Histone deacetylase inhibitors and compositions and methods of use thereof

Abstract

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

Claims

1. A method for treating a condition or disorder mediated by at least one histone deacetylase in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of Formula I: ##STR00240## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is C(O)NH(OH) or N(OH)C(O)R.sup.9; R.sup.2 is aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile; A is aryl or heteroaryl; R.sup.3 is chosen from hydrogen, alkyl, halo, NHSO.sub.2R.sup.10, C(O)NR.sup.11R.sup.12, NR.sup.11R.sup.12, nitrile, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl, heteroaryl, and nitrile, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino; R.sup.4 is absent or is chosen from hydrogen, alkyl, halo, NHSO.sub.2R.sup.10, C(O)NR.sup.11R.sup.12, NR.sup.11R.sup.12, nitrile, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl, heteroaryl, and nitrile, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino; for each occurrence, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently chosen from hydrogen and lower alkyl; R.sup.9 is hydrogen or lower alkyl; R.sup.10 is lower alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R.sup.11 and R.sup.12 are independently chosen from hydrogen, lower alkyl, alkoxy, lower haloalkyl and cycloalkyl, wherein alkyl and alkoxy are optionally substituted with amino, (alkyl)amino or di(alkyl)amino, and m and m are independently chosen from 0, 1, 2, 3 and 4, provided that 2(m+m)4.

2. The method of claim 1, wherein said at least one histone deacetylase is HDAC4.

3. The method of claim 1, wherein said condition or disorder involves a neurodegenerative pathology.

4. The method of claim 1, wherein said condition or disorder is Huntington's disease.

5. The method of claim 1, wherein the compound of Formula I is a compound of Formula II: ##STR00241##

6. The method of claim 1, wherein the compound of Formula I is a compound of Formula III: ##STR00242##

7. The method of claim 1, wherein the compound of Formula I is a compound of Formula VI: ##STR00243##

8. The method of claim 1, wherein the compound of Formula I is a compound of Formula VII: ##STR00244##

9. The method of claim 1, wherein the compound of Formula I is a compound of Formula IV: ##STR00245##

10. The method of claim 1, wherein the compound of Formula I is a compound of Formula V: ##STR00246##

11. The method of claim 1, wherein the compound of Formula I is a compound of Formula VIII: ##STR00247##

12. A method for treating a condition or disorder mediated by at least one histone deacetylase in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(3-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-1-(3-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(4-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(p-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(3-Chloro-2-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(2,6-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(2,5-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(2,6-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(2-Chloro-6-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluoro-6-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-1-(5-fluoropyridin-2-yl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(2,4-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-Cyclopentyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(pyrazin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-2-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-2-(3-Chloropyridin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluoropyridin-2-yl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide; E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide; E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide; E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide; 5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide; and 5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide; 5-(3-Fluoro-2-methylphenyl)-1-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and 5-(3-fluoro-2-methylphenyl)-2-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide; E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide; E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide; 3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide; 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxamide; 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide; 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide; 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide; 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide; 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide; 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide; 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxamide; (S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide; (R)-2-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide; (R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide; (S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-isopropyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (R)-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide; (S)-6-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide; (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide; (R)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide; (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide; (S)-1-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (R)-1-Cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide; (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide; E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; 5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-(trifluoromethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; (R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; (R)-2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide; (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(o-tolyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide; E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; E1-(abs)-2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; E2-(abs)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide; (S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide; (R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; E1-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide; E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide; 2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide; 2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxamide; E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide; E2-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide; and N-Hydroxy-6-phenyl-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide; E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide; E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide; N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2-carboxamide; (S)-1-(2-Chloro-4-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-2-(4,6-Dimethylpyrimidin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide; (R)-1-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide; (R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide; (R)-4-(3-fluoro-2-methylphenyl)-2-(2-fluorobenzyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide; and (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide.

13. The method of claim 9, wherein said condition or disorder is Huntington's disease.

14. The method of claim 10, wherein said condition or disorder is Huntington's disease.

15. The method of claim 11, wherein said condition or disorder is Huntington's disease.

16. The method of claim 12, wherein said condition or disorder is Huntington's disease.

17. The method of claim 10, wherein m is 1 and m is 1.

18. The method of claim 10, wherein, for each occurrence, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen.

19. The method of claim 10, wherein R.sup.2 is phenyl optionally substituted with 1 to 3 substituents independently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

20. The method of claim 19, wherein R.sup.2 is phenyl optionally substituted with 1 to 3 substituents independently chosen from halo and alkyl.

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) aq. Aqueous

(4) DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

(5) DCM: Dichloromethane

(6) DDQ: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

(7) DME: Dimethoxyethane

(8) DIPEA: Diisopropylethylamine

(9) DMAP: Dimethylaminopyridine

(10) DMF: Dimethylformamide

(11) DMSO: Dimethylsulfoxide

(12) ES+: Electrospray Positive Ionisation

(13) ES: Electrospray Negative Ionisation

(14) Et.sub.2O: Diethyl ether

(15) EtOAc: Ethyl acetate

(16) h: Hour(s)

(17) HPLC: High Performance Liquid Chromatography

(18) i-hex: iso-Hexane

(19) IPA: iso-Propyl alcohol

(20) LCMS: Liquid Chromatography Mass Spectrometry

(21) LiHMDS: Lithium bis(trimethylsilyl)amide

(22) M: Mass

(23) MeCN: Acetonitrile

(24) MeOH: Methanol

(25) min: Minute(s)

(26) MS: Mass spectrum

(27) NBS: N-Bromosuccinimide

(28) NMR: Nuclear Magnetic Resonance

(29) RT: Retention time

(30) r.t.: Room temperature

(31) sat.: Saturated

(32) SFC: Supercritical Fluid Chromatography

(33) TBAF: Tetrabutylammonium fluoride

(34) tBu: tert-Butyl

(35) TFA: Trifluoroacetic acid

(36) TFFH: Fluoro-N,N,N,N-tetramethylformamidinium hexafluorophosphate

(37) THF: Tetrahydrofuran

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

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

(40) Analytical Conditions

(41) TABLE-US-00001 Analytical Method # Description Analytical method 1 Solvents: Acetonitrile (far UV grade) with 0.1% (v/v) formic acid. Water (high purity via PureLab Option unit) with 0.1% formic acid Column: Phenomenex Luna 5 m 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 L (concentration~0.2- 1.0 mg/mL) Analytical method 2 Solvents: Acetonitrile (Far UV grade) with 0.1% (V/V) 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 L Analytical method 3 Solvents: -Acetonitrile (Far UV grade) with 0.1% (V/V) formic acid Water (High purity via PureLab Ultra unit) with 0.1% formic acid Column: Supelco, Ascentis Express C18 or Hichrom Halo C18, 2.7 m C18, 150 4.6 mm. Both latest technology fused core columns 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 0.2-10 ul

Preparation of Intermediates 1 and 2: (1S,4R)-4-(3-Fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one and (R)-methyl-1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate

(42) Method 1

(43) ##STR00011##

Step 1: (S)-1,4-Dibromobutan-2-ol

(44) To a stirred solution of (S)-butane-1,2,4-triol (2 g, 18.9 mmol) and triphenylphosphine (9.9 g, 37.7 mmol) in DCM (100 mL) at 0 C. was added NBS (6.7 g, 37.7 mmol) portionwise. The mixture was allowed to warm to r.t. and stirred for 17 h. The reaction mixture was washed with water (2100 mL) and sat. brine solution (100 mL) and the organics passed through a phase separator before concentrating in vacuo. The residue was dissolved in DCM (10 mL) and added to rapidly stirred Et.sub.2O (200 mL). The resulting solid was removed by vacuum filtration. Additional solid precipitated in the filtrate during filtration, so this process was repeated several times to remove residual triphenylphosphine oxide. The filtrate was concentrated and the resulting oil purified by flash silica column chromatography (gradient elution 5% EtOAc in i-hex to 10% EtOAc in i-hex) to give the title compound as a colorless oil (1.5 g, 35%). .sup.1H NMR (ppm)(CHCl.sub.3-d): 4.09-4.01 (1H, m), 3.61-3.50 (3H, m), 3.42 (1H, dd, J=10.4, 6.7 Hz), 2.18 (1H, dd, J=5.4, 0.8 Hz), 2.13-2.01 (2H, m).

Step 2: (S)-1,4-Dibromobutan-2-yl 2-(3-fluoro-2-methylphenyl)acetate

(45) To a stirred solution of (S)-1,4-dibromobutan-2-ol (1.43 g, 6.16 mmol) in DCM (30 mL) was added 2-(3-fluoro-2-methylphenyl)acetic acid (941 mg, 5.60 mmol), dicyclohexylcarbodiimide (1.27 g, 6.16 mmol) and DMAP (20 mg, catalytic) and the mixture stirred at r.t. for 17 h. The reaction was filtered and a white solid was removed by filtration and washed with DCM (325 mL). The filtrate was collected and washed with 1 M HCl.sub.(aq) (30 mL), sat. brine solution (30 mL) and the organics passed through a phase separator and concentrated. Purification by flash silica chromatography (gradient elution i-hex to 20% EtOAc in i-hex) gave the title compound as a white crystalline solid (2.06 g, 96%). .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.15-7.07 (1H, m), 7.02-6.93 (2H, m), 5.20-5.12 (1H, m), 3.70 (2H, s), 3.58 (1H, dd, J=11.1, 4.7 Hz), 3.45 (1H, dd, J=11.1, 4.3 Hz), 3.34 (1H, ddd, J=10.3, 6.6, 5.5 Hz), 3.25 (1H, ddd, J=10.3, 8.4, 6.1 Hz), 2.35-2.26 (1H, m), 2.24 (3H, d, J=2.7 Hz), 2.26-2.12 (1H, m).

Step 3: (1S,4R)-4-(3-Fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one (Intermediate 1)

(46) To a stirred solution of (S)-1,4-dibromobutan-2-yl 2-(3-fluoro-2-methylphenyl)acetate (2.05 g, 5.37 mmol) in 1,4-dioxane (50 mL) at r.t., was added LiHMDS (11.8 mL, 11.8 mmol, 1 M in THF) at a rate of 1 mL/min. After complete addition, the mixture was stirred for 1 h and quenched with 1 M aq. HCl (20 mL) and then extracted into EtOAc (350 mL). The combined organics were washed with water (50 mL) and sat brine solution (50 mL), separated, dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica chromatography (gradient elution i-hex to 5% EtOAc in i-hex) gave the title compound as a white crystalline solid (890 mg, 75%). MS (ES+) 221 (M+H).sup.+; .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.17-7.08 (1H, m), 7.07-6.97 (2H, m), 5.00 (1H, d, J=2.10 Hz), 2.81 (1H, dd, J=10.4, 2.4 Hz), 2.40-2.18 (2H, m), 2.30 (3H, d, J=2.3 Hz), 2.13-2.07 (2H, m), 1.93 (1H, d, J=10.3 Hz).

Step 4: (1R,3S)-Methyl-1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate

(47) To a stirred solution of (1R,4S)-4-(3-fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one (890 mg, 4.05 mmol) in MeOH (30 mL) was added 4 M HCl in dioxane (1 mL). The mixture was heated to 60 C. for 17 h and then concentrated. Purification by flash silica chromatography (gradient elution i-hex to 30% EtOAc in i-hex) gave the title compound as a white crystalline solid (766 mg, 75% [95% based on recovered starting material]). .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.18-7.06 (2H, m), 6.98-6.89 (1H, m), 4.42-4.37 (1H, m), 3.66 (3H, s), 2.74-2.69 (1H, m), 2.66-2.58 (1H, m), 2.55 (1H, d, J=7.85 Hz), 2.29-2.13 (3H, m), 2.13 (3H, d, J=2.7 Hz), 1.83-1.72 (1H, m).

Step 5: (R)-Methyl-1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate (Intermediate 2)

(48) To a solution of (1S,3R)-methyl-1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (766 mg, 3.04 mmol) in anhydrous DCM (20 mL) was added Dess-Martin Periodinane (1.55 g, 3.64 mmol). The reaction mixture was stirred at r.t. for 4 h. Reaction mixture was quenched with a mixture of 10% Na.sub.2S.sub.2O.sub.3 and sat. NaHCO.sub.3 solution (1:1, 50 mL) and then rapidly stirred for 30 min. Organic layers were extracted with further DCM (250 mL), then dried, filtered (phase separation cartridge) and concentrated to give a pale yellow oil. The residue was purified by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) to give the title compound as a colorless solid (656 mg, 86%). MS (ES+) 251 (M+H).sup.+; .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.28-7.19 (1H, m), 7.17-7.02 (2H, m), 3.76 (3H, s), 3.23 (1H, d, J=17.9 Hz), 2.88-2.79 (1H, m), 2.69-2.33 (4H, m), 2.19 (3H, d, J=2.7 Hz). SFC (Analytical) (Chiralpak IA 5/95 IPA/CO.sub.2, 5.0 mL/min, 120 bar, 40 C.) RT 2.4 min; Chiral HPLC (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min) RT 10.35 min (95.7% ee). Double recrystallization from hot heptane gave enantioenriched product (1.5 g, >99.5% ee).

Preparation of Intermediate 3: (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate

(49) Following Method 1 starting from (S)-butane-1,2,4-triol.

(50) Method 2

(51) ##STR00012##

Step 1: (S)-2-Hydroxybutane-1,4-diyl dimethanesulfonate

(52) (S)-Butane-1,2,4-triol (20.0 g, 0.19 mol) was dissolved in anhydrous pyridine (85 mL). The reaction mixture was rapidly stirred whilst being cooled to 10 C. (NaCl/ice bath). Methanesulfonyl chloride (44.3 g, 30 mL, 0.40 mol) was then added drop-wise whilst maintaining internal flask temperature at <4 C. (3 h). Once addition was complete the reaction mixture was stirred at r.t. for a further 1 h. After this time reaction was cooled to 4 C. and 2 M aq. HCl (200 mL) was added over 20 min. The resulting solution was partitioned with EtOAc (300 mL), washed with further 2 M aq. HCl (200 mL), dried, filtered (phase separation cartridge) and concentrated to give a yellow oil which partially solidified on standing. The residue was dissolved in the minimum hot EtOAc and left to stand at 20 C. for 16 h. Precipitated solids were filtered and washed with cold Et.sub.2O/i-hex (1:9, 50 mL) to give the title compound as colorless crystals (26.8 g, 55%). [Purification can also be achieved via flash silica column chromatography (Et.sub.2O to EtOAc)this gives a close running impurity which can be easily separated at the next step.] R.sub.f=0.2 (66% EtOAc/i-hex); MS (ES+) 263 (M+H).sup.+; .sup.1H NMR (ppm): (DMSO-d.sub.6): 5.33 (1H, s), 4.35-4.23 (2H, m), 4.19-3.99 (2H, m), 3.89-3.81 (1H, m), 3.19 (3H, s), 3.18 (3H, s), 1.94-1.84 (1H, m), 1.77-1.66 (1H, m).

Step 2: (S)-2-((tert-Butyldiphenylsilyl)oxy)butane-1,4-diyl dimethanesulfonate

(53) To a 4 C. solution of (S)-2-hydroxybutane-1,4-diyl dimethanesulfonate (23.2 g, 0.09 mol) in anhydrous DMF (75 mL) was added tert-butylchlorodiphenylsilane (36.5 g, 34.5 mL, 0.11 mol) followed by imidazole (10.0 g, 0.15 mol). The reaction mixture was stirred at 4 C. for 1 h then at r.t. for a further 16 h. The reaction mixture was quenched using ice water (200 mL) with rapid stirring for 30 min. The corresponding solution was partitioned with EtOAc (300 mL), washed with water (2200 mL), and then sat. NaCl solution (250 mL). The combined organic layers were dried, filtered (phase separation cartridge) and concentrated to give a yellow oil. Purification by flash silica column chromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave the title compound as a colorless glass (42.0 g, 93%). R.sub.f=0.55 (66% EtOAc/i-hex); MS (ES+) 501 (M+H).sup.+; .sup.1H NMR (ppm)(DMSO-d.sub.6): 7.67-7.63 (4H, m), 7.52-7.41 (6H, m), 4.31-4.16 (2H, m), 4.13-4.01 (3H, m), 3.08 (3H, s), 3.02 (3H, s), 1.92 (2H, dd, J=12.2, 6.1 Hz), 1.02 (9H, s).

Step 3: (S)-tert-Butyl((1,4-dibromobutan-2-yl)oxy)diphenylsilane

(54) To a solution of (S)-2-((tert-butyldiphenylsilyl)oxy)butane-1,4-diyl dimethanesulfonate (42.0 g, 0.08 mol) in anhydrous DMF (320 mL) was added lithium bromide (22.0 g, 0.25 mol). The reaction mixture was stirred at 105 C. for 1.5 h. The reaction mixture was cooled to r.t. and partitioned between EtOAc (500 mL) and water (300 mL). Organic layers were washed with further water (2300 mL) and sat. NaCl solution (400 mL). The combined organic layers were dried, filtered (phase separation cartridge) and concentrated to give a yellow oil. Purification by flash silica column chromatography (gradient elution i-hex to 10% EtOAc in i-hex) gave the title compound as a colorless oil which darkens upon standing (30.0 g, 80%). R.sub.f=0.80 (60% EtOAc/i-hex); MS (ES+) 471 (M+H).sup.+; .sup.1H NMR (ppm)(DMSO-d.sub.6): 7.69-7.63 (4H, m), 7.52-7.41 (6H, m), 4.07-3.99 (1H, m), 3.53-3.40 (4H, m), 2.10 (2H, dd, J=13.0, 6.5 Hz), 1.04 (9H, s).

Step 4: (S,3S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate

(55) To a solution of (S)-tert-butyl((1,4-dibromobutan-2-yl)oxy)diphenylsilane (6.43 g, 0.014 mol) and methyl 2-(3-fluoro-2-methylphenyl)acetate (2.0 g, 0.011 mol) in anhydrous DMF (80 mL) was added 18-crown-6 (0.2 g, catalytic). The reaction mixture was stirred at r.t. for 10 min then sodium hydride (60% dispersion in mineral oil 1.05 g, 0.03 mol) was added portion-wise over 1.5 h. Reaction mixture was stirred at r.t. for a further 16 h. The reaction mixture was cooled to 4 C. and quenched by drop-wise addition of 5% NaH.sub.2PO.sub.4 solution (15 mL). The solution was then partitioned between EtOAc (250 mL) and water (200 mL). The organic layer was washed with further water (2150 mL), sat NaCl solution (200 mL), then dried, filtered (phase separation cartridge) and concentrated to give a yellow oil. The resultant oil was dissolved in anhydrous THF (80 mL) and TBAF (IM in THF, 0.03 mol, 30 mL) was added. Reaction mixture was then stirred at r.t. for 3 h. After this time the reaction mixture was concentrated under reduced pressure and purified by flash silica column chromatography (gradient elution i-hex to 33% EtOAc in i-hex) to give the title compound as a colorless oil (2.10 g, 78%, 5:1 mixture of isomers). R.sub.f=0.1 (20% EtOAc/i-hex); MS (ES+) 253 (M+H).sup.+.

Step 5: (1S,4R)-4-(3-Fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one

(56) To a solution of (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (5:1 (1S,3S):(1R:3S) mixture of isomers, 2.10 g, 0.0086 mol) in anhydrous acetonitrile (100 mL) was added DBU (1.44 g, 1.42 mL, 0.0095 mol). The reaction mixture was stirred at 80 C. for 20 h. The reaction mixture was cooled to r.t. and partitioned between DCM (125 mL) and 1 M HCl (100 mL). Organic layers were extracted, washed with water (100 mL), then dried, filtered (phase separation cartridge) and concentrated to give a yellow oil. The residue was purified by flash silica column chromatography (gradient elution i-hex to 40% EtOAc in i-hex) to give the title compound (1S,4R)-4-(3-fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one as a colorless oil (256 mg); R.sub.f=0.3 (33% EtOAc/i-hex); MS (ES+) 221 (M+H).sup.+; .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.18-7.10 (1H, m), 7.09-6.98 (2H, m), 5.00 (1H, d, J=2.1 Hz), 2.81 (1H, dd, J=10.4, 2.4 Hz), 2.39-2.32 (1H, m), 2.32 (3H, d, J=2.8 Hz), 2.30-2.21 (1H, m), 2.15-2.07 (2H, m), 1.93 (1H, d, J=10.3 Hz); .sup.19F NMR: 114.43; and unreacted starting material (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate as a colorless oil (1.63 g); R.sub.f=0.15 (33% EtOAc/i-hex); MS (ES+) consistent with target (M+H).sup.+; .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.24 (1H, d, J=8.03 Hz), 7.19-7.11 (1H, m), 6.97-6.90 (1H, m), 4.56-4.49 (1H, m), 3.62 (3H, s), 3.07 (1H, dd, J=13.8, 6.6 Hz), 2.47-2.42 (2H, m), 2.11 (3H, d, J=2.8 Hz), 2.10-2.01 (1H, m), 1.92 (1H, ddd, J=13.9, 4.5, 1.1 Hz), 1.79-1.70 (1H, m), 1.38 (1H, d, J=4.2 Hz); .sup.19F NMR: 114.83.

Step 6: (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate (Intermediate 3)

(57) To a solution of (1S,3S)-methyl 1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (1.60 g, 6.5 mmol) in anhydrous DCM (100 mL) was added Dess-Martin Periodinane (3.32 g, 7.8 mmol). The reaction mixture was stirred at r.t. for 4 h. Reaction mixture was quenched with a mixture of 10% Na.sub.2S.sub.2O.sub.3 and sat. NaHCO.sub.3 solution (1:1, 100 mL) and then rapidly stirred for 30 min. Organic layers were extracted with further DCM (250 mL), then dried, filtered (phase separation cartridge) and concentrated to give a pale yellow oil. The residue was purified by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) to give the title compound as a colorless solid (1.42 g, 84%). R.sub.f=0.25 (33% EtOAc/i-hex); .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.28-7.19 (1H, m), 7.17-7.02 (2H, m), 3.76 (3H, s), 3.28 (1H, d, J=17.9 Hz), 2.88-2.79 (1H, m), 2.69-2.33 (4H, m), 2.19 (3H, d, J=2.7 Hz); SFC (Analytical) (Chiralpak IA 5/95 IPA/CO.sub.2, 5.0 mL/min, 120 bar, 40 C.) RT 2.1 min (>99.5% ee); Chiral HPLC (Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min) RT 9.48 min.

Preparation of Intermediates 4-8: 3-tert-butyl 1-methyl 3-fluoro-4-hydroxy-2-methyl-1,2,5,6-tetrahydro-[1,1-biphenyl]-1,3-dicarboxylate, methyl 1-(3-fluoro-2-methylphenyl)-4-oxocyclohexanecarboxylate, methyl 1-(3-fluoro-2-methylphenyl)-3-formyl-4-oxocyclohexanecarboxylate, methyl 2-amino-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate and methyl 2-bromo-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

(58) ##STR00013##

Step 1: 3-tert-Butyl 1-methyl 3-fluoro-4-hydroxy-2-methyl-1,2,5,6-tetrahydro-[1,1-biphenyl]-1,3-dicarboxylate (Intermediate 4)

(59) Methyl 2-(3-fluoro-2-methylphenyl)acetate (3.13 g, 17.2 mmol), DMF (30 mL) and t-butyl acrylate (5.22 mL, 36.12 mmol) were combined at room temperature under a nitrogen atmosphere. Reaction mixture was cooled with an ice bath and NaH (60% in oil) (3.44 g, 86 mmol) was added portionwise. Reaction mixture was stirred at room temperature for 20 h and then carefully quenched with sat. aq. NH.sub.4Cl solution, with ice bath cooling. The reaction mixture was extracted with EtOAc which was then washed with water, brine and evaporated to dryness onto silica, then purified by flash chromatography to give 3-tert-butyl 1-methyl 3-fluoro-4-hydroxy-2-methyl-1,2,5,6-tetrahydro-[1,1-biphenyl]-1,3-dicarboxylate as a white solid (2.14 g, 34%). .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.20-7.05 (1H, m), 7.00-6.85 (2H, m), 3.70 (3H, s), 2.75 (2H, m), 2.4-2.15 (3H, m), 2.13 (3H, d, J=2.4 Hz), 1.85-1.70 (1H, m), 1.55 (9H, s). OH resonance not observed.

Step 2: Methyl 1-(3-fluoro-2-methylphenyl)-4-oxocyclohexanecarboxylate (Intermediate 5)

(60) Intermediate 4 (2.14 g, 5.88 mmol) and TFA (10 mL) were combined and stirred at room temperature for 20 h. The TFA was then removed by evaporation in vacuo and the residue was azeotroped with toluene. Toluene (100 mL), MeOH (10 mL) and NaHCO.sub.3 (200 mg) were added and the mixture was heated to 105 C. for 20 h. The reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a white solid (799 mg, 52%). LCMS (ES+) 265 (M+H).sup.+; .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.22-7.15 (2H, m), 7.05-6.95 (1H, m), 3.72 (3H, s), 2.77-2.64 (4H, m), 2.46-2.41 (2H, m), 2.27-2.20 (2H, m), 2.21 (3H, d, J=2.4 Hz).

Step 3: Methyl 1-(3-fluoro-2-methylphenyl)-3-formyl-4-oxocyclohexanecarboxylate (Intermediate 6)

(61) tBuOK (233 mg, 2.08 mmol) and THF were combined under a nitrogen atmosphere. The reaction mixture was cooled with an ice bath and ethyl formate (0.61 mL, 7.56 mmol) was added dropwisecare: effervescence. After 20 min intermediate 5 (500 mg, 1.89 mmol) was added dropwise as a solution in ethyl formate (2.5 mL). The reaction mixture was stirred for a further 1 h with ice bath cooling then diluted with EtOAc and washed with 1 N HCl, dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a brown gum (516 mg, 94%). LCMS (ES) 291 (MH).sup..

Step 4: Methyl 2-amino-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate (Intermediate 7)

(62) Intermediate 5 (550 mg, 2.08 mmol), thiourea (228 mg, 3 mmol) and AcOH (10 mL) were combined in a sealed tube. Bromine (0.107 mL, 2.08 mmol) was added and the mixture was heated to 65 C. for 18 h. Reaction mixture was cooled and evaporated to dryness. Residue was partitioned between 2 N NaOH soln. and EtOAc. Extracted with EtOAc (2), organics were then dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a tan solid (641 mg, 96%). LCMS (ES+) 321 (M+H).sup.+.

Step 5: Methyl 2-bromo-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate (Intermediate 8)

(63) Intermediate 7 (1.94 g, 6.06 mmol), CuBr.sub.2 (1.49 g, 6.67 mmol) and MeCN (100 mL) were combined. t-Butyl nitrite (0.94 mL, 7.88 mmol) was added dropwisecare: exotherm. After stirring for 2 h the reaction mixture was quenched with 1N HCl and extracted with EtOAc (2), dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a brown solid (2.08 g, 89%). LCMS (ES+) 384/386 (M+H).sup.+.

Step 6: 4-Ethyl 1-methyl 1-(3-fluoro-2-methylphenyl)-5-oxocycloheptane-1,4-dicarboxylate (Intermediate 9)

(64) Intermediate 5 (1.0 g, 3.79 mmol) was dissolved in dry DCM (11 mL) and cooled to 0 C. under a nitrogen atmosphere. Triethyloxonium tetrafluoroborate (4.6 mL, 4.55 mmol, 1.0 M in DCM) was added in one portion. Ethyl diazoacetate (0.48 mL, 4.55 mmol) was added dropwise over 10 min maintaining the internal temperature at 0 C. The reaction was stirred at 0 C. for 3 h then quenched with saturated sodium bicarbonate solution. The reaction mixture was transferred to a separating funnel and extracted with DCM (2). The combined organic extracts were washed with water, dried (magnesium sulfate), filtered and evaporated to dryness to afford the title compound as a yellow oil (1.47 g, >100%). NMR indicated a mixture of enol and ketone forms. Used without further purification in the next step.

Preparation of Intermediate 10: (S)-Methyl 2-bromo-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate

(65) ##STR00014##

Step 1: (S)-Methyl 2-amino-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate

(66) Intermediate 3 (0.75 g, 3.0 mmol), thiourea (0.25 g, 3.3 mmol) and bromine (0.52 g, 3.3 mmol) were added to acetic acid (10 mL) and heated to 100 C. for 16.5 h. The reaction was cooled, diluted with EtOAc (50 mL) and washed with NaOH (2N, 250 mL), water then brine followed by concentration under vacuum to give the title compound (0.66 g) which was used in the next step without further purification. LCMS (ES+) 307 (M+H).sup.+.

Step 2: (S)-Methyl 2-bromo-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate

(67) To a solution of (S)-methyl 2-amino-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate (0.54 g, 1.79 mmol) and copper (II) bromide (0.44 g, 1.96 mmol) in MeCN (10 mL) was added tert-butyl nitrite, drop-wise and the reaction mixture stirred at 20 C. for 0.6 h. The reaction was quenched on HCl (1 N, 50 mL), extracted into DCM (75 mL) and subjected to an aqueous workup. Separation of the organic and concentration under vacuum gave crude the title compound (0.63 g) which was used in the next step without further purification. LCMS (ES+) 370/372 (M+H).sup.+.

Preparation of Intermediates 11 and 12: Methyl 3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate and methyl 2-bromo-5-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

(68) ##STR00015##

Step 1: Methyl 2-allyl-2-(3-fluoro-2-methylphenyl)pent-4-enoate

(69) A solution of methyl 2-(3-fluoro-2-methylphenyl)acetate (1.95 g, 10.7 mmol) and allyl bromide (0.96 mL, 10.7 mmol) in dry DMF (20 mL) was treated at r.t under N.sub.2 with NaH (60 wt % in oil, 448 mg, 10.7 mmol) and stirred for 2 h. After this time a further equivalent of allyl bromide and NaH were added, followed by a final addition of 0.5 equivalents of allyl bromide and NaH 1 h later. 1 h after the final addition the reaction was quenched with H.sub.2O (1 mL), diluted with EtOAc (100 mL) and washed with water (420 mL) and brine (20 mL). The organic layer was dried (Na.sub.2SO.sub.4) and concentrated to give 2.96 g yellow liquid that was used without further purification.

Step 2: Methyl 1-(3-fluoro-2-methylphenyl)cyclopent-3-enecarboxylate

(70) A solution of methyl 2-allyl-2-(3-fluoro-2-methylphenyl)pent-4-enoate (2.96 g from previous step, 10.7 mmol) and Grubbs 2.sup.nd generation catalyst (210 mg, 0.25 mmol) in DCM (300 mL) was stirred under N.sub.2 at r.t for 24 h. The mixture was concentrated onto silica and purified by flash silica chromatography (gradient elution, 0-50% EtOAc in i-hex) to give the title compound (1.85 g) as a pale brown liquid of approximately 80% purity.

Step 3: Methyl 3-bromo-1-(3-fluoro-2-methylphenyl)-4-hydroxycyclopentanecarboxylate

(71) A solution of methyl 1-(3-fluoro-2-methylphenyl)cyclopent-3-enecarboxylate (1.66 g, 7.09 mmol), NBS (1.39 g, 7.81 mmol) and ammonium acetate (80.3 mg, 1.04 mmol) in acetone (25 mL) and water (6 mL) was stirred at r.t for 2 h. After evaporating solvents the mixture was partitioned between water (20 mL) and DCM (40 mL) and the organic layer concentrated. The residue was purified by flash silica chromatography (gradient elution of 0% to 100% EtOAc in i-hex) to give the title compound as a colorless liquid (1.74 g, 5.25 mmol, 74%) as a mixture of stereoisomers.

Step 4: Methyl 3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate (Intermediate 11)

(72) A suspension of methyl 3-bromo-1-(3-fluoro-2-methylphenyl)-4-hydroxycyclopentanecarboxylate (1.74 g, 5.25 mmol) and Dess-Martin periodinane (2.44 g, 5.75 mmol) in DCM (50 mL) was stirred at r.t for 16 h. The reaction mixture was concentrated onto silica and purified by flash silica chromatography (gradient elution of 0% to 100% EtOAc in i-hex) to give the title compound as a colorless liquid (1.58 g, 4.80 mmol, 91%) as a mixture of stereoisomers.

Step 5: Methyl 1-(3-fluoro-2-methylphenyl)-3-oxo-4-thiocyanatocyclopentanecarboxylate

(73) A solution of intermediate 11 (800 mg, 2.43 mmol) and potassium thiocyanate (500 mg, 5.15 mmol) in dry acetonitrile (8 mL) was heated at 100 C. under microwave irradiation for 10 min. After cooling to r.t. the mixture was combined with two other identical reactions and partitioned between water (20 mL) and DCM (60 mL), dried (phase separator) and concentrated. Purification by flash silica chromatography (gradient elution, 0-100% EtOAc in i-hex) gave the title compound (2.07 g, 6.74 mmol, 93%) as white prisms in a 2:1 diastereomeric mixture.

Step 6: Methyl 2-bromo-5-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate (Intermediate 12)

(74) A solution of methyl 1-(3-fluoro-2-methylphenyl)-3-oxo-4-thiocyanatocyclopentanecarboxylate (338 mg, 1.10 mmol) in HBr (33 wt % in AcOH, 1 mL) and AcOH (3 mL) was heated at 100 C. under microwave irradiation for 10 min. After cooling to rt, the mixture was combined with three other identical reactions and poured into water (30 mL). DCM (50 mL) was added and the mixture was stirred vigorously at r.t for 5 min. The DCM layer was washed with sat. aq. NaHCO.sub.3 (40 mL), dried (phase separator) and concentrated. Purification by flash silica chromatography (gradient elution, 0-50% EtOAc in i-hex) gave the title compound (620 mg, 1.67 mmol, 51%) as a colorless liquid.

Preparation of Intermediates 13-16: (1R)-Methyl 3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate

(75) ##STR00016##

Step 1: (1R)-Methyl 3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate (Intermediate 13)

(76) To a cooled solution of Intermediate 2 (4.5 g, 18 mmol) in DCM (100 mL) at 78 C. was added 4 M HCl in dioxane (0.45 mL). This was stirred for 5 min before dropwise addition of bromine (2.88 g, 18 mmol). The reaction was stirred at 78 C. for 1 h then removed from the ice-bath. After an additional 1 h at r.t the reaction was diluted with water (100 mL) and the organics collected. The aqueous portion was re-extracted with DCM (100 mL), and the combined organics passed through a phase separator and concentrated. Purification by flash chromatography (10% EtOAc in i-hex) gave the title compound as a colorless oil which crystallized on standing (2.37 g, 40%). LCMS (ES+) 329/331 (M+H).sup.+.

Step 2: (S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-oxo-4-thiocyanatocyclopentanecarboxylate

(77) A solution of Intermediate 13 (800 mg, 2.43 mmol) and potassium thiocyanate (500 mg, 5.15 mmol) in dry acetonitrile (8 mL) was heated at 100 C. under microwave irradiation for 10 min. After cooling to r.t. the mixture was combined with two other identical reactions and partitioned between water (20 mL) and DCM (60 mL), dried (phase separator) and concentrated. Purification by flash silica chromatography (gradient elution, 0-100% EtOAc in i-hex) gave the title compound (2.07 g, 6.74 mmol, 93%) as white prisms in a 2:1 diastereomeric mixture. LCMS (ES+) 308 (M+H).sup.+.

Step 3: (S)-Methyl 2-bromo-5-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate (Intermediate 14)

(78) A solution of (S)-methyl 1-(3-fluoro-2-methylphenyl)-3-oxo-4-thiocyanatocyclopentanecarboxylate (338 mg, 1.10 mmol) in HBr (33 wt % in AcOH, 1 mL) and AcOH (3 mL) was heated at 100 C. under microwave irradiation for 10 min. After cooling to r.t. the mixture was combined with three other identical reactions and poured into water (30 mL). DCM (50 mL) was added and the mixture was stirred vigorously at r.t. for 5 min. The DCM layer was washed with sat. aq. NaHCO.sub.3 (40 mL), dried (phase separator) and concentrated. Purification by flash silica chromatography (gradient elution, 0-50% EtOAc in i-hex) gave the title compound (620 mg, 1.67 mmol, 51%) as a colorless liquid.

(79) Steps 1-3 can be performed starting from Intermediate 3 to access Intermediate 15 and Intermediate 16.

PREPARATION OF EXAMPLES

Example 1: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(80) ##STR00017##

Step 1: (1 S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-formyl-4-oxocyclopentanecarboxylate

(81) tBuOK (247 mg, 2.2 mmol) and THF (15 mL) were combined under a nitrogen atmosphere. The reaction mixture was cooled with an ice bath and ethyl formate (0.64 mL, 8 mmol) was added dropwisecare effervescence. After 15 min, Intermediate 3 (500 mg, 2 mmol) was added dropwise as a solution in ethyl formate (2.5 mL). The reaction mixture was stirred for a further 1 h with ice bath cooling then diluted with EtOAc and washed with 1N HCl, dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a tan oil (569 mg, 100%). LCMS (ES+) 279 (M+H).sup.+.

Step 2: (S)-Methyl 5-(3-fluoro-2-methylphenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate

(82) (1S)-Methyl 1-(3-fluoro-2-methylphenyl)-3-formyl-4-oxocyclopentanecarboxylate (569 mg, 2 mmol), acetic acid (10 mL) and phenylhydrazine (0.2 mL, 2 mmol) were combined in a sealed tube and heated to 70 C. for 1 h. Reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a brown gum (451 mg, 64%). LCMS (ES+) 351 (M+H).sup.+.

Step 3: (S)-5-(3-Fluoro-2-methylphenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylic acid

(83) (S)-Methyl 5-(3-fluoro-2-methylphenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate (451 mg, 1.29 mmol), MeOH (15 mL) and 15% aq. NaOH soln. (4 mL) were combined in a sealed tube and heated to 70 C. for 1 day. Reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 1N HCl and evaporated to dryness once more to give the title compound as a brown gum (315 mg, 73%). LCMS (ES+) 337 (M+H).sup.+.

Step 4: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(84) (S)-5-(3-Fluoro-2-methylphenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylic acid (315 mg, 0.94 mmol), TFFH (264 mg, 1 mmol), DMF (2 mL) and triethylamine (0.5 mL) were combined and stirred at room temperature for 1.5 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (234 mg, 2 mmol) was then added and stirring continued for 1 day. Volatile solvents were removed in vacuo. MeOH (5 mL) and 2N HCl in Et.sub.2O (2 mL) were added and reaction mixture was stirred for 2 h. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as an off white solid (256 mg). LCMS (ES+) 352 (M+H).sup.+, RT 3.52 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.26 (1H, s), 8.80 (1H, br s), 7.70-7.60 (2H, m), 7.55-7.45 (3H, m), 7.30 (1H, m), 7.25-7.00 (3H, m), 4.12 (1H, d), 3.40 (1H, d), 3.25 (1H, d), 3.20 (1H, d), 2.20 (3H, d, J=2.4 Hz).

Example 2: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(85) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a tan solid (64 mg). LCMS (ES+) 366 (M+H).sup.+, RT 9.93 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.23 (1H, s), 8.79 (1H, br s), 7.45-7.00 (8H, m), 3.76 (1H, d, 16 Hz), 3.45 (1H, d, J=15 Hz), 3.25 (1H, d, J=15 Hz), 2.51 (1H, d, J=16 Hz), 2.11 (3H, d, J=2.4 Hz), 2.01 (3H, s).

Example 3: (S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(86) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a white solid (115 mg). LCMS (ES+) 370 (M+H).sup.+, RT 3.43 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, s), 8.81 (1H, s), 7.70-7.30 (5H, m), 7.25-6.95 (3H, m), 3.83 (1H, d, J=16 Hz), 3.45 (1H, d, J=15 Hz), 3.13 (1H, d, J=15 Hz), 3.03 (1H, d, J=16 Hz), 2.12 (3H, d, J=2.8 Hz).

Example 4: (S)-1-(3-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(87) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a white solid (85 mg). LCMS (ES+) 386/388 (M+H).sup.+, RT 3.78 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.27 (1H, s), 8.85 (1H, s), 7.75-7.45 (5H, m), 7.25-7.00 (3H, m), 4.11 (1H, d, J=16 Hz), 3.41 (1H, d, J=16 Hz), 3.33 (1H, d, J=16 Hz), 3.15 (1H, d, J=16 Hz), 2.17 (3H, d, J=2.4 Hz).

Example 5: (S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(88) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as an off white solid (41 mg). LCMS (ES+) 370 (M+H).sup.+, RT 3.65 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.24 (1H, s), 8.81 (1H, s), 810 (1H, s), 7.78-7.74 (2H, m), 7.35-7.25 (2H, m) 7.25-7.00 (3H, m), 3.65 (1H, d, J=16 Hz), 3.50 (1H, d, J=16 Hz), 3.10 (1H, d, J=16 Hz), 3.05 (1H, d, J=16 Hz), 2.17 (3H, d, J=2.4 Hz).

Example 6: (S)-5-(3-Fluoro-2-methylphenyl)-1-(3-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(89) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a tan solid (129 mg). LCMS (ES+) 370 (M+H).sup.+, RT 3.67 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.26 (1H, s), 8.83 (1H, br s), 7.60-7.45 (4H, m), 7.25-7.00 (4H, m), 4.13 (1H, d, J=16 Hz), 3.39 (1H, d, J=16 Hz), 3.31 (1H, d, J=16 Hz), 3.17 (1H, d, J=16 Hz), 2.18 (3H, d, J=2.4 Hz).

Example 7: (S)-1-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(90) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as an off white solid (108 mg). LCMS (ES+) 386/388 (M+H).sup.+, RT 3.37 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, s), 8.80 (1H, br s), 7.75-7.45 (5H, m), 7.25-7.00 (3H, m), 3.7 (1H, d, J=16 Hz), 3.45 (1H, d, J=16 Hz), 3.5 (1H, d, J=15 Hz), 2.89 (1H, d, J=16 Hz), 2.11 (3H, d, J=2.8 Hz).

Example 8: (S)-1-(4-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(91) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as an off white solid (15 mg). LCMS (ES+) 386/388 (M+H).sup.+, RT 3.52 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.24 (1H, s), 8.81 (1H, s), 8.15 (1H, s), 7.80-7.70 (2H, m), 7.60-7.50 (2H, m), 7.25-7.00 (3H, m), 3.65 (1H, d, J=16 Hz), 3.50 (1H, d, J=16 Hz), 3.11 (1H, d, J=16 Hz), 3.06 (1H, d, J=16 Hz), 2.1 (3H, d, J=2.8 Hz).

Example 9: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(p-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(92) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a brown solid (60 mg). LCMS (ES+) 366 (M+H).sup.+, RT 9.08 min (Analytical method 3); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.26 (1H, s), 8.80 (1H, br s), 7.52 (2H, d, J=8.4 Hz), 7.43 (1H, s), 7.28 (2H, d, J=8 Hz), 7.25-7.20 (3H, m), 4.10 (1H, d, J=16 Hz), 3.40 (1H, d, J=16 Hz), 3.22 (1H, d, J=16 Hz), 3.15 (1H, d, J=16 Hz), 2.32 (3H, s), 2.17 (3H, d, J=2.8 Hz).

Example 10: (S)-1-(3-Chloro-2-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(93) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as tan solid (124 mg). LCMS (ES+) 404/406 (M+H).sup.+, RT 9.05 min (Analytical method 3); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.23 (1H, s), 8.80 (1H, br s), 7.70-7.60 (2H, m), 7.56 (1H, s), 7.40-7.30 (1H, m), 7.25-7.00 (3H, m), 3.84 (1H, d, J=15 Hz), 3.40 (1H, d, J=15 Hz), 3.15 (1H, d, J=15 Hz), 3.00 (1H, d, J=15 Hz), 2.12 (3H, d, J=2.8 Hz).

Example 11: (S)-1-(2,6-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(94) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as beige solid (131 mg). LCMS (ES+) 388 (M+H).sup.+, RT 8.52 min (Analytical method 3); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.21 (1H, s), 8.81 (1H, br s), 7.65-7.50 (2H, m), 7.45-7.30 (2H, m), 7.25-6.95 (3H, m), 3.73 (1H, d, J=16 Hz), 3.53 (1H, d, J=16 Hz), 3.15 (1H, d, J=16 Hz), 2.90 (1H, d, J=16 Hz), 2.10 (3H, d, J=2.8 Hz).

Example 12: (S)-1-(2,5-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(95) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as grey solid (108 mg). LCMS (ES+) 380 (M+H).sup.+, RT 9.03 min (Analytical method 3); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, s), 8.80 (1H, br s), 7.39 (1H, s), 7.30-7.00 (6H, m), 3.76 (1H, d, J=16 Hz), 3.44 (1H, d, J=16 Hz), 3.17 (1H, d, J=16 Hz), 2.79 (1H, d, J=16 Hz), 2.33 (3H, s), 2.10 (3H, d, J=2.8 Hz), 2.00 (3H, s).

Example 13: (S)-1-(2,6-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(96) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a tan solid (80 mg). LCMS (ES+) 380 (M+H).sup.+, RT 3.50 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.23 (1H, s), 8.80 (1H, br s), 7.43 (1H, s), 7.30-7.00 (5H, m), 3.66 (1H, d, J=15.6 Hz), 3.39 (1H, d, J=15.2 Hz), 3.27 (1H, d, J=15.2 Hz), 2.54 (1H, d, J=15.6 Hz), 2.08 (3H, d, J=32.4 Hz), 2.01 (3H, s), 1.63 (1H, s).

Example 14: (S)-1-(2-Chloro-6-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(97) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a tan solid (146 mg). LCMS (ES+) 404/406 (M+H).sup.+, RT 9.86 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, s), 8.80 (1H, br s), 7.65-7.40 (4H, m), 7.25-7.00 (3H, m), 3.69 (1H, d, J=16 Hz), 3.43 (1H, d, J=15.2 Hz), 3.17 (1H, d, J=15.2 Hz), 2.80 (1H, d, J=16 Hz), 2.09 (3H, d, J=3.6 Hz).

Example 15: (S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluoro-6-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(98) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a tan solid (157 mg). LCMS (ES+) 384 (M+H).sup.+, RT 10.13 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, s), 8.81 (1H, br s), 7.50-7.00 (7H, m), 3.81 (1H, d, J=16 Hz), 3.46 (1H, d, J=14.8 Hz), 3.12 (1H, d, J=15.2 Hz), 3.02 (1H, d, J=16 Hz), 2.32 (3H, d, J=2 Hz), 2.12 (3H, d, J=2.4 Hz).

Example 16: (S)-5-(3-Fluoro-2-methylphenyl)-1-(5-fluoropyridin-2-yl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(99) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as an off white solid (126 mg). LCMS (ES+) 371 (M+H).sup.+, RT 3.55 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.24 (1H, s), 8.80 (1H, br s), 8.46 (1H, s), 8.00-7.85 (2H, m), 7.52 (1H, s), 7.20-7.00 (3H, m), 4.03 (1H, d, J=16.8 Hz), 3.45 (1H, d, J=16.8 Hz), 3.42 (1H, d, J=15.6 Hz), 3.06 (1H, d, J=15.2 Hz), 2.15 (3H, d, J=2.8 Hz).

Example 17: (S)-1-(2,4-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(100) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as an off white solid (118 mg). LCMS (ES+) 388 (M+H).sup.+, RT 9.99 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, s), 8.80 (1H, br s), 7.70-7.60 (1H, m), 7.60-7.50 (2H, m), 7.30-7.00 (4H, m), 3.82 (1H, d, J=15 Hz), 3.45 (1H, d, J=15 Hz), 3.14 (1H, d, J=15 Hz), 3.01 (1H, d, J=16 Hz), 2.12 (3H, d, J=2.8 Hz).

Example 18: (S)-1-Cyclopentyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(101) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as an off white solid (41 mg). LCMS (ES+) 344 (M+H).sup.+, RT 3.31 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.18 (1H, s), 8.80 (1H, br s), 7.20-7.00 (4H, m), 4.60-4.50 (1H, m), 3.74 (1H, d, J=16 Hz), 3.37 (1H, d, J=16 Hz), 3.02 (1H, d, J=16 Hz), 2.98 (1H, d, J=16 Hz), 2.15 (3H, d, J=2.8 Hz), 2.10-1.90 (2H, m), 1.90-1.65 (4H, m), 1.65-1.52 (2H, m).

Example 19: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(pyrazin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(102) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as a brown solid (43 mg). LCMS (ES+) 354 (M+H).sup.+, RT 3.09 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.25 (1H, s), 9.15 (1H, s), 8.82 (1H, br s), 8.56 (1H, d, J=2.8 Hz), 8.52 (1H, m), 7.64 (1H, s), 7.20-7.00 (3H, m), 4.06 (1H, d, J=16.8 Hz), 3.46 (1H, d, J=17.2 Hz), 3.43 (1H, d, J=15.2 Hz), 3.09 (1H, d, J=15.2 Hz), 2.18 (3H, d, J=2.8 Hz).

Examples 20 and 21: (S)-1-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide and (S)-2-(4-(difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(103) Prepared following the method described for Example 1. Two regioisomers observed. Preparative HPLC gave (S)-2-(4-(difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide as an off white solid (21 mg); LCMS (ES+) 418 (M+H).sup.+, RT 3.7 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.25 (1H, s), 8.82 (1H, s), 8.13 (1H, s), 7.78 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=9.2 Hz), 7.25 (1H, t, J=74 Hz), 7.20-7.05 (2H, m), 3.66 (1H, d, J=16 Hz), 3.52 (1H, d, J=16 Hz), 3.11 (1H, d, J=16 Hz), 3.06 (1H, d, J=16 Hz), 2.18 (3H, d, J=2.4 Hz) and also (S)-1-(4-(difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide as an off white solid (38 mg); LCMS (ES+) 418 (M+H).sup.+, RT 10.55 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.27 (1H, s), 8.82 (1H, br s), 7.69 (2H, d, J=10 Hz), 7.46 (1H, s), 7.29 (2H, d, J=10 Hz), 7.26 (1H, t, J=74 Hz), 7.20-7.00 (2H, m), 4.12 (1H, d, J=16 Hz), 3.38 (1H, d, J=16 Hz), 3.23 (1H, d, J=16 Hz), 3.19 (1H, d, J=16 Hz), 2.17 (3H, d, J=2.4 Hz).

Examples 22 and 23: (S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide and (S)-5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(104) Prepared following the method described for Example 1. Two regioisomers observed. Preparative HPLC gave (S)-5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide as an off white solid (4 mg); LCMS (ES+) 384 (M+H).sup.+, RT 10.09 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, s), 8.80 (1H, br s), 7.62 (1H, s), 7.40-7.00 (6H, m), 3.64 (1H, d, J=16 Hz), 3.51 (1H, d, J=16 Hz), 3.08 (1H, d, J=16 Hz), 3.06 (1H, d, J=16 Hz), 2.18 (6H, s) and also (S)-5-(3-fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide as an off white solid (44 mg); LCMS (ES+) 384 (M+H).sup.+, RT 3.62 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.23 (1H, s), 8.82 (1H, br s), 7.42 (1H, s), 7.38-7.00 (6H, m), 3.75 (1H, d, J=16 Hz), 3.43 (1H, d, J=16 Hz), 3.19 (1H, d, J=16 Hz), 2.79 (1H, d, J=16 Hz), 2.11 (3H, d, J=2.8 Hz), 2.04 (3H, s).

Examples 24 and 25: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide and (S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(105) Prepared following the method described for Example 1. Two regioisomers observed. Preparative HPLC gave(S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide as an off white solid (47 mg); LCMS (ES+) 366 (M+H).sup.+, RT 3.62 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.26 (1H, s), 8.80 (1H, br s), 7.50-7.30 (4H, m), 7.25-7.00 (4H, m), 4.09 (1H, d, J=16 Hz), 3.50 (1H, d, J=16 Hz), 3.25 (1H, d, J=16 Hz), 3.14 (1H, d, J=16 Hz), 2.37 (3H, s), 2.16 (3H, d, J=2.8 Hz) and also (S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide as an off white solid (39 mg); LCMS (ES+) 366 (M+H).sup.+, RT 10.59 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.24 (1H, s), 8.09 (1H, s), 7.58 (1H, s), 7.55-7.50 (1H, m), 7.35-7.25 (1H, m), 7.20-7.00 (5H, m), 3.64 (1H, d, J=16 Hz), 3.50 (1H, d, J=16 Hz), 3.09 (1H, d, J=16 Hz), 3.05 (1H, d, J=16 Hz), 2.35 (3H, s), 2.17 (3H, d, J=2.4 Hz).

Examples 26 and 27: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide and (S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(106) Prepared following the method described for Example 1. The two pyrazole regioisomers were separated by preparative HPLC at the carboxylic acid stage and both isomers progressed to the final step. Preparative HPLC gave (S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide as an off-white solid (27 mg); LCMS (ES+) 367 (M+H).sup.+, RT 2.32 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.25 (1H, s), 8.82 (1H, br s), 8.58 (1H, s), 8.51 (1H, d, J=5.2 Hz), 7.55 (1H, s), 7.37 (1H, d, J=5.2 Hz), 7.20-7.00 (3H, m), 3.94 (1H, d, J=16 Hz), 3.45 (1H, d, J=14.8 Hz), 3.20 (1H, d, J=13.6 Hz), 3.06 (1H, d, J=16 Hz), 2.31 (3H, s), 2.14 (3H, d, J=2.8 Hz). (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide as an off-white solid (29 mg). LCMS (ES+) 367 (M+H).sup.+, RT 2.46 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.25 (1H, s), 8.82 (1H, br s), 8.55 (1H, s), 8.47 (1H, d, J=5.2 Hz), 7.96 (1H, s), 7.48 (1H, d, J=5.2 Hz), 7.20-7.00 (3H, m), 3.68 (1H, d, J=16 Hz), 3.53 (1H, d, J=16 Hz), 3.14 (1H, d, J=16 Hz), 3.08 (1H, d, J=16 Hz), 2.42 (3H, s), 2.18 (3H, d, J=2.8 Hz).

Example 28: (S)-2-(3-Chloropyridin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(107) Prepared following the method described for Example 1. The two pyrazole regioisomers were separated by preparative HPLC at the carboxylic acid stage and only one regioisomer was progressed. Preparative HPLC gave the title compound as an off-white solid (13 mg). LCMS (ES+) 387/389 (M+H).sup.+, RT 3.25 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.26 (1H, s), 8.80 (1H, br s), 8.46 (1H, dd, J=4.4 and 1.6 Hz), 8.15 (1H, dd, J=8 and 1.6 Hz), 7.95 (1H, s), 7.46 (1H, dd, J=8 and 4.4 Hz), 7.20-7.00 (3H, m), 3.69 (1H, d, J=16 Hz), 3.51 (1H, d, J=16 Hz), 3.14 (1H, d, J=16 Hz), 3.08 (1H, d, J=16 Hz), 2.18 (3H, d, J=2.4 Hz).

Example 29: (S)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluoropyridin-2-yl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(108) Prepared following the method described for Example 1. Purification by preparative HPLC at the carboxylic acid and also the hydroxamic acid stage gave the title compound as an off-white solid (45 mg). LCMS (ES+) 371 (M+H).sup.+, RT 3.12 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.26 (1H, s), 8.82 (1H, br s), 8.32-8.28 (1H, m), 8.10 (1H, s), 7.98-7.90 (1H, m), 7.45-7.40 (1H, m), 7.20-7.00 (3H, m), 3.69 (1H, d, J=16 Hz), 3.51 (1H, d, J=16 Hz), 3.14 (1H, d, J=16 Hz), 3.08 (1H, d, J=16 Hz), 2.18 (3H, d, J=2.4 Hz).

Example 30: (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(109) Prepared following the method described for Example 1 starting from Intermediate 2. Preparative HPLC gave the title compound as a tan solid (12 mg). LCMS (ES+) 352 (M+H).sup.+, RT 3.53 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.26 (1H, s), 8.80 (1H, br s), 7.70-7.60 (2H, m), 7.55-7.45 (3H, m), 7.30 (1H, m), 7.25-7.00 (3H, m), 4.12 (1H, d), 3.40 (1H, d), 3.25 (1 h, d), 3.20 (1H, d), 2.20 (3H, d, J=2.4 Hz).

Examples 31 and 32: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

(110) ##STR00018##

Step 1: Methyl 5-(3-fluoro-2-methylphenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

(111) Intermediate 6 (515 mg, 1.76 mmol), AcOH (10 mL) and phenylhydrazine (0.174 mL, 1.76 mmol) were combined in a sealed tube and heated to 70 C. for 1 h. Reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a yellow gum (288 mg, 45%). LCMS (ES+) 365 (M+H).sup.+; .sup.1H NMR (ppm)(CHCl.sub.3-d) 7.58 (1H, s), 7.45-7.35 (4H, m), 7.35-7.25 (1H, m), 7.10-6.85 (3H, m), 3.73 (3H, s), 3.31 (1H, d, J=16.4 Hz), 3.12 (1H, d, J=16.4 Hz), 2.75-2.65 (1H, m), 2.55-2.30 (2H, m), 2.25-2.10 (1H, m), 2.20 (3H, d, J=2.4 Hz).

Step 2: 5-(3-Fluoro-2-methylphenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid

(112) Methyl 5-(3-fluoro-2-methylphenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (280 mg), MeOH (10 mL) and 15% aq. NaOH soln. (2 mL) were combined in a sealed tube and heated to 70 C. for 5 days. Reaction was cooled and evaporated to dryness. Residue was partitioned between 1N HCl and EtOAc. Organics were dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a tan gum (225 mg, 84%). LCMS (ES+) 351 (M+H).sup.+.

Step 3: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

(113) 5-(3-Fluoro-2-methylphenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid (225 mg, 0.64 mmol), TFFH (185 mg, 0.7 mmol), DMF (2 mL) and triethylamine (0.28 mL) were combined and stirred for 1 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was then added and stirring continued for 2 days. Volatile solvents were removed in vacuo. MeOH (5 mL) and 2N HCl in Et.sub.2O (2 mL) were added and reaction mixture was stirred for 4 h. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC. Chiral preparative HPLC gave the Eland E2 enantiomers (Chiralpak IA, Method 50/50 THF (0.1% formic acid)/heptane 5.0 mL/min, RT 5.4 (E1-(abs)) and 10.1 min (E2-(abs))). E1-enantiomer was obtained as a white solid (22 mg). LCMS (ES+) 366 (M+H).sup.+, RT 3.45 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.21 (1H, s), 8.74 (1H, s), 7.58 (1H, s), 7.50-7.40 (4H, m), 7.33-7.27 (1H, m), 7.15-6.95 (3H, m), 3.15-2.98 (2H, m), 2.75-2.65 (1H, m), 2.45-2.10 (3H, m), 2.20 (3H, d, J=2.4 Hz). E2-enantiomer was obtained as a white solid (23 mg). LCMS (ES+) 366 (M+H).sup.+, RT 3.39 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.21 (1H, s), 8.74 (1H, s), 7.58 (1H, s), 7.50-7.40 (4H, m), 7.33-7.27 (1H, m), 7.15-6.95 (3H, m), 3.15-2.98 (2H, m), 2.75-2.65 (1H, m), 2.45-2.10 (3H, m), 2.20 (3H, d, J=2.4 Hz).

Examples 33 and 34: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide and E2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

(114) Prepared following the method described for Example 31 and 32. The two observed pyrazole regioisomers were separated by flash chromatography at the carboxylic ester stage and only one regioisomer was progressed. Purification by preparative HPLC followed by chiral preparative HPLC gave the Eland E2 enantiomers. (Chiralpak IC, Method 10/90 EtOH (0.1% formic acid)/Heptane 5.0 mL/min, RT 21.0 (E1-(abs)) and 15.6 min (E2-(abs))). E1-enantiomer was obtained as an off-white solid (8 mg). LCMS (ES+) 384 (M+H).sup.+, RT 3.57 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, br s), 8.73 (1H, s), 8.01 (1H, d, J=2.8 Hz), 7.79-7.75 (1H, m), 7.50-7.40 (1H, m), 7.40-7.25 (2H, m), 7.20-7.00 (3H, m), 3.10 (2H, s), 2.70-2.60 (1H, m), 2.45-2.30 (2H, m), 2.20 (3H, d, J=2.8 Hz), 2.15-2.05 (1H, m). E2-enantiomer was obtained as an off-white solid (7 mg). LCMS (ES+) 384 (M+H).sup.+, RT 3.55 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, br s), 8.73 (1H, s), 8.01 (1H, d, J=2.8 Hz), 7.79-7.75 (1H, m), 7.50-7.40 (1H, m), 7.40-7.25 (2H, m), 7.20-7.00 (3H, m), 3.10 (2H, s), 2.70-2.60 (1H, m), 2.45-2.30 (2H, m), 2.20 (3H, d, J=2.8 Hz), 2.15-2.05 (1H, m).

Example 35: 5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and 5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

(115) Prepared following the method described for Example 31 and 32. The two observed pyrazole regioisomers were obtained as an inseparable mixture. Preparative HPLC gave a regioisomeric racemic mixture of the title compounds as an off-white solid (105 mg). LCMS (ES+) 372 (M+H).sup.+, RT 9.33 (Analytical method 2). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.18 (0.5H, s), 10.16 (0.5H, s), 8.73 (1H, br s), 7.59 (0.5H, s), 7.42 (0.5H, s), 7.15-6.80 (3H, m), 5.04-4.86 (2H, m), 3.15-2.85 (2H, m), 2.70-2.50 (1H, m), 2.40-2.15 (2H, m), 2.17 (3H, d, J=2.8 Hz), 2.00-1.75 (1H, m).

Example 36: 5-(3-Fluoro-2-methylphenyl)-1-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and 5-(3-fluoro-2-methylphenyl)-2-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

(116) Prepared following the method described for Example 31 and 32. The two observed pyrazole regioisomers were obtained as an inseparable mixture. Purification by preparative HPLC gave a regioisomeric racemic mixture of the title compounds as a white solid (29 mg). LCMS (ES+) 398 (M+H).sup.+, RT 3.36 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.17 (0.5H, s), 10.14 (0.5H, s), 8.70 (1H, br s), 7.57 (0.5H, s), 7.36 (0.5H, s), 7.30-6.80 (6H, m), 5.19 (1H, s), 5.14 (1H, s), 3.20-2.80 (2H, m), 2.65-2.40 (1H, m), 2.40-2.15 (2H, m), 2.16 (1.5H, d, J=2.8 Hz), 2.14 (1.5H, d, J=2.8 Hz), 1.90-1.80 (1H, m), 1.65-1.50 (1H, m).

Examples 37 and 38: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

(117) Prepared following the method described for Example 31 and 32. Purification by preparative HPLC followed by chiral preparative HPLC gave the Eland E2 enantiomers. (Chiralpak IA, Method 20/80 EtOH (0.1% formic acid)/heptane 5.0 mL/min, RT 9.4 (E1-(abs)) and 17.0 min (E2-(abs))). E1-enantiomer was obtained as an off white solid (43 mg). LCMS (ES+) 380 (M+H).sup.+, RT 3.49 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.19 (1H, s), 8.74 (1H, s), 7.54 (1H, s), 7.35-7.20 (3H, m), 7.15-7.00 (3H, m), 7.00-6.90 (1H, m), 3.21 (1H, d, J=16 Hz), 2.96 (1H, d, J=16 Hz), 2.40-2.20 (3H, m), 2.15 (3H, d, J=2.8 Hz), 1.79 (3H, s), 1.65-1.50 (1H, m). E2-enantiomer was obtained as an off white solid (43 mg). LCMS (ES+) 380 (M+H).sup.+, RT 3.49 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.19 (1H, s), 8.74 (1H, s), 7.54 (1H, s), 7.35-7.20 (3H, m), 7.15-7.00 (3H, m), 7.00-6.90 (1H, m), 3.21 (1H, d, J=16 Hz), 2.96 (1H, d, J=16 Hz), 2.40-2.20 (3H, m), 2.15 (3H, d, J=2.8 Hz), 1.79 (3H, s), 1.65-1.50 (1H, m).

Example 39: 3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

(118) ##STR00019##

Step 1: Methyl 5-(3-fluoro-2-methylphenyl)-3-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate and methyl 5-(3-fluoro-2-methylphenyl)-3-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

(119) Intermediate 4 (1.12 g, 3.07 mmol), acetic acid (10 mL) and 2, 2, 2-trifluoroethyl hydrazine (70% in water) (0.5 mL, 3.1 mmol) were combined and heated to 65 C. for 19 h. Reaction mixture was evaporated to dryness onto silica and purified by flash chromatography to give a mixture of the title compounds as a clear gum (1.04 g, 88%). LCMS (ES+) 387 (M+H).sup.+.

Step 2: Methyl 5-(3-fluoro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate and methyl 5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

(120) The crude mixture of methyl 5-(3-fluoro-2-methylphenyl)-3-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate and methyl 5-(3-fluoro-2-methylphenyl)-3-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (0.925 mg, 2.39 mmol) from reaction above was combined with DCM (80 mL) and triethylamine (0.5 mL) under nitrogen. The reaction mixture was ice bath cooled and trifluoromethanesulfonic anhydride (0.4 mL, 2.4 mmol) was added dropwise. The reaction mixture was stirred with continued ice bath cooling for 1 h then evaporated to dryness in vacuo onto silica and purified by flash chromatography to give methyl 5-(3-fluoro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate as a clear oil (48 mg). LCMS (ES+) 519 (M+H).sup.+; and methyl 5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate as a clear oil (639 mg). LCMS (ES+) 519 (M+H).sup.+.

Step 3: 3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

(121) Methyl 5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate (205 mg, 0.397 mmol), THF (10 mL), cyclopropyl zinc bromide (0.5N in THF) (4 mL, 2 mmol) and palladium tetrakis triphenylphosphine (10 mg) were combined under a nitrogen atmosphere and heated to 70 C. for 3 days. The reaction mixture was then diluted with EtOAc, washed with sat. aq. NH.sub.4Cl soln. and evaporated to dryness in vacuo. The crude product was purified by preparative HPLC to give the title compound as a tan solid (17.9 mg). LCMS (ES+) 411 (M+H).sup.+.

Step 4: 3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid

(122) Methyl 3-cyclopropyl-5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate (17.9 mg), MeOH (7 mL) and 15% NaOH soln. (0.5 mmol) were combined and heated to 70 C. for 15 days. Reaction mixture was then evaporated to dryness in vacuo, then partitioned between EtOAc and 1N HCl. Organic layer was dried (MgSO.sub.4) and evaporated to dryness in vacuo to give the title compound (16 mg) as a clear glass. LCMS (ES+) 397 (M+H).sup.+.

Step 5: 3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

(123) 3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid (16 mg), TFFH (100 mg), DMF (1 mL) and triethylamine (0.5 mL) were combined and stirred at room temperature for 1 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (60 mg, 0.5 mmol) was then added and stirring continued for 1 day. Volatile solvents were removed in vacuo. MeOH (5 mL) and 2N HCl in Et.sub.2O (2 mL) were added and reaction mixture was stirred for 1 h. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as a white solid (4 mg). LCMS (ES+) 412 (M+H).sup.+, RT 9.89 (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.15 (1H, s), 8.75 (1H, br s), 7.15-6.95 (2H, m), 6.85-6.80 (1H, m), 5.05-4.85 (2H, m), 3.08 (1H, d, J=16 Hz), 2.86 (1H, d, J=16 Hz), 2.50-2.40 (1H, m), 2.35-2.25 (1H, m), 2.25-2.15 (1H, m), 2.17 (3H, d, J=2.8 Hz), 1.85-1.70 (2H, m), 1.05-0.90 (2H, m), 0.85-0.65 (2H, m).

Example 40: 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxamide

(124) ##STR00020##

Step 1: Methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxylate

(125) Intermediate 4 (1 g, 2.74 mmol), cyclopropylcarbamidine.HCl (361 mg, 3 mmol), MeOH (20 mL) and DIPEA (1 mL) were combined in a sealed tube and heated to 65 C. for 14 days. Reaction mixture was then evaporated to dryness in vacuo onto silica and purified by flash chromatography to give the title compound as a clear glass (99 mg). LCMS (ES+) 357 (M+H).sup.+.

Step 2: 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxylic acid

(126) Methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxylate (99 mg), MeOH (10 mL) and 15% aq. NaOH soln. (2 mL) were combined in a sealed tube and heated to 65 C. for 19 days. The reaction mixture was then evaporated to dryness in vacuo, then partitioned between EtOAc and 1N HCl. The organic layer was dried (MgSO.sub.4) and evaporated to dryness in vacuo to give the title compound as a clear glass (25 mg). LCMS (ES+) 343 (M+H).sup.+.

Step 3: 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxamide

(127) 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxylic acid (25 mg), TFFH (25 mg), DMF (1 mL) and triethylamine (0.1 mL) were combined and stirred at room temperature for 2 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (30 mg, 0.25 mmol) was then added and stirring was continued for 2 days. Volatile solvents were removed in vacuo. MeOH (2 mL) and 2N HCl in Et.sub.2O (2 mL) were added and the reaction mixture was stirred for 1.5 h. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as an off-white solid (4 mg). LCMS (ES+) 358 (M+H).sup.+, RT 2.65 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 12.44 (1H, s), 10.17 (1H, s), 8.71 (1H, s), 7.20-6.95 (2H, m), 6.90-6.80 (1H, m), 3.55-3.40 (1H, m), 2.70-2.60 (1H, m0, 2.40-2.30 (1H, m), 2.30-2.15 (2H, m), 2.17 (3H, d, J=2.8 Hz), 1.95-1.75 (2H, m), 1.00-0.85 (4H, m).

Example 41: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

(128) ##STR00021##

Step 1: Methyl 6-(3-fluoro-2-methylphenyl)-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

(129) Intermediate 7 (200 mg, 0.625 mmol), pyridine (5 mL), and phenylsulfonyl chloride (0.091 mL, 0.65 mmol) were combined and stirred for 4 days. Reaction mixture was then diluted with EtOAc, washed with 1N HCl (2), dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a tan solid (234 mg, 81%). LCMS (ES+) 461 (M+H).sup.+.

Step 2: 6-(3-Fluoro-2-methylphenyl)-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid

(130) Methyl 6-(3-fluoro-2-methylphenyl)-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate (230 mg, 0.5 mmol), MeOH (10 mL) and 15% aq. NaOH soln. (2 mL) were combined in a sealed tube and heated to 70 C. for 5 days. Reaction was cooled and evaporated to dryness. Residue was partitioned between 1N HCl and EtOAc. Organics were dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a yellow gum (181 mg, 81%). LCMS (ES+) 447 (M+H).sup.+.

Step 3: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

(131) 6-(3-Fluoro-2-methylphenyl)-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid (181 mg, 0.4 mmol), TFFH (127 mg, 0.48 mmol), DMF (2 mL) and triethylamine (0.5 mL) were combined and stirred for 16 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was then added and stirring continued for 2 days. Volatile solvents were removed in vacuo. MeOH (5 mL) and 2N HCl in Et.sub.2O (2 mL) were added and reaction mixture was stirred for 2 h. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as an off-white solid (26 mg). LCMS (ES+) 462 (M+H).sup.+, RT 9.49 (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 12.45 (1H, br s), 10.22 (1H, s), 8.77 (1H, s), 7.82 (2H, m), 7.65-7.50 (3H, m), 7.25-7.10 (1H, m), 7.10-7.00 (1H, m), 6.95-6.85 (1H, m), 3.10-2.95 (1H, m), 2.85-2.75 (1H, m), 2.45-2.25 (3H, m), 2.15 (3H, d, J=2.4 Hz), 1.95-1.75 (1H, m).

Example 42: 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

(132) ##STR00022##

Step 1: Methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

(133) Intermediate 8 (300 mg, 0.78 mmol), THF (10 mL), tetrakis(triphenylphosphine)palladium(0) (10 mg) and cyclopropylzinc bromide (0.5N in THF) (3 mL, 1.5 mmol) were combined under a nitrogen atmosphere and heated to 60 C. for 16 h. Further tetrakis(triphenylphosphine)palladium(0) (20 mg) and cyclopropylzinc bromide (0.5N in THF) (3 mL, 1.5 mmol) were added and heating continued for 23 h. The reaction mixture was evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a tan solid (177 mg, 66%). LCMS (ES+) 346 (M+H).sup.+.

Step 2: 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid

(134) Methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate (170 mg, 0.49 mmol), MeOH (10 mL) and 15% aq. NaOH soln. (1 mL) were combined in a sealed tube and heated to 65 C. for 5 days. Reaction was cooled and evaporated to dryness. Residue was partitioned between 1N HCl and EtOAc. The organic phase was dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a grey solid (136 mg, 84%). LCMS (ES+) 332 (M+H).sup.+.

Step 3: 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

(135) 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid (136 mg, 0.41 mmol), TFFH (132 mg, 0.5 mmol), DMF (2 mL) and triethylamine (2 mL) were combined and stirred for 1.5 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was then added and stirring continued for 1 day. Volatile solvents were removed in vacuo. MeOH (2 mL) and 2N HCl in Et.sub.2O (2 mL) were added and reaction mixture was stirred for 2 h. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as a yellow glass (54 mg). LCMS (ES+) 347 (M+H).sup.+, RT 3.2 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.21 (1H, s), 8.80 (1H, br s), 7.15-7.05 (2H, m), 6.90 (1H, m), 3.30-3.05 (2H, m), 2.65-2.50 (1H, m), 2.40-2.25 (3H, m), 2.20 (3H, d, J=2.4 Hz), 2.10-2.00 (1H, m), 1.10-1.00 (2H, m), 1.90-1.80 (2H, m).

Example 43: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

(136) ##STR00023##

Step 1: Methyl 6-(3-fluoro-2-methylphenyl)-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

(137) Intermediate 8 (275 mg, 0.716 mmol), pyrimidine-5-boronic acid (99 mg, 0.8 mmol), CsF (150 mg), DME (15 mL), MeOH (2 mL) and tetrakis(triphenylphosphine)palladium(0) (10 mg) were combined in a sealed tube and microwave heated to 120 C. for 2 h. Reaction mixture was evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a tan glass (217 mg, 79%). LCMS (ES+) 384 (M+H).sup.+.

Step 2: 6-(3-Fluoro-2-methylphenyl)-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid

(138) Methyl 6-(3-fluoro-2-methylphenyl)-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate (200 mg, 0.52 mmol), MeOH (10 mL) and 15% aq. NaOH soln. (1 mL) were combined in a sealed tube and heated to 65 C. for 2 days. The reaction mixture was cooled and evaporated to dryness. Residue was partitioned between AcOH/H.sub.2O and EtOAc. The organic phase was dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a pale yellow glass (151 mg) which was used crude in next step.

Step 3: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

(139) 6-(3-Fluoro-2-methylphenyl)-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid (151 mg, 0.4 mmol), TFFH (132 mg, 0.5 mmol), DMF (2 mL) and triethylamine (2 mL) were combined and stirred for 1 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was then added and stirring continued for 1 day. Volatile solvents were removed in vacuo. MeOH (2 mL) and 2N HCl in Et.sub.2O (2 mL) were added and reaction mixture was stirred for 30 min. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as an off white solid (11 mg). LCMS (ES+) 385 (M+H).sup.+, RT 9.03 (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.30 (1H, s), 9.25 (1H, s), 9.24 (2H, s), 8.80 (1H, s), 7.20-6.95 (3H, m), 3.55-3.45 (1H, m), 3.30-3.15 (1H, m), 2.80-2.70 (1H, m), 2.60-2.40 (2H, m), 2.40-2.30 (1H, m), 2.20 (3H, d, J=2.4 Hz).

Example 44: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

(140) ##STR00024##

Step 1: Methyl 6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

(141) Intermediate 8 (300 mg, 0.78 mmol), AcOH (10 mL) and Zn dust (300 mg) were combined and heated to 65 C. for 1 h. Zn residues were removed by filtering through a celite plug washing through with EtOAc. Organics were then evaporated to dryness to give the title compound as a tan solid which was used crude in next step. LCMS (ES+) 306 (M+H).sup.+.

Step 2: 6-(3-Fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid

(142) Methyl 6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate (0.78 mmol), MeOH (15 mL) and 15% aq. NaOH soln. (3 mL) were combined in a sealed tube and heated to 65 C. for 19 h. Reaction was cooled and evaporated to dryness. The residue was partitioned between 1N HCl and EtOAc. Organics were dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a tan glass (191 mg, 84% over two steps). LCMS (ES+) 292 (M+H).sup.+.

Step 3: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

(143) 6-(3-Fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid (196 mg, 0.67 mmol), TFFH (264 mg, 1 mmol), DMF (2 mL) and triethylamine (0.3 mL) were combined and stirred for 1 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was then added and stirring continued for 2 days. Volatile solvents were removed in vacuo. MeOH (2 mL) and 2N HCl in Et.sub.2O (2 mL) were added and reaction mixture was stirred for 5 h. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as an off-white solid (43 mg). LCMS (ES+) 307 (M+H).sup.+, RT 2.87 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.24 (1H, s), 8.86 (1H, s), 8.77 (1H, s), 7.15-7.00 (2H, m), 6.90 (1H, m), 3.40-3.30 (1H, m), 3.25-3.15 (1H, m), 2.75-2.65 (1H, m), 2.60-2.50 (1H, m), 2.45-2.35 (1H, m), 2.25-2.10 (1H, m), 2.20 (3H, d, J=2.4 Hz).

Example 45: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide

(144) ##STR00025##

Step 1: Methyl 6-(3-fluoro-2-methylphenyl)-5,6,7,8-tetrahydroquinazoline-6-carboxylate

(145) Intermediate 6 (516 mg, 1.77 mmol), formamidine.AcOH (198 mg, 1.9 mmol), MeOH (10 mL) and DIPEA (2 mL) were combined in a sealed tube and heated to 70 C. for 2.5 h. The reaction mixture was then evaporated to dryness onto silica and purified by flash chromatography to give the title compound as a clear gum (264 mg, 50%). LCMS (ES+) 301 (M+H).sup.+.

Step 2: 6-(3-Fluoro-2-methylphenyl)-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid

(146) Methyl 6-(3-fluoro-2-methylphenyl)-5,6,7,8-tetrahydroquinazoline-6-carboxylate (264 mg, 0.88 mmol), MeOH (10 mL) and 15% aq. NaOH soln. (2 mL) were combined in a sealed tube and heated to 70 C. for 4 days. The reaction mixture was cooled and evaporated to dryness. The residue was partitioned between 1N HCl and EtOAc. Organics were dried (MgSO.sub.4) and evaporated to dryness to give the title compound as a pale yellow gum (194 mg, 77%). LCMS (ES+) 287 (M+H).sup.+.

Step 3: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide

(147) 6-(3-Fluoro-2-methylphenyl)-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid (194 mg, 0.68 mmol), TFFH (211 mg, 0.8 mmol), DMF (2 mL) and triethylamine (0.28 mL) were combined and stirred for 4 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was then added and stirring continued for 16 h. Volatile solvents were removed in vacuo. MeOH (5 mL) and 2N HCl in Et.sub.2O (2 mL) were added and reaction mixture was stirred for 2.5 h. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as a white solid (17 mg). LCMS (ES+) 302 (M+H).sup.+, RT 2.59 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.28 (1H, s), 8.85 (1H, s), 8.76 (1H, s), 8.57 (1H, s), 7.25-7.00 (3H, m), 3.50-3.35 (1H, m), 3.00-2.90 (1H, m), 2.80-2.70 (1H, m), 2.65-2.55 (1H, m), 2.50-2.40 (2H, m), 2.21 (3H, d, J=2.4 Hz).

Example 46: 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide

(148) Prepared following the method described for Example 45. Preparative HPLC gave the title compound as a white solid (90 mg). LCMS (ES+) 342 (M+H)+, RT 2.96 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.28 (1H, s), 8.75 (1H, br s), 8.39 (1H, s), 7.20-6.95 (3H, m), 3.40-3.30 (2H, m), 2.9 (1H, m), 2.75-2.65 (1H, m), 2.50-2.35 (2H, m), 2.21 (3H, d, J=2.4 Hz), 2.10 (1H, m), 1.00-0.85 (4H, m).

Example 47: 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxamide

(149) Prepared following the method described for Example 45. Preparative HPLC gave the title compound as a white solid (53 mg). LCMS (ES+) 378 (M+H).sup.+, RT 3.66 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.31 (1H, s), 8.78 (1H, br s), 8.68 (1H, s), 8.35 (2H, m), 7.55-7.45 (3H, m), 7.25-7.00 (3H, m), 3.50-3.40 (2H, m), 3.05-2.95 (1H, m), 2.90-2.80 (1H, m), 2.70-2.55 (2H, m), 2.24 (3H, d, J=2.4 Hz).

Examples 48 and 49: (S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide and (R)-2-(2-chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

(150) ##STR00026##

Step 1: (S)-Methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentane carboxylate and (R)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate

(151) Intermediate 3 (2.5 g, 1.0 mmol) was dissolved in dimethylformamide dimethylacetal (5.0 mL) and heated to 80 C. for 16 h. The cooled mixture was concentrated onto silica and purified by flash silica column chromatography (gradient elution i-hex to 100% EtOAc in i-hex) to yield the title compounds as a pale yellow oil (1.8 g, 58%). LCMS (ES+) 306 (M+H).sup.+.

Step 2: Methyl (6S)-2-(2-chlorophenyl)-6-(3-fluoro-2-methyl-phenyl)-5,7-dihydrocyclopenta[d]pyrimidine-6-carboxylate and methyl (5R)-2-(2-chlorophenyl)-5-(3-fluoro-2-methyl-phenyl)-6,7-dihydrocyclopenta[d]pyrimidine-5-carboxylate

(152) A mixture of (S)-methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentane carboxylate and (R)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate (0.305 g, 1 mmol) and 2-chlorobenzamidine hydrochloride (0.28 g, 1.5 mmol) in methanol (5 mL) was heated to 130 C. for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between DCM (15 mL) and water (15 mL). The DCM was separated (phase separator) and evaporated under reduced pressure to give an oil which was purified by flash chromatography to give (S)-methyl 2-(2-chlorophenyl)-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate as a colorless oil. LCMS (ES+) 397 (M+H).sup.+; .sup.1H NMR (ppm)(CHCl.sub.3-d): 8.68 (1H, s), 7.74-7.68 (1H, m), 7.53-7.47 (1H, m), 7.40-7.33 (2H, m), 7.19-7.06 (1H, m), 7.07-6.94 (2H, m), 4.07-3.94 (2H, m), 3.73 (3H, s), 3.63 (1H, s), 3.59-3.48 (1H, m), 2.23 (3H, s). (R)-Methyl 2-(2-chlorophenyl)-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate was obtained as a colorless oil. LCMS (ES+) 398 (M+H).sup.+; .sup.1H NMR (ppm)(CHCl.sub.3-d): 8.83 (1H, s), 7.81-7.75 (1H, m), 7.55-7.48 (1H, m), 7.48-7.26 (2H, m), 7.16-7.04 (1H, m), 7.01 (1H, m), 6.56 (1H, m), 3.79 (3H, s), 3.51 (1H, m), 3.30 (1H, m), 3.12 (1H, m), 2.27-2.18 (4H, m).

Step 3: (S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

(153) Trimethylaluminum (1.56 mL, 2 M in toluene, 3.12 mmol) was added to a stirred solution of hydroxylamine hydrochloride (240 mg, 10.1 mmol) in dry DCM (5 mL) under nitrogen and the resulting solution was stirred for 30 min at room temperature under nitrogen. A solution of (6S)-2-(2-chlorophenyl)-6-(3-fluoro-2-methyl-phenyl)-5,7-dihydrocyclopenta[d]pyrimidine-6-carboxylate (0.234 g, 0.59 mmol) in DCM (8 mL) was added and stirring was continued for 1 h. Saturated ammonium chloride solution (1 mL) was added followed by water (2.5 mL) and the resulting mixture was evaporated to dryness, the residue was stirred with methanol (25 mL) for 10 min. and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was stirred with EtOAc (30 mL) and filtered. The EtOAc was evaporated and the resulting oil was purified by preparative HPLC to give the title compound (78 mg, 33%) as a colorless solid. LCMS (ES+) 398 (M+H).sup.+, RT 3.44 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.30 (1H, br), 8.86 (1H, br), 8.81-8.69 (1H, m), 7.73-7.65 (1H, m), 7.59-7.53 (1H, m), 7.51-7.42 (2H, m), 7.24-7.05 (3H, m), 3.98-3.93 (1H, m), 3.84-3.78 (1H, m), 3.53-3.47 (1H, m), 3.43-3.23 (1H, m), 2.27-2.19 (3H, m).

Step 4: (R)-2-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

(154) The same method as for Step 3 from (R)-methyl 2-(2-chlorophenyl)-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate. Preparative HPLC gave the title compound (14 mg) as a colorless solid. LCMS (ES+) 398 (M+H).sup.+, RT 8.91 (Analytical method 3); .sup.1H NMR (ppm)(DMSO-d.sub.6): 8.95 (1H, s), 7.79-7.75 (1H, m), 7.63-7.58 (1H, m), 7.55-7.46 (2H, m), 7.21-7.11 (2H, m), 6.63 (1H, s), 3.5-3.30 (1H, m), 3.20-3.05 (1H, m), 3.05-2.96 (1H, m), 2.19 (3H, d, J=2 Hz), 2.07-1.98 (1H, m), two exchangeable protons not seen.

Examples 50 and 51: (R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide and (S)-2-cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

(155) ##STR00027##

Step 1: (R)-Methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentane carboxylate and (S)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate

(156) Intermediate 2 (2.5 g, 1.0 mmol) was dissolved in dimethylformamide dimethylacetal (5.0 mL) and heated to 80 C. for 16 h. Concentrated onto silica and purified by flash silica column chromatography (gradient elution i-hex to 100% EtOAc in i-hex) to yield the title compounds as a pale yellow oil (1.8 g, 58.8%). LCMS (ES+) 306 (M+H).sup.+.

Step 2: (R)-Methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate and (S)-methyl 2-cyclopropyl-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate

(157) To a solution of (R)-methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentane carboxylate and (S)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate (0.23 g, 0.75 mmol) in methanol (10 mL) was added cyclopropanecarboximidamide (91 mg, 0.755 mmol) and NaOMe (41 mg, 0.755 mmol) and the reaction mixture was stirred at 100 C. overnight. The mixture was concentrated onto silica and purified by flash silica column chromatography (gradient elution i-hex to 70% EtOAc in i-hex) to yield (R)-methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate as a yellow oil (0.12 g, 50%). LCMS (ES+) 327 (M+H).sup.+. (S)-Methyl 2-cyclopropyl-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate was obtained as a yellow oil (68 mg, 28%). LCMS (ES+) 327 (M+H).sup.+.

Step 3: (R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylic acid

(158) (R)-Methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate (68 mg, 0.19 mmol), MeOH (3 mL) and 15% aq. NaOH soln. (0.5 mL) were combined in a sealed tube and heated to 70 C. for 4 days. The reaction mixture was cooled and evaporated to dryness. The residue was partitioned between 1N HCl and EtOAc. Organics were dried (MgSO.sub.4) and evaporated to dryness to give the title compound as an off white solid. LCMS (ES+) 313 (M+H).sup.+.

Step 4: (S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylic acid

(159) Following the same method as Step 3. Preparative HPLC gave the title compound as a white solid. LCMS (ES+) 313 (M+H).sup.+.

Step 5: (R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

(160) (R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylic acid (51 mg, 0.19 mmol), TFFH (58 mg, 0.22 mmol), DMF (1 mL) and triethylamine (1 mL) were combined and stirred for 1 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (51 mg, 0.28 mmol) was then added and stirring continued for 1 day. Volatile solvents were removed in vacuo. MeOH (1 mL) and 2N HCl in Et.sub.2O (1 mL) were added and reaction mixture was stirred for 30 min. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give the title compound as an off white solid (29 mg). LCMS (ES+) 328 (M+H).sup.+, RT 2.90 (Analytical method 1); .sup.1H NMR (ppm)(CH.sub.3OH-d.sub.4): 8.39 (1H, s), 7.19-7.10 (1H, m), 7.09-6.97 (2H, m), 3.90 (1H, d, J=17.2 Hz), 3.80 (1H, d, J=16.4 Hz), 3.44 (1H, d, J=16.4 Hz), 3.29 (1H, d, J=17.2 Hz), 2.26 (3H, s), 2.22-2.13 (1H, m), 1.12-1.04 (4H, m) two exchangeable protons not seen.

Step 6: (S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

(161) Following the same method as Step 5. Preparative HPLC gave the title compound as a white solid (28 mg). LCMS (ES+) 328 (M+H).sup.+, RT 9.15 (Analytical method 2). .sup.1H NMR (ppm)(CH.sub.3OH-d.sub.4): 8.59 (1H, s), 7.16-7.08 (1H, m), 7.05 (1H, t, J=9.0 Hz), 6.54 (1H, d, J=7.78 Hz), 3.50 (1H, ddd, J=13.20, 9.30, 7.12 Hz), 3.16-3.05 (1H, m), 2.92 (1H, ddd, J=17.9, 9.2, 7.2 Hz), 2.32-2.23 (4H, m), 2.11 (1H, ddd, J=13.1, 9.2, 4.9 Hz), 1.22-1.10 (4H, m) two exchangeable protons not seen.

Example 52: (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

(162) Prepared following the method described for Examples 50 and 51, from Intermediate 3. Purification by preparative HPLC gave the title compound as a white solid (12 mg). LCMS (ES+) 328 (M+H).sup.+, RT 8.81 (Analytical method 2). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.24 (1H, s), 8.81 (1H, s), 8.43 (1H, s), 7.19-7.12 (1H, m), 7.09-7.03 (2H, m), 3.81 (1H, d, J=17.1 Hz), 3.65 (1H, d, J=16.3 Hz), 3.38 (1H, obscured by water), 3.17 (1H, d, J=17.2 Hz), 2.18 (3H, d, J=2.8 Hz), 2.16-2.11 (1H, m), 1.00-0.92 (4H, m).

Example 53: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-isopropyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(163) Prepared following the method described for Example 50 and 51, starting from intermediate 3. Only one regioisomer was isolated. Preparative HPLC gave the title compound as a white solid (5 mg). LCMS (ES+) 318 (M+H).sup.+, RT 8.89 (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.18 (1H, s), 8.77 (1H, br s), 7.20-6.90 (4H, m), 4.40-4.30 (1H, m), 3.74 (1H, d, J=16 Hz), 3.30 (1H, d, J=16 Hz), 3.02 (1H, d, J=16 Hz), 2.98 (1H, d, J=16 Hz), 2.15 (3H, d, J=2.8 Hz), 1.35 (6H, d, J=6.8 Hz).

Example 54: (R)-4-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

(164) Prepared following the method described for Example 48 and 49. Only one regioisomer was isolated. Preparative HPLC gave the title compound as a white solid (11 mg). LCMS (ES+) 352 (M+H).sup.+, RT 9.08 (Analytical method 3). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.21 (1H, s), 8.80 (1H, br s), 8.78 (1H, s), 7.76-7.66 (3H, m), 7.55-7.47 (2H, m), 7.35-7.30 (1H, m), 7.22-7.14 (1H, m), 7.13-7.04 (2H, m), 3.95-3.80 (1H, m), 3.22-3.12 (1H, m), 3.11-3.02 (1H, m), 2.42-2.33 (1H, m), 2.15 (3H, s).

Example 55: (S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

(165) Prepared following the method described for Example 50 and 51 starting from intermediate 3. Only one regioisomer was isolated. Preparative HPLC gave the title compound as an off white solid (23 mg). LCMS (ES+) 382 (M+H).sup.+, RT 10.55 (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.30 (1H, s), 8.80 (1H, br s), 8.72 (1H, s), 8.44-8.37 (2H, m), 7.38-7.28 (2H, m), 7.21-7.04 (3H, m), 3.95 (1H, d, J=17.2 Hz), 3.76 (1H, d, J=16.8 Hz), 3.47 (1H, d, 16.8 Hz), 3.29 (1H, d, J=17.2 Hz), 2.26-2.20 (3H, s).

Example 56: (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

(166) Prepared following the method described for Example 50 and 51 starting from intermediate 3. Only one regioisomer was isolated. Preparative HPLC gave the title compound as a colorless solid (35 mg). LCMS (ES+) 356 (M+H).sup.+, RT 3.40 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.30 (1H, s), 8.87 (2H, s), 7.23-7.14 (1H, m), 7.14-7.05 (2H, m), 4.02-3.97 (1H, m), 3.85-3.80 (1H, m), 3.60-3.56 (1H, m), 3.46-3.42 (1H, m), 2.20 (3H, s).

Example 57: (R)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

(167) Prepared following the method described for Example 50 and 51 starting from intermediate 3. Only one regioisomer was isolated. Preparative HPLC gave the title compound as a colorless solid (21 mg). LCMS (ES+) 328 (M+H).sup.+, RT 3.17 (Analytical method 1), .sup.1H NMR (ppm)(CH.sub.3OH-d.sub.4): 8.59 (1H, s), 7.16-7.00 (2H, m), 6.54 (1H, d, J=7.8 Hz), 3.56-3.44 (1H, m), 3.18-3.06 (1H, m), 2.98-2.85 (1H, m), 2.32-2.23 (4H, m), 2.11-2.05 (1H, m), 1.22-1.09 (4H, m) two exchangeable protons not seen.

Examples 58 and 59: (S)-1-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide and (R)-1-cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

(168) Prepared following the method described for Example 50 and 51 starting from intermediate 3. Preparative HPLC gave(S)-1-cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide was obtained as a white solid (10 mg). LCMS (ES+) 316 (M+H).sup.+, RT 7.86 (Analytical method 3). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.19 (1H, s), 8.78 (1H, s), 7.20-7.01 (4H, m), 3.76 (1H, d, J=16 Hz), 3.53-3.45 (1H, m), 3.26 (1H, d, J=14.8 Hz), 3.05 (1H, d, J=16 Hz), 2.95 (1H, d, J=14.8 Hz), 2.18-2.11 (3H, m), 0.97-0.87 (4H, m). (R)-1-Cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide was obtained as a white solid (8 mg). LCMS (ES+) 316 (M+H).sup.+, RT 8.22 (Analytical method 3). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.07 (1H, s), 8.68 (1H, s), 7.39 (1H, s), 7.18-7.09 (1H, m), 7.09-7.02 (2H, m), 3.80 (1H, ddd, J=13.1, 8.7, 3.9 Hz), 3.56-3.48 (1H, m), 2.91-2.81 (1H, m), 2.77-2.67 (1H, m), 2.31-2.21 (1H, m), 2.10 (3H, d, =16 Hz), 1.04-0.90 (4H, m).

Example 60: (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

(169) Prepared following the method described for Example 50 and 51, starting from intermediate 3. Only one regioisomer was isolated. Preparative HPLC gave the title compound as a white solid (9 mg). LCMS (ES+) 365 (M+H).sup.+, RT 2.50 (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.32 (1H, s), 9.5 (1H, s), 8.89 (1H, s), 8.8 (1H, s), 8.72-8.64 (2H, m), 8.64 (1H, s), 7.60-7.53 (1H, m), 7.21-7.06 (2H, m), 4.03-3.97 (1H, m), 3.84-3.76 (1H, m), 3.57-3.41 (2H, m), 2.24-2.19 (3H, s).

Examples 61 and 62: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide and E2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(170) ##STR00028##

Step 1: ()-Methyl 5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

(171) To a solution of Intermediate 11 (500 mg, 1.52 mmol) in ethanol (5 mL) was added 2-fluorobenzothioamide (283 mg, 1.82 mmol). The reaction mixture was heated to 110 C. under microwave irradiation for 1 h. The reaction mixture was concentrated to give a yellow gum. The crude reaction material was purified by flash silica chromatography (gradient elution, 0-40% EtOAc in iso-hexane) to give the title compound as a pale yellow gum (190 mg, 0.49 mmol, 32%). LCMS (ES+) 386 (M+H).sup.+; .sup.1H NMR (ppm)(400 MHz, CDCl.sub.3): 8.20 (1H, dt, J=7.9, 7.5 Hz), 7.24-7.10 (5H, m), 7.00-6.96 (1H, m), 4.01 (1H, d, J=16.0 Hz), 3.85 (1H, d, J=16.0 Hz), 3.74 (3H, s), 3.49 (1H, d, J=16.0 Hz), 3.39 (1H, d, J=16.0 Hz), 2.20 (3H, d, J=2.7 Hz).

Step 2: ()-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid

(172) ()-Methyl 5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate (180 mg, 0.46 mmol), methanol (5 mL) and NaOH (3.75 M in water, 1.25 mL, 4.69 mmol) were combined in a sealed tube and heated to 65 C. for 18 h. The yellow reaction mixture was concentrated in vacuo. The residue was dissolved in H.sub.2O (20 mL) and the solution adjusted to pH 7 with 1 M HCl. The aqueous mixture was extracted with EtOAc (220 mL); the organic extracts were dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by flash silica chromatography (gradient elution, 0-100% EtOAc in iso-hexane) to give the title compound as a yellow gum (180 mg, 0.49 mmol, 98%), which was used without further purification.

Step 3: E2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide and E1-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(173) 5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid (180 mg, 0.485 mmol), TFFH (148 mg, 0.56 mmol), DMF (2 mL) and triethylamine (2 mL) were combined and stirred for 1 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (130 mg, 0.71 mmol) was then added and stirring continued for 1 day. Volatile solvents were removed in vacuo. MeOH (2 mL) and 2N HCl in Et.sub.2O (2 mL) were added and the reaction mixture was stirred for 30 min. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC and chiral HPLC to give the title compounds as off-white solids. (Chiralpak IA, Method 50/50 IPA/MeOH (50/50/0.1% formic acid)/Heptane 1.0 mL/min, RT 5.55 min (proposed (E2-(abs)) enantiomer) and 20.58 min. (proposed (E1-(abs)-enantiomer)). (E2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide (27 mg). LCMS (ES+) 387 (M+H).sup.+, RT 10.82 min (Analytical method 2); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.27 (1H, s), 8.82 (1H, s), 8.13 (1H, td, J=7.8, 1.8 Hz), 7.51-7.44 (1H, m), 7.41-7.28 (2H, m), 7.19-7.02 (3H, m), 3.77 (2H, dd, J=16.0, 11.9 Hz), 3.40 (1H, d, J=16.5 Hz), 3.21 (1H, d, J=16.0 Hz), 2.15 (3H, d, J=2.7 Hz). And (E1-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide (32 mg). LCMS (ES+) 387 (M+H).sup.+, RT 10.82 min (Analytical method 2); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.27 (1H, s), 8.82 (1H, s), 8.13 (1H, td, J=7.8, 1.8 Hz), 7.51-7.44 (1H, m), 7.41-7.28 (2H, m), 7.19-7.02 (3H, m), 3.77 (2H, dd, J=16.0, 11.9 Hz), 3.40 (1H, d, J=16.5 Hz), 3.21 (1H, d, J=16.0 Hz), 2.15 (3H, d, J=2.7 Hz).

Example 63: 5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-(trifluoromethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(174) Prepared following the same method as for Example 61 and 62. Purification by preparative HPLC gave the title compound as an off-white solid (12 mg). LCMS (ES+) 451 (M+H).sup.+, RT 11.05 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.22 (1H, s), 8.80 (1H, s), 7.72 (1H, s), 7.67-7.61 (2H, m), 7.61-7.54 (1H, m), 7.19-7.11 (1H, m), 7.11-7.01 (2H, m), 4.41 (2H, s), 3.65 (2H, d, J=15.6 Hz), 3.26 (1H, d, J=16.0 Hz), 3.09 (1H, d, J=15.6 Hz), 2.13 (3H, d, J=2.7 Hz).

Examples 64 and 65: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide and E2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(175) Prepared following the same method as for Example 61 and 62. Purification by preparative HPLC and chiral HPLC gave the title compounds as off-white solids (30 mg and 24 mg, respectively). (Chiralpak IA, Method 50/50 IPA/MeOH (50/50/0.1% formic acid)/Heptane 1.0 mL/min, RT 6.73 min (proposed E2-(abs) enantiomer) and 17.40 min. (proposed E1-(abs) enantiomer)); E2-(abs)-enantiomer. LCMS (ES+) 387 (M+H).sup.+, RT 10.90 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.27 (1H, s), 8.82 (1H, s), 7.71-7.61 (2H, m), 7.54-7.47 (1H, m), 7.28 (1H, td, J=8.5, 2.7 Hz), 7.18-7.02 (3H, m), 3.75 (2H, dd, J=21.0, 16.4 Hz), 3.31 (1H, d, J=16.4 Hz), 3.20 (1H, d, J=15.6 Hz), 2.15 (3H, d, J=2.7 Hz). E1-(abs)-enantiomer:LCMS (ES+) 387 (M+H).sup.+, RT 10.90 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.27 (1H, s), 8.82 (1H, s), 7.71-7.61 (2H, m), 7.54-7.47 (1H, m), 7.28 (1H, td, J=8.5, 2.7 Hz), 7.18-7.02 (3H, m), 3.75 (2H, dd, J=21.0, 16.4 Hz), 3.31 (1H, d, J=16.4 Hz), 3.20 (1H, d, J=15.6 Hz), 2.15 (3H, d, J=2.7 Hz).

Example 66: (R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(176) Prepared following the same method as for Example 61 and 62 starting from Intermediate 15. Purification by preparative HPLC gave the title compound as a white solid (54 mg). LCMS (ES+) 387 (M+H).sup.+, RT 10.85 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.29 (1H, s), 8.84 (1H, s), 7.95-7.89 (2H, m), 7.32 (2H, t, J=8.8 Hz), 7.21-7.05 (3H, m), 3.76 (2H, t, J=17.7 Hz), 3.37 (1H, d, J=16.5 Hz), 3.20 (1H, d, J=15.5 Hz), 2.17 (3H, d, J=2.7 Hz).

Examples 66 and 67: (R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide and (S)-5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(177) ##STR00029##

Step 1: Methyl 5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

(178) A suspension of Intermediate 12 (50 mg, 0.14 mmol), 4-fluorophenyl boronic acid (20.6 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (23.6 mg, 0.02 mmol) and Cs.sub.2CO.sub.3 (278 mg, 0.85 mmol) in dioxane (0.6 mL) and water (0.1 mL) was purged with N.sub.2 and stirred at 100 C. for 17 h. The mixture was purified by flash silica chromatography (gradient elution of 0% to 100% EtOAc in i-hex) to give the title compound as a pale yellow liquid (15 mg, 39 mol, 29%).

Step 2: 5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid

(179) A suspension of methyl 5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate (50 mg, 0.13 mmol) and KOH (111 mg, 1.98 mmol) in MeOH (1 mL) was stirred at 65 C. for 16 h. The reaction was acidified to pH 1 using 1 M HCl, then extracted with DCM (20 mL). The organic layer was dried by passage through a phase separator and concentrated to yield 40 mg of a yellow liquid that was used without further purification.

Step 3: (R)-5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide and (S)-5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(180) A stirred solution of 5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid (40 mg of mixture from previous step) in DCM (1 mL) at r.t was treated with oxalyl chloride (10 L, 0.12 mmol) and DMF (10 L) and stirred for 30 min until effervescence ceased. MeCN (1 mL) and aqueous hydroxylamine (50 wt % hydroxylamine, 20 L, 0.33 mmol) were added and the reaction heated to 100 C. under microwave irradiation for 10 min. The mixture was concentrated and purification by preparative HPLC and chiral preparative HPLC gave the title compounds (15 mg and 19 mg, respectively). (Chiralpak IA, Method 50/50 IPA/MeOH (50/50/0.1% formic acid)/heptane 1.0 mL/min, RT 6.1 min ((R) enantiomer) and 18.0 min ((S) enantiomer). (R)-Enantiomer LCMS (ES+) 387 (M+H).sup.+, RT 10.85 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.29 (1H, s), 8.84 (1H, s), 7.95-7.89 (2H, m), 7.32 (2H, t, J=8.8 Hz), 7.21-7.05 (3H, m), 3.76 (2H, t, J=17.7 Hz), 3.37 (1H, d, J=16.5 Hz), 3.20 (1H, d, J=15.5 Hz), 2.17 (3H, d, J=2.7 Hz). (S)-Enantiomer. LCMS (ES+) 387 (M+H).sup.+, RT 10.85 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.29 (1H, s), 8.84 (1H, s), 7.96-7.90 (2H, m), 7.32 (2H, t, J=8.8 Hz), 7.20-7.05 (3H, m), 3.76 (2H, t, J=17.7 Hz), 3.37 (2H, d, J=16.5 Hz), 3.20 (1H, d, J=15.5 Hz), 2.17 (3H, d, J=2.7 Hz).

Example 68: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(181) ##STR00030##

Step 1: (S)-Methyl 5-(3-fluoro-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d] thiazole-5-carboxylate

(182) A suspension of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (529 mg, 2.54 mmol), Intermediate 14 (620 mg, 1.67 mmol), tetrakis(triphenylphosphine)palladium(0) (93 mg, 80 mol) and CsF (398 mg, 2.62 mmol) in DME (11 mL) and MeOH (2.7 mL) was purged with N.sub.2 and stirred in a microwave reactor at 120 C. for 10 min. The mixture was concentrated and purified by flash silica chromatography (gradient elution of 0% to 100% EtOAc in i-hex) to give the title compound as an impure brown oil (548 mg), which was used without further purification.

Step 2: (S)-5-(3-Fluoro-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid

(183) A solution of (S)-methyl 5-(3-fluoro-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate (548 mg from previous step) and KOH (876 mg, 15.6 mmol) in MeOH (6 mL) was stirred in a sealed tube at 70 C. for 17 h. The mixture was acidified to pH 0 using 10% HCl, extracted with DCM (220 mL), dried (phase separator) and concentrated. The title compound was obtained as an impure brown oil (451 mg), which was used without further purification.

Step 3: (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(184) A stirred solution of (S)-5-(3-fluoro-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid (451 mg from previous step) and triethylamine (0.53 mL, 3.80 mmol) in dry DMF (12 mL) was treated with TFFH (451 mg, 1.71 mmol) at 0 C. under N.sub.2. After stirring at r.t for 40 min, the mixture was cooled to 0 C. and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (240 mg, 2.05 mmol) was added. The mixture was stirred at r.t for 18 h before being diluted with MeOH (15 mL) and treated with HCl (4 M in dioxane, 6 mL). After 1.5 h at r.t., the reaction mixture was diluted with EtOAc (30 mL) and washed with H.sub.2O (220 mL). The combined aqueous washes were extracted with EtOAc (220 mL); the combined organic layers were washed with H.sub.2O (20 mL), dried (phase separator) and concentrated. LCMS analysis showed target material remained in the aqueous washes, which were therefore treated with brine (30 mL) and extracted with EtOAc (320 mL). LCMS analysis of the aqueous layer showed no target material now remained. The organic extracts were dried (phase separator), concentrated and combined with the earlier organic residue. This mixture was purified by preparative HPLC to give the title compound (140 mg) as a white solid. LCMS (ES+) 373 (M+H).sup.+, RT 9.75 min (Analytical method 3); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.30 (1H, s), 8.85 (1H, s), 7.50 (1H, d, J=2.1 Hz), 7.23-7.12 (2H, m), 7.10-7.05 (1H, m), 6.75 (1H, d, J=2.1 Hz), 4.12 (3H, s), 3.79 (2H, d, J=16.0 Hz), 3.41 (1H, d, J=16.6 Hz), 3.21 (1H, d, J=15.5 Hz), 2.18 (3H, d, J=2.7 Hz).

Example 69: (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(185) Prepared following the same method as for Example 68 starting from Intermediate 16. Preparative HPLC gave the title compound as a white solid (133 mg). LCMS (ES+) 373 (M+H).sup.+, RT 9.55 min (Analytical method 2); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.30 (1H, s), 8.85 (1H, s), 7.50 (1H, d, J=2.1 Hz), 7.23-7.12 (2H, m), 7.10-7.05 (1H, m), 6.75 (1H, d, J=2.1 Hz), 4.12 (3H, s), 3.79 (2H, d, J=16.0 Hz), 3.41 (1H, d, J=16.6 Hz), 3.21 (1H, d, J=15.5 Hz), 2.18 (3H, d, J=2.7 Hz).

Example 70: (R)-2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(186) Prepared following the method described for Example 68 starting from Intermediate 16. Preparative HPLC gave the title compound (54 mg). LCMS (ES+) 387 (M+H).sup.+, RT 9.35 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.27 (1H, s), 8.82 (1H, d, J=1.6 Hz), 7.22-7.04 (3H, m), 6.48-6.44 (1H, m), 3.83-3.61 (5H, m), 3.28 (1H, dd, J=4.9, 1.2 Hz), 3.18 (1H, dd, J=13.5, 11.0 Hz), 2.49-2.14 (3H, m), 2.18-2.14 (3H, m).

Example 71: (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(187) ##STR00031##

Step 1: (R)-5-(3-Fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-5-((methylperoxy)methyl)-5,6-dihydro-4H-cyclopenta[d]thiazole

(188) To a solution of Intermediate 15 (500 mg, 1.52 mmol) in ethanol (5 mL) was added 5-fluoropyridine-2-carbothioamide (356 mg, 2.28 mmol). The reaction mixture was heated to 110 C. under microwave conditions for 1 h. The reaction mixture was concentrated to give a dark red gum. The crude reaction material was purified by flash silica chromatography (gradient elution i-hex to 40% EtOAc in i-hex) to give the title compound as a bright orange gum (200 mg, 34%). Progressed without further purification.

Step 2: (R)-5-(3-Fluoro-2-methylphenyl)-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid

(189) (R)-5-(3-fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-5-((methylperoxy)methyl)-5,6-dihydro-4H-cyclopenta[d]thiazole (160 mg, 0.41 mmol), methanol (5 mL) and 15% aq. NaOH solution (1.10 mL, 4.1 mmol) were combined in a sealed tube and heated to 65 C. for 18 h. The orange reaction mixture was evaporated in vacuo then diluted with EtOAc and H.sub.2O. The aqueous layer was adjusted to pH 7 with 1 M HCl and the layers separated. The organic layer was dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by flash silica chromatography (gradient elution i-hex to 100% EtOAc in i-hex) to give the title compound as an orange solid (85 mg, 53%). .sup.1H NMR (ppm)(CH.sub.3OH-d.sub.4): 8.26 (1H, dd, J=20.1, 2.9 Hz), 8.04 (1H, dd, J=20.1, 8.8 Hz), 7.46 (1H, dt, J=8.8, 3.0 Hz), 7.18-7.13 (2H, m), 7.01-6.94 (1H, m), 3.95-3.82 (5H, m), 3.53-3.42 (1H, m), 3.35 (1H, d, J=7.7 Hz), 2.27 (3H, d, J=2.7 Hz). Acid OH not seen Used crude without further purification.

Step 3: (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(190) A stirred solution of (R)-5-(3-Fluoro-2-methylphenyl)-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid (82 mg, 0.21 mmol) and triethylamine (0.096 mL, 0.68 mmol) in dry DMF (2 mL) was treated with TFFH (81 mg, 0.31 mmol) at 0 C. under N.sub.2. After stirring at r.t. for 40 min, the mixture was cooled to 0 C. and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (43 mg, 0.37 mmol) was added. The mixture was stirred at r.t. for 18 h before being diluted with MeOH (2 mL) and treated with HCl (4 M in dioxane, 1 mL). After 1.5 h at rt, the reaction mixture was diluted with EtOAc (10 mL) and washed with H.sub.2O (210 mL). The combined aqueous washes were extracted with EtOAc (210 mL); the combined organic layers were washed with H.sub.2O (20 mL), dried (phase separator) and concentrated. Preparative HPLC gave the title compound as an off-white solid (36 mg). LCMS (ES+) 400 (M+H).sup.+, RT 3.51 min (Analytical method 1). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.26 (1H, s), 8.82 (1H, s), 8.30 (1H, dd, J=2.9, 0.6 Hz), 7.97 (1H, dd, J=8.8, 0.6 Hz), 7.50 (1H, dd, J=8.8, 2.9 Hz), 7.21-7.03 (3H, m), 3.87 (3H, s), 3.73 (2H, t, J=15.6 Hz), 3.34 (1H, d, J=13.7 Hz), 3.18 (1H, d, J=15.6 Hz), 2.18-2.14 (3H, m).

Example 72: (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide

(191) ##STR00032##

Step 1: (S)-Methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate

(192) A suspension of intermediate 10 (0.114 g, 0.31 mmol), cyclopropyl boronic acid (0.029 g, 0.34 mmol), palladium tetrakis(triphenylphosphine) (0.015 g) and cesium carbonate (0.5 g, 1.54 mmol) in a mixture of degassed dioxane/water (9:1, 10 mL) was stirred at 110 C. for 16 h. The reaction was cooled to r.t., diluted with EtOAc (75 mL) and subjected to an aqueous workup. The organic layer was concentrated under vacuum to give the title compound as an impure yellow oil, which was used without further purification in the next step. LCMS (ES+) 332 (M+H).sup.+.

Step 2: (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylic acid

(193) (S)-Methyl 2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate (26 mg, 0.07 mmol), MeOH (2 mL) and 15% aq. NaOH soln. (0.5 mL) were combined in a sealed tube and heated to 70 C. for 4 days. The reaction mixture was cooled and evaporated to dryness. Residue was partitioned between 1N HCl and EtOAc. Organics were dried (MgSO.sub.4) and evaporated to dryness to give the title compound as an off white solid. LCMS (ES+) 318 (M+H).sup.+.

Step 3: (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide

(194) (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylic acid (53 mg, 0.16 mmol), TFFH (49 mg, 0.18 mmol), DMF (2 mL) and triethylamine (0.12 mL) were combined and stirred for 1 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (22 mg, 0.184 mmol) was then added and stirring continued for 1 day. Volatile solvents were removed in vacuo. MeOH (1 mL) and 2N HCl in Et.sub.2O (1 mL) were added and reaction mixture was stirred for 30 min. Volatile solvents were removed in vacuo and remaining crude material was purified by preparative HPLC to give (S)-2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide (1 mg). LCMS (ES+) 333 (M+H).sup.+, 331 (MH).sup., RT 9.68 min (Analytical method 2); .sup.1H NMR (400 MHz, CHCl.sub.3-d) 8.19 (1H, s) 7.03-6.86 (3H, m), 3.85-3.70 (1H, m) 3.05-2.95 (1H, m) 2.92-2.75 (1H, m) 2.50-2.38 (1H, m), 2.41-2.17 (4H, m) 1.20-0.90 (4H, m). OH resonance not observed.

Example 73: (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(o-tolyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide

(195) Prepared following the method described for Example 72. Preparative HPLC gave the title compound as an off-white solid (4 mg). LCMS (ES+) 383 (M+H).sup.+, RT 11.0 min. (Analytical method 2); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.55 (1H, s), 8.92 (1H, s), 7.76 (1H, d, J=7.4 Hz), 7.40-7.34 (3H, m), 7.21-7.09 (2H, m), 7.02 (1H, dd, J=7.8, 7.8 Hz), 3.77-3.60 (1H, m), 3.06-2.83 (2H, m), 2.59 (3H, s), 2.43-2.31 (1H, m), 2.17 (3H, d, J=2.4 Hz).

Examples 74 and 75: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide and E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(196) ##STR00033##

Step 1: Methyl 5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

(197) A suspension of 4-fluoro-2-methylphenylboronic acid (105 mg, 0.68 mmol), Intermediate 12 (188 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium(0) (93 mg, 80 mol) and CsF (100 mg, 0.66 mmol) in DME (3 mL) and MeOH (0.75 mL) was purged with N.sub.2 and stirred in a microwave reactor at 120 C. for 10 min. The mixture was concentrated and purified by flash silica chromatography (gradient elution of 0% to 100% EtOAc in i-hex) to give the title compound (79 mg) in 75% purity as a colorless oil, which was used without further purification.

Step 2: 5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid

(198) To a solution of methyl 5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate (79 mg mixture from previous step) in methanol (2 mL) was added KOH (122 mg). The reaction mixture was capped and heated at 70 C. for 20 h. After this time the contents were cooled to r.t. and acidified to pH 0 with 10% HCl. The mixture was extracted with DCM (220 mL), dried (phase separation cartridge) and concentrated to give the title compound (58 mg) in 85% purity as a brown oil, which was used without further purification.

Step 3: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide and E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(199) A stirred solution of 5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylic acid (58 mg, mixture from the previous step) in DCM (1 mL) at 20 C. was treated sequentially with oxalyl chloride (14 L) and DMF (10 L). The mixture was stirred for 25 min until gas evolution ceased. MeCN (1 mL) and hydroxylamine (28 L) were added and the mixture heated to 100 C. in a microwave reactor for 10 min. Purification by preparative HPLC and chiral preparative HPLC gave the E1-(abs) and E2-(abs) enantiomers (1 mg and 2 mg respectively) which were arbitrarily assigned. (Chiralpak IA 50/50 EtOH (0.1% formic acid)/Heptane, 1.0 mL/min, r.t., RT 11.3 min (E2-(abs)) and 6.1 min (E1-(abs)). E2-(abs): LCMS (ES+) 401 (M+H).sup.+, RT 4.06 min (Analytical method 1); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.31 (1H, s), 8.82 (1H, s), 7.76-7.71 (1H, m), 7.25 (1H, dd, J=2.4, 10.0 Hz), 7.20-7.05 (4H, m), 3.90-3.76 (2H, m), 3.40-3.31 (1H, m), 3.26-3.17 (1H, m), 2.56 (3H, s), 2.21-2.18 (3H, m). E1-(abs): LCMS (ES+) 401 (M+H).sup.+, RT 4.06 min (Analytical method 1); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.31 (1H, s), 8.82 (1H, s), 7.76-7.71 (1H, m), 7.25 (1H, dd, J=2.4, 10.0 Hz), 7.20-7.05 (4H, m), 3.90-3.76 (2H, m), 3.40-3.31 (1H, m), 3.26-3.17 (1H, m), 2.56 (3H, s), 2.21-2.18 (3H, m).

Example 76 and 77: E1-(abs)-2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide and E2-(abs)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(200) Prepared following the same method as for Example 74 and 75. Purification by preparative HPLC and chiral HPLC gave the E1-(abs) and E2-(abs) enantiomers (3 mg and 5 mg respectively) which were arbitrarily assigned. (Chiralpak IC 50/50 EtOH (0.1% formic acid)/heptane, 1.0 mL/min, RT 6.1 min (E1-(abs)) and 11.6 min (E2-(abs)). E1-(abs) Enantiomer LCMS (ES+) 387 (M+H).sup.+, RT 3.15 min (Analytical method 1); .sup.1H NMR S (ppm)(400 MHz, DMSO-d.sub.6): 10.28 (1H, s), 8.82 (1H, s), 7.74 (1H, s), 7.19-7.05 (3H, m), 3.78 (3H, s), 3.77-3.67 (2H, m), 3.14 (1H, d, J=15.8 Hz), 2.53 (3H, s), 2.21-2.16 (3H, m), 1H obscured by water. E2-(abs) Enantiomer LCMS (ES+) 387 (M+H)+, RT 3.16 min (Analytical method 1); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.28 (1H, s), 8.82 (1H, s), 7.74 (1H, s), 7.19-7.05 (3H, m), 3.78 (3H, s), 3.77-3.67 (2H, m), 3.14 (1H, d, J=15.8 Hz), 2.53 (3H, s), 2.21-2.16 (3H, m), 1H obscured by water resonance.

Example 78: (S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide

(201) Prepared following the same method as for Example 72. Preparative HPLC gave the title compound as a white solid (8 mg). LCMS (ES+) 387 (M+H).sup.+, RT 3.8 min (Analytical method 1); .sup.1H NMR (ppm)(400 MHz, DMSO-d.sub.6): 10.57 (1H, d, J=1.4 Hz), 8.93-8.91 (1H, m), 8.02-7.97 (2H, m), 7.38-7.33 (2H, m), 7.21-7.09 (2H, m), 6.98 (1H, d, J=7.5 Hz), 3.73-3.65 (1H, m), 3.02-2.94 (1H, m), 2.91-2.82 (1H, m), 2.40-2.32 (1H, m), 2.16 (3H, d, J=2.4 Hz) (data reported for major rotamer).

Example 79: (R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(202) ##STR00034## ##STR00035##

Step 1: (R)-Methyl 3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate

(203) .sup.tBuOK (124 mg, 1.1 mmol) and THF (6 mL) were combined under a nitrogen atmosphere. The reaction mixture was cooled with an ice bath and ethyl formate (0.24 mL, 4 mmol) was added drop-wise. After 15 min Intermediate 2 (250 mg, 1 mmol) was added drop-wise as a solution in ethyl formate (2 mL). The reaction mixture was stirred for a further 1 h with ice bath cooling then diluted with EtOAc, washed with 1N HCl, then brine, dried (phase separator) and evaporated to dryness to give the crude aldehyde as a pale brown oil. The crude residue was dissolved in anhydrous THF (6 mL) and dimethylamine (2 mL, 4 mmol, 2 M in THF) added. The reaction mixture was then stirred for a further 36 h. After this time the reaction mixture was concentrated under reduced pressure and purified by flash silica column chromatography (gradient elution i-hex to 66% EtOAc in i-hex) to give the title compound as a pale yellow solid (0.25 g, 83% over 2 steps). LCMS (ES+) 306 (M+H).sup.+.

Step 2: (R)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(4-fluorobenzylidene)-4-oxocyclopentanecarboxylate

(204) (R)-Methyl 3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate (250 mg, 0.8 mmol) and THF (5 mL) were combined under a nitrogen atmosphere. The reaction mixture was cooled with an ice bath and 4-fluorophenyl magnesium bromide (2 mL, 2 mmol, 1 M in THF) was added drop-wise. The reaction mixture was stirred for 1 h with ice bath cooling then quenched with aq. NH.sub.4Cl (2 mL). The solution was then diluted with EtOAc, washed with water, then brine, dried (phase separator) and evaporated to dryness and purified by flash silica column chromatography (gradient elution i-hex to 20% EtOAc in i-hex) to give the title compound as a colorless solid (0.28 g, 95%). LCMS (ES+) 357 (M+H).sup.+.

Step 3: (5R)-Methyl 5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,3,3a,4,5,6-hexahydrocyclopenta[c]pyrazole-5-carboxylate

(205) (R)-Methyl 1-(3-fluoro-2-methylphenyl)-3-(4-fluorobenzylidene)-4-oxocyclopentanecarboxylate (130 mg, 0.4 mmol), indium chloride (20 mg, 0.15 mmol), methylhydrazine (25 L, 0.44 mmol) and ethanol (6 mL) were combined under a nitrogen atmosphere. The reaction mixture was then refluxed for 2 h. After this time the reaction mixture was cooled to room temperature and passed through a pad of silica gel eluting with 50% EtOAc in i-hex to give crude hydrazide as a 3:1 mixture of syn/anti isomers. LCMS (ES+) 385 (M+H).sup.+.

Step 4: (R)-Methyl 5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate

(206) (SR)-Methyl 5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,3,3a,4,5,6-hexahydro cyclopenta[c]pyrazole-5-carboxylate (80 mg, 0.2 mmol), DDQ (52 mg, 0.23 mmol) and anhydrous dioxane (3 mL) were combined under a nitrogen atmosphere. The reaction mixture was then refluxed for 2 h. After this time the reaction mixture was cooled to r.t, concentrated under reduced pressure and purified by flash silica column chromatography (gradient elution i-hex to 60% EtOAc in i-hex) to give the title compound as a pale yellow oil (53 mg, 66%). LCMS (ES+) 383 (M+H).sup.+.

Step 5: (R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylic acid

(207) To a solution of (R)-methyl 5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate (52 mg, 0.14 mmol) in THF/methanol/water (1:1:0.5, 2.5 mL) was added lithium hydroxide hydrate (0.03 g, 0.70 mmol). The reaction mixture was capped and heated at 65 C. for 18 h. After this time the contents were cooled to r.t. and methanol was removed under reduced pressure. Aqueous residues were partitioned between EtOAc (15 mL) and 1 M aqueous HCl (15 mL). Organic layers were extracted, washed with brine (20 mL), dried, filtered (phase separation cartridge) and concentrated to give the title compound as a pale yellow oil which was used directly (42 mg, 84%).

Step 6: (R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(208) To a solution of (R)-5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylic acid (0.40 g, 1.1 mmol), and triethylamine (0.33 g, 468 L, 3.3 mmol) in anhydrous DMF (10 mL) was added TFFH (0.36 g, 1.42 mmol) at 0 C. The reaction mixture was stirred at this temperature for 15 min, then O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.2 g, 1.67 mmol) was added in a single portion. The reaction mixture was then stirred at r.t for 24 h. After this time the reaction mixture was quenched by the addition of 1 M HCl solution (5 mL). The reaction was partitioned between EtOAc (30 mL) and 1 M HCl (15 mL). The organic layer was separated, washed with brine (40 mL), dried, filtered (phase separation cartridge) and concentrated to give the crude THP protected hydroxamic acid as a pale yellow oil. To this oil was added anhydrous methanol (3 mL) and 4 M HCl in dioxane (2 mL). The reaction mixture was stirred at r.t. for 30 min. After this time solvents were removed under reduced pressure to give crude hydroxamic acid which was purified by preparative HPLC to give the title compound as a colorless solid (20 mg). LCMS (ES+) 384 (M+H).sup.+, RT 3.43 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.19 (1H, s), 8.76 (1H, s), 7.58-7.53 (2H, m), 7.38-7.32 (2H, m), 7.14 (1H, t, J=7.3 Hz), 7.04 (2H, t, J=7.8 Hz), 3.78 (3H, s), 3.64-3.53 (2H, m), 3.02 (1H, d, J=7.2 Hz), 2.98 (1H, d, J=7.6 Hz), 2.16 (3H, d, J=2.7 Hz).

Examples 80 and 81: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide and E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide

(209) ##STR00036##

Step 1: 5-Phenyl-1,3,4-oxathiazol-2-one

(210) To a stirred solution of amide (24.8 mmol) in THF (50 mL) was added chlorocarbonylsulfenyl chloride (29.8 mmol). The solution was stirred at r.t for 17 h, concentrated in vacuo. Purification by flash chromatography (5% EtOAc in i-hex) gave the title compound as an off-white solid (3.9 g, 88%). LCMS (ES+) 180 (M+H).sup.+

Step 2: Dimethyl 3-phenylisothiazole-4,5-dicarboxylate

(211) A solution of 5-phenyl-1,3,4-oxathiazol-2-one (12.7 mmol) and dimethyl acetylenedicarboxylate (38.1 mmol) in CHCl.sub.3 (10 mL) was heated in the microwave at 160 C. for 1 h, or until evolution of gas stopped. The mixture was then concentrated and purified by flash chromatography (5% EtOAc in i-hex) to give the title compound as a colorless oil (3.09 g, 88%). LCMS (ES+) 278 (M+H).sup.+

Step 3: (3-Phenylisothiazole-4,5-diyl)dimethanol

(212) To a cooled solution of dimethyl 3-phenylisothiazole-4,5-dicarboxylate (10.7 mmol) in THF (180 mL) was added Super-Hydride (53.3 mmol) over a 10 min period and the reaction then stirred at r.t for 1.5 h. The mixture was quenched with IM HCl (70 mL), the volume reduced to half and extracted into EtOAc. The aqueous was re-extracted with further portions of EtOAc and the organics combined, dried (MgSO.sub.4), filtered and concentrated. Purification by flash chromatography (5% to 15% MeOH in DCM gradient) gave the title compound as a colorless oil (2.36 g, >99%). LCMS (ES+) 222 (M+H).sup.+

Step 4: 4,5-Bis(bromomethyl)-3-phenylisothiazole

(213) To a stirred solution of (3-phenylisothiazole-4,5-diyl)dimethanol (13.6 mmol) in DCM/Et.sub.2O (1:1, 100 mL) was added phosphorous tribromide (27.2 mmol) dropwise. The mixture was heated to 30 C. for 3 h. The mixture was diluted with H.sub.2O (50 mL) and the volatiles concentrated before extraction with DCM (250 mL). The combined organics were passed through a phase separator and concentrated. Purification by flash chromatography (5% EtOAc in i-hex) gave the title compound as a colorless oil (3.02 g, 64%). LCMS (ES+) 348 (M+H).sup.+

Step 5: Methyl 5-(3-fluoro-2-methylphenyl)-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxylate

(214) To a stirred solution of methyl 2-(3-fluoro-2-methylphenyl)acetate (5.4 mmol) in DMF (200 mL) was added NaH (5.4 mmol). This was stirred for 1 h with occasional heating until no more H.sub.2 gas evolution was observed. This solution was then added slowly dropwise to a stirred solution of 4,5-bis(bromomethyl)-3-phenylisothiazole (4.9 mmol) in DMF (200 mL) at 0 C. A further portion of NaH (5.4 mmol) was added and the reaction mixture heated to 60 C. for 1 h. An additional portion of NaH (5.4 mmol) was added and stirring continued for 1 h. The reaction was quenched with H.sub.2O (in ice-bath) and the volatiles removed under reduced pressure. The remaining residue was partitioned between EtOAc and H.sub.2O. The organics were collected, dried (MgSO.sub.4), filtered and concentrated. Purification by flash chromatography (3% to 5% EtOAc in i-hex) gave the title compound (125 mg, 7%). LCMS (ES+) 367 (M+H).sup.+

Step 6: 5-(3-Fluoro-2-methylphenyl)-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxylic acid

(215) To a solution of methyl 5-(3-fluoro-2-methylphenyl)-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxylate (97 mg, 0.26 mmol) in THF/methanol (1:1, 2 mL) was added sodium hydroxide (2.0 mL, 2 M aqueous solution). The reaction mixture was capped and heated at 70 C. for 18 h. After this time the contents were cooled to r.t. and methanol was removed under reduced pressure. Aqueous residues were partitioned between EtOAc (15 mL) and 1 M aqueous HCl (15 mL). Organic layers were extracted, washed with brine (20 mL), dried, filtered (phase separation cartridge) and concentrated to give the title compound as a colorless oil which was used directly in the next step (60 mg, 65%).

Step 7: E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide and E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide

(216) To a solution of 5-(3-fluoro-2-methylphenyl)-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxylic acid (60 mg from previous step), triethylamine (92 l, 0.65 mmol) in anhydrous DMF (1 mL) was added TFFH (49 mg, 0.19 mmol) at 0 C. The reaction mixture was stirred at this temperature for 15 min, then O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (39 mg, 0.34 mmol) was added in a single portion. Reaction mixture was then stirred at r.t for 24 h. After this time the reaction mixture was quenched by the addition of 1 M HCl solution (2 mL). The reaction was partitioned between EtOAc (5 mL) and 1 M HCl (5 mL). The organic layer was separated, washed with brine (10 mL), dried, filtered (phase separation cartridge) and concentrated to give the crude THP protected hydroxamic acid as a pale yellow oil. To this oil was added anhydrous methanol (2 mL) and 4 M HCl in dioxane (1 mL). The reaction mixture was stirred at r.t. for 30 min. After this time solvents were removed under reduced pressure to give crude hydroxamic acid which was purified by preparative HPLC and chiral HPLC to give the E1-(abs) and E2-(abs) enantiomers (2 mg and 3 mg respectively) which were arbitrarily assigned. (Chiralpak IC 40/60 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 13.2 min (E1-(abs)) and 4.9 min (E2-(abs)). E1-(abs) LCMS (ES+) 369 (M+H).sup.+, RT 3.77 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.3 (1H, s), 8.84 (1H, s), 7.90-7.85 (2H, m), 7.55-7.40 (3H, m), 7.20-7.00 (3H, m), 3.95 (1H, d, J=15.2 Hz), 3.92 (1H, d, J=17.2 Hz), 3.45 (1H, d, J=17.2 Hz), 3.42 (1H, d, J=15.2 Hz), 2.17 (3H, d, J=2.4 Hz). E2-(abs) LCMS (ES+) 369 (M+H).sup.+, RT 3.77 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.3 (1H, s), 8.84 (1H, s), 7.90-7.85 (2H, m), 7.55-7.40 (3H, m), 7.20-7.00 (3H, m), 3.95 (1H, d, J=15.2 Hz), 3.92 (1H, d, J=17.2 Hz), 3.45 (1H, d, J=17.2 Hz), 3.42 (1H, d, J=15.2 Hz), 2.17 (3H, d, J=2.4 Hz).

Example 82: 2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide

(217) ##STR00037##

Step 1: 2-(3-Fluoro-2-methylphenyl)-2,3-dihydro-1H-indene-2-carbonitrile

(218) To a solution of 2-(3-fluoro-2-methylphenyl)acetonitrile (0.298 g, 2.0 mmol) in DMF (30 mL) was added NaH (0.176 g, 4.4 mmol) stirred at RT under N.sub.2 for 30 min, ,-dibromo-o-xylene (0.58 g, 2.2 mmol) added and the reaction mixture was stirred at RT under N.sub.2 for 92 h. Saturated NH.sub.4Cl solution (30 mL) added extracted with EtOAc (330 mL). Combined organics were extracted with brine (20 mL). EtOAc layers were then dried, filtered (phase separation cartridge) and concentrated onto silica and purified by flash silica column chromatography (gradient elution i-hex to 100% EtOAc in i-hex) to yield the title compound as a pale yellow oil (0.098 g, 19%). LCMS (ES+) 252 (M+H).sup.+

Step 2: 2-(3-Fluoro-2-methylphenyl)-2,3-dihydro-1H-indene-2-carboxylic acid

(219) 2-(3-Fluoro-2-methylphenyl)-2,3-dihydro-1H-indene-2-carbonitrile (98 mg, 0.39 mmol) was dissolved in dioxane (2 mL) and 4M HCl in dioxane (1 mL) was added. The mixture was stirred at 120 C. for 96 h to give the title compound as a white solid (63 mg, 97%) and used crude in next step. LCMS (ES+) 271 (M+H).sup.+.

Step 3: 2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide

(220) To a solution of 2-(3-fluoro-2-methylphenyl)-2,3-dihydro-1H-indene-2-carboxylic acid (63 mg from previous step) and triethylamine (92 l, 0.65 mmol) in anhydrous DMF (1 mL) was added TFFH (49 mg, 0.19 mmol) at 0 C. The reaction mixture was stirred at this temperature for 15 min, then O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (39 mg, 0.34 mmol) was added in a single portion. The reaction mixture was then stirred at r.t. for 24 h. After this time the reaction mixture was quenched by the addition of 1 M HCl solution (2 mL). The reaction was partitioned between EtOAc (5 mL) and 1 M HCl (5 mL). The organic layer was separated, washed with brine (10 mL), dried, filtered (phase separation cartridge) and concentrated to give the crude THP protected hydroxamic acid as a pale yellow oil. To this oil was added anhydrous methanol (2 mL) and 4 M HCl in dioxane (1 mL). The reaction mixture was stirred at r.t for 30 min. After this time solvents were removed under reduced pressure to give crude hydroxamic acid which was purified by preparative HPLC to give the title compound as a colorless solid (20 mg). LCMS (ES+) 285 (M+H).sup.+, RT 3.58 min (Analytical method 1). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.19 (1H, s), 8.74 (1H, s), 7.30-7.15 (2H, m), 7.15-6.95 (5H, m), 3.71 (2H, d, J=16.8 Hz), 3.20 (2H, d, J=16.8 Hz), 2.17 (3H, d, J=2.4 Hz).

Example 83: 2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d] pyrimidine-7-carboxamide

(221) ##STR00038##

Step 1: Methyl 2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-4-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate

(222) Cyclopropanecarboximidamide hydrochloride (0.27 g, 2.2 mmol) was added to a solution of intermediate 9 (0.77 g, 2.2 mmol) in dry methanol (15 mL). Sodium methoxide (0.24 g, 4.44 mmol) was added and the reaction mixture heated at reflux for 3.25 h. Additional cyclopropanecarboximidamide hydrochloride (0.10 g, 0.83 mmol), sodium methoxide (0.10 g, 1.85 mmol) and methanol (3 mL) were added and the reaction heated at reflux for 3 h. Additional cyclopropanecarboximidamide hydrochloride (0.05 g, 0.41 mmol), sodium methoxide (0.06 g, 1.11 mmol) and methanol (10 mL) were added and the reaction stirred at room temperature. After 18 h the reaction mixture was quenched with saturated ammonium chloride solution. The reaction mixture was concentrated to a volume, diluted with DCM and water and transferred to a separating funnel. The mixture was extracted with DCM (3), dried (phase separating cartridge) and evaporated to dryness. The crude mixture was purified by silica gel column chromatography (25 g SNAP column), eluting with 0-70% EtOAc in i-hex to afford the title compound as a solid (0.44 g, 54%). .sup.1H NMR (ppm)(CHCl.sub.3-d): 12.32 (1H, br. s), 7.23-7.14 (2H, m), 7.04-6.95 (1H, m), 3.71 (3H, s), 3.02 (1H, dd, J=17.2, 10.3 Hz), 2.88-2.67 (3H, m), 2.64-2.53 (2H, m), 2.33-2.21 (2H, m), 2.16 (3H, d, J=3.1 Hz), 1.87-1.79 (1H, m), 1.20-1.14 (2H, m), 1.08-1.01 (2H, m).

Step 2: Methyl 2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-4-(((trifluoromethyl)sulfinyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate

(223) Methyl 2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-4-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate (0.44 g, 1.19 mmol) was dissolved in DCM (15 mL) and cooled to 0 C. Pyridine (0.15 mL, 1.79 mmol) was added followed by dropwise addition of triflic anhydride (0.24 mL, 1.42 mmol). The reaction mixture was stirred at 0 C. for 2 h. The reaction mixture was transferred to a separating funnel with DCM and washed with water. The combined organic extracts were dried (phase separating cartridge), and concentrated under reduced pressure. Purified by silica gel column chromatography eluting with 0-100% EtOAc in i-hex to afford the title compound as a yellow oil (153 mg, 26%). .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.23-7.12 (2H, m), 7.05-6.97 (1H, m), 3.75 (3H, s), 3.33 (1H, dd, J=16.6, 10.8 Hz), 3.09-2.97 (2H, m), 2.92-2.83 (1H, m), 2.71-2.62 (2H, m), 2.29-2.10 (5H, m), 1.17-1.06 (4H, m).

Step 3: Methyl 2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate

(224) Palladium on carbon (100 mg), triethylamine (0.06 mL, 0.43 mmol) and 3 molecular sieves were added to methyl 2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-4-(((trifluoromethyl)sulfinyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate (153 mg, 0.30 mmol) in EtOAc (10 mL) at room temperature. The reaction mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 21 h. The reaction mixture was filtered over celite washing with EtOAc and methanol. The filtrate was condensed and the resultant oil partitioned between water and DCM. The mixture was extracted with DCM (2) and the combined organic extracts dried (phase separating cartridge) and evaporated to dryness to afford the title compound as a yellow oil (120 mg, >100%). Used without further purification in the next step.

Step 4: 2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylic acid

(225) Methyl 2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate (0.30 mmol), lithium hydroxide (100 mg), THF (2 mL), MeOH (2 mL) and water (1 mL) were combined in a sealed tube at 65 C. for 15 h. Additional LiOH (50 mg) was added and heated for a further 21 h. The reaction mixture was cooled to room temperature and partially concentrated under reduced pressure. Water was added and the aqueous mixture acidified with 1N hydrochloric acid. The resultant white precipitate was collected by filtration and dried. There was evidence of the target material in the filtrate. This was condensed, extracted with DCM (3), dried (phase separating cartridge) and evaporated to dryness. This was combined with the filtered solid and used without further purification in the next step (58 mg, 57%).

Step 5: 2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxamide

(226) 2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylic acid (58 mg, 0.17 mmol), TFFH (68 mg, 0.26 mmol), DMF (1.5 ml) and Triethylamine (47 l) were combined and stirred at 0 C. for 0.5 h. Triethylamine (59 l, 0.43 mmol) and hydroxylamine hydrochloride (24 mg, 0.34 mmol) were added and the reaction stirred at room temperature for 20 h. The reaction mixture was diluted with water (2-3 drops), filtered and purified by preparative HPLC to afford the title compound as a white solid (5 mg). LCMS (ES+) 356 (M+H).sup.+, RT 3.04 min (Analytical method 1); .sup.1H NMR (ppm)(CH.sub.3OH-d.sub.4): 8.27 (1H, s), 7.20-7.18 (1H, m), 7.17-7.07 (1H, m), 6.96-6.87 (1H, m), 3.40-3.31 (1H, m), 3.12-2.99 (1H, m), 2.86 (1H, dd, J=16.7, 8.7 Hz), 2.79-2.66 (1H, m), 2.60-2.47 (2H, m), 2.22-2.01 (6H, m), 1.08-1.00 (4H, m).

Examples 84 and 85: E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide and E2-(abs)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide

(227) ##STR00039## ##STR00040##

Step 1: Methyl 6-(3-fluoro-2-methylphenyl)-3-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate

(228) 2,2,2-Trifluoroethylhydrazine (0.32 mL, 70% aqueous solution) was added to a solution of intermediate 9 (0.64 g, 1.8 mmol) in dry ethanol (7 mL) in a sealed tube and heated at 95 C. for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resultant gum was allowed to stand at room temperature. Partial crystallization occurred over 2 weeks. The solid was triturated sequentially with EtOAc then 20% EtOAc in iso-hexane. The resultant solid was collected by filtration, washing with 20% EtOAc in i-hexane and dried in the vacuum oven to afford the title compound as an off-white solid (360 mg, 50%). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.55 (0.67H, s), 10.39 (0.33H, s), 7.35 (1H, d, J=8.08 Hz), 7.23 (1H, dd, J=14.82, 7.41 Hz), 7.13-7.04 (1H, m), 4.62 (1.33H, dd, J=18.38, 9.19 Hz), 4.40 (0.67H, d, J=10.33 Hz), 3.64 (3H, s), 2.72-2.58 (2H, m), 2.50-2.32 (4H, m), 2.25-2.12 (2H, m), 2.06 (3H, s). The NMR spectrum was consistent with a mixture of tautomers.

Step 2: Methyl 6-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate

(229) Methyl 6-(3-fluoro-2-methylphenyl)-3-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c] pyrazole-6-carboxylate (0.36 g, 0.90 mmol) was dissolved in DCM (10 mL). Pyridine (0.11 mL, 1.35 mmol) was added at room temperature followed by dropwise addition of a triflic anhydride (0.06 mL, 0.36 mmol) in DCM (1 mL). The reaction mixture was cooled to 0 C. and triflic anhydride (0.12 mL, 0.72 mmol) in DCM (3 mL) was added dropwise. After 1.5 h the reaction mixture was transferred to a separating funnel with DCM and washed with water. The combined organic extracts were dried (phase separating cartridge) and evaporated to dryness. The crude material was purified by silica gel column chromatography eluting with 0-70% EtOAc in i-hex to afford the title compound as a colorless gum (380 mg, 80%). .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.21-7.15 (2H, m), 7.03-6.95 (1H, m), 4.57 (2H, dd, J=16.20, 8.10 Hz), 3.70 (3H, s), 3.01-2.92 (1H, m), 2.84-2.72 (2H, m), 2.66-2.49 (3H, m), 2.31-2.18 (2H, m), 2.15 (3H, d, J=3.13 Hz).

Step 3: Methyl 6-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate

(230) Palladium on carbon (300 mg), triethylamine (0.14 mL, 1.00 mmol) and 3 molecular sieves were added to methyl 6-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate (0.38 g, 0.70 mmol) in EtOAc (20 mL) at room temperature. The reaction mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 20 h. The reaction mixture was filtered over celite washing with methanol. The filtrate was condensed and the resultant oil partitioned between water and DCM. The mixture was extracted with DCM (2) and the combined organics dried (phase separating cartridge), filtered and evaporated to dryness to afford the title compound as a yellow oil (331 mg, >100%). Used without further purification in the next step. .sup.1H NMR (ppm)(CHCl.sub.3-d): 7.22-7.14 (3H, m), 7.02-6.95 (1H, m), 4.58 (2H, dd, J=16.98, 8.49 Hz), 3.72 (3H, s), 2.94-2.91 (1H, m), 2.86-2.73 (2H, m), 2.67-2.56 (3H, m), 2.34-2.19 (2H, m), 2.18 (3H, d, J=3.13 Hz).

Step 4: 6-(3-Fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylic acid

(231) Methyl 6-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate (0.33 g, 0.86 mmol), lithium hydroxide (180 mg), THF (2 mL), MeOH (2 mL) and water (1 mL) were combined in a sealed tube at 65 C. for 18.5 h. Additional LiOH (135 mg) was added and heated for a further 54 h. The reaction mixture was cooled to room temperature and evaporated to dryness. The mixture was partitioned between water and DCM, acidified to pH 1 using 2N hydrochloric acid. The mixture was extracted with DCM (3 times), dried (phase separating cartridge) and evaporated to dryness to afford the title compound as a white solid (250 mg, 79%). .sup.1H NMR (ppm)(DMSO-d.sub.6): 12.72 (1H, s), 7.50-7.46 (1H, m), 7.32 (1H, d, J=8.1 Hz), 7.25-7.17 (1H, m), 7.11-7.04 (1H, m), 4.94 (2H, dd, J=18.4, 9.2 Hz), 2.81 (1H, dd, J=16.2, 10.5 Hz), 2.71-2.58 (3H, m), 2.56-2.47 (2H, m), 2.48-2.37 (2H, m), 2.17 (3H, d, J=3.1 Hz).

Step 5: E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide and E2-(abs)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide

(232) 6-(3-Fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylic acid (210 mg, 0.57 mmol) was suspended in dry DCM (4 mL). Oxalyl chloride (53 L, 0.62 mmol) and DMF (1 drop) were added with stirring at room temperature. After 2 h MeCN (4 mL) was added and the reaction transferred to a 20 mL microwave tube. Hydroxylamine (200 L, 50% aqueous solution) was added and the reaction heated in the microwave at 100 C. for 10 min. The reaction is evaporated to dryness and suspended in methanol. The slurry was triturated with water to afford a white powder which was purified by silica gel column chromatography (gradient elution 0-5% MeOH in DCM). Chiral preparative HPLC gave the E1-(abs)- and E2-(abs)-enantiomers which were arbitrarily assigned. (Chiralpak IA, Method 40/60 EtOH (0.1% formic acid)/Heptane 1.0 mL/min, RT 6.3 (E1-(abs)) and 17.3 min (E2-(abs)). E1-(abs)-enantiomer was obtained as a cream solid (34 mg). LCMS (ES+) 386 (M+H).sup.+, RT 9.85 (Analytical method 2). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.11 (1H, s), 8.68 (1H, s), 7.44 (1H, s), 7.36-7.30 (1H, m), 7.20 (1H, q, J=7.40 Hz), 7.10-7.03 (1H, m), 4.92 (2H, q, J=9.18 Hz), 2.82 (1H, dd, J=15.69, 10.24 Hz), 2.70-2.39 (7H, m), 2.13 (3H, d, J=2.8 Hz). E2-(abs)-enantiomer was obtained as a white solid (31 mg). LCMS (ES+) 386 (M+H).sup.+, RT 3.36 min (Analytical method 1). .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.11 (1H, s), 8.68 (1H, s), 7.44 (1H, s), 7.32 (1H, d, J=8.1 Hz), 7.20 (1H, dd, J=14.8, 7.4 Hz), 7.10-7.03 (1H, m), 4.92 (2H, dd, J=18.4, 9.2 Hz), 2.82 (1H, dd, J=15.7, 10.2 Hz), 2.70-2.41 (7H, m), 2.13 (3H, d, J=3.2 Hz).

Example 86: N-Hydroxy-6-phenyl-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide

(233) The title compound was prepared according to Example 83 and 84, using the TFFH method of hydroxamic acid formation as in Step 5 of Example 82. Preparative HPLC gave the title compound as a white solid (38 mg). LCMS (ES+) 354 (M+H).sup.+, RT 9.44 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.46 (1H, s), 8.75 (1H, s), 7.46 (1H, s), 7.39-7.28 (4H, m), 7.25-7.18 (1H, m), 4.92 (2H, dd, J=18.4, 9.2 Hz), 2.78 (1H, dd, J=15.8, 10.8 Hz), 2.72-2.55 (3H, m), 2.48-2.39 (2H, m), 2.02-1.87 (2H, m).

Examples 87 and 88: E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide and E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide

(234) ##STR00041##

(235) To a solution of methyl 2,3-dihydro-1H-indene-1-carboxylate (545 mg, 3.10 mmol) in toluene (3.8 mL) was added dicyclohexylamine (632 L, 3.17 mmol) followed by BuLi (2 mL, 3.2 mmol, 1.6 M in hexane). In a separate flask, Pd(OAc).sub.2 (8 mg, 0.037 mmol), P(tBu).sub.3.HBF.sub.4 (24 mg, 0.084 mmol), bromobenzene (163 L, 1.55 mmol) and toluene (2 mL) were combined sequentially and heated to 100 C. for 1 min. The enolate solution was then added to the reaction mixture via syringe. The combined mixture was heated at 100 C. for 1 h. The mixture was left to cool to r.t, then water (8 mL) and DCM (20 mL) added and the biphasic mixture passed through a phase separator. The organics were concentrated and purified by silica gel column chromatography (10% EtOAc in i-hex), to give the title compound as a yellow oil (277 mg, 77%). LCMS (ES+) 253 (M+H).sup.+.

Step 2: 1-Phenyl-2,3-dihydro-1H-indene-1-carboxylic acid

(236) To a stirred suspension of tBuOK (813 mg, 7.25 mmol) in dry ether (14 mL) at 0 C., was added H.sub.2O (33.5 L, 1.86 mmol). To this was added methyl 1-phenyl-2,3-dihydro-1H-indene-1-carboxylate (211 mg, 0.84 mmol) and the reaction mixture was left to warm to r.t and stirred for 96 h. The mixture was cooled (ice-bath) and acidified with 2 M HCl (4 mL) and diluted with H.sub.2O (15 mL). The reaction mixture was then extracted into EtOAc (250 mL) and the combined organic layer was dried (MgSO.sub.4), filtered and evaporated to dryness to give the title compound as a yellow oil (213 mg, 80%).

Step 3: E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide and E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide

(237) To a solution of 1-phenyl-2,3-dihydro-1H-indene-1-carboxylic acid (210 mg, 0.88 mmol) in DCM (7 mL) was added oxalyl chloride (149 L, 1.76 mmol). The reaction mixture was stirred at r.t for 20 h under an atmosphere of nitrogen. The reaction mixture was concentrated to dryness and redissolved in DCM (8 mL). To this was added aqueous hydroxylamine (1.5 mL, 50% solution) and the mixture stirred at r.t for 4 h. The mixture was cooled (ice-bath) and acidified with 2 M HCl (4 mL) and diluted with H.sub.2O (15 mL). The reaction mixture was then extracted into EtOAc (250 mL) and the combined organics washed with brine (10 mL), dried (MgSO.sub.4), filtered and concentrated. Purification by preparative HPLC and chiral HPLC to give the E1-(abs) and E2-(abs) enantiomers (2 mg and 3 mg respectively) which were arbitrarily assigned. (Chiralpak IA 20/80 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 7.8 min (E1-(abs)) and 10.9 min (E2-(abs)). E1-(abs) LCMS (ES+) 254 (M+H).sup.+, RT 3.40 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.36 (1H, s), 8.80 (1H, s), 7.55-7.51 (1H, m), 7.32-7.20 (6H, m), 7.11 (2H, d, J=7.3 Hz), 3.00-2.86 (2H, m), 2.80-2.67 (1H, m), 2.20-2.11 (1H, m). E2-(abs) LCMS (ES+) 254 (M+H).sup.+, RT 3.40 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.38 (1H, s), 8.82 (1H, s), 7.54-7.51 (1H, m), 7.32-7.20 (6H, m), 7.11 (2H, d, J=7.2 Hz), 2.99-2.86 (2H, m), 2.80-2.67 (1H, m), 2.20-2.11 (1H, m).

Example 89: N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2-carboxamide

(238) ##STR00042##

Step 1: 2-Phenyl-2,3-dihydro-1H-indene-2-carbonitrile

(239) Benzyl cyamide (117 mg, 1.00 mmol), ,-dibromo-o-xylene (396 mg, 1.50 mmol), NaOH (2 mL, 2 M aqueous solution, 4.00 mmol), benzyl triethylammonium bromide (408 mg, 1.50 mmol) and toluene (10 mL) were combined and stirred at r.t. for 8 days. The reaction mixture was washed with H.sub.2O and the organics concentrated. Purification by flash chromatography (33% EtOAc in i-hex) gave the title compound as a clear oil (110 mg, 50%). LCMS (ES+) 220 (M+H).sup.+.

Step 2: 2-Phenyl-2,3-dihydro-1H-indene-2-carboxylic acid

(240) To a stirred solution of 2-phenyl-2,3-dihydro-1H-indene-2-carbonitrile (110 mg, 0.5 mmol) in EtOH/H.sub.2O (5 mL, 3:2) was added NaOH (100 mg, 2.5 mmol), and the mixture stirred at reflux for 2 days. The mixture was diluted with H.sub.2O and washed with DCM. The aqueous portion was collected, acidified with 2 M HCl and extracted into EtOAc. The organics were dried (MgSO.sub.4), filtered and concentrated to give the title compound as a white solid (97 mg, 82 mmol). LCMS (ES+) 239 (M+H).sup.+.

Step 3: Ethyl 2-phenyl-2,3-dihydro-1H-indene-2-carboxylate

(241) A solution of 2-phenyl-2,3-dihydro-1H-indene-2-carboxylic acid (97 mg, 0.4 mmol) and cone. H.sub.2SO.sub.4 (1 drop) in EtOH (20 mL) was heated at reflux temperature overnight. The reaction mixture was allowed to cool to r.t, diluted with 2 M aqueous K.sub.2CO.sub.3 solution and extracted into DCM. The organics were passed through a phase separator and concentrated to give the title compound as a white solid (95 mg, 88%). LCMS (ES+) 267 (M+H).sup.+.

Step 4: N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2-carboxamide

(242) Ethyl 2-phenyl-2,3-dihydro-1H-indene-2-carboxylate (96 mg, 0.37 mmol), aqueous hydroxylamine (2 mL, 50% solution) and sodium hydroxide (1 mL, 15% solution) in MeOH (20 mL) were stirred at r.t. for 6 h. The reaction mixture was extracted with DCM, passed through a phase separator and concentrated to give a white solid which was then triturated with petroleum ether 60-80/Et.sub.2O (1:1) to give the title compound as a white solid. LCMS (ES+) 254 (M+H).sup.+. .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.67 (1H, s), 8.69 (1H, s), 7.40 (2H, d, J=7.4 Hz), 7.36-7.29 (2H, m), 7.26-7.21 (3H, m), 7.14-7.10 (2H, m), 3.84 (2H, d, J=15.7 Hz), 3.18 (2H, d, J=15.7 Hz).

Example 90: (S)-1-(2-Chloro-4-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(243) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as an off-white solid (23 mg). LCMS (ES+) 404 (M+H).sup.+, RT 3.48 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.25-10.18 (1H, br s), 8.83-8.77 (1H, br s), 7.68 (1H, dd, J=2.8, 8.6 Hz), 7.58 (1H, dd, J=5.6, 8.9 Hz), 7.47 (1H, s), 7.41-7.34 (1H, m), 7.20-7.13 (1H, m), 7.11-7.04 (2H, m), 3.77 (1H, d, J=15.9 Hz), 3.45 (1H, d, J=14.8 Hz), 3.19-3.13 (1H, m), 2.88 (1H, d, J=16.1 Hz), 2.11 (3H, d, J=2.6 Hz).

Example 91: (S)-2-(4,6-Dimethylpyrimidin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(244) Prepared following the method described for Example 1. Preparative HPLC gave the title compound as an off-white solid (6 mg). LCMS (ES+) 382 (M+H).sup.+, RT 3.16 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.24 (1H, s), 8.85 (1H, s), 8.24 (1H, s), 7.14-7.03 (4H, m), 3.62 (1H, d, J=16.2 Hz), 3.49 (1H, d, J=16.7 Hz), 3.08 (2H, dd, J=6.4, 16.1 Hz), 2.44 (6H, s), 2.17 (3H, d, J=2.6 Hz).

Examples 92, 93 and 94 (S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide, (R)-1-benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide and (R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

(245) ##STR00043##

Step 1: (S)-Methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentane carboxylate and (R)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate

(246) Intermediate 3 (2.5 g, 1.0 mmol) was dissolved in dimethylformamide dimethylacetal (5.0 mL) and heated to 80 C. for 16 h. The cooled mixture was concentrated onto silica and purified by flash silica column chromatography (gradient elution i-hex to 100% EtOAc in i-hex) to yield the title compounds as a pale yellow oil (1.8 g, 58%). LCMS (ES+) 306 (M+H).sup.+.

Step 2: (S)-Methyl 5-(3-fluoro-2-methylphenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate and (R)-methyl 4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate

(247) To a solution of (S)-methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentane carboxylate and (R)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate (2.75 g, 9.02 mmol) in acetic acid (9 mL) was added hydrazine (9 mL, 9.00 mmol, 1 M in THF), and the mixture stirred at r.t for 15 min before heating to 55 C. for 3 h. The solvent was removed in vacuo and water added and then extracted with DCM. The organics were passed through a phase separator and concentrated. Purification by flash silica chromatography (elution with Et.sub.2O) gave the title compounds (1.7 g, 68%).

Step 3: (S)-Methyl 1-benzyl-5-(3-fluoro-2-methylpIyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate, (R)-methyl 1-benzyl-4-(3-fluoro-2-methylphenI-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate and (R)-methyl 2-benzyl-4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate

(248) To a stirred suspension of (S)-methyl 5-(3-fluoro-2-methylphenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate and (R)-methyl 4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate (0.77 g, 2.8 mmol) in DMF (5 mL) was added benzyl chloride (0.38 g, 3.0 mmol) and cesium carbonate (1.0 g, 3.1 mmol) and the mixture stirred at r.t. for 3 days. The reaction was then diluted with water and extracted into Et.sub.2O. The combined organics were dried (MgSO.sub.4), filtered and concentrated. Purification by flash silica chromatography (elution with Et.sub.2O) and preparative HPLC gave (S)-methyl 1-benzyl-5-(3-fluoro-2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate (143 mg, 14%) and (R)-methyl 1-benzyl-4-(3-fluoro-2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate (142 mg, 14%) and (R)-methyl 2-benzyl-4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate (156 mg, 15%) as a separable mixture of isomers. LCMS (ES+) 365 (M+H).sup.+.

Step 4: (S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(249) To a stirred suspension of hydroxylamine hydrochloride (180 mg, 2.61 mmol) in DCM (6 mL), under a nitrogen atmosphere, was added trimethyl aluminium (1.2 mL, 2.4 mmol, 2 M THF solution). The mixture was stirred at r.t for 20 min before a solution of (S)-methyl 1-benzyl-5-(3-fluoro-2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate (143 mg, 0.4 mmol) in DCM (4 mL) was added, and the mixture stirred for an additional 1.5 h. Additional hydroxylamine hydrochloride (180 mg, 2.61 mmol) and trimethyl aluminium (1.2 mL, 2.4 mmol, 2 M THF solution) were added and stirring continued for 2 h. The reaction mixture was quenched with 2 M HCl (3 mL), then the mixture concentrated to dryness, and partitioned between water and EtOAc. The organics were dried (MgSO.sub.4), filtered and concentrated. Purification by preparative HPLC gave the title compound as a colorless solid (67 mg). LCMS (ES+) 366 (M+H).sup.+, RT 3.29 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.14 (1H, s), 8.76 (1H, s), 7.33-7.28 (3H, m), 7.15-7.11 (3H, m), 7.08-7.02 (2H, m), 6.87 (1H, dd, J=2.1, 6.7 Hz), 5.27-5.20 (2H, m), 3.51 (1H, d, J=16 Hz), 3.34 (1H, d, J=16 Hz), 2.98 (1H, d, J=16 Hz), 2.83 (1H, d, J=16 Hz), 2.08 (3H, d, J=2.5 Hz).

Step 5: (R)-1-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

(250) Following the same method as Step 4 starting from (R)-methyl 1-benzyl-4-(3-fluoro-2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate (142 mg, 0.39 mmol). Purification by preparative HPLC gave the title compound as a colorless solid (99 mg). LCMS (ES+) 366 (M+H).sup.+, RT 10.11 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.09 (1H, s), 8.69 (1H, s), 7.46-7.45 (1H, m), 7.39-7.34 (2H, m), 7.33-7.27 (1H, m), 7.26-7.22 (2H, m), 7.17-7.10 (1H, m), 7.09-7.02 (2H, m), 5.23 (2H, s), 3.84-3.75 (1H, m), 2.78-2.68 (1H, m), 2.61-2.52 (1H, m), 2.30-2.20 (1H, m), 2.11 (3H, s).

Step 6: (R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

(251) Following the same method as Step 4 starting from (R)-methyl 2-benzyl-4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate (156 mg, 0.43 mmol). Purification by preparative HPLC gave the title compound as a colorless solid (104 mg). LCMS (ES+) 366 (M+H).sup.+, RT 9.94 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.11 (1H, s), 8.70 (1H, d, J=1.4 Hz), 7.68 (1H, s), 7.40-7.36 (2H, m), 7.33-7.28 (3H, m), 7.16-7.03 (2H, m), 6.99 (1H, d, J=7.5 Hz), 5.33 (2H, s), 3.67-3.58 (1H, m), 2.79-2.70 (1H, m), 2.60-2.56 (1H, m), 2.21-2.15 (1H, m), 2.14 (3H, d, J=2.4 Hz).

Example 95: (R)-4-(3-fluoro-2-methylphenyl)-2-(2-fluorobenzyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

(252) Prepared following the method described for Example 91, using 2-fluoro benzyl chloride (432 mg, 3.0 mmol) gave the title compound as a colorless solid (89 mg). LCMS (ES+) 384 (M+H).sup.+, RT 10.01 min (Analytical method 2); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.11 (1H, s), 8.71 (1H, s), 7.69 (1H, s), 7.43-7.36 (1H, m), 7.32-7.27 (1H, m), 7.25-7.20 (2H, m), 7.16-7.04 (2H, m), 6.99 (1H, d, J=7.5 Hz), 5.39 (2H, s), 3.67-3.58 (1H, m), 2.77-2.69 (1H, m), 2.59-2.53 (1H, m), 2.20-2.15 (1H, m), 2.13 (3H, d, J=2.5 Hz).

Example 96: (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Step 1: Methyl 5-(3-fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

(253) To a solution of methyl 3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate (500 mg, 1.52 mmol) in ethanol (5 mL) was added 5-fluoropyridine-2-carbothioamide (356 mg, 2.28 mmol). The reaction mixture heated to 110 C. under microwave conditions for 1 h. The reaction mixture was concentrated to give a dark red gum. The crude reaction material was purified by flash silica chromatography (gradient elution i-hex to 40% EtOAc in i-hex) to give the title compound as a bright orange solid (226 mg, 34%). Used crude (45% pure) without further purification.

Step 2: 5-(3-Fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

(254) To a solution of hydroxylamine hydrochloride (0.25 g, 3.68 mmol) in DCM (10 mL) was added trimethyl aluminum in heptane (1.6 mL, 3.3 mmol). Then a solution of methyl 5-(3-fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate (226 mg, 0.58 mmol) in DCM (7 mL) was added dropwise and stirred for 1 h. The reaction was treated with 2N HCl (6 mL) with cooling then MeOH (25 mL) was added and adjusted pH to 1 with 2N HCl. The solvent was evaporated to leave the aqueous which was added to pH 5 with NaHCO.sub.3 to precipitate the aluminum which was filtered off through Celite washing well with ethyl acetate. The phases were separated and the organics evaporated to give a yellow solid which was purified by preparative HPLC to give the title compound as an off white solid (39 mg). LCMS (ES+) 388 (M+H).sup.+, RT 3.57 min (Analytical method 1); .sup.1H NMR (ppm)(DMSO-d.sub.6): 10.29 (1H, s), 8.84 (1H, s), 8.62 (1H, d, J=2.9 Hz), 8.09 (1H, dd, J=4.5, 8.9 Hz), 7.90-7.85 (1H, m), 7.19-7.06 (3H, m), 3.77 (2H, dd, J=15.6, 15.6 Hz), 3.42-3.36 (1H, m), 3.22 (1H, d, J=15.8 Hz), 2.17 (3H, d, J=2.6 Hz).

(255) TABLE-US-00002 Table of examples Example Structure IUPAC Name 1 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl- 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 2 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o- tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 3 (S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluorophenyl)- N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 4 (S)-1-(3-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)- N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 5 (S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluorophenyl)- N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 6 (S)-5-(3-Fluoro-2-methylphenyl)-1-(3-fluorophenyl)- N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 7 0 (S)-1-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)- N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 8 (S)-1-(4-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)- N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 9 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(p- tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 10 (S)-1-(3-Chloro-2-fluorophenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 11 (S)-1-(2,6-Difluorophenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 12 (S)-1-(2,5-Dimethylphenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 13 (S)-1-(2,6-Dimethylphenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 14 (S)-1-(2-Chloro-6-fluorophenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 15 (S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluoro-6- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 16 (S)-5-(3-Fluoro-2-methylphenyl)-1-(5-fluoropyridin-2- yl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 17 0 (S)-1-(2,4-Difluorophenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 18 (S)-1-Cyclopentyl-5-(3-fluoro-2-methylphenyl)-N- hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 19 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1- (pyrazin-2-yl)-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 20 (S)-1-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 21 (S)-2-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-2,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 22 (S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 23 (S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2- methylphenyl)-N-hydroxy-2,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 24 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(m- tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 25 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(m- tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 26 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(3- methylpyridin-4-yl)-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 27 0 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3- methylpyridin-4-yl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 28 (S)-2-(3-Chloropyridin-2-yl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-2,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 29 (S)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluoropyridin-2- yl)-N-hydroxy-2,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 30 (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl- 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 31 E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1- phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 32 E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1- phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 33 E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2- fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H- indazole-5-carboxamide 34 E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2- fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H- indazole-5-carboxamide 35 5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(2,2,2- trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5- carboxamide and 5-(3-fluoro-2-methylphenyl)-N- hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro- 2H-indazole-5-carboxamide 36 0 5-(3-Fluoro-2-methylphenyl)-1-(4-fluorobenzyl)-N- hydroxy-4,5,6,7-tetrahydro-1H-indazole-5- carboxamide and 5-(3-fluoro-2-methylphenyl)-2-(4- fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-2H- indazole-5-carboxamide 37 E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1- (o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5- carboxamide 38 E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1- (o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5- carboxamide 39 3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N- hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro- 2H-indazole-5-carboxamide 40 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N- hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6- carboxamide 41 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2- (phenylsulfonamido)-4,5,6,7- tetrahydrobenzo[d]thiazole-6-carboxamide 42 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N- hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6- carboxamide 43 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin- 5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6- carboxamide 44 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7- tetrahydrobenzo[d]thiazole-6-carboxamide 45 0 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8- tetrahydroquinazoline-6-carboxamide 46 2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N- hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide 47 6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-phenyl- 5,6,7,8-tetrahydroquinazoline-6-carboxamide 48 (S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)- N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 6-carboxamide 49 (R)-2-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)- N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 5-carboxamide 50 (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N- hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6- carboxamide 51 (S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N- hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5- carboxamide 52 (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N- hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6- carboxamide 53 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1- isopropyl-1,4,5,6-tetrahydrocyclopenta[d]pyrazole-5- carboxamide 54 (R)-4-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl- 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4- carboxamide 55 00 (S)-6-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N- hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6- carboxamide 56 01 (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-6-carboxamide 57 02 (R)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N- hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5- carboxamide 58 03 (S)-1-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N- hydroxy-1,4,5,6-tetrahydrocyclopenta[d]pyrazole-5- carboxamide 59 04 (R)-1-Cyclopropyl-4-(3-fluoro-2-methylphenyl)-N- hydroxy-1,4,5,6-tetrahydrocyclopenta[d]pyrazole-4- carboxamide 60 05 (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2- (pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-6-carboxamide 61 06 E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2- fluorophenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 62 07 E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2- fluorophenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 63 08 5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3- (trifluoromethyl)benzyl)-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 64 09 E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3- fluorophenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 65 0 E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3- fluorophenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 66 (R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)- N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5- carboxamide 67 (S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)- N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5- carboxamide 68 (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1- methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 69 (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1- methyl-1H-pyrazol-3-yl)-3,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 70 (R)-2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 71 (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5- methoxypyridin-2-yl)-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 72 (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N- hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6- carboxamide 73 (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(o- tolyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6- carboxamide 74 E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2- methylphenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 75 0 E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2- methylphenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 76 E1-(abs)-2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(3- fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 77 E2-(abs)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3- fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide 78 (S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)- N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6- carboxamide 79 (R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)- N-hydroxy-2-methyl-2,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 80 E1-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3- phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5- carboxamide 81 E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3- phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5- carboxamide 82 2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro- 1H-indene-2-carboxamide 83 2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N- hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d] pyrimidine-7-carboxamide 84 E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2- (2,2,2-trifluoroethyl)-2,4,5,6,7,8- hexahydrocyclohepta[c]pyrazole-6-carboxamide 85 0 E2-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2- (2,2,2-trifluoroethyl)-2,4,5,6,7,8- hexahydrocyclohepta[c]pyrazole-6-carboxamide 86 N-Hydroxy-6-phenyl-2-(2,2,2-trifluoroethyl)- 2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6- carboxamide 87 E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene- 1-carboxamide 88 E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene- 1-carboxamide 89 N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2- carboxamide 96 (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5- fluoropyridin-2-yl)-5,6-dihydro-4H- cyclopentane[d]thiazole-5-carboxamide 90 (S)-1-(2-Chloro-4-fluorophenyl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 91 (S)-2-(4,6-Dimethylpyrimidin-2-yl)-5-(3-fluoro-2- methylphenyl)-N-hydroxy-2,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 92 (S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy- 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 93 (R)-1-Benzyl-4-(3-fIuoro-2-methylphenyl)-N-hydroxy- 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4- carboxamide 94 0 (R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy- 2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4- carboxamide 95 (R)-4-(3-fluoro-2-methylphenyl)-2-(2- fluorobenzyl)-N-hydroxy-2,4,5,6- tetrahydrocyclopenta[c]pyrazole-4-carboxamide

BIOLOGICAL EXAMPLES

Example A: Analysis of Inhibition of HDAC4 with the Compounds

(256) The potency of compounds is quantified by measuring the Histone Deacetylase 4 (HDAC4) catalytic domain enzymatic activity using the fluorogenic 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.

(257) Serially Dilute the Compounds.

(258) Serial dilutions of the compounds being tested 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 L 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 1 using a 125 L 16-channel Matrix multi-channel pipette (Matrix Technologies Ltd).

(259) TABLE-US-00003 TABLE 1 Serial Dilution of Compounds Con- Diluted centration Dilution Solutions Well (M) ratio Volumes Concentration 1 A 10000 60 L 10 mM Test compound/ reference control Concentration 2 B 5000 1:2 30 L A + 30 L DMSO Concentration 3 C 2500 1:2 30 L B + 30 L DMSO Concentration 4 D 1000 1:2.5 30 L C + 45 L DMSO Concentration 5 E 500 1:2 30 L D + 30 L DMSO Concentration 6 F 250 1:2 30 L E + 30 L DMSO Concentration 7 G 125 1:2 30 L F + 30 L DMSO Concentration 8 H 62.5 1:2 30 L G + 30 L DMSO Concentration 9 I 31.25 1:2 30 L H + 30 L DMSO Concentration 10 J 15.63 1:2 30 L I + 30 L DMSO Concentration 11 K 7.81 1:2 30 L J + 30 uL DMSO Concentration 12 L 3.91 1:2 30 L K + 30 L DMSO Concentration 13 M 1.95 1:2 30 L L + 30 L DMSO Concentration 14 N 0.98 1:2 30 L M + 30 L DMSO Concentration 15 O 0.49 1:2 30 L N + 30 L DMSO Concentration 16 P 0.24 1:2 30 L O + 30 L DMSO

(260) 2 L (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 L 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 L 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).

(261) Prepare HDAC4 Catalytic Domain Enzyme (0.2 g/mL).

(262) The HDAC4 catalytic domain enzyme is human catalytic domain HDAC4 protein (amino acids 648-1032) with a C-terminal 6 histidine tag, produced by BioFocus. A working solution of enzyme is prepared from a 500 g/mL stock aliquot of HDAC4 catalytic domain (thawed on ice) diluted to 0.2 g/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.

(263) Prepare 5 (50 M) Boc-Lys(Tfa)-AMC Substrate.

(264) 5 (50 M) 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.

(265) Prepare 3 (30 M) Developer/Stop Solution.

(266) 3 (30 M) 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.

(267) Assay.

(268) 5 L 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 L of the working solution of HDAC4 catalytic domain enzyme (0.2 g/mL in assay buffer) is transferred to the assay plate. The assay is then started by adding 10 L of 5 (50 M) 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 L of 3 (30 M) 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 B: Analysis of Inhibition of HDAC5 with the Compounds

(269) The potency of the compounds is quantified by measuring the Histone Deacetylase 5 (HDAC5) enzymatic activity using the fluorogenic 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.

(270) Serially Dilute the Compounds.

(271) Serial dilutions of the compounds 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 L 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 1 using a 125 L 16-channel Matrix multi-channel pipette.

(272) 2 L (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 L 16-channel Matrix multi-channel pipette. Each well with the 2 L of the 200 stamped compound solution is diluted 1:20 by the addition of 38 l 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.).

(273) Prepare HDAC5 Catalytic Domain Enzyme (0.57 g/mL).

(274) 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 g/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.

(275) Prepare 5 (40 M) Boc-Lys(Tfa)-AMC Substrate.

(276) 5 (40 M) 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.

(277) Prepare 3 (30 M) Developer/Stop Solution.

(278) 3 (30 M) 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.

(279) Assay.

(280) 5 L of each solution of the 1:20 diluted 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 L of the working solution of the HDAC5 catalytic domain enzyme (0.57 g/mL in assay buffer) is transferred to the assay plate. The assay is then started by adding 10 L of 5 (40 M) 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 L of 3 (30 M) 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 C: Analysis of Inhibition of HDAC7 with the Compounds

(281) The potency of the compounds is quantified by measuring the Histone Deacetylase 7 (HDAC7) enzymatic activity using the fluorogenic 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.

(282) Serially Dilute HDAC Inhibitor Compounds.

(283) Serial dilutions of the compounds to be tested 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 L 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 1 using a 125 L 16-channel Matrix multi-channel pipette.

(284) 2 L (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 L 16-channel Matrix multi-channel pipette. Each well with the 200 compound solution is diluted 1:20 by the addition of 38 L 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.).

(285) Prepare HDAC7 Enzyme (71 ng/nL).

(286) 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.

(287) Prepare 5 (50 M) Boc-Lys(Tfa)-AMC Substrate.

(288) 5 (50 M) 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.

(289) Prepare 3 (30 M) Developer/Stop Solution.

(290) 3 (30 M) 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.

(291) Assay.

(292) 5 L 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 L 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 L of 5 (50 M) 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 L of 3 (30 M) 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 D: Analysis of Inhibition of HDAC9 with the Compounds

(293) The potency of the compounds is quantified by measuring the Histone Deacetylase 9 (HDAC9) enzymatic activity using the fluorogenic 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.

(294) Serially Dilute the Compounds.

(295) Serial dilutions of the compounds 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 L 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 1 using a 125 L 16-channel Matrix multi-channel pipette.

(296) 2 L (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 L 16-channel Matrix multi-channel pipette. Each well with the stamped 200 compound solution is diluted 1:20 by the addition of 38 L 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.).

(297) Prepare HDAC9 Enzyme (0.57 g/mL).

(298) 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 g/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.

(299) Prepare 5 (125 M) Boc-Lys(Tfa)-AMC Substrate.

(300) 5 (125 M) 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.

(301) Prepare 3 (30 M) Developer/Stop Solution.

(302) 3 (30 M) 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.

(303) Assay.

(304) 5 L 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 L of the working solution of the HDAC9 enzyme (0.57 g/mL in assay buffer) is transferred to the assay plate. The assay is then started by adding 10 L of 5 (125 M) 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 L 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 E: Analysis of Inhibition of Cellular HDAC Activity with the Compounds

(305) The potency of the compounds is quantified by measuring the cellular histone deacetylase enzymatic activity using the fluorogenic 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 fluorescence of the sample is directly related to the histone deacetylase activity in the sample.

(306) Jurkar E6.1 Cell Culture and Plating.

(307) 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 L. 35 L 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.

(308) Serially Dilute the Compounds.

(309) Serial dilutions of the compounds being tested 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 L 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 1 using a 125 L 16-channel Matrix multi-channel pipette.

(310) 2 L (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 L 16-channel Matrix multi-channel pipette. Each well with the 200 compound solution is diluted 1:20 by the addition of 38 L 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)

(311) Prepare 5 (500 M) Boc-Lys(Tfa)-AMC Substrate.

(312) 5 (500 M) 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.

(313) Prepare 3 Lysis Buffer.

(314) 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.

(315) Assay.

(316) 5 L 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 L of 5 (500 M) 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 L of 3 lysis buffer is added to each well using either the 125 L 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 F

(317) Using the assay protocols described above, the following compounds synthesized by the above synthetic methods were tested.

(318) TABLE-US-00004 Biochemical Cell (Lys- Cell (Lys-Ac) IC.sub.50 TFA) IC.sub.50 IC.sub.50 Example Structure (M) (M) (M) 1 0.028 0.059 >50 2 0.023 0.014 >50 3 0.017 0.033 >50 4 0.061 0.072 >50 5 0.053 0.099 >50 6 0.044 0.067 >50 7 0.015 0.013 >50 8 0.112 0.103 >50 9 0 0.039 0.082 >50 10 0.017 0.017 >50 11 0.012 0.027 >50 12 0.021 0.018 >50 13 0.027 0.012 >50 14 0.015 0.011 >50 15 0.019 0.032 >50 16 0.031 0.069 >50 17 0.029 0.039 >50 18 0.037 0.163 >50 19 0 0.038 0.053 >50 20 0.109 0.25 >50 21 0.147 0.175 >50 22 0.044 0.011 >50 23 0.197 0.134 >50 24 0.028 0.064 >50 25 0.076 0.160 >50 26 0.057 0.071 >50 27 0.053 0.116 >50 28 0.065 0.069 >50 29 0 0.104 0.069 >50 30 1.0 1.7 >50 31 0.82 0.072 >50 32 17.3 2.9 >50 33 0.71 0.41 >50 34 19.8 26.7 >50 35 1.7 0.77 >50 36 0.60 0.37 >50 37 0 1.1 0.086 >50 38 7.9 11.2 >50 39 4.4 1.8 >50 40 1.6 0.58 >50 41 0.19 1.6 >50 42 0.77 0.32 >50 43 1.9 0.66 >50 44 1.0 1.5 >50 45 3.7 2.6 >50 46 1.6 0.76 >50 47 0 3.2 1.1 >50 48 0.156 0.060 >50 49 0.102 0.25 >50 50 0.22 0.12 >50 51 0.27 1.4 >50 52 0.16 0.21 >50 53 0.067 0.23 >50 54 0.072 0.32 >50 55 0.29 0.26 >50 56 0.88 1.8 >50 57 00 19.4 >50 >50 58 01 0.048 0.125 >50 59 02 0.100 0.72 >50 60 03 0.22 0.20 >50 61 04 0.48 0.12 >50 62 05 0.193 0.049 >50 63 06 0.49 0.038 >50 64 07 0.21 0.11 >50 65 08 0.53 0.22 >50 66 09 0.081 0.098 >50 67 0 0.193 0.29 >50 68 0.24 0.12 >50 69 0.044 0.035 >50 70 0.122 0.079 >50 71 0.095 0.056 >50 72 0.094 0.79 >50 73 0.143 0.63 >50 74 0.78 0.54 >50 75 0.27 0.051 >50 76 0.068 0.036 >50 77 0 0.20 0.128 >50 78 0.12 0.50 >50 79 0.053 0.026 36.5 80 0.079 0.045 >50 81 9.7 5.6 >50 82 0.11 1.8 >50 83 1.3 0.49 >50 84 0.48 1.4 >50 85 0.79 1.8 >50 86 8.2 46.7 >50 87 0 5.67 45.7 >50 88 >50 >50 >50 89 15.3 >50 >50 96 0.051 0.060 >50 90 0.036 0.015 >50 91 0.28 0.46 >50 92 0.048 0.027 >50 93 0.027 0.17 >50 94 0.82 2.78 >50 95 0.71 2.98 >50

(319) 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.