2-chloro-6- fluoro-3- methoxybenzyl)- 3,3-dimethyl- 2-oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.28 (s, 6H), 3.83 (s, 3H), 4.42 (d, J = 4.25 Hz, 2H), 5.04 (s, 2H), 7.14-7.24 (m, 4H), 7.28 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 8.77 (bs, 1H). 521.14 67 [00121] 1-(2-chloro-6- fluoro-3- hydroxybenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.28 (s, 6H), 4.42 (d, J = 4.75 Hz, 2H), 5.01 (s, 2H), 6.92-6.95 (m, 1H), 7.03-7.07 (m, 1H), 7.17- 7.20 (m, 2H), 7.27 (s, 1H), 7.41 (d, J = 7.65 Hz, 1H), 7.49 (d, J = 7.65 Hz, 1H), 8.77 (t, J = 4.9 Hz, 1H), 10.24 (s, 1H). 507.13 Exam- LCMS ple Structure IUPAC Name [M + H] 68 [00122] 3,3-dimethyl-1-((1-methyl-1H- pyrazol-4-yl)methyl)-2-oxo-N- (2,4,6-trifluorobenzyl)indoline-6- carboxamide 443.33 69 [00123] 1-(3,5-difluorobenzyl)-N-((5- fluorofuran-2-yl)methyl)-3,3- dimethyl-2-oxoindoline-6- carboxamide 429.1 70 [00124] 3,3-dimethyl-1-((5- methylisoxazol-3-yl)methyl)-2- oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 444.18 71 [00125] N-(benzofuran-5-ylmethyl)-1-(2- chloro-6-fluorobenzyl)-3,3- dimethyl-2-oxoindoline-6- carboxamide 477.19 72 [00126] 1-(2-chloro-6-fluorobenzyl)-N-(2- fluorobenzyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 455.17 73 [00127] 1-(2-fluoro-3-methylbenzyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 471.2 74 [00128] 1-(2-chloro-6-fluorobenzyl)-N- ((6-fluorobenzofuran-2- yl)methyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 495.19 75 [00129] 1-(2-chloro-6-fluorobenzyl)-N- ((5-fluorobenzofuran-2- yl)methyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 495.13 76 [00130] 1-(2-cyano-6-fluorobenzyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 482.2 77 [00131] 3,3-dimethyl-1-((1-methyl-1H- pyrazol-5-yl)methyl)-2-oxo-N- (2,4,6-trifluorobenzyl)indoline-6- carboxamide 443.24 78 [00132] 3,3-dimethyl-1-((5-methyl-2-(m- tolyl)oxazol-4-yl)methyl)-2-oxo- N-(2,4,6-trifluorobenzyl)indoline- 6-carboxamide 534.27 79 [00133] 1-(3-carbamoyl-2-fluorobenzyl)- 3,3-dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 500.31 80 [00134] 1-((1,3-dimethyl-1H-pyrazol-4- yl)methyl)-3,3-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl)indoline-6- carboxamide 457.26 81 [00135] 1-((1,5-dimethyl-1H-pyrazol-3- yl)methyl)-3,3-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl)indoline-6- carboxamide 457.29 82 [00136] 1-((1,3-dimethyl-1H-pyrazol-5- yl)methyl)-3,3-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl)indoline-6- carboxamide 457.29 83 [00137] 3,3-dimethyl-1-((2-methyloxazol- 4-yl)methyl)-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 444.29 84 [00138] 1-(2-fluoro-6- (trifluoromethyl)benzyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 525.3 85 [00139] N-(4-aminobenzyl)-1-(2-chloro-6- fluorobenzyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 452.24 86 [00140] N-(benzo[d][1,3]dioxol-5- ylmethyl)-1-(2-chloro-6- fluorobenzyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 481.18 87 [00141] N-(benzo[d][1,3]dioxol-4- ylmethyl)-1-(2-chloro-6- fluorobenzyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 481.19 88 [00142] 1-(2-chloro-6-fluorobenzyl)-N- ((5-hydroxybenzofuran-2- yl)methyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 493.19 89 [00143] 1-(3-fluoro-5-methoxybenzyl)- 3,3-dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 487.2 90 [00144] N-(benzofuran-6-ylmethyl)-1-(2- chloro-6-fluorobenzyl)-3,3- dimethyl-2-oxoindoline-6- carboxamide 477.2 91 [00145] 3,3-dimethyl-1-((5-methyl-2- phenyloxazol-4-yl)methyl)-2-oxo- N-(2,4,6-trifluorobenzyl)indoline- 6-carboxamide 520.29 92 [00146] N-(benzofuran-2-ylmethyl)-3- cyano-1-(3,5-difluorobenzyl)-3- methyl-2-oxoindoline-6- carboxamide 472.21 93 [00147] N-(benzofuran-4-ylmethyl)-1-(2- chloro-6-fluorobenzyl)-3,3- dimethyl-2-oxoindoline-6- carboxamide 477.2 94 [00148] 1-(2-chloro-6-fluorobenzyl)-3,3- dimethyl-N-((5-nitrobenzofuran- 2-yl)methyl)-2-oxoindoline-6- carboxamide 522.21 95 [00149] 1-(2-chloro-6-fluorobenzyl)-3,3- dimethyl-2-oxo-N-((2- oxoindolin-5-yl)methyl)indoline- 6-carboxamide 492.21 96 [00150] 3,3-dimethyl-1-((1-methyl-1H- indazol-7-yl)methyl)-2-oxo-N- (2,4,6-trifluorobenzyl)indoline-6- carboxamide 493.26 97 [00151] 1-(isoxazolo[5,4-b]pyridin-3- ylmethyl)-3,3-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl)indoline-6- carboxamide 481.23 98 [00152] 1-(benzo[d]isoxazol-3-ylmethyl)- 3,3-dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 480.22 99 [00153] 3,3-dimethyl-2-oxo-1-(pyridin-2- ylmethyl)-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 440.25 100 [00154] 1-(benzofuran-3-ylmethyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 479.29 101 [00155] 1-(benzo[d]oxazol-2-ylmethyl)- 3,3-dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 480.27 102 [00156] 1-(2-fluoro-6-methoxybenzyl)- 3,3-dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 487.24 103 [00157] 1-(2-fluoro-6-methylbenzyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 471.26 104 [00158] 1-(2-fluoro-3-methoxybenzyl)- 3,3-dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 487.24 105 [00159] 1-((2,2- difluorobenzo[d][1,3]dioxol-4- yl)methyl)-3,3-dimethyl-2-oxo-N- (2,4,6-trifluorobenzyl)indoline-6- carboxamide 519.22 106 [00160] 1-((4-bromo-1,3-dimethyl-1H- pyrazol-5-yl)methyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 535.18 107 [00161] N-(benzofuran-2-ylmethyl)-1- ((1,3-dimethyl-1H-pyrazol-5- yl)methyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 443.28 108 [00162] 1-(2-bromo-6-fluorobenzyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 535.13 109 [00163] 1-(2,6-difluorobenzyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 475.16 110 [00164] 1-(2,6-dimethylbenzyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 467.21 111 [00165] 1-(2-(difluoromethoxy)-6- fluorobenzyl)-3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 523.2 112 [00166] N-(benzofuran-2-ylmethyl)-1-((4- bromo-1,3-dimethyl-1H-pyrazol- 5-yl)methyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 521.15 113 [00167] 3,3-dimethyl-1-((1-methyl-3- (trifluoromethyl)-1H-pyrazol-5- yl)methyl)-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 511.17 114 [00168] N-((5,6-difluorobenzofuran-2- yl)methyl)-1-((4-fluoro-1,3- dimethyl-1H-pyrazol-5- yl)methyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 497.2 115 [00169] 1-((4-fluoro-1,3-dimethyl-1H- pyrazol-5-yl)methyl)-N-((5- fluorobenzofuran-2-yl)methyl)- 3,3-dimethyl-2-oxoindoline-6- carboxamide 479.23 116 [00170] 1-((1-ethyl-3-methyl-1H-pyrazol- 5-yl)methyl)-N-((5- fluorobenzofuran-2-yl)methyl)- 3,3-dimethyl-2-oxoindoline-6- carboxamide 475.25 117 [00171] 1-((1-ethyl-3-methyl-1H-pyrazol- 5-yl)methyl)-3,3-dimethyl-2-oxo- N-(2,4,6-trifluorobenzyl)indoline- 6-carboxamide 471.24 118 [00172] 1-((4-fluoro-1-(2-methoxyethyl)- 3-methyl-1H-pyrazol-5- yl)methyl)-N-((5- fluorobenzofuran-2-yl)methyl)- 3,3-dimethyl-2-oxoindoline-6- carboxamide 523.22 119 [00173] 1-((4-fluoro-1-(2-hydroxyethyl)-3- methyl-1H-pyrazol-5-yl)methyl)- N-((5-fluorobenzofuran-2- yl)methyl)-3,3-dimethyl-2- oxoindoline-6-carboxamide 509.25 120 [00174] 1-(4-carbamoylbenzyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 482.34 121 [00175] 1-(4-carbamoyl-2-fluorobenzyl)- 3,3-dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 500.37 122 [00176] 1-(3,4-difluorobenzyl)-3,3- dimethyl-N-((5-methylfuran-2- yl)methyl)-2-oxoindoline-6- carboxamide 425.36 123 [00177] 1-(1-(4-fluorophenyl)ethyl)-3,3- dimethyl-N-((5-methylfuran-2- yl)methyl)-2-oxoindoline-6- carboxamide 421.4 124 [00178] 1-(2-cyanobenzyl)-3,3-dimethyl- 2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 464.4 125 [00179] N-(3,5-difluorobenzyl)-3,3- dimethyl-1-((5-methylfuran-2- yl)methyl)-2-oxoindoline-6- carboxamide 425.36 126 [00180] 1-(2-chloro-6-fluorobenzyl)-3,3- dimethyl-N-((5-methyloxazol-2- yl)methyl)-2-oxoindoline-6- carboxamide 442.14 127 [00181] 1-(2-chloro-6-fluorobenzyl)-3,3- dimethyl-N-((1-methyl-1H- pyrrol-2-yl)methyl)-2- oxoindoline-6-carboxamide 440.15 128 [00182] 3,3-dimethyl-1-((2-methyloxazol- 5-yl)methyl)-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 444.29 129 [00183] 3,3-dimethyl-1-((5-methyl-2-(p- tolyl)oxazol-4-yl)methyl)-2-oxo- N-(2,4,6-trifluorobenzyl)indoline- 6-carboxamide 534.27 130 [00184] 1-((2-(4-fluorophenyl)-5- methyloxazol-4-yl)methyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 538.27 131 [00185] 1-(benzofuran-2-ylmethyl)-3,3- dimethyl-2-oxo-N-(2,4,6- trifluorobenzyl)indoline-6- carboxamide 479.29

Example 132: 1-(2-Chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)-3-dimethylindoline-6-carboxamide

[0343] ##STR00186##

[0344] Example 132 was prepared according to the methods described in General Procedures 1-3 and 12, and the methods described below.

Preparation 5: Methyl 3,3-dimethyl-2-oxoindoline-6-carboxylate

[0345] ##STR00187##

[0346] To a stirred solution of methyl 2-oxoindoline-6-carboxylate (5.0 g, 26.16 mmol) in DMF (150 mL) was added MeI (7.42 g, 52.34 mmol) and the mixture cooled to between 0 and 10 C. followed by portionwise addition of NaH (2.19 g, 54.27 mmol, 60% suspension in mineral oil). The whole was allowed to stir at between 0 and 10 C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The dried organics were evaporated under reduced pressure to obtain a crude residue which was purified by Combi-flash using 35-50% EtOAc in hexanes as eluent to afford methyl 3,3-dimethyl-2-oxoindoline-6-carboxylate (4.4 g, 20.09 mmol, 77% yield) as a faint pink solid. LCMS m/z: 220.03 [M+H].

Preparation 6: Methyl 3,3-dimethylindoline-6-carboxylate

[0347] ##STR00188##

[0348] To a stirred solution of methyl 3,3-dimethyl-2-oxoindoline-6-carboxylate (Preparation 5) (0.2 g, 2.29 mmole) in THF (10 mL) was added borane-THF (2.28 mL, 5.74 mmol, 1M solution in THF) at RT. The reaction mixture was allowed to stir at reflux for 8 h. On completion, the reaction was quenched by dropwise addition of MeOH (15 mL) under ice cooling. The solvent was evaporated under reduced pressure. The residue obtained was partitioned between EtOAc and water; the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness. The crude residue was purified by Combi-flash using 15% EtOAc in hexanes as eluent to afford the methyl 3,3-dimethylindoline-6-carboxylate (0.1 g, 0.49 mmol, 53% yield) as a colourless oil. LCMS m/z: 206.09 [M+H].

Preparation 7: Methyl 1-(2-chloro-6-fluorobenzoyl)-3,3-dimethylindoline-6-carboxylate

[0349] ##STR00189##

[0350] To a stirred solution of methyl 3,3-dimethylindoline-6-carboxylate (Preparation 6) (0.1 g, 0.49 mmol) in DCM (5 mL) was added DIPEA (0.18 mL, 0.98 mmol) followed by addition of 2-chloro-6-fluorobenzoyl chloride (0.068 mL, 0.53 mmol) and the resulting mixture allowed to stir at RT for 2 h. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was diluted with water, extracted with EtOAc, and the organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organics were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using 20% EtOAc in hexanes as eluent to afford methyl 1-(2-chloro-6-fluorobenzoyl)-3,3-dimethylindoline-6-carboxylate (0.12 g, 0.33 mmol, 68% yield) as a white solid. LCMS m/z: 362.23 [M+H].

Preparation 8: 1-(2-Chloro-6-fluorobenzoyl)-3,3-dimethylindoline-6-carboxylic acid

[0351] ##STR00190##

[0352] To a stirred solution of methyl 1-(2-chloro-6-fluorobenzoyl)-3,3-dimethylindoline-6-carboxylate (Preparation 7) (0.12 g, 0.33 mmol) in a mixture of THF (10 mL) and water (5 mL) was added LiOH (0.07 g, 1.66 mmol) at RT and the resulting reaction mixture was stirred at RT for 16 h. TLC showed complete consumption of the ester, upon which the solvent was evaporated under reduced pressure and the resulting residue was washed with diethyl ether. The residue was then acidified with 1N HCl to pH 4, which resulted in the formation of a precipitate, which was filtered and washed with water and then dried under reduced pressure at 50-60 C. to afford 1-(2-chloro-6-fluorobenzoyl)-3,3-dimethylindoline-6-carboxylic acid (0.1 g, 0.29 mmol, 87% yield) as a brown solid.

Preparation 9: 1-(2-Chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,3-dimethylindoline-6-carboxamide

[0353] ##STR00191##

[0354] To a stirred solution of 1-(2-chloro-6-fluorobenzoyl)-3,3-dimethylindoline-6-carboxylic acid (Preparation 8) (0.1 g, 0.29 mmol) in DCM (5 mL) was added furan-2-ylmethanamine (0.030 g, 0.32 mmol) and a coupling reagent HATU (0.165 g, 0.43 mmol) followed by addition of TEA (0.083 mL, 0.58 mmol) dropwise to the solution and the mixture allowed to stir at RT for 1 h. When UPLC and TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO.sub.3 solution followed by dilute aqueous HCl and finally with brine, and then dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to obtain the crude material which was purified by Combi-flash using 58% EtOAc in hexanes as eluent to afford 1-(2-chloro-6-fluorobenzoyl)-N-(furan-2-ylmethyl)-3,3-dimethylindoline-6-carboxamide, i.e. Example 132, (0.05 g, 0.12 mmol, 41% yield) as a pale yellow solid. LCMS m/z: 426.97 [M+H]. .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.28 (d, J=1.3.6 Hz, 6H), 3.54-3.61 (q, J=10.45 Hz, 2H), 4.47 (d, J=5.5 Hz, 2H), 6.28 (d, J=2.3 Hz, 1H), 6.41 (d, J=6.1 HZ, 1H), 740-7.48 (m, 2H), 7.52 (d, J=6.48 Hz, 1H), 7.56-7.66 (m, 2H), 7.69 (d, J=7.85 Hz, 1H), 8.59 (s, 1H), 9.06 (t, J=5.4 Hz, 1H).

Example 133: 3.3-Difluoro-1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxoindoline-6-carboxamide

[0355] ##STR00192##

[0356] Example 133 was prepared using the method described in General procedure 8, and the methods described below.

Preparation 10: Methyl 1-(2-fluorobenzyl)-2,3-dioxoindoline-6-carboxylate

[0357] ##STR00193##

[0358] To a stirred solution of methyl 2,3-dioxoindoline-6-carboxylate (0.8 g, 3.89 mmol) in MeCN (15 mL) was added K.sub.2CO.sub.3 (1.61 g, 11.6 mmol) followed by addition of 1-(bromomethyl)-2-fluorobenzene (1.47 g, 7.79 mmol) at RT, and then the mixture allowed to stir at 60 C. for 8 h. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was diluted with water, extracted with EtOAc, and the organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organics were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using 30% EtOAc in hexanes as eluent to give methyl 1-(2-fluorobenzyl)-2,3-dioxoindoline-6-carboxylate (1.4 g, 4.46 mmol, 87% yield) as a white solid. LCMS m/z: 314.17 [M+H].

Preparation 11: 1-(2-Fluorobenzyl)-2,3-dioxoindoline-6-carboxylic acid

[0359] ##STR00194##

[0360] To a stirred a solution of methyl 1-(2-fluorobenzyl)-2,3-dioxoindoline-6-carboxylate (Preparation 10) (0.2 g, 0.64 mmol) in a mixture of HCl (conc.)-AcOH (1:1; 4 mL) was heated at 80 C. for 12 h. The reaction was monitored by TLC, and after completion, the reaction mass was cooled to RT. The resulting precipitate was diluted with water and extracted with DCM. The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give 1-(2-fluorobenzyl)-2,3-dioxoindoline-6-carboxylic acid (0.18 g, 0.60 mmol, 99% yield) as a yellowish solid. LCMS m/z: 298.05 [MH].

Preparation 12: 1-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-2,3-dioxoindoline-6-carboxamide

[0361] ##STR00195##

[0362] To a stirred solution of 1-(2-fluorobenzyl)-2,3-dioxoindoline-6-carboxylic acid (Preparation 11) (0.11 g, 0.37 mmol) in DCM (3 mL) was added TEA (0.205 mL, 1.46 mmol) followed by HATU (0.167 g, 0.44 mmol) at RT. Furan-2-ylmethanamine (0.042 g, 0.44 mmol) was then added dropwise to the solution and the reaction mixture allowed to stir at RT for 1 h. When TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with 1N HCl followed by saturated NaHCO.sub.3 solution and finally with brine. The combined organics were dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to obtain the crude material which was purified by Combi-flash using 20% EtOAc in hexanes as eluent to give 1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-2,3-dioxoindoline-6-carboxamide (0.065 g, 0.17 mmol, 47% yield) as a yellow solid. LCMS m/z: 377.24 [MH]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 4.45 (d, J=5.6 Hz, 2H), 4.98 (s, 2H), 6.27 (s, J=3.1 Hz, 1H), 6.39-6.40 (m, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.27-7.29 (m, 1H), 7.36-7.38 (m, 1H), 7.41 (s, 1H), 7.49 (m, 1H), 7.58-7.61 (m, 2H), 7.69 (d, J=7.7 Hz, 1H), 9.17 (t, J=5.65 Hz, 1H).

Preparation 13: 3.3-Difluoro-1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxoindoline-6-carboxamide

[0363] ##STR00196##

[0364] To a stirred solution of 1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-2,3-dioxoindoline-6-carboxamide (Preparation 12) (0.104 g, 0.28 mmol) in DCM (10 mL) was added DAST (0.110 g, 0.69 mmol) at 0-5 C. under an argon atmosphere and the reaction mixture then stirred at RT for 12 h. The progress of the reaction was monitored by TLC. After completion, it was quenched with saturated NaHCO.sub.3 solution and extracted with DCM.

[0365] The combined organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by prep-HPLC to give 3,3-difluoro-1-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxoindoline-6-carboxamide, i.e. Example 133, (0.040 g, 0.1 mmol, 37% yield) as an off white solid. LCMS m/z: 400.93 [M+H]. .sup.1H NMR (500 MHz; DMSO-d.sub.6): 4.46 (d, J=4.65 Hz, 2H), 5.04 (s, 2H), 6.28 (s, 1H), 6.41 (s, 1H), 7.20-7.28 (m, 2H), 7.34-7.40 (m, 2H), 7.59 (s, 2H), 7.73 (d, J=7.3 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 9.16 (bs, 1H).

Example 134: 1-(2-Chloro-6-fluorobenzyl)-3,3-dimethyl-N-(2,4,6-trifluorobenzyl)-1,3-dihydrobenzo[c]isothiazole-6-carboxamide 2,2-dioxide

[0366] ##STR00197##

[0367] Example 134 was prepared using the methods described in General procedures 13-16, and the methods described below.

Preparation 14: Methyl 4-(bromomethyl)-3-nitrobenzoate

[0368] ##STR00198##

[0369] To a stirred solution of methyl 4-methyl-3-nitrobenzoate (5.0 g, 25.64 mmol) in trifluoromethyl-benzene (100 mL) was added NBS (6.85 g, 38.46 mmol) and benzoyl peroxide (0.932 g, 3.85 mmol) at RT. The resulting reaction mixture was heated at 100 C. for 16 h. After completion of the reaction, the reaction mixture was quenched with a saturated solution of Na.sub.2S.sub.2O.sub.3 and extracted with EtOAc. The combined organics were concentrated under reduced pressure to give the crude product which was purified by column chromatography using 5% EtOAc in hexanes to afford methyl 4-(bromomethyl)-3-nitrobenzoate as a yellow oil (1.5 g, 5.47 mmol, 31% yield). LCMS m/z: 273.3 [M+H]

Preparation 15: Sodium (4-(methoxycarbonyl)-2-nitrophenyl)methanesulfonate

[0370] ##STR00199##

[0371] To a stirred solution of sodium sulfite (5.52 g, 43.80 mmol) in water (80 mL) was added TBAB (0.235 g, 0.73 mmol) at RT. To this was added methyl 4-(bromomethyl)-3-nitrobenzoate (Preparation 14) (4.0 g, 14.60 mmol) in MeOH (15 mL) and the resultant mixture was then refluxed at 90-100 C. for 3 h. After completion of the reaction, water and MeOH were removed by evaporation under reduced pressure. The residual water was then azeotroped with toluene and dried to obtain a crude solid product which was triturated twice with acetone, EtOAc and diethyl ether respectively to obtain sodium (4-(methoxycarbonyl)-2-nitrophenyl)-methanesulfonate (10.0 g) which was used in the next step without further purification.

Preparation 16: Sodium (2-amino-4-(methoxycarbonyl)phenyl)methanesulfonate

[0372] ##STR00200##

[0373] To a stirred solution of crude sodium (4-(methoxycarbonyl)-2-nitrophenyl)-methanesulfonate (Preparation 15) (10.0 g, 36.63 mmol) in MeOH (100 mL) was added Pd/C (1.0 g, 10% w/w) under a N.sub.2 gas atmosphere. The resulting reaction mixture was stirred at RT for 16 h under a hydrogen gas balloon pressure. After completion of the reaction, the mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure to give sodium (2-amino-4-(methoxycarbonyl)phenyl)-methanesulfonate (2.0 g, 7.49 mmol, 23% yield) as a crude product which was used in the next step without further purification.

Preparation 17: Methyl 1,-dihydrobenzo[c]isothiazole-6-carboxylate 2,2-dioxide

[0374] ##STR00201##

[0375] POCl.sub.3 (20 mL) was added to sodium (2-amino-4-(methoxycarbonyl)phenyl)-methanesulfonate (Preparation 16) (2 g, 7.49 mmol) at RT and the reaction mixture was then heated to reflux at 140-150 C. for 3 h. After this time, the reaction mixture was allowed to cool to RT. Excess POCl.sub.3 was then distilled off under reduced pressure. Traces of POCl.sub.3 were then removed by co-distilling with DCM and diethyl ether respectively. The crude material was purified by column chromatography using 30% EtOAc in hexanes as eluent to afford methyl 1,3-dihydrobenzo[c]isothiazole-6-carboxylate 2,2-dioxide (0.3 g, 1.32 mmol, 17% yield). LCMS m/z: 228 [M+H]

Preparation 18: Methyl 1-(2-chloro-6-fluorobenzyl)-1,3-dihydrobenzo[c]isothiazole-6-carboxylate 2,2-dioxide

[0376] ##STR00202##

[0377] To a stirred solution of methyl 1,3-dihydrobenzo[c]isothiazole-6-carboxylate 2,2-dioxide (Preparation 17) (0.3 g, 1.32 mmol) in DMF (6 mL) was added K.sub.2CO.sub.3 (0.365 g, 2.64 mmol) and stirred for 15 min., then 2-chloro-6-fluoro-benzylbromide (0.27 mL, 1.98 mmol) was added and the whole heated at 90 C. for 2 h. After completion of the reaction, the reaction mixture was diluted with EtOAc and washed with water followed by brine. The organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude material which was purified by column chromatography eluting with 30% EtOAc in hexanes to afford methyl 1-(2-chloro-6-fluorobenzyl)-1,3-dihydrobenzo[c]-isothiazole-6-carboxylate 2,2-dioxide (0.13 g, 0.35 mmol, 27% yield) as an off white solid. LCMS m/z: 370 [M+H].

Preparation 19: Methyl 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-1,3-dihydrobenzo[c]isothiazole-6-carboxylate 2,2-dioxide

[0378] ##STR00203##

[0379] To a stirred solution of methyl 1-(2-chloro-6-fluorobenzyl)-1,3-dihydrobenzo[c]-isothiazole-6-carboxylate 2,2-dioxide (Preparation 18) (0.090 g, 0.24 mmol) in DMF (2 mL) was added NaH (0.023 g, 0.56 mmol, 60% dispersion in oil) at ice bath temperature and the whole stirred for 15 min. MeI (0.04 mL, 0.61 mmol) was added and the mixture stirred at RT for a further 2 h. The progress of the reaction was monitored by TLC and after completion; the reaction mixture was quenched with a saturated solution of NH.sub.4Cl, diluted with water and extracted with EtOAc. The organics were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the crude product which was purified by prep TLC to afford methyl 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-1,3-dihydrobenzo[c]isothiazole-6-carboxylate 2,2-dioxide (0.065 g, 0.16 mmol, 67% yield) as an off white solid. LCMS m/z: 398 [M+H].

Preparation 20: 1-(2-Chloro-6-fluorobenzyl)-3,3-dimethyl-1,3-dihydrobenzo[c]isothiazole-6-carboxylic acid 2,2-dioxide

[0380] ##STR00204##

[0381] To a stirred solution of methyl 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-1,3-dihydrobenzo[c]isothiazole-6-carboxylate 2,2-dioxide (Preparation 19) (0.1 g, 0.25 mmol) in a THF-H.sub.2O mixture (1:1; 6 mL) was added LiOH.H.sub.2O (0.022 g, 0.53 mmol) and the whole stirred for 14 h at RT. After completion of the reaction, the reaction mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified with 1N HCl to pH 3 and extracted with EtOAc. The combined organics were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-1,3-dihydrobenzo[c]-isothiazole-6-carboxylic acid 2,2-dioxide (0.05 g, 0.13 mmol, 57% yield) as a yellowish solid.

Preparation 21: 1-(2-Chloro-6-fluorobenzyl)-3,3-dimethyl-N-(2,4,6-trifluorobenzyl)-1,3-dihydrobenzo[c]isothiazole-6-carboxamide 2,2-dioxide

[0382] ##STR00205##

[0383] To a stirred solution of 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-1,3-dihydrobenzo[c]-isothiazole-6-carboxylic acid 2,2-dioxide (Preparation 20) (0.03 g, 0.078 mmol) in DCM (2 mL) was added HATU (0.06 g, 0.16 mmol) and the mixture stirred for 30 min. at RT. 2,4,6-Benzyl amine (0.014 mL, 0.12 mmol) and TEA (0.0045 mL, 0.31 mmol) were added sequentially and the whole stirred for 14 h. Progress of the reaction was monitored by TLC and LCMS and after completion of the reaction, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO.sub.3 solution, water and brine. The combined 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 TLC to afford 1-(2-chloro-6-fluorobenzyl)-3,3-dimethyl-N-(2,4,6-trifluorobenzyl)-1,3-dihydrobenzo[c]isothiazole-6-carboxamide 2,2-dioxide, i.e. Example 134, (0.018 g, 0.035 mmol, 44% yield) as an off white solid. LCMS m/z: 527 [M+H]; .sup.1H NMR (400 MHz; DMSO-d.sub.6): 1.55 (s, 6H), 4.47 (d, J=4.52 Hz, 2H), 4.93 (s, 2H), 6.19 (t, J=8.68 Hz, 2H), 7.27 (m, 1H), 7.38 (m, 1H), 7.42 (m, 1H), 7.53-7.55 (m, 3H), 8.87 (bs, 1H).

Examples 135-140

[0384] Examples 135-140 were prepared according to the above method used to make Examples 132, 133 and 134 using the appropriate starting materials according to the methods described in General procedures 1-3 and 13-16.

TABLE-US-00002 LCMS Example Structure IUPAC Name .sup.1H-NMR (M + H) 135 [00206] 1-(2-chloro-6- fluorobenzoyl)- N-(furan-2- ylmethyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 3.20 (t, J = 8.15 Hz, 2H), 3.81-3.85 (m, 2H), 4.47 (d, J = 5.6 Hz, 2H), 6.28 (d, J = 2.9 Hz, 1H), 6.42 (d, J = 2.7 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 744- 7.48 (m, 1H), 7.52 (d, J = 8.05 HZ, 1H), 7.57- 7.65 (m, 3H), 8.62 (s, 1H), 9.06 (t, J = 5.55 Hz, 1H). 398.93 136 [00207] 3,3-dimethyl- 1-(2- phenylacetyl)- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.29 (s, 6H), 3.86 (s, 2H), 3.96 (s, 2H), 4.40 (s, 2H), 7.17-7.19 (m, 2H), 7.26-7.32 (m, 6H), 7.51 (d, J = 6.75 Hz, 1H), 8.47 (s, 1H), 8.80 (s, 1H). 453.22 137 [00208] 1(3,5- difluorobenzyl)- 2-oxo-N- (2,4,6- trifluorobenzyl) spiro[cyclo- pentane- 1,3- indoline]-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.81-1.84 (m, 2H), 1.94-2.04 (m, 6H), 4.41 (d, J = 5.04 Hz, 2H), 4.92 (s, 2H), 6.93 (d, J = 6.2 Hz, 2H), 7.12-7.17 (m, 3H), 7.32 (d, J = 1.08 Hz,, 1H), 7.39 (d, J = 7.76 Hz, 1H), 7.52- 7.54 (dd, J.sub.1 = 1.36 Hz, J.sub.2 = 7.8 Hz, 1H), 8.81 (t, J = 5.12 Hz, 1H). 501.38 138 [00209] 1-(3,5- difluorobenzyl)- 7-fluoro-2- oxo-N-(2,4,6- trifluorobenzyl) spiro[cyclo- hexane-1,3- indoline]-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.58-1.66 (m, 8H), 1.69-1.88 (m, 2H), 4.41 (d, J = 5.04 Hz, 2H), 4.92 (s, 2H), 6.91 (d, J = 6.2 Hz, 2H), 7.12-7.16 (m, 3H), 7.32 (s, 1H), 7.51-7.53 (dd, J.sub.1= 1.2 Hz, J.sub.2 = 7 .76 Hz, 1H), 7.59 (d, J = 7 .76 Hz, 1H), 8.82 (t, J = 5.08 Hz, 1H). 515.33 139 [00210] 1-(2-chloro-6- fluorobenzyl)- N-(furan-2- ylmethyl)-2- oxospiro[cyclo- propane-1,3- indoline]-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.58 (s, 2H), 1.69 (s, 2H), 4.43 (d, J = 4.88 Hz, 2H), 5.12 (s, 2H), 6.25 (s, 1H), 6.39 (s, 1H), 7.10 (d, J = 7.68 Hz, 1H), 7.22 (t, J = 8.8 Hz, 1H), 7.34-7.40 (m, 2H), 7.52-7.57 (m, 3H), 8.84 (bs, 1H). 425.0 140 [00211] 1-(2-chloro-6- fluorobenzyl)- N-(furan-2- ylmethyl)-1,3- dihydrobenzo [c]isothiazole- 6-carboxamide 2,2-dioxide (400 MHz; DMSO-d.sub.6): 4.48 (d, J = 5.36 Hz, 2H), 4.73 (s, 2H), 4.93 (s, 2H), 6.29 (s, 1H), 6.40 (s, 1H), 7.26 (t, J = 9.16 Hz, 1H), 7.37-7.45 (m, 3H), 7.54-7.58 (m, 2H), 7.65 (s, 1H), 8.97 (bs, 1H). 435.0

Example 141: 1-(3,5-Difluorobenzyl)-2,3-dioxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide

[0385] ##STR00212##

[0386] Example 141 was prepared using the method described in General procedure 8, and the methods described below.

Preparation 22: Methyl 2,3-dioxoindoline-6-carboxylate

[0387] ##STR00213##

[0388] To a stirred solution of methyl 2-oxoindoline-6-carboxylate (10.0 g, 52.33 mmol) in 1,4-dioxane (500 mL) was added selenium dioxide (27.9 g, 261.68 mmol) and the resulting reaction mixture was stirred vigorously at 100 C. for 1 h. After completion of the reaction, the reaction mixture was diluted with EtOAc and water and filtered through a bed of celite. The filtrate layers were separated and the organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4 and then evaporated under reduced pressure to provide the crude product. This was purified by Combi-flash using 50% EtOAc in hexanes as eluent to afford methyl 2,3-dioxoindoline-6-carboxylate (3.5 g, 17.06 mmol, 34% yield) as a light yellow solid.

Preparation 23: Methyl 1-(2,5-difluorobenzyl)-2,3-dioxoindoline-6-carboxylate

[0389] ##STR00214##

[0390] To a stirred solution of methyl 2,3-dioxoindoline-6-carboxylate (Preparation 22) (0.5 g, 2.44 mmol) in MeCN (10 mL) was added K.sub.2CO.sub.3 (1.01 g, 7.32 mmol) followed by the addition of 1-(bromomethyl)-3,5-difluorobenzene (0.555 g, 2.68 mmol) at RT, and then the mixture allowed to stir at 80 C. for 16 h. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The dried organics were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using 25% EtOAc in hexane as eluent to give methyl 1-(3,5-difluorobenzyl)-2,3-dioxoindoline-6-carboxylate (0.7 g, 2.11 mmol, 87% yield) as a brown solid. LCMS m/z: 332.17 [M+H].

Preparation 24: 1-(3,5-Difluorobenzyl)-2,3-dioxoindoline-6-carboxylic acid

[0391] ##STR00215##

[0392] A stirred solution of methyl 1-(3,5-difluorobenzyl)-2,3-dioxoindoline-6-carboxylate (Preparation 23) (0.4 g, 1.21 mmol) in a mixture of HCl (conc.)-AcOH (1:1; 8 mL) was heated at 80 C. for 6 h. The reaction was monitored by TLC, and after completion, the reaction mixture was cooled to 0-5 C. The resulting precipitate was filtered, washed with cold water and hexane, and then dried under reduced pressure at 50-60 C. to afford 1-(3,5-difluorobenzyl)-2,3-dioxoindoline-6-carboxylic acid (0.3 g, 0.95 mmol, 78% yield) as a yellowish solid.

Preparation 25: 1-(3,5-Difluorobenzyl)-2,3-dioxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide

[0393] ##STR00216##

[0394] To a stirred solution of 1-(3,5-difluorobenzyl)-2,3-dioxoindoline-6-carboxylic acid (Preparation 24) (0.09 g, 0.28 mmol) in DCM (2.5 mL) was added (2,4,6-trifluorophenyl)methanamine (0.048 g, 0.30 mmol) and HATU (0.135 g, 0.36 mmol) followed by addition of TEA (0.1 mL, 0.71 mmol) dropwise to the solution and the mixture allowed to stir at RT for 3 h. When TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, and then dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to obtain the crude material which was purified by prep-HPLC to afford 1-(3,5-difluorobenzyl)-2,3-dioxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide, i.e. Example 141 (0.065 g, 0.14 mmol, 50% yield) as a yellow solid. LCMS m/z: 502.24 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 4.44 (d, J=4.85 Hz, 2H), 4.96 (s, 2H), 7.14-7.20 (m, 3H), 7.23-7.26 (m, 3H), 7.54 (d, J=7.7 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 9.09 (t, J=5.0 Hz, 1H).

Example 142: 1-(2-Chloro-6-fluorobenzyl)-2,3-dioxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide

[0395] Example 142 was prepared according to the above method used to make Example 141 and General procedure 8 using the appropriate amines and benzyl halides. Purification was as stated in the aforementioned method.

TABLE-US-00003 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 142 [00217] 1-(2-chloro-6- fluorobenzyl)- 2,3-dioxo-N- (2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO- d.sub.6): 4.46 (d, J = 5 Hz, 2H), 5.04 (s, 2H), 7.21-7.30 (m, 3H), 7.38-7.46 (m, 2H), 7.50-7.53 (m, 2H), 7.66 (d, J = 7.75 Hz, 1H), 9.11 (t, J = 5.05 Hz, 1H). 477.19

Example 143: 1-(2-Chloro-6-fluorobenzyl)-3-hydroxy-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide

[0396] ##STR00218##

[0397] Example 143 was prepared using the methods described in General procedures 8 and 9, and the methods described below.

Preparation 26: Methyl 1-(2-chloro-6-fluorobenzyl)-2,3-dioxoindoline-6-carboxylate

[0398] ##STR00219##

[0399] The title compound was prepared using methyl 2,3-dioxoindoline-6-carboxylate (Preparation 22) according to the method described in Preparation 23 but using 2-chloro-6-fluoro-benzyl amine instead of 1-(bromomethyl)-3,5-difluorobenzene.

Preparation 27: Methyl 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-3-methyl-2-oxoindoline-6-carboxylate

[0400] ##STR00220##

[0401] To a stirred solution of methyl 1-(2-chloro-6-fluorobenzyl)-2,3-dioxoindoline-6-carboxylate (Preparation 26) (0.8 g, 2.30 mmol) in dry THF (25 mL) at 0-5 C. was added a solution of MeMgBr (1.15 mL, 3.45 mmol, 3M solution in diethyl ether) and the resulting reaction mixture was stirred at 0-25 C. for 16 h. The reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was quenched with aqueous 1N HCl solution and extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using 60% EtOAc in hexane as eluent to afford methyl 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-3-methyl-2-oxoindoline-6-carboxylate (0.6 g, 0.17 mmol, 71% yield) as a yellow solid. LCMS m/z: 346.18 [M-17].

Preparation 28: 1-(2-Chloro-6-fluorobenzyl)-3-hydroxy-2-methyl-2-oxoindoline-6-carboxylic acid

[0402] ##STR00221##

[0403] A stirred solution of methyl 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-3-methyl-2-oxoindoline-6-carboxylate (Preparation 27) (0.4 g, 1.10 mmol) in a mixture of HCl (conc.)-AcOH (1:1; 8 mL) was heated at 80 C. for 5 h. After reaction completion, the reaction mixture was cooled to 0-5 C. The resulting precipitate was filtered, washed with cold water and hexane, and then dried under reduced pressure at 50-60 C. to afford the title compound (0.34 g, 0.97 mmol, 97% yield) as a pink solid. LCMS m/z: 350.17 [M+H] & 332.12 [M-17].

Preparation 29: 1-(2-Chloro-6-fluorobenzyl)-3-hydroxy-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamid

[0404] ##STR00222##

[0405] To a stirred solution of 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-3-methyl-2-oxoindoline-6-carboxylic acid (Preparation 28) (0.34 g, 1.06 mmol) in DCM (15 mL) was added (2,4,6-trifluorophenyl)methanamine (0.156 g, 1.23 mmol) and HATU (0.555 g, 1.54 mmol) followed by addition of TEA (0.54 mL, 2.26 mmol) dropwise to the solution and the mixture allowed to stir at RT for 16 h. When TLC showed completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO.sub.3 solution followed by dilute aqueous HCl and finally with brine, and then dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to obtain the crude material which was purified by Combi-flash using 78% EtOAc in hexane as eluent to afford 1-(2-chloro-6-fluorobenzyl)-3-hydroxy-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide, i.e. Example 143, (0.25 g, 0.51 mmol, 52% yield) as an off white solid. LCMS m/z: 493.26 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.38 (s, 3H), 4.43 (d, J=4.95 Hz, 2H), 4.90 (d, J=15.5 Hz, 1H), 5.11 (d, J=15.4 Hz, 1H), 6.20 (s, 1H), 7.19-7.27 (m, 3H), 7.32-7.43 (m, 4H), 7.50 (d, J=7.75 Hz, 1H), 8.83 (t, J=5.05 Hz, 1H).

Example 144: 3-Chloro-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6 trifluorobenzyl) indoline-6-carboxamide

[0406] ##STR00223##

[0407] Example 144 was prepared according to the method described in General procedure 10, and the below method.

[0408] To a stirred solution of 1-(3,5-difluorobenzyl)-3-hydroxy-3-methyl-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide (Example 143, 1.5 g, 3.15 mmol) in DCM (50 mL) at 0-5 C. was added pyridine (0.5 mL) followed by SOCl.sub.2 (0.92 mL, 12.6 mmol) and the whole maintained at 0-5 C. for 30 min. After complete consumption of the starting material, the reaction mixture was diluted with water and extracted with DCM. The organic layers were washed with dilute 1N HCl solution followed by dilute NaHCO.sub.3 solution and finally with brine. The organics were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude product which was purified by Combi-flash using 35% EtOAc in hexanes as eluent to afford 3-chloro-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6 trifluorobenzyl) indoline-6-carboxamide, i.e. Example 144, (1.1 g, 2.22 mmol, 70% yield) as a pale yellow solid. LCMS m/z: 495.24 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.95 (s, 3H), 4.45 (d, J=4.95 Hz, 2H), 4.97-5.06 (q, J=16.55 Hz, 2H), 7.00 (d, J=6.5 Hz, 2H), 7.17-7.23 (m, 3H), 7.38 (s, 1H), 7.64 (d, J=7.85 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 8.95 (t, J=4.95 Hz, 1H).

Example 145: 1-(3,5-Difluorobenzyl)-3-methyl-3-(methylamino)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide

[0409] ##STR00224##

[0410] Example 145 was prepared according to the method described in General procedure 11, and the below method.

[0411] To a stirred solution of 3-chloro-1-(3,5-difluorobenzyl)-3-methyl-2-oxo-N-(2,4,6 trifluorobenzyl) indoline-6-carboxamide (Example 144, 0.1 g, 0.20 mmol) in MeCN (2 mL) was added TEA (0.146 mL 1.01 mmol) followed by addition of MeNH.sub.2.HCl (0.2 g, 3.04 mmol) and the mixture was maintained at 80 C. for 16 h. The reaction was monitored by LCMS, and after completion of the reaction, solvents were evaporated and the crude product was purified by prep-HPLC to afford 1-(3,5-difluorobenzyl)-3-methyl-3-(methylamino)-2-oxo-N-(2,4,6-trifluorobenzyl)indoline-6-carboxamide, i.e. Example 145, (0.015 g, 0.03 mmol, 15% yield) as an off white solid. LCMS m/z: 490.32 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 1.35 (s, 3H), 1.86 (s, 3H), 4.44 (d, J=4.85 Hz, 2H), 4.91-5.02 (q, J=16.4 Hz, 2H), 6.99 (d, J=6.45 Hz, 2H), 7.18 (t, J=8.2 Hz, 3H), 7.37-7.40 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 8.88 (t, J=4.75 Hz, 1H).

Examples 146-178

[0412] Examples 146-178 were prepared according to the above methods used to make Examples 143, 144 and 145 and General procedures 8-11 starting from the requisite isatin derivative, and using the appropriate nucleophile. Purification was as stated in the aforementioned methods.

TABLE-US-00004 IUPAC LCMS Example Structure Name .sup.1H-NMR [M + H] 146 [00225] 3-chloro-1(2- chloro-6- fluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.85 (s, 3H), 4.44 (d, J = 4.9 Hz, 2H), 5.04 (d, J = 15.6 Hz, 1H), 5.14 (d, J = 15.6 Hz, 1H), 7.19-7.22 (m, 2H), 7.25-7.29 (m, 1H), 7.37-7.45 (m, 3H), 7.58 (d, J = 7.81 Hz, 1H), 766 (d, J = 8.7 Hz, 1H), 8.91 (t, J = 5.0 Hz, 1H). 511.28 147 [00226] 3-chloro-1- (3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.94 (s, 3H), 4.44 (d, J = 4.92 Hz, 2H), 4.99-5.01 (m, 2H), 6.99 (d, J = 6.48 Hz, 2H), 7.14-7.18 (m, 3H), 7.43 (s, 1H), 7.62 (d, J = 7.84 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 8.92 (t, J = 4.92 Hz, 1H). 495.1 148 [00227] 3-chloro-1- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.94 (s, 3H), 4.44 (d, J = 5.04 Hz, 2H), 4.99 (dd, J.sub.1 = 16.6 Hz, J.sub.2 = 25.52 Hz, 2H), 6.99 (d, J = 6.44 Hz, 2H), 7.14-7.21 (m, 3H), 7.43 (s, 1H), 7.62 (d, J = 8.04 Hz, 1H), 7.70 (d, J = 7.84 Hz, 1H), 8.91 (t, J = 5.08 Hz, 1H). 495.1 149 [00228] 1-(2- fluorobenzyl)- N-(furan-2- ylmethyl)-3- hydroxy-3- methyl-2- oxoindoline- 6- carboxamide (500 MHz; DMSO-d.sub.6): 1.46 (s, 3H), 4.43 (d, J = 5.65 Hz, 2H), 4.90-5.00 (m, 2H), 6.24 (s, 2H), 6.39-6.40 (m, 1H), 7.14- 7.21 (m, 2H), 7.24-7.28 (m, 1H), 7.33-7.37 (m, 2H), 7.48 (d, J = 7.65 Hz, 1H), 7.57-7.61 (m, 2H), 8.95 (t, J = 5.55 Hz, 1H) 395.31 150 [00229] 1-(3,5- difluorobenzyl)- 3-fluoro-3- methyl-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.80 (d, J = 23.05 Hz, 3H), 4.44 (d, J = 4.9 Hz, 2H), 4.98 (s, 2H), 7.02- (d, J = 6.7 Hz, 2H), 7.17- 7.22 (m, 3H), 7.43 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 7.75 Hz, 1H), 8.98 (t, J = 4.9 Hz, 1H). 479.30 151 [00230] 1-(2-chloro-6- fluorobenzyl)- 3-methoxy-3- methyl-2-oxo)- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.41 (s, 3H), 2.86 (s, 3H), 4.42-4.47 (m, 2H), 5.02- 5.10 (q, J.sub.1 = 15.5 Hz, J.sub.2 = 23.45 Hz, 2H), 7.19-7.27 (m, 3H), 7.31-7.44 (m, 4H), 7.57 (d, J = 7.65 Hz, 1H), 8.88 (t, J = 5.0 Hz, 1H). 507.31 152 [00231] 1-(2-chloro-6- fluorobenzyl)- 3- (dimethylamino)- 3-methyl- 2-oxo-N- (2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.36 (s, 3H), 2.14 (s, 6H), 4.41 (t, J = 4.4 Hz, 2H), 4.99 (d, J = 3.56 Hz, 2H), 7.15-7.23 (m, 3H), 7.31- 7.48 (m, 4H), 7.49 (d, J = 6.6 Hz, 1H), 8.79 (t, J = 5.12 Hz, 1H). 520.34 153 [00232] 3-azido-1(2- chloro-6- fluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.60 (s, 3H), 4.42 (d, J = 4.92 Hz, 2H), 5.00-5.09 (q, J.sub.1 = 15.64 Hz, J.sub.2 = 21.04 Hz, 2H), 7.15-7.26 (m, 3H), 7.34-7.43 (m, 3H), 7.54 (s, 1H), 8.86 (t, J = 5.16 Hz, 1H). 518.35 154 [00233] 3-amino-1-(2- fluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.35 (s, 3H), 4.42 (d, J = 5.0 Hz, 2H), 4.89 (d, J = 16.4 Hz, 1H), 4.98 (d, J = 16.45 Hz, 1H), 7.12-7.19 (m, 4H), 7.25 (t, J = 10 Hz, 1H), 7.30 (s, 1H), 7.33-7.37 (m, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.54-7.56 (m, 1H), 8.83 (t, J = 5.05 Hz, 1H). 502.30 155 [00234] 3-chloro-1-(2- chloro-6- fluorobenzyl)- 3-ethyl-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 0.67 (t, J = 7.3 Hz, 3H), 2.15-2.19 (m, 2H), 4.45 (d, J = 3.5 Hz, 2H), 5.10 (s, 2H), 7.19-7.28 (m, 3H), 7.37-7.47 (m, 3H), 7.58- 7.61 (m 2H), 8.92 (t, J = 4.85 Hz, 1H). 525.30 156 [00235] 3-chloro-1-(2- chloro-6- fluorobenzyl)- 2-oxo-3- phenyl-N- (2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 4.42-4.50 (m, 2H), 5.09- 5.18 (m, 2H), 7.21 (t, J = 8.6 Hz, 2H), 7.27 (t, J = 9.35 Hz, 1H), 7.36-7.43 (m, 7H), 7.52 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 8.95 (t, J = 4.95 Hz, 1H). 573.28 157 [00236] 3-chloro-1-(2- chloro-6- fluorobenzyl)- 3-isopropyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 0.77 (d, J = 6.7 Hz, 3H), 1.08 (d, J = 6.85 Hz, 3H), 2.40-2.46 (m, 1H), 4.42- 4.50 (m, 2H), 5.09 (s, 2H), 7.19-7.28 (n, 3H), 7.37-7.45 (m, 2H), 7.53- 7.59 (m, 3H), 8.94 (t, J = 5.1 Hz, 1H). 539.29 158 [00237] 1-(2-chloro-6- fluorobenzyl)- 3-ethyl-3- hydroxy-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 0.57 (t, J = 7.4 Hz, 3H), 1.74-1.85 (m, 2H), 4.44 (d, J = 4.35 Hz, 2H), 4.88 (d, J = 15.3 Hz, 1H), 5.09 (d, J = 15.3 Hz, 1H), 6.08 (s, 1H), 7.19-7.27 (m, 3H), 7.37-7.4 (m, 4H), 7.51- 7.52 (m, 1H), 8.84 (t, J = 5.15 Hz, 1H). 507.28 159 [00238] 1-(2-chloro-6- fluorobenzyl)- 3-hydroxy-3- isopropyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 0.56 (d, J = 6.75 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 2.06-2.11 (m, 1H), 4.41- 4.50 (m, 2H), 4.88 (d, J = 15.15 Hz, 1H), 5.06 (d, J = 15.2 Hz, 1H), 6.02 (s, 1H), 7.19-7.26 (m, 3H), 7.34- 7.42 (m, 3H), 7.49-7.51 (m, 2H), 8.86 (t, J = 5.1 Hz, 1H). 521.34 160 [00239] 1-(2-chloro-6- fluorobenzyl)- 3-hydroxy-2- oxo-3-phenyl- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 4.46 (s, 2H), 4.97 (d, J = 15.55 Hz, 1H), 5.13 (d, J = 15.3 Hz, 1H), 6.88 (s, 1H), 7.20-7.44 (m, 11H), 7.50 (d, J = 6.75 Hz, 2H), 8.87 (t, J = 4.6 Hz, 1H). 555.31 161 [00240] 1-(2-chloro-6- fluorobenzyl)- 3-ethyl-3- methoxy-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 0.60 (t, J = 7.4 Hz, 3H), 1.75-1.89 (m, 2H), 2.86 (s, 3H), 4.46 (d, J = 4.75 Hz, 2H), 5.01-5.10 (q, J = 15.4 Hz, 2H), 7.19-7.27 (m, 3H), 7.37-7.44 (m, 3H), 7.48 (bs, 1H), 7.58 (d, J = 7.6 Hz, 1H), 8.90 (t, J = 4.85 Hz, 1H) 521.34 162 [00241] 1-(3,5)- difluorobenzyl)- 3-hydroxy- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.45 (s, 3H), 4.43 (d, J = 5 Hz, 2H), 4.88 (d, J = 16.5 Hz, 1H), 4.99 (d, J = 16.55 Hz, 1H), 6.23 (s, 1H), 7.03 (d, J = 6.5Hz, 2H), 7.18 (t, J = 8.3 Hz, 3H), 7.29 (s, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 8.87 (t, J = 5.05 Hz, 1H). 477.30 163 [00242] 3-cyano-1- (3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.85 (s, 3H), 4.46 (d, J = 5.0 Hz, 2H), 4.97-5.06 (q, J = 16.55 Hz, 2H), 7.04 (d, J = 6.35 Hz, 2H), 7.16- 7.23 (m, 3H), 7.49 (s, 1H), 7.68 (d, J = 7.85 Hz, 1H), 7.80 (d, J = 7.85 Hz, 1H), 8.97 (t, J = 5.1 Hz, 1H). 486.33 164 [00243] 1-(2-chloro-6- fluorobenzyl)- 3-cyano-3- methyl-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.77 (s, 3H), 4.46 (s, 2H), 5.12 (s, 2H), 7.2 (t, J = 7.05 Hz, 2H), 7.28 (t, J = 8.6 Hz, 1H), 7.38-7.45 (m, 3H), 7.63 (d, J = 6.8 Hz, 1H), 7.75 (d, J = 7.35 Hz, 1H), 8.90 (bs, 1H). 502.12 165 [00244] 1-(2-chloro-6- fluorobenzyl)- 3-cyano-3- methyl-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.23 (s, 3H), 4.44 (s, 2H), 5.10 (s, 2H), 7.18 (bs, 2H), 7.27 (s, 1H), 7.38-7.43 (m, 3H), 7.62 (bs, 1H), 7.74 (s, 1H), 8.90 (bs, 1H). 502.2 166 [00245] 1-(2-chloro-6- fluorobenzyl)- 3-cyano-3- methyl-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.76 (s, 3H), 4.44 (s, 2H), 5.10 (s, 2H), 7.19 (t, J = 8.48 Hz, 2H), 7.27 (t, J = 9.68 Hz, 1H), 7.36-7.43 (m, 3H), 7.61 (d, J = 7.76 Hz, 1H), 7.74 (d, J = 7.68 Hz, 1H), 8.90 (bs, 1H). 502.2 167 [00246] 3-cyano-1- (3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6 ): 1.84 (s, 3H), 4.44 (d, J = 4.04 Hz, 2H), 5.00 (dd, J.sub.1 = 16.6 Hz, J.sub.2 = 25.4 Hz, 2H), 7.03 (d, J = 6.12 Hz, 2H), 7.15-7.19 (m, 3H), 7.48 (s, 1H), 7.67 (d, J = 7.24 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 8.95 (bs, 1H). 486.2 168 [00247] 3-cyano-1- (3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (400 MHz; DMSO-d.sub.6): 1.84 (s, 3H), 4.44 (d, J = 4.44 Hz, 2H), 5.00 (dd, J.sub.1 = 16.6 Hz, J.sub.2 = 25.4 Hz, 2H), 7.03 (d, J = 6.36 Hz, 2H), 7.14-7.19 (m, 3H), 7.48 (s, 1H), 7.67 (d, J = 7.36 Hz, 1H), 7.78 (d, J = 7.84 Hz, 1H), 8.94 (bs, 1H). 486.2 169 [00248] 2-(1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-6-((2,4,6- trifluorobenzyl) carbamoyl) indolin-3- yl)acetic acid (400 MHz; DMSO-d.sub.6): 1.24 (s, 3H), 2.93 (d, J = 17.16 Hz, 1H), 3.11 (d, J = 17.08 Hz, 1H), 4.39 (d, J = 4.64 Hz, 2H), 4.79 (d, J = 16.88 Hz, 1H), 5.07 (d, J = 16.68 Hz, 1H), 7.11-7.16 (m, 6H), 7.43-7.50 (q, J = 7.68 Hz, 2H), 8.78 (bs, 1H). 519.29 170 [00249] 1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N6- trifluorobenzyl) indoline- 3,6- dicarboxamide (400 MHz; DMSO-d.sub.6): 1.57 (s, 3H), 4.41 (d, J = 5.0 Hz, 2H), 4.89 (d, J = 16.76 Hz, 1H), 5.00 (d, J = 16.68 Hz, 1H), 7.04 (d, J = 6.48 Hz, 2H), 7.09-7.15 (m, 3H), 7.30 (d, J = 0.88 Hz, 1H), 7.40-7.43 (m, 3H), 7.54-7.56 (dd, J.sub.1 = 1.24 Hz, J.sub.2 = 7.76 Hz, 1H), 8.81 (t, J = 5.08 Hz, 1H). 504.34 171 [00250] 1-(3,5- difluorobenzyl)- 3-methyl-3- (2- morpholinoethyl)- 2-oxo-N- (2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.32 (s, 3H), 1.84-1.88 (m, 4H), 1.99-2.06 (m, 1H), 2.13-2.16 (m, 3H), 3.40- 3.43 (m, 4H), 4.44 (t, J = 4.45 Hz, 2H), 4.88 (d, J = 16.3 Hz, 1H), 5.05 (d, J = 16.1 Hz, 1H), 7.00 (d, J = 6.65 Hz, 2H), 7.18 (t, J = 8.4 Hz, 3H), 7.37 (s, 1H), 7.45 (d, J = 7.70 Hz, 1H), 7.57 (d, J = 7.65 Hz, 1H), 8.85 (t, J = 4.55 Hz, 1H). 574.45 172 [00251] 3- (aminomethyl)- 1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.26 (s, 3H), 2.95 (d, J = 12.4 Hz, 1H), 3.06 (d, J = 12.4 Hz, 1H), 4.43 (d, J = 4.5 Hz, 2H), 4.85 (d, J = 16.7 Hz, 1H), 5.09 (d, J = 16.7 Hz, 1H), 7.06-7.18 (m, 5H), 7.26 (s, 1H), 7.45 (d, J = 7.65 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 8.82 (bs, 1H) 490.39 173 [00252] 3-(2- aminoethyl)- 1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.32 (s, 3H), 1.95-1.99 (m, 2H), 2.08 (s, 1H), 2.15- 2.20 (m, 2H), 4.44 (d, J = 4.90 Hz, 2H), 4.89 (d, J = 16.5 Hz, 1H), 4.99 (d, J = 16.5 Hz, 1H), 7.01 (d, J = 6.85 Hz, 2H), 7.17 (t, J = 8.5 Hz, 3H), 7.35 (s, 1H), 7.43 (d, J = 7.75 Hz, 1H), 7.58 (d, J = 7.65 Hz, 1H), 8.85 (t, J = 4.8 Hz, 1H). 504.39 174 [00253] N-(2,4- difluorobenzyl)- 1-(3,5- difluorobenzyl)- 3-(2- hydroxyethyl)- 3-methyl-2- oxoindoline- 6- carboxamide (500 MHz, DMSO-d.sub.6): 1.33 (s, 3H), 2.16-2.02 (m, 2H), 3.06-3.02 (m, 1H), 3.14 (bs, 1H), 4.46 (bs, 3H), 4.86 (d, J = 16.5 Hz, 1H), 5.03 (d, J = 16.5 Hz, 1H), 7.06-7.03 (m, 3H), 7.24-7.14 (m, 2H), 7.40- 7.35 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.63 (d, 7.6 Hz, 1H), 8.98 (t, J = 5.4 Hz, 1H). 487.36 175 [00254] 3-allyl-1-((1- ethyl-3- methyl-1H- pyrazol-5- yl)methyl)-3- methyl-2-oxo- N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz, DMSO-d.sub.6): 1.28 (t, J = 7.1 Hz, 3H), 1.34 (s, 3H), 2.05 (s, 3H), 2.62-2.58 (m, 1H), 2.69 (s, 1H), 4.13-4.04 (m, 1H), 4.46 (bs, 2H), 4.96-4.86 (m, 4H), 5.36-5.27 (m, 1H), 5.80 (s, 1H), 7.19 (t, J = 8.5 Hz, 2H), 7.46-7.42 (m, 2H), 7.57 (d, J = 7.6 Hz, 1H), 8.88 (t, J = 4.9 Hz, 1H). 497.21 176 [00255] N-(2,4- difluorobenzyl)- 1-(3,5- difluorobenzyl)- 3- (hydroxymethyl)- 3-methyl- 2-oxoindoline- 6-carboxamide (500 MHz, DMSO-d.sub.6): 1.26 (s, 3H), 3.80-3.78 (m, 2H), 4.45 (s, 2H), 4.87-4.83 (m, 1H), 5.15- 5.11 (m, 2H), 7.05 (bs, 3H), 7.37-7.13 (m, 4H), 7.64-7.48 (m, 2H), 8.96 (s, 1H). 473.60 177 [00256] 1-(2-chloro-6- fluorobenzyl)- 3-(3- hydroxypropyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz, DMSO-d.sub.6): 1.26 (s, 2H), 1.41 (s, 1H), 1.54 (t, J = 6.2 Hz, 1H), 1.76 (bs, 1H), 3.06-2.94 (m, 1H), 3.20 (d, J = 4.6 Hz, 1H), 3.34 (s, 1H), 4.33 (d, J = 19.8 Hz, 1H), 4.44 (s, 2H), 5.10-5.00 (m, 2H), 7.27-7.18 (m, 3H), 7.42-7.37 (m, 5H), 7.56- 7.51 (m, 1H), 8.81 (bs, 1H). 535.11 178 [00257] 3- (cyanomethyl)- 1-(3,5- difluorobenzyl)- 3-methyl-2- oxo-N-(2,4,6- trifluorobenzyl) indoline-6- carboxamide (500 MHz; DMSO-d.sub.6): 1.43 (s, 3H), 3.15 (d, J = 16.9 Hz, 1H), 3.29 (s, 1H), 4.44 (d, J = 4.70 Hz, 2H), 4.92 (d, J = 16.7 Hz, 1H), 5.09 (d, J = 16.5 Hz, 1H), 7.04 (d, J = 6.65 Hz, 2H), 7.17 (t, J = 8.55 Hz, 3H), 7.38 (s, 1H), 7.62 (s, 2H), 8.90 (bs, 1H). 500.32

[0413] Example 179: 1-(3,5-Difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide

##STR00258##

[0414] Example 179 was made using the methods described in General procedures 1-7 and the below methods.

Preparation 30: Diethyl 2-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)malonate

[0415] ##STR00259##

[0416] To a stirred suspension of NaH (0.33 g, 8.31 mmol, 60% suspension in oil) in dry THF (15 mL) in a 2-neck round-bottomed flask fitted with a condenser was added diethylmalonate (1.162 mL, 7.62 mmol) at 0 C. and further stirred for 15 min. under an inert atmosphere. 6-chloro-5-nitro-nicotinic acid methyl ester (1.5 g, 6.93 mmol) was added into the suspension by dissolving in dry THF (5 mL). The mixture was allowed to stir at RT for 1.5 h and at 80 C. for 3 h. After completion of the reaction by TLC, it was quenched with saturated aqueous NH.sub.4Cl solution, diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to provide a crude solid, which was triturated with pentane to afford diethyl 2-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)malonate (2.1 g, 6.18 mmol, 89% yield) as a yellow solid. LCMS m/z: 341 [M+H].

Preparation 31: Methyl 6-(2-ethoxy-2-oxoethyl)-5-nitronicotinate

[0417] ##STR00260##

[0418] To a stirred solution of diethyl 2-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)malonate (Preparation 30) (1.0 g, 2.94 mmol) in DMSO containing H.sub.2O (0.25 mL) was added anhydrous LiCl (0.187 g, 4.41 mmol) and stirred at 100 C. for 16 h. The reaction mixture was cooled, diluted with water, and extracted with EtOAc. The combined organic layers were washed successively with water and brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5%-8% EtOAc in hexanes as eluent to afford methyl 6-(2-ethoxy-2-oxoethyl)-5-nitronicotinate (0.4 g, 1.49 mmol, 50% yield) as a red liquid. LCMS m/z: 269 [M+H].

Preparation 32: Methyl 6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-5-nitronicotinate

[0419] ##STR00261##

[0420] To a stirred solution of methyl 6-(2-ethoxy-2-oxoethyl)-5-nitronicotinate (Preparation 31) (0.450 g, 1.68 mmol), MeI (0.314 mL, 5.04 mmol) and 18-crown-6 (0.044 g, 0.17 mmol) in DMF (6 mL) under an inert atmosphere was added NaH (0.153 g, 3.86 mmol, 60% suspension in oil) portionwise at 0 C. The resulting reaction mixture was allowed to stir at 0 C. for 1 h then at RT for 1 h. After completion of the reaction, it was quenched with saturated aqueous NH.sub.4Cl solution, 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 and evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 5% EtOAc in hexanes as eluent to afford methyl 6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-5-nitronicotinate (0.4 g, 1.35 mmol, 80% yield) as a yellowish gum. LCMS m/z: 297 [M+H].

Preparation 33: Methyl 3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate

[0421] ##STR00262##

[0422] To a purged solution of methyl 6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-5-nitronicotinate (Preparation 32) (0.3 g, 1.01 mmol) in EtOH (4 mL) was added ammonium formate (0.255 g, 4.05 mmol) and wet Pd/C (0.090 g, 10% w/w). The mixture was refluxed for 2 h under an Ar atmosphere. After filtering the reaction mixture, the filtrate was evaporated, diluted with EtOAc and water, and the organic layer separated, dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to provide a crude residue which upon trituration with n-pentane furnished methyl 3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (0.13 g, 0.59 mmol, 58%) as a fluffy white solid. LCMS m/z: 219 [M+H].

Preparation 34: Methyl 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate

[0423] ##STR00263##

[0424] To a stirred solution of methyl 3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (Preparation 33) (0.13 g, 0.59 mmol) in dry DMF under an Ar atmosphere was added Cs.sub.2CO.sub.3 (0.231 g, 0.71 mmol) at ice-cold temperature. After 30 min. of stirring, 3,5-difluorobenzyl bromide (0.084 mL, 0.65 mmol) was added into the reaction mixture and the whole stirred at RT for 2 h. After completion of the reaction, the reaction mixture was filtered. The filtrate 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 and evaporated under reduced pressure. The resulting crude material was triturated with n-pentane to afford methyl 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (0.145 g, 0.42 mmol, 71% yield) as a white crystalline solid. LCMS m/z: 347 [M+H].

Preparation 35: 1-(3,5-Difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid

[0425] ##STR00264##

[0426] To a stirred solution of methyl 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (Preparation 34) (0.185 g, 0.54 mmol) in a THF-H.sub.2O mixture (1:1; 3 mL) was added LiOH.H.sub.2O (0.027 g, 0.64 mmol) and the whole stirred for 12 h at RT. After completion of the reaction, the reaction mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified with 1N HCl to pH 3 and extracted with EtOAc. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (0.16 g, 0.48 mmol, 90% yield) as an off white solid. LCMS m/z: 333 [M+H].

Preparation 36: 1-(3,5-Difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide

[0427] ##STR00265##

[0428] To a stirred solution of 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (Preparation 35) (0.06 g, 0.17 mmol) in DCM at RT (5 mL) was added HATU (0.099 g, 0.26 mmol) and the mixture stirred for 30 min. 2,4,6-trifluorobenzyl amine (0.023 mL, 0.19 mmol) and TEA (0.048 mL, 0.35 mmol) were added and stirring continued for a further 14 h. After complete consumption of starting material, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO.sub.3 solution, water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a crude residue which was purified by prep-TLC using 40% EtOAc in hexanes as eluent followed by lyophilization to afford 1-(3,5-difluorobenzyl)-3,3-dimethyl-2-oxo-N-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide, i.e. Example 179, (0.04 g, 0.084 mmol, 48% yield) as a white solid. LCMS m/z: 476.1 [M+H]; .sup.1H NMR (400 MHz; DMSO-d.sub.6): 1.35 (s, 6H), 4.46 (d, J=5.0 Hz, 2H), 4.98 (s, 2H), 6.99 (d, J=6.48 Hz, 2H), 7.17 (t, J=8.96 Hz, 3H), 7.65 (bs, 1H), 8.61 (d, J=1.08 Hz, 1H), 9.01 (t, J=4.96 Hz, 1H).

Examples 180-199

[0429] Examples 180-199 were prepared according to the above method used to make Example 179 and General procedures 1-7, using the appropriate starting aryl ester, amine and halide. Purification was as stated in the aforementioned method.

TABLE-US-00005 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 180 [00266] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.33 (s, 6H), 4.54 (d, J = 5.76 Hz, 2H), 5.03 (s, 2H), 7.09-7.16 (m, 5H), 7.71 (d, J = 7.44 Hz, 1H), 7.90 (d, J = 7.48 Hz, 1H), 9.05 (t, J = 5.72 Hz, 1H) 476.3 181 [00267] 1-(4- fluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.31 (s, 6H), 4.55 (d, J = 5.32 Hz, 2H), 4.99 (s, 2H), 7.10 (t, J = 8.76 Hz, 2H), 7.21 (t, J = 8.8 Hz, 2H), 7.45 (t, J = 7.96 Hz, 2H), 7.68 (d, J = 7.4 Hz, 1H), 7.88 (d, J = 7.52 Hz, 1H), 9.01 458.3 (bs, 1H). 182 [00268] N-(benzofuran- 2-ylmethyl)-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.35 (s, 6H), 4.69 (d, J = 6.12 Hz, 2H), 5.08 (s, 2H), 6.68 (s, 1H), 7.03- 7.11-7.21 (m, 3H), 7.22-7.27 (m, 2H), 7.51 (d, J = 7.76 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.77 (d, J = 7.44 Hz, 1H), 7.94 (d, J = 7.44 Hz, 1H), 9.39 (t, J = 6.08 Hz, 1H). 462.2 183 [00269] N-(benzofuran- 2-ylmethyl)- 3,3-dimethyl-1- ((2- methylpyridin- 4-yl)methyl)-2- oxo-2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.37 (s, 6H), 2.36 (s, 3H), 4.67 (d, J = 6.04 Hz, 2H), 5.04 (s, 2H), 6.67 (s, 1H), 7.09 (d, J = 5.0 Hz, 1H), 7.19-7.27 (m, 3H), 7.51 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.95 441.1 (d, J = 7.44 Hz, 1H), 8.32 (d, J = 5.08 Hz, 1H), 9.28 (t, J = 5.96 Hz, 1H). 184 [00270] 3,3-dimethyl-2- oxo-1-(pyridin- 4-ylmethyl)-N- (2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.35 (s, 6H), 4.52 (d, J = 5.68 Hz, 2H), 5.05 (s, 2H), 7.18 (t, J = 9.08 Hz, 2H), 7.32 (d, J = 5.44 Hz, 2H), 7.70 (d, J = 7.44 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 8.48 (d, J = 5.6 Hz, 2H), 8.96- 8.97 (m, 1H). 441.1 185 [00271] 3,3-dimethyl-1- ((2- methylpyridin- 4-yl)methyl)-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.35 (s, 6H), 2.39 (s, 3H), 4.52 (d, J = 5.72 Hz, 2H), 5.00 (s, 2H), 7.10 (d, J = 5.04 Hz, 1H), 7.15-7.19 (m, 3H), 7.71 (d, J = 7.44 Hz, 1H), 7.91 (d, J = 7.48 Hz, 1H), 8.34 454.9 (d, J = 5.04 Hz, 1H), 8.97 (t, J = 5.88 Hz, 1H). 186 [00272] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluorobenzyl)- 2,3-dihydro- 1H-pyrrolo[3,2- c]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.42 (s, 6H), 4.48 (d, J = 5.16 Hz, 2H), 5.02 (s, 2H), 6.98 (d, J = 6.0 Hz, 2H), 7.11-7.17 (m, 3H), 7.59 (bs, 1H), 8.53 (bs, 1H), 9.08 (bs, 1H). 476.3 187 [00273] 1-(3,5- difluorobenzyl)- N-(furo[2,3- c]pyridin-2- ylmethyl)-3,3- dimethyl-2-oxo- 2,3-dihydro- 1H-pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.32 (s, 6H), 4.71 (d, J = 5.72 Hz, 2H), 5.04 (s, 2H), 6.80 (s, 1H), 7.12 (d, J = 7.28 Hz, 3H), 7.58 (m, 1H), 5.75 (d, J = 6.88 Hz, 1H), 7.91 (d, J = 7.56 Hz, 1H), 8.39 (d, J = 6.0 Hz, 1H), 8.83 (bs, 1H), 9.40 (bs, 1H). 463.3 188 [00274] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxo-2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.34 (s, 6H), 2.21 (s, 3H), 4.45 (d, J = 5.68 Hz, 2H), 5.06 (s, 2H), 5.97 (s, 1H), 6.08 (s, 1H), 7.11-7.13 (m, 3H), 7.75 (d, J = 7.36 Hz, 1H), 7.92 (d, J = 7.28 Hz, 1H), 9.15 (bs, 1H). 426.3 189 [00275] 1-(3,5- difluorobenzyl)- N-(4- fluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.34 (s, 6H), 4.51 (d, J = 6.44 Hz, 2H), 5.06 (s, 2H), 7.10-7.16 (m, 5H), 7.32-7.35 (m, 2H), 7.75 (d, J = 7.44 Hz, 1H), 7.92 (d, J = 7.48 Hz, 1H), 9.36 (bs, 1H). 440.2 190 [00276] 1-(3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-N-(2,4,6- trifluoro- phenethyl)- 2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz; DMSO- d.sub.6): 1.34 (s, 6H), 2.87 (bs, 2H), 3.50 (d, J = 6.44 Hz, 2H), 5.04 (s, 2H), 7.05-7.17 (m 5H), 7.70 (d, J = 7.28 Hz, 1H), 7.91 (d, J = 7.44 Hz, 1H), 8.90 (bs, 1H). 489.9 191 [00277] N-benzyl-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.35 (s, 6H), 4.54 (d, J = 6.1 Hz, 2H), 5.06 (s, 2H), 7.30-7.14 (m, 8H), 7.76 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 7.3 Hz, 1H), 9.37 (bs, 1H). 422.2 192 [00278] N-(4- cyanobenzyl)-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.35 (s, 6H), 4.62 (d, J = 6.2 Hz, 2H), 5.06 (s, 2H), 7.15 (bs, 3H), 7.48 (d, J = 8.0 Hz, 2H), 7.77 (t, J = 8.2 Hz, 3H), 7.93 (d, J = 7.3 Hz, 1H), 9.47 (bs, 1H). 447.3 193 [00279] N-(benzofuran- 2-ylmethyl)-1- (3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[3,2- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.37 (s, 6H), 4.64 (d, J = 5.2 Hz, 2H), 5.00 (s, 2H), 6.76 (s, 1H), 7.01 (d, J = 5.9 Hz, 2H), 7.27-7.17 (m, 3H), 7.58-7.50 (m, 2H), 7.72 (s, 1H), 8.70 (s,, 1H), 9.25 (bs, 1H). 462.2 194 [00280] 1-(2-fluoro-6- methylbenzyl)- N-(4- fluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.31 (s, 6H), 2.26 (s, 3H), 4.50 (d, J = 6.0 Hz, 2H), 5.02 (s, 2H), 6.79 (t, J = 9.1 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 7.21-7.13 (m, 3H), 7.37-7.34 (m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 8.61 (bs, 436.1 1H). 195 [00281] 1-(2-fluoro-6- methylbenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxo-2,3- dihydro-1H- pyrrolo[2,3- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.32 (s, 6H), 2.26 (s, 6H), 4.45 (d, J = 5.0 Hz, 2H), 5.00 (s, 2H), 6.06 (s, 1H), 6.23 (s, 1H), 6.82 (t, J = 9.1 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 7.17 (bs, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H), 422.11 8.28 (bs, 1H). 196 [00282] 1-(2-fluoro-6- methylbenzyl)- 3,3-dimethyl-N- ((5- methylfuran-2- yl)methyl)-2- oxo-2,3- dihydro-1H- pyrrolo[3,2- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.29 (s, 6H), 2.22 (s, 3H), 2.35 (s, 3H), 4.39 (d, J = 5.5 Hz, 2H), 4.98 (s, 2H), 5.99 (bs, 1H), 6.12 (d, J = 2.8 Hz, 1H), 7.06- 7.01 (m, 2H), 7.25- 7.21 (m, 1H), 7.56 (s, 1H), 8.61 (s, 1H), 9.03 (t, J = 5.4 Hz, 1H). 422.2 197 [00283] 1-(2-fluoro-6- methylbenzyl)- N-(4- fluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[3,2- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.36 (s, 6H), 2.35 (s, 3H), 4.44 (d, J = 5.8 Hz, 2H), 4.98 (s, 2H), 7.06-7.01 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.26-7.22 (m, 1H), 7.35-7.31 (m, 2H), 7.56 (s, 1H), 9.16 (t, J = 5.7 Hz, 1H). 436.0 198 [00284] 1-(3,5- difluorobenzyl)- N-(4- fluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[3,2- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.37 (s, 6H), 4.46 (d, J = 5.9 Hz, 2H), 4.99 (s, 2H), 7.01 (d, J = 6.4 Hz, 2H), 7.20-7.12 (m, 3H), 7.35-7.32 (m, 2H), 7.69 (d, J = 1.4 Hz, 1H), 8.69 (s, 1H), 9.16 (t, J = 5.8 Hz, 1H). 440.0 199 [00285] N-(2,4- difluorobenzyl)- 1-(3,5- difluorobenzyl)- 3,3-dimethyl-2- oxo-2,3- dihydro-1H- pyrrolo[3,2- b]pyridine-6- carboxamide (400 MHz, DMSO- d.sub.6): 1.36 (s, 6H), 4.47 (d, J = 5.4 Hz, 2H), 4.99 (s, 2H), 7.06-7.00 (m, 3H), 7.25-7.15 (m, 2H), 7.43-7.37 (m, 1H), 7.69 (s, 1H), 8.68 (d, J = 1.3 Hz, 1H), 9.14 (t, J = 5.5 Hz, 1H). 458.0

Example 200: 3-(2-Fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide

[0430] ##STR00286##

[0431] Example 200 was prepared according to the methods described in General procedures 17 and 18, and the below methods.

Preparation 37: Methyl 3-(2-fluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylate

[0432] ##STR00287##

To a stirred solution of methyl 2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylate (0.4 g, 2.07 mmol) in dry DMF (10 mL) was added NaH (0.083 g, 2.07 mmol) at RT and the mixture stirred for 10 min. at 0-5 C. To the resulting reaction mixture 1-(bromomethyl)-2-fluorobenzene (2.17 mmol, 0.248 mL) was added and the whole stirred for a further 1 h. The reaction was monitored by TLC. After completion of the reaction the reaction mixture was quenched with a saturated solution of NH.sub.4Cl then diluted with water, extracted with EtOAc, and the organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The organics were evaporated under reduced pressure to obtain the crude product which was purified by Combi-flash using 15% EtOAc in hexanes as eluent to afford methyl 3-(2-fluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylate (0.45 g, 1.5 mmol, 72% yield) as a yellowish solid. LCMS m/z: 302.13 [M+H].

Preparation 38: 3-(2-Fluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylic acid

[0433] ##STR00288##

[0434] A stirred solution of methyl 3-(2-fluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylate (Preparation 37) (0.1 g, 0.33 mmol) in a mixture of HCl (conc.)-AcOH (1:1; 2 mL) was heated at 80 C. for 5 h. The reaction was monitored by TLC, and after completion, the reaction mixture was cooled to RT. The resulting precipitate was filtered, washed with cold water and hexane. The solid formed was collected and dried by azeotropic distillation with MeCN three times to give 3-(2-fluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylic acid (0.05 g, 0.17 mmol, 52% yield) as a white solid. LCMS m/z: 286.07 [M+H].

Preparation 39: 3-(2-Fluorobenzyl)-N-(furan-2-ylmethyl-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide

[0435] ##STR00289##

[0436] To a stirred solution of 3-(2-fluorobenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxylic acid (Preparation 38) (0.045 g, 0.16 mmol) in DCM (2.0 mL) at 0 C. was added TEA (0.045 mL, 0.32 mmol) and HATU (0.070 g, 0.19 mmol), followed by furan-2-ylmethanamine (0.015 mL, 0.17 mmol) dropwise to the solution and the whole further stirred at 0 C. for 5 min. After this time, the reaction mixture was allowed to warm slowly to RT over 1 h. TLC showed completion of the reaction. The solvent was evaporated under reduced pressure and the resulting residue purified by Combi-flash using 30% EtOAc in hexanes as eluent to afford 3-(2-fluorobenzyl)-N-(furan-2-ylmethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide, i.e. Example 200, (0.045 g, 0.12 mmol, 78% yield) as a white solid. LCMS m/z: 366.88 [M+H]; .sup.1H NMR (500 MHz; DMSO-d.sub.6): 4.46 (d, J=5.65 Hz, 2H), 5.13 (s, 2H), 6.27 (d, J=3.1 Hz, 1H), 6.39-6.40 (m, 1H), 7.19-7.28 (m, 2H), 7.39-7.48 (m, 3H), 7.58 (d, J=0.8 Hz, 1H), 7.71-7.73 (m, 2H), 8.99 (t, J=5.65 Hz, 1H).

Examples 201 and 202

[0437] Examples 201 and 202 were prepared according to the above method used to make Example 200 and General procedures 1, 2, 17 and 18, using the appropriate starting aryl ester, amine and halides. Purification was as stated in the aforementioned method.

TABLE-US-00006 LCMS Example Structure IUPAC Name .sup.1H-NMR [M + H] 201 [00290] 3-(2-chloro-6- fluorobenzyl)- N-(furan-2- ylmethyl)-2- oxo-2,3- dihydrobenzo[d] thiazole-5- carboxamide (400 MHz; DMSO-d.sub.6): 4.45 (s, 2H), 5.34 (s, 2H), 6.27 (s, 1H), 6.39 (s, 1H), 7.21-7.25 (m, 1H), 7.38-7.40 (m, 2H), 7.57 (s, 1H), 7.69-7.78 (m, 3H), 8.95 (s, 1H) 417.1 202 [00291] 3-(2- chlorobenzyl)- N-(furan-2- ylmethyl)-1- methyl-2-oxo- 2,3-dihydro- 1H- benzo[d] imidazole- 5- carboxamide (500 MHz; DMSO-d.sub.6): 3.43 (s, 3H), 4.43 (d, J = 5.5 Hz, 2H), 5.15 (s, 2H), 6.24 (d, J = 2.25 Hz, 1H), 6.38 (s, 1H), 6.91 (d, J = 7.65 Hz, 1H), 7.25-7.35 (m, 3H), 7.53-7.62 (m, 3H), 7.73 (d, J = 8.3 Hz, 1H), 8.84 (t, J = 5.45 Hz, 1H). 396.20

Biological Assays

Stable Cell Line Generation

[0438] a) Stable STING expressing cellsStable HEK293T STING-expressing cell lines were generated using plasmids purchased from Invivogen, CA, USA, that contain STING cDNA cloned into the pUNO-1 vector under hEF1-HTLV promoter and containing the Blasticidin selection cassette. The plasmids hSTING (R232), hSTING (H232), hSTING (HAQ) were directly procured from Invivogen while hSTING (AQ) and hSTING (Q) were derived from hSTING (HAQ) and hSTING (R232) plasmids respectively by using a PCR based site directed mutagenesis method. These vectors were individually transfected into HEK293T cells using Lipofectamine (Invitrogen) and transfected cells were selected under Blasticidin selection. These transfected cells were further subjected to clonal selection using the limiting dilution method to obtain clonally pure populations of HEK cells transfected with each of the above mentioned human STING variants. Only those clones were selected in which ligand independent activation of STING was minimal. [0439] b) Stable Luciferase reporter gene expressing cellsStable HEK293T Luciferase reporter gene expressing cell lines were generated using pCDNA4 plasmids under an IRF-inducible promoter. This promoter is comprised of five tandem interferon-stimulated response elements (ISRE) fused to an ISG54 minimal promoter. This vector was transfected into HEK293T cells using Lipofectamine (Invitrogen) and transfected cells were selected under Zeocin selection. These transfected cells were further subjected to clonal selection using the limiting dilution method to obtain clonally pure populations of HEK cells transfected the Luciferase reporter construct. Only those clones were selected in which ligand independent induction of luciferase was minimal.

Luciferase Assay

[0440] 510.sup.5 clonally selected HEK293T-hSTING-Luciferase cells were seeded in 384-well plates in growth medium and stimulated with novel compounds. After 20 hr of stimulation supernatant were removed and secretary reporter gene activity were measured using the Quanti-Luc detection system (Invivogen) on a Spectramax i3X luminometer.

[0441] In the tables below, EC.sub.50 value ranges for exemplary compounds tested in the above assays are given. The EC.sub.50 ranges are indicated as A for values less than or equal to 1 M, B for values greater than 1 M and less than or equal to 10 M, and C for values greater than 10 M.

[0442] All compounds were first tested in a primary screen using WT/R232 STING protein to obtain a fold-induction over baseline levels of protein activity. Only those compounds that had a fold induction >1 have been included in the table of results and all are considered active. These active compounds were further tested to obtain an EC.sub.50 value.

TABLE-US-00007 R232 Example R232 Activity 1 B 2 A 3 C 4 B 5 A 6 A 7 B 8 A 9 B 10 B 11 A 12 A 13 A 14 A 15 B 16 B 17 B 18 A 19 A 20 A 21 C 22 B 23 A 24 B 25 A 26 A 27 A 28 C 29 C 30 B 31 C 32 C 33 A 34 C 35 C 36 A 37 B 38 B 39 C 40 B 41 B 42 C 43 C 44 C 45 C 46 B 47 B 48 B 49 B 50 B 51 B 52 C 53 C 54 B 55 C 56 A 57 B 58 B 59 B 60 B 61 B 62 C 63 A 64 A 65 A 66 A 67 A 68 B 69 B 70 B 71 B 72 A 73 A 74 A 75 A 76 B 77 B 78 C 79 B 80 C 81 B 82 A 83 C 84 B 85 B 86 B 87 C 88 B 89 A 90 A 91 C 92 B 93 C 94 B 95 C 96 B 97 A 98 A 99 B 100 B 101 C 102 A 103 A 104 B 105 B 106 A 107 A 108 A 109 A 110 B 111 A 112 A 113 B 114 A 115 A 116 A 117 A 118 A 119 A 120 C 121 B 122 B 123 B 124 A 125 C 126 B 127 C 128 C 129 C 130 C 131 C 132 C 133 C 134 C 135 C 136 B 137 B 138 C 139 C 140 C 141 C 142 C 143 C 144 A 145 B 146 A 147 A 148 B 149 C 150 B 151 B 152 B 153 A 154 C 155 A 156 C 157 A 158 C 159 C 160 C 161 B 162 C 163 A 164 A 165 A 166 A 167 A 168 B 169 C 170 C 171 C 172 C 173 C 174 C 175 B 176 C 177 C 178 B 179 B 180 B 181 C 182 B 183 B 184 B 185 B 186 C 187 C 188 B 189 A 190 C 191 B 192 B 193 C 194 B 195 B 196 C 197 C 198 B 199 B 200 C 201 C 202 C

STING Polymorphisms

[0443] Single nucleotide polymorphisms of human STING have been described, which can affect the functional potency of compounds that modulate the activity of the STING protein (see Yi et. al., PLoS One, October 2013, 8(10), e77846). The 5 major polymorphisms of human STING are shown in FIG. 1, with their prevalence in human populations indicated.

[0444] The tables below show the potency of selected compounds of the invention against the most common polymorphisms.

TABLE-US-00008 H232/REF H232/REF H232/REF H232/REF Example activity Example activity Example activity 12 B 189 B 102 A 13 B 60 C 103 A 14 B 61 B 104 B 16 B 63 B 106 A 18 B 147 C 107 B 19 B 148 B 108 C 20 B 118 B 109 A 23 B 124 B 111 A 25 B 191 B 112 A 26 A 168 B 114 A 27 B 164 A 115 A 30 B 136 C 116 A 33 A 70 B 117 B 36 B 71 B 118 B 37 B 72 B 119 B 153 B 73 A 2 A 137 B 165 A 146 B 182 B 166 B 4 B 155 C 74 A 5 A 157 B 75 A 6 A 48 B 76 B 8 B 144 B 81 B 11 B 163 A 82 B 161 B 50 B 89 A 167 A 54 B 90 B 92 B 56 B 97 B 175 B 57 B 98 A 188 B 100 B

TABLE-US-00009 HAQ HAQ HAQ HAQ Example activity Example activity Example activity 12 B 189 B 102 A 13 B 60 B 103 A 14 B 61 B 104 B 16 B 63 B 106 A 18 B 147 C 107 B 19 B 148 B 108 C 20 A 118 B 109 A 23 B 124 B 111 A 25 B 191 B 112 A 26 A 168 B 114 A 27 A 164 B 115 A 30 B 136 B 116 A 33 A 70 B 117 B 36 B 71 B 118 B 37 C 72 B 119 B 153 B 73 A 2 A 137 B 165 A 146 B 182 B 166 B 4 B 155 C 74 A 5 A 157 B 75 A 6 A 48 B 76 B 8 B 144 B 81 B 11 B 163 A 82 B 161 B 50 B 89 A 167 A 54 B 90 B 92 B 56 B 97 B 175 B 57 B 98 B 188 B 100 B

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

[0445] THP1-Dual cells (Invivogen) were derived from the human THP-1 monocyte cell line by stable integration of two inducible reporter constructs. As a result, THP1-Dual cells allow the simultaneous study of the NF-B pathway, by monitoring the activity of secreted SEAP, and the IRF pathway, by assessing the activity of a secreted luciferase (Lucia). 510.sup.5 THP1-Dual cells were seeded in 384-well plates in growth medium and stimulated with novel compounds. After 20 hr of stimulation supernatant were removed and reporter proteins were readily measured in the cell culture supernatant using QUANTI-Blue (Invivogen), a SEAP detection reagent, and QUANTI-Luc (Invivogen), a luciferase detection reagent on a Spectramax i3X luminometer. EC.sub.50 value ranges for exemplary compounds tested in the above assay are given. The EC.sub.50 ranges are indicated as A for values less than or equal to 1 M, B for values greater than 1 M and less than or equal to 10 M, and C for values greater than 10 M.

TABLE-US-00010 IRF/NF.sub.KB THP- THP- THP-IRF NF.sub.KB THP-IRF NF.sub.KB Example activity activity Example activity activity 12 C C 72 C B 13 C C 73 B B 14 B B 165 C B 16 C C 166 C C 18 C B 74 B B 19 C B 75 B B 20 B B 76 C C 23 C B 81 B B 25 C B 82 B B 26 B B 89 B B 27 B B 90 B B 30 C B 97 C C 33 B B 98 C C 36 B B 100 C C 37 C C 102 A A 153 C B 103 B B 137 C C 104 C C 182 C C 106 B B 155 C C 107 B B 157 C C 108 C C 48 C C 109 B B 144 C B 111 B B 163 B B 112 B B 50 C C 114 B B 54 C C 115 B B 56 C C 116 B B 57 C C 117 B B 188 C C 118 C C 189 C C 119 B B 60 C C 2 B B 61 C C 146 C B 63 C C 4 C C 147 C C 5 B B 148 C C 6 B B 118 C C 8 C B 124 C C 11 C B 191 C C 161 C C 168 C C 167 B B 164 C C 92 C C 136 C C 175 B B 70 C C 71 C B

Western Blot Assay

[0446] 510.sup.5 clonally selected HEK293T-hSTING-Luciferase cells were seeded in 24-well plates in 500 l growth medium and stimulated with novel compounds or a vehicle control (VC), i.e. the solvent with no compound. After 2 hr of stimulation cells were harvested through centrifugation and cells pellet were lysed in RIPA buffer (20 mM tris-Cl, 150 mM NaCl, 0.5 mM EDTA, 1% NP40, 0.05% SDS) containing 1 phosphatase inhibitor cocktail 3 (Sigma) and 1 protease inhibitor (Roche) to extract the soluble fraction of protein. 10 g of extracted protein was electrophoresed in 10% SDS-PAGE gels and transferred onto Immobilon-P membranes (Millipore). Blots were incubated with antibodies specific for phosphorylated STING (Ser366), phosphorylated IRF3 (Ser396), total STING, ACTIN (Cell Signaling) and IRF3 (Abcam). Anti-rabbit HRP label secondary antibody (Abcam) and Clarity Max western ECL substrate (Biorad) were used for visualization of bands with help of the BioRad XRS plus imager. The assays are shown in FIG. 2.

Analysis of Cytokines by ELISA

[0447] Freshly isolated 210.sup.5 human PBMCs using Histopaque (Sigma) from different healthy donors were stimulated with novel compounds (10 M) in 200 l growth medium for 6 hr. Post treatment supernatant media was harvested and stored at 80 C. in different aliquots for secreted Cytokine analysis. Key cytokines like IFN, IFN, IL6, CXCL10 and TNF were measured using respective manufacturers recommendations. IFN, IFN were purchased from PBL Assay science, IL6, CXCL10 were procured from Abcam and TNF was purchased from R&D systems. The results are shown in FIG. 3.

In Vivo Tumor Experiments

[0448] 110.sup.6 CT26 tumor cells stably expressing R232.hSTING were injected subcutaneously in 100 l RPMI on the right side of the flank of Balb/C mice. Following tumor implantation, when the average tumors size was around 50 mm.sup.3 to 70 mm.sup.3, mice were randomized into different groups. Total number of animals per group is around 5 to 8. New chemical entity which was tested in this tumor model was formulated in 100% PEG400. For the treatment groups compounds were dosed intra-tumorally thrice in a week. Control animals were injected with vehicle by the same route and same schedule of compound dosing, and are identified as vehicle controls (VC). Growth of the tumors was measured regularly during the course of the study, and the results are shown in FIG. 4.

CONCLUSION

[0449] The inventors have synthesised a large number of compounds which fall within the general formula (I). They have shown that these compounds activate the STING protein, and so could be used to treat a number of diseases, including cancer.