NOVEL NAPHTHYL AND ISOQUINOLINE SULFONAMIDE DERIVATIVES

Abstract

The invention relates to novel compounds having the general formula (I) wherein R.sup.1, R.sup.2, X.sup.1, X.sup.2, X.sup.3 and W are as described herein, composition including the compounds and methods of using the compounds.

##STR00001##

Claims

1. Compounds of formula I ##STR00184## wherein, R.sup.1 is selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl; R.sup.2 is selected from alkoxy, H or halo; X.sub.1 is N and X.sub.2 is CR.sup.4 and X.sub.3 is N, or X.sub.1 is CR.sup.3, X.sub.2 is CR.sup.4, and X.sub.3 is N or CR.sup.5, or X.sub.1 is CR.sup.3, X.sub.2 is N, and X.sub.3 is CR.sup.5; R.sup.3 is selected from alkoxy, H, halo, haloalkoxy; R.sup.4 is selected from alkoxy, H, halo; R.sup.5 is selected from H, halo; W is selected from Ring A, Ring B, or Ring C ##STR00185## Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is N, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is N; R.sup.6 is H or alkylamino; R.sup.7 is alkoxy, dimethylamino, H, methyl, methylamino, OH; R.sup.8 is cyano, dimethylamino, H, halo; R.sup.9 is alkoxy, cyclopropyl, haloalkyl dimethylamino, H, halo, alkyl; R.sup.10 is H or halo; Y.sub.5 is NR.sup.11, Y.sub.6 is C(O), and Y.sub.7 is CR.sup.13 or N, or Y.sub.5 is C(O), Y.sub.6 is NR.sup.12 and Y.sub.7 is CR.sup.13; R.sup.11 is alkyl or H; R.sup.12 is alkyl or H; R.sup.13 is H, alkyl or halo; R.sup.14 is H, alkyl, halo, or haloalkyl; Y.sub.8 is CH or N; Y.sub.9 is CH or N; Y.sub.10 is CH.sub.2 or O; R.sup.15 is H, alkyl, or haloalkyl; and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein R.sup.1 is cyanoalkyl, haloalkoxy, or cyclopropyl.

3. A compound according to claim 1, wherein R.sup.2 is alkoxy or halo.

4. A compound according to claim 1, wherein R.sup.3 is alkoxy, halo, or haloalkoxy.

5. A compound according to claim 1, wherein X.sub.1 is CR.sup.3, X.sub.2 is CR.sup.4, and X.sub.3 is N or CR.sup.5, or X.sub.1 is CR3, X.sub.2 is N, and X.sub.3 is CR.sup.5.

6. A compound according to claim 1, wherein R.sup.4 and R.sup.5 are H.

7. A compound according to claim 1, wherein Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9.

8. A compound according to claim 1, wherein R.sup.6 is H.

9. A compound according to claim 1, wherein R.sup.7 is H or methylamino.

10. A compound according to claim 1, wherein R.sup.8 is dimethylamino, H or halo.

11. A compound according to claim 1, wherein R.sup.9 is cyclopropyl, H, halo or alkyl.

12. A compound according to claim 1, wherein R.sup.10, R.sup.11 and R.sup.12 are H.

13. A compound according to claim 1, wherein R.sup.13 is H or halo.

14. A compound according to claim 1, wherein R.sup.14 is H or halo.

15. A compound according to claim 1, wherein R.sup.14 is halo.

16. A compound according to claim 1, wherein Y.sub.8 is CH, Y.sub.9 is CH and Y.sub.10 is CH or O.

17. A compound according to claim 1, wherein Y.sub.8 is CH, Y.sub.9 is CH and Y.sub.10 is O.

18. A compound according to claim 1, wherein R.sup.15 is H or alkyl.

19. A compound according to claim 1, wherein R.sup.15 is alkyl.

20. A compound according to claim 1, wherein when R.sup.2 is H, then X.sub.2 is CR.sup.4 and R.sup.4 is not H; when R.sup.1 is haloalkyl, then R.sup.2 is alkoxy; and when R.sup.1 is haloalkoxy and R.sup.2 is halo, then X.sub.2 is N.

21. A compound according to claim 1, wherein R.sup.1 is selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl; R.sup.2 is selected from alkoxy, H or halo; X.sub.1 is N and X.sub.2 is CR.sup.4 and X.sub.3 is N, or X.sub.1 is CR.sup.3, X.sub.2 is CR.sup.4, and X.sub.3 is N or CR.sup.5, or X.sub.1 is CR.sup.3, X.sub.2 is N, and X.sub.3 is CR.sup.5; R.sup.3 is selected from alkoxy, H, halo, haloalkoxy; R.sup.4 is selected from alkoxy, H, halo; R.sup.5 is selected from H, halo; W is selected from Ring A, Ring B, or Ring C ##STR00186## Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is N, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is N; R.sup.6 is H or alkylamino; R.sup.7 is alkoxy, dimethylamino, H, methyl, methylamino, OH; R.sup.8 is cyano, dimethylamino, H, halo; R.sup.9 is alkoxy, cyclopropyl, haloalkyl dimethylamino, H, halo, alkyl; R.sup.10 is H or halo; Y.sub.5 is NR.sup.11, Y.sub.6 is C(O), and Y.sub.7 is CR.sup.13 or N, or Y.sub.5 is C(O), Y.sub.6 is NR.sup.12 and Y.sub.7 is CR.sup.13; R.sup.11 is alkyl or H; R.sup.12 is alkyl or H; R.sup.13 is H, or halo: R.sup.14 is H or halo: Y.sub.8 is CH; Y.sub.9 is CH; Y.sub.10 is CH.sub.2 or O; R.sup.15 is H, or alkyl; and pharmaceutically acceptable salts thereof.

22. A compound according to claim 1, wherein R.sup.1 is selected from cyanoalkyl, haloalkoxy, haloalkyl, cyclopropyl and oxetanyl; R.sup.2 is selected from alkoxy, H or halo; X.sub.1 is N and X.sub.2 is CR.sup.4 and X.sub.3 is N, or X.sub.1 is CR.sup.3, X.sub.2 is CR.sup.4, and X.sub.3 is N or CR.sup.5, or X.sub.1 is CR.sup.3, X.sub.2 is N, and X.sub.3 is CR.sup.5; R.sup.3 is selected from alkoxy, H, halo, haloalkoxy; R.sup.4 is selected from alkoxy, H, halo; R.sup.5 is selected from H, halo; W is selected from Ring A, Ring B, or Ring C ##STR00187## Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is N, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is N; R.sup.6 is H or alkylamino; R.sup.7 is alkoxy, dimethylamino, H, methyl, methylamino, OH; R.sup.8 is cyano, dimethylamino, H, halo; R.sup.9 is alkoxy, cyclopropyl, haloalkyl dimethylamino, H, halo, alkyl; R.sup.10 is H or halo; Y.sub.5 is NR.sup.11, Y.sub.6 is C(O), and Y.sub.7 is CR.sup.13 or N, or Y.sub.5 is C(O), Y.sub.6 is NR.sup.12 and Y.sub.7 is CR.sup.13; R.sup.11 is alkyl or H; R.sup.12 is alkyl or H; R.sup.13 is H, or halo: R.sup.14 is H or halo: Y.sub.8 is CH; Y.sub.9 is CH; Y.sub.10 is CH.sub.2 or O; R.sup.15 is H, or alkyl; wherein, when R.sup.2 is H, then X.sub.2 is CR.sup.4 and R.sup.4 is not H; when R.sup.1 is haloalkyl, then R.sup.2 is alkoxy; when R.sup.1 is haloalkoxy and R.sup.2 is halo, then X.sub.2 is N; and pharmaceutically acceptable salts thereof.

23. A compound according to claim 1, wherein R.sup.1 is selected from cyanoalkyl, haloalkoxy, or cyclopropyl; R.sup.2 is selected from alkoxy or halo; X.sub.1 is CR.sup.3, X.sub.2 is CR.sup.4, and X.sub.3 is N or CR.sup.5, or X.sub.1 is CR.sup.3, X.sub.2 is N, and X.sub.3 is CR.sup.5. R.sup.3 is selected from alkoxy, halo, or haloalkoxy; R.sup.4 is H; R.sup.5 is H; W is selected from Ring A, Ring B, or Ring C ##STR00188## Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9. R.sup.6 is H; R.sup.7 is H or methylamino; R.sup.8 is dimethylamino, H or halo; R.sup.9 is cyclopropyl, H, halo or alkyl; R.sup.10 is H; Y.sub.5 is NR.sup.11, Y.sub.6 is C(O), and Y.sub.7 is CR.sup.13 or N, or Y.sub.5 is C(O), Y.sub.6 is NR.sup.12 and Y.sub.7 is CR.sup.13; R.sup.11 is H; R.sup.12 is; R.sup.13 is H, or halo: R.sup.14 is halo: Y.sub.8 is CH; Y.sub.9 is CH; Y.sub.10 is O; R.sup.15 is alkyl; and pharmaceutically acceptable salts thereof.

24. A compound according to claim 1, wherein R.sup.1 is selected from cyanoalkyl, haloalkoxy, or cyclopropyl; R.sup.2 is selected from alkoxy or halo; X.sub.1 is CR.sup.3, X.sub.2 is CR.sup.4, and X.sub.3 is N or CR.sup.5, or X.sub.1 is CR.sup.3, X.sub.2 is N, and X.sub.3 is CR.sup.5. R.sup.3 is selected from alkoxy, halo, or haloalkoxy; R.sup.4 is H; R.sup.5 is H; W is selected from Ring A, Ring B, or Ring C ##STR00189## Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is CR.sup.8 and Y.sub.4 is CR.sup.9, or Y.sub.1 is N, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9, or Y.sub.1 is CR.sup.6, Y.sub.2 is CR.sup.7, Y.sub.3 is N and Y.sub.4 is CR.sup.9. R.sup.6 is H; R.sup.7 is H or methylamino; R.sup.8 is dimethylamino, H or halo; R.sup.9 is cyclopropyl, H, halo or alkyl; R.sup.10 is H; Y.sub.5 is NR.sup.11, Y.sub.6 is C(O), and Y.sub.7 is CR.sup.13 or N, or Y.sub.5 is C(O), Y.sub.6 is NR.sup.12 and Y.sub.7 is CR.sup.13; R.sup.11 is H; R.sup.12 is; R.sup.13 is H, or halo: R.sup.14 is halo. Y.sub.5 is CH; Y.sub.9 is CH; Y.sub.10 is O; R.sup.15 is alkyl; wherein, when R.sup.2 is H, then X.sub.2 is CR.sup.4 and R.sup.4 is not H; when R.sup.1 is haloalkyl, then R.sup.2 is alkoxy; when R.sup.1 is haloalkoxy and R.sup.2 is halo, then X.sub.2 is N; and pharmaceutically acceptable salts thereof.

25. A compound according to claim 1, selected from N-(4-(cyanomethyl)-2,5-difluorophenyl)naphthalene-1-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 2-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-5-sulfonamide; 2-chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)quinoline-5-sulfonamide; 2-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[5-fluoro-2-methoxy-6-(oxetan-3-yl)-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide; 2-chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-2-chloro-quinoline-5-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]isoquinoline-4-sulfonamide; 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]isoquinoline-4-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-chromane-5-sulfonamide; 5-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]naphthalene-1-sulfonamide; 5-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 8-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-hydroxy-isoquinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-yl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[4-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-1-keto-2H-isoquinoline-4-sulfonamide; 2-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-8-oxo-7H-1,7-naphthyridine-5-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-keto-7H-1,7-naphthyridine-5-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-keto-1H-quinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(dimethylamino)quinoline-5-sulfonamide; N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-2-(dimethylamino)quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-quinoline-5-sulfonamide; 6-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(difluoromethyl)quinoline-5-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2-methyl-isoquinoline-4-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-keto-1-methyl-quinoline-4-sulfonamide; 7,8-dichloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7,8-dichloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2H-isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-(dimethylamino)isoquinoline-4-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(methylamino)isoquinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-(methylamino)isoquinoline-4-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-(methylamino)quinoline-4-sulfonamide; 7-chloro-8-cyano-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-methoxy-isoquinoline-4-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1,7-naphthyridine-5-sulfonamide; 2-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide; N-(4-(cyanomethyl)-2,5-difluorophenyl)-1-oxo-1,2-dihydroisoquinoline-4-sulfonamide; 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide; 2-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methoxy-quinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-5-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]tetralin-5-sulfonamide; and pharmaceutically acceptable salts thereof.

26. A compound according to claim 1, selected from 2-chloro-N-(6-cyclopropyl-5-fluoro-2-methoxy-3-pyridyl)quinoline-5-sulfonamide; 2-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-chromane-5-sulfonamide; 5-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-2-pyridyl]-1-oxo-2H-isoquinoline-4-sulfonamide; 7-chloro-N-[4-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-phenyl]-1-keto-2H-isoquinoline-4-sulfonamide; N-[2,6-bis(difluoromethoxy)-5-fluoro-3-pyridyl]-7-chloro-1-keto-2H-isoquinoline-4-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-8-keto-7H-1,7-naphthyridine-5-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-keto-1H-quinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methyl-quinoline-5-sulfonamide; 6-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]naphthalene-1-sulfonamide; 7,8-dichloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-keto-2H-isoquinoline-4-sulfonamide; N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide; 7-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(methylamino)isoquinoline-4-sulfonamide; 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1,7-naphthyridine-5-sulfonamide; 2-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; 2-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide; and pharmaceutically acceptable salts thereof.

27. A process to prepare a compound according to claim 1 comprising reacting a compound of formula III with a compound of formula II in the presence of a base selected from N-ethyldiisopropylamine, pyridine, potassium phosphate or sodium hydride, to provide a compound of formula I, ##STR00190## wherein R.sup.1, R.sup.2, R.sup.3, X.sub.1, X.sub.2, X.sub.3 and W are as described above.

28-29. (canceled)

30. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.

31-35. (canceled)

36. A method for the treatment or prophylaxis of conditions resulting from direct damage to myelin sheaths (including but not limited central pontine and extra-pontine myelinolysis, carbon monoxide poisoning, nutritional deficiency, and virus-induced demyelination), demyelinating disorders (including but not limited to multiple sclerosis, acute and multiphasic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and leukodystrophies), CNS disorders associated with myelin loss (including but not limited to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Ischemia due to stroke), and inflammation in the CNS for instance following encephalitis, primary angiitis, meningitis and obesity, which method comprises administering an effective amount of a compound according to claim 1 to a patient in need thereof.

37. A method for the treatment or prophylaxis of multiple sclerosis, which method comprises administering an effective amount of a compound according to claim 1 to a patient in need thereof.

38-39. (canceled)

Description

EXAMPLES

[0393] All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

Intermediates A

Intermediate A1: 1-naphthalenesulfonyl chloride

##STR00019##

Intermediate A1 is commercial (CAS: 85-46-1)

Intermediate A2: 7-chloroquinoline-4-sulfonyl fluoride

##STR00020##

[0394] In a three-necked flask, n-butyllithium, (1.6M solution in hexanes (2.0 ml, 4.95 mmol) was added dropwise to the solution of 4-bromo-7-chloro-quinoline (CAS 98519-65-4, 1.0 g, 4.12 mmol, 1.0 eq) in THE (20 ml) at 78 C. under argon. After 15 min of stirring sulfur dioxide (2.64 g, 41.24 mmol) was added thereto dropwise as a solution in THE (10 ml). The resulting mixture was warmed slowly to room temperature and stirred for 3 h. Precipitation of sulfinate salt was observed during this period. After cooling the resulting mixture to 0 C. N-fluorobenzenesulfonimide (1.43 mg, 4.54 mmol, 1.1 eq) was added as one portion and the resulting mixture was stirred for another 3 h. The resulting mixture was poured into brine (20 ml) and extracted with ethyl acetate (220 ml). The combined organic phase was evaporated. The residue was subjected to column chromatography on silica gel (heptanes/ethyl acetate) to afford 7-chloroquinoline-4-sulfonyl fluoride (103.9 mg, 0.42 mmol, 10.3% yield) as a yellow solid 1H NMR (500 MHz, CDCl.sub.3) =9.19 (br s, 1H), 8.43 (br d, J=9.1 Hz, 1H), 8.31 (br s, 1H), 8.10 (br d, J=3.0 Hz, 1H), 7.79 (br d, J=9.1 Hz, 1H).

Intermediate A3: 2-chloroquinoline-5-sulfonyl chloride

##STR00021##

[0395] 2-Chloroquinoline (4 g, 24.45 mmol) was dissolved in chlorosulfonic acid (37.41 g, 21.5 ml, 318 mmol). The reaction mixture was heated to 140 C. and stirred 2 days, then cooled to room temperature and carefully quenched into ice/ethyl acetate. The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (120 g, 0% to 10% ethyl acetate in heptane) to afford 2-chloroquinoline-5-sulfonyl chloride (383 mg, 6.0%) as white solid MS (ESI) m/z: 262.0 [M+H]+; 1H NMR (300 MHz, DMSO-d6) =9.21 (dd, J=0.8, 8.9 Hz, 1H), 8.00 (dd, J=1.4, 7.3 Hz, 1H), 7.92 (td, J=1.1, 8.3 Hz, 1H), 7.78-7.72 (m, 1H), 7.64 (d, J=8.9 Hz, 1H), and 2-chloroquinoline-6-sulfonyl chloride (406 mg, 6.2%) as white solid MS (ESI) m/z: 262.0 [M+H]+; 1H NMR (300 MHz, DMSO-d6) =8.55 (d, J=8.5 Hz, 1H), 8.28 (d, J=1.8 Hz, 1H), 7.99 (dd, J=1.9, 8.8 Hz, 1H), 7.93-7.88 (m, 1H), 7.61 (d, J=8.7 Hz, 1H).

Intermediate A4: 7-chloroisoquinoline-4-sulfonyl chloride

##STR00022##

Step 1: 4-(benzylthio)-7-chloro-isoquinoline

##STR00023##

[0396] A mixture of 4-bromo-7-chloro-isoquinoline (250 mg, 1.03 mmol), benzyl mercaptane (141 mg, 134 ul, 1.13 mmol), N,N-diethylisopropylamine (266 mg, 360 ul, 2.06 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (30 mg, 0.052 mmol) and tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.031 mmol) in 1,4-dioxane (2 ml) was heated to 80 C. and stirred for 1.5 h. The reaction mixture was filtered and washed (210 ml ethyl acetate) the filtrate was extracted with water/ethyl acetate. The organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (25 g, 20% to 100% ethyl acetate in heptane) and the collected fractions was evaporated to provide 4-(benzylthio)-7-chloro-isoquinoline (282 mg, 95.71%) as yellow oil. MS (ESI) m/z: 286.1 [M+H]+

Step 2: 7-chloroisoquinoline-4-sulfonyl chloride

##STR00024##

[0397] To a solution of 4-(benzylthio)-7-chloro-isoquinoline (282 mg, 0.99 mmol) in acetic acid (3 ml) and water (0.3 ml) was added N-chlorosuccinimide (395 mg, 2.96 mmol) in portions over 15 min at room temperature. The clear solution was stirred for 2 h at room temperature, then the solvent was evaporated. The residue was extracted 2with ethyl acetate and ice water, the organic layers were dried with MgSO4, filtered and concentrated under vacuum to afford 7-chloroisoquinoline-4-sulfonyl chloride (259 mg, 100%) as yellow solid, MS: 262.0 [M+H]+ ESI pos.

Intermediate A5: 1-oxo-2H-isoquinoline-4-sulfonyl chloride

##STR00025##

[0398] To isoquinolin-1(2H)-one (100 mg, 0.69 mmol) under nitrogen was added chlorosulfonic acid (496 mg, 285 l, 4.13 mmol). The reaction mixture was stirred for 2 h at 95 C. The mixture was cooled to 20 C. then ice (10 g) was added carefully. The grey-brown suspension was transfer into a plastic tube and centrifuged twice (water was decanted). The solid residue was transferred with ethyl acetate/acetonitrile into a flask and the solvent was evaporated to afford 1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (74 mg, 0.304 mmol, 44.1% yield) MS: 244.0 [M+H]+ ESI pos.

Intermediate A6: 2-methylchromane-5-sulfonyl chloride

##STR00026##

Step 1: 4-(2-bromo-6-hydroxy-phenyl)but-3-en-2-one

##STR00027##

[0399] To a solution of 2-bromo-6-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in acetone (6 ml) was added slowly at 25 C. NaOH (1M in water, 9.0 ml, 9.0 mmol) and stirred for 16 h. The mixture was acidified by dropwise addition of aqueous HCl (1.0 N, 12 mk) at <10 C. The resulting yellow solid was isolated by filtration and dried under vacuum to give the crude compound which was purified by silica gel column (petroleum ether/ethyl acetate=5/1) to give 4-(2-bromo-6-hydroxy-phenyl)but-3-en-2-one (0.85 g, 3.53 mmol, 71% yield) as white solid, 1H NMR (400 MHz, DMSO-d6) ppm 10.85-10.93 (m, 1H) 7.66-7.78 (m, 1H) 7.09-7.21 (m, 3H) 6.92-7.00 (m, 1H) 2.28-2.35 (m, 3H).

Step 2: 3-bromo-2-(3-hydroxybut-1-enyl)phenol

##STR00028##

[0400] To a solution of 4-(2-bromo-6-hydroxy-phenyl)but-3-en-2-one (700 mg, 2.9 mmol) in tetrahydrofuran (10 ml) was slowly added sodium borohydride (121 mg, 3.2 mmol) at 0 C. and the mixture was stirred for 2 h at 25 C. The reaction was poured into HCl (1M in water, 5 ml) slowly at 0 C. and stirred for 10 min and then adjust pH>=7 by NaHCO.sub.3(aq.). The mixture was taken up in ethyl acetate (20 ml) and the organic layers were washed with water (20 ml) and saturated brine solution (10 ml). The combined organic layers were dried (Na2SO4), concentrated to dryness in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3/1) to give 3-bromo-2-(3-hydroxybut-1-enyl)phenol (590 mg, 2.43 mmol, 83.6% yield) as light yellow gum.

Step 3: 3-bromo-2-(3-hydroxybutyl)phenol

##STR00029##

[0401] To a solution of 3-bromo-2-(3-hydroxybut-1-enyl)phenol (5.0 g, 20.57 mmol) in tetrahydrofuran (100 ml) was added tosylhydrazide (15.3 g, 82.3 mmol) and sodium acetate trihydrate (11.2 g, 82.3 mmol) and then stirred for 16 h at 70 C. The reaction was taken up in ethyl acetate (60 ml) and the organics washed with water (30 ml) and saturated brine solution (20 ml). The organics were separated and dried (Na2SO4) before concentration to dryness. The crude was purified by silica gel column (petroleum ether/ethyl acetate=3/1) to give 3-bromo-2-(3-hydroxybutyl)phenol (3.4 g, 13.87 mmol, 67.4% yield) as colorless oil. 1H NMR (400 MHz, DMSO-d6) ppm 9.71-9.78 (m, 1H) 6.88-7.06 (m, 2H) 6.74-6.84 (m, 1H) 4.43-4.54 (m, 1H) 3.96-4.09 (m, 1H) 3.57-3.70 (m, 1H) 2.72-2.86 (m, 1H) 2.56-2.68 (m, 1H) 1.38-1.62 (m, 2H) 1.08-1.13 (m, 2H).

Step 4: 5-bromo-2-methyl-chromane

##STR00030##

[0402] To a solution of 3-bromo-2-(3-hydroxybutyl)phenol (3.4 g, 13.0 mmol) in tetrahydrofuran (650 ml) was added diisopropyl azodicarboxylate (DIAD, 3.87 ml, 19.53 mmol) and triphenylphosphine (5.12 g, 19.53 mmol) at 0 C. and the mixture was stirred for 2 h at 25 C. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate (50 ml). The combined organic layers were washed with water (30 ml) and saturated brine solution (10 ml). The organics were then separated and dried (Na2SO4) before being concentrated to dryness. The crude was then purified by silica gel column (petroleum ether/ethyl acetate=10/1) to give 5-bromo-2-methyl-chromane (1.9 g, 7.81 mmol, 60% yield) as colorless oil. 1H NMR (400 MHz, DMSO-d6) ppm 7.12 (dd, J=7.95, 0.98 Hz, 1H) 6.98-7.06 (m, 1H) 6.73-6.80 (m, 1H) 4.02-4.16 (m, 1H) 2.56-2.76 (m, 2H) 1.96-2.09 (m, 1H) 1.51-1.70 (m, 1H) 1.29-1.34 (m, 3H).

Step 5: 5-benzylsulfanyl-2-methyl-chromane

##STR00031##

[0403] To a solution of 5-bromo-2-methyl-chromane (1.10 g, 4.84 mmol) in tetrahydrofuran (30 ml) was added n-butyllithium solution (2.91 ml, 7.27 mmol) at 78 C. The mixture was then stirred at 78 C. for 0.5 h. A solution of dibenzyl disulfide (1.43 g, 5.8 mmol) in tetrahydrofuran (10 ml) was added at 78 C. The mixture was then stirred at 78 C. for another 1 h. The reaction mixture was quenched by adding saturated ammonium chloride solution (10 ml) and extracted with ethyl acetate (20 ml3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel, petroleum ether) to give 5-benzylsulfanyl-2-methyl-chromane (0.3 g, 1.11 mmol, 23% yield) as colorless oil. 1H NMR (400 MHz, DMSO-d6) ppm 1.31 (d, J=6.24 Hz, 3H) 1.58 (dtd, J=13.45, 10.79, 10.79, 5.56 Hz, 1H) 1.92-2.00 (m, 1H) 2.62-2.73 (m, 1H) 2.74-2.87 (m, 1H) 3.74 (s, 2H) 4.06-4.16 (m, 1H) 6.70 (d, J=8.19 Hz, 1H) 6.74-6.83 (m, 1H) 7.00-7.08 (m, 2H) 7.24-7.37 (m, 5H)

Step 6: 2-methylchromane-5-sulfonyl chloride

##STR00032##

[0404] To a solution of 5-benzylsulfanyl-2-methyl-chromane (60 mg, 0.22 mmol, 1.0 eq) in acetic acid (1.8 ml) and water (0.2 ml) was added N-chlorosuccinimide (89 mg, 0.67 mmol, 3.0 eq) in three portions at 30 C. and the mixture was stirred for 16 h. The reaction was taken up in ethyl acetate (4 ml) and the combined organic layers were washed with water (2 ml) and saturated brine solution (2 ml). The combined organic layers were separated and dried (Na2SO4) before being concentrated to dryness. The crude was purified by preparative TLC (petroleum ether/ethyl acetate=20/1) to give 2-methylchromane-5-sulfonyl chloride (30 mg, 0.12 mmol, 55% yield) as colorless oil. For analysis an aliquot of this compound was reacted with aqueous ammonia and an LCMS sample of that reaction was measured: in accordance to the expected result MS m/z 226 ([M-Cl+NH2].sup.) was observed.

Intermediate A7: 2-chloro-1,7-naphthyridine-5-sulfonyl chloride

##STR00033##

Step 1: 5-bromo-1-oxido-1,7-naphthyridin-1-ium

##STR00034##

[0405] In a 25 ml round bottom flask, 5-bromo-1,7-naphthyridine (2.5 g, 12.0 mmol) was dissolved in dichloromethane (17.5 ml) and cooled to 0-3 C. Next, m-chloroperoxybenzoic acid (3.1 g, 12.56 mmol) was added in portions over 20 min at 2-4 C. The reaction mixture was stirred at 2-22 C. for 5 h, then the solvent was removed under vacuo. The residue was purified over 80 g silica column with methanol in dichloromethane (0 to 10% in 30 min) to get a mixture of both possible N-oxides. This mixture was purified further using SFC (column chiral AY-H, 5 m, 25020 mm, 0-40% MeOH) to afford 5-bromo-1-oxido-1,7-naphthyridin-1-ium (394 mg, 14%) as yellow solid. MS m/z: 225.0 [M+H]+. ESI pos.

Step 2: 5-benzylsulfanyl-1-oxido-1,7-naphthyridin-1-ium

##STR00035##

[0406] A mixture of 5-bromo-1-oxido-1,7-naphthyridin-1-ium (392 mg, 1.71 mmol), benzyl mercaptan (254 mg, 242 ul, 2.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (46.9 mg, 0.051 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (49 mg, 0.085 mmol), N,N-diisopropyl ethylamine (441 mg, 600 ul, 3.41 mmol) in 1,4-dioxane (12 ml) was heated at 90 C. for 5 h. After cooling down to room temperature, the mixture was concentrated under reduced pressure and purified by flash chromatography (25 g SiO2, gradient 0 to 20% methanol in dichloromethane) to afford 5-(benzylthio)-1-oxido-1,7-naphthyridin-1-ium (440 mg, 90%) as orange solid. MS m/z 269.1 [M+H]+, ESI pos.

Step 3: 5-benzylsulfanyl-2-chloro-1,7-naphthyridine

##STR00036##

[0407] To a stirred solution of 5-(benzylthio)-1-oxido-1,7-naphthyridin-1-ium (159 mg, 0.557 mmol) in dichloromethane (extra dry, 5.5 ml) at 0 C. was added phosphorus oxychloride (102 mg, 62 ul, 0.668 mmol) followed by dropwise addition of dimethylformamide (20 mg, 22 ul, 0.28 mmol) under argon. The resulting reaction mixture was warmed to 23 C. and stirred at this temperature for 6 h. Saturated aqueous sodium carbonate solution was added to the reaction mixture slowly to adjust the pH to 7-8. The resulting mixture was separated and the aqueous phase was extracted with dichloromethane thoroughly. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography column (silica gel, 10 to 70% ethyl acetate in heptane) to afford 5-(benzylthio)-2-chloro-1,7-naphthyridine (50 mg, 31%) as light yellow solid, MS m/z 287.1 [M+H]+, ESI pos

Step 4: 2-chloro-1,7-naphthyridine-5-sulfonyl chloride

##STR00037##

[0408] 5-(Benzylthio)-2-chloro-1,7-naphthyridine (45 mg, 0.155 mmol) was dissolved in a mixture of acetic acid (390 ul) and water (39 ul). N-Chlorosuccinimide (62 mg, 0.466 mmol) was added and the mixture was stirred at 23 C. for 1.5 h. Dichloromethane was added and the mixture was stirred at room temperature for 5 min. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-chloro-1,7-naphthyridine-5-sulfonyl chloride (47 mg, 34.5%) as yellow oil which was used crude directly in the next step without further purification MS m/z 263.0 [M+H]+, ESI pos.

Intermediate A8: 2-methylquinoline-5-sulfonyl chloride

##STR00038##

[0409] Chlorosulfonic acid (5.34 g, 3.07 ml, 45.4 mmol) was added carefully to quinaldine (500 mg, 472 ul, 3.49 mmol) and the reaction mixture was heated to 140 C. for 2 h. LCMS showed complete conversion and formation of 3 regioisomers. The reaction mixture was cooled to room temperature and carefully quenched with ice/ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (80 g, 0% to 100% ethyl acetate in heptane) to afford 2-methylquinoline-8-sulfonyl chloride (255.8 mg, 29.4%) as white solid, 2-methylquinoline-6-sulfonyl chloride (25 mg, 3.0%) as light brown solid and the title compound 2-methylquinoline-5-sulfonyl chloride (21.9 mg, 2.4%) as white solid. 1H NMR (600 MHz, DMSO-d6) ppm 9.69 (d, J=9.1 Hz, 1H), 8.20 (dt, J=8.5, 1.0 Hz, 1H), 8.18 (dd, J=7.3, 1.1 Hz, 1H), 8.14-8.15 (m, 1H), 8.01-8.07 (m, 2H), 2.95 (s, 3H).

Intermediate A9: 6-chloronaphthalene-1-sulfonyl chloride

##STR00039##

Step 1: 6-chloro-1-iodo-naphthalene

##STR00040##

[0410] To a solution of p-toluenesulfonic acid monohydrate (803.16 mg, 4.22 mmol) in acetonitrile (5 ml) was added (6-chloro-1-naphthyl)amine (CAS 50885-10-4, 250 mg, 1.41 mmol). The resulting suspension of amine salt was cooled to 0 C., and a solution of sodium nitrite (194 mg, 2.81 mmol) and potassium iodide (584 mg, 3.52 mmol) in water (0.85 ml) was added gradually. The reaction mixture was stirred for 30 min at 0 C., then allowed to come to room temperature and stirred for additional 2 h. The reaction mixture was diluted with saturated NaHCO.sub.3 solution and extracted two times with ethyl acetate. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (40 g, ethyl acetate in heptane 0-30%) to afford 6-chloro-1-iodo-naphthalene (20 mg, 5% yield) as yellow oil. 1H NMR (300 MHz, DMSO-d6) =8.17 (dd, J=1.0, 7.5 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H), 8.05-7.97 (m, 2H), 7.67 (dd, J=2.2, 8.9 Hz, 1H), 7.34 (dd, J=7.5, 8.3 Hz, 1H).

Step 2: 1-benzylsulfanyl-6-chloro-naphthalene

##STR00041##

[0411] 6-Chloro-1-iodo-naphthalene (18 mg, 0.062 mmol) was dissolved in 1,4-dioxane (extra dry, (0.6 ml), then benzyl mercaptan (8.52 mg, 8 ul, 0.069 mmol), tris(dibenzylidene-acetone)dipalladium(0) (1.7 mg, 0.002 mmol), Xantphos (1.8 mg, 0.003 mmol) and N.N-diisopropyl ethylamine (16 mg, 22 ul, 0.125 mmol) were added at room temperature under argon. The mixture was stirred at 90 C. for 3 hours. The reaction mixture was diluted with saturated NaHCO.sub.3-solution and extracted two times with ethyl acetate. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (12 g, ethyl acetate in heptane 0-30%) to afford 1-benzylsulfanyl-6-chloro-naphthalene (16 mg, 86%) as light yellow oil.

Step 3: 6-chloronaphthalene-1-sulfonyl chloride

##STR00042##

[0412] 1-benzylsulfanyl-6-chloro-naphthalene (16 mg, 0.054 mmol) was dissolved in acetic acid (0.5 ml) and water (0.05 ml). N-chlorosuccinimide (22 mg, 0.162 mmol) was added and the mixture was stirred at room temperature for 1 h. Dichloromethane and a few drops of water were added to the mixture. After stirring it at room temperature for 5 min the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow oil. The crude was used directly to the next step without further purification.

Intermediate A10: 5-chloronaphthalene-1-sulfonyl chloride

##STR00043##

[0413] Intermediate A10 is commercial (CAS: 6291-07-2)

Intermediate A11: 7-chloronaphthalene-1-sulfonyl chloride

##STR00044##

[0414] Intermediate A11 is commercial (CAS: 102153-62-8)

Intermediate A12: 8-chloro-1-hydroxy-isoquinoline-4-sulfonyl chloride

##STR00045##

Step 1: 8-chloro-2-oxido-isoquinolin-2-ium

##STR00046##

[0415] To the stirred solution of 8-chloroisoquinoline (10.0 g, 61.12 mmol, 1.0 eq) in dichloromethane (250 ml) was added portion wise 3-chloroperoxybenzoic acid (25.6 g, 103.9 mmol) and the reaction mixture was stirred at 25 C. for 3 h. Next, dichloromethane (300 ml) and methanol (50 ml) was added. The organic layer was washed with 2M sodium hydroxide solution (2300 ml), the organic layer was dried (Na2SO4) and evaporated to dryness to give 8-chloro-2-oxido-isoquinolin-2-ium (10.0 g, 55.68 mmol, 77.4% yield). 1H NMR (500 MHz, CDCl3) =9.11 (s, 1H), 8.14 (dd, J=1.6, 7.1 Hz, 1H), 7.72-7.60 (m, 3H), 7.51-7.44 (m, 1H)

Step 2: 8-chloroisoquinolin-1-ol

##STR00047##

[0416] 8-Chloro-2-oxido-isoquinolin-2-ium (10.0 g, 55.7 mmol) was stirred in acetic anhydride (250 ml) at 140 C. for 16 h. The reaction mixture was evaporated to dryness, then 350 ml of a 2M aqueous sodium hydroxide solution was added to the oily residue, and the reaction mixture was stirred at 80 C. for 3 h. The mixture was allowed to cool down and was acidified to pH 4-5 (4M aq. NaHSO4 solution) and extracted with dichloromethane (2300 ml). The combined organic layers were dried (Na2SO4) and evaporated to give 8-chloroisoquinolin-1-ol as a brown solid (11.0 g, 61.25 mmol, 82.5% yield). 1H NMR (500 MHz, DMSO-d6) =11.22 (br s, 7H), 7.59-7.50 (m, 3H), 7.50-7.36 (m, 2H), 7.20-7.11 (m, 1H), 6.50 (d, J=7.1 Hz, 1H)

Step 3: 8-chloro-1-hydroxy-isoquinoline-4-sulfonyl chloride

##STR00048##

[0417] To 8-chloroisoquinolin-1-ol (3.0 g, 16.7 mmol, 1.0 eq) was added chlorosulfonic acid (11.1 ml, 167 mmol) at 100 C. and the reaction mixture was left at 100 C. for 16 h. The reaction mixture was poured very carefully onto ice (200 g) and quickly extracted with ethyl acetate (300 ml). The organic layer was dried and evaporated to dryness, the residue was triturated in dichloromethane (530 ml), filtered under argon atmosphere and dried to give 8-chloro-1-hydroxy-isoquinoline-4-sulfonyl chloride (925 mg, 3.33 mmol, 19% yield. 1H NMR (500 MHz, CDCl3) =10.87 (br, s, 1H), 9.03-9.07 (m, 1H), 8.97-9.02 (m, 1H), 8.63 (q, J=7.8 Hz, 1H), 8.56-8.48 (m, 1H).

Intermediate A13: 7-chloro-1-oxo-2H-isoquinoline-4-sulfonyl chloride

##STR00049##

[0418] A solution of 7-chloroisoquinoline-1(2H)-one (CAS 24188-74-7, 14.5 mg, 0.081 mmol) and chlorosulfonic acid (261 mg, 150 ul, 2.17 mmol) was stirred at 95 C. for 2 hr. The reaction mixture was treated with water (5 ml) and extracted with ethyl acetate (35 ml). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated to dryness to afford 7-7-chloro-1-oxo-2H-isoquinoline-4-sulfonyl chloride (22.5 mg, 95%) as light yellow solid. MS 278.1 [M+H]+, ESI pos., 1H NMR (300 MHz, CDCl3) ppm 7.84-7.90 (m, 1H) 8.15-8.20 (m, 1H) 8.30-8.35 (m, 1H) 8.45-8.48 (m, 1H) 9.67-9.85 (m, 1H).

Intermediate A14: 2-chloro-8-oxo-7H-1,7-naphthyridine-5-sulfonyl chloride

##STR00050##

Step 1: 1-oxido-7H-1,7-naphthyridin-1-ium-8-one

##STR00051##

[0419] To the stirred solution of 1,7-naphthyridin-8-ol (CAS 67967-11-7, 0.5 g, 3.42 mmol) in acetic acid (15 ml) was added portionwise hydrogen peroxide (30% in water, 0.78 ml, 6.84 mmol) and the reaction mixture was stirred at 80 C. for 16 h. The reaction mixture was carefully evaporated to dryness to give 600 mg of a dark brown solid which was used in the next step without further purification.

Step 2: 2-chloro-7H-1,7-naphthyridin-8-one

##STR00052##

[0420] To a suspension of 1-oxido-7H-1,7-naphthyridin-1-ium-8-one (600 mg, 3.7 mmol) in dimethylformamide (15 ml) was added dropwise oxalyl chloride (0.44 ml, 5.18 mmol) at 0 C. After complete addition, the mixture was allowed to warm to room temperature and stirred for 30 min. Methanol was added (20 ml) to quench excess oxalyl chloride, and the mixture was evaporated to dryness. The residue was purified by chromatography (silica gel, ethyl acetate in heptane 0-50%) to give 2-chloro-7H-1,7-naphthyridin-8-one (200 mg, 1.11 mmol, 28% yield). 1H NMR (500 MHz, DMSO-d6) =7.90 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.43-7.34 (m, 1H), 7.29-7.22 (m, 1H), 6.54 (br d, J=6.4 Hz, 1H).

Step 3: 2-chloro-8-oxo-7H-1,7-naphthyridine-5-sulfonyl chloride

##STR00053##

[0421] To 2-chloro-7H-1,7-naphthyridin-8-one (200 mg, 1.11 mmol) was added chlorosulfonic acid (0.74 ml, 11.1 mmol) at 90 C. and the reaction mixture was left at 90 C. for 16 h. To the reaction mixture was added ice water (10 ml), then it was extracted with ethyl acetate (50 ml). The organic layer was dried and evaporated to give 2-chloro-8-oxo-7H-1,7-naphthyridine-5-sulfonyl chloride as a brown solid (91.8 mg, 0.33 mmol, 28.2% yield), 1H NMR (400 MHz, DMSO-d6) =11.60 (br, s, 1H), 8.77 (br d, J=8.7 Hz, 1H), 7.83 (br d, J=8.8 Hz, 1H), 7.52 (br s, 1H)

Intermediate A15: 7-chloro-2-oxo-1H-quinoline-4-sulfonyl chloride

##STR00054##

[0422] The title compound was prepared in analogy to Intermediate A4 from 4,7-dichloro-2-(1H)-quinolinone (CAS 156820-88-1) instead of 4-bromo-7-chloro-isoquinoline as a light yellow solid. MS (ESI) m/z: 278.0 [M+H]+.

Intermediate A16: 7-chloro-1-(methylamino)isoquinoline-4-sulfonyl chloride

##STR00055##

Step 1: 7-chloro-N-methyl-isoquinolin-1-amine

##STR00056##

[0423] A mixture of 1,7-dichloroisoquinoline (CAS 70810-24-1, 298 mg, 1.46 mmol), N,N-diisopropyl ethylamine (377 mg, 510 ul, 2.92 mmol) and methylamine (2M in THF, 2.19 ml, 4.38 mmol) in tetrahydrofuran (4 ml) was stirred 2 h at 60 C. for 72 h. The reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% ethyl acetate in heptane) to yield a light yellow solid (127 mg, 43% yield), MS m/z 193.1 [M+H]+, ESI pos.

Step 2: 4-bromo-7-chloro-N-methyl-isoquinolin-1-amine

##STR00057##

[0424] A mixture of 7-chloro-N-methyl-isoquinolin-1-amine (125 mg, 0.649 mmol) and N-bromosuccinimide (115.49 mg, 0.649 mmol) in acetonitrile (3 ml) was stirred 1 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 25 g, 0% to 50% ethyl acetate in heptane) to yield) an off-white solid yellow oil (134 mg, 73% yield). MS 273.1 [M+H]+, ESI pos.

Step 3: 4-benzylsulfanyl-7-chloro-N-methyl-isoquinolin-1-amine

##STR00058##

[0425] A mixture of 4-bromo-7-chloro-N-methyl-isoquinolin-1-amine (133 mg, 0.490 mmol), Xantphos (14.17 mg, 0.024 mmol), Pd2(dba)3 (13.46 mg, 0.015 mmol), N,N-diisopropyl ethylamine (126.6 mg, 171 ul, 0.98 mmol) and benzyl mercaptan (67 mg, 63.7 ul, 0.539 mmol) in 1,4-dioxane (3 ml) was heated to 90 C. and stirred for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% ethyl acetate in heptane) to afford a yellow oil (140 mg, 86% yield). MS m/z 315.1 [M+H]+, ESI pos.

Step 4: 7-chloro-1-(methylamino)isoquinoline-4-sulfonyl chloride

##STR00059##

[0426] To a solution of 4-benzylsulfanyl-7-chloro-N-methyl-isoquinolin-1-amine (133 mg, 0.422 mmol) in acetic acid (2 ml) and water (0.2 ml) was added N-chlorosuccinimide (169 mg, 1.27 mmol) at room temperature. The clear solution was stirred for 3 h at room temperature. The reaction was extracted with ice water and twice with dichloromethane. The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo to afford a yellow oil (120 mg, 70% purity, 97% yield). MS 291.0 [M+H]+, ESI pos. The crude material was directly used for the next step.

Intermediate A17: 7-chloro-2-(methylamino)quinoline-4-sulfonyl chloride

##STR00060##

Step 1: 4-benzylsulfanyl-7-chloro-1H-quinolin-2-one

##STR00061##

[0427] A mixture of 4,7-dichloro-1H-quinolin-2-one (CAS 156820-88-1, see patent WO2004/2960, 458 mg, 2.14 mmol), Xantphos (61.9 mg, 0.107 mmol), Pd2(dba)3 (58.78 mg, 0.064 mmol), N,N-diisopropyl ethylamine (553 mg, 748 ul, 4.28 mmol) and benzyl mercaptan (292 mg, 278 L, 2.35 mmol) in 1,4-dioxane (4 ml) was heated to 100 C. and stirred for 2 h to yield an off-white suspension The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with dichloromethane and filtrated. The mother liquor was concentrated and the residue was purified by flash chromatography (silica gel, 50 to 100% ethyl acetate in heptane) and the product was combined with the filter cake to afford an off-white solid (522 mg, 81%). MS m/z: 302.1 [M+H]+, ESI pos.

Step 2: 4-benzylsulfanyl-2,7-dichloro-quinoline

##STR00062##

[0428] A mixture of 4-benzylsulfanyl-7-chloro-1H-quinolin-2-one (549 mg, 1.73 mmol) and phosphorus oxychloride (2.38 g, 1.45 ml, 15.55 mmol) was stirred 1 h at 100 C. The excess of phosphorus oxychloride was removed in vacuo. The reaction mixture was diluted with dichloromethane and poured into saturated aqueous NaHCO.sub.3 solution containing ice. The mixture was stirred at room temperature for 20 min and extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and the residual solvent was removed under reduced pressure. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to afford an off-white solid (454 mg, 92% yield). MS m/z: 320.0 [M+H]+, ESI pos.

Step 3: 4-benzylsulfanyl-7-chloro-N-methyl-quinolin-2-amine

##STR00063##

[0429] A mixture of 4-benzylsulfanyl-2,7-dichloro-quinoline (250 mg, 0.781 mmol), N,N-diisopropyl ethylamine (303 mg, 409 ul, 2.34 mmol) and methylamine (2M in THF, 3 ml, 6 mmol) in tetrahydrofuran (1 ml) was stirred at 60 C. for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gelz, 0% to 50% ethyl acetate in heptane) to yield a white solid (180 mg, 73% yield). MS m/z 315.1 [M+H]+, ESI pos.

Step 4: 7-chloro-2-(methylamino)quinoline-4-sulfonyl chloride

##STR00064##

[0430] To a solution of 4-benzylsulfanyl-7-chloro-N-methyl-quinolin-2-amine (177 mg, 0.562 mmol) in acetic acid (2 ml) and water (0.2 ml) was added N-chlorosuccinimide (225 mg, 1.69 mmol) at room temperature. The clear solution was stirred for 3 h at room temperature, then water was added and the mixture was extracted with ethyl acetate twice. The combined organic layers were dried with Na2SO4, filtered, concentrated in vacuo and used directly in the next step. Yellow amorphous solid. MS m/z: 291.1 [M+H]+, ESI pos.

Intermediate A18: 2-(dimethylamino)quinoline-5-sulfonyl chloride

##STR00065##

Step 1: 5-bromo-N.N-dimethyl-quinolin-2-amine

##STR00066##

[0431] In a sealed glass tube, 5-bromo-2-chloro-quinoline (CAS 99455-13-7, 250 mg, 1.03 mmol) was dissolved in tetrahydrofuran (extra dry, 2 ml), then dimethylamine (2M in THF, 1.84 g, 2.06 ml, 4.12 mmol) and diisopropyl ethylamine (266 mg, 360 L, 2.06 mmol) was added. The reaction mixture was stirred for 24 h at 60 C. At room temperature ethyl acetate and water was added. The organic layer was washed with saturated NaCl-solution, dried over MgSO4 and concentrated in vacuo to get 5-bromo-N,N-dimethyl-quinolin-2-amine (260 mg, 98%) as light yellow solid. MS (ESI) m/z 251.1 [M+H]+.

Step 2: 5-benzylsulfanyl-N,N-dimethyl-quinolin-2-amine

##STR00067##

[0432] A mixture of 5-bromo-N,N-dimethyl-quinolin-2-amine (260 mg, 1.04 mmol), benzyl mercaptan (142 mg, 135 ul, 1.14 mmol), N,N-diisopropyl ethylamine (268 mg, 362 ul, 2.07 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (30 mg, 0.052 mmol) and tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.031 mmol) in 1,4-dioxane (3 ml) was heated to 95 C. and stirred for 16 h. The reaction mixture was filtered and washed with ethyl acetate twice. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 80% ethyl acetate in n-heptane) to afford an orange solid (204 mg, 67%). MS (ESI) m/z: 295.2 [M+H]+.

Step 3: 2-(dimethylamino)quinoline-5-sulfonyl chloride

##STR00068##

[0433] In a 20 ml glass tube, 5-benzylsulfanyl-N,N-dimethyl-quinolin-2-amine (66 mg, 0.224 mmol) was dissolved in acetic acid (0.9 ml) and water (0.1 ml). At room temperature N-chlorosuccinimide (90 mg, 0.673 mmol) was added in portions over 15 min. The reaction mixture was stirred 1 h at room temperature. The solvent was removed in vacuo. The residue was extracted with ethyl acetate twice. The combined organic layers were washed with water, saturated NaCl solution, dried over MgSO4, filtered and the solvent was removed in vacuo to afford 2-(dimethylamino)quinoline-5-sulfonyl chloride (65 mg, 96%) as yellow solid which was used in next step without further purification. MS (ESI) m/z 271.1[M+H].sup.+

Intermediate A19: 7-chloro-1-methoxy-isoquinoline-4-sulfonyl chloride

##STR00069##

Step 1: 4-bromo-7-chloro-1-methoxy-isoquinoline

##STR00070##

[0434] To a solution of freshly prepared sodium methylate (2.93 g, 54.2 mmol, 3.0 eq) in methanol (100 ml), 4-bromo-1,7-dichloro-isoquinoline (CAS 953421-74-4, 5.0 g, 18.05 mmol, 1.0 eq) was added under argon and the resulting mixture was refluxed overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between water and dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-bromo-7-chloro-1-methoxy-isoquinoline (4.3 g, 15.8 mmol, 87.5% yield) as brown powder. MS (ESI) m/z: 272.0/274.0/276.0 [M+H]+.

[0435] The following steps were performed in analogy to Intermediate A18 using 4-bromo-7-chloro-1-methoxy-isoquinoline instead of 5-bromo-N,N-dimethyl-quinolin-2-amine in step 2. The title compound was used without further purification in the next step.

Intermediate A20: 7-chloro-8-cyano-isoquinoline-4-sulfonyl chloride

##STR00071##

Step 1: 7-chloro-isoquinoline-8-carbonitrile

##STR00072##

[0436] 8-Bromo-7-chloro-isoquinoline (CAS 2092424-29-6, 300 mg, 1.24 mmol) was dissolved in N,N-dimethylacetamide (3 ml) and under argon, dicyanozinc (73 mg, 0.619 mmol) and tetrakis(triphenylphosphine)palladium(0) (71.5 mg, 0.062 mmol) were added. The mixture was stirred over night at 100 C. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, 0-100% ethyl acetate in heptane) to afford a light-yellow solid (85 mg, 36% yield), MS m/z 189.0 [M+H]+, ESI pos.

Step 2: 4-bromo-7-chloro-isoquinoline-8-carbonitrile

##STR00073##

[0437] 7-chloroisoquinoline-8-carbonitrile (85 mg, 0.451 mmol) was dissolved in 1,2-dichloroethane (extra dry, 2 ml). Iodobenzene diacetate (218 mg, 0.676 mmol) and potassium bromide (268 mg, 2.25 mmol) were added and the mixture was stirred at 70 C. for 16 h. The mixture was extracted with water and dichloromethane and the combined organic layers were dried and concentrated in vacuo. The crude was purified by flash column (silica gel, 0-80% ethyl acetate in heptane) to afford a white solid (65 mg, 54% yield), MS m/z 269.0[M+H]+, ESI pos.

Step 3: 4-benzylsulfanyl-7-chloro-isoquinoline-8-carbonitrile

##STR00074##

[0438] A mixture of 4-bromo-7-chloro-isoquinoline-8-carbonitrile (60 mg, 0.224 mmol), Xantphos (6.5 mg, 0.011 mmol), Pd2(dba)3 (6.2 mg, 0.0067 mmol), N,n-diisopropyl ethylamine (58 mg, 78 ul, 0.45 mmol) and benzyl mercaptan (30.6 mg, 29 ul, 1.37 mmol) in 1,4-dioxane (2 ml) was stirred for 1.5 h at 70 C. The reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to afford a yellow solid (28 mg, 40% yield), MS m/z 311.0 [M+H]+, ESI pos.

Step 4: 7-chloro-8-cyano-isoquinoline-4-sulfonyl chloride

##STR00075##

[0439] 4-Benzylsulfanyl-7-chloro-isoquinoline-8-carbonitrile (47 mg, 0.151 mmol) was dissolved in acetic acid (500 ul) and water (50 ul). N-chlorosuccinimide (60.6 mg, 0.454 mmol) was added and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with water and extracted two times with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to afford a yellow solid which was used directly in the next step.

Intermediate A21: 2-(difluoromethyl)quinoline-5-sulfonyl chloride

##STR00076##

[0440] 2-(Difluoromethyl)quinoline (CAS 1075184-01-8, 150 mg, 0.837 mmol) was added slowly to chlorosulfonic acid (1.27 g, 723 L, 10.88 mmol) at 0 C. The mixture was stirred at room temperature for 1 hr, then at 140 C. for 20 h. The reaction mixture was slowly added to an ice/ethyl acetate mixture under stirring, then extracted with ethyl acetate (3), dried over Na2SO4, filtered and concentrated in vacuo. The crude light orange oil was purified by flash chromatography (silica gel, 0 to 100% ethyl acetate in n-heptane) to afford 2-(difluoromethyl)quinoline-5-sulfonyl chloride (9.3 mg, 3.2%) as white solid. .sup.1H NMR (600 MHz, DMSO-d6) ppm 9.39 (d, J=8.9 Hz, 1H), 8.70 (d, J=8.6 Hz, 1H), 8.31 (d, J=1.5 Hz, 1H), 8.01-8.09 (m, 2H), 7.85 (d, J=8.9 Hz, 1H), 7.76-7.83 (m, 1H), 6.99-7.22 (m, 1H).

Intermediate A22: 5-(dimethylamino)naphthalene-1-sulfonyl chloride

##STR00077##

Intermediate A22 is commercial (CAS: 605-65-2)

[0441] Intermediate A23: 7-chloro-2-methyl-1-oxo-isoquinoline-4-sulfonyl chloride

##STR00078##

Step 1: 7-chloro-2-methyl-isoquinolin-1-one

##STR00079##

[0442] 7-Chloroisoquinolin-1-ol (CAS 24188-74-7, 100 mg, 0.557 mmol, 1 eq) was dissolved in N,N-dimethylformamide (extra dry, 1 ml). Cesium carbonate (272 mg, 0.835 mmol) and iodomethane (395 mg, 174 ul, 2.78 mmol) were added and the mixture was stirred at 60 C. After 90 min the mixture was cooled to room temperature, quenched with saturated Na2CO3 solution and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give a white solid (107 mg, 99% yield), 1H NMR (600 MHz, CDCl3) ppm 8.40 (d, J=2.3 Hz, 1H), 7.56 (dd, J=8.5, 2.3 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 6.46 (d, J=7.2 Hz, 1H), 3.60 (s, 3H).

Step 2: 7-chloro-2-methyl-1-oxo-isoquinoline-4-sulfonyl chloride

##STR00080##

[0443] 7-Chloro-2-methyl-isoquinolin-1-one (70 mg, 0.343 mmol) was dissolved in chlorosulfonic acid (522 mg, 300 ul, 4.48 mmol) and the reaction mixture was heated at 100 C. for 1 h. The mixture was poured onto ice with ethyl acetate and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to afford a white solid (73 mg, 73% yield). The material was directly used for the next step.

Intermediate A24: 7-chloro-1-methyl-2-oxo-quinoline-4-sulfonyl chloride

##STR00081##

[0444] The title compound was prepared in analogy to Intermediate A4 from 4,7-dichloro-1-methyl-quinolin-2-one (CAS 98994-41-3) instead of 4-bromo-7-chloro-isoquinoline as a yellow solid. MS (ESI) m/z: 292.0 [M+H]+.

Intermediate A25: 7,8-dichloro-1-oxo-2H-isoquinoline-4-sulfonyl chloride

##STR00082##

[0445] The title compound was prepared in analogy to Intermediate A13 from 7,8-dichloro-2H-isoquinolin-1-one (CAS 80233-87-0) instead of 7-chloroisoquinoline-1(2H)-one as an off-white solid, MS (ESI) m/z: 313.9 [M+H]+.

Intermediate A26: 7-chloro-1-(dimethylamino)isoquinoline-4-sulfonyl chloride

##STR00083##

[0446] The title compound was prepared in analogy to Intermediate A16 using dimethylamine instead of methylamine in step 1 as an orange oil, 1H NMR (300 MHz, CDCl3) =8.72 (s, 1H), 8.51 (d, J=9.1 Hz, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.77 (dd, J=2.1, 9.2 Hz, 1H), 3.41 (s, 6H).

Intermediate A27: 8-methylquinoline-5-sulfonyl chloride

##STR00084##

[0447] Intermediate A27 is commercial (CAS 120164-05-8)

Intermediate A28: tetralin-5-sulfonyl chloride

##STR00085##

[0448] Intermediate A28 is commercial (CAS 62686-69-5)

Intermediates B

Intermediate B1: 2-(4-amino-2,5-difluoro-phenyl)acetonitrile

##STR00086##

[0449] Intermediate B1 is known (CAS: 2092112-51-9) and was synthesized according to WO2018/122232 page 229.

Intermediate B2: 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine

##STR00087##

[0450] Intermediate B2 is known (CAS: 2407471-07-0) and was synthesized according to WO2019/243303 page 83.

Intermediate B3: 6-cyclopropyl-5-fluoro-2-methoxy-pyridin-3-amine

##STR00088##

[0451] Intermediate B3 is known (CAS: 2407471-10-5) and was synthesized according to WO2019/243303 page 86.

Intermediate B4: 2-(5-amino-3-fluoro-6-methoxy-2-pyridyl)acetonitrile

##STR00089##

Step 1: (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine

##STR00090##

[0452] A solution of (5-fluoro-2-methoxy-3-pyridyl)amine (3.9 g, 26.07 mmol) and N-bromosuccinimide (5.16 g, 28.67 mmol) in acetonitrile (400 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed once with saturated NaHCO.sub.3 solution, once with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in heptane) to afford (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (5.26 g, 86.7%) as dark brown solid. MS (ESI) m/z: 221.0 [M+H]+.

Step 2: (6-bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine

##STR00091##

[0453] To a stirred solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (2.5 g, 10.75 mmol) in N,N-dimethylacetamide (25 ml) was added sodium hydride (1.29 g, 32.24 mmol) portion-wise (5258 mg) at 0 C. After stirring at 0 C. for 30 min, 4-methoxybenzyl chloride (3.43 g, 3.0 ml, 21.49 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was carefully quenched with saturated NH4Cl solution, poured into water and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 10% ethyl acetate in heptane) to afford (6-bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine (4.93 g, 99.5%) as red viscous oil.

Step 3: [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]methanol

##STR00092##

[0454] A solution of (6-bromo-5-fluoro-2-methoxy-3-pyridyl)-bis(p-anisyl)amine (1 g, 2.17 mmol) in toluene (20 ml) was cooled to 78 C. 1.6 M n-butyllithium (1.75 g, 2.03 mL, 3.25 mmol) was added dropwise. The resulting dark blue solution was stirred at 78 C. for 30 min. N,N-dimethylformamide (396 mg, 419 ul, 5.42 mmol) was added and stirring was continued at 78 C. for 30 min. The reaction mixture was allowed to warm to room temperature. Methanol (4 ml) was added, followed by sodium borohydride (82 mg, 2.17 mmol). The stirring was continued at room temperature for 15 min. The reaction mixture was quenched with saturated NH4Cl solution and extracted twice with ethyl acetate. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to afford [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]methanol (297 mg, 32.5%) as light yellow viscous oil. MS (ESI) m/z: 413.3 [M+H]+.

Step 4: [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridyl]-bis(p-anisyl)amine

##STR00093##

[0455] To a stirred solution of [5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]methanol (144 mg, 0.342 mmol) in dichloromethane (1.5 ml) was added thionyl chloride (81.4 mg, 50 ul, 0.684 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridyl]-bis(p-anisyl)amine (150 mg, 100%) as light brown foam, which was directly used in the next step without further purification.

Step 5: 2-[5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]acetonitrile

##STR00094##

[0456] To a stirred solution of [6-(chloromethyl)-5-fluoro-2-methoxy-3-pyridyl]-bis(p-anisyl)amine (152 mg, 0.353 mmol) in dichloromethane (700 ul) was added tetrabutylammonium bromide (11.5 mg, 0.035 mmol), followed by a solution of sodium cyanide (21 mg, 0.423 mmol) in water (130 ul). After stirring the reaction mixture for 15 h at room temperature more sodium cyanide (21 mg, 0.423 mmol) was added and stirring was continued at room temperature for 15 h. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in heptane) to afford 2-[5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]acetonitrile (87 mg, 58.5%) as colorless viscous oil. MS (ESI) m/z: 422.3 [M+H]+

Step 6: 2-(5-amino-3-fluoro-6-methoxy-2-pyridyl)acetonitrile

##STR00095##

[0457] A solution of 2-[5-[bis(p-anisyl)amino]-3-fluoro-6-methoxy-2-pyridyl]acetonitrile (85 mg, 0.20 mmol) in dichloromethane (400 ul) was cooled to 0 C. Trifluoroacetic acid (1.38 g, 927 ul, 12.1 mmol) was added and the reaction mixture was stirred at 0 C. for 20 min and at room temperature for 4 h. The resulting purple solution was poured into saturated NaHCO.sub.3 solution and extracted with ethyl acetate twice. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate in heptane) to afford 2-(5-amino-3-fluoro-6-methoxy-2-pyridyl)acetonitrile (31 mg, 85%) as a light yellow solid. MS (ESI) m/z: 182.1 [M+H]+

Intermediate B5: 6-(difluoromethoxy)-5-fluoro-2-methoxy-pyridin-3-amine

##STR00096##

[0458] Intermediate B5 is known (CAS: 2407470-90-8) and was synthesized according to WO2019/243303 page 69.

Intermediate B6: 5-fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine

##STR00097##

Step 1: (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine

##STR00098##

[0459] A solution of (5-fluoro-2-methoxy-3-pyridyl)amine (3.9 g, 26.07 mmol) and N-bromosuccinimide (5.16 g, 28.67 mmol) in acetonitrile (400 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed once with saturated NaHCO.sub.3 solution, once with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in heptane) to afford (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (5.26 g, 86.7%) as dark brown solid. MS (ESI) m/z: 221.0 [M+H]+.

Step 2: 5-fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine

##STR00099##

[0460] A solution of [4,4-bis(1,1-dimethylethyl)-2,2-bipyridine-N1,N1]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy))PF6, CAS 870987-63-6, 7.6 mg, 0.007 mmol, 0.010 eq, 6.9 M in dichloromethane) was added to a vial and the solvent was evaporated. Sodium carbonate (142 mg, 1.36 mmol, 2 eq), (6-bromo-5-fluoro-2-methoxy-3-pyridyl)amine (150 mg, 0.679 mmol, 1 eq), 3-bromooxetane (186 mg, 113 ul, 1.36 mmol, 2 eq) and tris(trimethylsilyl)silane (226 mg, 281 ul, 0.909 mmol, 1.34 eq) were added. Ethylene glycol dimethyl ether (extra dry, 11 ml) was added and the reaction mixture was degassed by bubbling argon through the mixture for 2 min. Finally, nickel(ii) chloride ethylene glycol dimethyl ether complex (NiCl2*glyme/dtbbpy, CAS 29046-78-4, 746 ug, 0.003 mmol, 0.005 eq) and 4,4-bis(tert-butyl)-2,2-bipyridine (911 ug, 0.003 mmol, 0.005 eq) was added and the reaction was degassed again for 5 min. The vial was placed in a photoreactor and irradiated with 450 nm for 14 h (stirred at 900 rpm, LED 100% power). The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and purified by column chromatography (silica gel, 0 to 40% ethyl acetate in heptane) to afford 5-fluoro-2-methoxy-6-(oxetan-3-yl)pyridin-3-amine (47 mg, 35%) as an off-white solid. MS (ESI) m/z: 199.1 [M+H]+.

Intermediate B7: 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

##STR00100##

Step 1: diethyl 2-(2,2-difluoroethyl)propanedioate

##STR00101##

[0461] Diethyl malonate (75.8 ml, 500 mmol) was combined with tetrahydrofuran (450 ml). Sodium ethoxide (prepared from ethanol (150 mL) and sodium (11.48 g, 500 mmol)) was added at room temperature and the reaction mixture was stirred 15 min at room temperature. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (76 ml, 500 mmol) in tetrahydrofuran (10 ml) was added slowly. The reaction mixture was stirred for 18 hours at 20 C., then cooled to 0 C., quenched with a saturated ammonium chloride solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound (100.5 g, 90% yield). MS (ESI) m/z=225.0 [M+H]+

Step 2: 2-amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol

##STR00102##

[0462] To a stirred solution of diethyl 2-(2,2-difluoroethyl)propanedioate (46.8 g, 209 mmol) in ethanol (5 mL) was added guanidine hydrochloride (19.9 g, 208 mmol), followed by sodium ethoxide (prepared from ethanol and sodium (14.38 g, 625 mmol)). The resulting orange suspension was heated to 80 C. and stirred for 4 hours. The reaction mixture was concentrated by half, 50 ml of water was added, followed by acetic acid (42.57 g, 709 mmol). The mixture was heated to 80 C. and stirred for 10 min, then cooled to room temperature. The solid product was filtered off, washed successively with water, ethanol and methyl tert-butyl ether to provide the title compound (22.3 g, 50% yield). MS (ESI) m/z=192.0 [M+H]+

Step 3: 4,6-dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine

##STR00103##

[0463] 2-amino-5-(2,2-difluoroethyl)pyrimidine-4,6-diol (13.2 g, 69.1 mmol) was suspended in phosphorus oxychloride (80.5 ml, 863 mmol). The reaction mixture was heated to 100 C. and stirred for 18 hours and concentrated in vacuo. The residue was diluted with ethyl acetate and carefully poured into ice/saturated sodium bicarbonate solution. The resulting biphasic mixture was stirred at room temperature for 5 min and extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel to provide the title compound (7.35 g, 47% yield). MS (ESI) m/z=227.8 [M+H]+

Step 4: 5-(2,2-difluoroethyl)-4,6-dimethoxy-pyrimidin-2-amine

##STR00104##

[0464] In a sealed tube, a mixture of 4,6-dichloro-5-(2,2-difluoroethyl)pyrimidin-2-amine (7.6 g, 33.33 mmol) and sodium methylate (prepared from sodium (7.66 g, 333.29 mmol) in methanol (50 ml)) was heated to 75 C. and stirred for 18 hours. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a light yellow solid (6.6 g, 86% yield). MS (ESI) m/z=220.0 [M+H]+

Intermediate B8: 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

##STR00105##

Step 1: 5-bromo-4,6-dimethoxy-pyrimidin-2-amine

##STR00106##

[0465] To a stirred solution of (4,6-dimethoxypyrimidin-2-yl)amine (7 g, 44.22 mmol, CAS: 36315-01-2) in acetonitrile (100 ml) was added a solution of N-bromosuccinimide (10.33 g, 57.48 mmol) in acetonitrile (100 ml) dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. The resulting white suspension was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, diluted with heptane and concentrated in vacuo. The precipitate was filtered off and washed with heptane to provide the title compound as a white solid (9.26 g, 87% yield). MS (ESI) m/z=234.1 [M+H]+

Step 2: 5-bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

##STR00107##

[0466] A solution of 5-bromo-4,6-dimethoxy-pyrimidin-2-amine (517 mg, 2.21 mmol) in N,N-dimethylacetamide (9 ml) was cooled to 0 C. Sodium hydride (265 mg, 6.63 mmol) was added portionwise (388 mg). The stirring was continued at 0 C. for 30 min. 4-methoxybenzyl chloride (706 mg, 609 ul, 4.42 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour, carefully quenched with a saturated ammonium chloride solution, poured into water and extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a gradient ethyl acetate/heptane 0-20% to provide the title compound as a white solid (1.11 g, 100% yield). MS (ESI) m/z=476.2 [M+H]+

Step 3: 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol

##STR00108##

[0467] To a colorless solution of 5-bromo-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]-pyrimidin-2-amine (500 mg, 1 mmol) in tetrahydrofuran (3.5 ml) was added a 1.6 M n-butyllithium solution in hexanes (700 mg, 814 ul, 1.3 mmol) dropwise at 78 C. The resulting yellow solution was stirred at 78 C. for 30 min. Trimethyl borate (156 mg, 167 ul, 1.5 mmol) was added dropwise and the stirring was continued at 78 C. for 1.5 hours. The reaction mixture was allowed to warm to 0 C. and acetic acid (120 mg, 115 ul, 2 mmol) was added dropwise, followed by hydrogen peroxide 35% (146 mg, 132 ul, 1.5 mmol). The stirring was continued at 0 C. for 1.5 hours. The resulting pink suspension was poured into a 0.1 N sodium thiosulfate solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a gradient ethyl acetate/heptane 0-30% to provide the title compound as a light yellow viscous oil (194 mg, 47% yield). MS (ESI) m/z=412.3 [M+H]+

Step 4: 5-(difluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine

##STR00109##

[0468] To a solution of 2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-dimethoxy-pyrimidin-5-ol (130 mg, 0.316 mmol) in acetonitrile (5 ml) was added a 5 M potassium hydroxide solution (1.26 ml, 6.32 mmol) dropwise at 0 C., followed by addition of bromodifluoromethyl diethylphosphonate (169 mg, 112 ul, 0.632 mmol) in acetonitrile (1 ml) dropwise at 0 C. The reaction mixture was stirred at 0 C. for 10 min. The resulting light yellow biphasic mixture was poured into water and extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a gradient ethyl acetate/heptane 0-30% to provide the title compound as a white solid (57 mg, 39% yield). MS (ESI) m/z=462.3 [M+H]+

Step 5: 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine

##STR00110##

[0469] To a stirred solution of 5-(difluoromethoxy)-4,6-dimethoxy-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-2-amine (56 mg, 0.121 mmol) in dichloromethane (100 ul) was added trifluoroacetic acid (839 mg, 563 ul, 7.28 mmol). The reaction mixture was stirred at room temperature for 40 hours, at 50 C. for 6 hours and concentrated in vacuo. The residue was poured into sat. NaHCO.sub.3 and extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a gradient ethyl acetate/heptane 0-100% to provide the title compound as a white solid (24 mg, 89% yield). MS (ESI) m/z=222.1 [M+H]+

Intermediate B9: 5-(2,2-difluoroethoxy)-3-fluoro-6-methoxy-pyridin-2-amine

##STR00111##

[0470] Intermediate B9 is known (CAS 2404661-29-4) and was synthesized according to WO2019243398 page 55.

Intermediate B10: 5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-amine

##STR00112##

Step 1: (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine

##STR00113##

[0471] A suspension of 5-bromo-2-chloro-4-methoxy-pyrimidine (1.02 g, 4.48 mmol, CAS: 57054-92-9), bis(p-anisyl)amine (1.29 g, 4.92 mmol) and N-ethyl diisopropylamine (858 ul, 4.92 mmol) in acetonitrile (20 ml) was heated at 70 C. for 2 days. The resulting solution was poured into a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and dried in vacuo. The residue was purified by flash chromatography over silica gel using a gradient ethyl acetate/heptane 0-20% to provide the title compound as a colorless viscous oil (998 mg, 50% yield). MS (ESI): m/z=446.2 [M+H]+

Step 2: [4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-bis(p-anisyl)amine

##STR00114##

[0472] A suspension of (5-bromo-4-methoxy-pyrimidin-2-yl)-bis(p-anisyl)amine (500 mg, 1.13 mmol), bis(pinacolato)diboron (354 mg, 1.35 mmol) and potassium acetate (335 mg, 3.38 mmol) in 1,4-dioxane (10 ml) was purged with argon for 5 min. dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (91.9 mg, 0.113 mmol) was added. The reaction mixture was heated to 90 C. and stirred for 16 hours. The resulting dark suspension was poured into ethyl acetate and washed once with saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient ethyl acetate/heptane 0-30% to provide the title compound as a colorless viscous oil (157 mg, 29% yield). MS (ESI): m/z=492.4 [M+H]+

Step 3: 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol

##STR00115##

[0473] A solution of [4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-bis(p-anisyl)amine (130 mg, 0.265 mmol) in tetrahydrofuran (2.5 mL) was cooled to 0 C. Hydrogen peroxide 35% (500 ul, 5.71 mmol) was added. The reaction mixture was stirred at 0 C. for 15 min, allowed to warm to rt and stirred for 3 hours. The reaction mixture was poured into cold 0.1 N sodium sulfite solution and extracted twice with ethyl acetate. The organic layers were washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a light yellow viscous oil (103 mg, 100% yield). MS (ESI): m/z=382.3 [M+H]+

Step 4: [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine

##STR00116##

[0474] A suspension of 2-[bis(p-anisyl)amino]-4-methoxy-pyrimidin-5-ol (100 mg, 0.236 mmol), potassium carbonate (98.82 mg, 0.708 mmol) and 1-bromo-2-fluoroethane (61.14 mg, 35.75 uL, 0.472 mmol) in acetonitrile (2.5 ml) was stirred at room temperature for 15 min and at 80 C. for 6 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate/heptane 0-30% to provide the title compound as a colorless viscous oil (22 mg, 22% yield). MS (ESI): m/z=428.3 [M+H]+

Step 5: [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]amine

##STR00117##

[0475] A solution of [5-(2-fluoroethoxy)-4-methoxy-pyrimidin-2-yl]-bis(p-anisyl)amine (87 mg, 0.204 mmol) in dichloromethane (500 ul) was cooled to 0 C. Trifluoroacetic acid (1.41 g, 945 ul, 12.2 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours and at 55 C. for two additional hours. The resulting purple solution was poured into a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient ethyl acetate/heptane 0-100% to provide the title compound as an off-white solid (27 mg, 71% yield). MS (ESI): m/z=188.1 [M+H]+

Intermediate B11: 2,6-bis(difluoromethoxy)-5-fluoro-pyridin-3-amine

##STR00118##

Step 1: 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridin-2-ol

##STR00119##

[0476] To a solution of 2-(difluoromethoxy)-3-fluoro-6-methoxy-5-nitro-pyridine (CAS 2407470-89-5, see WO2020254289, 1.7 g, 7.14 mmol) in dichloromethane (24 ml) was added boron tribromide (3.34 ml, 35.7 mmol) at 0 C., then the reaction mixture was stirred at 20 C. for 1 h. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (50 ml3). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether to petroleum ether/ethyl acetate=2:1) to give 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridin-2-ol (1.48 g, 93% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) ppm 7.31-7.69 (m, 1H) 8.33 (d, J=7.70 Hz, 1H) 11.35 (br s, 1H)

Step 2: 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine

##STR00120##

[0477] To the solution of 6-(difluoromethoxy)-5-fluoro-3-nitro-pyridin-2-ol (1.48 g, 6.6 mmol) in acetonitrile (20 ml) was added a solution of potassium hydroxide (3.71 g, 66.0 mmol) in water (5 ml), and diethyl (bromodifluoromethyl)phosphonate (10.580 g, 39.63 mmol) at 40 C., then the reaction mixture was stirred at 40 C. for 16 h. The reaction mixture was extracted with dichloromethane (60 ml3). The organic layers was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether to petroleum ether/ethyl acetate=5:1) to give 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine (2.38 g, 46% yield) as light yellow oil. 1H NMR (400 MHz, DMSO-d6) ppm 7.64-8.12 (m, 2H) 8.98 (d, J=8.93 Hz, 1H).

Step 3: 2,6-bis(difluoromethoxy)-5-fluoro-pyridin-3-amine

##STR00121##

[0478] To the mixture of 2,6-bis(difluoromethoxy)-3-fluoro-5-nitro-pyridine (380 mg, 1.39 mmol) in ethanol (12 ml) and water (3 ml) was added iron (389 mg, 6.93 mmol) and ammonium chloride (367 mg, 6.93 mmol) at 25 C., then the reaction mixture was stirred at 25 C. for 1 h. The reaction mixture was diluted with water (3 ml) and extracted with ethyl acetate (310 ml). The combined organic layers were washed with saturated NaCl solution (5 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative TLC (SiO2, petroleum ether/ethyl acetate=2:1) to give 2,6-bis(difluoromethoxy)-5-fluoro-pyridin-3-amine (41 mg, 12% yield) as a yellow oil. MS (ESI): m/z=244.8 [M+H]+.

EXAMPLES

Example 1: N-(4-(cyanomethyl)-2,5-difluorophenyl)naphthalene-1-sulfonamide

##STR00122##

[0479] To naphthalene-1-sulfonyl chloride (50 mg, 0.223 mmol, intermediate A1) was added 2-(4-amino-2,5-difluoro-phenyl)acetonitrile (25 mg, 0.149 mmol, intermediate B1) followed by pyridine, extra dry (1 ml). The reaction mixture was stirred room temperature for 2 hours, then the solvent was evaporated. The crude material was purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 m, 10030 mm, gradient acetonitrile/water+0.1% HCOOH) to afford the title compound (37 mg, 69%) as white powder, MS (ESI): m/z=357.2 [MH].sup..

[0480] The following Examples 2-39 were prepared in analogy to Example 1 by coupling the indicated sulfonylchloride intermediates A and amine intermediates B.

TABLE-US-00002 MS (ESI): Ex. Structure Name Int. A Int. B m/z 2 [00123] N-[6-(2,2-difluoroethoxy)- 5-fluoro-2-methoxy-3- pyridyl]naphthalene-1- sulfonamide A1 B2 413.2 [M + H].sup.+ 3 [00124] 2-chloro-N-[ 4- (cyanomethyl)-2,5-difluoro- phenyl]quinoline-5- sulfonamide A3 B1 394.3 [M + H].sup.+ 4 [00125] 2-chloro-N-(6-cyclopropyl- 5-fluoro-2-methoxy-3- pyridyl)quinoline-5- sulfonamide A3 B3 408.1 [M + H].sup.+ 5 [00126] 2-chloro-N-[6- (cyanomethyl)-5-fluoro-2- methoxy-3- pyridyl]quinoline-5- sulfonamide A3 B4 407.0 [M + H].sup.+ 6 [00127] 2-chloro-N-[6- (difluoromethoxy)-5-fluoro- 2-methoxy-3- pyridyl]quinoline-5- sulfonamide A3 B5 434.1 [M + H].sup.+ 7 [00128] 2-chloro-N-[5-fluoro-2- methoxy-6-(oxetan-3-yl)-3- pyridyl]quinoline-5- sulfonamide A3 B6 424.1 [M + H].sup.+ 8 [00129] 2-chloro-N-[5-(2,2- difluoroethyl)-4,6- dimethoxy-pyrimidin-2- yl]quinoline-5-sulfonamide A3 B7 445.2 [M + H].sup.+ 9 [00130] 2-chloro-N-[5-(2,2- difluoroethoxy)-3-fluoro-6- methoxy-2- pyridyl]quinoline-5- sulfonamide A3 B9 448.1 [M + H].sup.+ 10 [00131] 2-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3- pyridyl]quinoline-5- sulfonamide A3 B2 448.3 [M + H].sup.+ 11 [00132] N-[2,6- bis(difluoromethoxy)-5- fluoro-3-pyridyl]-2-chloro- quinoline-5-sulfonamide A3 B11 470.1 [M + H].sup.+ 12 [00133] 7-chloro-N-[4- (cyanomethyl)-2,5-difluoro- phenyllisoquinoline-4- sulfonamide A4 B1 394.1 [M + H].sup.+ 13 [00134] 7-chloro-N-[6- (difluoromethoxy)-5-fluoro- 2-methoxy-3- pyridyl]isoquinoline-4- sulfonamide A4 B5 434.0 [M + H].sup.+ 14 [00135] 7-chloro-N-[5-(2,2- difluoroethoxy)-3-fluoro-6- methoxy-2- pyridyl]isoquinoline-4- sulfonamide A4 B9 447.8 [M + H].sup.+ 15 [00136] 7-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3- pyridyl]isoquinoline-4- sulfonamide A4 B2 448.2 [M + H].sup.+ 16 [00137] N-[6-(2,2-difluoroethoxy)- 5-fluoro-2-methoxy-3- pyridyl]-2-methyl- chromane-5-sulfonamide A6 B2 433.0 [M + H].sup.+ 17 [00138] 5-chloro-N-[4- (cyanomethyl)-2,5-difluoro- phenyl]naphthalene-1- sulfonamide A10 B1 391.0 [M + H].sup.+ 18 [00139] 5-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3- pyridyl]naphthalene-1- sulfonamide A10 B2 445.0 [M H].sup. 19 [00140] 7-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3- pyridyl]naphthalene-1- sulfonamide A11 B2 447.2 [M + H].sup.+ 20 [00141] 8-chloro-N-[4- (cyanomethyl)-2,5-difluoro- phenyl]-1-hydroxy- isoquinoline-4-sulfonamide A12 B1 410.2 [M + H].sup.+ 21 [00142] 7-chloro-N-[4- (cyanomethyl)-2,5-difluoro- phenyl]-1-keto-2H- isoquinoline-4-sulfonamide A13 B1 408.2 [M + H].sup.+ 22 [00143] 7-chloro-N-[5-(2- fluoroethoxy)-4-methoxy- pyrimidin-2-yl]-1-keto-2H- isoquinoline-4-sulfonamide A13 B10 429.2 [M + H].sup.+ 23 [00144] 7-chloro-N-[6- (difluoromethoxy)-5-fluoro- 2-methoxy-3-pyridyl]-1- keto-2H-isoquinoline-4- sulfonamide A13 B5 450.2 [M + H].sup.+ 24 [00145] 7-chloro-N-[5-(2,2- difluoroethyl)-4,6- dimethoxy-pyrimidin-2-yl]- 1-keto-2H-isoquinoline-4- sulfonamide A13 B7 459.2 [M H].sup. 25 [00146] 7-chloro-N-[5-(2,2- difluoroethoxy)-3-fluoro-6- methoxy-2-pyridyl]-1-oxo- 2H-isoquinoline-4- sulfonamide A13 B9 463.9 [M + H].sup.+ 26 [00147] 7-chloro-N-[4-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-phenyl]-1-keto- 2H-isoquinoline-4- sulfonamide A13 B2 464.2 [M + H].sup.+ 27 [00148] N-[2,6- bis(difluoromethoxy)-5- fluoro-3-pyridyl]-7-chloro- 1-keto-2H-isoquinoline-4- sulfonamide A13 B11 486.1 [M + H].sup.+ 28 [00149] 2-chloro-N-[4- (cyanomethyl)-2,5-difluoro- phenyl]-8-oxo-7H-1,7- naphthyridine-5- sulfonamide A14 B1 411.0 [M + H].sup.+ 29 [00150] 2-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3-pyridyl]-8-keto- 7H-1,7-naphthyridine-5- sulfonamide A14 B2 465.1 [M + H].sup.+ 30 [00151] 7-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3-pyridyl]-2-keto- 1H-quinoline-4-sulfonamide A15 B2 464.2 [M + H].sup.+ 31 [00152] N-[6-(2,2-difluoroethoxy)- 5-fluoro-2-methoxy-3- pyridyl]-2- (dimethylamino)quinoline- 5-sulfonamide A18 B2 457.3 [M + H].sup.+ 32 [00153] N-[4-(cyanomethyl)-2,5- difluoro-phenyl]-2- (dimethylamino)quinoline- 5-sulfonamide A18 B1 403.2 [M + H].sup.+ 33 [00154] N-[6-(2,2-difluoroethoxy)- 5-fluoro-2-methoxy-3- pyridyl]-2-methyl- quinoline-5-sulfonamide A8 B2 428.2 [M + H].sup.+ 34 [00155] 6-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3- pyridyl]naphthalene-1- sulfonamide A9 B2 447.1 [M + H].sup.+ 35 [00156] N-[6-(2,2-difluoroethoxy)- 5-fluoro-2-methoxy-3- pyridyl]-2- (difluoromethyl)quinoline- 5-sulfonamide A21 B2 464.1 [M + H].sup.+ 36 [00157] 7-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3-pyridyl]-1-keto- 2-methyl-isoquinoline-4- sulfonamide A23 B2 478.2 [M + H].sup.+ 37 [00158] 7-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3-pyridyl]-2-keto- 1-methyl-quinoline-4- sulfonamide A24 B2 476.3 [M + H].sup.+ 38 [00159] 7,8-dichloro-N-[4- (cyanomethyl)-2,5-difluoro- phenyl]-1-keto-2H- isoquinoline-4-sulfonamide A25 B1 444.1 [M + H].sup.+ 39 [00160] 7,8-dichloro-N-[6-(2,2- difluroethoxy)-5-fluoro-2- methoxy-3-pyridyl]-1-keto- 2H-isoquinoline-4- sulfonamide A25 B2 498.1 [M + H].sup.+

Example 40: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-5-(dimethylamino)naphthalene-1-sulfonamide

##STR00161##

[0481] A mixture of 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine (27 mg, 0.122 mmol, intermediate B2), 5-(dimethyl amino)naphthalene-1-sulfonyl chloride (36 mg, 0.134 mmol, intermediate A22) and pyridine (48 mg, 49 L, 0.608 mmol) in dichloromethane (4 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with dichloromethane twice. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to afford the title compound (30 mg, 540%) as a light-yellow solid, MS (ESI): m/z=456.3 [M+H]+.

[0482] The following Examples 41-46 were prepared in analogy to Example 40 by coupling the indicated sulfonylchloride intermediates A and amine intermediates B.

TABLE-US-00003 MS (ESI): Ex. Structure Name Int. A Int. B m/z 41 [00162] 7-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3-pyridyl]-1- (dimethylamino)isoquinoline- 4-sulfonamide A26 B2 491.2 [M + H].sup.+ 42 [00163] 7-chloro-N-[4- (cyanomethyl)-2,5-difluoro- phenyl]-1- (dimethylamino)isoquinoline- 4-sulfonamide A26 B1 437.2 [M + H].sup.+ 43 [00164] 7-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3-pyridyl]-1- (methylamino)isoquinoline- 4-sulfonamide A16 B2 477.2 [M + H].sup.+ 44 [00165] 7-chloro-N-[4- (cyanomethyl)-2,5-difluoro- phenyl]-1- (methylamino)isoquinoline- 4-sulfonamide A16 B1 423.1 [M + H].sup.+ 45 [00166] 7-chloro-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3-pyridyl]-2- (methylamino)quinoline-4- sulfonamide A17 B2 477.2 [M + H].sup.+ 46 [00167] 7-chloro-8-cyano-N-[6-(2,2- difluoroethoxy)-5-fluoro-2- methoxy-3- pyridyl] isoquinoline-4- sulfonamide A20 B2 473.1 [M + H].sup.+ 47 [00168] N-[4-(cyanomethyl)-2,5- difluoro-phenyl]-8-methyl- quinoline-5-sulfonamide A27 B1 374.0 [M + H].sup.+

Example 48: 7-chloro-N-[6-(difluoromethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-4-sulfonamide

##STR00169##

[0483] 6-(Difluoromethoxy)-5-fluoro-2-methoxy-pyridin-3-amine (25.6 mg, 0.123 mmol, Intermediate B5) was dissolved in tetrahydrofuran (0.5 ml). At 0 C. under argon atmosphere lithium hexamethyldisilazide solution (1M in THF, 244 ul, 0.244 mmol) was added dropwise. The reaction mixture was stirred for 15 min. Then, a solution of 7-chloroquinoline-4-sulfonyl fluoride (30 mg, 0.122 mmol, Intermediate A2) in tetrahydrofuran (0.3 ml) was added dropwise. The mixture was stirred at room temperature for 3 h. Brine was added to the reaction mixture and it was extracted with ethyl acetate (3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 m, 10030 mm, gradient acetonitrile/water+0.1% HCOOH) to afford the title compound as red solid (18 mg, 32%), MS (ESI): m/z=434.1 [M+H]+.

Example 49: 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]-1-methoxy-isoquinoline-4-sulfonamide

##STR00170##

[0484] 7-Chloro-1-methoxy-isoquinoline-4-sulfonyl chloride (64 mg, 0.22 mmol, Intermediate A19) was dissolved in pyridine (1 ml) and acetonitrile (1 ml). Then 2-(4-amino-2,5-difluoro-phenyl)acetonitrile (75 mg, 0.44 mmol, Intermediate B1) was added at room temperature and the mixture was stirred for 2 h, then the solvent was evaporated. The crude material was purified by preparative HPLC (column: SunFire C18 10019 mm 5 um, gradient 40-90% 0.5-6.5 min water-acetonitrile) to afford the title compound (10 mg, 11% yield) as light yellow solid, MS (ESI): m/z=424.0 [M+H]+.

Example 50: 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1,7-naphthyridine-5-sulfonamide

##STR00171##

[0485] A 3 ml glass tube was charged with 2-chloro-1,7-naphthyridine-5-sulfonyl chloride (47 mg, 0.179 mmol, Intermediate A7), 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine (40 mg, 0.179 mmol, Intermediate B2), dichloromethane (0.7 ml) and N,N-diethyl isopropylamine (23 mg, 31 ul, 0.179 mmol) and the mixture was stirred at room temperature for 3 h. The mixture was partitioned between dichloromethane and water. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (column: Gemini NX, 12 nm, 5 m, 10030 mm, gradient acetonitrile/water+0.1% HCOOH) to afford the title compound as orange solid (1.5 mg, 1.7%), MS m/z 449.1 [M+H]+, ESI pos.

Example 51: 2-chloro-N-[5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-yl]quinoline-5-sulfonamide

##STR00172##

[0486] A solution of 5-(difluoromethoxy)-4,6-dimethoxy-pyrimidin-2-amine (7 mg, 0.025 mmol, Intermediate B8) in N,N-dimethylformamide (100 ul) was cooled to 0 C. Sodium hydride (60%, 1.2 mg, 0.030 mmol) was added and the reaction mixture was stirred at 0 C. for 10 min. 2-Chloroquinoline-5-sulfonyl chloride (8.0 mg, 0.030 mmol, Intermediate A3) was added. The reaction mixture was allowed to warm to room temperature and stirred for 10 min. The resulting suspension was carefully quenched with water, poured into brine and extracted twice with ethyl acetate. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 40% ethyl acetate in heptane) to afford the title compound as white solid (5 mg, 43% yield). MS (ESI) m/z: 447.1 [M+H]+

Example 52: N-(4-(cyanomethyl)-2,5-difluorophenyl)-1-oxo-1,2-dihydroisoquinoline-4-sulfonamide

##STR00173##

[0487] To a stirred solution of 2-(4-amino-2,5-difluorophenyl)acetonitrile (25 mg, 0.149 mmol, Intermediate B1) and 4-dimethylamino pyridine (3.7 mg, 0.03 mmol) in pyridine (0.4 ml) was added 1-oxo-2H-isoquinoline-4-sulfonyl chloride (54.3 mg, 0.22 mmol, Intermediate A5). The reaction mixture was stirred at room temperature for 60 min, poured into dichloromethane and extracted with 10% citric acid solution. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, n-heptane/ethyl acetate 0 to 100%) to provide the title compound as a white solid (17 mg, 29% yield). MS (ESI) m/z: 376.0 [M+H].sup.+

Example 53: 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide

##STR00174##

Step 1: N-(4-bromo-2,5-difluoro-phenyl)-7-chloro-quinoline-4-sulfonamide

##STR00175##

[0488] A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.71 ml, 1.71 mmol) was added dropwise to a solution of 4-bromo-2,5-difluoroaniline (169 mg, 0.81 mmol) in tetrahydrofuran (10 ml) at 0 C. under argon atmosphere. After 30 min a solution of 7-chloroquinoline-4-sulfonyl fluoride (200 mg, 0.81 mmol, Intermediate A2) in tetrahydrofuran (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was poured into brine and extracted with ethyl acetate (230 ml). The combined organic layers were evaporated to obtain crude N-(4-bromo-2,5-difluoro-phenyl)-7-chloro-quinoline-4-sulfonamide (200 mg, 0.48 mmol, 59% yield), which was used in next step without purification.

Step 2: 7-chloro-N-[4-(cyanomethyl)-2,5-difluoro-phenyl]quinoline-4-sulfonamide

##STR00176##

[0489] N-(4-bromo-2,5-difluoro-phenyl)-7-chloro-quinoline-4-sulfonamide (200 mg, 0.46 mmol) was dissolved in dimethylsulfoxide (6 ml) and water (1 ml), then with potassium fluoride (80.4 mg, 1.38 mmol) and 4-isoxazoleboronic acid pinacol ester (180 mg, 0.92 mmol) were added. The resulting mixture was evacuated and backfilled with argon for 3 times. 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18.8 mg, 0.02 mmol) was added and the resulting mixture was heated to 120 C. for 48 h, then cooled to room temperature and filtered. The filtrate was subjected to HPLC (column: SunFire C18 10019 mm Sum, 4% water-acetonitrile+0.1% NH4OH) to obtain the title compound as brown gum (5 mg, 3% yield), MS (ESI) m/z: 394.0 [M+H].sup.+

Example 54: 2-bromo-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide

##STR00177##

[0490] To a solution of 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide (50 mg, 0.112 mmol, Example 10) in propionitrile (1.2 ml) was added bromotrimethylsilane (34 mg, 30 ul, 0.22 mmol) and the mixture was stirred overnight. Then it was poured onto mixture of 2N sodium hydroxide and ice, and extracted with ethyl acetate twice. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The yellow residue was purified by flash chromatography (silica gel, 0 to 100% ethyl acetate in n-heptane) to afford the title compound as red solid. (19.6 mg, 32%), MS (ESI) m/z: 494.1/492.0 [M+H].sup.+

Example 55: 2-cyclopropyl-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide

##STR00178##

[0491] In a reaction tube, 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide (50 mg, 0.112 mmol, Example 10), cyclopropylboronic acid (19 mg, 0.22 mmol), toluene (0.44 ml) and water (0.022 mL) were added and the mixture was purged with argon in ultrasonic bath for 5 min. Then, tricyclohexyl phosphine (6.3 mg, 0.022 mmol), palladium(II) acetate (2.5 mg, 0.011 mmol) and tripotassium phosphate (83 mg, 0.39 mmol) were added. The reaction mixture was stirred at 110 C. for 19 h, then concentrated in vacuo. To the residue was added dichloromethane and the insoluble parts were filtered off. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate in n-heptane) to afford the title compound as off-white solid (2.5 mg, 5%), MS m/z=454.3 (M+H).sup.+

Example 56: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-2-methoxy-quinoline-5-sulfonamide

##STR00179##

[0492] To a solution of 2-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]quinoline-5-sulfonamide (5 mg, 0.011 mmol, Example 10) in methanol (0.06 ml) under nitrogen at room temperature, sodium methoxide (1.9 mg, 0.035 mmol) was added. The reaction mixture was stirred at 100 C. for 19 h. The mixture was cooled to room temperature and the methanol was evaporated. The residue was extracted with ethyl acetate twice, and washed with water. The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 30%) to give the title compound as off-white solid (5 mg, 98%), MS: m/z=444.1 (M+H).sup.+

Example 57: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-5-sulfonamide

##STR00180##

Step 1: 1-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-5-sulfonamide

##STR00181##

[0493] To a solution of 1-chloroisoquinoline-5-sulfonyl chloride (CAS 141519-77-9, 50 mg, 0.19 mmol) in dichloromethane (1 ml) was added pyridine (0.05 ml, 0.57 mmol) and 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine (42 mg, 0.19 mmol, Intermediate B2). The mixture was stirred at 25 C. for 12 h. The mixture was concentrated under reduced pressure to give the crude material which was purified by column chromatography (petroleum ether-ethyl acetate 1:0 to 0:1) to give 1-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-5-sulfonamide as a yellow solid (89 mg, 99% yield), MS m/z=448.0 [M+H].sup.+ (ESI+).

Step 2: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]-1-(dimethylamino)isoquinoline-5-sulfonamide

##STR00182##

[0494] A solution of 1-chloro-N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]isoquinoline-5-sulfonamide (80.0 mg, 0.18 mmol) in dimethylamine solution (30% in ethanol, 3 ml) was stirred at 60 C. for 12 h. The mixture was concentrated under reduced pressure to give the crude material which was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25 mm*10 um, water, 0.2% TFA), acetonitrile) to give the title compound as a light red solid (74.5 mg, 91% yield), MS m/z=457.1, [M+H].sup.+ (ESI pos.)

Example 58: N-[6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-3-pyridyl]tetralin-5-sulfonamide

##STR00183##

[0495] The title compound was prepared in analogy to Example 1 using tetralin-5-sulfonyl chloride (Intermediate A28) instead of naphthalene-1-sulfonyl chloride and 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxy-pyridin-3-amine (Intermediate B2) instead of 2-(4-amino-2,5-difluoro-phenyl)acetonitrile as white solid, MS m/z=417.2 [M+H].sup.+ (ESI pos.).

Example A

[0496] A compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

TABLE-US-00004 Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

Example B

[0497] A compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

TABLE-US-00005 Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg