Histone deacetylase inhibitors and compositions and methods of use thereof

Abstract

Provided are certain histone deacetylase (HDAC) inhibitors of Formula I, compositions thereof, and methods of their use. ##STR00001##

Claims

1. A compound of Formula I: ##STR00137## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 and R.sub.2 are independently chosen from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R.sub.3 is —C(O)NH(OH); and R.sub.3 is hydrogen or lower alkyl optionally substituted with halo.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula II: ##STR00138##

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula III: ##STR00139##

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.3a is hydrogen or methyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.3a is —CF.sub.3.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula IV: ##STR00140##

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I a compound of Formula V: ##STR00141##

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is optionally substituted with one, two, or three groups independently chosen from —R.sub.21, —OR.sub.22, halo, and —NR.sub.23SO.sub.2R.sub.21, wherein R.sub.21 is chosen from optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl; R.sub.22 is chosen from H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; and R.sub.23 is chosen from hydrogen and optionally substituted C.sub.1-C.sub.4 alkyl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is cyclohexyl, thiophen-2-yl, thiazol-5-yl, or phenyl, each of which is optionally substituted with one, two, or three groups independently chosen from —R.sub.21, —OR.sub.22, and halo.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is thiophen-2-yl or phenyl, each of which is optionally substituted with one, two, or three groups independently chosen from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, trifluoromethyl, and halo.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 3-fluorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 5-methylthiophen-2-yl, 3-fluoro-5-methylthiophen-2-yl, 5-methyl-3-(trifluoromethyl)thiophen-2-yl, or 5-(trifluoromethyl)thiophen-2-yl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is phenyl, 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R.sub.2 is phenyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, each of which is optionally substituted with one, two, or three groups independently chosen from —R.sub.11, —OR.sub.12, halo, —NR.sub.12R.sub.13, —C(O)R.sub.12, —C(O)OR.sub.12, —C(O)NR.sub.12R.sub.13, —OC(O)R.sub.12, —OC(O)OR.sub.11, —OC(O)NR.sub.12R.sub.13, —NR.sub.13C(O)R.sub.12, —NR.sub.13C(O)OR.sub.11, —NR.sub.13C(O)NR.sub.12R.sub.13, —S(O)R.sub.11, —SO.sub.2—R.sub.11, —SO.sub.2NR.sub.12R.sub.13, and —NR.sub.13SO.sub.2R.sub.11, wherein R.sub.11 is chosen from optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, and optionally substituted heteroaryl; R.sub.12 is chosen from H, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; and R.sub.13 is chosen from hydrogen and optionally substituted C.sub.1-C.sub.4 alkyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is phenyl optionally substituted with one, two, or three groups independently chosen from —R.sub.11, —OR.sub.12, halo, —C(O)R.sub.12, —NR.sub.12R.sub.13, and —NR.sub.13SO.sub.2R.sub.11.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is phenyl optionally substituted with one, two or three groups independently selected from halo, C.sub.1-C.sub.6 alkyl, aryl optionally substituted with one or two groups independently chosen from lower alkyl, trifluoromethyl, cycloalkyl, phenyl, and benzyloxy, heteroaryl optionally substituted with one or two groups independently chosen from lower alkyl, trifluoromethyl, cycloalkyl, and phenyl, (cycloalkyl)sulfonamido, and heterocycloalkyl optionally substituted with one or two groups independently chosen from halo, lower alkyl, trifluoromethyl, cycloalkyl, heterocycloalkyl, and phenyl.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is phenyl optionally substituted with one, two or three groups independently selected from halo, lower alkyl, oxazol-2-yl, oxazol-5-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, 1H-pyrazol-1-yl, (cycloalkyl)sulfonamido, 1H-imidazol-1-yl, imidazol-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, azetidin-1-yl, pyrrolidin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, phenyl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, piperidin-1-yl, piperazin-1-yl, and 6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl, each of which is optionally substituted with one or two groups independently chosen from halo, lower alkyl, trifluoromethyl, phenyl, cycloalkyl, benzyl, benzyloxy, and pyrrolidin-1-yl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is chosen from phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-5-yl)phenyl, 4-(5-methylpyrimidin-2-yl)phenyl, 3-(5-fluoropyrimidin-2-yl)phenyl, 4-(5-chloropyrimidin-2-yl)phenyl, 4-(5-fluoropyrimidin-2-yl)phenyl, 4-(4-(trifluoromethyl)pyrimidin-2-yl)phenyl, 4-(5-trifluoromethylpyrimidin-2-yl)phenyl, 4-(5-cyclopropylpyrimidin-2-yl)phenyl, 4-(pyridazin-3-yl)phenyl, 4-(pyridazin-4-yl)phenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(1-methyl-1H-imidazol-2-yl)phenyl, 4-(5-methyl-1H-imidazol-2-yl)phenyl), 4-(1H-pyrazol-1-yl)phenyl, 4-(3-methyl-1H-pyrazol-1-yl)phenyl, 4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl, 3-(oxazol-5-yl)phenyl, 4-(oxazol-2-yl)phenyl, 4-(oxazol-5-yl)phenyl, 4-(2-methyloxazol-5-yl)phenyl, 4-(2-cyclopropyloxazol-5-yl)phenyl, 4-(2-phenyloxazol-5-yl)phenyl, 4-(cyclopropanesulfonamido)phenyl, 4-(3,3-dimethylazetidin-1-yl)phenyl, 4-(3,3-difluoropyrrolidin-1-yl)phenyl, 4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl, 3′-(benzyloxy)biphenyl-4-yl, 3-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl, 3-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-(4-isopropylpiperazin-1-yl)phenyl, or 3-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)phenyl.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is 4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(5-methylpyrimidin-2-yl)phenyl, 4-(5-chloropyrimidin-2-yl)phenyl, 4-(5-fluoropyrimidin-2-yl)phenyl, 4-(4-(trifluoromethyl)pyrimidin-2-yl)phenyl, 4-(5-cyclopropylpyrimidin-2-yl)phenyl, 4-(pyridazin-3-yl)phenyl, 4-(pyridazin-4-yl)phenyl, 4-(5-methyl-1H-imidazol-2-yl)phenyl), 4-(5-(trifluoromethyl)-1H-imidazol-2-yl)phenyl, 3-chloro-4-(5-methyl-1H-imidazol-2-yl)phenyl, 3-fluoro-4-(5-methyl-1H-imidazol-2-yl)phenyl, 4-(1H-pyrazol-1-yl)phenyl, 3-(oxazol-5-yl)phenyl, 4-(oxazol-2-yl)phenyl, 4-(oxazol-5-yl)phenyl, 4-(2-cyclopropyloxazol-5-yl)phenyl, 4-(4-isopropylpiperazin-1-yl)phenyl, or 3-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)phenyl.

20. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is 1,2,3,4-tetrahydroquinolin-6-yl, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-4-yl, 1,5-naphthyridin-4-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzo[d][1,3]dioxol-5-yl, or 1-oxo-isoindolin-5-yl, each of which is optionally substituted with one or two groups independently chosen from halo and C.sub.1-C.sub.6 alkyl optionally substituted with one, two, or three halo groups.

21. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is heteroaryl optionally substituted with one, two, or three groups independently chosen from —R.sub.11, —OR.sub.12, halo, and —NR.sub.13SO.sub.2R.sub.11.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is chosen from pyridin-3-yl, pyridin-4-yl, 1H-pyrazol-4-yl, pyrimidin-5-yl, pyridazin-4-yl, benzo[d]isoxazol-3-yl, benzo[d]oxazol-6-yl, or thiazol-5-yl, each of which is optionally substituted with one, two, or three groups independently chosen from —R.sub.11, —OR.sub.12, halo, and —NR.sub.13SO.sub.2R.sub.11.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is pyridin-3-yl, pyridin-4-yl, 1H-pyrazol-4-yl, pyrimidin-5-yl, pyridazin-4-yl, benzo[d]isoxazol-3-yl, benzo[d]oxazol-6-yl, or thiazol-5-yl, each of which is optionally substituted with one or two groups independently chosen from halo, lower alkyl, 2,2,2-trifluoroethylamino, trifluoromethyl, 2,2,2-trifluoroethyl, cycloalkyl, cyclopropylmethyl, 1H-pyrazol-1-yl optionally substituted with lower alkyl, pyrimidin-2-yl optionally substituted with lower alkyl or halo, oxazol-5-yl optionally substituted with lower alkyl, piperazin-1-yl optionally substituted with lower alkyl, piperidin-4-yl optionally substituted with 2,2,2-trifluoroethyl, and pyridin-2-yl optionally substituted with lower alkyl or trifluoromethyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is 2 cyclopropylpyridin-4-yl, 6-(trifluoromethyl)pyridin-3-yl, 2-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 2-(2,2,2-trifluoroethylamino)pyridin-4-yl, 6-(2,2,2-trifluoroethylamino)pyridin-3-yl, 6-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl, 6-(5-methylpyrimidin-2-yl)pyridin-3-yl, 6-(2-methyloxazol-5-yl)pyridin-3-yl, 6-(5-chloropyrimidin-2-yl)pyridin-3-yl, 6-(4-isopropylpiperazin-1-yl)pyridin-3-yl, 2,6-dicyclopropylpyridin-4-yl, 6-(5-fluoropyrimidin-2-yl)pyridin-3-yl, 2-(5-chloropyrimidin-2-yl)-6-cyclopropylpyridin-4-yl, 1-methyl-1H-pyrazol-4-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl, 1-(cyclopropylmethyl)-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl, 1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl, pyrimidin-5-yl, 2-cyclopropylpyrimidin-5-yl, 3-cyclopropylpyrimidin-5-yl, pyridazin-4-yl, 6-cyclopropylpyridazin-4-yl, benzo[d]isoxazol-3-yl, 2-isopropylbenzo[d]oxazol-6-yl, or 2-methylthiazol-5-yl.

25. A compound chosen from trans-N-Hydroxy-2,3-diphenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-Cyclohexyl-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(2-isopropoxyphenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(2-Fluorophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S*,2R*,3R*)-2-(2-Fluorophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(2-Bromophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(3-Bromophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-Bromophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-o-tolylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-m-tolylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-p-tolylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(cyclopropanesulfonamido)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S*,2R*,3R*)-2-Cyclopentyl-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-Hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(pyrimidin-5-yl)cyclopropanecarboxamide; (1R,2R,3R)-2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(8-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S,2R,3R)-2-(8-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-fluorophenyl)-N-hydroxycyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(pyridazin-4-yl)cyclopropanecarboxamide; (1R,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)-3-(2-fluorophenyl)-N-hydroxycyclopropanecarboxamide; (1R,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)-3-(4-fluorophenyl)-N-hydroxycyclopropanecarboxamide; (1R,2R,3R)-2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-Hydroxy-2-phenyl-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-Hydroxy-2-phenyl-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-Hydroxy-2-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(2-isopropylbenzo[d]oxazol-6-yl)-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-Hydroxy-2-(3-(oxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-Hydroxy-2-(4-(oxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(1H-imidazol-1-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(4-(2-Cyclopropyloxazol-5-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(4-(2-phenyloxazol-5-yl)phenyl)cyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(5-Fluoropyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(3-(5-Fluoropyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(5-Cyclopropylpyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(4-Trifluoromethylpyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(4-(5-Trifluoromethylpyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(4-(pyridazin-3-yl)phenyl)cyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(4-(pyridazin-4-yl)phenyl)cyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(4-(pyrimidin-2-yl)phenyl)cyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(4-(pyrimidin-5-yl)phenyl)cyclopropanecarboxamide; (1R,2R,3R)-2-(4-(5-Chloropyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(4-(5-methylpyrimidin-2-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(4-(5-methyl-1H-imidazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(2-cyclopropylisoindolin-5-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(3′-(Benzyloxy)-[1,1′-biphenyl]-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4′-(9H-carbazol-9-yl)-[1,1′-biphenyl]-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(4-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(3-(4-isopropylpiperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(4-(3,3-difluoropyrrolidin-1-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(3,3-Dimethylazetidin-1-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(3-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(3-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)cyclopropanecarboxamide; (1R,2R,3R)-2-(3-(6,7-Dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(4-(oxazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)—N-Hydroxy-2-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide; (1R*,2S*,3S*)-2-(4-(5-Fluoropyrimidin-2-yl)phenyl)-N-hydroxy-1-methyl-3-phenylcyclopropanecarboxamide; (1R*,2R*,3R*)-2-(4-(1H-pyrazol-1-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-Hydroxy-2-phenyl-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxamide; (1R,2R,3R)-2-(4-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(4-(2-methyloxazol-5-yl)phenyl)cyclopropanecarboxamide; (1S,2R,3S)-2-(2-fluorophenyl)-N-hydroxy-1-methyl-3-(4-(2-methyloxazol-5-yl)phenyl)cyclopropanecarboxamide; (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(4-(3-methyl-1H-pyrazol-1-yl)phenyl)cyclopropanecarboxamide; (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)cyclopropanecarboxamide; (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(4-(isopropyl(2-morpholinoethyl)amino)phenyl)cyclopropanecarboxamide; (1R,2R,3R)-2-(2-cyclopropylpyrimidin-5-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(benzo[d]isoxazol-3-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(6-cyclopropylpyridazin-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(6-(3-methyl-1H-pyrazol-1-yl)pyridin-3-yl)cyclopropanecarboxamide; (1S,2R,3R)-2-(6-(5-chloropyrimidin-2-yl)pyridin-3-yl)-3-(2-fluorophenyl)-N-hydroxycyclopropanecarboxamide; (1R,2R,3R)-2-(5-chloro-6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S,2R,3R)-2-(2-fluorophenyl)-3-(6-(5-fluoropyrimidin-2-yl)pyridin-3-yl)-N-hydroxycyclopropanecarboxamide; (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(6-(5-methylpyrimidin-2-yl)pyridin-3-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(6-(2-methyloxazol-5-yl)pyridin-3-yl)-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(5-chloro-6-(2-methyloxazol-5-yl)pyridin-3-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(2-(2,2,2-trifluoroethylamino)pyridin-4-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-phenyl-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)cyclopropanecarboxamide; (1R,2R,3R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-phenyl-3-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)cyclopropanecarboxamide; (1R,2R,3R)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3S)—N-hydroxy-2-(2-methylthiazol-5-yl)-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(8-chloro-1,2,3,4-tetrahydroquinolin-6-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-phenyl-3-(4-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(1-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-3-phenylcyclopropanecarboxamide; (1R,2R,3R)-2-(1-fluoro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-phenyl-3-(2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-phenyl-3-(7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-phenyl-3-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-7-yl)cyclopropanecarboxamide (1R,2R,3R)—N-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)-3-phenylcyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-phenyl-3-(pyrrolo[1,2-a]pyrimidin-4-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(1,5-naphthyridin-4-yl)-3-phenylcyclopropanecarboxamide; (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-N-hydroxy-3-(2-methylthiazol-5-yl)cyclopropanecarboxamide; (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-N-hydroxy-3-(5-(trifluoromethyl)thiophen-2-yl)cyclopropanecarboxamide; (1R,2R,3R)-2-(1-((5-fluoropyridin-2-yl)methyl)-1H-pyrazol-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide; (1S,2R,3S)-2-(3-fluoro-5-methylthiophen-2-yl)-N-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide; (1S,2S,3R)—N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-(5-methyl-3-(trifluoromethyl)thiophen-2-yl)cyclopropanecarboxamide; (1S,2S,3R)—N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-(5-methylthiophen-2-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-o-tolylcyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-(2-(trifluoromethyl)phenyl)cyclopropanecarboxamide; (1S,2R,3R)-2-(2-chlorophenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide; (1R,2R,3R)-2-(3-fluorophenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-m-tolylcyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-(3-(trifluoromethyl)phenyl)cyclopropanecarboxamide; (1R,2R,3R)-2-(3-chlorophenyl)-N-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide; (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-3-(3-fluoro-5-methylthiophen-2-yl)-N-hydroxycyclopropanecarboxamide; (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-N-hydroxy-3-(5-methyl-3-(trifluoromethyl)thiophen-2-yl)cyclopropanecarboxamide; (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-N-hydroxy-3-(5-methylthiophen-2-yl)cyclopropanecarboxamide; (1R,2R,3R)—N-hydroxy-2-phenyl-3-(4-(5-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropanecarboxamide; (1R,2R,3R)-2-(3-chloro-4-(5-methyl-1H-imidazol-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide; and (1R,2R,3R)-2-(3-fluoro-4-(5-methyl-1H-imidazol-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

27. A pharmaceutical composition comprising a compound of claim 25, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Description

EXAMPLES

(1) The compounds, or pharmaceutically acceptable salts thereof, compositions, and methods described herein are further illustrated by the following non-limiting examples.

(2) As used herein, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

Abbreviations

(3) [bmim][PF.sub.6]: 1-Butyl-3-methylimidazolium hexafluorophosphate BOP: Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate DCM: Dichloromethane DCE: Dichloroethane DIPEA: Diisopropylethylamine DMA: Dimethylacetamide DME: Dimethoxyethane DMF: Dimethylformamide DMSO: Dimethylsulfoxide ES+: Electrospray Positive Ionisation ES−: Electrospray Negative Ionisation Et.sub.2O: Diethyl ether EtOAc: Ethyl acetate h: Hour HPLC: High Performance Liquid Chromatography i-hex: iso-Hexane LCMS: Liquid Chromatography Mass Spectrometry LiHMDS: Lithium bis(trimethylsilyl)amide M: Mass MeCN: Acetonitrile MeOH: Methanol NMP: N-Methyl pyrrolidinone Pd/C: Palladium on carbon Pd.sub.2(dba).sub.3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)C.sub.2: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh.sub.3).sub.4: Tetrakis(triphenylphosphine)palladium(0) o-tol: ortho-Tolyl Rh.sub.2(OAc).sub.4: Rhodium(II) acetate RT: Retention time r.t.: Room temperature RuPhos: 2-Dicyclohexylphosphino-2′,6′-di-iso-propoxy-1,1′-biphenyl THF: Tetrahydrofuran Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Analytical Conditions

(4) Compounds were named with the aid of the Cambridgesoft Chemistry Cartridge (v. 9.0.0.182) software.

(5) All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.

(6) Racemic mixtures of the cyclopropyl core are denoted using asterisks e.g. (1R*,2R*,3R*). Chirally pure compounds are denoted without asterisks e.g. (1R,2R,3R).

(7) TABLE-US-00001 Analytical Condition Method Description 10 cm_ESI_Formic_ 1 Solvents: Acetonitrile (far UV grade) MeCN, 10 cm_ with 0.1% (v/v) formic acid. ESCl_Formic_ Water (high purity via MeCN PureLab Option unit) with 0.1% formic acid Column: Phenomenex Luna 5 μm C18 (2), 100 × 4.6 mm (Plus guard cartridge) Flow Rate: 2 mL/min gradient: A: Water/formic acid B: MeCN/formic acid Time A % B % 0.00 95  5 3.50  5 95 5.50  5 95 5.60 95  5 6.50 95  5 Typical Injections 2-7 μL (concentration ~0.2-1.0 mg/mL) 15 cm_Bicarb_ 2 Solvents: 100% Acetonitrile (Far UV GeminiNX_HPLC_ grade) Water (High purity via MeCN PureLab Ultra unit) with 10 mM Ammonium Bicarbonate Column: Phenomenex, Gemini NX, 3 μm C18, 150 × 4.6 mm. Flow Rate: 1 mL/min gradient: A: 10 mM Ammonium Bicarbonate in water B: 100% MeCN Time A % B %  0.00 95.5  4.5  3.00 95.5  4.4  9.00  0 100 13.6  0 100 13.7 95.5  4.5 15 95.5  4.5 Typical Injections 2-7 μL (concentration ~0.2-1 mg/mL) 15 cm_Formic_ 3 Solvents: Acetonitrile (Far UV grade) Ascentis_HPLC_ with 0.1% (V/V) formic acid MeCN Water (High purity via PureLab Ultra unit) with 0.1% formic acid Column: Supelco, Ascentis ® Express C18 or Hichrom Halo C18, 2.7 μm C18, 150 × 4.6 mm. Flow Rate: 1 mL/min gradient: A: Water/formic B: MeCN/formic Time A % B %  0.00 96  4  3.00 96  4  9.00  0 100 13.6  0 100 13.7 96  4 15 96  4 Typical Injections 2-7 μL (concentration ~0.2-1 mg/mL) 10 cm_ESCl_ 4 Solvents: Acetonitrile (Far UV grade) bicarb_MeCN Water (High purity via PureLab Option unit) with 10 mM ammonium bicarbonate (ammonium hydrogen carbonate) Column: Waters Xterra MS 5 m C18, 100 × 4.6 mm. (Plus guard cartridge) Flow Rate: 2 mL/min gradient: A: Water/Bicarb B: MeCN Time A % B % 0.00 95  5 0.50 95  5 4.00  5 95 5.50  5 95 5.60 95  5 6.50 95  5 Typical Injections 2-7 μL (concentration ~0.2-1 mg/mL) 10 cm_Formic_ 5 Solvents: Acetonitrile (Far UV ACE-AR_HPLC_ grade) with 0.1% (VN) CH3CN formic acid Water (High purity via PureLab Ultra unit) with 0.1% formic acid Column: Hichrom ACE 3 C18-AR mixed mode column 100 × 4.6 mm Flow Rate: 1 mL/min gradient: A: Water/formic B: MeCN/formic Time A % B %  0.00 98  2  3.00 98  2 12.00  0 100 15.4  0 100 15.5 98  2 17 98  2 Typical Injections 0.2-10 μL

(8) TABLE-US-00002 Analytical Condition Method Description 10 cm_Formic_ACE- 6 Solvents: Methanol (AR grade) AR_HPLC_CH3OH_ with 0.1% (V/V) formic Slow acid Water (High purity via PureLab Ultra unit) with 0.1% formic acid Column: Hichrom ACE 3 C18- AR mixed mode column 100 × 4.6 mm Flow Rate: 1 mL/min gradient: A: Water/formic B: MeOH/formic Time A % B %  0.00 98  2  3.00 98  2 12.00  0 100 15.4  0 100 15.5 98  2 17 98  2 Typical Injections 0.2-10 μL
Synthetic Section
Method A (Hydroxamic Acid Formation)

(9) To a stirred solution of ester (0.30 mmol) in THF/MeOH (1:1, 3 mL) was added hydroxylamine (0.2 mL, 50% aqueous solution, 3.00 mmol) and potassium hydroxide (33 mg, 0.60 mmol). The mixture was stirred at r.t. for 2 h, neutralized with 1 M HCl.sub.(aq) and extracted with DCM. The combined organic layers were washed with brine (10 mL), passed through a phase separator and concentrated.

(10) Method B (Hydroxamic Acid Formation)

(11) To a stirred solution of acid (0.26 mmol), BOP (0.29 mmol) and triethylamine (0.78 mmol) in pyridine (1 mL) was added hydroxylamine hydrochloride (0.29 mmol). The reaction mixture was stirred at r.t. for 2 h, diluted with water (10 mL) and extracted into EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), dried (MgSO.sub.4) and concentrated.

(12) Method C (Wittig Reaction)

(13) To a stirred solution of triethyl phosphonoacetate (24.4 mmol) in THF (30 mL) at 0° C. was added sodium hydride (24.4 mmol) portionwise. The mixture was stirred for 1 h before addition of aldehyde (12.2 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 17 h, before quenching with water (50 mL) and extracting into EtOAc (2×50 mL). The organic layers were combined and washed with water (2×50 mL), dried (MgSO.sub.4), filtered and concentrated.

(14) Method D (Heck Reaction-1)

(15) To a stirred solution of aryl bromide (4.42 mmol) in anhydrous DMF (16 mL) was added ethyl acrylate (5.75 mmol), Pd(OAc).sub.2 (0.44 mmol), DABCO (8.84 mmol) and potassium carbonate (8.84 mmol). The solution was degassed under nitrogen for 15 min before heating to 125° C. for 17 h. The mixture was cooled, diluted with H.sub.2O (30 mL) and extracted into DCM (2×30 mL). The organic layers were washed with H.sub.2O (3×50 mL) and brine (2×50 mL), passed through a phase separator and concentrated.

(16) Method E (Heck Reaction-2)

(17) A stirred mixture of aryl bromide (10.0 mmol), ethyl acrylate (15.0 mmol), palladium acetate (1.00 mmol), P(o-tol).sub.3 (2.00 mmol) and triethylamine (20.0 mmol) in MeCN (50 mL) was degassed with nitrogen for 15 min and heated to 80° C. for 3-18 h. The reaction mixture was cooled and the MeCN removed in vacuo. The residue was partitioned between DCM and H.sub.2O and the organic layers were passed through a phase separator and concentrated.

(18) Method F (Cyclopropanation Reaction)

(19) A mixture of sulfonium salt (8.92 mmol), acrylate (5.96 mmol) and 12-crown-4 (8.92 mmol) in DCM (20 mL) was cooled to −20° C. LiHMDS (8.92 mL) was then added dropwise. After complete addition, the mixture was warmed to r.t, stirred for 2 h and quenched with H.sub.2O (30 mL). The layers were separated and the organic phase was washed with brine (2×30 mL), separated, dried (MgSO.sub.4), filtered and concentrated.

(20) Method G (Suzuki Coupling from Boronate on Scaffold)

(21) To a stirred solution of cyclopropyl bromo scaffold (3.02 mmol) in dioxane (5 mL) was added bis-pinacolato diboron (3.32 mmol), Pd(dppf)Cl.sub.2 (0.30 mmol) and potassium acetate (15.1 mmol). The mixture was degassed with nitrogen and heated to 100° C. for 2 h. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted into DCM (2×20 mL). The organic layers were passed through a phase separator and concentrated. The crude residue was dissolved in dioxane and an aliquot (0.66 mmol) was added to a reaction tube. To this was added heterocyclic halide (0.69 mmol), Pd(PPh.sub.3).sub.4 (0.066 mmol), and aqueous Na.sub.2CO.sub.3 (5 mL, 1 M solution). The reaction was heated at 100° C. for 2 h. The mixture was diluted with H.sub.2O (10 mL) and extracted into DCM (20 mL). The organic layers were passed through a phase separator and concentrated.

(22) Method H (Suzuki Coupling)

(23) A mixture of cyclopropyl bromo scaffold (2.00 mmol), boronic ester (or acid) (2.40 mmol), 1 N Na.sub.2CO.sub.3 (6.00 mmol) and Pd(PPh.sub.3).sub.4 (0.10 mmol) in dioxane (6 mL) was stirred at 100° C. for 3 h. The reaction mixture was diluted with water and extracted into DCM. The organic layer was dried and concentrated and the crude mixture was purified by flash silica column chromatography.

(24) Method I (Buchwald Reaction)

(25) To a stirred solution of aryl bromide (0.76 mmol) and amine (0.86 mmol) in dioxane (4 mL), was added XantPhos (0.048 mmol), cesium carbonate (1.66 mmol) and Pd.sub.2(dba).sub.3 (0.024 mmol). The mixture was stirred for 16 h at 90° C., diluted with water and extracted into DCM (20 mL). The organic layers were passed through a phase separator and concentrated and the crude mixture was purified by flash silica column chromatography.

Example 1

(26) ##STR00008##

trans-2,3-Diphenylcyclopropanecarboxylic acid (1)

(27) To a stirred solution of trans-stilbene (1.0 g, 5.6 mmol) and copper sulphate (44 mg, 0.28 mmol) in toluene (50 mL) at 75° C. was added ethyl diazoacetate (1.16 mL, 11.1 mmol) dropwise. Evolution of nitrogen was observed. The mixture was stirred for 15 min, allowed to cool to r.t. and concentrated in vacuo. The residue was taken-up in EtOH (25 mL) and filtered. The filtrate was concentrated and purified by flash silica column chromatography (gradient elution petroleum ether to 2.5% EtOAc in petroleum ether). The ethyl ester intermediate was then dissolved in MeOH (5 mL) and aqueous 2 M LiOH (10 mL) and stirred at 50° C. for 16 h. The mixture was washed with Et.sub.2O (30 mL) and the basic aqueous solution acidified using aqueous 1 M HCl. The resulting precipitate was collected by filtration to give the title compound (62 mg, 5%) as a white solid.

trans-N-Hydroxy-2,3-diphenylcyclopropanecarboxamide (2)

(28) Following method B, from compound I (62 mg, 0.26 mmol). The crude material was purified by preparative HPLC and PEAX cartridge (DCM:MeOH, 1:1). The solvent was removed in vacuo to afford the title compound (25 mg, 38%) as a white solid. LCMS (ES+) 254 (M+H)+, (ES−) 252 (M−H)−, RT 2.97 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.55 (1H, s), 8.69 (1H, s), 7.36-7.16 (10H, m), 3.09 (1H, dd, J=6.8, 5.4 Hz), 2.83 (1H, dd, J=9.6, 6.8 Hz), 2.20 (1H, dd, J=9.6, 5.4 Hz).

Example 2

(29) ##STR00009##

(E)-(2-Cyclohexylvinyl)benzene (3)

(30) To a stirred solution of K.sub.3PO.sub.4 (11.4 g, 53.8 mmol) in DMA (15 mL) was added bromobenzene (3.0 g, 19 mmol), vinylcyclohexane (5.04 g, 45.8 mmol) and palladium acetate (213 mg, 0.95 mmol). The mixture was stirred at 140° C. for 16 h, allowed to cool to r.t., diluted with water (50 mL) and extracted into EtOAc (2×50 mL). The combined organic layers were washed with water (2×50 mL) and brine (2×50 mL), separated, dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (i-hex) gave the title compound as a colourless oil (2.30 g, 65%).

(1R*,2R*,3R*)-Ethyl-2-cyclohexyl-3-phenylcyclopropanecarboxylate (4)

(31) To a stirred solution of 3 (1.50 g, 8.06 mmol) and Rh.sub.2(OAc).sub.4 (106 mg, 0.806 mmol) in anhydrous DCM (10 mL) was added ethyl diazoacetate (0.85 mL, 8.06 mmol) in DCM (10 mL) at a rate of 0.2 mL/h. After complete addition the mixture was stirred for 1 h at r.t. Purification by flash silica column chromatography (gradient elution of i-hex to 2% EtOAc in i-hex) gave the title compound as a colourless oil (400 mg, 18%).

(1R*,2R*,3R*)-2-Cyclohexyl-N-hydroxy-3-phenylcyclopropanecarboxamide (5)

(32) Following method A from compound 4 (750 mg, 2.76 mmol). Purification by preparative HPLC gave the title compound as a white solid (10 mg, 3%). LCMS (ES+) 260 (M+H)+, 258 (M−H)−, RT 9.41 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.51 (1H, s), 8.76 (1H, s), 7.30-7.22 (2H, m), 7.18-7.12 (1H, m), 7.08 (2H, d, J=7.6 Hz), 2.33-2.27 (1H, m), 1.82-1.58 (7H, m), 1.31-1.00 (6H, m).

Example 3

(33) ##STR00010##

1-Benzyltetrahydrothiophenium bromide (6a)

(34) To a stirred solution of benzyl bromide (27 mL, 227 mmol) in acetone at r.t. was added tetrahydrothiophene (10.0 mL, 114 mmol). The solution was stirred for 16 h and the resulting precipitate filtered and washed with acetone (3×50 mL) and dried under air, to give the title compound as a white solid (51.9 g, 88%).

1-(2-Fluorobenzyl)tetrahydrothiophenium bromide (6b)

(35) 2-Fluorobenzyl bromide (8 g, 42.3 mmol) was added to tetrahydrothiophene (25 mL, 284 mmol) and the mixture was stirred for 17 h. The resulting precipitate was collected by vacuum filtration and then slurried in Et.sub.2O for 1 h before collecting by vacuum filtration, to give the title compound as a white solid (7.7 g, 66%).

1-(4-Fluorobenzyl)tetrahydrothiophenium bromide (6c)

(36) To a stirred solution of 4-fluorobenzyl bromide (4.0 g, 21.1 mmol) in acetone (30 mL) was added tetrahydrothiophene (1.8 mL, 21.1 mmol) and the mixture was stirred for 17 h. The resulting precipitate was filtered to give the title compound as a white solid (160 mg, 3%).

Example 4

(37) ##STR00011##

(E)-Ethyl-3-(2-nitrophenyl)acrylate (7)

(38) Following method C from 2-nitrobenzaldehyde (5.0 g, 34.2 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 50% DCM in i-hex) gave the title compound as a white solid (2.9 g, 38%).

(1R*,2R*,3R)-Ethyl-2-(2-nitrophenyl)-3-phenylcyclopropanecarboxylate (8)

(39) To a stirred solution of 7 (2.90 g, 13.1 mmol) in anhydrous DCM/THF (75 mL/30 mL) was added sulfonium salt 6a (5.10 g, 19.7 mmol) and the mixture was cooled to −78° C. LiHMDS (26.2 mL, 1 M solution in THF) was slowly added via syringe pump (1 mL/min). After complete addition, the mixture was warmed to r.t., stirred for 16 h, quenched with water (50 mL) and extracted into DCM (2×100 mL). The combined organic layers were washed with water (2×250 mL) and brine (100 mL). The biphasic mixture was separated and the organic layer was dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a yellow oil (2.10 g, 51%).

(1R*,2R*,3R)-Ethyl-2-(2-aminophenyl)-3-phenylcyclopropanecarboxylate (9)

(40) A solution of 8 (2.10 g, 6.75 mmol) and 10% Pd/C (200 mg) in MeOH (75 mL) was stirred at r.t. under H.sub.2 (1 atmosphere), for 17 h. The mixture was filtered through Celite and purified by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) to give the title compound as a red oil (1.55 g, 82%). LCMS (ES+) 282 (M+H).sup.+.

(1R*,2R*,3R)-Ethyl-2-(2-isopropoxyphenyl)-3-phenylcyclopropanecarboxylate (10a)

(41) To a stirred solution of compound 9 (500 mg, 1.78 mmol) in water (10 mL) was added concentrated H.sub.2SO.sub.4 (0.85 mL) and NaNO.sub.2 (184 mg, 2.67 mmol). The reaction mixture was stirred at 00° C. for 1 h, then poured into boiling water (20 mL) and stirred for 30 min. The solution was allowed to cool to r.t. and extracted into DCM (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO.sub.4) and concentrated. The resulting red oil was dissolved in DMF (5 mL) and 2-bromopropane (0.17 mL, 1.77 mmol) and cesium carbonate (434 mg, 1.34 mmol) were added. The mixture was stirred at 80° C. for 16 h, then diluted with water (20 mL) and extracted into DCM (2×30 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (125 mg, 44%). LCMS (ES+) 325 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(2-fluorophenyl)-3-phenylcyclopropanecarboxylate (10b)

(42) A solution of nitrosonium tetrafluoroborate (125 mg, 1.07 mmol) and [bmim][PF.sub.6](1.8 mL) was cooled to 0° C. Compound 9 (300 mg, 1.07 mmol) was added and the mixture was stirred for 30 min at 00° C., and 17 h at r.t. The mixture was then heated to 100° C. for 2 h (gas evolution observed) and cooled to r.t. DIPEA (0.18 mL, 1.07 mmol) and Et.sub.2O (10 mL) were added. The organic layer was decanted from the ionic liquid and this process repeated twice more. The combined organic layers were concentrated and purified by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) to give the title compound as a colourless oil (135 mg, 45%). LCMS (ES+) 285 (M+H).sup.+.

(1R,2R,3R*)—N-Hydroxy-2-(2-isopropoxyphenyl)-3-phenylcyclopropanecarboxamide (11a)

(43) Following method A from compound 100a (125 mg, 0.39 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the title compound as a white solid (28 mg, 23%). LCMS (ES+) 312 (M+H)+, (ES−) 310 (M−H)−, RT 3.41 min (Analytical method 1). .sup.1H NMR δ (ppm)(CHCl.sub.3-d): 7.99 (1H, s), 7.41 (2H, d, J=7.6 Hz), 7.31 (2H, t, J=7.1 Hz), 7.27-7.18 (2H, m), 7.11-7.07 (1H, m), 6.92-6.87 (2H, m), 4.66-4.59 (1H, septet, J=6.0), 3.29 (1H, t, J=6.4 Hz), 2.81 (1H, dd, J=9.2, 7.3 Hz), 2.02 (1H, br m), 1.36 (6H, dd, J=10.1, 6.0 Hz), OH not observed.

(1R*,2R*,3R*)-2-(2-Fluorophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (11b)

(44) Following method A from compound 100b (130 mg, 0.46 mmol). Purification by flash silica column chromatography (gradient elution DCM to 1% MeOH in DCM) gave the title compound as a white solid (18 mg, 14%). LCMS (ES+) 272 (M+H)+, (ES−) 270 (M−H)−, RT 3.02 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.60 (1H, s), 8.74 (1H, s), 7.34-7.14 (9H, m), 3.17 (1H, dd, J=7.0, 5.6 Hz), 2.86 (1H, dd, J=9.5, 7.0 Hz), 2.25 (1H, dd, J=9.5, 5.4 Hz).

Example 5

(45) ##STR00012##

(1S*,2R*,3R*)-Ethyl-2-(2-fluorophenyl)-3-phenylcyclopropanecarboxylate (12)

(46) A mixture of sulfonium salt 6b (500 mg, 1.80 mmol), ethyl cinnamate (0.20 mL, 1.20 mmol) and 12-crown-4 (0.19 mL, 1.20 mmol) in DCM (10 mL) was cooled to −78° C. LiHMDS (2.41 mL, 1 M solution in THF) was slowly added via syringe pump (2 mL/h). After complete addition, the mixture was warmed to r.t. and stirred for 16 h. The reaction mixture was quenched with H.sub.2O (30 mL). The biphasic mixture was separated and the organic layers were washed with brine (2×30 mL), dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a colourless oil (190 mg, 56%). LCMS (ES+) 285 (M+H).sup.+.

(1S*,2R*,3R)-2-(2-Fluorophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (13)

(47) Following method A from compound 12 (190 mg, 0.67 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the title compound as a white solid (50 mg, 28%). LCMS (ES+) 272 (M+H)+, (ES−) 270 (M−H)−, RT 3.06 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.60 (1H, s), 8.73 (1H, s), 7.42-7.20 (7H, m), 7.13-7.06 (2H, m), 3.03 (1H, dd, J=6.8, 5.3 Hz), 2.77 (1H, dd, J=9.3, 6.9 Hz), 2.23 (1H, dd, J=9.3, 5.3 Hz).

Example 6

(48) ##STR00013##

(E)-Ethyl-3-(2-bromophenyl)acrylate (14a)

(49) Following method C from 2-bromobenzaldehyde (4.66 g, 25.2 mmol). Purification by flash silica column chromatography (gradient elution i-hex to i-hex:DCM, 5:2) gave the title compound as a colourless oil (2.52 g, 39%). LCMS (ES+) 255, 257 (M+H).sup.+.

(E)-Ethyl-3-(3-bromophenyl)acrylate (14b)

(50) Following method C from 3-bromobenzaldehyde (10 g, 54.1 mmol). Purification by flash silica column chromatography (gradient elution i-hex to i-hex:DCM, 1:1) gave the title compound as a colourless oil (7.8 g, 56%). LCMS (ES+) 255, 257 (M+H).sup.+.

(1R*,2R*,3R)-Ethyl-2-(2-bromophenyl)-3-phenylcyclopropanecarboxylate (15a)

(51) A mixture of sulfonium salt 6a (1.52 g, 5.88 mmol) and cinnamate 14a (1.00 g, 3.92 mmol) in DCM/THF (5:2, 35 mL) was cooled to −78° C. LiHMDS (7.84 mL, 1 M solution in THF) was slowly added via syringe pump (1 mL/h). After complete addition, the mixture was warmed to r.t., stirred for 16 h and quenched with H.sub.2O (30 mL). The biphasic mixture was separated and the aqueous portion re-extracted with DCM (30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), separated, dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 2.5% EtOAc in i-hex) gave the title compound as a colourless oil (1.05 g, 78%). LCMS (ES+) 345, 347 (M+H).

(1R*,2R*,3R*)-Ethyl-2-(3-bromophenyl)-3-phenylcyclopropanecarboxylate (15b)

(52) A mixture of sulfonium salt 6a (2.10 g, 8.10 mmol) and cinnamate 14b (1.03 g, 4.04 mmol) in DCM (20 mL) was cooled to −78° C. LiHMDS (6.00 mL, 1 M solution in THF) was slowly added via syringe pump (6 mL/h). After complete addition, the mixture was warmed to r.t., stirred for 16 h and quenched with H.sub.2O (30 mL). The biphasic mixture was separated and the aqueous layer was re-extracted with DCM (30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (350 mg, 25%). LCMS (ES+) 345, 347 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl 2-(4-bromophenyl)-3-phenylcyclopropanecarboxylate (15c)

(53) A mixture of sulfonium salt 6a (3.39 g, 13.1 mmol) and (E)-methyl 3-(4-bromophenyl)acrylate (2.10 g, 8.71 mmol) in DCM (50 mL) was cooled to −78° C. and slowly treated with LiHMDS (13.1 mL, 1 M solution in THF) (via syringe pump, 1 mL/h). After complete addition, the mixture was warmed to r.t., stirred for 16 h and was quenched with H.sub.2O (50 mL). The biphasic mixture was separated and the organic layer washed with brine (2×50 mL), dried (MgSO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (600 mg, 20%). LCMS (ES+) 345, 347 (M+H).sup.+.

(1R*,2R*,3R*)-2-(2-Bromophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (16a)

(54) Following method A from compound 15a (100 mg, 0.30 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM), then passage through a PEAX cartridge (DCM:MeOH, 1:1) gave the title compound as a white solid (32 mg, 33%). LCMS (ES+) 332, 334 (M+H)+, 330, 332 (M−H)−, RT 10.44 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.57 (1H, s), 8.73 (1H, s), 7.66 (1H, dd, J=7.9, 1.2 Hz), 7.41-7.33 (3H, m), 7.30-7.15 (5H, m), 3.28 (1H, dd, J=5.9, 6.9 Hz), 2.83 (1H, dd, J=9.5, 7.1 Hz), 2.20 (1H, dd, J=9.5, 5.6 Hz).

(1R*,2R*,3R*)-2-(3-Bromophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (16b)

(55) Following method A from compound 15b (100 mg, 0.29 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the title compound as a white solid (28 mg, 28%). LCMS (ES+) 332, 334 (M+H)+, 330, 332 (M−H)−, RT 3.81 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.54 (1H, s), 8.71 (1H, s), 7.50 (1H, s), 7.44-7.40 (1H, m), 7.35-7.22 (6H, m), 7.18 (1H, t, J=7.2 Hz), 3.12 (1H, dd, J=6.8, 5.4 Hz), 2.88 (1H, dd, J=9.6, 6.8 Hz), 2.23 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R*)-2-(4-Bromophenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (16c)

(56) Following method A from compound 15c (100 mg, 0.30 mmol). The residue after work-up was passed through a PEAX cartridge (elution DCM-MeOH, 1:1) to give the title compound as a white solid (34 mg, 34%). LCMS (ES+) 332, 334 (M+H)+, 330, 332 (M−H)−. RT 3.30 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.54 (1H, s), 8.67 (1H, s), 7.51-7.45 (2H, m), 7.31-7.18 (6H, m), 7.15 (1H, t, J=7.2 Hz), 3.07 (1H, dd, J=6.9, 5.4 Hz), 2.81 (1H, dd, J=9.6, 6.9 Hz), 2.17 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R*)-Ethyl-2-phenyl-3-o-tolylcyclopropanecarboxylate (17a)

(57) To a stirred solution of 15a (200 mg, 0.58 mmol) in dioxane/water (9:1, 3 mL) was added trimethylboroxine (80 μl, 0.58 mmol), Pd(PPh.sub.3).sub.4 (67 mg, 0.058 mmol) and cesium carbonate (566 mg, 1.74 mmol). The mixture was degassed with nitrogen for 10 min and heated in the microwave at 115° C. for 10 min. The mixture was allowed to cool to r.t. and partitioned between DCM and H.sub.2O (15 mL each). The organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (140 mg, 86%).

(1R*,2R*,3R)-Ethyl-2-phenyl-3-m-tolylcyclopropanecarboxylate (17b)

(58) To a stirred solution of 15b (200 mg, 0.58 mmol) in dioxane/water (9:1, 3 mL) was added trimethylboroxine (80 μl, 0.58 mmol), Pd(PPh.sub.3).sub.4 (67 mg, 0.058 mmol) and cesium carbonate (566 mg, 1.74 mmol). The mixture was degassed with nitrogen for 10 min and heated in the microwave at 115° C. for 10 min. The mixture was allowed to cool to r.t. and partitioned between DCM and H.sub.2O (15 mL each). The organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (120 mg, 73%).

(1R*,2R*,3R*)-Methyl-2-phenyl-3-p-tolylcyclopropanecarboxylate (17c)

(59) To a stirred solution of 15c (200 mg, 0.60 mmol) in dioxane/water (9:1, 3 mL) was added trimethylboroxine (80 μl, 0.60 mmol), Pd(PPh.sub.3).sub.4 (69 mg, 0.06 mmol) and cesium carbonate (585 mg, 1.80 mmol). The mixture was degassed with nitrogen for 10 min and heated in the microwave at 115° C. for 10 min. The mixture was allowed to cool to r.t. and partitioned between DCM and H.sub.2O (15 mL each). The organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (120 mg, 75%).

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-o-tolylcyclopropanecarboxamide (18a)

(60) Following method A from compound 17a. Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM), then passage through a PEAX cartridge (DCM/MeOH, 1:1) gave the title compound as a white solid (10 mg, 7%). LCMS (ES+) 266 (M−H)−, RT 9.54 min (Analytical method 2). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.54 (1H, s), 8.71 (1H, s), 7.36 (2H, d, J=7.5 Hz), 7.27 (2H, t, J=7.5 Hz), 7.21-7.10 (5H, m), 3.12 (1H, dd, J=7.2, 5.7 Hz), 2.76 (1H, dd, J=9.4, 7.3 Hz), 2.34 (3H, s), 2.07 (1H, dd, J=9.4, 5.6 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-m-tolylcyclopropanecarboxamide (18b)

(61) Following method A from compound 17b. Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the title compound as a white solid (67 mg, 56%). LCMS (ES+) 268 (M+H)+, RT 3.71 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.54 (1H, s), 8.68 (1H, s), 7.32 (2H, d, J=7.5 Hz), 7.25 (2H, t, J=7.4 Hz), 7.20-7.09 (5H, m), 3.05 (1H, dd, J=6.9, 5.4 Hz), 2.77 (1H, dd, J=9.6, 6.9 Hz), 2.28 (3H, s), 2.15 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-p-tolylcyclopropanecarboxamide (18c)

(62) Following method A from compound 17c. Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) followed by elution through PEAX cartridge (1:1, DCM:MeOH) gave the title compound as a white solid (21 mg, 17%). LCMS (ES+) 268 (M+H)+, RT 3.71 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.54 (1H, s), 8.68 (1H, s), 7.32 (2H, d, J=7.5 Hz), 7.25 (2H, t, J=7.4 Hz), 7.20-7.10 (5H, m), 3.04 (1H, dd, J=6.9, 5.4 Hz), 2.77 (1H, dd, J=9.6, 6.9 Hz), 2.28 (3H, s), 2.15 (1H, dd, J=9.6, 5.4 Hz).

Example 7

(63) ##STR00014##

(1R*,2R,3R)-Ethyl-2-(4-nitrophenyl)-3-phenylcyclopropanecarboxylate (19)

(64) A mixture of sulfonium salt 6a (1.00 g, 3.76 mmol) and ethyl-4-nitrocinnamate (553 mg, 2.51 mmol) in DCM (10 mL) was cooled to −78° C. LiHMDS (3.76 mL, 1 M solution in THF) was slowly added via syringe pump (1 mL/h). After complete addition, the mixture was warmed to r.t., stirred for 1 h and quenched with H.sub.2O (30 mL). The biphasic mixture was separated and the aqueous layer was re-extracted with DCM (30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a yellow oil (180 mg, 23%). LCMS (ES+) 312 (M+H).sup.+.

(1R*,2R*,3R)-Ethyl-2-(4-aminophenyl)-3-phenylcyclopropanecarboxylate (20)

(65) A solution of compound 19 (180 mg, 0.58 mmol) in MeOH (6 mL) was hydrogenated using a H-cube apparatus (Full H.sub.2 mode, 10% Pd/C cartridge, 1 mL/min, r.t.). The reaction mixture was concentrated to give a yellow oil (165 mg, 100%) which was used directly in the next step of the synthesis.

(1R*,2R*,3R*)-Ethyl-2-(4-(cyclopropanesulfonamido)phenyl)-3-phenylcyclopropanecarboxylate (21)

(66) To a stirred solution of compound 20 (165 mg, 0.59 mmol) in DCM (5 mL) was added cyclopropylsulfonyl chloride (248 mg, 1.76 mmol) and triethylamine (0.24 mL, 1.76 mmol). The mixture was stirred at r.t. for 16 h and washed with water (10 mL). The organic layers were collected by phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a pale yellow solid (175 mg, 77%). LCMS (ES+) 386 (M+H).sup.+.

(1R*,2R*,3R*)-2-(4-(cyclopropanesulfonamido)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (22)

(67) Following method A from compound 21 (175 mg, 0.45 mmol). The carboxylic acid was obtained as the major product. The mixture was acidified with aqueous 1M HCl and extracted into EtOAc (3×10 mL). The organic layers were combined, dried (MgSO.sub.4) and concentrated. The sample was then subjected to method B. Purification by preparative HPLC and passage through a PEAX cartridge (DCM/MeOH, 1:1) gave the title compound as a white solid (15 mg, 8%). LCMS (ES+) 373 (M+H)+, RT 8.20 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.55 (1H, s), 9.62 (1H, s), 8.68 (1H, s), 7.33-7.13 (9H, m), 3.05 (1H, dd, J=6.9, 5.4 Hz), 2.79 (1H, dd, J=9.5, 6.9 Hz), 2.60-2.53 (1H, qt, J=6.0 Hz), 2.15 (1H, dd, J=9.5, 5.3 Hz), 0.91 (4H, d, J=6.3 Hz).

Example 8

(68) ##STR00015##

(69) TABLE-US-00003 TABLE 1 R1 R2 Compound Ph 25a Ph 25b Ph 25c Ph 25d 0 Ph 25e 25f

(E)-Ethyl-3-cyclopentylacrylate (23a)

(70) Following method C from cyclopentanecarbaldehyde (2.00 g, 20.4 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 5:2 i-hex:DCM) gave the title compound as a colourless oil (2.00 g, 58%). LCMS (ES+) 259 (M+H).sup.+.

(E)-Ethyl-3-(1-methyl-1H-pyrazol-4-yl)acrylate (23b)

(71) Following method C from 1-methyl-1H-pyrazole-4-carbaldehyde (500 mg, 4.50 mmol). Purification by flash silica column chromatography (gradient elution i-hex to EtOAc) gave the title compound as a yellow oil (900 mg, 99%). LCMS (ES+) 181 (M+H).sup.+.

(E)-Ethyl-3-(pyrimidin-5-yl)acrylate (23c)

(72) Following method C from pyrimidine-5-carbaldehyde (2 g, 19.2 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a colourless oil (2.34 g, 68%, 3:1 trans:cis). LCMS (ES+) 179 (M+H).sup.+.

(E)-Ethyl-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylate (23d)

(73) Following method C from 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (2.00 g, 12.2 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a white solid (2.64 g, 93%). LCMS (ES+) 235 (M+H).sup.+.

(E)-Ethyl-3-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylate (23e)

(74) Following method C from 8-chloro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (700 mg, 3.53 mmol). The resulting yellow oil was used without further purification. LCMS (ES+) 269, 271 (M+H).sup.+.

(1S*,2R*,3R)-Ethyl-2-cyclopentyl-3-phenylcyclopropanecarboxylate (24a)

(75) A mixture of 6a (2.30 g, 8.92 mmol), compound 23a (1.00 g, 5.96 mmol) and 12-crown-4 (1.44 mL, 8.92 mmol) in DCM (20 mL) was cooled to −78° C. LiHMDS (8.92 mL, 1 M solution in THF) was slowly added via syringe pump (4 mL/h). After complete addition, the reaction mixture was warmed to r.t. and stirred for 16 h. The reaction mixture was quenched with H.sub.2O (30 mL). The biphasic mixture was separated and the organic layers washed with brine (2×30 mL), separated, dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (263 mg, 7%).

(1R*,2R*,3R*)-Ethyl-2-(1-methyl-1H-pyrazol-4-yl)-3-phenylcyclopropanecarboxylate (24b)

(76) Following method F from compound 23b (810 mg, 4.50 mmol) and 6a (1.94 mg, 7.50 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 75% EtOAc in i-hex) gave the title compound as a colourless oil (493 mg, 41%, 3:1 trans:cis). LCMS (ES+) 271 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-phenyl-3-(pyrimidin-5-yl)cyclopropanecarboxylate (24c)

(77) Following method F from 23c (1.00 g, 5.62 mmol) and 6a (2.18 g, 8.43 mmol). The addition was performed at −78° C. and allowed to stir at RT for 17 h. Purification by flash silica column chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a colourless oil (270 mg, 19%). LCMS (ES+) 269 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylcyclopropanecarboxylate (24d)

(78) Following method F from compound 23d (2.64 g, 11.3 mmol) and 6a (4.4 g, 16.9 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 7.5% EtOAc in i-hex) gave the title compound as a colourless oil (652 mg, 18%). LCMS (ES+) 325 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylcyclopropanecarboxylate (24e)

(79) Following method F from 23e (946 mg, 3.52 mmol) and 6a (1.37 mg, 5.28 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (484 mg, 38%, 4:1 trans:cis). LCMS (ES+) 359, 361 (M+H).sup.+.

(1S*,2R*,3R*)-Ethyl-2-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-fluorophenyl)-cyclopropanecarboxylate (24f)

(80) Following method F from 23e (860 mg, 3.20 mmol) and 6b (1.33 mg, 4.80 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (472 mg, 39%, 3:1 trans:cis). LCMS (ES+) 377 (M+H).sup.+ RT 3.48 min (Analytical method 1).

(1S*,2R*,3R)-2-Cyclopentyl-N-hydroxy-3-phenylcyclopropanecarboxamide (25a)

(81) Using method A from compound 24a (1.05 g, 4.06 mmol). Purification by flash silica column chromatography (gradient elution DCM to 4% MeOH in DCM) and preparative HPLC gave the title compound as a white solid (23 mg, 9%). LCMS (ES+) 246 (M+H)+, RT 3.18 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.57 (1H, s), 8.76 (1H, s), 7.35-7.27 (2H, m), 7.24-7.18 (3H, m), 1.88 (1H, t, J=5.0 Hz), 1.71-1.60 (1H, m), 1.58-1.47 (2H, m), 1.50-1.16 (8H, m).

(1R,2R,3R)—N-Hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-phenylcyclopropanecarboxamide (25b)

(82) Following method A from 24b (493 mg, 1.83 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and then preparative HPLC gave the racemic mixture as a white solid (235 mg, 50%). Preparative chiral HPLC gave the title compound (Chiralpak IC 30/70 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 10.3 min). LCMS (ES+) 258 (M+H)+, (ES−) 256 (M+H)−, RT 2.65 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.50 (1H, s), 8.63 (1H, s), 7.61 (1H, s), 7.34 (1H, s), 7.28-7.13 (5H, m), 3.78 (3H, s), 2.86 (1H, dd, J=6.9, 5.3 Hz), 2.63 (1H, dd, J=9.4, 6.9 Hz), 1.97 (1H, dd, J=9.4, 5.3 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(pyrimidin-5-yl)cyclopropanecarboxamide (25c)

(83) Using method A, from compound 24c (270 mg, 1.08 mmol). Purification by flash silica chromatography gradient elution DCM to 7% MeOH in DCM) and reversed phase HPLC gave the title compound as a yellow solid (9 mg, 5%). LCMS (ES+) 256 (M+H)+, RT 2.52 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.61 (1H, s), 9.06 (1H, s), 8.79 (2H, s), 8.72 (1H, s), 7.34 (2H, d, J=7.6 Hz), 7.27 (2H, t, J=7.5 Hz), 7.22-7.17 (1H, m), 3.15 (1H, dd, J=6.8, 5.5 Hz), 3.04 (1H, dd, J=9.6, 6.9 Hz), 2.37 (1H, dd, J=9.7, 5.5 Hz).

(1R,2R,3R)-2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide (25d)

(84) Following method A from compound 24d (652 mg, 2.01 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (420 mg, 67%). Preparative chiral HPLC gave the title compound (Chiralpak IC 30/70 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min, RT 8.1 min). LCMS (ES+) 312 (M+H)+, RT 8.59 min (Analytical method 5). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.57 (1H, s), 8.73 (1H, s), 7.35 (2H, d, J=7.59 Hz), 7.29 (2H, t, J=7.5 Hz), 7.24-7.17 (1H, m), 6.85 (1H, d, J=8.5 Hz), 6.80-6.74 (2H, m), 4.26 (4H, s), 3.02 (1H, dd, J=6.8, 5.4 Hz), 2.78 (1H, dd, J=9.6, 6.8 Hz), 2.14 (1H, dd, J=9.6, 5.4 Hz).

(1R,2R,3R)-2-(8-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide (25e)

(85) Following method A from 24e (484 mg, 1.35 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and then preparative HPLC gave the racemic product as a white solid (174 mg, 37%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 10.4 min). LCMS (ES+) 346, 348 (M+H)+, RT 3.57 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.50 (1H, s), 8.68 (1H, s), 7.31 (2H, d, J=7.6 Hz), 7.25 (2H, t, J=7.4 Hz), 7.21-7.13 (1H, m), 6.93 (1H, d, J=2.1 Hz), 6.77 (1H, d, J=2.1 Hz), 4.34-4.26 (4H, m), 3.00 (1H, dd, J=6.8, 5.4 Hz), 2.79 (1H, dd, J=9.6, 6.8 Hz), 2.14 (1H, dd, J=9.8, 5.4 Hz).

(1S,2R,3R)-2-(8-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2-fluorophenyl)-N-hydroxycyclopropanecarboxamide (25f)

(86) Following method A from 24f (472 mg, 1.25 mmol) to yield a white glass (480 mg). Purification by preparative HPLC gave the racemic product as a white glass (180 mg, 39%). Preparative chiral HPLC gave the title compound (Chiralpak IA 50/50 EtOH (0.1% formic acid)/Heptane, 1.0 mL/min). LCMS (ES+) 364 (M+H)+, RT 3.60 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.55 (1H, s), 8.72 (1H, s), 7.38 (1H, t, J=7.6 Hz), 7.28-7.20 (1H, m), 7.13-7.05 (2H, m), 6.95 (1H, d, J=2.1 Hz), 6.80 (1H, d, J=2.1 Hz), 4.36-4.24 (4H, m), 2.93 (1H, dd, J=6.9, 5.3 Hz), 2.72 (1H, dd, J=9.3, 6.9 Hz), 2.17 (1H, dd, J=9.4, 5.3 Hz).

Example 9

(87) ##STR00023##

(88) TABLE-US-00004 TABLE 2 R1 R2 Compound Ph 28a Ph 28b 28c 28d 0 Ph 28e Ph 28f Ph 28g

(E)-Ethyl 3-(pyridazin-4-yl)acrylate (26a)

(89) Following method E from 4-bromopyridazine (500 mg, 3.14 mmol). Purification by flash silica column chromatography (gradient elution i-hex to EtOAc) gave the title compound as a colourless oil (94 mg, 17%). LCMS (ES+) 179 (M+H).sup.+.

(E)-Ethyl-3-(2-cyclopropylpyridin-4-yl)acrylate (26b)

(90) Following method D from 4-bromo-2-(cyclopropyl)pyridine (1.00 g, 5.05 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a white solid (530 mg, 48%). LCMS (ES+) 218 (M+H).sup.+.

(E)-Ethyl-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acrylate (26c)

(91) Following method E from 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (2.00 g, 8.44 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 7.5% EtOAc in i-hex) gave the title compound as a white solid (1.62 g, 75%). LCMS (ES+) 257 (M+H).sup.+.

(E)-Ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)acrylate (26d)

(92) Following method D from 5-bromo-2-(trifluoromethyl)pyridine (1.0 g, 4.42 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a white solid (700 mg, 65%). LCMS (ES+) 246 (M+H).sup.+.

(E)-Ethyl-3-(2-(trifluoromethyl)pyridin-4-yl)acrylate (26e)

(93) Following method D from 4-bromo-2-(trifluoromethyl)pyridine (1.0 g, 4.42 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 15% EtOAc in i-hex) gave the title compound as a white solid (100 mg, 9%). LCMS (ES+) 246 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-phenyl-3-(pyridazin-4-yl)cyclopropanecarboxylate (27a)

(94) Following method F from 26a (94 mg, 0.53 mmol) and 6a. As the reaction was incomplete after 1 h, the reaction was cooled to −20° C. and additional amounts of sulfonium salt, 12-crown-4 and LiHMDS (0.5 eq each) were added. Purification by flash silica column chromatography (gradient elution i-hex to EtOAc) gave the title compound as a colourless oil (45 mg, 32%). LCMS (ES+) 269 (M+H).

(1R*,2R*,3R*)-Ethyl-2-(2-cyclopropylpyridin-4-yl)-3-phenylcyclopropanecarboxylate (27b)

(95) Following method F from compound 26b (530 mg, 2.44 mmol) and 6a. Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (330 mg, 44%, 5:4 trans:cis). LCMS (ES+) 308 (M+H).

(1S*,2R*,3R*)-Ethyl-2-(2-cyclopropylpyridin-4-yl)-3-(2-fluorophenyl)cyclopropanecarboxylate (27c)

(96) Following method F from 26b (130 mg, 0.60 mmol) and 6b (249 mg, 0.90 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (150 mg, 77%, 3:1 trans:cis). LCMS (ES+) 326 (M+H).

(1R*,2R*,3R*)-Ethyl-2-(2-cyclopropylpyridin-4-yl)-3-(4-fluorophenyl)cyclopropanecarboxylate (27d)

(97) Following method F from 26b (481 mg, 2.22 mmol) and 6c (921 mg, 3.32 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (510 mg, 71%, 4:1 trans:cis). LCMS (ES+) 326 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-phenylcyclopropanecarboxylate (27e)

(98) Following method F from compound 26c (1.62 g, 6.33 mmol) and 6a (2.46 g, 9.49 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (400 mg, 18%). LCMS (ES+) 347 (M+H).sup.+.

(1R*,2R*,3R)-Ethyl-2-phenyl-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylate (27f)

(99) Following method F from compound 26d (700 mg, 2.86 mmol) and 6a (1.11 g, 4.29 mmol). The reaction was incomplete after 2 h. The reaction was cooled to 00° C. and additional 1 equivalent of sulfonium salt, 12-crown-4 and LiHMDS were added and the mixture was stirred at r.t. for 10 min. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (720 mg, 2:1 trans:cis, 65%). LCMS (ES+) 322 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-phenyl-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopropanecarboxylate (27g)

(100) Following method F from compound 26e (100 mg, 0.41 mmol) and 6a (159 mg, 0.61 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (130 mg, 2:1 trans:cis, 100%). LCMS (ES+) 322 (M+H).

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(pyridazin-4-yl)cyclopropanecarboxamide (28a)

(101) Following method A, from 27a (45 mg, 0.17 mmol). Purification by flash silica column chromatography (gradient elution DCM to 4% MeOH in DCM) and reversed phase HPLC gave the title compound as a white solid (3 mg, 21%). LCMS (ES+) 256 (M+H).sup.+, RT 7.02 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.69 (1H, s), 9.34 (1H, s), 9.15 (1H, d, J=5.4 Hz), 8.81 (1H, s), 7.63-7.61 (1H, m), 7.40-7.30 (4H, m), 7.27-7.24 (1H, m), 3.22 (1H, dd, J=5.2, 6.4 Hz), 3.13 (1H, dd, J=6.4, 9.5 Hz), 2.45 (1H, dd, J=9.5, 5.3 Hz).

(1R,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide (28b)

(102) Following method A from compound 27b (330 mg, 1.07 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (60 mg, 19%). Preparative chiral HPLC gave the title compound (Chiralpak IC 30/70 IPA/MeOH (50/50/0.1 formic acid)/heptane, 1.0 mL/min, RT 9.6 min). LCMS (ES+) 295 (M+H).sup.+, (ES−) 293 (M−H).sup.−, RT 2.12 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.65 (1H, s), 8.78 (1H, s), 8.32 (1H, d, J=5.1 Hz), 7.37 (2H, d, J=7.6 Hz), 7.34-7.28 (2H, m), 7.25 (2H, d, J=8.2 Hz), 7.07 (1H, dd, J=5.2, 1.7 Hz), 3.10 (1H, dd, J=6.7, 5.6 Hz), 2.99 (1H, dd, J=9.7, 6.7 Hz), 2.34 (1H, dd, J=9.7, 5.6 Hz), 2.12-2.07 (1H, m), 0.98-0.93 (4H, m).

(1S,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)-3-(2-fluorophenyl)-N-hydroxycyclopropanecarboxamide (28c)

(103) Following method A from 27c (150 mg, 0.46 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as an off-white solid (50 mg, 35%). Preparative chiral HPLC gave the title compound (Chiralpak IC 40/60 EtOH (0.1 formic acid)/heptanes, 1.0 mL/min, RT 9.3 min). LCMS (ES+) 313 (M+H)+, RT 2.18 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.68 (1H, s), 8.81 (1H, s), 8.34 (1H, d, J=5.1 Hz), 7.44 (1H, t, J=7.7 Hz), 7.34-7.27 (2H, m), 7.18-7.08 (3H, m), 3.04 (1H, dd, J=6.6, 5.0 Hz), 2.95 (1H, dd, J=9.2, 6.9 Hz), 2.36 (1H, dd, J=9.4, 5.3 Hz), 2.14-2.09 (1H, m), 0.99-0.92 (4H, m).

(1R,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)-3-(4-fluorophenyl)-N-hydroxycyclopropanecarboxamide (28d)

(104) Following method A from 27d (510 mg, 1.57 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (145 mg, 30%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 13.7 min). LCMS (ES+) 313 (M+H)+, RT 2.87 min (Analytical method 4). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.65 (1H, br s), 8.82 (1H, br s), 8.33 (1H, d, J=5.1 Hz), 7.40 (2H, dd, J=8.4, 5.6 Hz), 7.25 (1H, s), 7.14 (2H, t, J=8.8 Hz), 7.07 (1H, dd, J=5.2, 1.7 Hz), 3.07 (1H, dd, J=6.8, 5.4 Hz), 2.99 (1H, dd, J=9.6, 6.8 Hz), 2.32 (1H, dd, J=9.6, 5.4 Hz), 2.14-2.06 (1H, m), 0.99-0.92 (4H, m).

(1R,2R,3R)-2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide (28e)

(105) Following method A from compound 27e (400 mg, 1.17 mmol). Purification by flash silica column chromatography (gradient elution DCM to 2% MeOH in DCM) gave the racemic mixture as a white solid (300 mg, 78%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.5 mL/min, RT 6.3 min). LCMS (ES+) 334 (M+H)+, RT 3.89 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.63 (1H, s), 8.76 (1H, s), 7.44-7.33 (4H, m), 7.31 (2H, t, J=7.44 Hz), 7.25-7.18 (2H, m), 3.21 (1H, dd, J=6.8, 5.4 Hz), 2.92 (1H, dd, J=9.6, 6.8 Hz), 2.25 (1H, dd, J=9.6, 5.4 Hz).

(1R,2R,3R)—N-Hydroxy-2-phenyl-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxamide (28f)

(106) Following method A from compound 27f (720 mg, 2.24 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) followed by preparative HPLC, gave the racemic mixture as a white solid (83 mg, 11%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1 formic acid)/heptane, 1.0 mL/min, RT 14.5 min). LCMS (ES+) 323 (M+H)+, RT 8.60 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.70 (1H, s), 8.84 (1H, s), 8.82 (1H, s), 8.02-7.97 (1H, m), 7.91 (1H, d, J=8.2 Hz), 7.40 (2H, d, J=7.6 Hz), 7.33 (2H, t, J=7.5 Hz), 7.28-7.22 (1H, m), 3.32 (1H, dd, J=6.7 and 5.6 Hz), 3.09 (1H, dd, J=9.7, 6.8 Hz), 2.43 (1H, dd, J=9.7 and 5.6 Hz).

(1R,2R,3R)—N-Hydroxy-2-phenyl-3-(2-(trifluoromethyl)pyridin-4-yl)cyclopropanecarboxamide (28g)

(107) Following method A from compound 27g (130 mg, 0.41 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) followed by preparative HPLC, gave the racemic mixture as a white solid (90 mg, 68%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1 formic acid)/heptane, 1.0 mL/min, RT 10.3 min). LCMS (ES+) 323 (M+H)+, RT 3.50 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.66 (1H, s), 8.81 (1H, s), 8.71 (1H, d, J=5.0 Hz), 7.92 (1H, s), 7.70 (1H, d, J=5.1 Hz), 7.40 (2H, d, J=7.5 Hz), 7.32 (2H, t, J=7.5 Hz), 7.27-7.22 (1H, m), 3.35 (1H, dd, J=6.6, 5.4 Hz), 3.16 (1H, dd, J=9.5, 6.6 Hz), 2.48 (1H, dd, J=9.5, 5.4 Hz).

Example 10

(108) ##STR00033##

4-Bromo-2-(hydroxymethyl)-N-(2,2,2-trifluoroethyl)benzamide (29)

(109) To a stirred suspension of aluminium trichloride (5.30 g, 39.8 mmol) in DCE (50 mL) at 000° C. was added 2,2,2-trifluoroethylamine (5 g, 50.5 mmol). This was stirred for 4 h before addition of 5-bromophthalide (5.30 g, 39.8 mmol) in one portion, and then heated to 80° C. for 17 h. The mixture was quenched with iced water (100 mL) and stirred for 30 min. DCM (50 mL) was added and the mixture was filtered through silica. The organic layers were washed with H.sub.2O (3×100 mL) and the aqueous layers were back-extracted into DCM (50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated to give an off-white solid. The crude mixture (2.2 g) containing ˜50% residual 5-bromophthalide was progressed to the next step. LCMS (ES+) 312, 314 (M+H).sup.+.

5-Bromo-2-(2,2,2-trifluoroethyl)isoindolin-1-one (30)

(110) To a stirred solution of 29 (2.2 g, 7.05 mmol) and NMP (13 mL) in anhydrous THF (40 mL) at 5° C. was added i-PrMgCl.LiCl (10.8 mL, 14.1 mmol) keeping the temperature below 10° C. After addition (30 min), the reaction was stirred at 5° C. for 1 h and at r.t. for 1 h. The reaction was then cooled to 5° C. and N,N,N′,N′-tetramethyphosphorodiamidic chloride (1.57 mL, 10.6 mmol) was added dropwise. The reaction mixture was heated at reflux for 2 days. The mixture was cooled, quenched with H.sub.2O (50 mL), acidified with aqueous 1 M HCl and extracted into EtOAc (3×50 mL). The organic layers were dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) gave the title compound as a white solid (3 g). The crude material was used in the next step. LCMS (ES+) 294, 296 (M+H).sup.+.

(E)-Ethyl 3-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)acrylate (31)

(111) A stirred mixture of 30 (2.96 g, 10.0 mmol), ethyl acrylate (1.62 mL, 15.0 mmol), palladium acetate (224 mg, 1.00 mmol), P(o-tol).sub.3 (608 mg, 2.00 mmol) and triethylamine (2.78 mL, 20.0 mmol) in MeCN (50 mL) was degassed under nitrogen for 15 min and heated to 80° C. for 3 h. An additional amount of palladium acetate (224 mg, 1.00 mmol), P(o-tol).sub.3 (608 mg, 2.00 mmol) and ethyl acrylate (1.00 mL, 9.26 mmol) were added and stirred at 80° C. for a further 2 h. The reaction mixture was cooled and the MeCN was removed in vacuo. The residue was partitioned between DCM and H.sub.2O and the organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 75% EtOAc in i-hex) gave the title compound as a white solid (1.7 g). The crude material was used in the next step. LCMS (ES+) 314 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-3-phenylcyclopropanecarboxylate (32)

(112) Following method F from 31 (1.70 g, 5.40 mmol) and 6a (2.10 g, 8.10 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 15% EtOAc in i-hex) gave the title compound as a white solid (340 mg). LCMS (ES+) 404 (M+H).sup.+.

(1R,2R,3R)—N-Hydroxy-2-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-3-phenylcyclopropanecarboxamide (33)

(113) Following method A from 32 (340 mg, 0.84 mmol). Purification by flash silica column chromatography (gradient elution DCM to 6% MeOH in DCM) and then preparative HPLC gave the racemic mixture as a white solid. Preparative chiral HPLC gave the title compound (Chiralpak IC 30/70 EtOH (0.1 formic acid)/heptanes, 1.0 mL/min, RT 12.1 min). LCMS (ES+) 391 (M+H)+, RT 3.47 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.61 (1H, s), 8.72 (1H, s), 7.70 (1H, d, J=7.9 Hz), 7.56 (1H, s), 7.45 (1H, d, J=8.0 Hz), 7.35 (2H, d, J=7.6 Hz), 7.27 (2H, t, J=7.5 Hz), 7.19 (1H, t, J=7.2 Hz), 4.60 (2H, s), 4.39 (2H, q, J=9.7 Hz), 3.24 (1H, dd, J=6.8, 5.4 Hz), 2.93 (1H, dd, J=9.7, 6.8 Hz), 2.30 (1H, dd, J=9.7, 5.4 Hz).

Example 11

(114) ##STR00034##

(E)-Ethyl-3-(3-bromo-4-nitrophenyl)acrylate (34)

(115) Following method C from 3-bromo-4-nitrobenzaldehyde (5 g, 21.7 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound (2.4 g, 37%). LCMS (ES+) 300, 302 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(3-bromo-4-nitrophenyl)-3-phenylcyclopropanecarboxylate (35)

(116) Following method F from compound 34 (2.35 g, 7.8 mmol) and 6a (4.04 g, 15.6 mmol). The reaction was incomplete after stirring at r.t. for 72 h. The reaction was cooled to −20° C. and an additional 1 equivalent of sulfonium salt, 12-crown-4 and LiHMDS were added and the mixture was stirred at r.t. for 3 h. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a yellow oil (630 mg, 21%). LCMS (ES+) 390, 391 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(4-amino-3-bromophenyl)-3-phenylcyclopropanecarboxylate (36)

(117) To a solution of compound 35 (580 mg, 1.51 mmol) in ethanol (12 mL) and acetic acid (12 mL) was added iron powder (824 mg, 15.1 mmol) and the reaction mixture was stirred at r.t. for 3 h. The reaction mixture was filtered through Celite and concentrated. The residue was partitioned between 1N HCl and DCM-MeOH. The aqueous layer was extracted several times with DCM. The combined organic layers were concentrated to afford the title compound (470 mg, 88%). LCMS (ES+) 360, 362 (M+H).sup.+

(1R*,2R*,3R*)-Ethyl-2-(3-bromo-4-isobutyramidophenyl)-3-phenylcyclopropanecarboxylate (37)

(118) To a solution of compound 36 (470 mg, 1.31 mmol) in DCM (10 mL) was added DIPEA (0.23 mL, 1.31 mmol) and isobutyryl chloride (140 mg, 1.31 mmol). The reaction mixture was stirred for 2 h, water was added, the organic phase isolated by phase separator and concentrated to afford the title compound (488 mg, 87%). LCMS (ES+) 430, 432 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(2-isopropylbenzo[d]oxazol-6-yl)-3-phenylcyclopropanecarboxylate (38)

(119) A mixture of compound 37 (488 mg, 1.14 mmol), K.sub.2CO.sub.3 (314 mg, 2.28 mmol), pyridine (5 mL) in DMF (15 mL) was degassed for 30 min. Then copper(I)bromide (326 mg, 2.28 mmol) was added and the reaction mixture was heated under microwave irradiation at 140° C. for 4 h. The reaction mixture was diluted with DCM and washed several times with water and brine. The organic layers were combined, dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound (350 mg, 88%) as a yellow oil. LCMS (ES+) 350, 352 (M+H).sup.+.

(1R,2R,3R)—N-hydroxy-2-(2-isopropylbenzo[d]oxazol-6-yl)-3-phenylcyclopropanecarboxamide (39)

(120) Following method A from compound 38 (350 mg, 1.00 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a tan solid (126 mg, 36%). Preparative chiral HPLC gave the title compound (Chiralpak IC, 20/80 EtOH (0.1% formic)/heptane, 1.0 mL/min, RT 15.7 min). LCMS (ES+) 337 (M+H)+, RT 3.59 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.63 (1H, s), 8.76 (1H, s), 7.66-7.64 (2H, m), 7.39 (2H, d, J=7.60 Hz), 7.35-7.29 (3H, m), 7.26-7.20 (1H, m), 3.36-3.23 (2H, m), 2.96 (1H, dd, J=9.6, 6.9 Hz), 2.30 (1H, dd, J=9.6, 5.4 Hz), 1.42 (6H, d, J=6.9 Hz).

Example 12

(121) ##STR00035##

(1R*,2R*,3R*)-Ethyl-2-(3-(oxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxylate (40a)

(122) A stirred solution of 15b (500 mg, 1.45 mmol), oxazole (0.19 mL, 2.90 mmol), Pd(OAc).sub.2 (16 mg, 0.07 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (67 mg, 0.14 mmol), K.sub.2CO.sub.3 (600 mg, 4.35 mmol), pivalic acid (59 mg, 0.58 mmol) in DMA (8 mL) was degassed with nitrogen for 15 min before heating at 110° C. for 16 h. The mixture was cooled and diluted with DCM (20 mL) and washed with H.sub.2O (3×30 mL). The organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (494 mg, 100%). LCMS (ES+) 334 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl 2-(4-(oxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxylate (40b)

(123) A stirred solution of 15c (482 mg, 1.46 mmol), oxazole (0.19 mL, 2.42 mmol), Pd(OAc).sub.2 (16 mg, 0.07 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (70 mg, 0.146 mmol), K.sub.2CO.sub.3 (604 mg, 4.38 mmol), pivalic acid (59 mg, 0.58 mmol) in DMA (7.5 mL) was degassed with nitrogen for 15 min before heating at 110° C. for 16 h. The mixture was cooled and diluted with DCM (20 mL) and washed with H.sub.2O (3×30 mL). The organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (300 mg, 65%). LCMS (ES+) 320 (M+H).sup.+.

(1R,2R,3R)—N-Hydroxy-2-(3-(oxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxamide (41a)

(124) Following method A from compound 40a (482 mg, 1.45 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (233 mg, 50%). Preparative chiral HPLC gave the title compound (Chiralpak IC 40/60 EtOH (0.1 formic acid)/heptane, 1.0 mL/min, RT 7.7 min). LCMS (ES+) 321 (M+H)+, RT 2.82 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.62 (1H, s), 8.76 (1H, s), 8.52 (1H, s), 7.80 (1H, s), 7.70 (1H, s), 7.64 (1H, d, J=7.8 Hz), 7.49 (1H, t, J=7.7 Hz), 7.42-7.28 (5H, m), 7.24 (1H, t, J=7.2 Hz), 3.22 (1H, dd, J=6.9, 5.4 Hz), 2.98 (1H, dd, J=9.6, 6.9 Hz), 2.32 (1H, dd, J=9.6, 5.4 Hz).

(1R,2R,3R)—N-Hydroxy-2-(4-(oxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxamide (41b)

(125) Following method A from compound 40b. Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (88 mg, 29%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 EtOH (0.1 formic acid)/heptane, 1.0 mL/min, RT 18.7 min). LCMS (ES+) 321 (M+H)+, RT 2.77 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.63 (1H, s), 8.76 (1H, s), 8.49 (1H, s), 7.76-7.72 (3H, m), 7.47-7.36 (4H, m), 7.35-7.29 (2H, m), 7.25-7.20 (1H, m), 3.18 (1H, dd, J=6.8, 5.4 Hz), 2.94 (1H, dd, J=9.6, 6.8 Hz), 2.30 (1H, dd, J=9.6, 5.4 Hz).

Example 13

(126) ##STR00036##

(1R*,2R*,3R*)-2-(4-(1H-imidazol-1-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (42)

(127) A stirred solution of 15c (100 mg, 0.30 mmol), CuCl (3 mg, 0.03 mmol) and K.sub.2CO.sub.3 (41 mg, 0.30 mmol) in NMP (0.1 mL) was degassed with nitrogen before addition of acetylacetone (7 μl, 0.075 mmol) and imidazole (26 mg, 0.39 mmol). The mixture was stirred at 130° C. for 17 h, cooled to r.t., diluted with DCM and washed with 1 M NaHCO.sub.3 (2×20 mL). The organic layers were passed through a phase separator and concentrated (150 mg). The crude material was dissolved in THF:MeOH (1:1, 3 mL) and hydroxylamine (0.1 mL, 50% aqueous solution, 1.51 mmol) and potassium hydroxide (67 mg, 1.20 mmol) were added. The mixture was stirred at r.t. for 2 h., neutralized with 1 M HCl and extracted into EtOAc. The organic layers were concentrated and the residue re-dissolved in pyridine (1 mL). To this solution was added hydroxylamine hydrochloride (20 mg, 0.29 mmol), BOP (87 mg, 0.20 mmol) and triethylamine (82 μl, 0.59 mmol). The mixture was stirred at r.t. for 2 h, concentrated and partitioned between DCM and H.sub.2O. The organic layers were isolated by phase separator and concentrated. Purification by preparative HPLC gave the racemic mixture as a white solid (10 mg, 11% over 3 steps). LCMS (ES+) 320 (M+H)+, RT 2.24 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.58 (1H, s), 8.71 (1H, s), 8.30 (1H, s), 7.77 (1H, s), 7.62 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.35 (2H, d, J=7.6 Hz), 7.31-7.24 (2H, m), 7.22-7.16 (2H, m), 3.17 (1H, dd, J=6.8, 5.4 Hz), 2.89 (1H, dd, J=9.6, 6.9 Hz), 2.24 (1H, dd, J=9.5, 5.3 Hz).

Example 14

(128) ##STR00037##

5-(4-Bromophenyl)-2-cyclopropyloxazole (43)

(129) Triflic acid (18.6 mL, 0.113 mol) was added dropwise to a solution of thallium acetate (14.37 g, 0.037 mol) in cyclopropylnitrile (200 mL) at r.t. under nitrogen. The solution was stirred for 15 min before a solution of 4-bromoacetophenone in cyclopropylnitrile (120 mL) was added and the solution was heated to 90° C. for 2 h. The reaction mixture was concentrated and the red residue was taken up in DCM (500 mL), washed with saturated NaHCO.sub.3 and water. The organic layers were separated, dried (Mg.sub.2SO.sub.4), filtered and concentrated to give a dark red gum. Purification by flash silica column chromatography (gradient elution i-hex to 40% EtOAc in i-hex) gave the title compound as a pale yellow solid (3.97 g, 60%). LCMS (ES+) 264, 266 (M+H).sup.+.

(E)-Ethyl-3-(4-(2-cyclopropyloxazol-5-yl)phenyl)acrylate (44)

(130) Compound 43 (3.97 g, 15 mmol), ethyl acrylate (2.1 mL, 19.5 mmol), Pd(OAc).sub.2 (337 mg, 1.5 mmol), tri-ortho-tolylphoshine (915 mg, 3 mmol), triethylamine (4.2 mL, 30 mmol) in MeCN (55 mL) were degassed with nitrogen for 15 min before heating the mixture to 80° C. for 18 h. The reaction mixture was concentrated and the brown residue was taken up in DCM (150 mL), washed with water, separated, dried (Mg.sub.2SO.sub.4), filtered and concentrated to give a brown gum. Purification by flash silica column chromatography (gradient elution i-hex to EtOAc) gave the title compound as a pale yellow solid (3.44 g, 80%). LCMS (ES+) 284 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(4-(2-cyclopropyloxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxylate (45)

(131) Following method F from compound 44 (360 mg, 1.27 mmol) and 6a (494 mg, 1.91 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (300 mg, 7:2, trans:cis, 63%). LCMS (ES+) 374 (M+H).sup.+.

(1R,2R,3R)-2-(4-(2-Cyclopropyloxazol-5-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (46)

(132) Following method A from compound 45 (300 mg, 0.80 mmol). Purification by flash silica column chromatography (gradient elution DCM to 3% MeOH in DCM) gave the racemic mixture as a white solid (300 mg, 78%). Preparative chiral HPLC gave the title compound (Chiralpak IC 30/70 EtOH (0.1 formic acid)/heptane, 1.0 mL/min, RT 19.8 min). LCMS (ES+) 361 (M+H)+, (ES−) 359 (M−H)−, RT 3.67 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.62 (1H, s), 8.76 (1H, s), 7.65 (2H, d, J=8.2 Hz), 7.52 (1H, s), 7.42-7.35 (4H, m), 7.31 (2H, t, J=7.5 Hz), 7.23 (1H, t, J=7.2 Hz), 3.17 (1H, dd, J=6.9, 5.4 Hz), 2.92 (1H, dd, J=9.7, 6.9 Hz), 2.28 (1H, dd, J=9.6, 5.4 Hz), 2.23-2.17 (1H, m), 1.15-1.08 (2H, m), 1.09-1.03 (2H, m).

Example 15

(133) ##STR00038##

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(2-phenyloxazol-5-yl)phenyl)cyclopropanecarboxylate (47)

(134) Compound 40b (75 mg, 0.23 mmol), pivalic acid (14 mg, 0.14 mmol), potassium tert-butoxide (78 mg, 0.69 mmol) and RuPhos (16 mg, 0.034 mmol) were dissolved in dry toluene (5 mL) and the reaction flask was evacuated and back-filled with nitrogen three times. Pd(OAc).sub.2 (4 mg, 0.017 mmol) and bromobenzene (54 mg, 0.34 mmol) were then added and the mixture was heated to 110° C. overnight. The reaction mixture was cooled and treated with 0.1 M HCl (5 mL) and extracted with Et.sub.2O (3×10 mL). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a colourless oil (22 mg, 26%). LCMS (ES+) 396 (M+H).sup.+.

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(4-(2-phenyloxazol-5-yl)phenyl)cyclopropanecarboxamide (48)

(135) Following method A from compound 47 (22 mg, 0.06 mmol). Purification by preparative HPLC gave the title compound as a white solid (16 mg, 70%). LCMS (ES+) 397 (M+H)+, RT 4.09 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.58 (1H, s), 8.71 (1H, s), 8.12-8.08 (2H, m), 7.81 (3H, d, J=8.2 Hz), 7.62-7.54 (3H, m), 7.42 (2H, d, J=8.0 Hz), 7.36 (2H, d, J=7.6 Hz), 7.31-7.23 (2H, m), 7.22-7.15 (1H, m), 3.17 (1H, dd, J=6.8, 5.3 Hz), 2.91 (1H, dd, J=9.6, 6.8 Hz), 2.27 (1H, dd, J=9.6, 5.3 Hz).

Example 16

(136) ##STR00039##

(137) TABLE-US-00005 TABLE 3 3 or 4 R2 Substitution Compound 0 4 50a 3 50b 4 50c 4 50d 4 50e 4 50f 4 50g 4 50h 4 50i 4 50j 0 4 50k 4 50l

(1R*,2R*,3R*)-Methyl 2-(4-(5-fluoropyrimidin-2-yl)phenyl)-3-phenylcyclopropanecarboxylate (49a)

(138) Following method G from the crude boronate derived from 15c (250 mg) and 2-chloro-5-fluoropyrimidine (91 mg, 0.69 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (240 mg, 100%). LCMS (ES+) 349 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(3-(5-fluoropyrimidin-2-yl)phenyl)-3-phenylcyclopropanecarboxylate (49b)

(139) Following method G from the crude boronate derived from 15b (300 mg) and 2-chloro-5-fluoropyrimidine (107 mg, 0.81 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (140 mg, 50%). LCMS (ES+) 363 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4-(5-cyclopropylpyrimidin-2-yl)phenyl)-3-phenylcyclopropanecarboxylate (49c)

(140) Following method G from the crude boronate derived from 15c (250 mg) and 2-bromo-5-cyclopropylpyrimidine (137 mg, 0.69 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (240 mg, 98%). LCMS (ES+) 371 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(4-(trifluoromethyl)pyrimidin-2-yl)phenyl)cyclopropanecarboxylate (49d)

(141) Following method G from the crude boronate derived from 15c (250 mg) and 2-chloro-4-trifluoromethylpyrimidine (126 mg, 0.69 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (220 mg, 84%). LCMS (ES+) 399 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)cyclopropanecarboxylate (49e)

(142) Following method G from the crude boronate derived from 15c (480 mg) and 2-chloro-5-trifluoromethylpyrimidine (243 mg, 1.33 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) gave the title compound as a white solid (180 mg, 36%). LCMS (ES+) 399 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(pyridazin-3-yl)phenyl)cyclopropanecarboxamide (49f)

(143) Following method G from the crude boronate derived from 15c (400 mg), and 3-bromopyridazine (160 mg, 1.00 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (220 mg, 84%). LCMS (ES+) 331 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(pyridazin-4-yl)phenyl)cyclopropanecarboxamide (49g)

(144) Following method G from the crude boronate derived from 15c (400 mg), and 4-bromopyridazine (160 mg, 1.00 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a pale yellow solid (210 mg, 61%). LCMS (ES+) 331 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(pyrimidin-2-yl)phenyl)cyclopropanecarboxylate (49h)

(145) Following method G from the crude boronate derived from 15c (274 mg), and 2-chloropyrimidine (87 mg, 0.76 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a pale yellow oil (110 mg, 46%). LCMS (ES+) 331 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(pyrimidin-5-yl)phenyl)cyclopropanecarboxylate (49i)

(146) To a stirred solution of 15c (130 mg, 0.39 mmol) in MeOH:DME (1:5, 5 mL), was added Pd(PPh.sub.3).sub.4 (45 mg, 0.039 mmol), cesium fluoride (119 mg, 0.78 mmol) and 5-pyrimidine boronic acid (58 mg, 0.47 mmol). The mixture was degassed with nitrogen for 15 min before heating in the microwave at 120° C. for 1 h. The reaction mixture was diluted with H.sub.2O (10 mL) and extracted into DCM (50 mL). The organic layers were dried over MgSO.sub.4, filtered and concentrated. Purification by column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a colourless oil (120 mg, 93%). LCMS (ES+) 331 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4-(5-chloropyrimidin-2-yl)phenyl)-3-phenylcyclopropanecarboxylate (49j)

(147) Following method G from the crude boronate derived from 15c (1.5 mmol), and 2,5-dichloropyrimidine (298 mg, 2.00 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a pale yellow oil (305 mg, 56%). LCMS (ES+) 365 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4-(5-methylpyrim idin-2-yl)phenyl)-3-phenylcyclopropanecarboxylate (49k)

(148) Following method G from the crude boronate derived from 15c (250 mg), and 2-chloro-5-methylpyrimidine (89 mg, 0.69 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a pale yellow oil (180 mg, 79%). LCMS (ES+) 345 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4-(5-methyl-1H-imidazol-2-yl)phenyl)-3-phenylcyclopropanecarboxylate (49l)

(149) Following method G from crude boronate derived from 15c (1.5 mmol) and 2-bromo-4-methylimidazole (242 mg, 1.5 mmol). The mixture was stirred at 100° C. for 48 h, diluted with H.sub.2O (20 mL) and extracted into DCM (50 mL). The layers were passed through a phase separator and concentrated. Purification Following flash silica column chromatography (gradient elution DCM/MeOH 0% to 10%) gave the ester intermediate as a yellow oil (285 mg). The crude material was used in the next step. LCMS (ES+) 335 (M+H).sup.+.

(1R*,2R*,3R*)-2-(4-(5-Fluoropyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (50a)

(150) Following method A from compound 49a (220 mg, 0.63 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the title compound as a white solid (81 mg, 37%). LCMS (ES+) 350 (M+H)+, RT 3.13 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.58 (1H, s), 8.97 (2H, d, J=0.8 Hz), 8.70 (1H, s), 8.30 (2H, d, J=8.2 Hz), 7.44 (2H, d, J=8.2 Hz), 7.36 (2H, d, J=7.6 Hz), 7.27 (2H, t, J=7.5 Hz), 7.20 (1H, d, J=7.2 Hz), 3.18 (1H, dd, J=6.7, 5.6 Hz), 2.93 (1H, dd, J=9.6, 6.7 Hz), 2.30 (1H, dd, J=9.6, 5.4 Hz)

(1R*,2R*,3R)-2-(3-(5-Fluoropyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (50b)

(151) Following method A from compound 49b (140 mg, 0.39 mmol). Purification by flash silica column chromatography (gradient elution DCM to 7% MeOH in DCM) and preparative HPLC gave the title compound as a racemic mixture (12 mg, 9%). LCMS (ES+) 350 (M+H)+, RT 3.61 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.59 (1H, s), 9.01 (2H, s), 8.71 (1H, s), 8.20 (2H, t, J=4.0 Hz), 7.51-7.48 (2H, m), 7.37 (2H, d, J=7.6 Hz), 7.29-7.24 (2H, m), 7.20 (1H, d, J=7.3 Hz), 3.22 (1H, dd, J=6.8, 5.5 Hz), 2.85 (1H, dd, J=9.6, 6.8 Hz), 2.32 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R*)-2-(4-(5-Cyclopropylpyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (50c)

(152) Following method A from compound 49c (240 mg, 0.65 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the title compound as a white solid (155 mg, 64%). LCMS (ES+) 372 (M+H)+, RT 3.89 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.58 (1H, s), 8.70 (1H, s), 8.64 (1H, d, J=5.2 Hz), 8.30 (2H, d, J=8.2 Hz), 7.40 (2H, d, J=8.2 Hz), 7.38-7.29 (3H, m), 7.27 (2H, t, J=7.5 Hz), 7.22-7.15 (1H, m), 3.17 (1H, dd, J=6.8, 5.4 Hz), 2.90 (1H, dd, J=9.6, 6.9 Hz), 2.28 (1H, dd, J=9.6, 5.4 Hz), 2.21-2.13 (1H, m), 1.19-1.09 (4H, m).

(1R*,2R*,3R*)-2-(4-(4-Trifluoromethylpyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (50d)

(153) Following method A from compound 49d (220 mg, 0.55 mmol). The carboxylic acid was obtained as the major product. The reaction mixture was acidified with aqueous 1M HCl and extracted into EtOAc (3×10 mL). The organic layers were combined, dried (MgSO.sub.4), filtered and concentrated. The compound was then subjected to method B. Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the title compound as a white solid (77 mg, 37%). LCMS (ES+) 400 (M+H)+, 398 (M−H)−, RT 13.26 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.60 (1H, s), 9.26 (1H, d, J=5.0 Hz), 8.71 (1H, s), 8.38 (2H, d, J=8.2 Hz), 7.93 (1H, d, J=5.0 Hz), 7.50 (2H, d, J=8.2 Hz), 7.36 (2H, d, J=7.6 Hz), 7.28 (2H, t, J=7.5 Hz), 7.22-7.15 (1H, m), 3.21 (1H, dd, J=6.8, 5.4 Hz), 2.94 (1H, dd, J=9.7, 6.9 Hz), 2.32 (1H, dd, J=9.7, 5.3 Hz).

(1R,2R,3R)-2-(4-(5-Trifluoromethylpyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (50e)

(154) Following method A from compound 49e (180 mg, 0.45 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (99 mg, 55%). Preparative chiral HPLC gave the title compound (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 16.2 min). LCMS (ES+) 400 (M+H)+, RT 3.96 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.66 (1H, s), 9.39 (2H, s), 8.79 (1H, s), 8.47 (2H, d, J=8.2 Hz), 7.55 (2H, d, J=8.2 Hz), 7.41 (2H, d, J=7.6 Hz), 7.33 (2H, t, J=7.5 Hz), 7.24 (1H, t, J=7.2 Hz), 3.26 (1H, dd, J=6.8, 5.3 Hz), 3.00 (1H, dd, J=9.6, 6.8 Hz), 2.38 (1H, dd, J=9.6, 5.3 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(4-(pyridazin-3-yl)phenyl)cyclopropanecarboxamide (50f)

(155) Following method A from compound 49f (68 mg, 0.21 mmol). Purification using an Isolute anion exchange SPE (elution DCM-MeOH, 1:1) gave the racemic mixture as a white solid (49 mg, 70%). LCMS (ES+) 332 (M+H)+, RT 2.95 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.59 (1H, s), 9.20 (1H, dd, J=4.8, 1.5 Hz), 8.71 (1H, s), 8.23 (1H, dd, J=8.6, 1.5 Hz), 8.14 (2H, d, J=8.1 Hz), 7.78 (1H, dd, J=8.6, 4.9 Hz), 7.48 (2H, d, J=8.1 Hz), 7.37 (2H, d, J=7.5 Hz), 7.32-7.24 (2H, m), 7.22-7.16 (1H, m), 3.19 (1H, dd, J=6.8, 5.4 Hz), 2.93 (1H, dd, J=9.6, 6.8 Hz), 2.31 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(4-(pyridazin-4-yl)phenyl)cyclopropanecarboxamide (50g)

(156) Following method A from compound 49g (190 mg, 0.58 mmol). Purification by flash silica column chromatography (gradient elution DCM to 10% MeOH in DCM) gave the racemic mixture as an off-white solid (75 mg, 39%). LCMS (ES+) 332 (M+H)+, RT 2.77 min (Analytical method 4). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.59 (1H, s), 9.66 (1H, dd, J=2.5, 1.2 Hz), 9.26 (1H, dd, J=5.4, 1.23 Hz), 8.71 (1H, d, J=1.7 Hz), 8.02 (1H, dd, J=5.5, 2.5 Hz), 7.92 (2H, d, J=8.1 Hz), 7.48 (2H, d, J=8.1 Hz), 7.36 (2H, d, J=7.6 Hz), 7.31-7.23 (2H, m), 7.22-7.16 (1H, m), 3.22-3.16 (1H, m), 2.93 (1H, dd, J=9.6, 6.8 Hz), 2.29 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R)—N-Hydroxy-2-phenyl-3-(4-(pyrimidin-2-yl)phenyl)cyclopropanecarboxamide (50h)

(157) Following method A from compound 49h (110 mg, 0.33 mmol). Purification by column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the title compound as a white solid (75 mg, 67%). LCMS (ES+) 332 (M+H)+, (ES−) 330 (M+H)−, RT 2.78 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.59 (1H, s), 8.90 (2H, d, J=4.8 Hz), 8.72 (1H, s), 8.36 (2H, d, J=8.2 Hz), 7.48-7.40 (3H, m), 7.36 (2H, d, J=7.6 Hz), 7.27 (2H, t, J=7.6 Hz), 7.19 (1H, t, J=7.3 Hz), 3.18 (1H, dd, J=6.8, 5.4 Hz), 2.93 (1H, dd, J=9.6, 6.8 Hz), 2.30 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R)—N-Hydroxy-2-phenyl-3-(4-(pyrimidin-5-yl)phenyl)cyclopropanecarboxamide (50i)

(158) Following method A from compound 49i (120 mg, 0.36 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and passage through an Isolute anion exchange SPE (elution DCM-MeOH, 1:1) gave the title compound as a white solid (21 mg, 17%). LCMS (ES+) 332 (M+H).sup.+, RT 3.07 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.60 (1H, s), 9.18 (1H, s), 9.15 (2H, s), 8.72 (1H, s), 7.79 (2H, d, J=8.1 Hz), 7.45 (2H, d, J=8.1 Hz), 7.35 (2H, d, J=7.6 Hz), 7.27 (2H, t, J=7.6 Hz), 7.19 (1H, t, J=7.2 Hz), 3.18 (1H, dd, J=6.8, 5.4 Hz), 2.92 (1H, dd, J=9.6, 6.8 Hz), 2.27 (1H, dd, J=9.6, 5.4 Hz).

(1R,2R,3R)-2-(4-(5-Chloropyrimidin-2-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (50j)

(159) Following method A from compound 49j (300 mg, 0.82 mmol). The racemic mixture (119 mg, 40%) was obtained after purification using flash silica column chromatography (gradient elution DCM/MeOH 0% to 10%). Preparative chiral HPLC gave the title compound (Chiralpak IC 30/70 IPA/MeOH (50/50/0.1 formic acid)/heptanes, 1.0 mL/min, RT 8.21 min). LCMS (ES+) 366 (M+H), RT 3.90 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.64 (1H, s), 9.06 (2H, s), 8.77 (1H, s), 8.37 (2H, d, J=8.2 Hz), 7.50 (2H, d, J=8.2 Hz), 7.40 (2H, d, J=7.6 Hz), 7.32 (2H, t, J=7.5 Hz), 7.26-7.21 (1H, m), 3.23 (1H, dd, J=6.8, 5.4 Hz), 2.98 (1H, dd, J=9.7, 6.8 Hz), 2.35 (1H, dd, J=9.7, 5.4 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-(4-(5-methylpyrimidin-2-yl)phenyl)-3-phenylcyclopropanecarboxamide (50k)

(160) Following method A from compound 49k (180 mg, 0.52 mmol). The carboxylic acid was obtained as the major product. The reaction mixture was acidified with aqueous 1M HCl and extracted into EtOAc (3×10 mL). The organic layers were combined, dried (MgSO.sub.4), concentrated and the residue subjected to method B. Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and preparative HPLC gave the title compound as a white solid (16 mg, 7%). LCMS (ES+) 346 (M+H)+, RT 3.50 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.58 (1H, s), 8.74 (2H, d, J=0.8 Hz), 8.70 (1H, s), 8.35-8.28 (2H, m), 7.45-7.32 (4H, m), 7.30-7.23 (2H, m), 7.22-7.15 (1H, m), 3.17 (1H, dd, J=6.7, 5.4 Hz), 2.91 (1H, dd, J=9.6, 6.8 Hz), 2.31 (3H, s), 2.29 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-(4-(5-methyl-1H-imidazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide (50l)

(161) Following method A from compound 49l (280 mg, 0.84 mmol). Purification by preparative HPLC gave the title compound as a white solid (4.8 mg, 1% yield over 3 steps). LCMS (ES+) 334 (M+H).sup.+, RT 7.93 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.62 (1H, s), 8.42 (1H, s), 7.88 (2H, d, J=8.0 Hz), 7.41-7.28 (6H, m), 7.25-7.20 (1H, m), 6.84 (1H, s), 3.16 (1H, dd, J=6.9, 5.5 Hz), 2.92 (1H, dd, J=9.4, 6.7 Hz), 2.31-2.20 (4H, m), OH not observed.

Example 17

(162) ##STR00052##

5-Bromo-2-cyclopropyl isoindoline

(163) To a solution of phthalic anhydride (4.5 g, 20 mmol) in toluene (25 mL) was added cyclopropylamine (1.52 mL) at 0° C. and the reaction mixture was stirred at 90° C. for 17 h. The solvent was evaporated and THF (20 mL) was added. To this was added BH.sub.3.Me.sub.2S THF complex 1 M (80 mL, 80 mmol) and the mixture was stirred at 50° C. for 48 h. The reaction was cooled to 00° C. and poured onto a solution of 3 M HCl (27 mL) and stirred at 60° C. for 1 h. The mixture was washed with ethyl acetate, the aqueous phase was basified (pH 12) and extracted with DCM. The organic layer was dried, filtered and concentrated to afford the title compound as a yellow oil (1.6 g, 34%). LCMS (ES+) 238, 240 (M+H).sup.+.

(164) ##STR00053##

Example 18

(1R*,2R*,3R*)-methyl-2-(4-(2-cyclopropylisoindolin-5-yl)phenyl)-3-phenylcyclopropanecarboxylate (51)

(165) Following method G from the boronate derived from 15c (1.5 mmol) and 5-bromo-2-cyclopropylisoindoline (240 mg, 1 mmol). The mixture was stirred at 90° C. for 2 h, diluted with H.sub.2O (20 mL) and extracted into DCM (50 mL). The organic layers were passed through a phase separator and concentrated. Purification using flash silica column chromatography (gradient elution DCM/MeOH 1% to 7%) gave the ester intermediate as a yellow oil (360 mg, 59%). LCMS (ES+) 410 (M+H).sup.+.

(1R*,2R*,3R*)-2-(4-(2-cyclopropylisoindolin-5-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (52)

(166) Following method A from compound 51 (40 mg, 0.098 mmol). Purification by preparative HPLC gave the title compound as a white solid (6.9 mg, 17%). LCMS (ES+) 411 (M+H)+, RT 7.48 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.63 (1H, s), 8.75 (1H, s), 7.65 (2H, d, J=8.1 Hz), 7.56 (1H, s), 7.53 (1H, d, J=7.9 Hz), 7.44-7.27 (7H, m), 7.26-7.20 (1H, m), 4.05 (4H, d, J=9.3 Hz), 3.17 (1H, dd, J=6.7, 5.3 Hz), 2.90 (1H, dd, J=9.5, 6.8 Hz), 2.29 (1H, dd, J=9.5, 5.4 Hz), 2.14-2.08 (1H, m), 0.56-0.50 (2H, m), 0.51-0.45 (2H, m).

Example 19

(167) ##STR00054##

(168) TABLE-US-00006 TABLE 4 R Compound 54a 54b 54c

(1R*,2R*,3R*)-Methyl-2-(3′-(benzyloxy)-[1,1′-biphenyl]-4-yl)-3-phenylcyclopropanecarboxylate (53a)

(169) Following method H from compound 15c (660 mg, 2 mmol) and 3-(benzyloxy)phenyl boronic acid (547 mg, 2.40 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a yellow oil (710 mg, 82%). LCMS (ES+) 435 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4′-(9H-carbazol-9-yl)-[1,1′-biphenyl]-4-yl)-3-phenylcyclopropanecarboxylate (53b)

(170) Following method H from compound 15c (660 mg, 2.0 mmol) and 4-(9H-carbazol-9-yl)phenyl boronic acid (886 mg, 2.40 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 30% EtOAc in i-hex) gave the title compound as a yellow oil (310 mg, 31%). LCMS (ES+) 494 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)-3-phenylcyclopropanecarboxylate (53c)

(171) Following method H from compound 15c (330 mg, 1.0 mmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (331 mg, 1.2 mmol). Purification by flash silica column chromatography (gradient elution i-hex-5% to 80% EtOAc in i-hex) gave the title compound as a yellow oil (280 mg, 70%). LCMS (ES+) 400 (M+H).sup.+.

(1R,2R,3R)-2-(3′-(Benzyloxy)-[1,1′-biphenyl]-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide (54a)

(172) Following method A from compound 53a (700 mg, 1.61 mmol). Purification by flash silica column chromatography (gradient elution EtOAc from 5% to 100% in i-hex) followed by PEAX cartridge (elution DCM-MeOH 1:1) gave the racemic mixture as a white solid (450 mg, 64%). Purification by chiral preparative HPLC gave the title compound (Chiralpak IC 20/80 EtOH (0.1% FA)/heptane, 1.0 mL/min, RT 13.0 min). LCMS (ES+) 436 (M+H)+, RT 4.47 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.63 (1H, s), 8.76 (1H, s), 7.68 (2H, d, J=8.1 Hz), 7.54 (2H, d, J=7.5 Hz), 7.50-7.21 (13H, m), 7.05 (1H, dd, J=8.1, 2.4 Hz), 5.25 (2H, s), 3.19 (1H, dd, J=6.8, 5.4 Hz), 2.93 (1H, dd, J=9.6, 6.8 Hz), 2.30 (1H, dd, J=9.6, 5.4 Hz).

(1R*,2R*,3R*)-2-(4′-(9H-carbazol-9-yl)-[1,1′-biphenyl]-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide (54b)

(173) Following method A from compound 53b (300 mg, 0.61 mmol). Purification by preparative HPLC gave the title compound as a white solid (8 mg, 3%). LCMS (ES+) 495 (M+H)+, RT 11.55 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.66 (1H, s), 8.79 (1H, s), 8.33 (2H, d, J=7.8 Hz), 8.03 (2H, d, J=8.2 Hz), 7.83 (2H, d, J=8.0 Hz), 7.78 (2H, d, J=8.2 Hz), 7.54-7.47 (6H, m), 7.44-7.30 (6H, m), 7.25 (1H, t, J=7.2 Hz), 3.23 (1H, dd, J=6.8, 5.4 Hz), 2.98 (1H, dd, J=9.6, 6.9 Hz), 2.34 (1H, dd, J=9.6, 5.4 Hz).

(1R,2R,3R)—N-hydroxy-2-(4-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenyl)-3-phenylcyclopropanecarboxamide (54c)

(174) Following method A from compound 53c (280 mg, 0.70 mmol). The carboxylic acid was obtained as the major product. The reaction mixture was acidified with aqueous 1 M HCl and extracted into EtOAc (3×10 mL). The organic layers were combined, dried (MgSO.sub.4), filtered and concentrated. The sample was then subjected to method B. Purification by chiral preparative HPLC (Chiralpak IC 20/80 EtOH (0.1% FA)/heptane, 1.0 mL/min, RT 15.9 min) gave the title compound as a white solid. LCMS (ES+) 401 (M+H)+, RT 4.02 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.63 (1H, s), 8.75 (1H, s), 7.56 (2H, d, J=8.1 Hz), 7.38 (2H, d, J=7.6 Hz), 7.35-7.27 (3H, m), 7.26-7.20 (1H, m), 7.15 (1H, dd, J=8.3, 2.1 Hz), 7.02 (1H, d, J=2.1 Hz), 6.81 (1H, d, J=8.4 Hz), 4.33-4.29 (2H, m), 3.33-3.28 (3H, m), 3.14 (1H, dd, J=6.8, 5.3 Hz), 2.91 (3H, s), 2.91-2.85 (1H, m), 2.26 (1H, dd, J=9.6, 5.3 Hz).

Example 20

(175) ##STR00058##

(176) TABLE-US-00007 TABLE 5 3 or 4 R2 Substitution Compound 4 56a 0 3 56b 4 56c 4 56d 4 56e 3 56f 3 56g 3 56h 4 56i

(1R*,2R*,3R*)-Methyl-2-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxylate (55a)

(177) Following method I from compound 15c (250 mg, 0.76 mmol) and iso-propylpiperazine (125 μl, 0.86 mmol). Purification using flash silica column chromatography (gradient elution i-hex/EtOAc 0% to 100%) gave the title compound as a yellow oil (187 mg, 65%). LCMS (ES+) 379 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(3-(4-isopropylpiperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxylate (55b)

(178) Following method I from compound 15b (250 mg, 0.76 mmol) and iso-propylpiperazine (125 μl, 0.86 mmol). Purification using flash silica column chromatography (gradient elution DCM/MeOH 0% to 8%) gave the title compound as a yellow oil (180 mg, 58%). LCMS (ES+) 393 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4-(3,3-difluoropyrrolidin-1-yl)phenyl)-3-phenylcyclopropanecarboxylate (55c)

(179) Following method I from compound 15c (250 mg, 0.76 mmol) and 3,3-difluoropyrrolidine (124 mg, 0.86 mmol). Purification by flash silica column chromatography (gradient elution i-hex/EtOAc 0% to 100%) gave the title compound as a clear oil (210 mg, 59%). LCMS (ES+) 358 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4-(3,3-dimethylazetidin-1-yl)phenyl)-3-phenylcyclopropanecarboxylate (55d)

(180) Following method I from compound 15c (250 mg, 0.76 mmol) and 3,3-dimethylazatidine (105 mg, 0.86 mmol). Purification by flash silica column chromatography (gradient elution i-hex/EtOAc 0% to 100%) gave the title compound as a clear oil (210 mg, 59%). LCMS (ES+) 336 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-3-phenylcyclopropanecarboxylate (55e)

(181) Following method I from compound 15c (250 mg, 0.76 mmol) and 2-oxa-6-azaspiro[3.3]heptane formate salt (160 mg, 0.86 mmol). Purification by flash silica column chromatography (gradient elution i-hex/EtOAc 0% to 100%) gave the title compound as a clear oil (210 mg, 59%). LCMS (ES+) 350 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(3-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-3-phenylcyclopropanecarboxylate (55f)

(182) Following method I from compound 15b (500 mg, 1.56 mmol) and octahydropyrrolo[1,2-a]pyrazine (195 mg, 1.72 mmol). Purification by flash silica column chromatography (gradient elution DCM/MeOH 0% to 8%) gave the title compound as a yellow oil (265 mg, 44%). LCMS (ES+) 391 (M+H).sup.+.

(1R*,2R,3R*)-Ethyl-2-phenyl-3-(3-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)cyclopropanecarboxylate (55g)

(183) Following method I from compound 15b (500 mg, 1.56 mmol) and 4-(pyrrolidin-1-yl)piperidine (241 mg, 1.72 mmol). Purification by flash silica column chromatography (gradient elution DCM/MeOH 0% to 8%) gave the title compound as a yellow oil (230 mg, 35%). LCMS (ES+) 491 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(3-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)phenyl)-phenylcyclopropanecarboxylate (55h)

(184) Following method I from compound 15b (250 mg, 0.78 mmol) and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (106 mg, 0.86 mmol). Purification by flash silica column chromatography (gradient elution DCM/MeOH 0% to 8%) gave the title compound as a yellow oil (165 mg, 42%). LCMS (ES+) 388 (M+H).

(1R*,2R*,3R*)-Methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxylate (55i)

(185) Following method I from compound 15c (250 mg, 0.76 mmol) and N-methylpiperazine (95 μl, 0.86 mmol). Purification using Isolute cation exchange SCX (elution DCM-MeOH 50% and 5-10% 7N NH.sub.3 in MeOH) gave the title compound as a yellow oil (72 mg, 27%). LCMS (ES+) 351 (M+H).sup.+.

(1R*,2R*,3R*)—N-Hydroxy-2-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxamide (56a)

(186) Following method A from compound 55a (170 mg, 0.49 mmol). Purification by preparative HPLC gave the title compound as a white solid (36 mg, 21%). LCMS (ES+) 380 (M+H).sup.+, RT 2.30 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.50 (1H, d, J=1.9 Hz), 8.64 (1H, d, J=1.7 Hz), 7.31 (2H, m), 7.25 (2H, m), 7.20-7.07 (3H, m), 6.88 (2H, d, J=8.4 Hz), 3.08 (4H, m), 2.99 (1H, m), 2.75-2.61 (2H, m), 2.56 (4H, dd, J=7.4, 4.1 Hz), 2.12-2.06 (1H, m), 1.00 (6H, d, J=6.5 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-(3-(4-isopropylpiperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxamide (56b)

(187) Following method A from compound 55b (180 mg, 0.46 mmol). Purification by preparative HPLC gave the title compound as a white solid (73 mg, 42%). LCMS (ES+) 380 (M+H)+, RT 7.23 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.56 (1H, s), 7.37 (2H, d, J=7.6 Hz), 7.30 (2H, t, J=7.5 Hz), 7.25-7.17 (2H, m), 6.88 (1H, s), 6.84-6.80 (1H, m), 6.69 (1H, d, J=7.5 Hz), 3.18 (5H, t, J=4.5 Hz), 3.08 (1H, dd, J=6.8, 5.4 Hz), 2.87 (1H, dd, J=9.5, 6.9 Hz), 2.73 (1H, t, J=6.5 Hz), 2.62 (4H, t, J=4.6 Hz), 2.22 (1H, dd, J=9.6, 5.4 Hz), 1.06 (6H, d, J=6.5 Hz).

(1R*,2R*,3R*)—N-Hydroxy-2-(4-(3,3-difluoropyrrolidin-1-yl)phenyl)-3-phenylcyclopropanecarboxamide (56c)

(188) Following method A from compound 55c (205 mg, 0.57 mmol). Purification by preparative HPLC gave the title compound as a white solid (35 mg, 17%). LCMS (ES+) 359 (M+H)+, RT 9.27 min (Analytical method 6). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.50 (1H, s), 8.64 (1H, d, J=1.8 Hz), 7.31 (2H, d, J=7.6 Hz), 7.25 (2H, t, J=7.4 Hz), 7.19-7.08 (3H, m), 6.60 (2H, d, J=8.2 Hz), 3.66 (2H, t, J=13.4 Hz), 3.44 (2H, m), 2.99 (1H, m), 2.70-2.65 (2H, m), 2.33 (1H, m), 2.08 (1H, dd, J=9.5, 5.4 Hz).

(1R*,2R*,3R*)-2-(4-(3,3-Dimethylazetidin-1-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (56d)

(189) Following method A from compound 55d (200 mg, 0.59 mmol). Purification by preparative HPLC gave the title compound as a white solid (23 mg, 14%). LCMS (ES+) 337 (M+H)+, RT 3.42 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.49 (1H, s), 8.63 (1H, s), 7.33-7.20 (4H, m), 7.19-7.12 (1H, m), 7.05 (2H, d, J=8.2 Hz), 6.37 (2H, d, J=8.2 Hz), 3.48 (4H, s), 2.97 (1H, dd, J=6.9, 5.4 Hz), 2.68 (1H, dd, J=9.5, 6.9 Hz), 2.06 (1H, dd, J=9.5, 5.4 Hz), 1.27 (6H, s).

(1R*,2R*,3R*)-2-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (56e)

(190) Following method A from compound 55e (214 mg, 0.61 mmol). Purification by preparative HPLC gave the title compound as a white solid (23 mg, 14%). LCMS (ES+) 351 (M+H)+, RT 8.07 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.50 (1H, s), 8.64 (1H, d, J=1.8 Hz), 7.31 (2H, d, J=7.6 Hz), 7.28-7.21 (2H, m), 7.19-7.08 (3H, m), 6.60 (2H, d, J=8.2 Hz), 3.70-3.61 (4H, m), 3.48-3.39 (4H, m), 2.99 (1H, dd, J=6.9, 5.4 Hz), 2.70 (1H, dd, J=9.5, 6.9 Hz), 2.08 (1H, dd, J=9.5, 5.4 Hz).

(1R*,2R*,3R*)-2-(3-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (56f)

(191) Following method A from compound 55f (265 mg, 0.68 mmol). Purification by preparative HPLC gave the title compound as a white solid (9 mg, 4%). LCMS (ES+) 378 (M+H)+, RT 8.26 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.56 (1H, s), 7.38 (2H, d, J=7.6 Hz), 7.30 (2H, t, J=7.5 Hz), 7.24-7.15 (2H, m), 6.89 (1H, s), 6.84 (1H, dd, J=8.4, 2.4 Hz), 6.69 (1H, d, J=7.6 Hz), 3.87 (1H, d, J=11.2 Hz), 3.71 (2H, d, J=12.2 Hz), 3.13-3.03 (4H, m), 2.87 (1H, dd, J=9.6, 6.9 Hz), 2.81-2.71 (1H, m), 2.30-2.19 (2H, m), 2.16-2.04 (2H, m), 1.91-1.83 (1H, m), 1.81-1.70 (2H, m), 1.48-1.39 (1H, m).

(1R*,2R*,3R*)—N-Hydroxy-2-phenyl-3-(3-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)cyclopropanecarboxamide (56g)

(192) Following method A from compound 55g (230 mg, 0.55 mmol). Purification by preparative HPLC gave the title compound as a white solid (40 mg, 10%). LCMS (ES+) 406 (M+H)+, RT 2.42 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.56 (1H, s), 8.72 (1H, s), 7.38 (2H, d, J=7.61 Hz), 7.33-7.24 (2H, m), 7.25-7.14 (2H, m), 6.90 (1H, s), 6.90-6.80 (1H, m), 6.67 (1H, d, J=7.59 Hz), 3.84-3.69 (2H, m), 3.08 (1H, dd, J=6.93 5.4 Hz), 2.90-2.82 (1H, m), 2.82-2.72 (7H, m), 2.22 (1H, dd, J=9.6, 5.4 Hz), 2.00 (2H, d, J=12.01 Hz), 1.79 (4H, s), 1.65-1.51 (2H, m).

(1R,2R,3R)-2-(3-(6,7-Dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (56h)

(193) Following method A from compound 55h (180 mg, 0.46 mmol). The racemic mixture was obtained after purification by preparative HPLC as a white solid (41.5 mg, 24%). Purification by chiral preparative HPLC (Chiralpak IA 40/60 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min, RT 10.1 min) gave the title compound. LCMS (ES+) 375 (M+H)+, RT 2.90 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.59 (1H, s), 8.74 (1H, s), 7.39-7.28 (5H, m), 7.26-7.20 (4H, m), 7.02 (1H, d, J=1.4 Hz), 5.66 (1H, d, J=1.9 Hz), 4.15 (2H, t, J=6.1 Hz), 3.74 (2H, t, J=5.2 Hz), 3.14 (1H, dd, J=6.8, 5.4 Hz), 2.88 (1H, dd, J=9.5, 6.8 Hz), 2.28-2.22 (3H, m).

(1R*,2R*,3R*)—N-Hydroxy-2-(4-(4-methyl piperazin-1-yl)phenyl)-3-phenylcyclopropanecarboxamide (56i)

(194) Following method A from compound 55i (70 mg, 0.20 mmol). Purification by preparative HPLC gave the title compound as a white solid (49 mg, 70%). LCMS (ES+) 352 (M+H)+, RT 6.86 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6) 10.50 (1H, s), 8.64 (1H, s), 7.31 (2H, d, J=7.6 Hz), 7.25 (2H, t, J=7.4 Hz), 7.20-7.08 (3H, m), 6.89 (2H, d, J=8.5 Hz), 3.09 (4H, t, J=4.8 Hz), 2.99 (1H, dd, J=6.8, 5.4 Hz), 2.71 (1H, dd, J=9.5, 6.9 Hz), 2.44 (4H, t, J=4.7 Hz), 2.22 (3H, s), 2.09 (1H, dd, J=9.5, 5.4 Hz).

Example 21

(195) ##STR00068##

(1R*,2R*,3R*)-Methyl-2-(4-(oxazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide (57)

(196) A mixture of compound 15c (250 mg, 0.75 mmol), 2-(tri-n-butylstannyl)oxazole (0.230 mL, 1.1 mmol), Pd(PPh.sub.3).sub.4 (43 mg, 0.038 mmol) in 1,4-dioxane (4 mL) was heated in the microwave at 150° C. for 1 h. The mixture was concentrated and purified by flash silica column chromatography (gradient elution DCM to 10% MeOH in DCM) to afford the title compound as a white solid (175 mg, 73%). LCMS (ES+) 320 (M+H).sup.+.

(1R*2R*,3R*)—N-Hydroxy-2-(4-(oxazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide (58)

(197) Following method A from compound 57 (160 mg, 0.50 mmol). Crystallization from MeOH gave the title compound as a white solid (71 mg, 45%). LCMS (ES+) 321 (M+H)+, RT 2.80 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.58 (1H, s), 8.70 (1H, s), 8.21 (1H, d, J=0.8 Hz), 7.94 (2H, d, J=8.1 Hz), 7.45 (2H, d, J=8.1 Hz), 7.39-7.33 (3H, m), 7.31-7.23 (2H, m), 7.22-7.15 (1H, m), 3.20-3.13 (1H, m), 2.91 (1H, dd, J=9.6, 6.8 Hz), 2.28 (1H, dd, J=9.6, 5.3 Hz).

Example 22

(198) ##STR00069##

(1R*,2R*,3R*)-Methyl-2-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide (59)

(199) Following the method described for compound 57, from 15c (222 mg, 0.67 mmol) and 1-methyl-2-(tributylstannyl)imidazole (300 mg, 0.81 mmol). Purification by flash silica column chromatography (gradient elution DCM to 10% MeOH in DCM) gave the title compound as a yellow solid (187 mg, 84%). LCMS (ES+) 333 (M+H).sup.+.

(1R*,2R*,3R*)—N-Hydroxy-2-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide (60)

(200) Following method A from compound 59 (187 mg, 0.56 mmol). Crystallization from DCM and washes with MeOH, gave the title compound as a white solid (98 mg, 53%). LCMS (ES+) 334 (M+H)+, RT 9.74 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.58 (1H, s), 8.70 (1H, s), 7.65 (2H, d, J=8.1 Hz), 7.44-7.31 (4H, m), 7.30-7.24 (3H, m), 7.23-7.15 (1H, m), 6.99 (1H, d, J=1.1 Hz), 3.75 (3H, s), 3.19-3.13 (1H, dd, J=6.8, 5.4 Hz), 2.90 (1H, dd, J=9.6, 6.8 Hz), 2.26 (1H, dd, J=9.6, 5.4 Hz).

Example 23

(201) ##STR00070##

(1R*,2S*,3S*)-Methyl-2-(4-bromophenyl)-1-methyl-3-phenylcyclopropanecarboxylate (61)

(202) To a solution of 15c (331 mg, 1 mmol) in dry THF at −78° C., was added LDA (2 M in THF, 0.5 mL) dropwise and the reaction mixture was stirred at −78° C. for 30 min. Methyl iodide (0.065 mL, 1 mmol) was added and the reaction mixture was allowed to warm up to r.t. and stirred for 1 h. The reaction mixture was quenched with water and the compound was extracted into DCM. The organic phase was dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a colourless oil (346 mg, 100%). LCMS (ES+) 346 (M+H).sup.+.

(1R*,2S*,3S*)-Methyl-2-(4-(5-fluoropyrimidin-2-yl)phenyl)-1-methyl-3-phenylcyclopropanecarboxylate (62)

(203) Following method G from 61 (346 mg, 1.0 mmol) and 2-chloro-5-fluoropyrimidine (170 μl, 1.1 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (160 mg, 44%). LCMS (ES+) 363 (M+H).sup.+.

(1R*,2S*,3S*)-2-(4-(5-Fluoropyrimidin-2-yl)phenyl)-N-hydroxy-1-methyl-3-phenylcyclopropanecarboxamide (63)

(204) Following method A from 62 (350 mg, 0.97 mmol). Purification by flash silica column chromatography (gradient elution DCM to 10% MeOH in DCM) followed by preparative HPLC gave the title compound as a white solid (2 mg, 2%). LCMS (ES+) 364 (M+H)+, RT 10.83 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.62 (1H, s), 8.98 (2H, d, J=0.7 Hz), 8.64 (1H, s), 8.31 (2H, d, J=8.1 Hz), 7.51 (2H, d, J=8.1 Hz), 7.31-7.23 (4H, m), 7.22-7.15 (1H, m), 3.46 (1H, d, J=7.2 Hz), 2.78 (1H, d, J=7.2 Hz), 1.12 (3H, s).

Example 24

(205) ##STR00071##

(1R*,2R*,3R*)-Methyl-2(4-(1H-pyrazol-1-yl)phenyl)-3-phenylcyclopropanecarboxylate (64)

(206) To a stirred solution of compound 15c (1.0 g, 3.02 mmol) in dioxane (5 mL) was added bis-pinacolato diboron (844 mg, 3.32 mmol), Pd(dppf)Cl.sub.2 (246 mg, 0.30 mmol) and potassium acetate (1.48 g, 15.1 mmol). The mixture was degassed with nitrogen, heated to 100° C. for 2 h, diluted with H.sub.2O (20 mL) and extracted into DCM (2×20 mL). The organic layers were passed through a phase separator and concentrated. Part of this crude residue (400 mg, 1.00 mmol) was dissolved in a mixture of MeOH (4 mL) and THF (2 mL) and to this was added pyrazole (82 mg, 1.2 mmol) and Cu.sub.2O (8 mg, 0.056 mmol). The mixture was stirred at 100° C. for 16 h, diluted with H.sub.2O (10 mL) and extracted into DCM (20 mL). The organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) afforded the title compound as a cream solid (161 mg, 51%). LCMS (ES+) 319 (M+H).sup.+.

(1R*,2R*,3R*)-2-(4-(1H-pyrazol-1-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (65)

(207) Following method A from compound 64 (121 mg, 0.38 mmol) The carboxylic acid was obtained as the major product. The acid (43 mg, 0.14 mmol) was subjected to method B. Purification by preparative HPLC gave the title compound as a cream solid (9 mg, 21%). LCMS (ES+) 320 (M+H)+, RT 8.49 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6) 10.56 (1H, s), 8.69 (1H, s), 8.48 (1H, d, J=2.5 Hz), 7.80 (2H, d, J=8.4 Hz), 7.73 (1H, d, J=1.7 Hz), 7.40 (2H, d, J=8.3 Hz), 7.35 (2H, d, J=7.6 Hz), 7.27 (2H, m), 7.19 (1H, m), 6.54 (1H, dd, J=2.4, 1.7 Hz), 3.19-3.13 (1H, dd, J=6.8, 5.3 Hz), 2.89 (1H, dd, J=9.6, 6.8 Hz), 2.24 (1H, dd, J=9.6, 5.3 Hz).

Example 25

(208) ##STR00072##

(E)-Methyl-3-(5-(trifluoromethyl)pyridin-3-yl)acrylate (66)

(209) A stirred solution of 5-bromo-3-(trifluoromethyl)pyridine (1.0 g, 4.42 mmol), (E)-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1.0 g, 4.43 mmol), Pd(PPh.sub.3).sub.4 (511 mg, 0.44 mmol) and Na.sub.2CO.sub.3 (13.3 mL, 1 M solution, 13.3 mmol) was degassed with nitrogen for 10 min and then heated to 100° C. for 17 h. The mixture was allowed to cool, diluted with water (20 mL), and extracted into DCM (3×20 mL). The product was extracted from the organic layers with sat. NaHCO.sub.3 (20 mL). The pH was adjusted to 5.5 and the resulting white precipitate collected by vacuum filtration (431 mg, 45%). LCMS indicated that the corresponding carboxylic acid had formed. In a separate flask, thionyl chloride (0.19 mL, 1.99 mmol) was added slowly to MeOH (5 mL) at −78° C., and the acid (431 mg, 1.99 mmol) was added. The mixture was refluxed for 1.5 h, cooled to r.t. and concentrated. The residue was dissolved in sat. NaHCO.sub.3 (20 mL) and extracted into DCM (3×20 mL), and the combined organic layers passed through a phase separator and concentrated to give the title compound as a colourless oil (403 mg, 88%). LCMS (ES+) 232 (M+H).sup.+.

(1R*,2R*,3R)-Ethyl-2-phenyl-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylate (67)

(210) Following method F from compound 66 (403 mg, 1.74 mmol) and 6a (678 mg, 2.62 mmol). After stirring at 00° C. for 2 h an additional 1.5 equivalents of LiHMDS were added. Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (250 mg, 2:1 trans:cis, 45%). LCMS (ES+) 322 (M+H).sup.+.

(1R,2R,3R)—N-Hydroxy-2-phenyl-3-(5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxamide (68)

(211) Following method A from compound 67 (250 mg, 0.78 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) followed by preparative HPLC gave the racemic mixture as a white solid (83 mg, 11%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 EtOH (0.1% formic acid)/heptane, 1.0 mL/min, RT 11.3 min). LCMS (ES+) 323 (M+H).sup.+, RT 3.30 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.64 (1H, s), 8.96 (1H, s), 8.88 (1H, s), 8.79 (1H, s), 8.15 (1H, s), 7.41 (2H, d, J=7.6 Hz), 7.32 (2H, t, J=7.4 Hz), 7.24 (1H, t, J=7.2 Hz), 3.41 (1H, obscured by water), 3.15 (1H, dd, J=9.8, 6.9 Hz), 2.44 (1H, dd, J=9.8, 5.4 Hz).

Example 26

(212) ##STR00073##

tert-Butyl-4-(4-((1R*,2R*,3R*)-2-(methoxycarbonyl)-3-phenylcyclopropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (69)

(213) Following method H from compound 15c (660 mg, 2 mmol) and (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (750 mg, 2.4 mmol). The crude compound was used in the next step without further purification.

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)cyclopropanecarboxylate (70)

(214) A solution of 69 (2 mmol) in a mixture of TFA (6 mL) and DCM (14 mL) was stirred at r.t. for 3 h. The reaction mixture was concentrated and the residue dissolved in DCM-MeOH 1:1 (2 mL) and passed through a SCX cartridge (elution 7 M NH.sub.3 in MeOH). The free amine was isolated as a yellow oil (655 mg, 96%). This was dissolved in CH.sub.3CN (20 mL) and Cs.sub.2CO.sub.3 (1.2 g, 3.9 mmol) and benzyl bromide (255 μL, 2.15 mmol) were added. The reaction mixture was stirred for 17 h and concentrated. The residue was dissolved in DCM and washed with water and brine. The organic layer was passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 15% EtOAc in i-hex) gave the title compound as a yellow oil (305 mg, 36%). LCMS (ES+) 424 (M+H).sup.+.

(1R,2R,3R)-2-(4-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (71)

(215) Following method A from compound 70 (300 mg, 0.71 mmol). Purification by PEAX cartridge (elution DCM-MeOH 1:1) gave the racemic mixture as a yellow solid (230 mg, 94%). Purification by chiral preparative HPLC (Chiralpak IC 40/60 EtOH (0.1% FA)/heptane, 1.0 mL/min, RT 14.2 min) gave the title compound as a yellow solid. LCMS (ES+) 425 (M+H)+, RT 7.59 min (Analytical method 3). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.61 (1H, s), 8.75 (1H, s), 7.45-7.20 (14H, m), 6.18 (1H, s), 3.63 (2H, s), 3.15-3.08 (3H, m), 2.86 (1H, dd, J=9.4, 6.7 Hz), 2.69 (2H, t, J=5.6 Hz), 2.55-2.46 (2H, m), 2.23 (1H, dd, J=9.6, 5.3 Hz).

Example 27

(216) ##STR00074##

5-(4-Bromophenyl)-2-methyloxazole (72)

(217) Triflic acid (37 mL, 0.22 mol) was added dropwise to a solution of thallium acetate (28.7 g, 0.07 mol) in acetonitrile (400 mL) at r.t under nitrogen. The solution was stirred for 15 min before a solution of 4-bromobenzaldehyde in acetonitrile (200 mL) was added and the solution heated to 90° C. for 2.5 h. The reaction mixture was concentrated and the red residue was taken up in DCM (600 mL), washed with saturated NaHCO.sub.3, water, dried (MgSO.sub.4) and concentrated to give a brown gum (12.7 g). Purification by flash silica column chromatography (gradient elution i-hex to 70% EtOAc in i-hex) gave the title compound as an orange solid (8.68 g, 72%). LCMS (ES+) 238,240 (M+H).sup.+.

Ethyl-3-(4-(2-methyloxazol-5-yl)phenyl)acrylate (73)

(218) Following method E from compound 72 (8.68 g, 36 mmol).mLmLmL The reaction solution was decanted from the palladium residues and salts and then concentrated to give an orange solid. This was taken up in DCM (150 mL), washed with water, dried (MgSO.sub.4) and concentrated to give an orange solid. This was triturated with diethyl ether to give the title compound as a beige solid (6.18 mg, 66%). LCMS (ES+) 258 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(4-(2-methyloxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxylate (74a)

(219) Following method F from compound 73 (500 mg, 1.95 mmol) and 6a (756 mg, 2.92 mmol). The reaction was incomplete after 2 h. The reaction was cooled to −20° C. and an additional 1.5 equivalents of sulfonium salt, 12-crown-4 and LiHMDS were added and the mixture stirred at r.t. overnight. Purification by flash silica column chromatography (gradient elution i-hex to 30% EtOAc in i-hex) gave the title compound as an orange oil (460 mg, 12:2:1 cinnammate:trans:cis). LCMS (ES+) 348 (M+H).sup.+.

(1S*,2R*,3R*)-Ethyl-2-(2-fluorophenyl)-3-(4-(2-methyloxazol-5-yl)phenyl)cyclopropanecarboxylate (74b)

(220) Following method F from compound 73 (500 mg, 1.95 mmol) and 1-(2-fluorobenzyl)tetrahydrothiophenium bromide (811 mg, 2.93 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as an orange oil (888 mg, >100%, 3:1, trans:cis). LCMS (ES+) 366 (M+H).sup.+.

(1R,2R,3R)—N-Hydroxy-2-(4-(2-methyloxazol-5-yl)phenyl)-3-phenylcyclopropanecarboxamide (75a)

(221) Following method A from compound 74a (460 mg, 13% pure). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and then preparative HPLC gave the racemic mixture as a white solid (35 mg, 59%). Preparative chiral HPLC gave the title compound (Chiralpak IC 40/60 EtOH (0.1% formic acid)/Heptane, 1.0 mL/min, RT 12.0 min). LCMS (ES+) 335 (M+H).sup.+. RT 3.28 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.50 (1H, s), 8.63 (1H, s), 7.55 (2H, d, J=8.1 Hz), 7.43 (1H, s), 7.34-7.23 (4H, m), 7.23-7.15 (2H, m), 7.14-7.07 (1H, m), 3.05 (1H, dd, J=6.8, 5.4 Hz), 2.81 (1H, dd, J=9.6, 6.8 Hz), 2.40 (3H, s), 2.16 (1H, dd, J=9.6, 5.4 Hz).

(1S,2R,3R)-2-(2-Fluorophenyl)-N-hydroxy-3-(4-(2-methyloxazol-5-yl)phenyl)cyclopropanecarboxamide (75b)

(222) Following method A from compound 74b (200 mg, 0.55 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and then preparative HPLC gave the racemic mixture as a white solid (99 mg, 54%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 17.4 min). LCMS (ES+) 353 (M+H).sup.+. RT 3.41 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.67 (1H, s), 8.80 (1H, s), 7.68 (2H, d, J=8.1 Hz), 7.56 (1H, s), 7.45 (3H, dd, J=12.1, 7.7 Hz), 7.33-7.26 (1H, m), 7.21-7.11 (2H, m), 3.12 (1H, dd, J=6.9, 5.3 Hz), 2.88 (1H, dd, J=9.3, 6.9 Hz), 2.53 (3H, s), 2.32 (1H, dd, J=9.3, 5.3 Hz).

Example 28

(223) ##STR00075##

(1R*,2R*,3R*)-Ethyl-2-(3-(5-methylpyrimidin-2-yl)phenyl)-3-phenylcyclopropanecarboxylate (76)

(224) Following method G from the crude boronate derived from 15b (565 mg) and 2-chloro-5-methylpyrimidine (194 mg, 1.51 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (260 mg, 50%). LCMS (ES+) 359 (M+H).sup.+.

(1R,2R,3R)—N-Hydroxy-2-(3-(5-methylpyrimidin-2-yl)phenyl)-3-phenylcyclopropanecarboxamide (77)

(225) Following method A from compound 76 (260 mg, 0.73 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (220 mg, 88%). Preparative chiral HPLC gave the title compound (Chiralpak IC 40/60 EtOH (0.1% formic acid)/Heptane, 1.0 mL/min, RT 18.0 min). LCMS (ES+) 346 (M+H).sup.+. RT 3.47 min (Analytical method 1). .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.52 (1H, s), 8.70 (2H, s), 8.65 (1H, s), 8.19-8.13 (2H, m), 7.40 (2H, d, J=5.2 Hz), 7.30 (2H, d, J=7.6 Hz), 7.20 (2H, t, J=7.5 Hz), 7.12 (1H, t, J=7.2 Hz), 3.15 (1H, dd, J=6.8, 5.4 Hz), 2.78 (1H, dd, J=9.6, 6.8 Hz), 2.30-2.20 (4H, m).

Example 29

(226) ##STR00076##

(1R*,2R*,3R*)-Methyl 2-(4-(3-methyl-1H-pyrazol-1-yl)phenyl)-3-phenylcyclopropanecarboxylate (78)

(227) To a stirred solution of 15c (1.0 g, 3.02 mmol) in dioxane (5 mL) was added bis-pinacolato diboron (844 mg, 3.32 mmol), Pd(dppf)Cl.sub.2 (246 mg, 0.30 mmol) and potassium acetate (1.48 g, 15.1 mmol). The mixture was degassed with nitrogen, heated to 100° C. for 2 h, diluted with H.sub.2O (20 mL) and extracted into DCM (2×20 mL). The organic layers were passed through a phase separator and concentrated. Part of this crude residue (600 mg, 1.5 mmol) was dissolved in a mixture of MeOH (6 mL) and THF (4 mL) and to this was added 3-methylpyrazole (145 μL, 1.8 mmol) and Cu.sub.2O (15 mg, 0.11 mmol). The mixture was stirred at 100° C. for 48 h, diluted with H.sub.2O (20 mL) and extracted into DCM (50 mL). The organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 60% EtOAc in i-hex) afforded the title compound as a cream solid (150 mg, 30%). LCMS (ES+) 333 (M+H).sup.+.

(1R,2R,3R)—N-Hydroxy-2-(4-(3-methyl-1H-pyrazol-1-yl)phenyl)-3-phenylcyclopropanecarboxamide (79)

(228) Following method A from compound 78 (148 mg, 0.45 mmol). Purification by preparative HPLC gave the racemic mixture as a cream solid (69.8 mg, 47%). Preparative chiral HPLC gave the title compound (Chiralpak IC 40/60 IPA/MeOH (50/50/0.1 formic acid)/heptane, 1.0 mL/min, RT 9.0 min). RT 3.56 min (Analytical method 1). LCMS (ES+) 334 (M+H).sup.+, RT 8.67 min. .sup.1H NMR δ (ppm) (DMSO-d.sub.6) 10.62 (1H, s), 8.75 (1H, s), 8.40 (1H, d, J=2.4 Hz), 7.79 (2H, d, J=8.4 Hz), 7.47-7.37 (4H, m), 7.32 (2H, t, J=7.5 Hz), 7.27-7.19 (1H, m), 6.37 (1H, d, J=2.4 Hz), 3.18 (1H, dd, J=6.8, 5.4 Hz), 2.91 (1H, dd, J=9.6, 6.8 Hz), 2.32 (3H, s), 2.27 (1H, dd, J=9.6, 5.4 Hz).

Example 30

(229) ##STR00077##

(E)-Ethyl-3-(6-chloropyridin-3-yl)acrylate (80)

(230) NaH (792 mg, 20.0 mmol) was added portion wise to stirred anhydrous DMSO (18 mL). The mixture was heated to 80° C. until evolution of gas ceased and then cooled to 0° C. A solution of (carbethoxymethyl)-triphenylphosphonium bromide (4.3 g, 10.0 mmol) in DMSO (36 mL) was then added and the mixture stirred at r.t for 30 min. The mixture was cooled to 000° C. and a solution of 6-chloroisonicotinaldehyde (1.4 g, 10.0 mmol) in DMSO (36 mL) was added and the mixture was stirred at r.t for 1 h. The mixture was then poured into aqueous 1 M HCl and extracted into DCM (3×70 mL). The organics were combined and washed with H.sub.2O (3×100 mL) and brine (3×100 mL), separated, dried (MgSO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 80% EtOAc in i-hex) gave the title compound as a yellow solid (0.95 g, 45%). LCMS (ES+) 212 (M+H).sup.+.

(1S*,2R*,3R*)-Ethyl-2-(6-chloropyridin-3-yl)-3-(2-fluorophenyl)cyclopropanecarboxylate (81)

(231) Following method F from compound 80 (730 mg, 3.45 mmol) and 6b (1.43 g, 5.18 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 40% EtOAc in i-hex) gave the title compound (810 mg, 73%). LCMS (ES+) 320 (M+H).sup.+.

(1S*,2R,3R)-Ethyl-2-(2-fluorophenyl)-3-(6-(4-isopropyl piperazin-1-yl)pyridin-3-yl)cyclopropanecarboxylate (82)

(232) A mixture of compound 81 (200 mg, 0.63 mmol) and isopropylpiperazine (0.75 mL) was heated in the microwave at 180° C. for 1 h. The reaction mixture was dissolved in DCM (30 mL) and washed with water (2×20 mL). The organic layer was passed through a phase separator and concentrated to afford a crude compound used in the next step (205 mg). LCMS (ES+) 412 (M+H).sup.+.

(1S,2R,3R)-2-(2-Fluorophenyl)-N-hydroxy-3-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)cyclopropanecarboxamide (83)

(233) Following method A from compound 82 (200 mg, 0.45 mmol). Purification by preparative HPLC gave the racemic mixture as a white solid (49.8 mg, 26%). Preparative chiral HPLC gave the title compound (Chiralpak IC 50/50 IPA/MeOH (50/50/0.1 formic acid)/heptane, 1.0 mL/min, RT 13.2 min). RT 2.18 min (Analytical method 1). LCMS (ES+) 399. .sup.1H NMR δ (ppm) (DMSO-d.sub.6) 10.63 (1H, s), 8.77 (1H, s), 8.17 (1H, s), 7.46-7.41 (2H, m), 7.30-7.27 (1H, m), 7.17-7.14 (2H, m), 6.86 (1H, d, J=8.8 Hz), 3.55-3.42 (5H, m), 2.99-2.95 (1H, m), 2.78-2.74 (2H, m), 2.67-2.57 (3H, m), 2.19 (1H, dd, J=9.0, 5.2 Hz), 1.06 (6H, d, J=6.4 Hz).

Example 31

(234) ##STR00078##

(E)-Ethyl-3-(2,6-dichloropyridin-4-yl)acrylate (84)

(235) NaH (613 mg, 15.4 mmol) was added portion wise to stirred anhydrous DMSO (10 mL). The mixture was heated to 80° C. until evolution of gas ceased and then cooled to 000° C. A solution of (carbethoxymethyl)-triphenylphosphonium bromide (3.29 g, 7.74 mmol) in DMSO (5 mL) was then added and the mixture stirred at r.t for 30 min. The mixture was cooled to 0° C. and a solution of 2,6-dichloroisonicotinaldehyde (1.35 g, 7.74 mmol) in DMSO (5 mL) was added and the mixture was stirred at r.t for 1 h. The mixture was then poured into aqueous 1 M HCl and extracted into DCM (3×50 mL). The organics were combined and washed with H.sub.2O (3×100 mL) and brine (2×100 mL), separated, dried (MgSO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) gave the title compound as a yellow solid (1.25 g, 66%). LCMS (ES+) 247 (M+H).sup.+.

(E)-Ethyl-3-(2-chloro-6-cyclopropyl pyridin-4-yl)acrylate (85)

(236) A stirred solution of compound 84 (1.29 g, 5.24 mmol), cyclopropyl boronic acid (496 mg, 5.77 mmol), potassium phosphate (tribasic) (3.88 g, 18.3 mmol), Pd(OAc).sub.2 (117 mg, 0.52 mmol) and tricyclohexylphosphine (1.05 mL, 1 M in toluene, 1.05 mmol) in toluene/H.sub.2O (30 mL/1.5 mL) was degassed using nitrogen for 15 min and then heated at 100° C. for 17 h. The reaction mixture was allowed to cool, diluted with H.sub.2O (50 mL) and extracted into DCM (3×50 mL). The combined organics were washed with H.sub.2O (2×50 mL) and brine (50 mL), separated, dried (MgSO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a yellow solid (561 mg, 43%). LCMS (ES+) 252.5 (M+H).sup.+.

(1S*,2R*,3R*)-Ethyl-2-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(2-fluorophenyl)cyclopropanecarboxylate (86)

(237) Following method F from compound 85 and 6b (894 mg, 3.23 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 4% EtOAc in i-hex) gave the title compound (790 mg, 99%, 5:1 trans:cis). LCMS (ES+) 360.5 (M+H).sup.+.

(1S*,2R*,3R*)-Ethyl-2-(2,6-dicyclopropylpyridin-4-yl)-3-(2-fluorophenyl)cyclopropanecarboxylate (87)

(238) A stirred solution of compound 86 (162 mg, 0.45 mmol), cyclopropyl boronic acid (62 mg, 0.72 mmol), potassium phosphate (tribasic) (0.49 g, 2.30 mmol), Pd(OAc).sub.2 (14 mg, 0.065 mmol) and tricyclohexylphosphine (0.13 mL, 1 M in toluene, 0.13 mmol) in toluene/H.sub.2O (5 mL/0.25 mL) was degassed using nitrogen for 15 min and then heated at 100° C. for 17 h. The mixture was allowed to cool, diluted with H.sub.2O (10 mL) and extracted into DCM (3×10 mL). The combined organics were washed with H.sub.2O (2×10 mL) and brine (10 mL), separated, dried (MgSO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound (164 mg, 100%). LCMS (ES+) 366 (M+H).sup.+.

(1S,2R,3R)-2-(2,6-Dicyclopropylpyridin-4-yl)-3-(2-fluorophenyl)-N-hydroxycyclopropanecarboxamide (88)

(239) Following method A from compound 87 (164 mg, 0.45 mmol). Purification by flash silica column chromatography (gradient elution DCM to 3% MeOH in DCM) gave the racemic mixture as a white solid (85 mg, 53%). Preparative chiral HPLC gave the title compound (Chiralpak IC 15/85 IPA/MeOH (50/50)/heptane, 1.0 mL/min, RT 9.3 min). RT 2.48 min (Analytical method 1). LCMS (ES+) 353 (M+H).sup.+. .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.86 (1H, s), 9.01 (1H, s), 7.64-7.59 (1H, m), 7.53-7.46 (1H, m), 7.38-7.31 (2H, m), 7.24 (0.2H, s), 7.20 (1.8H, s), 3.20-3.10 (2H, m), 2.54 (1H, dd, J=9.3, 5.3 Hz), 2.26-2.17 (2H, m), 1.12-1.07 (8H, m).

Example 32

(240) ##STR00079##

1-(Cyclopropylmethyl)-4-iodo-1H-pyrazole (89a)

(241) To a solution of 4-iodopyrazole (960 mg, 5 mmol) in DMF (6 mL) at 0° C. was added NaH (227 mg, 5.9 mmol) and the mixture was stirred for 1 h. Then cyclopropyl bromide (755 mg, 5.9 mmol) was added and the reaction mixture was stirred at r.t. overnight. The reaction mixture was quenched with sat NaHCO.sub.3 and extracted with EtOAc. The organic layer was dried (MgSO.sub.4), filtered and concentrated to afford a crude used in the next step without further purification (905 mg, 73%). LCMS (ES+) 249 (M+H).sup.+.

2-(4-Iodo-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyridine (89b)

(242) To a solution of 4-iodopyrazole (960 mg, 5 mmol) in DMF (10 mL) at 0° C. was added Cs.sub.2CO.sub.3 (2.4 g, 7.4 mmol) and 5-trifluoromethyl-2-chloropyridine (1.5 g, 8.3 mmol). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was quenched with H.sub.2O and extracted with EtOAc. The organic layer was dried (MgSO.sub.4), filtered and concentrated to afford a crude used in the next step without further purification (1.29 g, 76%). LCMS (ES+) 340 (M+H).sup.+.

(E)-Ethyl-3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)acrylate (90a)

(243) A mixture of compound 89a (900 mg, 3.6 mmol), palladium acetate (10 mg, 0.04 mmol), P(OEt).sub.3 (27 μL, 0.16 mmol), Et.sub.3N (1 mL, 7.2 mmol) and ethyl acrylate in DMF (10 mL) was stirred at 80° C. for 17 h. The reaction mixture was partitioned between water and EtOAc, the organic layer was washed with water and 4% aq. LiCl, dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 40% EtOAc in i-hex) gave the title compound as a yellow oil (489 mg, 62%). LCMS (ES+) 221 (M+H).sup.+.

(E)-Ethyl 3-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)acrylate (90b)

(244) To a solution of compound 89b (960 mg, 5 mmol) in DMF (10 mL) at 0° C. was added Cs.sub.2CO.sub.3 (2.4 g, 7.4 mmol) and 5-trifluoromethyl-2-chloropyridine (1.5 g, 8.3 mmol). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was quenched with H.sub.2O and extracted with EtOAc. The organic layer was dried (MgSO.sub.4), filtered and concentrated to afford a crude used in the next step without further purification (1.29 g, 76%). LCMS (ES+) 340 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-phenylcyclopropanecarboxylate (91a)

(245) Following method F from compound 90a (195 mg, 0.89 mmol) and 1-benzyltetrahydrothiophenium triflate (436 mg, 1.33 mmol). The reaction was incomplete after 1 h. The reaction was cooled to −20° C. and an additional 1.5 equivalents of sulfonium salt, 12-crown-4 and LiHMDS were added and the mixture stirred at r.t. overnight. Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a yellow oil (250 mg, 93%, 1:1 trans:cis). LCMS (ES+) 311 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-phenyl-3-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)cyclopropanecarboxylate (91b)

(246) Following method F from compound 90b (263 mg, 0.85 mmol) and 1-benzyltetrahydrothiophenium triflate (416 mg, 1.27 mmol). The reaction was incomplete after 1 h. The reaction was cooled to −20° C. and an additional 1.5 equivalents of sulfonium salt, 12-crown-4 and LiHMDS were added and the mixture stirred at r.t. overnight. Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a yellow oil (207 mg, 61%, 5:4 trans:cis). LCMS (ES+) 402 (M+H).sup.+.

(1R,2R,3R)-2-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide (92a)

(247) Following method A from compound 91a (250 mg, 0.81 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (65 mg, 27%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 12.0 min). RT 3.12 min (Analytical method 1). LCMS (ES+) 298 (M+H).sup.+. NMR δ (ppm) (DMSO-d.sub.6): 10.42 (1H, s), 8.57 (1H, s), 7.65 (0.1H, s), 7.63 (0.9H, s), 7.31 (0.1H, s), 7.28 (0.9H, s), 7.24-7.13 (4H, m), 7.11-7.06 (1H, m), 3.82 (2H, d, J=7.1 Hz), 2.80 (1H, dd, J=6.8, 5.3 Hz), 2.59 (1H, dd, J=9.4, 6.8 Hz), 1.91 (1H, dd, J=9.4, 5.3 Hz), 1.17-1.07 (1H, m), 0.46-0.39 (2H, m), 0.29-0.24 (2H, m)

(1R,2R,3R)—N-Hydroxy-2-phenyl-3-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)cyclopropanecarboxamide (92b)

(248) Following method A from compound 91b (263 mg, 0.85 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM), then preparative chiral HPLC (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 10.2 min) and preparative achiral HPLC gave the title compound (15 mg, 20%). RT 3.12 min (Analytical method 4). LCMS (ES+) 389 (M+H).sup.+. .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.51 (1H, s), 8.84 (1H, s), 8.64 (1H, s), 8.61 (1H, s), 8.33 (1H, dd, J=8.7, 2.4 Hz), 8.03 (1H, d, J=8.7 Hz), 7.89 (1H, s), 7.27 (2H, d, J=7.5 Hz), 7.22 (2H, t, J=7.5 Hz), 7.14 (1H, d, J=7.2 Hz), 2.99 (1H, dd, J=6.9, 5.3 Hz), 2.84 (1H, dd, J=9.4, 6.9 Hz), 2.12 (1H, dd, J=9.4, 5.3 Hz)

Example 33

(249) ##STR00080##

(E)-3-(4-(tert-Butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[t][1,4]oxazepin-7-yl)acrylic acid (93)

(250) To a stirred solution of tert-butyl-7-bromo-2,3-dihydrobenzo[t][1,4]oxazepine-4(5H)-carboxylate (480 mg, 1.46 mmol) in dioxane (20 mL) was added (E)-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (360 mg, 1.61 mmol), aqueous Na.sub.2CO.sub.3 (1.44 mL, 2 M, 2.92 mmol) and Pd(dppf)Cl.sub.2 (33 mg, 0.04 mmol). The mixture was degassed with nitrogen and then heated at 90° C. for 17 h. The reaction mixture was diluted with H.sub.2O and extracted into DCM. The organic layer was passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a yellow oil (267 mg, 57%). LCMS (ES+) 320 (M+H).sup.+.

(E)-tert-Butyl-7-(3-methoxy-3-oxoprop-1-en-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (94)

(251) To a stirred solution of compound 93 (267 mg, 0.84 mmol) in MeOH (30 mL) was added H.sub.2SO.sub.4 (3 drops) and the mixture heated to 80° C. for 17 h. The reaction mixture was concentrated and purified by flash silica column chromatography (gradient elution DCM to 25% MeOH in DCM) to give the deprotected amine (270 mg, 1.16 mmol). This was dissolved in DCM (10 mL) and di-tert-butyl dicarbonate (304 mg, 1.39 mmol) and DIPEA (0.4 mL, 2.32 mmol) added. The solution was stirred at r.t for 2 h and then diluted with H.sub.2O (50 mL) and DCM (40 mL). The biphasic mixture was shaken and the organics collected. The aqueous layer was re-extracted with DCM (50 mL) and the combined organics passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a yellow oil (230 mg, 60%). LCMS (ES+) 333 (M+H).sup.+.

tert-Butyl-7-((1R*,2R*,3R*)-2-(methoxycarbonyl)-3-phenylcyclopropyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (95)

(252) Following method F from compound 94 (200 mg, 0.60 mmol) and 1-benzyltetrahydrothiophenium triflate (296 mg, 0.90 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) gave the title compound as a colourless oil (206 mg, 84%, 5:4 trans:cis). LCMS (ES+) 424 (M+H).sup.+.

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)cyclopropanecarboxylate (96)

(253) To a stirred solution of compound 95 (206 mg, 0.50 mmol) in MeOH (10 mL) was added H.sub.2SO.sub.4 (3 drops) and the mixture heated to 80° C. for 1 h. The reaction mixture was concentrated, dissolved in a minimum quantity of DCM:MeOH (1:1) and loaded onto an SCX-cartridge (elution with 5% (7 M NH.sub.3 in MeOH) in DCM:MeOH (1:1)). The sample was concentrated to give a colourless oil (137 mg, 88%).

(1R*,2R*,3R*)-Methyl-2-phenyl-3-(4-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)cyclopropanecarboxylate (97)

(254) To a stirred solution of compound 96 (137 mg, 0.45 mmol) in DMF (5 mL) was added DIPEA (0.23 mL, 1.35 mmol) and 2,2,2-trifluoroethyl-4-methylbenzenesulfonate (172 mg, 0.68 mmol) and the mixture heated to 80° C. for 2 h. The reaction was partitioned between DCM (50 mL) and H.sub.2O (50 mL), and the organics collected. The aqueous portion was extracted with DCM (50 mL), and the combined organics washed with H.sub.2O (5×50 mL) and 4% aqueous LiCl (100 ml). The organics were collected, dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colourless oil (126 mg, 72%). LCMS (ES+) 390 (M+H).sup.+.

(1R*,2R,3R*)—N-Hydroxy-2-phenyl-3-(4-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)cyclopropanecarboxamide (98)

(255) Following method A from compound 97 (126 mg, 0.32 mmol). Purification by preparative HPLC gave the racemic mixture as a white solid (33 mg, 25%). Preparative chiral HPLC gave the title compound (Chiralpak IC 10/90 EtOH (0.1% formic acid)/heptane, 1.0 mL/min, RT 12.9 min). RT 3.70 min (Analytical method 1). LCMS (ES+) 407 (M+H).sup.+. .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.46 (1H, s), 8.60 (1H, s), 7.24 (2H, d, J=7.6 Hz), 7.21-7.15 (2H, m), 7.13-7.07 (1H, m), 7.05-7.01 (2H, m), 6.87 (1H, d, J=7.9 Hz), 3.92-3.88 (2H, m), 3.84 (2H, s), 3.19-3.03 (4H, m), 2.97 (1H, dd, J=6.8, 5.4 Hz), 2.72 (1H, dd, J=9.5, 6.8 Hz), 2.07 (1H, dd, J=9.5, 5.4 Hz).

Example 34

(256) ##STR00081##

(1S*,2R*,3R*)-Ethyl-2-(3-chlorophenyl)-3-(2-cyclopropylpyridin-4-yl)cyclopropanecarboxylate (99a)

(257) 1-(3-Chlorobenzyl)tetrahydro-1H-thiophen-1-ium bromide was synthesized using the same preparation as compound 6b, from 1-(bromomethyl)-3-chlorobenzene. Following method F from compound 26b (190 mg, 0.88 mmol) and 1-(3-chlorobenzyl)tetrahydro-1H-thiophen-1-ium bromide (385 mg, 1.31 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (299 mg, >99%, 3:2 trans:cis). LCMS (ES+) 342.5 (M+H).sup.+.

(1S*,2R*,3R*)-Ethyl-2-(3-fluorophenyl)-3-(2-cyclopropylpyridin-4-yl)cyclopropanecarboxylate (99b)

(258) 1-(3-Fluorobenzyl)tetrahydro-1H-thiophen-1-ium bromide was synthesized using the same preparation as compound 6b, from 1-(bromomethyl)-3-fluorobenzene. Following method F from compound 26b (190 mg, 0.88 mmol) and 1-(3-chlorobenzyl)tetrahydro-1H-thiophen-1-ium bromide (363 mg, 1.31 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a colourless oil (243 mg, 85%, 3:2 trans:cis). LCMS (ES+) 326 (M+H).sup.+.

(1S,2R,3R)-2-(3-Chlorophenyl)-3-(2-cyclopropylpyridin-4-yl)-N-hydroxycyclopropanecarboxamide (100a)

(259) Following method A from compound 99a (299 mg, 0.88 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and preparative HPLC gave the racemic mixture as a white solid (100 mg, 35%). Preparative chiral HPLC gave the title compound (Chiralpak IC 30/70 EtOH (0.1% formic acid)/heptane, 1.0 mL/min, RT 8.6 min). RT 2.36 min (Analytical method 1). LCMS (ES+) 329 (M+H).sup.+. .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.56 (1H, s), 8.72 (1H, s), 8.21 (1H, d, J=5.1 Hz), 7.32 (1H, s), 7.27-7.13 (4H, m), 6.96 (1H, dd, J=5.2, 1.7 Hz), 3.03 (1H, dd, J=6.7, 5.3 Hz), 2.92 (1H, dd, J=9.6, 6.8 Hz), 2.23 (1H, dd, J=9.6, 5.4 Hz), 2.02-1.94 (1H, m), 0.88-0.80 (4H, m).

(1S,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)-3-(3-fluorophenyl)-N-hydroxycyclopropanecarboxamide (100b)

(260) Following method A from compound 99b (243 mg, 0.75 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and preparative HPLC gave the racemic mixture as a white solid (95 mg, 41%). Preparative chiral HPLC gave the title compound (Chiralpak IC 20/80 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min, RT 12.1 min). RT 2.21 min (Analytical method 1). LCMS (ES+) 313 (M+H).sup.+. .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.55 (1H, s), 8.70 (1H, s), 8.21 (1H, d, J=5.1 Hz), 7.27-7.18 (1H, m), 7.16-7.04 (3H, m), 6.97-6.90 (2H, m), 3.02 (1H, dd, J=6.6, 5.2 Hz), 2.91 (1H, dd, J=9.6, 6.7 Hz), 2.24 (1H, dd, J=9.7, 5.4 Hz), 2.01-1.94 (1H, m), 0.88-0.80 (4H, m).

Example 35

(261) ##STR00082##

(1S*,2R*,3R)-2-(2,6-Dicyclopropylpyridin-4-yl)-3-(2-fluorophenyl)-N-hydroxycyclopropanecarboxamide (101)

(262) A mixture of 15c (250 mg, 0.75 mmol), 5-methyl-2-(tributylstannyl)thiazole (350 mg, 0.90 mmol) and Pd(PPh.sub.3).sub.4 (43 mg, 0.037 mmol) in dioxane (4 mL) was heated under microwave irradiation at 150° C. for 1 h. The reaction mixture was concentrated and purified by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) to give the title compound (180 mg, 69%). LCMS (ES+) 350 (M+H).sup.+.

(1R,2R,3R)—N-hydroxy-2-(4-(5-methylthiazol-2-yl)phenyl)-3-phenylcyclopropanecarboxamide (102)

(263) Following method A from compound 101 (160 mg, 0.46 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) gave the racemic mixture as a white solid (150 mg, 93%). Preparative chiral HPLC gave the title compound (Chiralpak IC 40/60 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min, RT 11.8 min). RT 3.72 min (Analytical method 1). LCMS (ES+) 351 (M+H).sup.+. .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.53 (1H, s), 8.65 (1H, s), 7.75 (2H, d, J=8.1 Hz), 7.51 (1H, d, J=1.4 Hz), 7.34-7.23 (4H, m), 7.19 (2H, t, J=7.5 Hz), 7.11 (1H, t, J=7.2 Hz), 3.07 (1H, dd, J=6.8, 5.4 Hz), 2.82 (1H, dd, J=9.6, 6.8 Hz), 2.42 (3H, under DMSO), 2.19 (1H, dd, J=9.6, 5.4 Hz).

Example 36

(264) ##STR00083##

(E)-Ethyl-3-(6-chloropyridin-3-yl)acrylate (103)

(265) NaH (792 mg, 20.0 mmol) was added portion wise to stirred anhydrous DMSO (18 mL). The mixture was heated to 80° C. until evolution of gas ceased and then cooled to 0° C. A solution of (carbethoxymethyl)-triphenylphosphonium bromide (4.3 g, 10.0 mmol) in DMSO (36 mL) was then added and the mixture stirred at r.t for 30 min. The mixture was cooled to 00° C. and a solution of 6-chloroisonicotinaldehyde (1.4 g, 10 mmol) in DMSO (36 mL) was added and the mixture was stirred at r.t for 1 h. The mixture was then poured into aqueous 1 M HCl and extracted into DCM (3×70 mL). The organics were combined and washed with H.sub.2O (3×100 mL) and brine (3×100 mL), separated, dried (MgSO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 80% EtOAc in i-hex) gave the title compound as a yellow solid (0.95 g, 45%). LCMS (ES+) 212 (M+H).sup.+.

(1S*,2R*,3R*)-Ethyl-2-(6-chloropyridin-3-yl)-3-(2-fluorophenyl)cyclopropanecarboxylate (104)

(266) Following method F from compound 103 (730 mg, 3.45 mmol) and 6b (1.43 g, 5.18 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 40% EtOAc in i-hex) gave the title compound (810 mg, 73%). LCMS (ES+) 320 (M+H).sup.+.

(1S*,2R*,3R*)-Ethyl-2-(2-fluorophenyl)-3-(6-((2,2,2-trifluoroethyl)amin)pyridin-3-yl)cyclopropanecarboxylate (105)

(267) A mixture of compound 104 (65 mg, 0.203 mmol), trifluoroethylamine (1.0 mL) and NMP (1.0 mL) was heated in the microwave at 225° C. for 1.30 h. The reaction mixture was concentrated and the crude compound purified by flash silica column chromatography (gradient elution DCM to 10% MeOH in DCM) gave the title compound as a yellow solid (42 mg, 54%). LCMS (ES+) 383 (M+H).sup.+.

(1S,2R,3R)-2-(2-Fluorophenyl)-N-hydroxy-3-(6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)cyclopropanecarboxamide (106)

(268) Following method A from compound 105 (40 mg, 0.105 mmol). Post work-up the racemic compound was obtained as a white solid (38 mg, 98%). Preparative chiral HPLC gave the title compound (Chiralpak IC 15/85 EtOH/heptane, 1.0 mL/min, RT 9.2 min). RT 2.60 min (Analytical method 1) LCMS (ES+) 370. .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.52 (1H, s), 8.65 (1H, s), 7.96 (1H, t, J=2.4 Hz), 7.33-7.25 (2H, m), 7.20-7.13 (1H, m), 7.07-6.93 (3H, m), 6.53 (1H, d, J=8.6 Hz), 4.14-4.01 (2H, m), 2.83 (1H, dd, J=6.9, 5.3 Hz), 2.63 (1H, dd, J=9.2, 7.0 Hz), 2.05 (1H, dd, J=9.2, 5.3 Hz).

Example 37

(269) ##STR00084##

(E)-Ethyl-3-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-7-yl)acrylate (107)

(270) A stirred mixture of 7-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (1.00 g, 3.77 mmol), ethyl acrylate (0.53 mL, 4.91 mmol), palladium acetate (84.6 mg, 0.38 mmol), P(o-tol).sub.3 (33 mg, 0.76 mmol) and triethylamine (1.05 mL, 7.55 mmol) in MeCN (10 mL) was degassed under nitrogen for 15 min and heated to 80° C. for 18 h. The reaction mixture was cooled and the MeCN was removed in vacuo. The residue was partitioned between DCM and H.sub.2O and the organic layers were passed through a phase separator and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 100% EtOAc) gave the title compound as a pale yellow solid (1.09 g, 100%). LCMS (ES+) 285 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-phenyl-3-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-7-yl)cyclopropanecarboxylate (108)

(271) Following method F from compound 107 (0.83 mg, 2.92 mmol) and 1-(2-fluorobenzyl)tetrahydro-1H-thiophenium triflate (1.44 mg, 4.38 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 30% EtOAc in i-hex) gave the title compound as a pale yellow oil (540 mg, 49%, 2:1 trans:cis). LCMS (ES+) 375 (M+H).sup.+.

(1R,2R,3R)—N-Hydroxy-2-phenyl-3-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-7-yl)cyclopropanecarboxamide (109)

(272) Following method A from compound 108 (540 mg, 1.44 mmol). Purification by preparative-HPLC gave the racemic product as a pale yellow solid (215 mg, 41%). Preparative chiral purification afforded the title compound (Chiralpak IC 40/60 IPA/MeOH (50/50)/Heptane 5.0 ml/min, RT 7.46 min.) LCMS (ES+) 362 (M+H).sup.+, RT 3.35 min. (Analytical method 1); .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.62 (1H, s), 8.72 (1H, s), 8.64 (1H, s), 8.43 (1H, s), 7.66 (1H, d, J=9.4 Hz), 7.39-7.33 (3H, m), 7.32-7.24 (2H, m), 7.23-7.16 (1H, m), 3.19 (1H, dd, J=6.8, 5.4 Hz), 2.91 (1H, dd, J=9.6, 6.9 Hz), 2.26 (1H, dd, J=9.6, 5.4 Hz).

Example 38

(273) ##STR00085##

(E)-Ethyl-3-(2-methylthiazol-5-yl)acrylate (110)

(274) Following method C to a stirred solution of 2-methyl-1,3 thiazole-50 carboxaldehyde (1.00 g, 7.86 mmol) in anhydrous THF (10 mL) at −10° C. was added sodium hydride (0.63 g, 16.0 mmol) portionwise over 10 min. This was stirred for a further 30 min at −10° C. then triethylphoshonoacetate (3.12 mL, 16.0 mmol) in THF (10 mL) was added dropwise at −10° C. The solution was warmed to RT and stirred for 18 h. The reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO.sub.4), filtered and concentrated to give a dark brown gum (1.97 g). Purification by flash silica column chromatography (gradient elution i-hex to 100% EtOAc in i-hex) gave the title compound as a pale yellow solid (1.39 g, 89%). LCMS (ES+) 198 (M+H).sup.+.

(1R*,2R*,3S*)-Ethyl-2-(2-methylthiazol-5-yl)-3-phenylcyclopropanecarboxy (111)

(275) Following method F from compound 110 (0.72 g, 3.65 mmol) and 1-(2-fluorobenzyl)tetrahydro-1H-thiophenium triflate (1.80 g, 5.48 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 30% EtOAc in i-hex) gave the title compound as a pale yellow oil (392 mg, 37%, 4:1 trans:cis). LCMS (ES+) 287 (M+H).sup.+.

(1R,2R,3S)—N-Hydroxy-2-(2-methylthiazol-5-yl)-3-phenylcyclopropanecarboxamide (112)

(276) Following method A from 111 (390 mg, 1.36 mmol). Purification by preparative-HPLC gave the racemic product as a pale yellow solid (240 mg, 64%). Preparative chiral purification gave the title compound (Chiralpak IC 40/60 IPA/MeOH (50/50)/Heptane 5.0 ml/min, RT 6.05 min). LCMS (ES+) 275 (M+H).sup.+, RT 2.86 min. (Analytical method 1); .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.59 (1H, s), 8.72 (1H, s), 7.53 (1H, s), 7.33-7.21 (4H, m), 7.22-7.15 (1H, m), 3.26-3.20 (1H, m), 2.81 (1H, dd, J=9.6, 6.8 Hz), 2.60 (3H, s), 2.16 (1H, dd, J=9.6, 5.3 Hz).

Example 39

(277) ##STR00086##

(E)-Ethyl-3-(imidazo[1,2-a]pyridin-3-yl)acrylate (113)

(278) Following method C from imidazo[1,2-a]pyridine-3-carbaldehyde (1 g, 6.85 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 75% EtOAc in i-hex) gave the title compound (800 mg, 54%). LCMS (ES+) 217 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(imidazo[1,2-a]pyridin-3-yl)-3-phenylcyclopropanecarboxylate (114)

(279) Following method F from 113 (800 mg, 3.70 mmol) and 1-(2-fluorobenzyl)tetrahydro-1H-thiophenium triflate (1.82 mg, 5.56 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 100% EtOAc in i-hex) gave the title compound (813 mg, 72%). LCMS (ES+) 307 (M+H).sup.+.

(1R,2R,3R)—N-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)-3-phenylcyclopropanecarboxamide (115)

(280) Following method A from 114 (813 mg, 2.66 mmol). Precipitation from DCM gave the title compound as a white solid (400 mg, 51%). Preparative chiral purification gave 8 (Chiralpak IC 40/60 IPA/MeOH (50/50)/Heptane 5.0 ml/min, RT 10.4 min). LCMS (ES+) 294 (M+H).sup.+, RT 2.05 min. (Analytical method 1); .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.56 (1H, s), 8.72 (1H, s), 8.14 (1H, d, J=6.7 Hz), 7.52 (1H, d, J=9.0 Hz), 7.43 (0.1H, s), 7.41 (1H, s), 7.35 (2H, d, J=7.5 Hz), 7.26-7.13 (4H, m), 6.97-6.93 (1H, m), 3.20 (1H, dd, J=6.8, 5.4 Hz), 2.84 (1H, dd, J=9.5, 6.8 Hz), 2.09 (1H, dd, J=9.5, 5.4 Hz).

Example 40

(281) ##STR00087##

(E)-Ethyl-3-(5-chloropyridin-3-yl)acrylate (116)

(282) NaH (570 mg, 14.24 mmol) was added portion wise to stirred anhydrous DMSO (10 mL). The mixture was heated to 80° C. until evolution of gas ceased and then cooled to 0° C. A solution of (carbethoxymethyl)-triphenylphosphonium bromide (3.05 g, 7.12 mmol) in DMSO (10 mL) was then added and the mixture stirred at r.t for 30 min. The mixture was cooled to 00° C. and a solution of 5-chloronicotinaldehyde (1.0 g, 7.12 mmol) in DMSO (10 mL) was added and the mixture was stirred at r.t for 1 h. The mixture was then poured into aqueous 1 M HCl and extracted into DCM (3×50 mL). The organics were combined and washed with H.sub.2O (3×100 mL) and brine (3×100 mL), separated, dried (MgSO.sub.4) and concentrated. Purification by flash silica column chromatography (gradient elution i-hex to 25% EtOAc in i-hex) gave the title compound as a yellow solid (1.1 g, 57%). LCMS (ES+) 271 (M+H).sup.+.

(1R*,2R*,3R*)-Ethyl-2-(5-chloropyridin-3-yl)-3-phenylcyclopropanecarboxylate (117)

(283) Following method F from 116 (1.1 g, 4.07 mmol) and 1-(2-fluorobenzyl)tetrahydro-1H-thiophenium triflate (2.0 g, 6.10 mmol). Purification by flash silica column chromatography (gradient elution i-hex to 15% EtOAc in i-hex) gave the title compound (396 mg, 54%). LCMS (ES+) 361 (M+H).sup.+.

(1R,2R,3R)-2-(5-Chloropyridin-3-yl)-N-hydroxy-3-phenylcyclopropanecarboxamide (118)

(284) Following method A from 117 (396 mg, 1.10 mmol). Purification by flash silica column chromatography (gradient elution DCM to 5% MeOH in DCM) and preparative HPLC purification gave the racemic compound (161 mg, 51%). Preparative chiral purification gave the title compound (Chiralpak IC 40/60 IPA/MeOH (50/50/0.1% formic acid)/heptane 5.0 ml/min, RT 7.74 min). LCMS (ES+) 289 (M+H).sup.+, RT 3.10 min. (Analytical method 1); .sup.1H NMR δ (ppm) (DMSO-d.sub.6): 10.47 (1H, s), 8.61 (1H, s), 8.49 (1H, d, J=1.9 Hz), 8.40 (1H, d, J=2.3 Hz), 7.78-7.73 (1H, m), 7.26 (2H, d, J=7.6 Hz), 7.19 (2H, t, J=7.5 Hz), 7.11 (1H, t, J=7.2 Hz), 3.10 (1H, dd, J=6.8, 5.4 Hz), 2.93 (1H, dd, J=9.6, 6.9 Hz), 2.26 (1H, dd, J=9.6, 5.4 Hz).

Example 41

(285) The following examples may be prepared according to methods substantially as described above.

(286) TABLE-US-00008 TABLE 6 Structure IUPAC Name (1S,2R,3S)-2-(2-fluorophenyl)-N-hydroxy-1-methyl-3-(4- (2-methyloxazol-5-yl)phenyl)cyclopropanecarboxamide (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(4-(3-methyl- 1H-pyrazol-1-yl)phenyl)cyclopropanecarboxamide 0 (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(4-(3- (trifluoromethyl)-1H-pyrazol-1- yl)phenyl)cyclopropanecarboxamide (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(4- (isopropyl(2-morpholinoethyl)amino) phenyl)cyclopropanecarboxamide (1R,2R,3R)-2-(2-cyclopropylpyrimidin-5-yl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(benzo[d]isoxazol-3-yl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(6-cyclopropylpyridazin-4-yl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(6-(3-methyl- 1H-pyrazol-1-yl)pyridin-3-yl)cyclopropanecarboxamide (1S,2R,3R)-2-(6-(5-chloropyrimidin-2-yl)pyridin-3-yl)-3- (2-fluorophenyl)-N-hydroxycyclopropanecarboxamide (1R,2R,3R)-2-(5-chloro-6-(4-isopropylpiperazin-1- yl)pyridin-3-yl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1S,2R,3R)-2-(2-fluorophenyl)-3-(6-(5-fluoropyrimidin-2- yl)pyridin-3-yl)-N-hydroxycyclopropanecarboxamide (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(6-(5- methylpyrimidin-2-yl)pyridin-3- yl)cyclopropanecarboxamide 00 (1R,2R,3R)-N-hydroxy-2-(6-(2-methyloxazol-5-yl)pyridin- 3-yl)-3-phenylcyclopropanecarboxamide 01 (1R,2R,3R)-2-(5-chloro-6-(2-methyloxazol-5-yl)pyridin-3- yl)-N-hydroxy-3-phenylcyclopropanecarboxamide 02 (1S,2R,3R)-2-(2-fluorophenyl)-N-hydroxy-3-(2-(2,2,2- trifluoroethylamino)pyridin-4- yl)cyclopropanecarboxamide 03 (1R,2R,3R)-N-hydroxy-2-phenyl-3-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-4-yl)cyclopropanecarboxamide 04 (1R,2R,3R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-hydroxy- 3-phenylcyclopropanecarboxamide 05 (1R,2R,3R)-N-hydroxy-2-phenyl-3-(1-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4- yl)cyclopropanecarboxamide 06 (1R,2R,3R)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-N-hydroxy- 3-phenylcyclopropanecarboxamide 07 (1R,2R,3S)-N-hydroxy-2-(2-methylthiazol-5-yl)-3- phenylcyclopropanecarboxamide 08 (1R,2R,3R)-2-(8-chloro-1,2,3,4-tetrahydroquinolin-6-yl)- N-hydroxy-3-phenylcyclopropanecarboxamide 09 (1R,2R,3R)-N-hydroxy-2-phenyl-3-(4-(2,2,2- trifluoroethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7- yl)cyclopropanecarboxamide 0 (1R,2R,3R)-N-hydroxy-2-(1-methyl-2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7- yl)-3-phenylcyclopropanecarboxamide (1R,2R,3R)-2-(1-fluoro-2-(2,2,2-trifluoroethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-phenyl-3-(2-(2,2,2- trifluoroethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7- yl)cyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-phenyl-3-(7-(2,2,2- trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2- yl)cyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-phenyl-3-(2- (trifluoromethyl)imidazo[1,2-a]pyridin-7- yl)cyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)-3- phenylcyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-phenyl-3-(pyrrolo[1,2- a]pyrimidin-4-yl)cyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(1,5-naphthyridin-4-yl)-3- phenylcyclopropanecarboxamide (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-N-hydroxy-3-(2- methylthiazol-5-yl)cyclopropanecarboxamide (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-N-hydroxy-3-(5- (trifluoromethyl)thiophen-2-yl)cyclopropanecarboxamide 0 (1R,2R,3R)-2-(1-((5-fluoropyridin-2-yl)methyl)-1H- pyrazol-4-yl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1S,2R,3S)-2-(3-fluoro-5-methylthiophen-2-yl)-N- hydroxy-3-(1-methyl-1H-pyrazol-4- yl)cyclopropanecarboxamide (1S,2S,3R)-N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-(5- methyl-3-(trifluoromethyl)thiophen-2- yl)cyclopropanecarboxamide (1S,2S,3R)-N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-(5- methylthiophen-2-yl)cyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-o- tolylcyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-(2- (trifluoromethyl)phenyl)cyclopropanecarboxamide (1S,2R,3R)-2-(2-chlorophenyl)-N-hydroxy-3-(1-methyl- 1H-pyrazol-4-yl)cyclopropanecarboxamide (1R,2R,3R)-2-(3-fluorophenyl)-N-hydroxy-3-(1-methyl- 1H-pyrazol-4-yl)cyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-m- tolylcyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-3-(3- (trifluoromethyl)phenyl)cyclopropanecarboxamide 0 (1R,2R,3R)-2-(3-chlorophenyl)-N-hydroxy-3-(1-methyl- 1H-pyrazol-4-yl)cyclopropanecarboxamide (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-3-(3-fluoro-5- methylthiophen-2-yl)-N- hydroxycyclopropanecarboxamide (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-N-hydroxy-3-(5- methyl-3-(trifluoromethyl)thiophen-2- yl)cyclopropanecarboxamide (1S,2S,3R)-2-(2-cyclopropylpyridin-4-yl)-N-hydroxy-3-(5- methylthiophen-2-yl)cyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-phenyl-3-(4-(5-(trifluoromethyl)- 1H-imidazol-2-yl)phenyl)cyclopropanecarboxamide (1R,2R,3R)-2-(3-chloro-4-(5-methyl-1H-imidazol-2- yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide (1R,2R,3R)-2-(3-fluoro-4-(5-methyl-1H-imidazol-2- yl)phenyl)-N-hydroxy-3-phenylcyclopropanecarboxamide

Example 42: Analysis of inhibition of HDAC4 with Class IIa Histone Deacetylase (HDAC) Inhibitors

(287) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors is quantified by measuring the Histone Deacetylase 4 (HDAC4) catalytic domain enzymatic activity using the Class IIa selective substrate, Boc-Lys(Tfa)-AMC. The substrate is deacetylated to Boc-Lys-AMC by HDAC4. Cleavage by trypsin results in the release of the fluorophore AMC from the deacetylated substrate. The fluorescence of the sample is directly related to the histone deacetylase activity in the sample.

(288) Serially Dilute HDAC Inhibitor Compounds.

(289) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% dimethyl sulfoxide (DMSO). Stocks of 60 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −20° C. From one stock aliquot of each compound to be tested and the reference compound, a 16-point serial dilution is prepared according to Table 7 using a 125 μl 16-channel Matrix multi-channel pipette (Matrix Technologies Ltd).

(290) TABLE-US-00009 TABLE 7 Serial Dilution of Compounds Concen- Diluted tration Dilution Solutions Well (μM) ratio Volumes Concentration 1 A 10000 — 60 μl 10 mM Test compound/ reference control Concentration 2 B 5000 1:2 30 μl A + 30 μl DMSO Concentration 3 C 2500 1:2 30 μl B + 30 μl DMSO Concentration 4 D 1000   1:2.5 30 μl C + 45 μl DMSO Concentration 5 E 500 1:2 30 μl D + 30 μl DMSO Concentration 6 F 250 1:2 30 μl E + 30 μl DMSO Concentration 7 G 125 1:2 30 μl F + 30 μl DMSO Concentration 8 H 62.5 1:2 30 μl G + 30 μl DMSO Concentration 9 I 31.25 1:2 30 μl H + 30 μl DMSO Concentration 10 J 15.63 1:2 30 μl I + 30 μl DMSO Concentration 11 K 7.81 1:2 30 μl J + 30 μl DMSO Concentration 12 L 3.91 1:2 30 μl K + 30 μl DMSO Concentration 13 M 1.95 1:2 30 μl L + 30 μl DMSO Concentration 14 N 0.98 1:2 30 μl M + 30 μl DMSO Concentration 15 O 0.49 1:2 30 μl N + 30 μl DMSO Concentration 16 P 0.24 1:2 30 μl O + 30 μl DMSO

(291) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottomed polypropylene 384-well compound plates using either the Bravo (384-well head from Agilent) or 12.5 μl 16-channel Matrix multi-channel pipette (Matrix Technologies Ltd). Each well with the 200× compound solution is diluted 1:20 by the addition of 38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl.sub.2 at pH 8.0 and equilibrated to room temperature).

(292) Prepare HDAC4 Catalytic Domain Enzyme (0.86 μg/ml).

(293) The HDAC4 catalytic domain enzyme is human catalytic domain HDAC4 protein (amino acids 648-1057, but with a replacement of amino acids 730-744 with 4 amino acid GSGS linker) made from VCID 3428 and provided by Emerald Biostructures at 1.2 mg/ml. A working solution of enzyme is prepared from a 1.2 mg/ml stock aliquot of HDAC4 catalytic domain (thawed on ice) diluted to 0.86 μg/ml with assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl, and 1 mM MgCl.sub.2 at pH 8 and equilibrated to room temperature) just prior to the addition of the enzyme to the assay.

(294) Prepare 5× (50 μM) Boc-Lys(Tfa)-AMC Substrate.

(295) 5× (50 μM) substrate is prepared just prior to the addition to the assay. A 1 mM substrate stock is made by diluting a 100 mM Boc-Lys(Tfa)-AMC in DMSO solution 1:100 by adding it drop-wise to assay buffer (equilibrated to room temperature) while vortexing at slow speed to prevent precipitation. The 5× substrate is prepared by diluting the 1 mM substrate solution 1:20 by adding it drop-wise to assay buffer (equilibrated to room temperature) while vortexing at slow speed to prevent precipitation.

(296) Prepare 3× (30 μM) Developer/Stop Solution.

(297) 3× (30 μM) Developer/Stop Solution is prepared just prior to addition to the plate by diluting a stock solution of 10 mM reference compound 1:333 in 25 mg/ml trypsin (PAA Laboratories Ltd.) equilibrated to room temperature.

(298) Assay.

(299) 5 μl of each solution of 1:20 diluted compound from above is transferred to a clear bottomed, black, 384-well assay plate using the Bravo or the Janus (384-well MDT head from Perkin Elmer). Using a 16-channel Matrix multi-channel pipette, 35 pII of the working solution of HDAC4 catalytic domain enzyme (0.86 μg/ml in assay buffer) is transferred to the assay plate. The assay is then started by adding 10 μl of 5× (50 μM) substrate to the assay plates using either the Bravo, Janus or 16-channel Matrix multi-channel pipette. The assay plate is then shaken for two minutes on an orbital shaker at 900 rpm (rotations per minute). Next the plate is incubated for 15 minutes at 37° C. The reaction is stopped by adding 25 μl of 3× (30 μM) developer/stop solution to the assay plates using either the Bravo, Janus or a 16-channel Matrix multi-channel pipette. Assay plates are then shaken for 5 minutes on an orbital shaker at 1200 rpm. Next, the assay plates are incubated at 37° C. for 1 hour in a tissue culture incubator. Finally, the fluorescence is measured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmer EnVision in top read mode.

Example 43: Analysis of Inhibition of HDAC5 with Class IIa Histone Deacetylase (HDAC) Inhibitors

(300) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors is quantified by measuring the Histone Deacetylase 5 (HDAC5) enzymatic activity using the Class IIa selective substrate, Boc-Lys(Tfa)-AMC. The substrate is deacetylated to Boc-Lys-AMC by HDAC5. Cleavage by trypsin results in the release of the fluorophore AMC from the deacetylated substrate. The fluorescence of the sample is directly related to the histone deacetylase activity in the sample.

(301) Serially Dilute HDAC Inhibitor Compounds.

(302) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% DMSO. Stocks of 60 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −20° C. From one stock aliquot of each compound to be tested and the reference compound, a 16-point serial dilution is prepared according to Table 7 using a 125 μl 16-channel Matrix multi-channel pipette.

(303) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottom polypropylene 384-well compound plates using either Bravo, Janus, or a 12.5 μl 16-channel Matrix multi-channel pipette. Each well with the 2 μl of the 200× stamped compound solution is diluted 1:20 by the addition of 38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl.sub.2 at pH 8.0 and equilibrated to 37° C.).

(304) Prepare HDAC5 Catalytic Domain Enzyme (0.57 μg/ml).

(305) The HDAC5 catalytic domain enzyme is human HDAC5 catalytic domain (GenBank Accession No. NM_001015053), amino acids 657-1123 with a C-terminal His tag and can be obtained from BPS BioScience. The protein is 51 kDa and is expressed in a baculovirus expression system. A working solution of enzyme is prepared from a 1.65 mg/ml stock aliquot of HDAC5 catalytic domain (thawed on ice) diluted to 0.57 μg/ml with assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl, and 1 mM MgCl.sub.2 at pH 8 and equilibrated to 37° C.) just prior to the addition of the enzyme to the assay.

(306) Prepare 5× (40 μM) Boc-Lys(Tfa)-AMC Substrate.

(307) 5× (40 μM) substrate is prepared just prior to the addition to the assay. The 5× substrate is prepared by diluting the 100 mM Boc-Lys(Tfa)-AMC in DMSO solution 1:2500 by adding it drop-wise to assay buffer (equilibrated to 37° C.) while vortexing at slow speed to prevent precipitation.

(308) Prepare 3× (30 μM) Developer/Stop Solution.

(309) 3× (30 μM) Developer/Stop Solution is prepared just prior to addition to the plate by diluting a stock solution of 10 mM reference compound 1:333 in 25 mg/ml trypsin equilibrated to 37° C.

(310) Assay.

(311) 5 μl of each solution of the 1:20 diluted inhibitor compounds and controls from above is transferred to a clear bottomed, black, 384-well assay plate using the Bravo or Janus. Using a 16-channel Matrix multi-channel pipette, 35 μl of the working solution of the HDAC5 catalytic domain enzyme (0.57 μg/ml in assay buffer) is transferred to the assay plate. The assay is then started by adding 10 μl of 5× (40 μM) substrate to the assay plates using either the Bravo, Janus or 16-channel Matrix multi-channel pipette. The assay plate is then shaken for one minute on an orbital shaker at 900 rpm. Next, the plates are incubated for 15 minutes at 37° C. The reaction is stopped by adding 25 μl of 3× (30 μM) developer/stop solution to the assay plates using either the Bravo, Janus or a 16-channel Matrix multi-channel pipette. Assay plates are then shaken for 2 minutes on an orbital shaker at 900 rpm. Next, the assay plates are incubated at 37° C. for 1 hour in a tissue culture incubator followed by shaking for 1 minute at the maximum rpm on an orbital shaker before reading on the EnVision. Finally, the fluorescence is measured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmer EnVision in top read mode.

Example 44: Analysis of Inhibition of HDAC7 with Class IIa Histone Deacetylase (HDAC) Inhibitors

(312) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors is quantified by measuring the Histone Deacetylase 7 (HDAC7) enzymatic activity using the Class IIa selective substrate, Boc-Lys(Tfa)-AMC. The substrate is deacetylated to Boc-Lys-AMC by HDAC7. Cleavage by trypsin results in the release of the fluorophore AMC from the deacetylated substrate. The fluorescence of the sample is directly related to the histone deacetylase activity in the sample.

(313) Serially Dilute HDAC Inhibitor Compounds.

(314) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% DMSO. Stocks of 60 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −20° C. From one stock aliquot of each compound to be tested and the reference compound, a 16-point serial dilution is prepared according to Table 7 using a 125 μl 16-channel Matrix multi-channel pipette.

(315) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottom polypropylene 384-well compound plates using either the Bravo, Janus, or a 12.5 μl 16-channel Matrix multi-channel pipette. Each well with the 200× compound solution is diluted 1:20 by the addition of 38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl.sub.2 at pH 8.0 and equilibrated to 37° C.).

(316) Prepare HDAC7 Enzyme (71 ng/ml).

(317) The HDAC7 enzyme is human HDAC7 (GenBank Accession No. AY302468) amino acids 518-end with a N-terminal Glutathione S-transferase (GST) tag and can be obtained from BPS BioScience. The protein is 78 kDa and is expressed in a baculovirus expression system. A working solution of enzyme is prepared from a 0.5 mg/ml stock aliquot of HDAC7 (thawed on ice) diluted to 71 ng/ml with assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl, and 1 mM MgCl.sub.2 at pH 8 and equilibrated to 37° C.) just prior to the addition of enzyme to the assay.

(318) Prepare 5× (50 μM) Boc-Lys(Tfa)-AMC Substrate.

(319) 5× (50 μM) substrate is prepared just prior to the addition to the assay. The 5× substrate is prepared by diluting a 100 mM Boc-Lys(Tfa)-AMC in DMSO solution 1:2000 by adding it drop-wise to assay buffer (equilibrated to 37° C.) while vortexing at slow speed to prevent precipitation.

(320) Prepare 3× (30 μM) Developer/Stop Solution.

(321) 3× (30 μM) Developer/Stop Solution is prepared just prior to addition to the plate by diluting a stock solution of 10 mM reference compound 1:333 in 25 mg/ml trypsin equilibrated to 37° C.

(322) Assay.

(323) 5 μl of each solution of 1:20 diluted compound from above is transferred to a clear bottomed, black, 384-well assay plate using the Bravo or Janus. Using a 16-channel Matrix multi-channel pipette, 35 μl of the working solution of the HDAC7 enzyme (71 ng/ml in assay buffer) is transferred to the assay plate. The assay is then started by adding 10 μl of 5× (50 μM) substrate to the assay plate using either the Bravo, Janus or 16-channel Matrix multi-channel pipette. The assay plate is then shaken for one minute on an orbital shaker at 900 rpm. Next, the plate is incubated for 15 minutes at 37° C. The reaction is then stopped by adding 25 μl of 3× (30 μM) developer/stop solution to the assay plates using either the Bravo, Janus or a 16-channel Matrix multi-channel pipette. The assay plate is then shaken for 2 minutes on an orbital shaker at 900 rpm. Next, the assay plate is incubated at 37° C. for 1 hour in a tissue culture incubator followed by shaking for 1 minute at maximum rpm on an orbital shaker. Finally, the fluorescence is measured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmer EnVision in top read mode.

Example 45: Analysis of Inhibition of HDAC9 with Class IIa Histone Deacetylase (HDAC) Inhibitors

(324) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors is quantified by measuring the Histone Deacetylase 9 (HDAC9) enzymatic activity using the Class IIa selective substrate, Boc-Lys(Tfa)-AMC. The substrate is deacetylated to Boc-Lys-AMC by HDAC9. Cleavage by trypsin results in the release of the fluorophore AMC from the deacetylated substrate. The fluorescence of the sample is directly related to the histone deacetylase activity in the sample.

(325) Serially Dilute HDAC Inhibitor Compounds.

(326) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% DMSO. Stocks of 60 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −20° C. From one stock aliquot of each compound to be tested and the reference compound, a 16-point serial dilution is prepared according to Table 7 using a 125 μl 16-channel Matrix multi-channel pipette.

(327) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottom polypropylene 384-well compound plates using either the Bravo, Janus, or 12.5 μl 16-channel Matrix multi-channel pipette. Each well with the stamped 200× compound solution is diluted 1:20 by the addition of 38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl.sub.2 at pH 8.0 and equilibrated to 37° C.).

(328) Prepare HDAC9 Enzyme (0.57 μg/ml).

(329) The HDAC9 enzyme is human HDAC9 (GenBank Accession No. NM_178423) amino acids 604-1066 with a C-terminal His tag and can be obtained from BPS BioScience. The protein is 50.7 kDa and is expressed in a baculovirus expression system. A working solution of enzyme is prepared from a 0.5 mg/ml stock aliquot of HDAC9 (thawed on ice) diluted to 0.57 μg/ml with assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl, and 1 mM MgCl.sub.2 at pH 8 and equilibrated to 37° C.) just prior to the addition of enzyme to the assay.

(330) Prepare 5× (125 μM) Boc-Lys(Tfa)-AMC Substrate.

(331) 5× (125 μM) substrate is prepared just prior to the addition to the assay. The 5× substrate is prepared by diluting a 100 mM Boc-Lys(Tfa)-AMC in DMSO solution 1:800 by adding it drop-wise to assay buffer (equilibrated to 37° C.) while vortexing at slow speed to prevent precipitation.

(332) Prepare 3× (30 μM) Developer/Stop Solution.

(333) 3× (30 μM) Developer/Stop Solution is prepared just prior to addition to the plate by diluting a stock solution of 10 mM reference compound 1:333 in 25 mg/ml trypsin equilibrated to 37° C.

(334) Assay.

(335) 5 μl of each solution of 1:20 diluted compound from above is transferred to a clear bottomed, black, 384-well assay plate using the Bravo or Janus. Using a 16-channel Matrix multi-channel pipette, 35 μl of the working solution of the HDAC9 enzyme (0.57 μg/ml in assay buffer) is transferred to the assay plate. The assay is then started by adding 10 μl of 5× (125 μM) substrate to the assay plate using either the Bravo, Janus or 16-channel Matrix multi-channel pipette. The assay plate is then shaken for one minute on an orbital shaker at 900 rpm. Next, the plate is incubated for 15 minutes at 37° C. The reaction is stopped by adding 25 μl of 3× developer/stop solution to the assay plates using either the Bravo, Janus or a 16-channel Matrix multi-channel pipette. The assay plate is then shaken for 2 minutes on an orbital shaker at 900 rpm. Next, the assay plate is incubated at 37° C. for 1 hour in a tissue culture incubator followed by shaking for 1 minute at maximum rpm on an orbital shaker before reading on the enVision. Finally, the fluorescence is measured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmer EnVision in top read mode.

Example 46: Analysis of Inhibition of Cellular HDAC Activity with Class IIa Histone Deacetylase (HDAC) Inhibitors

(336) The potency of Class IIa Histone Deacetylase (HDAC) inhibitors is quantified by measuring the cellular histone deacetylase enzymatic activity using the Class IIa selective substrate, Boc-Lys(Tfa)-AMC. After penetration in Jurkat E6-1 cells, the substrate is deacetylated to Boc-Lys-AMC. After cell lysis and cleavage by trypsin, the fluorophore AMC is released from the deacetylated substrate only. The fluoresence of the sample is directly related to the histone deacetylase activity in the sample.

(337) Jurkat E6.1 Cell Culture and Plating.

(338) Jurkat E6.1 cells are cultured according to standard cell culture protocols in Jurkat E6.1 Growth Media (RPMI without phenol red, 10% FBS, 10 mM HEPES, and 1 mM Sodium Pyruvate). Jurkat E6.1 cells are counted using a Coulter Counter and resuspended in Jurkat E6.1 growth media at a concentration of 75,000 cells/35 μl. 35 μl or 75,000 cells is seeded into Greiner microtitre assay plates. The plates are then incubated at 37° C. and 5% CO.sub.2 while other assay components are being prepared.

(339) Serially Dilute HDAC Inhibitor Compounds.

(340) Serial dilutions of the HDAC inhibitors and control reference compound (1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone) are made by first resuspending the lyophilized compound to a final concentration of 10 mM in 100% DMSO. Stocks of 70 μl aliquots of the 10 mM compound in DMSO are prepared and stored at −20° C. From one stock aliquot of each compound to be tested and the reference compound, a 16-point serial dilution is prepared according to Table 7 using a 125 μl 16-channel Matrix multi-channel pipette.

(341) 2 μl (200×) of each diluted solution and each control (full activity: 100% DMSO alone or full inhibition 1 mM) is stamped into V-bottom polypropylene 384-well compound plates using either the Bravo, Janus, or 12.5 pII 16-channel Matrix multi-channel pipette. Each well with the 200× compound solution is diluted 1:20 by the addition of 38 μl Jurkat assay buffer+DMSO (9.5% DMSO, RPMI without phenol red, 0.09% FBS, 9 mM Hepes, and 0.9 mM Sodium Pyruvate equilibrated to room temperature)

(342) Prepare 5× (500 μM) Boc-Lys(Tfa)-AMC Substrate.

(343) 5× (500 μM) substrate is prepared just prior to the addition to the assay. The 5× substrate is prepared by diluting a 100 mM Boc-Lys(Tfa)-AMC in DMSO solution 1:200 by adding it drop-wise to Jurkat assay medium (RPMI without phenol red, 0.1% FBS, 10 mM Hepes, and 1 mM Sodium Pyruvate equilibrated to 37° C.) while vortexing at slow speed to prevent precipitation.

(344) Prepare 3× Lysis Buffer.

(345) 10 ml of 3× lysis buffer is prepared with 8.8 ml of 3× stock lysis buffer (50 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl.sub.2, 1% Nonidet P40 Substitute equilibrated to room temperature) and 1.2 ml of 3 mg/ml Trypsin equilibrated to room temperature.

(346) Assay.

(347) 5 μl of each solution of 1:20 diluted compound from above is transferred to the Greiner microtitre assay plates with 75,000 cells/well using the Bravo. Cells are then incubated for 2 hours at 37° C. and 5% CO.sub.2. The assay is then started by adding 10 μl of 5× (500 μM) substrate to the assay plate using either the Bravo or 16-channel Matrix multi-channel pipette. The cells are then incubated for 3 hours at 37° C. and 5% CO.sub.2. Next, 25 μl of 3× lysis buffer is added to each well using either the 125 μl 16 channel pipette or the Bravo. The assay plate is then incubated overnight (15-16 hours) at 37° C. and 5% CO.sub.2. The following day, the plates are shaken on an orbital shaker for 1 minute at 900 rpm. Finally the top read fluorescence (Excitation: 355 nm, Emission: 460 nm) is measured using PerkinElmer EnVision.

Example 47

(348) Using the synthetic methods similar to those described above and the assay protocols described above, the following compounds were synthesized and tested.

(349) TABLE-US-00010 TABLE 8 Biochemical Cellular Compound HDAC-4 IC.sub.50 IC.sub.50 Chemical Name Number (μM) (μM) (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-(4- 50i 0.10 1.25 (pyrimidin-5- yl)phenyl)cyclopropanecarboxamide (1R*,2R*,3R*)-2-(2-Bromophenyl)-N- 16a 0.62 6.53 hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-o- 18a 1.72 13.16 tolylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-(4- 50h 0.06 0.62 (pyrimidin-2- yl)phenyl)cyclopropanecarboxamide (1S*,2R*,3R*)-2-(2-Fluorophenyl)-N- 13 0.94 7.67 hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(2- 11a 20.57 50 isopropoxyphenyl)-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(2-Fluorophenyl)-N- 11b 0.32 1.83 hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3- 25c 1.81 19.68 (pyrimidin-5-yl)cyclopropanecarboxamide (1S*,2R*,3R*)-2-Cyclopentyl-N-hydroxy- 25a 8.96 48.08 3-phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(4-(5- 50k 0.09 0.48 methylpyrimidin-2-yl)phenyl)-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-(4- 50d 0.21 0.88 Trifluoromethylpyrimidin-2-yl)phenyl)-N- hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-(5- 50c 0.22 0.81 Cyclopropylpyrimidin-2-yl)phenyl)-N- hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-(5-Fluoropyrimidin-2- 50a 0.06 0.39 yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(3-(5-Fluoropyrimidin-2- 50b 0.10 1.02 yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3- 28a 1.09 23.52 (pyridazin-4-yl)cyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-(4-(oxazol-5- 41b 0.02 0.22 yl)phenyl)-3- phenylcyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-(3-(oxazol-5- 41a 0.04 0.39 yl)phenyl)-3- phenylcyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(2- 39 0.02 0.22 isopropylbenzo[d]oxazol-6-yl)-3- phenylcyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-phenyl-3-(5- 68 0.23 2.31 (trifluoromethyl)pyridin-3- yl)cyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-phenyl-3-(6- 28f 0.34 5.67 (trifluoromethyl)pyridin-3- yl)cyclopropanecarboxamide (1R,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)- 28b 0.02 0.67 N-hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)- 25d 0.03 0.62 3-(4-fluorophenyl)-N- hydroxycyclopropanecarboxamide (1R,2R,3R)-2-(2,2- 28e 0.12 2.03 Difluorobenzo[d][1,3]dioxol-5-yl)-N- hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(4-(2-Cyclopropyloxazol-5- 46 0.04 0.28 yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-phenyl-3-(2- 28g 0.30 2.58 (trifluoromethyl)pyridin-4- yl)cyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-(1-oxo-2-(2,2,2- 33 0.03 0.34 trifluoroethyl)isoindolin-5-yl)-3- phenylcyclopropanecarboxamide (1S,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)- 28c 0.04 0.53 3-(2-fluorophenyl)-N- hydroxycyclopropanecarboxamide (1R,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)- 28d 0.12 0.79 3-(4-fluorophenyl)-N- hydroxycyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-(1-methyl-1H- 25b 0.54 2.62 pyrazol-4-yl)-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(4-(5- 50e 0.18 0.69 Trifluoromethylpyrimidin-2-yl)phenyl)-N- hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(8-Chloro-2,3- 25e 0.02 0.13 dihydrobenzo[b][1,4]dioxin-6-yl)-N- hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-(4- 50f 0.08 0.62 (pyridazin-3- yl)phenyl)cyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-(4- 50g 0.11 0.66 (pyridazin-4- yl)phenyl)cyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(4-(4- 56i 0.14 1.31 methylpiperazin-1-yl)phenyl)-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(4-(oxazol-2- 58 0.05 0.35 yl)phenyl)-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(4-(1-methyl- 60 0.29 2.05 1H-imidazol-2-yl)phenyl)-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-(1H-pyrazol-1- 65 0.09 0.97 yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-(3,3-Dimethylazetidin- 56d 0.33 3.17 1-yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(4-(4- 56a 0.09 0.76 isopropylpiperazin-1-yl)phenyl)-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(4-(3,3- 56c 0.15 1.77 difluoropyrrolidin-1-yl)phenyl)-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-(2-Oxa-6- 56e 0.15 1.33 azaspiro[3.3]heptan-6-yl)phenyl)-N- hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(3′-(Benzyloxy)-[1,1′- 54a 0.99 8.85 biphenyl]-4-yl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(4-(1-Benzyl-1,2,3,6- 71 0.35 0.75 tetrahydropyridin-4-yl)phenyl)-N-hydroxy- 3-phenylcyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(4-(4-methyl-3,4- 54c 0.26 1.43 dihydro-2H-benzo[b][1,4]oxazin-7- yl)phenyl)-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-(2- 52 0.48 1.79 cyclopropylisoindolin-5-yl)phenyl)-N- hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4′-(9H-carbazol-9-yl)- 54b 5.66 50 [1,1′-biphenyl]-4-yl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2S*,3S*)-2-(4-(5-Fluoropyrimidin-2- 63 0.27 1.55 yl)phenyl)-N-hydroxy-1-methyl-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(3-(4- 56b 1.43 5.08 isopropylpiperazin-1-yl)phenyl)-3- phenylcyclopropanecarboxamide (1R,2R,3R)-2-(3-(6,7- 56h 0.17 0.77 Dihydropyrazolo[1,5-a]pyrimidin-4(5H)- yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(3- 56f 0.63 1.85 (Hexahydropyrrolo[1,2-a]pyrazin-2(1H)- yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-(3- 56g 0.39 2.18 (4-(pyrrolidin-1-yl)piperidin-1- yl)phenyl)cyclopropanecarboxamide (1R,2R,3R)-2-(4-(5-Chloropyrimidin-2- 50j 0.14 0.42 yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-(4-(5-methyl- 50l 0.10 0.46 1H-imidazol-2-yl)phenyl)-3- phenylcyclopropanecarboxamide (1S,2R,3R)-2-(8-Chloro-2,3- 25f 0.03 0.24 dihydrobenzo[b][1,4]dioxin-6-yl)-3-(2- fluorophenyl)-N- hydroxycyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-(4- 48 0.28 1.26 (2-phenyloxazol-5- yl)phenyl)cyclopropanecarboxamide trans-N-Hydroxy-2,3- 2 0.34 2.52 diphenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-Cyclohexyl-N-hydroxy-3- 5 6.22 36.91 phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-Bromophenyl)-N- 16c 0.37 2.87 hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4-(1H-imidazol-1- 42 0.20 1.63 yl)phenyl)-N-hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(4- 22 0.05 1.32 (cyclopropanesulfonamido)phenyl)-N- hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-p- 18c 0.15 2.25 tolylcyclopropanecarboxamide (1R*,2R*,3R*)-2-(3-Bromophenyl)-N- 16b 0.07 1.41 hydroxy-3- phenylcyclopropanecarboxamide (1R*,2R*,3R*)-N-Hydroxy-2-phenyl-3-m- 18b 0.15 2.74 tolylcyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-(4-(2- 75a 0.03 0.33 methyloxazol-5-yl)phenyl)-3- phenylcyclopropanecarboxamide (1S,2R,3R)-2-(2-Fluorophenyl)-N- 75b 0.05 0.47 hydroxy-3-(4-(2-methyloxazol-5- yl)phenyl)cyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-(3-(5- 77 0.16 0.78 methylpyrimidin-2-yl)phenyl)-3- phenylcyclopropanecarboxamide (1S,2R,3R)-2-(2,6-Dicyclopropylpyridin-4- 88 0.20 1.48 yl)-3-(2-fluorophenyl)-N- hydroxycyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-(4-(3-methyl- 79 0.09 0.65 1H-pyrazol-1-yl)phenyl)-3- phenylcyclopropanecarboxamide (1S,2R,3R)-2-(2-Fluorophenyl)-N- 83 0.12 0.75 hydroxy-3-(6-(4-isopropylpiperazin-1- yl)pyridin-3-yl)cyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-phenyl-3-(1-(5- 92b 0.18 1.17 (trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4- yl)cyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(imidazo[1,2- 115 0.55 6.66 a]pyridin-3-yl)-3- phenylcyclopropanecarboxamide (1R,2R,3R)-N-Hydroxy-2-phenyl-3-(2- 109 0.23 2.5 (trifluoromethyl)imidazo[1,2-a]pyridin-7- yl)cyclopropanecarboxamide (1S,2R,3R)-2-(2-Cyclopropylpyridin-4-yl)- 100b 0.02 0.42 3-(3-fluorophenyl)-N- hydroxycyclopropanecarboxamide (1R,2R,3R)-N-hydroxy-2-(4-(5- 102 0.04 0.44 methylthiazol-2-yl)phenyl)-3- phenylcyclopropanecarboxamide (1S,2R,3R)-2-(2-Fluorophenyl)-N- 106 0.17 1.41 hydroxy-3-(6-((2,2,2- trifluoroethyl)amino)pyridin-3- yl)cyclopropanecarboxamide

(350) While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations on the scope of the claims.